A Study to Evaluate SAGE-217 in Participants With Moderate to Severe Major Depressive Disorder

• Sponsor: Sage Therapeutics (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03000530
• Collaborator: (none)
• Enrollment: 102
• Locations: 8
• Arms: 3
• Actual Duration (Months): 11
• Patients Per Site: 12.8
• Patients Per Site Per Month: 1.2

Study Details

Study Description

Brief Summary

This is a two-part (open-label followed by double-blind) study evaluating the safety, tolerability, pharmacokinetics, and efficacy of SAGE-217 in 102 participants diagnosed with moderate to severe Major Depressive Disorder.

Condition or Disease	Intervention/Treatment	Phase
Major Depression	Drug: SAGE-217; Drug: Placebo	Phase 2

Detailed Description

Part A of the study is an open-label design with dosing of SAGE-217 for 14 days.

Part B of the study is a randomized, double-blind, parallel-group, placebo-controlled design. Eligible participants were randomized to SAGE-217 or placebo for 14 days.

Study Design

• Study Type: Interventional
• Actual Enrollment: 102 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Two-Part (Open-Label Followed by Double-Blind) Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Efficacy of SAGE-217 in the Treatment of Adult Subjects With Moderate to Severe Major Depressive Disorder
• Actual Study Start Date: Dec 7, 2016
• Actual Primary Completion Date: Oct 4, 2017
• Actual Study Completion Date: Nov 8, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Part A: SAGE-217 Participants received SAGE-217, 30 milligrams (mg), oral solution, once daily for 14 days, as tolerated.	Drug: SAGE-217
Placebo Comparator: Part B: Placebo Eligible participants received matching placebo capsules once daily for 14 days.	Drug: Placebo
Experimental: Part B: SAGE-217 Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.	Drug: SAGE-217

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) - Part A [Day 1 up to Day 21]

   An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug-related. A TEAE was defined as an adverse event with onset after the start of study drug, or any worsening of a pre-existing medical condition/adverse event with onset after the start of study drug and until 7 days after the last dose. The analysis was performed in participants included in Part A of the study.

2. Percentage of Participants With TEAEs, Graded by Severity - Part A [Day 1 up to Day 21]

   Severity was assessed according to the following scale: mild (awareness of sign or symptom, but easily tolerated); moderate (discomfort sufficient to cause interference with normal activities); severe (incapacitating, with inability to perform normal activities). The analysis was performed in participants included in Part A of the study.

3. Change From Baseline in Basophils - Part A [Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28]

   Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes and leukocytes. The analysis was performed in participants included in Part A of the study. ET = Early Termination.

4. Change From Baseline in Basophils to Leukocytes Ratio [Percentage (%)] - Part A [Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28]

   Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes and leukocytes. The analysis was performed in participants included in Part A of the study. ET = Early Termination. The blood cell differential (ratio) data are presented as International System (SI) unit, percentage (%).

5. Change From Baseline in Eosinophils - Part A [Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28]

   Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes and leukocytes. The analysis was performed in participants included in Part A of the study. ET = Early Termination.

6. Change From Baseline in Eosinophils to Leukocytes Ratio (%) - Part A [Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28]

   Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes and leukocytes. The analysis was performed in participants included in Part A of the study. ET = Early Termination. The blood cell differential (ratio) data are presented as SI unit, percentage (%).

7. Change From Baseline in Hematocrit - Part A [Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28]

   Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes and leukocytes. The analysis was performed in participants included in Part A of the study. ET = Early Termination.

8. Change From Baseline in Hemoglobin - Part A [Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28]

   Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes and leukocytes. The analysis was performed in participants included in Part A of the study. ET = Early Termination.

9. Change From Baseline in Lymphocytes - Part A [Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28]

   Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes and leukocytes. The analysis was performed in participants included in Part A of the study. ET = Early Termination.

10. Change From Baseline in Lymphocytes to Leukocytes Ratio (%) - Part A [Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28]

    Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes and leukocytes. The analysis was performed in participants included in Part A of the study. ET = Early Termination. The blood cell differential (ratio) data are presented as SI unit, percentage (%).

11. Change From Baseline in Monocytes - Part A [Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28]

    Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes and leukocytes. The analysis was performed in participants included in Part A of the study. ET = Early Termination.

12. Change From Baseline in Monocytes to Leukocytes Ratio (%) - Part A [Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28]

    Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes and leukocytes. The analysis was performed in participants included in Part A of the study. ET = Early Termination. The blood cell differential (ratio) data are presented as SI unit, percentage (%).

13. Change From Baseline in Neutrophils - Part A [Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28]

    Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes and leukocytes. The analysis was performed in participants included in Part A of the study. ET = Early Termination.

14. Change From Baseline in Neutrophils to Leukocytes Ratio (%) - Part A [Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28]

    Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes and leukocytes. The analysis was performed in participants included in Part A of the study. ET = Early Termination. The blood cell differential (ratio) data are presented as SI unit, percentage (%).

15. Change From Baseline in Platelets - Part A [Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28]

    Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes and leukocytes. The analysis was performed in participants included in Part A of the study. ET = Early Termination.

16. Change From Baseline in Erythrocytes - Part A [Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28]

    Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes and leukocytes. The analysis was performed in participants included in Part A of the study. ET = Early Termination.

17. Change From Baseline in Reticulocytes - Part A [Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28]

    Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes and leukocytes. The analysis was performed in participants included in Part A of the study. ET = Early Termination.

18. Change From Baseline in Leukocytes - Part A [Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28]

    Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes and leukocytes. The analysis was performed in participants included in Part A of the study. ET = Early Termination.

19. Change From Baseline in Albumin - Part A [Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28]

    Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, chloride, carbon dioxide, creatinine, potassium, protein, sodium, and urea nitrogen. The analysis was performed in participants included in Part A of the study. ET = Early Termination.

20. Change From Baseline in Alkaline Phosphatase - Part A [Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28]

    Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, chloride, carbon dioxide, creatinine, potassium, protein, sodium, and urea nitrogen. The analysis was performed in participants included in Part A of the study. ET = Early Termination.

21. Change From Baseline in Alanine Aminotransferase - Part A [Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28]

    Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, chloride, carbon dioxide, creatinine, potassium, protein, sodium, and urea nitrogen. The analysis was performed in participants included in Part A of the study. ET = Early Termination.

22. Change From Baseline in Aspartate Aminotransferase - Part A [Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28]

    Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, chloride, carbon dioxide, creatinine, potassium, protein, sodium, and urea nitrogen. The analysis was performed in participants included in Part A of the study. ET = Early Termination.

23. Change From Baseline in Bilirubin - Part A [Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28]

    Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, chloride, carbon dioxide, creatinine, potassium, protein, sodium, and urea nitrogen. The analysis was performed in participants included in Part A of the study. ET = Early Termination.

24. Change From Baseline in Chloride - Part A [Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28]

    Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, chloride, carbon dioxide, creatinine, potassium, protein, sodium, and urea nitrogen. The analysis was performed in participants included in Part A of the study. ET = Early Termination.

25. Change From Baseline in Carbon Dioxide - Part A [Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28]

    Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, chloride, carbon dioxide, creatinine, potassium, protein, sodium, and urea nitrogen. The analysis was performed in participants included in Part A of the study. ET = Early Termination.

26. Change From Baseline in Creatinine - Part A [Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28]

    Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, chloride, carbon dioxide, creatinine, potassium, protein, sodium, and urea nitrogen. The analysis was performed in participants included in Part A of the study. ET = Early Termination.

27. Change From Baseline in Potassium - Part A [Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28]

    Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, chloride, carbon dioxide, creatinine, potassium, protein, sodium, and urea nitrogen. The analysis was performed in participants included in Part A of the study. ET = Early Termination.

28. Change From Baseline in Protein - Part A [Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28]

    Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, chloride, carbon dioxide, creatinine, potassium, protein, sodium, and urea nitrogen. The analysis was performed in participants included in Part A of the study. ET = Early Termination.

29. Change From Baseline in Sodium - Part A [Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28]

    Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, chloride, carbon dioxide, creatinine, potassium, protein, sodium, and urea nitrogen. The analysis was performed in participants included in Part A of the study. ET = Early Termination.

30. Change From Baseline in Urea Nitrogen - Part A [Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28]

    Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, chloride, carbon dioxide, creatinine, potassium, protein, sodium, and urea nitrogen. The analysis was performed in participants included in Part A of the study. ET = Early Termination.

31. Change From Baseline in Activated Partial Thromboplastin Time - Part A [Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28]

    Coagulation measures included activated partial thromboplastin time, prothrombin international normalized ratio, and prothrombin time. The analysis was performed in participants included in Part A of the study. ET = Early Termination.

32. Change From Baseline in Prothrombin International Normalized Ratio (%) - Part A [Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28]

    Coagulation measures included activated partial thromboplastin time, prothrombin international normalized ratio, and prothrombin time. The analysis was performed in participants included in Part A of the study. ET = Early Termination. The data for prothrombin international normalized ratio are presented as SI unit, percentage (%).

33. Change From Baseline in Prothrombin Time - Part A [Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28]

    Coagulation measures included activated partial thromboplastin time, prothrombin international normalized ratio, and prothrombin time. The analysis was performed in participants included in Part A of the study. ET = Early Termination.

34. Change From Baseline in pH - Part A [Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28]

    Urinalysis measures included pH and specific gravity. The analysis was performed in participants included in Part A of the study. ET = Early Termination.

35. Change From Baseline in Specific Gravity - Part A [Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28]

    Urinalysis measures included pH and specific gravity. The analysis was performed in participants included in Part A of the study. ET = Early Termination.

36. Change From Baseline (CFB) in Supine Systolic Blood Pressure - Part A [Baseline, Day 1 (0.25, 0.5, 1, 2, 12 hours postdose), Days 2, 3, 4, 5, 6 and 7 (predose, 0.25, 0.5, 1, 2, 12 hours postdose), Days 8, 9, 10, 11, 12, 13 and 14 (predose, 1 hour postdose), Day 15/ET, follow-up Day 21, follow-up Day 28]

    Vital signs measures included supine systolic blood pressure, supine diastolic blood pressure, standing systolic blood pressure, standing diastolic blood pressure, heart rate, respiratory rate, oral temperature, and oxygen saturation. The analysis was performed in participants included in Part A of the study. H = Hour(s). ET = Early Termination.

37. Change From Baseline (CFB) in Supine Diastolic Blood Pressure - Part A [Baseline, Day 1 (0.25, 0.5, 1, 2, 12 hours postdose), Days 2, 3, 4, 5, 6 and 7 (predose, 0.25, 0.5, 1, 2, 12 hours postdose), Days 8, 9, 10, 11, 12, 13 and 14 (predose, 1 hour postdose), Day 15/ET, follow-up Day 21, follow-up Day 28]

    Vital signs measures included supine systolic blood pressure, supine diastolic blood pressure, standing systolic blood pressure, standing diastolic blood pressure, heart rate, respiratory rate, oral temperature, and oxygen saturation. The analysis was performed in participants included in Part A of the study. H = Hour(s). ET = Early Termination.

38. Change From Baseline (CFB) in Standing Systolic Blood Pressure - Part A [Baseline, Day 1 (0.25, 0.5, 1, 2, 12 hours postdose), Days 2, 3, 4, 5, 6 and 7 (predose, 0.25, 0.5, 1, 2, 12 hours postdose), Days 8, 9, 10, 11, 12, 13 and 14 (predose, 1 hour postdose), Day 15/ET, follow-up Day 21, follow-up Day 28]

    Vital signs measures included supine systolic blood pressure, supine diastolic blood pressure, standing systolic blood pressure, standing diastolic blood pressure, heart rate, respiratory rate, oral temperature, and oxygen saturation. The analysis was performed in participants included in Part A of the study. H = Hour(s). ET = Early Termination.

39. Change From Baseline (CFB) in Standing Diastolic Blood Pressure - Part A [Baseline, Day 1 (0.25, 0.5, 1, 2, 12 hours postdose), Days 2, 3, 4, 5, 6 and 7 (predose, 0.25, 0.5, 1, 2, 12 hours postdose), Days 8, 9, 10, 11, 12, 13 and 14 (predose, 1 hour postdose), Day 15/ET, follow-up Day 21, follow-up Day 28]

    Vital signs measures included supine systolic blood pressure, supine diastolic blood pressure, standing systolic blood pressure, standing diastolic blood pressure, heart rate, respiratory rate, oral temperature, and oxygen saturation. The analysis was performed in participants included in Part A of the study. H = Hour(s). ET = Early Termination.

40. Change From Baseline (CFB) in Heart Rate - Part A [Baseline, Day 1 (0.25, 0.5, 1, 2, 12 hours postdose), Days 2, 3, 4, 5, 6 and 7 (predose, 0.25, 0.5, 1, 2, 12 hours postdose), Days 8, 9, 10, 11, 12, 13 and 14 (predose, 1 hour postdose), Day 15/ET, follow-up Day 21, follow-up Day 28]

    Vital signs measures included supine systolic blood pressure, supine diastolic blood pressure, standing systolic blood pressure, standing diastolic blood pressure, heart rate, respiratory rate, oral temperature, and oxygen saturation. The analysis was performed in participants included in Part A of the study. H = Hour(s). ET = Early Termination.

41. Change From Baseline (CFB) in Respiratory Rate - Part A [Baseline, Day 1 (0.25, 0.5, 1, 2, 12 hours postdose), Days 2, 3, 4, 5, 6 and 7 (predose, 0.25, 0.5, 1, 2, 12 hours postdose), Days 8, 9, 10, 11, 12, 13 and 14 (predose, 1 hour postdose), Day 15/ET, follow-up Day 21, follow-up Day 28]

    Vital signs measures included supine systolic blood pressure, supine diastolic blood pressure, standing systolic blood pressure, standing diastolic blood pressure, heart rate, respiratory rate, oral temperature, and oxygen saturation. The analysis was performed in participants included in Part A of the study. H = Hour(s). ET = Early Termination.

42. Change From Baseline (CFB) in Oral Temperature - Part A [Baseline, Day 1 (0.25, 0.5, 1, 2, 12 hours postdose), Days 2, 3, 4, 5, 6 and 7 (predose, 0.25, 0.5, 1, 2, 12 hours postdose), Days 8, 9, 10, 11, 12, 13 and 14 (predose, 1 hour postdose), Day 15/ET, follow-up Day 21, follow-up Day 28]

    Vital signs measures included supine systolic blood pressure, supine diastolic blood pressure, standing systolic blood pressure, standing diastolic blood pressure, heart rate, respiratory rate, oral temperature, and oxygen saturation. The analysis was performed in participants included in Part A of the study. H = Hour(s). ET = Early Termination.

43. Change From Baseline (CFB) in Oxygen Saturation - Part A [Baseline, Day 1 (0.25, 0.5, 1, 2, 12 hours postdose), Days 2, 3, 4, 5, 6 and 7 (predose, 0.25, 0.5, 1, 2, 12 hours postdose), Day 8 (predose, 1 hour postdose)]

    Vital signs measures included supine systolic blood pressure, supine diastolic blood pressure, standing systolic blood pressure, standing diastolic blood pressure, heart rate, respiratory rate, oral temperature, and oxygen saturation. The analysis was performed in participants included in Part A of the study. H = Hour(s).

44. Change From Baseline in QT Interval - Part A [Baseline, Days 1, 2, 7, 14 and follow-up Day 21]

    Electrocardiogram (ECG) measures included QT interval, QTc based on Fridericia formula (QTcF interval), ECG mean heart rate, RR interval, PR interval, and QRS duration. The analysis was performed in participants included in Part A of the study.

45. Change From Baseline in QTcF Interval - Part A [Baseline, Days 1, 2, 7, 14 and follow-up Day 21]

    ECG measures included QT interval, QTcF interval, ECG mean heart rate, RR interval, PR interval, and QRS duration. The analysis was performed in participants included in Part A of the study.

46. Change From Baseline in ECG Mean Heart Rate - Part A [Baseline, Days 1, 2, 7, 14 and follow-up Day 21]

    ECG measures included QT interval, QTcF interval, ECG mean heart rate, RR interval, PR interval, and QRS duration. The analysis was performed in participants included in Part A of the study.

47. Change From Baseline in RR Interval - Part A [Baseline, Days 1, 2, 7, 14 and follow-up Day 21]

    ECG measures included QT interval, QTcF interval, ECG mean heart rate, RR interval, PR interval, and QRS duration. The analysis was performed in participants included in Part A of the study.

48. Change From Baseline in PR Interval - Part A [Baseline, Days 1, 2, 7, 14 and follow-up Day 21]

    ECG measures included QT interval, QTcF interval, ECG mean heart rate, RR interval, PR interval, and QRS duration. The analysis was performed in participants included in Part A of the study.

49. Change From Baseline in QRS Interval - Part A [Baseline, Days 1, 2, 7, 14 and follow-up Day 21]

    ECG measures included QT interval, QTcF interval, ECG mean heart rate, RR interval, PR interval, and QRS duration. The analysis was performed in participants included in Part A of the study.

50. Percentage of Participants With a Response of 'Yes' to Any Columbia Suicide Severity Rating Scale (C-SSRS) Suicidal Ideation Item - Part A [Day 1 up to Day 28]

    The C-SSRS scale consisted of a baseline evaluation (at screening) that assessed the lifetime experience of participants with suicidal ideation (SI) and behavior and a postbaseline evaluation that focused on suicidality since the last study visit. The C-SSRS included "yes" or "no"' responses for assessment of suicidal ideation and behavior as well as numeric ratings for severity of ideation, if present (from 1 to 5, with 5 being the most severe). The C-SSRS SI items involved wish to be dead, non-specific active suicidal thoughts, active SI with any methods, active SI with some intent and active SI with specific plan. The analysis was performed in participants included in Part A of the study.

51. Change From Baseline in Stanford Sleepiness Scale (SSS) Score at Day 15 - Part A [Baseline, Day 15]

    The SSS was participant-rated scale designed to quickly assess how alert a participant was feeling. Degrees of sleepiness and alertness were rated on a scale of one to seven, where the lowest score of 'one' indicated the participant was 'feeling active, vital, alert, or wide awake' and the highest score of 'seven' indicated the participant was 'no longer fighting sleep, sleep onset soon; having dream-like thoughts'. A negative change from baseline indicated less sleepiness. A positive change from baseline indicated more sleepiness. The analysis was performed in participants included in Part A of the study.

52. Change From Baseline in the 17-item Hamilton Rating Scale for Depression (HAM-D) Total Score at Day 15 - Part B [Baseline, Day 15]

    The HAM-D total score comprised a sum of 17 individual item scores. Items scored in a range of 0 to 2 included: insomnia (early, middle, late), somatic symptoms (gastrointestinal and general), genital symptoms, loss of weight, and insight. The following items were scored in a range of 0 to 4: agitation, depressed mood, feelings of guilt, suicide, work and activities, retardation, anxiety (psychic and somatic), and hypochondriasis. The total score could range from 0 to 52. Higher scores indicated a greater degree of depression. A negative change from baseline indicated less depression. A positive change from baseline indicated more depression. The analysis was performed in participants included in Part B of the study.

Secondary Outcome Measures

1. Change From Baseline in the HAM-D Total Score at Day 15 and All Other Time Points - Part A [Baseline, Days 2, 3, 4, 5, 6, 7, 8, 15, 21 and 28]

   The HAM-D total score comprised a sum of 17 individual item scores. Items scored in a range of 0 to 2 included: insomnia (early, middle, late), somatic symptoms (gastrointestinal and general), genital symptoms, loss of weight, and insight. The following items were scored in a range of 0 to 4: agitation, depressed mood, feelings of guilt, suicide, work and activities, retardation, anxiety (psychic and somatic), and hypochondriasis. The total score could range from 0 to 52. Higher scores indicate a greater degree of depression. A negative change from baseline indicated less depression. A positive change from baseline indicated more depression. The analysis was performed in participants included in Part A of the study.

2. Percentage of Participants With TEAEs - Part B [Day 1 up to Day 21]

   An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. A TEAE was defined as an adverse event with onset after the start of study drug, or any worsening of a pre-existing medical condition/adverse event with onset after the start of study drug and until 7 days after the last dose. The analysis was performed in participants included in Part B of the study.

3. Percentage of Participants With AEs During Post-TEAE Period [Day 21 up to Day 42]

   An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. TEAE was defined as an adverse event with onset after the start of study drug, or any worsening of a pre-existing medical condition/adverse event with onset after the start of study drug and until 7 days after the last dose. Post-TEAE period was defined as 7 days after final dose through last follow-up (Day 42). The analysis was performed in participants included in Part B of the study.

4. Percentage of Participants With TEAEs, Graded by Severity - Part B [Day 1 up to Day 21]

   Severity was assessed according to the following scale: mild (awareness of sign or symptom, but easily tolerated); moderate (discomfort sufficient to cause interference with normal activities); severe (incapacitating, with inability to perform normal activities). The analysis was performed in participants included in Part B of the study.

5. Change From Baseline in Basophils - Part B [Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42]

   Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes, reticulocytes to erythrocytes ratio and leukocytes. The analysis was performed in participants included in Part B of the study. ET = Early Termination.

6. Change From Baseline in Basophils to Leukocytes Ratio (%) - Part B [Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42]

   Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes, reticulocytes to erythrocytes ratio and leukocytes. The analysis was performed in participants included in Part B of the study. ET = Early Termination. The blood cell differential (ratio) data are presented as SI unit, percentage (%).

7. Change From Baseline in Eosinophils - Part B [Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42]

   Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes, reticulocytes to erythrocytes ratio and leukocytes. The analysis was performed in participants included in Part B of the study. ET = Early Termination.

8. Change From Baseline in Eosinophils to Leukocytes Ratio (%) - Part B [Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42]

   Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes, reticulocytes to erythrocytes ratio and leukocytes. The analysis was performed in participants included in Part B of the study. ET = Early Termination. The blood cell differential (ratio) data are presented as SI unit, percentage (%).

9. Change From Baseline in Hematocrit - Part B [Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42]

   Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes, reticulocytes to erythrocytes ratio and leukocytes. The analysis was performed in participants included in Part B of the study. ET = Early Termination.

10. Change From Baseline in Hemoglobin - Part B [Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42]

    Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes, reticulocytes to erythrocytes ratio and leukocytes. The analysis was performed in participants included in Part B of the study. ET = Early Termination.

11. Change From Baseline in Lymphocytes - Part B [Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42]

    Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes, reticulocytes to erythrocytes ratio and leukocytes. The analysis was performed in participants included in Part B of the study. ET = Early Termination.

12. Change From Baseline in Lymphocytes to Leukocytes Ratio (%) - Part B [Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42]

    Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes, reticulocytes to erythrocytes ratio and leukocytes. The analysis was performed in participants included in Part B of the study. ET = Early Termination. The blood cell differential (ratio) data are presented as SI unit, percentage (%).

13. Change From Baseline in Monocytes - Part B [Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42]

    Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes, reticulocytes to erythrocytes ratio and leukocytes. The analysis was performed in participants included in Part B of the study. ET = Early Termination.

14. Change From Baseline in Monocytes to Leukocytes Ratio (%) - Part B [Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42]

    Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes, reticulocytes to erythrocytes ratio and leukocytes. The analysis was performed in participants included in Part B of the study. ET = Early Termination. The blood cell differential (ratio) data are presented as SI unit, percentage (%).

15. Change From Baseline in Neutrophils - Part B [Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42]

    Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes, reticulocytes to erythrocytes ratio and leukocytes. The analysis was performed in participants included in Part B of the study. ET = Early Termination.

16. Change From Baseline in Neutrophils to Leukocytes Ratio (%) - Part B [Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42]

    Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes, reticulocytes to erythrocytes ratio and leukocytes. The analysis was performed in participants included in Part B of the study. ET = Early Termination. The blood cell differential (ratio) data are presented as SI unit, percentage (%).

17. Change From Baseline in Platelets - Part B [Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42]

    Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes, reticulocytes to erythrocytes ratio and leukocytes. The analysis was performed in participants included in Part B of the study. ET = Early Termination.

18. Change From Baseline in Erythrocytes - Part B [Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42]

    Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes, reticulocytes to erythrocytes ratio and leukocytes. The analysis was performed in participants included in Part B of the study. ET = Early Termination.

19. Change From Baseline in Reticulocytes - Part B [Baseline, Day 8, Day 15/ET]

    Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes, reticulocytes to erythrocytes ratio and leukocytes. The analysis was performed in participants included in Part B of the study. ET = Early Termination.

20. Change From Baseline in Reticulocytes to Erythrocytes Ratio (%) - Part B [Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42]

    Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes, reticulocytes to erythrocytes ratio and leukocytes. The analysis was performed in participants included in Part B of the study. ET = Early Termination. The blood cell differential (ratio) data are presented as SI unit, percentage (%).

21. Change From Baseline in Leukocytes - Part B [Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42]

    Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes, reticulocytes to erythrocytes ratio and leukocytes. The analysis was performed in participants included in Part B of the study. ET = Early Termination.

22. Change From Baseline in Albumin - Part B [Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42]

    Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium, chloride, carbon dioxide, creatinine, glucose, potassium, magnesium, phosphate, protein, sodium, thyrotropin, and urea nitrogen. The analysis was performed in participants included in Part B of the study. ET = Early Termination.

23. Change From Baseline in Alkaline Phosphatase - Part B [Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42]

    Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium, chloride, carbon dioxide, creatinine, glucose, potassium, magnesium, phosphate, protein, sodium, thyrotropin, and urea nitrogen. The analysis was performed in participants included in Part B of the study. ET = Early Termination.

24. Change From Baseline in Alanine Aminotransferase - Part B [Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42]

    Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium, chloride, carbon dioxide, creatinine, glucose, potassium, magnesium, phosphate, protein, sodium, thyrotropin, and urea nitrogen. The analysis was performed in participants included in Part B of the study. ET = Early Termination.

25. Change From Baseline in Aspartate Aminotransferase - Part B [Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42]

    Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium, chloride, carbon dioxide, creatinine, glucose, potassium, magnesium, phosphate, protein, sodium, thyrotropin, and urea nitrogen. The analysis was performed in participants included in Part B of the study. ET = Early Termination.

26. Change From Baseline in Bilirubin - Part B [Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42]

    Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium, chloride, carbon dioxide, creatinine, glucose, potassium, magnesium, phosphate, protein, sodium, thyrotropin, and urea nitrogen. The analysis was performed in participants included in Part B of the study. ET = Early Termination.

27. Change From Baseline in Calcium - Part B [Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42]

    Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium, chloride, carbon dioxide, creatinine, glucose, potassium, magnesium, phosphate, protein, sodium, thyrotropin, and urea nitrogen. The analysis was performed in participants included in Part B of the study. ET = Early Termination.

28. Change From Baseline in Chloride - Part B [Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42]

    Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium, chloride, carbon dioxide, creatinine, glucose, potassium, magnesium, phosphate, protein, sodium, thyrotropin, and urea nitrogen. The analysis was performed in participants included in Part B of the study. ET = Early Termination.

29. Change From Baseline in Carbon Dioxide - Part B [Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42]

    Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium, chloride, carbon dioxide, creatinine, glucose, potassium, magnesium, phosphate, protein, sodium, thyrotropin, and urea nitrogen. The analysis was performed in participants included in Part B of the study. ET = Early Termination.

30. Change From Baseline in Creatinine - Part B [Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42]

    Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium, chloride, carbon dioxide, creatinine, glucose, potassium, magnesium, phosphate, protein, sodium, thyrotropin, and urea nitrogen. The analysis was performed in participants included in Part B of the study. ET = Early Termination.

31. Change From Baseline in Glucose - Part B [Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42]

    Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium, chloride, carbon dioxide, creatinine, glucose, potassium, magnesium, phosphate, protein, sodium, thyrotropin, and urea nitrogen. The analysis was performed in participants included in Part B of the study. ET = Early Termination.

32. Change From Baseline in Potassium - Part B [Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42]

    Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium, chloride, carbon dioxide, creatinine, glucose, potassium, magnesium, phosphate, protein, sodium, thyrotropin, and urea nitrogen. The analysis was performed in participants included in Part B of the study. ET = Early Termination.

33. Change From Baseline in Magnesium - Part B [Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42]

    Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium, chloride, carbon dioxide, creatinine, glucose, potassium, magnesium, phosphate, protein, sodium, thyrotropin, and urea nitrogen. The analysis was performed in participants included in Part B of the study. ET = Early Termination.

34. Change From Baseline in Phosphate - Part B [Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42]

    Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium, chloride, carbon dioxide, creatinine, glucose, potassium, magnesium, phosphate, protein, sodium, thyrotropin, and urea nitrogen. The analysis was performed in participants included in Part B of the study. ET = Early Termination.

35. Change From Baseline in Protein - Part B [Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42]

    Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium, chloride, carbon dioxide, creatinine, glucose, potassium, magnesium, phosphate, protein, sodium, thyrotropin, and urea nitrogen. The analysis was performed in participants included in Part B of the study. ET = Early Termination.

36. Change From Baseline in Sodium - Part B [Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42]

    Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium, chloride, carbon dioxide, creatinine, glucose, potassium, magnesium, phosphate, protein, sodium, thyrotropin, and urea nitrogen. The analysis was performed in participants included in Part B of the study. ET = Early Termination.

37. Change From Baseline in Thyrotropin - Part B [Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42]

    Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium, chloride, carbon dioxide, creatinine, glucose, potassium, magnesium, phosphate, protein, sodium, thyrotropin, and urea nitrogen. The analysis was performed in participants included in Part B of the study. ET = Early Termination.

38. Change From Baseline in Urea Nitrogen - Part B [Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42]

    Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium, chloride, carbon dioxide, creatinine, glucose, potassium, magnesium, phosphate, protein, sodium, thyrotropin, and urea nitrogen. The analysis was performed in participants included in Part B of the study. ET = Early Termination.

39. Change From Baseline in Activated Partial Thromboplastin Time - Part B [Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42]

    Coagulation measures included activated partial thromboplastin time, prothrombin international normalized ratio, and prothrombin time. The analysis was performed in participants included in Part B of the study. ET = Early Termination.

40. Change From Baseline in Prothrombin International Normalized Ratio (%) - Part B [Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42]

    Coagulation measures included activated partial thromboplastin time, prothrombin international normalized ratio, and prothrombin time. The analysis was performed in participants included in Part B of the study. ET = Early Termination. The data for prothrombin international normalized ratio are presented as SI unit, percentage (%).

41. Change From Baseline in Prothrombin Time - Part B [Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42]

    Coagulation measures included activated partial thromboplastin time, prothrombin international normalized ratio, and prothrombin time. The analysis was performed in participants included in Part B of the study. ET = Early Termination.

42. Change From Baseline in pH - Part B [Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42]

    Urinalysis measures included pH and specific gravity. The analysis was performed in participants included in Part B of the study. ET = Early Termination.

43. Change From Baseline in Specific Gravity - Part B [Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42]

    Urinalysis measures included pH and specific gravity. The analysis was performed in participants included in Part B of the study. ET = Early Termination.

44. Change From Baseline (CFB) in Supine Systolic Blood Pressure - Part B [Baseline, Day 1 (0.25, 0.5, 1, 2, 12 hours postdose), Days 2, 3, 4, 5, 6 and 7 (predose, 0.25, 0.5, 1, 2, 12 hours postdose), Days 8, 9, 10, 11, 12, 13 and 14 (predose, 1 hour postdose), Day 15/ET, follow-up Days 21, 28, 35 and 42]

    Vital signs measures included supine systolic blood pressure, supine diastolic blood pressure, standing systolic blood pressure, standing diastolic blood pressure, heart rate, respiratory rate, oral temperature, and oxygen saturation. The analysis was performed in participants included in Part B of the study. H = Hour(s). ET = Early Termination.

45. Change From Baseline (CFB) in Supine Diastolic Blood Pressure - Part B [Baseline, Day 1 (0.25, 0.5, 1, 2, 12 hours postdose), Days 2, 3, 4, 5, 6 and 7 (predose, 0.25, 0.5, 1, 2, 12 hours postdose), Days 8, 9, 10, 11, 12, 13 and 14 (predose, 1 hour postdose), Day 15/ET, follow-up Days 21, 28, 35 and 42]

    Vital signs measures included supine systolic blood pressure, supine diastolic blood pressure, standing systolic blood pressure, standing diastolic blood pressure, heart rate, respiratory rate, oral temperature, and oxygen saturation. The analysis was performed in participants included in Part B of the study. H = Hour(s). ET = Early Termination.

46. Change From Baseline (CFB) in Standing Systolic Blood Pressure - Part B [Baseline, Day 1 (0.25, 0.5, 1, 2, 12 hours postdose), Days 2, 3, 4, 5, 6 and 7 (predose, 0.25, 0.5, 1, 2, 12 hours postdose), Days 8, 9, 10, 11, 12, 13 and 14 (predose, 1 hour postdose), Day 15/ET, follow-up Days 21, 28, 35 and 42]

    Vital signs measures included supine systolic blood pressure, supine diastolic blood pressure, standing systolic blood pressure, standing diastolic blood pressure, heart rate, respiratory rate, oral temperature, and oxygen saturation. The analysis was performed in participants included in Part B of the study. H = Hour(s). ET = Early Termination.

47. Change From Baseline (CFB) in Standing Diastolic Blood Pressure - Part B [Baseline, Day 1 (0.25, 0.5, 1, 2, 12 hours postdose), Days 2, 3, 4, 5, 6 and 7 (predose, 0.25, 0.5, 1, 2, 12 hours postdose), Days 8, 9, 10, 11, 12, 13 and 14 (predose, 1 hour postdose), Day 15/ET, follow-up Days 21, 28, 35 and 42]

    Vital signs measures included supine systolic blood pressure, supine diastolic blood pressure, standing systolic blood pressure, standing diastolic blood pressure, heart rate, respiratory rate, oral temperature, and oxygen saturation. The analysis was performed in participants included in Part B of the study. H = Hour(s). ET = Early Termination.

48. Change From Baseline (CFB) in Heart Rate - Part B [Baseline, Day 1 (0.25, 0.5, 1, 2, 12 hours postdose), Days 2, 3, 4, 5, 6 and 7 (predose, 0.25, 0.5, 1, 2, 12 hours postdose), Days 8, 9, 10, 11, 12, 13 and 14 (predose, 1 hour postdose), Day 15/ET, follow-up Days 21, 28, 35 and 42]

    Vital signs measures included supine systolic blood pressure, supine diastolic blood pressure, standing systolic blood pressure, standing diastolic blood pressure, heart rate, respiratory rate, oral temperature, and oxygen saturation. The analysis was performed in participants included in Part B of the study. H = Hour(s). ET = Early Termination.

49. Change From Baseline (CFB) in Respiratory Rate - Part B [Baseline, Day 1 (0.25, 0.5, 1, 2, 12 hours postdose), Days 2, 3, 4, 5, 6 and 7 (predose, 0.25, 0.5, 1, 2, 12 hours postdose), Days 8, 9, 10, 11, 12, 13 and 14 (predose, 1 hour postdose), Day 15/ET, follow-up Days 21, 28, 35 and 42]

    Vital signs measures included supine systolic blood pressure, supine diastolic blood pressure, standing systolic blood pressure, standing diastolic blood pressure, heart rate, respiratory rate, oral temperature, and oxygen saturation. The analysis was performed in participants included in Part B of the study. H = Hour(s). ET = Early Termination.

50. Change From Baseline (CFB) in Oral Temperature - Part B [Baseline, Day 1 (0.25, 0.5, 1, 2, 12 hours postdose), Days 2, 3, 4, 5, 6 and 7 (predose, 0.25, 0.5, 1, 2, 12 hours postdose), Days 8, 9, 10, 11, 12, 13 and 14 (predose, 1 hour postdose), Day 15/ET, follow-up Days 21, 28, 35 and 42]

    Vital signs measures included supine systolic blood pressure, supine diastolic blood pressure, standing systolic blood pressure, standing diastolic blood pressure, heart rate, respiratory rate, oral temperature, and oxygen saturation. The analysis was performed in participants included in Part B of the study. H = Hour(s). ET = Early Termination.

51. Change From Baseline (CFB) in Oxygen Saturation - Part B [Baseline, Day 1 (0.25, 0.5, 1, 2, 12 hours postdose), Days 2, 3, 4, 5, 6 and 7 (predose, 0.25, 0.5, 1, 2, 12 hours postdose), Day 8 (predose, 1 hour postdose)]

    Vital signs measures included supine systolic blood pressure, supine diastolic blood pressure, standing systolic blood pressure, standing diastolic blood pressure, heart rate, respiratory rate, oral temperature, and oxygen saturation. The analysis was performed in participants included in Part B of the study. H = Hour(s). ET = Early Termination.

52. Change From Baseline in QT Interval - Part B [Baseline, Days 1, 2, 7, 14 and follow-up Day 21]

    ECG measures included QT interval, QTcF interval, ECG mean heart rate, RR interval, PR interval, and QRS duration. The analysis was performed in participants included in Part B of the study.

53. Change From Baseline in QTcF Interval - Part B [Baseline, Days 1, 2, 7, 14 and follow-up Day 21]

    ECG measures included QT interval, QTcF interval, ECG mean heart rate, RR interval, PR interval, and QRS duration. The analysis was performed in participants included in Part B of the study.

54. Change From Baseline in ECG Mean Heart Rate - Part B [Baseline, Days 1, 2, 7, 14 and follow-up Day 21]

    ECG measures included QT interval, QTcF interval, ECG mean heart rate, RR interval, PR interval, and QRS duration. The analysis was performed in participants included in Part B of the study.

55. Change From Baseline in RR Interval - Part B [Baseline, Days 1, 2, 7, 14 and follow-up Day 21]

    ECG measures included QT interval, QTcF interval, ECG mean heart rate, RR interval, PR interval, and QRS duration. The analysis was performed in participants included in Part B of the study.

56. Change From Baseline in PR Interval - Part B [Baseline, Days 1, 2, 7, 14 and follow-up Day 21]

    ECG measures included QT interval, QTcF interval, ECG mean heart rate, RR interval, PR interval, and QRS duration. The analysis was performed in participants included in Part B of the study.

57. Change From Baseline in QRS Duration - Part B [Baseline, Days 1, 2, 7, 14 and follow-up Day 21]

    ECG measures included QT interval, QTcF interval, ECG mean heart rate, RR interval, PR interval, and QRS duration. The analysis was performed in participants included in Part B of the study.

58. Percentage of Participants With a Response of "Yes" to Any C-SSRS Suicidal Ideation (SI) Item - Part B [Screening, Days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 21, 28, 35 and 42]

    The C-SSRS scale consisted of a baseline evaluation (at screening) that assessed the lifetime experience of participants with suicidal ideation and behavior and a postbaseline evaluation that focused on suicidality since the last study visit. The C-SSRS included "yes" or "no"' responses for assessment of suicidal ideation and behavior as well as numeric ratings for severity of ideation, if present (from 1 to 5, with 5 being the most severe). The C-SSRS SI items involved wish to be dead, non-specific active suicidal thoughts, active SI with any methods, active SI with some intent and active SI with specific plan. The analysis was performed in participants included in Part B of the study. SCLR = screening: lifetime recall.

59. Percentage of Participants With HAM-D Response - Part A [Days 2, 3, 4, 5, 6, 7, 8, 15, 21 and 28]

    HAM-D response was defined as having a 50% or greater reduction from baseline in HAM-D total score. The HAM-D total score comprised a sum of 17 individual item scores. Items scored in a range of 0 to 2 included: insomnia (early, middle, late), somatic symptoms (gastrointestinal and general), genital symptoms, loss of weight, and insight. The following items were scored in a range of 0 to 4: agitation, depressed mood, feelings of guilt, suicide, work and activities, retardation, anxiety (psychic and somatic), and hypochondriasis. The total score could range from 0 to 52. Higher scores indicate a greater degree of depression. A negative change from baseline indicated less depression. A positive change from baseline indicated more depression. The analysis was performed in participants included in Part A of the study. Data is reported for participants who had HAM-D response.

60. Percentage of Participants With HAM-D Remission - Part A [Days 2, 3, 4, 5, 6, 7, 8, 15, 21 and 28]

    HAM-D remission was defined as having a HAM-D total score of ≤7. The HAM-D total score comprised a sum of the 17 individual item scores. Items scored in a range of 0 to 2 included: insomnia (early, middle, late), somatic symptoms (gastrointestinal and general), genital symptoms, loss of weight, and insight. The following items were scored in a range of 0 to 4: agitation, depressed mood, feelings of guilt, suicide, work and activities, retardation, anxiety (psychic and somatic), and hypochondriasis. The total score could range from 0 to 52. Higher scores indicated a greater degree of depression. A negative change from baseline indicated less depression. A positive change from baseline indicated more depression. The analysis was performed in participants included in Part A of the study.

61. Change From Baseline in the Montgomery and Åsberg Depression Rating Scale (MADRS) Total Score at Day 15 and All Other Time Points - Part A [Baseline, Days 2, 3, 4, 5, 6, 7, 8, 15, 21 and 28]

    The MADRS was a ten-item diagnostic questionnaire which psychiatrists used to measure the severity of depressive episodes in participants with mood disorders. It was designed as an adjunct to the HAM-D, to be more sensitive than the Hamilton Scale to the changes brought on by antidepressants and other forms of treatment. Each item yielded a score of 0 to 6. The MADRS total score was calculated as the sum of the 10 individual item scores, which ranged from 0 to 60. Higher MADRS scores indicated more severe depression. A negative change from baseline indicated less severe depression. A positive change from baseline indicated more severe depression. The analysis was performed in participants included in Part A of the study.

62. Change From Baseline in HAM-D Subscale Scores at Day 15 and All Other Time Points - Part A [Baseline, Days 2, 3, 4, 5, 6, 7, 8, 15, 21 and 28]

    HAM-D subscales were: Core, symptoms: depressed mood (DM), feelings of guilt (FG), suicide, work and activities (WA), and retardation (RE); Anxiety, symptoms: anxiety (psychic and somatic), somatic symptoms (SS) (gastrointestinal and general), hypochondriasis, and loss of weight; Bech-6, symptoms: DM, FG, WA, RE, anxiety psychic (AP), and SS general; and Maier, symptoms: DM, FG, WA, RE, agitation, and AP. Each item was scored in a range of 0 to 2 or 0 to 4. Higher scores indicated a greater degree of depression. Subscale scores were calculated as sum of individual rating scores related to each subscale, divided by total possible score within subscale, multiplied by 100, and rounded to a whole number. Therefore, subscale scores would be within range of 0-100 and might be larger than total score. A negative change from baseline indicated less depression. A positive change from baseline indicated more depression. The analysis was performed in participants included in Part A of study.

63. Change From Baseline (CFB) in HAM-D Individual Item Scores at Day 15 and All Other Time Points - Part A [Baseline, Days 2, 3, 4, 5, 6, 7, 8, 15, 21 and 28]

    The HAM-D comprised individual ratings of the following symptoms scored in a range of 0 to 2: insomnia (early, middle, late), somatic symptoms [gastrointestinal (GI) and general], genital symptoms, loss of weight, and insight. The following symptoms were scored in a range of 0 to 4: agitation, depressed mood, feelings of guilt, suicide, work and activities, retardation, anxiety (psychic and somatic), and hypochondriasis. Higher scores indicated a greater degree of depression. A negative change from baseline indicated less depression. A positive change from baseline indicated more depression. The analysis was performed in participants included in Part A of the study.

64. Change From Baseline in Hamilton Anxiety Rating Scale (HAM-A) Total Score at All Time Points - Part A [Baseline, Days 2, 3, 8, 15, 21 and 28]

    The 14-item HAM-A was used to rate the severity of symptoms of anxiety. Each of the 14 items was defined by a series of symptoms, and measured both psychic anxiety (mental agitation and psychological distress) and somatic anxiety (physical complaints related to anxiety). Scoring for HAM-A was calculated by assigning scores of 0 (not present) to 4 (very severe), with a total score range of 0 to 56, where 0-13=Normal, 14-17 Mild Anxiety, 18-24 Moderate Anxiety, >=25 Severe Anxiety, per the Psych Congress Network. The HAM-A total score was calculated as the sum of the 14 individual item scores. A negative change from baseline indicated less anxiety. A positive change from baseline indicated more anxiety. The analysis was performed in participants included in Part A of the study.

65. Percentage of Participants With Clinical Global Impression - Improvement (CGI-I) Response - Part A [Days 2, 3, 8, 15, 21 and 28]

    The CGI-I item employed a 7-point Likert scale to measure the overall improvement in the participant's condition post-treatment. The investigator rated the participant's total improvement whether or not it was due entirely to drug treatment. Response choices included: 0 = not assessed, 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse. The CGI-I was only rated at post-treatment assessments. By definition, all CGI-I assessments were evaluated against baseline conditions. CGI-I response was defined as having a CGI-I global improvement score of 1 (very much improved) or 2 (much improved). The analysis was performed in participants included in Part A of the study. Data is reported for participants who had CGI-I response.

66. Change From Baseline (CFB) in the SSS Score - Part B [Baseline, Day 1 (0.25, 0.5, 1, 2 hours postdose), Days 2, 3, 4, 5, 6 and 7 (predose, 0.25, 0.5, 1, 2 hours postdose), Days 8, 9, 10, 11, 12, 13 and 14 (predose, 1 hour postdose), Day 15]

    The SSS was participant-rated scale designed to quickly assess how alert a participant was feeling. Degrees of sleepiness and alertness were rated on a scale of one to seven, where the lowest score of 'one' indicated the participant was 'feeling active, vital, alert, or wide awake' and the highest score of 'seven' indicated the participant was 'no longer fighting sleep, sleep onset soon; having dream-like thoughts'. A negative change from baseline indicated less sleepiness. A positive change from baseline indicated more sleepiness. The analysis was performed in participants included in Part B of the study. H = Hour(s).

67. Change From Baseline in the 17-item HAM-D Total Score at All Time Points - Part B [Baseline, Days 2, 3, 4, 5, 6, 7, 8, 15, 21, 28, 35 and 42]

    The HAM-D total score comprised a sum of 17 individual item scores. Items scored in a range of 0 to 2 included: insomnia (early, middle, late), somatic symptoms (gastrointestinal and general), genital symptoms, loss of weight, and insight. The following items were scored in a range of 0 to 4: agitation, depressed mood, feelings of guilt, suicide, work and activities, retardation, anxiety (psychic and somatic), and hypochondriasis. The total score could range from 0 to 52. Higher scores indicated a greater degree of depression. A negative change from baseline indicated less depression. A positive change from baseline indicated more depression. The analysis was performed in participants included in Part B of the study.

68. Percentage of Participants With HAM-D Response - Part B [Days 2, 8, 15, 21, 28, 35 and 42]

    HAM-D response was defined as having a 50% or greater reduction from baseline in HAM-D total score. The HAM-D total score comprised a sum of 17 individual item scores. Items scored in a range of 0 to 2 included: insomnia (early, middle, late), somatic symptoms (gastrointestinal and general), genital symptoms, loss of weight, and insight. The following items were scored in a range of 0 to 4: agitation, depressed mood, feelings of guilt, suicide, work and activities, retardation, anxiety (psychic and somatic), and hypochondriasis. The total score could range from 0 to 52. Higher scores indicated a greater degree of depression. A negative change from baseline indicated less depression. A positive change from baseline indicated more depression. The analysis was performed in participants included in Part B of the study. Data is reported for participants who had HAM-D response.

69. Percentage of Participants With HAM-D Remission - Part B [Days 2, 8, 15, 21, 28, 35 and 42]

    HAM-D remission was defined as having a HAM-D total score of ≤7. The HAM-D total score comprised a sum of the 17 individual item scores. Items scored in a range of 0 to 2 included: insomnia (early, middle, late), somatic symptoms (gastrointestinal and general), genital symptoms, loss of weight, and insight. The following items were scored in a range of 0 to 4: agitation, depressed mood, feelings of guilt, suicide, work and activities, retardation, anxiety (psychic and somatic), and hypochondriasis. The total score could range from 0 to 52. Higher scores indicated a greater degree of depression. A negative change from baseline indicated less depression. A positive change from baseline indicated more depression. The analysis was performed in participants included in Part B of the study.

70. Change From Baseline in the MADRS Total Score at Day 15 and All Other Time Points - Part B [Baseline, Days 2, 8, 15, 21, 28, 35 and 42]

    The MADRS was a ten-item diagnostic questionnaire which psychiatrists used to measure the severity of depressive episodes in participants with mood disorders. It was designed as an adjunct to the HAM-D, to be more sensitive than the Hamilton Scale to the changes brought on by antidepressants and other forms of treatment. Each item yielded a score of 0 to 6. The MADRS total score was calculated as the sum of the 10 individual item scores, which ranged from 0 to 60. Higher MADRS scores indicated more severe depression. A negative change from baseline indicated less severe depression. A positive change from baseline indicated more severe depression. The analysis was performed in participants included in Part B of the study.

71. Change From Baseline in HAM-D Subscale Scores at All Time Points - Part B [Baseline, Days 2, 3, 4, 5, 6, 7, 8, 15, 21, 28, 35 and 42]

    HAM-D subscales were: Core, symptoms: depressed mood (DM), feelings of guilt (FG), suicide, work and activities (WA), and retardation (RE); Anxiety, symptoms: anxiety (psychic and somatic), somatic symptoms (SS) (gastrointestinal and general), hypochondriasis, and loss of weight; Bech-6, symptoms: DM, FG, WA, RE, anxiety psychic (AP), and SS general; and Maier, symptoms: DM, FG, WA, RE, agitation, and AP. Each item was scored in a range of 0 to 2 or 0 to 4. Higher scores indicated a greater degree of depression. Subscale scores were calculated as sum of individual rating scores related to each subscale, divided by total possible score within subscale, multiplied by 100, and rounded to a whole number. Therefore, subscale scores would be within range of 0-100 and might be larger than total score. A negative change from baseline indicated less depression. A positive change from baseline indicated more depression. The analysis was performed in participants included in Part B of study.

72. Change From Baseline (CFB) in HAM-D Individual Item Scores at All Time Points - Part B [Baseline, Days 2, 3, 4, 5, 6, 7, 8, 15, 21, 28, 35 and 42]

    The HAM-D comprised individual ratings of the following symptoms scored in a range of 0 to 2: insomnia (early, middle, late), somatic symptoms (GI and general), genital symptoms, loss of weight, and insight. The following symptoms were scored in a range of 0 to 4: agitation, depressed mood, feelings of guilt, suicide, work and activities, retardation, anxiety (psychic and somatic), and hypochondriasis. Higher scores indicated a greater degree of depression. A negative change from baseline indicated less depression. A positive change from baseline indicated more depression. The analysis was performed in participants included in Part B of the study.

73. Change From Baseline in HAM-A Total Score at Day 15 and All Other Time Points - Part B [Baseline, Days 2, 8, 15, 21, 28, 35 and 42]

    The 14-item HAM-A was used to rate the severity of symptoms of anxiety. Each of the 14 items was defined by a series of symptoms, and measured both psychic anxiety (mental agitation and psychological distress) and somatic anxiety (physical complaints related to anxiety). Scoring for HAM-A was calculated by assigning scores of 0 (not present) to 4 (very severe), with a total score range of 0 to 56, where 0-13=Normal, 14-17 Mild Anxiety, 18-24 Moderate Anxiety, >=25 Severe Anxiety, per the Psych Congress Network. The HAM-A total score was calculated as the sum of the 14 individual item scores. A negative change from baseline indicated less anxiety. A positive change from baseline indicated more anxiety. The analysis was performed in participants included in Part B of the study.

74. Percentage of Participants With CGI-I Response - Part B [Days 2, 8, 15, 21, 28, 35 and 42]

    The CGI-I item employed a 7-point Likert scale to measure the overall improvement in the participant's condition post-treatment. The investigator rated the participant's total improvement whether or not it was due entirely to drug treatment. Response choices included: 0 = not assessed, 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse. The CGI-I was only rated at post-treatment assessments. By definition, all CGI-I assessments were evaluated against baseline conditions. CGI-I response was defined as having a score of 1 (very much improved) or 2 (much improved). The analysis was performed in participants included in Part B of the study. Data is reported for participants who had CGI-I response.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Participant has a diagnosis of Major Depressive Disorder that has been present for at least a 4-week period as diagnosed by Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I)

Exclusion Criteria:

• Participant has a history of suicide attempt

• Participant has a history of treatment-resistant depression, defined as persistent depressive symptoms despite treatment with adequate doses of antidepressants from two different classes for an adequate amount of time

• Participant has active psychosis

• Participant has a medical history of seizures

• Participant has a medical history of bipolar disorder, schizophrenia, and/or schizoaffective disorder

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Sage Investigational Site	Garden Grove	California	United States	92845
2	Sage Investigational Site	Orlando	Florida	United States	32806
3	Sage Investigational Site	Atlanta	Georgia	United States	30331
4	Sage Investigational Site	Lake Charles	Louisiana	United States	70629
5	Sage Investigational Site	Berlin	New Jersey	United States	08009
6	Sage Investigational Site	Dayton	Ohio	United States	45417
7	Sage Investigational Site	Austin	Texas	United States	78754
8	Sage Investigational Site	Charlottesville	Virginia	United States	22908

Sponsors and Collaborators

• Sage Therapeutics

Investigators

• Study Director: Christopher Silber, MD, Sage Therapeutics

Study Documents (Full-Text)

• Study Protocol - Jan 13, 2017
• Statistical Analysis Plan - Nov 16, 2017

More Information

Additional Information:

• Related Info

Publications

• Gunduz-Bruce H, Silber C, Kaul I, Rothschild AJ, Riesenberg R, Sankoh AJ, Li H, Lasser R, Zorumski CF, Rubinow DR, Paul SM, Jonas J, Doherty JJ, Kanes SJ. Trial of SAGE-217 in Patients with Major Depressive Disorder. N Engl J Med. 2019 Sep 5;381(10):903-911. doi: 10.1056/NEJMoa1815981.

• Responsible Party: Sage Therapeutics
• ClinicalTrials.gov Identifier: NCT03000530
• Other Study ID Numbers: 217-MDD-201
• First Posted: Dec 22, 2016
• Last Update Posted: Jan 27, 2022
• Last Verified: Jan 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Sage Therapeutics: Depression
• Additional relevant MeSH terms: Depression; Depressive Disorder; Depressive Disorder, Major

Study Results

Participant Flow

Recruitment Details	In Part A, 21 participants were screened; 13 received at least one dose of study drug. In Part B, 169 participants were screened; 89 received at least one dose of study drug.

Arm/Group Title	Part A: SAGE-217	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 milligrams (mg), oral solution, once daily for 14 days, as tolerated.	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Period Title: Overall Study
STARTED	13	44	45
COMPLETED	13	39	41
NOT COMPLETED	0	5	4

Baseline Characteristics

Arm/Group Title	Part A: SAGE-217	Part B: Placebo	Part B: SAGE-217	Total
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.	Total of all reporting groups
Overall Participants	13	44	45	102
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	48.0 (12.83)	38.3 (12.15)	49.1 (13.61)	44.3 (13.83)
Sex: Female, Male (Count of Participants)
Female	9 69.2%	30 68.2%	25 55.6%	64 62.7%
Male	4 30.8%	14 31.8%	20 44.4%	38 37.3%
Race/Ethnicity, Customized (Count of Participants)
Asian	0 0%	0 0%	1 2.2%	1 1%
Black or African American	9 69.2%	28 63.6%	36 80%	73 71.6%
White	4 30.8%	16 36.4%	7 15.6%	27 26.5%
Other	0 0%	0 0%	1 2.2%	1 1%
Race/Ethnicity, Customized (Count of Participants)
Hispanic or Latino	1 7.7%	7 15.9%	1 2.2%	9 8.8%
Not Hispanic or Latino	12 92.3%	37 84.1%	44 97.8%	93 91.2%
17-item Hamilton Rating Scale for Depression (HAM-D) Total Score - Part B (score on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [score on a scale]	25.7 (2.42)	25.2 (2.58)	25.5 (2.50)

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) - Part A
Description	An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug-related. A TEAE was defined as an adverse event with onset after the start of study drug, or any worsening of a pre-existing medical condition/adverse event with onset after the start of study drug and until 7 days after the last dose. The analysis was performed in participants included in Part A of the study.
Time Frame	Day 1 up to Day 21

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Number [percentage of participants]	92.3 710%

2. Primary Outcome

Title	Percentage of Participants With TEAEs, Graded by Severity - Part A
Description	Severity was assessed according to the following scale: mild (awareness of sign or symptom, but easily tolerated); moderate (discomfort sufficient to cause interference with normal activities); severe (incapacitating, with inability to perform normal activities). The analysis was performed in participants included in Part A of the study.
Time Frame	Day 1 up to Day 21

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Mild	69.2 532.3%
Moderate	23.1 177.7%
Severe	0 0%

3. Primary Outcome

Title	Change From Baseline in Basophils - Part A
Description	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes and leukocytes. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Baseline	0.032 (0.0286)
Change from Baseline at Day 8	-0.002 (0.0388)
Change from Baseline at Day 15/ET	0.005 (0.0445)
Change from Baseline at Follow-up Day 21	-0.003 (0.0273)
Change from Baseline at Follow-up Day 28	-0.007 (0.0244)

4. Primary Outcome

Title	Change From Baseline in Basophils to Leukocytes Ratio [Percentage (%)] - Part A
Description	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes and leukocytes. The analysis was performed in participants included in Part A of the study. ET = Early Termination. The blood cell differential (ratio) data are presented as International System (SI) unit, percentage (%).
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Baseline	0.56 (0.323)
Change from Baseline at Day 8	0.38 (1.308)
Change from Baseline at Day 15/ET	0.13 (0.681)
Change from Baseline at Follow-up Day 21	0.02 (0.453)
Change from Baseline at Follow-up Day 28	-0.05 (0.310)

5. Primary Outcome

Title	Change From Baseline in Eosinophils - Part A
Description	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes and leukocytes. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Baseline	0.155 (0.0990)
Change from Baseline at Day 8	0.031 (0.0749)
Change from Baseline at Day 15/ET	0.044 (0.0906)
Change from Baseline at Follow-up Day 21	0.018 (0.0796)
Change from Baseline at Follow-up Day 28	0.011 (0.1030)

6. Primary Outcome

Title	Change From Baseline in Eosinophils to Leukocytes Ratio (%) - Part A
Description	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes and leukocytes. The analysis was performed in participants included in Part A of the study. ET = Early Termination. The blood cell differential (ratio) data are presented as SI unit, percentage (%).
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Baseline	2.20 (1.155)
Change from Baseline at Day 8	0.68 (1.174)
Change from Baseline at Day 15/ET	0.98 (1.438)
Change from Baseline at Follow-up Day 21	0.52 (1.382)
Change from Baseline at Follow-up Day 28	0.43 (1.865)

7. Primary Outcome

Title	Change From Baseline in Hematocrit - Part A
Description	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes and leukocytes. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Baseline	0.419 (0.0341)
Change from Baseline at Day 8	0.001 (0.0123)
Change from Baseline at Day 15/ET	-0.006 (0.0203)
Change from Baseline at Follow-up Day 21	-0.020 (0.0239)
Change from Baseline at Follow-up Day 28	-0.017 (0.0256)

8. Primary Outcome

Title	Change From Baseline in Hemoglobin - Part A
Description	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes and leukocytes. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Baseline	136.7 (11.28)
Change from Baseline at Day 8	0.2 (4.30)
Change from Baseline at Day 15/ET	-2.4 (5.25)
Change from Baseline at Follow-up Day 21	-5.7 (5.79)
Change from Baseline at Follow-up Day 28	-4.8 (6.21)

9. Primary Outcome

Title	Change From Baseline in Lymphocytes - Part A
Description	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes and leukocytes. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Baseline	2.356 (0.4184)
Change from Baseline at Day 8	-0.302 (0.3742)
Change from Baseline at Day 15/ET	-0.339 (0.4330)
Change from Baseline at Follow-up Day 21	-0.260 (0.4550)
Change from Baseline at Follow-up Day 28	-0.204 (0.3183)

10. Primary Outcome

Title	Change From Baseline in Lymphocytes to Leukocytes Ratio (%) - Part A
Description	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes and leukocytes. The analysis was performed in participants included in Part A of the study. ET = Early Termination. The blood cell differential (ratio) data are presented as SI unit, percentage (%).
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Baseline	34.89 (9.321)
Change from Baseline at Day 8	-1.75 (4.741)
Change from Baseline at Day 15/ET	-1.25 (7.573)
Change from Baseline at Follow-up Day 21	-1.11 (5.716)
Change from Baseline at Follow-up Day 28	-0.62 (7.047)

11. Primary Outcome

Title	Change From Baseline in Monocytes - Part A
Description	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes and leukocytes. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Baseline	0.485 (0.1785)
Change from Baseline at Day 8	-0.042 (0.1673)
Change from Baseline at Day 15/ET	-0.074 (0.1373)
Change from Baseline at Follow-up Day 21	-0.090 (0.1513)
Change from Baseline at Follow-up Day 28	-0.103 (0.1369)

12. Primary Outcome

Title	Change From Baseline in Monocytes to Leukocytes Ratio (%) - Part A
Description	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes and leukocytes. The analysis was performed in participants included in Part A of the study. ET = Early Termination. The blood cell differential (ratio) data are presented as SI unit, percentage (%).
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Baseline	6.72 (1.263)
Change from Baseline at Day 8	0.35 (1.805)
Change from Baseline at Day 15/ET	-0.03 (1.625)
Change from Baseline at Follow-up Day 21	-0.67 (2.364)
Change from Baseline at Follow-up Day 28	-0.82 (2.403)

13. Primary Outcome

Title	Change From Baseline in Neutrophils - Part A
Description	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes and leukocytes. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Baseline	4.126 (1.7922)
Change from Baseline at Day 8	-0.485 (1.0690)
Change from Baseline at Day 15/ET	-0.528 (1.1266)
Change from Baseline at Follow-up Day 21	-0.411 (1.1296)
Change from Baseline at Follow-up Day 28	-0.190 (1.2929)

14. Primary Outcome

Title	Change From Baseline in Neutrophils to Leukocytes Ratio (%) - Part A
Description	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes and leukocytes. The analysis was performed in participants included in Part A of the study. ET = Early Termination. The blood cell differential (ratio) data are presented as SI unit, percentage (%).
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Baseline	55.63 (8.925)
Change from Baseline at Day 8	0.76 (5.123)
Change from Baseline at Day 15/ET	0.16 (8.428)
Change from Baseline at Follow-up Day 21	1.23 (7.037)
Change from Baseline at Follow-up Day 28	1.06 (8.908)

15. Primary Outcome

Title	Change From Baseline in Platelets - Part A
Description	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes and leukocytes. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Baseline	265.5 (50.99)
Change from Baseline at Day 8	-13.4 (26.77)
Change from Baseline at Day 15/ET	-7.8 (25.00)
Change from Baseline at Follow-up Day 21	8.8 (19.68)
Change from Baseline at Follow-up Day 28	-9.9 (34.29)

16. Primary Outcome

Title	Change From Baseline in Erythrocytes - Part A
Description	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes and leukocytes. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Baseline	4.661 (0.4521)
Change from Baseline at Day 8	0.021 (0.1406)
Change from Baseline at Day 15/ET	-0.050 (0.1920)
Change from Baseline at Follow-up Day 21	-0.198 (0.2302)
Change from Baseline at Follow-up Day 28	-0.164 (0.2382)

17. Primary Outcome

Title	Change From Baseline in Reticulocytes - Part A
Description	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes and leukocytes. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Baseline	51.926 (21.8233)
Change from Baseline at Day 8	-3.694 (22.4664)
Change from Baseline at Day 15/ET	-6.163 (24.9724)
Change from Baseline at Follow-up Day 21	6.174 (27.1013)
Change from Baseline at Follow-up Day 28	13.012 (24.3634)

18. Primary Outcome

Title	Change From Baseline in Leukocytes - Part A
Description	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes and leukocytes. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Baseline	7.16 (2.098)
Change from Baseline at Day 8	-0.82 (1.446)
Change from Baseline at Day 15/ET	-0.91 (1.388)
Change from Baseline at Follow-up Day 21	-0.75 (1.331)
Change from Baseline at Follow-up Day 28	-0.49 (1.387)

19. Primary Outcome

Title	Change From Baseline in Albumin - Part A
Description	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, chloride, carbon dioxide, creatinine, potassium, protein, sodium, and urea nitrogen. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Baseline	42.8 (2.82)
Change from Baseline at Day 8	-1.5 (2.07)
Change from Baseline at Day 15/ET	-1.0 (2.45)
Change from Baseline at Follow-up Day 21	-1.5 (2.57)
Change from Baseline at Follow-up Day 28	-0.8 (2.34)

20. Primary Outcome

Title	Change From Baseline in Alkaline Phosphatase - Part A
Description	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, chloride, carbon dioxide, creatinine, potassium, protein, sodium, and urea nitrogen. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	10
Baseline	84.3 (43.15)
Change from Baseline at Day 8	6.1 (20.73)
Change from Baseline at Day 15/ET	16.5 (30.62)
Change from Baseline at Follow-up Day 21	2.3 (9.93)
Change from Baseline at Follow-up Day 28	2.5 (10.34)

21. Primary Outcome

Title	Change From Baseline in Alanine Aminotransferase - Part A
Description	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, chloride, carbon dioxide, creatinine, potassium, protein, sodium, and urea nitrogen. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Baseline	18.8 (10.85)
Change from Baseline at Day 8	8.8 (11.31)
Change from Baseline at Day 15/ET	11.0 (21.63)
Change from Baseline at Follow-up Day 21	2.8 (7.73)
Change from Baseline at Follow-up Day 28	-1.7 (9.39)

22. Primary Outcome

Title	Change From Baseline in Aspartate Aminotransferase - Part A
Description	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, chloride, carbon dioxide, creatinine, potassium, protein, sodium, and urea nitrogen. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Baseline	18.7 (8.07)
Change from Baseline at Day 8	3.7 (8.63)
Change from Baseline at Day 15/ET	5.7 (17.50)
Change from Baseline at Follow-up Day 21	0.0 (7.59)
Change from Baseline at Follow-up Day 28	0.5 (12.60)

23. Primary Outcome

Title	Change From Baseline in Bilirubin - Part A
Description	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, chloride, carbon dioxide, creatinine, potassium, protein, sodium, and urea nitrogen. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Baseline	8.945 (4.5860)
Change from Baseline at Day 8	-1.052 (2.5687)
Change from Baseline at Day 15/ET	-1.973 (2.9491)
Change from Baseline at Follow-up Day 21	-1.842 (3.7243)
Change from Baseline at Follow-up Day 28	-1.184 (2.7382)

24. Primary Outcome

Title	Change From Baseline in Chloride - Part A
Description	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, chloride, carbon dioxide, creatinine, potassium, protein, sodium, and urea nitrogen. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Baseline	102.9 (3.07)
Change from Baseline at Day 8	1.2 (2.55)
Change from Baseline at Day 15/ET	1.5 (2.96)
Change from Baseline at Follow-up Day 21	1.3 (1.97)
Change from Baseline at Follow-up Day 28	1.1 (2.10)

25. Primary Outcome

Title	Change From Baseline in Carbon Dioxide - Part A
Description	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, chloride, carbon dioxide, creatinine, potassium, protein, sodium, and urea nitrogen. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Baseline	26.4 (2.50)
Change from Baseline at Day 8	-1.0 (2.35)
Change from Baseline at Day 15/ET	-0.8 (1.63)
Change from Baseline at Follow-up Day 21	0.0 (2.24)
Change from Baseline at Follow-up Day 28	-0.5 (1.56)

26. Primary Outcome

Title	Change From Baseline in Creatinine - Part A
Description	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, chloride, carbon dioxide, creatinine, potassium, protein, sodium, and urea nitrogen. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Baseline	73.848 (18.2228)
Change from Baseline at Day 8	-0.748 (6.7791)
Change from Baseline at Day 15/ET	0.136 (8.4394)
Change from Baseline at Follow-up Day 21	0.952 (9.4279)
Change from Baseline at Follow-up Day 28	0.816 (7.6084)

27. Primary Outcome

Title	Change From Baseline in Potassium - Part A
Description	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, chloride, carbon dioxide, creatinine, potassium, protein, sodium, and urea nitrogen. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Baseline	4.25 (0.273)
Change from Baseline at Day 8	0.12 (0.365)
Change from Baseline at Day 15/ET	0.02 (0.349)
Change from Baseline at Follow-up Day 21	-0.04 (0.423)
Change from Baseline at Follow-up Day 28	-0.10 (0.416)

28. Primary Outcome

Title	Change From Baseline in Protein - Part A
Description	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, chloride, carbon dioxide, creatinine, potassium, protein, sodium, and urea nitrogen. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Baseline	71.8 (3.59)
Change from Baseline at Day 8	-0.6 (5.36)
Change from Baseline at Day 15/ET	-0.2 (4.85)
Change from Baseline at Follow-up Day 21	-2.5 (4.33)
Change from Baseline at Follow-up Day 28	-0.1 (3.57)

29. Primary Outcome

Title	Change From Baseline in Sodium - Part A
Description	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, chloride, carbon dioxide, creatinine, potassium, protein, sodium, and urea nitrogen. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Baseline	138.5 (2.18)
Change from Baseline at Day 8	-0.2 (2.05)
Change from Baseline at Day 15/ET	-0.1 (2.43)
Change from Baseline at Follow-up Day 21	0.5 (2.76)
Change from Baseline at Follow-up Day 28	0.5 (2.90)

30. Primary Outcome

Title	Change From Baseline in Urea Nitrogen - Part A
Description	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, chloride, carbon dioxide, creatinine, potassium, protein, sodium, and urea nitrogen. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Baseline	4.888 (1.4234)
Change from Baseline at Day 8	-0.275 (1.6435)
Change from Baseline at Day 15/ET	-0.412 (1.4563)
Change from Baseline at Follow-up Day 21	-0.357 (0.9885)
Change from Baseline at Follow-up Day 28	-0.741 (1.3552)

31. Primary Outcome

Title	Change From Baseline in Activated Partial Thromboplastin Time - Part A
Description	Coagulation measures included activated partial thromboplastin time, prothrombin international normalized ratio, and prothrombin time. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Baseline	28.00
Change from Baseline at Day 8	1.00
Change from Baseline at Day 15/ET	1.20
Change from Baseline at Follow-up Day 21	0.70
Change from Baseline at Follow-up Day 28	1.00

32. Primary Outcome

Title	Change From Baseline in Prothrombin International Normalized Ratio (%) - Part A
Description	Coagulation measures included activated partial thromboplastin time, prothrombin international normalized ratio, and prothrombin time. The analysis was performed in participants included in Part A of the study. ET = Early Termination. The data for prothrombin international normalized ratio are presented as SI unit, percentage (%).
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Baseline	1.02 (0.055)
Change from Baseline at Day 8	0.04 (0.087)
Change from Baseline at Day 15/ET	-0.04 (0.051)
Change from Baseline at Follow-up Day 21	-0.01 (0.049)
Change from Baseline at Follow-up Day 28	-0.02 (0.038)

33. Primary Outcome

Title	Change From Baseline in Prothrombin Time - Part A
Description	Coagulation measures included activated partial thromboplastin time, prothrombin international normalized ratio, and prothrombin time. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Baseline	10.50
Change from Baseline at Day 8	0.10
Change from Baseline at Day 15/ET	-0.40
Change from Baseline at Follow-up Day 21	-0.10
Change from Baseline at Follow-up Day 28	0.00

34. Primary Outcome

Title	Change From Baseline in pH - Part A
Description	Urinalysis measures included pH and specific gravity. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Baseline	6.46 (0.803)
Change from Baseline at Day 8	-0.15 (1.049)
Change from Baseline at Day 15/ET	-0.35 (0.826)
Change from Baseline at Follow-up Day 21	-0.31 (1.407)
Change from Baseline at Follow-up Day 28	-0.19 (1.300)

35. Primary Outcome

Title	Change From Baseline in Specific Gravity - Part A
Description	Urinalysis measures included pH and specific gravity. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Baseline	1.014 (0.0083)
Change from Baseline at Day 8	0.001 (0.0075)
Change from Baseline at Day 15/ET	0.000 (0.0066)
Change from Baseline at Follow-up Day 21	0.003 (0.0084)
Change from Baseline at Follow-up Day 28	-0.001 (0.0076)

36. Primary Outcome

Title	Change From Baseline (CFB) in Supine Systolic Blood Pressure - Part A
Description	Vital signs measures included supine systolic blood pressure, supine diastolic blood pressure, standing systolic blood pressure, standing diastolic blood pressure, heart rate, respiratory rate, oral temperature, and oxygen saturation. The analysis was performed in participants included in Part A of the study. H = Hour(s). ET = Early Termination.
Time Frame	Baseline, Day 1 (0.25, 0.5, 1, 2, 12 hours postdose), Days 2, 3, 4, 5, 6 and 7 (predose, 0.25, 0.5, 1, 2, 12 hours postdose), Days 8, 9, 10, 11, 12, 13 and 14 (predose, 1 hour postdose), Day 15/ET, follow-up Day 21, follow-up Day 28

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Baseline	122.8 (15.92)
CFB at Day 1: 0.25 H Postdose	-1.7 (10.82)
CFB at Day 1: 0.5 H Postdose	-4.2 (9.50)
CFB at Day 1: 1 H Postdose	-2.4 (13.88)
CFB at Day 1: 2 H Postdose	-4.9 (13.47)
CFB at Day 1: 12 H Postdose	-0.8 (12.12)
CFB at Day 2: Predose	-0.8 (17.66)
CFB at Day 2: 0.25 H Postdose	8.2 (17.46)
CFB at Day 2: 0.5 H Postdose	0.8 (16.21)
CFB at Day 2: 1 H Postdose	2.3 (16.65)
CFB at Day 2: 2 H Postdose	-4.7 (13.88)
CFB at Day 2: 12 H Postdose	-0.5 (12.01)
CFB at Day 3: Predose	-2.1 (14.33)
CFB at Day 3: 0.25 H Postdose	5.8 (15.21)
CFB at Day 3: 0.5 H Postdose	0.5 (17.08)
CFB at Day 3: 1 H Postdose	2.5 (13.51)
CFB at Day 3: 2 H Postdose	-0.8 (16.49)
CFB at Day 3: 12 H Postdose	1.7 (12.98)
CFB at Day 4: Predose	-0.5 (17.70)
CFB at Day 4: 0.25 H Postdose	-0.4 (15.23)
CFB at Day 4: 0.5 H Postdose	1.8 (18.69)
CFB at Day 4: 1 H Postdose	-0.4 (19.35)
CFB at Day 4: 2 H Postdose	-3.4 (13.58)
CFB at Day 4: 12 H Postdose	-2.7 (18.63)
CFB at Day 5: Predose	-0.1 (20.01)
CFB at Day 5: 0.25 H Postdose	3.1 (18.18)
CFB at Day 5: 0.5 H Postdose	0.3 (16.94)
CFB at Day 5: 1 H Postdose	-4.8 (20.99)
CFB at Day 5: 2 H Postdose	-2.9 (16.11)
CFB at Day 5: 12 H Postdose	-1.5 (15.90)
CFB at Day 6: Predose	-0.2 (15.95)
CFB at Day 6: 0.25 H Postdose	-0.2 (17.21)
CFB at Day 6: 0.5 H Postdose	1.8 (14.62)
CFB at Day 6: 1 H Postdose	0.9 (15.86)
CFB at Day 6: 2 H Postdose	-3.5 (16.79)
CFB at Day 6: 12 H Postdose	-1.9 (22.35)
CFB at Day 7: Predose	-1.2 (21.17)
CFB at Day 7: 0.25 H Postdose	4.0 (16.40)
CFB at Day 7: 0.5 H Postdose	1.5 (17.47)
CFB at Day 7: 1 H Postdose	-3.2 (19.95)
CFB at Day 7: 2 H Postdose	0.3 (13.45)
CFB at Day 7: 12 H Postdose	-4.3 (13.04)
CFB at Day 8: Predose	4.3 (17.77)
CFB at Day 8: 1 H Postdose	-4.5 (13.15)
CFB at Day 9: Predose	9.4 (15.86)
CFB at Day 9: 1 H Postdose	3.3 (15.54)
CFB at Day 10: Predose	8.4 (14.93)
CFB at Day 10: 1 H Postdose	2.4 (14.19)
CFB at Day 11: Predose	8.8 (19.16)
CFB at Day 11: 1 H Postdose	-1.7 (14.26)
CFB at Day 12: Predose	7.4 (16.59)
CFB at Day 12: 1 H Postdose	-0.2 (18.93)
CFB at Day 13: Predose	3.2 (19.62)
CFB at Day 13: 1 H Postdose	1.3 (16.31)
CFB at Day 14: Predose	-3.8 (18.20)
CFB at Day 14: 1 H Postdose	-3.9 (15.01)
CFB at Day 15/ET	3.8 (17.10)
CFB at Follow-up Day 21	3.9 (10.84)
CFB at Follow-up Day 28	7.3 (15.19)

37. Primary Outcome

Title	Change From Baseline (CFB) in Supine Diastolic Blood Pressure - Part A
Description	Vital signs measures included supine systolic blood pressure, supine diastolic blood pressure, standing systolic blood pressure, standing diastolic blood pressure, heart rate, respiratory rate, oral temperature, and oxygen saturation. The analysis was performed in participants included in Part A of the study. H = Hour(s). ET = Early Termination.
Time Frame	Baseline, Day 1 (0.25, 0.5, 1, 2, 12 hours postdose), Days 2, 3, 4, 5, 6 and 7 (predose, 0.25, 0.5, 1, 2, 12 hours postdose), Days 8, 9, 10, 11, 12, 13 and 14 (predose, 1 hour postdose), Day 15/ET, follow-up Day 21, follow-up Day 28

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Baseline	79.4 (8.84)
CFB at Day 1: 0.25 H Postdose	-1.1 (5.50)
CFB at Day 1: 0.5 H Postdose	-1.6 (6.27)
CFB at Day 1: 1 H Postdose	-2.0 (7.51)
CFB at Day 1: 2 H Postdose	-5.2 (11.69)
CFB at Day 1: 12 H Postdose	1.3 (7.94)
CFB at Day 2: Predose	-3.5 (9.40)
CFB at Day 2: 0.25 H Postdose	-0.2 (8.36)
CFB at Day 2: 0.5 H Postdose	-2.4 (7.84)
CFB at Day 2: 1 H Postdose	-2.5 (10.52)
CFB at Day 2: 2 H Postdose	-5.4 (11.14)
CFB at Day 2: 12 H Postdose	-2.4 (7.94)
CFB at Day 3: Predose	0.3 (6.94)
CFB at Day 3: 0.25 H Postdose	1.9 (10.33)
CFB at Day 3: 0.5 H Postdose	0.2 (9.12)
CFB at Day 3: 1 H Postdose	-0.2 (9.13)
CFB at Day 3: 2 H Postdose	-3.9 (10.21)
CFB at Day 3: 12 H Postdose	0.0 (9.64)
CFB at Day 4: Predose	-0.8 (10.94)
CFB at Day 4: 0.25 H Postdose	-1.1 (12.13)
CFB at Day 4: 0.5 H Postdose	0.1 (14.80)
CFB at Day 4: 1 H Postdose	-3.5 (12.03)
CFB at Day 4: 2 H Postdose	-2.3 (10.27)
CFB at Day 4: 12 H Postdose	-1.1 (13.51)
CFB at Day 5: Predose	-1.3 (13.28)
CFB at Day 5: 0.25 H Postdose	-1.5 (11.49)
CFB at Day 5: 0.5 H Postdose	-1.3 (12.14)
CFB at Day 5: 1 H Postdose	-6.0 (12.64)
CFB at Day 5: 2 H Postdose	-4.3 (12.63)
CFB at Day 5: 12 H Postdose	-1.1 (10.16)
CFB at Day 6: Predose	-2.6 (12.05)
CFB at Day 6: 0.25 H Postdose	-0.8 (10.38)
CFB at Day 6: 0.5 H Postdose	1.8 (10.30)
CFB at Day 6: 1 H Postdose	0.8 (11.96)
CFB at Day 6: 2 H Postdose	-0.8 (13.04)
CFB at Day 6: 12 H Postdose	-2.5 (14.08)
CFB at Day 7: Predose	2.2 (13.53)
CFB at Day 7: 0.25 H Postdose	2.0 (11.31)
CFB at Day 7: 0.5 H Postdose	0.2 (10.39)
CFB at Day 7: 1 H Postdose	-0.2 (12.87)
CFB at Day 7: 2 H Postdose	-1.8 (9.16)
CFB at Day 7: 12 H Postdose	-2.5 (8.27)
CFB at Day 8: Predose	2.3 (11.27)
CFB at Day 8: 1 H Postdose	-2.9 (9.28)
CFB at Day 9: Predose	3.2 (11.91)
CFB at Day 9: 1 H Postdose	0.5 (11.72)
CFB at Day 10: Predose	1.6 (10.02)
CFB at Day 10: 1 H Postdose	-3.7 (9.77)
CFB at Day 11: Predose	5.2 (10.54)
CFB at Day 11: 1 H Postdose	0.0 (9.41)
CFB at Day 12: Predose	0.4 (8.87)
CFB at Day 12: 1 H Postdose	2.1 (12.11)
CFB at Day 13: Predose	3.2 (9.86)
CFB at Day 13: 1 H Postdose	3.7 (8.86)
CFB at Day 14: Predose	-1.3 (10.16)
CFB at Day 14: 1 H Postdose	-0.2 (9.08)
CFB at Day 15/ET	-0.7 (8.73)
CFB at Follow-up Day 21	3.1 (10.64)
CFB at Follow-up Day 28	1.8 (11.26)

38. Primary Outcome

Title	Change From Baseline (CFB) in Standing Systolic Blood Pressure - Part A
Description	Vital signs measures included supine systolic blood pressure, supine diastolic blood pressure, standing systolic blood pressure, standing diastolic blood pressure, heart rate, respiratory rate, oral temperature, and oxygen saturation. The analysis was performed in participants included in Part A of the study. H = Hour(s). ET = Early Termination.
Time Frame	Baseline, Day 1 (0.25, 0.5, 1, 2, 12 hours postdose), Days 2, 3, 4, 5, 6 and 7 (predose, 0.25, 0.5, 1, 2, 12 hours postdose), Days 8, 9, 10, 11, 12, 13 and 14 (predose, 1 hour postdose), Day 15/ET, follow-up Day 21, follow-up Day 28

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Baseline	126.8 (15.09)
CFB at Day 1: 0.25 H Postdose	-0.1 (9.67)
CFB at Day 1: 0.5 H Postdose	-3.8 (8.60)
CFB at Day 1: 1 H Postdose	-6.5 (10.94)
CFB at Day 1: 2 H Postdose	-3.9 (8.90)
CFB at Day 1: 12 H Postdose	-4.2 (10.40)
CFB at Day 2: Predose	-3.5 (11.74)
CFB at Day 2: 0.25 H Postdose	-0.9 (15.14)
CFB at Day 2: 0.5 H Postdose	-1.2 (11.29)
CFB at Day 2: 1 H Postdose	-3.8 (13.64)
CFB at Day 2: 2 H Postdose	-3.2 (14.52)
CFB at Day 2: 12 H Postdose	-1.7 (13.68)
CFB at Day 3: Predose	-0.5 (9.57)
CFB at Day 3: 0.25 H Postdose	-0.4 (12.39)
CFB at Day 3: 0.5 H Postdose	-1.2 (15.23)
CFB at Day 3: 1 H Postdose	-0.6 (15.80)
CFB at Day 3: 2 H Postdose	3.3 (16.41)
CFB at Day 3: 12 H Postdose	-1.0 (15.56)
CFB at Day 4: Predose	-1.1 (15.94)
CFB at Day 4: 0.25 H Postdose	0.4 (13.26)
CFB at Day 4: 0.5 H Postdose	-0.8 (13.55)
CFB at Day 4: 1 H Postdose	-0.8 (14.81)
CFB at Day 4: 2 H Postdose	-5.8 (13.50)
CFB at Day 4: 12 H Postdose	-7.1 (20.47)
CFB at Day 5: Predose	-3.8 (16.67)
CFB at Day 5: 0.25 H Postdose	-1.9 (16.51)
CFB at Day 5: 0.5 H Postdose	-7.0 (15.51)
CFB at Day 5: 1 H Postdose	-7.4 (13.74)
CFB at Day 5: 2 H Postdose	-4.4 (10.26)
CFB at Day 5: 12 H Postdose	-7.2 (17.29)
CFB at Day 6: Predose	-3.7 (16.20)
CFB at Day 6: 0.25 H Postdose	1.2 (12.65)
CFB at Day 6: 0.5 H Postdose	0.3 (11.73)
CFB at Day 6: 1 H Postdose	-3.2 (15.96)
CFB at Day 6: 2 H Postdose	-7.1 (12.51)
CFB at Day 6: 12 H Postdose	-5.6 (17.41)
CFB at Day 7: Predose	-2.2 (21.07)
CFB at Day 7: 0.25 H Postdose	-1.8 (12.25)
CFB at Day 7: 0.5 H Postdose	-1.0 (19.46)
CFB at Day 7: 1 H Postdose	-6.8 (12.60)
CFB at Day 7: 2 H Postdose	-3.6 (11.35)
CFB at Day 7: 12 H Postdose	-5.5 (14.01)
CFB at Day 8: Predose	1.5 (12.27)
CFB at Day 8: 1 H Postdose	-6.6 (12.91)
CFB at Day 9: Predose	-0.9 (12.05)
CFB at Day 9: 1 H Postdose	-1.9 (15.18)
CFB at Day 10: Predose	2.8 (15.82)
CFB at Day 10: 1 H Postdose	-4.0 (14.63)
CFB at Day 11: Predose	5.9 (13.63)
CFB at Day 11: 1 H Postdose	-4.9 (10.18)
CFB at Day 12: Predose	4.1 (19.31)
CFB at Day 12: 1 H Postdose	-3.8 (19.88)
CFB at Day 13: Predose	0.5 (14.77)
CFB at Day 13: 1 H Postdose	0.8 (13.04)
CFB at Day 14: Predose	-0.8 (12.19)
CFB at Day 14: 1 H Postdose	-8.9 (12.53)
CFB at Day 15/ET	-1.4 (11.39)
CFB at Follow-up Day 21	7.8 (14.23)
CFB at Follow-up Day 28	3.8 (13.53)

39. Primary Outcome

Title	Change From Baseline (CFB) in Standing Diastolic Blood Pressure - Part A
Description	Vital signs measures included supine systolic blood pressure, supine diastolic blood pressure, standing systolic blood pressure, standing diastolic blood pressure, heart rate, respiratory rate, oral temperature, and oxygen saturation. The analysis was performed in participants included in Part A of the study. H = Hour(s). ET = Early Termination.
Time Frame	Baseline, Day 1 (0.25, 0.5, 1, 2, 12 hours postdose), Days 2, 3, 4, 5, 6 and 7 (predose, 0.25, 0.5, 1, 2, 12 hours postdose), Days 8, 9, 10, 11, 12, 13 and 14 (predose, 1 hour postdose), Day 15/ET, follow-up Day 21, follow-up Day 28

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Baseline	83.9 (8.17)
CFB at Day 1: 0.25 H Postdose	-0.2 (7.60)
CFB at Day 1: 0.5 H Postdose	-1.5 (6.33)
CFB at Day 1: 1 H Postdose	-1.8 (5.10)
CFB at Day 1: 2 H Postdose	-1.5 (9.13)
CFB at Day 1: 12 H Postdose	-3.5 (7.49)
CFB at Day 2: Predose	-4.9 (5.41)
CFB at Day 2: 0.25 H Postdose	-3.3 (9.53)
CFB at Day 2: 0.5 H Postdose	-1.8 (7.46)
CFB at Day 2: 1 H Postdose	-3.4 (9.90)
CFB at Day 2: 2 H Postdose	-5.8 (9.63)
CFB at Day 2: 12 H Postdose	-3.2 (13.06)
CFB at Day 3: Predose	-4.2 (13.31)
CFB at Day 3: 0.25 H Postdose	-3.6 (10.79)
CFB at Day 3: 0.5 H Postdose	-1.9 (9.84)
CFB at Day 3: 1 H Postdose	-0.8 (9.58)
CFB at Day 3: 2 H Postdose	-2.2 (13.80)
CFB at Day 3: 12 H Postdose	0.7 (10.23)
CFB at Day 4: Predose	-0.8 (13.05)
CFB at Day 4: 0.25 H Postdose	-1.4 (10.91)
CFB at Day 4: 0.5 H Postdose	-2.6 (11.00)
CFB at Day 4: 1 H Postdose	-3.3 (9.02)
CFB at Day 4: 2 H Postdose	-2.9 (10.16)
CFB at Day 4: 12 H Postdose	-2.6 (12.31)
CFB at Day 5: Predose	-2.1 (10.54)
CFB at Day 5: 0.25 H Postdose	-2.6 (11.99)
CFB at Day 5: 0.5 H Postdose	-5.3 (10.71)
CFB at Day 5: 1 H Postdose	-5.9 (13.51)
CFB at Day 5: 2 H Postdose	-5.4 (13.26)
CFB at Day 5: 12 H Postdose	-2.2 (12.98)
CFB at Day 6: Predose	-2.2 (10.86)
CFB at Day 6: 0.25 H Postdose	-0.9 (9.27)
CFB at Day 6: 0.5 H Postdose	1.2 (7.97)
CFB at Day 6: 1 H Postdose	-1.8 (9.08)
CFB at Day 6: 2 H Postdose	-2.6 (6.70)
CFB at Day 6: 12 H Postdose	-4.5 (9.75)
CFB at Day 7: Predose	-0.2 (14.31)
CFB at Day 7: 0.25 H Postdose	0.8 (9.86)
CFB at Day 7: 0.5 H Postdose	-0.4 (12.76)
CFB at Day 7: 1 H Postdose	-2.5 (11.33)
CFB at Day 7: 2 H Postdose	-2.4 (7.97)
CFB at Day 7: 12 H Postdose	-3.0 (8.23)
CFB at Day 8: Predose	1.3 (9.91)
CFB at Day 8: 1 H Postdose	-4.5 (11.97)
CFB at Day 9: Predose	-2.5 (10.83)
CFB at Day 9: 1 H Postdose	-4.2 (10.61)
CFB at Day 10: Predose	-2.0 (9.70)
CFB at Day 10: 1 H Postdose	-3.7 (9.64)
CFB at Day 11: Predose	2.0 (9.03)
CFB at Day 11: 1 H Postdose	-7.1 (8.61)
CFB at Day 12: Predose	-3.8 (10.40)
CFB at Day 12: 1 H Postdose	-2.5 (10.62)
CFB at Day 13: Predose	0.5 (4.88)
CFB at Day 13: 1 H Postdose	1.4 (7.08)
CFB at Day 14: Predose	-0.7 (9.76)
CFB at Day 14: 1 H Postdose	-3.2 (9.24)
CFB at Day 15/ET	0.5 (8.39)
CFB at Follow-up Day 21	0.8 (10.64)
CFB at Follow-up Day 28	1.7 (6.80)

40. Primary Outcome

Title	Change From Baseline (CFB) in Heart Rate - Part A
Description	Vital signs measures included supine systolic blood pressure, supine diastolic blood pressure, standing systolic blood pressure, standing diastolic blood pressure, heart rate, respiratory rate, oral temperature, and oxygen saturation. The analysis was performed in participants included in Part A of the study. H = Hour(s). ET = Early Termination.
Time Frame	Baseline, Day 1 (0.25, 0.5, 1, 2, 12 hours postdose), Days 2, 3, 4, 5, 6 and 7 (predose, 0.25, 0.5, 1, 2, 12 hours postdose), Days 8, 9, 10, 11, 12, 13 and 14 (predose, 1 hour postdose), Day 15/ET, follow-up Day 21, follow-up Day 28

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Baseline	80.0 (13.10)
CFB at Day 1: 0.25 H Postdose	-2.7 (9.91)
CFB at Day 1: 0.5 H Postdose	-5.9 (13.44)
CFB at Day 1: 1 H Postdose	-4.6 (13.07)
CFB at Day 1: 2 H Postdose	-2.6 (14.77)
CFB at Day 1: 12 H Postdose	-2.2 (15.22)
CFB at Day 2: Predose	-6.6 (14.66)
CFB at Day 2: 0.25 H Postdose	-6.6 (13.64)
CFB at Day 2: 0.5 H Postdose	-6.4 (12.96)
CFB at Day 2: 1 H Postdose	-2.8 (16.75)
CFB at Day 2: 2 H Postdose	-3.5 (13.97)
CFB at Day 2: 12 H Postdose	-10.7 (14.68)
CFB at Day 3: Predose	-4.8 (15.82)
CFB at Day 3: 0.25 H Postdose	-6.1 (18.02)
CFB at Day 3: 0.5 H Postdose	-6.1 (14.23)
CFB at Day 3: 1 H Postdose	-1.2 (13.83)
CFB at Day 3: 2 H Postdose	-1.4 (16.19)
CFB at Day 3: 12 H Postdose	-8.2 (15.60)
CFB at Day 4: Predose	-6.8 (15.33)
CFB at Day 4: 0.25 H Postdose	-8.5 (15.58)
CFB at Day 4: 0.5 H Postdose	-5.3 (14.09)
CFB at Day 4: 1 H Postdose	-5.0 (15.46)
CFB at Day 4: 2 H Postdose	0.7 (12.21)
CFB at Day 4: 12 H Postdose	-5.2 (12.39)
CFB at Day 5: Predose	-5.2 (12.39)
CFB at Day 5: 0.25 H Postdose	-6.7 (16.93)
CFB at Day 5: 0.5 H Postdose	-4.4 (16.11)
CFB at Day 5: 1 H Postdose	-3.2 (13.57)
CFB at Day 5: 2 H Postdose	-1.0 (13.21)
CFB at Day 5: 12 H Postdose	-2.6 (14.71)
CFB at Day 6: Predose	-2.2 (13.98)
CFB at Day 6: 0.25 H Postdose	-4.8 (13.49)
CFB at Day 6: 0.5 H Postdose	-4.8 (14.90)
CFB at Day 6: 1 H Postdose	-0.5 (15.98)
CFB at Day 6: 2 H Postdose	-3.5 (13.48)
CFB at Day 6: 12 H Postdose	-5.8 (20.85)
CFB at Day 7: Predose	-3.0 (20.13)
CFB at Day 7: 0.25 H Postdose	-4.6 (16.86)
CFB at Day 7: 0.5 H Postdose	-6.2 (15.53)
CFB at Day 7: 1 H Postdose	-1.0 (16.64)
CFB at Day 7: 2 H Postdose	-0.1 (16.12)
CFB at Day 7: 12 H Postdose	-7.0 (18.16)
CFB at Day 8: Predose	-2.1 (15.74)
CFB at Day 8: 1 H Postdose	-1.0 (16.07)
CFB at Day 9: Predose	-0.1 (15.18)
CFB at Day 9: 1 H Postdose	0.2 (18.44)
CFB at Day 10: Predose	-1.8 (15.39)
CFB at Day 10: 1 H Postdose	0.7 (13.91)
CFB at Day 11: Predose	3.3 (12.80)
CFB at Day 11: 1 H Postdose	-5.2 (13.56)
CFB at Day 12: Predose	1.9 (10.30)
CFB at Day 12: 1 H Postdose	-1.2 (16.61)
CFB at Day 13: Predose	0.2 (16.69)
CFB at Day 13: 1 H Postdose	2.9 (13.76)
CFB at Day 14: Predose	-3.7 (15.16)
CFB at Day 14: 1 H Postdose	-2.2 (17.24)
CFB at Day 15/ET	-3.5 (16.06)
CFB at Follow-up Day 21	-6.5 (17.66)
CFB at Follow-up Day 28	-6.8 (13.53)

41. Primary Outcome

Title	Change From Baseline (CFB) in Respiratory Rate - Part A
Description	Vital signs measures included supine systolic blood pressure, supine diastolic blood pressure, standing systolic blood pressure, standing diastolic blood pressure, heart rate, respiratory rate, oral temperature, and oxygen saturation. The analysis was performed in participants included in Part A of the study. H = Hour(s). ET = Early Termination.
Time Frame	Baseline, Day 1 (0.25, 0.5, 1, 2, 12 hours postdose), Days 2, 3, 4, 5, 6 and 7 (predose, 0.25, 0.5, 1, 2, 12 hours postdose), Days 8, 9, 10, 11, 12, 13 and 14 (predose, 1 hour postdose), Day 15/ET, follow-up Day 21, follow-up Day 28

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Baseline	16.9 (1.75)
CFB at Day 1: 0.25 H Postdose	0.5 (1.45)
CFB at Day 1: 0.5 H Postdose	0.5 (1.45)
CFB at Day 1: 1 H Postdose	0.3 (1.80)
CFB at Day 1: 2 H Postdose	0.4 (1.57)
CFB at Day 1: 12 H Postdose	-0.1 (1.26)
CFB at Day 2: Predose	0.5 (1.56)
CFB at Day 2: 0.25 H Postdose	0.3 (2.10)
CFB at Day 2: 0.5 H Postdose	-0.1 (1.66)
CFB at Day 2: 1 H Postdose	-0.2 (1.72)
CFB at Day 2: 2 H Postdose	-0.5 (1.66)
CFB at Day 2: 12 H Postdose	-0.5 (1.71)
CFB at Day 3: Predose	-0.4 (1.61)
CFB at Day 3: 0.25 H Postdose	0.4 (1.76)
CFB at Day 3: 0.5 H Postdose	-0.3 (1.65)
CFB at Day 3: 1 H Postdose	-0.2 (1.17)
CFB at Day 3: 2 H Postdose	-0.7 (1.35)
CFB at Day 3: 12 H Postdose	-0.1 (1.66)
CFB at Day 4: Predose	0.1 (1.55)
CFB at Day 4: 0.25 H Postdose	0.3 (1.55)
CFB at Day 4: 0.5 H Postdose	0.3 (1.60)
CFB at Day 4: 1 H Postdose	0.5 (1.20)
CFB at Day 4: 2 H Postdose	0.3 (1.67)
CFB at Day 4: 12 H Postdose	0.4 (1.94)
CFB at Day 5: Predose	0.2 (1.57)
CFB at Day 5: 0.25 H Postdose	0.4 (1.39)
CFB at Day 5: 0.5 H Postdose	0.4 (1.50)
CFB at Day 5: 1 H Postdose	0.2 (1.64)
CFB at Day 5: 2 H Postdose	-0.5 (1.75)
CFB at Day 5: 12 H Postdose	-0.5 (2.99)
CFB at Day 6: Predose	0.2 (1.83)
CFB at Day 6: 0.25 H Postdose	0.2 (1.83)
CFB at Day 6: 0.5 H Postdose	0.1 (1.89)
CFB at Day 6: 1 H Postdose	0.1 (1.55)
CFB at Day 6: 2 H Postdose	0.1 (2.10)
CFB at Day 6: 12 H Postdose	-0.1 (1.12)
CFB at Day 7: Predose	0.1 (1.55)
CFB at Day 7: 0.25 H Postdose	0.8 (1.99)
CFB at Day 7: 0.5 H Postdose	0.2 (0.83)
CFB at Day 7: 1 H Postdose	0.5 (1.85)
CFB at Day 7: 2 H Postdose	-0.1 (2.02)
CFB at Day 7: 12 H Postdose	-0.3 (2.53)
CFB at Day 8: Predose	1.2 (2.28)
CFB at Day 8: 1 H Postdose	-0.3 (1.84)
CFB at Day 9: Predose	0.5 (2.18)
CFB at Day 9: 1 H Postdose	0.5 (2.67)
CFB at Day 10: Predose	0.6 (2.50)
CFB at Day 10: 1 H Postdose	0.0 (1.96)
CFB at Day 11: Predose	0.8 (1.95)
CFB at Day 11: 1 H Postdose	-0.2 (1.80)
CFB at Day 12: Predose	0.5 (1.85)
CFB at Day 12: 1 H Postdose	0.5 (2.54)
CFB at Day 13: Predose	0.3 (2.39)
CFB at Day 13: 1 H Postdose	0.5 (1.00)
CFB at Day 14: Predose	0.3 (1.55)
CFB at Day 14: 1 H Postdose	0.0 (2.12)
CFB at Day 15/ET	0.1 (2.10)
CFB at Follow-up Day 21	0.8 (1.92)
CFB at Follow-up Day 28	0.3 (1.60)

42. Primary Outcome

Title	Change From Baseline (CFB) in Oral Temperature - Part A
Description	Vital signs measures included supine systolic blood pressure, supine diastolic blood pressure, standing systolic blood pressure, standing diastolic blood pressure, heart rate, respiratory rate, oral temperature, and oxygen saturation. The analysis was performed in participants included in Part A of the study. H = Hour(s). ET = Early Termination.
Time Frame	Baseline, Day 1 (0.25, 0.5, 1, 2, 12 hours postdose), Days 2, 3, 4, 5, 6 and 7 (predose, 0.25, 0.5, 1, 2, 12 hours postdose), Days 8, 9, 10, 11, 12, 13 and 14 (predose, 1 hour postdose), Day 15/ET, follow-up Day 21, follow-up Day 28

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Baseline	36.71 (0.278)
CFB at Day 1: 0.25 H Postdose	-0.17 (0.457)
CFB at Day 1: 0.5 H Postdose	0.12 (0.302)
CFB at Day 1: 1 H Postdose	0.11 (0.468)
CFB at Day 1: 2 H Postdose	0.03 (0.438)
CFB at Day 1: 12 H Postdose	-0.09 (0.433)
CFB at Day 2: Predose	-0.05 (0.410)
CFB at Day 2: 0.25 H Postdose	0.04 (0.532)
CFB at Day 2: 0.5 H Postdose	0.00 (0.493)
CFB at Day 2: 1 H Postdose	0.20 (0.555)
CFB at Day 2: 2 H Postdose	0.01 (0.497)
CFB at Day 2: 12 H Postdose	-0.05 (0.399)
CFB at Day 3: Predose	0.02 (0.580)
CFB at Day 3: 0.25 H Postdose	-0.08 (0.563)
CFB at Day 3: 0.5 H Postdose	-0.17 (0.497)
CFB at Day 3: 1 H Postdose	-0.02 (0.597)
CFB at Day 3: 2 H Postdose	-0.11 (0.459)
CFB at Day 3: 12 H Postdose	-0.22 (0.389)
CFB at Day 4: Predose	-0.05 (0.525)
CFB at Day 4: 0.25 H Postdose	0.00 (0.473)
CFB at Day 4: 0.5 H Postdose	0.26 (0.459)
CFB at Day 4: 1 H Postdose	-0.05 (0.619)
CFB at Day 4: 2 H Postdose	-0.04 (0.373)
CFB at Day 4: 12 H Postdose	-0.11 (0.373)
CFB at Day 5: Predose	-0.06 (0.498)
CFB at Day 5: 0.25 H Postdose	0.01 (0.350)
CFB at Day 5: 0.5 H Postdose	-0.05 (0.418)
CFB at Day 5: 1 H Postdose	-0.08 (0.458)
CFB at Day 5: 2 H Postdose	-0.18 (0.523)
CFB at Day 5: 12 H Postdose	-0.09 (0.499)
CFB at Day 6: Predose	0.09 (0.560)
CFB at Day 6: 0.25 H Postdose	0.13 (0.512)
CFB at Day 6: 0.5 H Postdose	-0.05 (0.405)
CFB at Day 6: 1 H Postdose	0.06 (0.601)
CFB at Day 6: 2 H Postdose	-0.12 (0.526)
CFB at Day 6: 12 H Postdose	-0.04 (0.566)
CFB at Day 7: Predose	-0.11 (0.722)
CFB at Day 7: 0.25 H Postdose	-0.11 (0.566)
CFB at Day 7: 0.5 H Postdose	-0.08 (0.639)
CFB at Day 7: 1 H Postdose	-0.14 (0.588)
CFB at Day 7: 2 H Postdose	-0.02 (0.453)
CFB at Day 7: 12 H Postdose	-0.10 (0.534)
CFB at Day 8: Predose	-0.02 (0.589)
CFB at Day 8: 1 H Postdose	0.02 (0.351)
CFB at Day 9: Predose	-0.28 (0.675)
CFB at Day 9: 1 H Postdose	-0.17 (0.609)
CFB at Day 10: Predose	-0.20 (0.471)
CFB at Day 10: 1 H Postdose	-0.23 (0.624)
CFB at Day 11: Predose	0.03 (0.483)
CFB at Day 11: 1 H Postdose	-0.28 (0.506)
CFB at Day 12: Predose	-0.18 (0.504)
CFB at Day 12: 1 H Postdose	-0.10 (0.512)
CFB at Day 13: Predose	-0.12 (0.448)
CFB at Day 13: 1 H Postdose	-0.23 (0.342)
CFB at Day 14: Predose	0.01 (0.475)
CFB at Day 14: 1 H Postdose	0.05 (0.570)
CFB at Day 15/ET	-0.05 (0.326)
CFB at Follow-up Day 21	-0.10 (0.372)
CFB at Follow-up Day 28	-0.12 (0.326)

43. Primary Outcome

Title	Change From Baseline (CFB) in Oxygen Saturation - Part A
Description	Vital signs measures included supine systolic blood pressure, supine diastolic blood pressure, standing systolic blood pressure, standing diastolic blood pressure, heart rate, respiratory rate, oral temperature, and oxygen saturation. The analysis was performed in participants included in Part A of the study. H = Hour(s).
Time Frame	Baseline, Day 1 (0.25, 0.5, 1, 2, 12 hours postdose), Days 2, 3, 4, 5, 6 and 7 (predose, 0.25, 0.5, 1, 2, 12 hours postdose), Day 8 (predose, 1 hour postdose)

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	12
Baseline	98.6 (1.08)
CFB at Day 1: 0.25 H Postdose	0.0 (1.65)
CFB at Day 1: 0.5 H Postdose	-0.4 (2.02)
CFB at Day 1: 1 H Postdose	0.3 (1.22)
CFB at Day 1: 2 H Postdose	-0.3 (2.16)
CFB at Day 1: 12 H Postdose	0.3 (1.07)
CFB at Day 2: Predose	-0.4 (1.62)
CFB at Day 2: 0.25 H Postdose	-0.1 (1.83)
CFB at Day 2: 0.5 H Postdose	-0.3 (1.44)
CFB at Day 2: 1 H Postdose	0.1 (1.62)
CFB at Day 2: 2 H Postdose	-0.2 (1.34)
CFB at Day 2: 12 H Postdose	-0.6 (1.62)
CFB at Day 3: Predose	0.3 (1.60)
CFB at Day 3: 0.25 H Postdose	-0.9 (1.68)
CFB at Day 3: 0.5 H Postdose	-1.3 (2.23)
CFB at Day 3: 1 H Postdose	-0.3 (1.87)
CFB at Day 3: 2 H Postdose	0.1 (1.37)
CFB at Day 3: 12 H Postdose	-0.9 (1.68)
CFB at Day 4: Predose	-1.1 (2.23)
CFB at Day 4: 0.25 H Postdose	-0.2 (1.85)
CFB at Day 4: 0.5 H Postdose	-0.6 (2.19)
CFB at Day 4: 1 H Postdose	-0.5 (1.68)
CFB at Day 4: 2 H Postdose	-0.4 (1.50)
CFB at Day 4: 12 H Postdose	-0.5 (2.07)
CFB at Day 5: Predose	-0.4 (1.78)
CFB at Day 5: 0.25 H Postdose	-0.6 (2.11)
CFB at Day 5: 0.5 H Postdose	-0.2 (1.53)
CFB at Day 5: 1 H Postdose	-0.5 (1.88)
CFB at Day 5: 2 H Postdose	-0.7 (2.21)
CFB at Day 5: 12 H Postdose	-0.2 (1.34)
CFB at Day 6: Predose	-0.4 (1.00)
CFB at Day 6: 0.25 H Postdose	-0.5 (1.51)
CFB at Day 6: 0.5 H Postdose	-0.5 (1.98)
CFB at Day 6: 1 H Postdose	-0.3 (0.97)
CFB at Day 6: 2 H Postdose	-0.3 (1.22)
CFB at Day 6: 12 H Postdose	0.3 (1.42)
CFB at Day 7: Predose	-0.5 (1.44)
CFB at Day 7: 0.25 H Postdose	-0.4 (2.06)
CFB at Day 7: 0.5 H Postdose	-0.5 (1.51)
CFB at Day 7: 1 H Postdose	-1.1 (1.93)
CFB at Day 7: 2 H Postdose	-0.6 (1.31)
CFB at Day 7: 12 H Postdose	-0.5 (1.63)
CFB at Day 8: Predose	0.2 (1.53)
CFB at Day 8: 1 H Postdose	-0.3 (1.82)

44. Primary Outcome

Title	Change From Baseline in QT Interval - Part A
Description	Electrocardiogram (ECG) measures included QT interval, QTc based on Fridericia formula (QTcF interval), ECG mean heart rate, RR interval, PR interval, and QRS duration. The analysis was performed in participants included in Part A of the study.
Time Frame	Baseline, Days 1, 2, 7, 14 and follow-up Day 21

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Baseline	401.0
Change from Baseline at Day 1	-8.0
Change from Baseline at Day 2	-12.0
Change from Baseline at Day 7	-22.0
Change from Baseline at Day 14	-16.0
Change from Baseline at Follow-up Day 21	-17.5

45. Primary Outcome

Title	Change From Baseline in QTcF Interval - Part A
Description	ECG measures included QT interval, QTcF interval, ECG mean heart rate, RR interval, PR interval, and QRS duration. The analysis was performed in participants included in Part A of the study.
Time Frame	Baseline, Days 1, 2, 7, 14 and follow-up Day 21

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Baseline	423.0
Change from Baseline at Day 1	2.0
Change from Baseline at Day 2	-5.0
Change from Baseline at Day 7	-4.0
Change from Baseline at Day 14	-8.0
Change from Baseline at Follow-up Day 21	-7.0

46. Primary Outcome

Title	Change From Baseline in ECG Mean Heart Rate - Part A
Description	ECG measures included QT interval, QTcF interval, ECG mean heart rate, RR interval, PR interval, and QRS duration. The analysis was performed in participants included in Part A of the study.
Time Frame	Baseline, Days 1, 2, 7, 14 and follow-up Day 21

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Baseline	65.6 (7.74)
Change from Baseline at Day 1	5.8 (7.83)
Change from Baseline at Day 2	5.6 (7.05)
Change from Baseline at Day 7	8.8 (9.72)
Change from Baseline at Day 14	6.0 (10.79)
Change from Baseline at Follow-up Day 21	7.0 (6.06)

47. Primary Outcome

Title	Change From Baseline in RR Interval - Part A
Description	ECG measures included QT interval, QTcF interval, ECG mean heart rate, RR interval, PR interval, and QRS duration. The analysis was performed in participants included in Part A of the study.
Time Frame	Baseline, Days 1, 2, 7, 14 and follow-up Day 21

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Baseline	952.0
Change from Baseline at Day 1	-65.0
Change from Baseline at Day 2	-45.0
Change from Baseline at Day 7	-88.0
Change from Baseline at Day 14	-107.0
Change from Baseline at Follow-up Day 21	-97.0

48. Primary Outcome

Title	Change From Baseline in PR Interval - Part A
Description	ECG measures included QT interval, QTcF interval, ECG mean heart rate, RR interval, PR interval, and QRS duration. The analysis was performed in participants included in Part A of the study.
Time Frame	Baseline, Days 1, 2, 7, 14 and follow-up Day 21

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Baseline	158.0
Change from Baseline at Day 1	1.0
Change from Baseline at Day 2	-8.0
Change from Baseline at Day 7	2.0
Change from Baseline at Day 14	5.0
Change from Baseline at Follow-up Day 21	-3.5

49. Primary Outcome

Title	Change From Baseline in QRS Interval - Part A
Description	ECG measures included QT interval, QTcF interval, ECG mean heart rate, RR interval, PR interval, and QRS duration. The analysis was performed in participants included in Part A of the study.
Time Frame	Baseline, Days 1, 2, 7, 14 and follow-up Day 21

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Baseline	94.0
Change from Baseline at Day 1	0.0
Change from Baseline at Day 2	-2.0
Change from Baseline at Day 7	-1.0
Change from Baseline at Day 14	4.0
Change from Baseline at Follow-up Day 21	-0.5

50. Primary Outcome

Title	Percentage of Participants With a Response of 'Yes' to Any Columbia Suicide Severity Rating Scale (C-SSRS) Suicidal Ideation Item - Part A
Description	The C-SSRS scale consisted of a baseline evaluation (at screening) that assessed the lifetime experience of participants with suicidal ideation (SI) and behavior and a postbaseline evaluation that focused on suicidality since the last study visit. The C-SSRS included "yes" or "no"' responses for assessment of suicidal ideation and behavior as well as numeric ratings for severity of ideation, if present (from 1 to 5, with 5 being the most severe). The C-SSRS SI items involved wish to be dead, non-specific active suicidal thoughts, active SI with any methods, active SI with some intent and active SI with specific plan. The analysis was performed in participants included in Part A of the study.
Time Frame	Day 1 up to Day 28

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Number [percentage of participants]	0 0%

51. Primary Outcome

Title	Change From Baseline in Stanford Sleepiness Scale (SSS) Score at Day 15 - Part A
Description	The SSS was participant-rated scale designed to quickly assess how alert a participant was feeling. Degrees of sleepiness and alertness were rated on a scale of one to seven, where the lowest score of 'one' indicated the participant was 'feeling active, vital, alert, or wide awake' and the highest score of 'seven' indicated the participant was 'no longer fighting sleep, sleep onset soon; having dream-like thoughts'. A negative change from baseline indicated less sleepiness. A positive change from baseline indicated more sleepiness. The analysis was performed in participants included in Part A of the study.
Time Frame	Baseline, Day 15

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Baseline	2.3 (1.60)
Change from Baseline at Day 15	-0.6 (1.50)

52. Primary Outcome

Title	Change From Baseline in the 17-item Hamilton Rating Scale for Depression (HAM-D) Total Score at Day 15 - Part B
Description	The HAM-D total score comprised a sum of 17 individual item scores. Items scored in a range of 0 to 2 included: insomnia (early, middle, late), somatic symptoms (gastrointestinal and general), genital symptoms, loss of weight, and insight. The following items were scored in a range of 0 to 4: agitation, depressed mood, feelings of guilt, suicide, work and activities, retardation, anxiety (psychic and somatic), and hypochondriasis. The total score could range from 0 to 52. Higher scores indicated a greater degree of depression. A negative change from baseline indicated less depression. A positive change from baseline indicated more depression. The analysis was performed in participants included in Part B of the study.
Time Frame	Baseline, Day 15

Outcome Measure Data

Analysis Population Description

The efficacy set included all participants who were randomized and received at least 1 dose of the double-blind study drug and had a baseline and at least 1 post-baseline efficacy evaluation.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Least Squares Mean (Standard Error) [score on a scale]	-10.3 (1.33)	-17.4 (1.31)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part A: SAGE-217, Part B: SAGE-217
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments
	Method	Mixed Effect Model for Repeated Measures
	Comments	The Mixed Effect Model for Repeated Measures (MMRM) included the change from baseline in HAM-D total score at each visit as the dependent variables.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-7.0
	Confidence Interval	(2-Sided) 95%; -10.2 to -3.9
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.60
	Estimation Comments

53. Secondary Outcome

Title	Change From Baseline in the HAM-D Total Score at Day 15 and All Other Time Points - Part A
Description	The HAM-D total score comprised a sum of 17 individual item scores. Items scored in a range of 0 to 2 included: insomnia (early, middle, late), somatic symptoms (gastrointestinal and general), genital symptoms, loss of weight, and insight. The following items were scored in a range of 0 to 4: agitation, depressed mood, feelings of guilt, suicide, work and activities, retardation, anxiety (psychic and somatic), and hypochondriasis. The total score could range from 0 to 52. Higher scores indicate a greater degree of depression. A negative change from baseline indicated less depression. A positive change from baseline indicated more depression. The analysis was performed in participants included in Part A of the study.
Time Frame	Baseline, Days 2, 3, 4, 5, 6, 7, 8, 15, 21 and 28

Outcome Measure Data

Analysis Population Description

The efficacy set included all participants who received at least one dose of the study drug and had a baseline and at least one postbaseline efficacy evaluation.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Baseline	27.2 (3.06)
Change from Baseline at Day 2	-5.9 (4.44)
Change from Baseline at Day 3	-9.1 (4.82)
Change from Baseline at Day 4	-12.4 (5.74)
Change from Baseline at Day 5	-14.4 (5.68)
Change from Baseline at Day 6	-16.0 (5.48)
Change from Baseline at Day 7	-16.2 (6.01)
Change from Baseline at Day 8	-18.2 (5.94)
Change from Baseline at Day 15	-19.9 (5.78)
Change from Baseline at Day 21	-20.5 (7.11)
Change from Baseline at Day 28	-19.7 (8.09)

54. Secondary Outcome

Title	Percentage of Participants With TEAEs - Part B
Description	An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. A TEAE was defined as an adverse event with onset after the start of study drug, or any worsening of a pre-existing medical condition/adverse event with onset after the start of study drug and until 7 days after the last dose. The analysis was performed in participants included in Part B of the study.
Time Frame	Day 1 up to Day 21

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Number [percentage of participants]	45.5 350%	53.3 121.1%

55. Secondary Outcome

Title	Percentage of Participants With AEs During Post-TEAE Period
Description	An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. TEAE was defined as an adverse event with onset after the start of study drug, or any worsening of a pre-existing medical condition/adverse event with onset after the start of study drug and until 7 days after the last dose. Post-TEAE period was defined as 7 days after final dose through last follow-up (Day 42). The analysis was performed in participants included in Part B of the study.
Time Frame	Day 21 up to Day 42

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Number [percentage of participants]	22.7 174.6%	8.9 20.2%

56. Secondary Outcome

Title	Percentage of Participants With TEAEs, Graded by Severity - Part B
Description	Severity was assessed according to the following scale: mild (awareness of sign or symptom, but easily tolerated); moderate (discomfort sufficient to cause interference with normal activities); severe (incapacitating, with inability to perform normal activities). The analysis was performed in participants included in Part B of the study.
Time Frame	Day 1 up to Day 21

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Moderate or Severe	5 38.5%	6 13.6%
Severe	0 0%	0 0%

57. Secondary Outcome

Title	Change From Baseline in Basophils - Part B
Description	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes, reticulocytes to erythrocytes ratio and leukocytes. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Baseline	0.038 (0.0478)	0.041 (0.0489)
Change from Baseline at Day 8	0.012 (0.0495)	-0.004 (0.0520)
Change from Baseline at Day 15/ET	0.005 (0.0486)	0.001 (0.0359)
Change from Baseline at Follow-up Day 21	0.000 (0.0484)	-0.013 (0.0396)
Change from Baseline at Follow-up Day 28	0.008 (0.0497)	-0.018 (0.0436)
Change from Baseline at Follow-up Day 35	0.008 (0.0561)	0.007 (0.0352)
Change from Baseline at Follow-up Day 42	0.011 (0.0483)	-0.006 (0.0494)

58. Secondary Outcome

Title	Change From Baseline in Basophils to Leukocytes Ratio (%) - Part B
Description	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes, reticulocytes to erythrocytes ratio and leukocytes. The analysis was performed in participants included in Part B of the study. ET = Early Termination. The blood cell differential (ratio) data are presented as SI unit, percentage (%).
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Baseline	0.63 (0.302)	0.63 (0.274)
Change from Baseline at Day 8	0.11 (0.241)	0.04 (0.229)
Change from Baseline at Day 15/ET	0.05 (0.174)	0.11 (0.231)
Change from Baseline at Follow-up Day 21	0.06 (0.227)	0.02 (0.240)
Change from Baseline at Follow-up Day 28	0.05 (0.258)	-0.01 (0.318)
Change from Baseline at Follow-up Day 35	0.04 (0.265)	0.10 (0.180)
Change from Baseline at Follow-up Day 42	0.10 (0.240)	0.07 (0.255)

59. Secondary Outcome

Title	Change From Baseline in Eosinophils - Part B
Description	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes, reticulocytes to erythrocytes ratio and leukocytes. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Baseline	0.147 (0.0818)	0.126 (0.0801)
Change from Baseline at Day 8	0.004 (0.0578)	0.025 (0.0795)
Change from Baseline at Day 15/ET	0.027 (0.0804)	0.037 (0.0890)
Change from Baseline at Follow-up Day 21	0.020 (0.0789)	0.027 (0.0696)
Change from Baseline at Follow-up Day 28	0.022 (0.0940)	0.015 (0.0724)
Change from Baseline at Follow-up Day 35	0.006 (0.0799)	0.012 (0.0760)
Change from Baseline at Follow-up Day 42	0.017 (0.0772)	0.017 (0.0735)

60. Secondary Outcome

Title	Change From Baseline in Eosinophils to Leukocytes Ratio (%) - Part B
Description	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes, reticulocytes to erythrocytes ratio and leukocytes. The analysis was performed in participants included in Part B of the study. ET = Early Termination. The blood cell differential (ratio) data are presented as SI unit, percentage (%).
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Baseline	1.95 (1.018)	1.96 (1.267)
Change from Baseline at Day 8	0.15 (0.780)	0.44 (1.102)
Change from Baseline at Day 15/ET	0.53 (1.042)	0.60 (1.166)
Change from Baseline at Follow-up Day 21	0.48 (1.080)	0.53 (0.916)
Change from Baseline at Follow-up Day 28	0.48 (1.221)	0.39 (1.092)
Change from Baseline at Follow-up Day 35	0.42 (0.996)	0.37 (1.015)
Change from Baseline at Follow-up Day 42	0.55 (1.089)	0.46 (1.192)

61. Secondary Outcome

Title	Change From Baseline in Hematocrit - Part B
Description	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes, reticulocytes to erythrocytes ratio and leukocytes. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Baseline	0.424 (0.0372)	0.436 (0.0389)
Change from Baseline at Day 8	-0.004 (0.0240)	-0.004 (0.0281)
Change from Baseline at Day 15/ET	-0.006 (0.0210)	-0.010 (0.0230)
Change from Baseline at Follow-up Day 21	-0.015 (0.0233)	-0.020 (0.0249)
Change from Baseline at Follow-up Day 28	-0.015 (0.0235)	-0.015 (0.0220)
Change from Baseline at Follow-up Day 35	-0.011 (0.0253)	-0.015 (0.0244)
Change from Baseline at Follow-up Day 42	-0.015 (0.0223)	-0.019 (0.0245)

62. Secondary Outcome

Title	Change From Baseline in Hemoglobin - Part B
Description	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes, reticulocytes to erythrocytes ratio and leukocytes. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Baseline	136.1 (13.79)	141.0 (14.98)
Change from Baseline at Day 8	-1.3 (7.72)	-2.3 (9.09)
Change from Baseline at Day 15/ET	-1.8 (6.88)	-3.8 (7.80)
Change from Baseline at Follow-up Day 21	-5.2 (7.41)	-6.6 (7.91)
Change from Baseline at Follow-up Day 28	-4.9 (7.44)	-4.9 (7.29)
Change from Baseline at Follow-up Day 35	-3.8 (8.16)	-5.1 (8.18)
Change from Baseline at Follow-up Day 42	-4.7 (6.44)	-5.6 (8.18)

63. Secondary Outcome

Title	Change From Baseline in Lymphocytes - Part B
Description	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes, reticulocytes to erythrocytes ratio and leukocytes. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Baseline	2.294 (0.6093)	2.162 (0.6275)
Change from Baseline at Day 8	-0.053 (0.4033)	-0.054 (0.4501)
Change from Baseline at Day 15/ET	0.066 (0.5139)	0.025 (0.4944)
Change from Baseline at Follow-up Day 21	-0.106 (0.5656)	-0.104 (0.5341)
Change from Baseline at Follow-up Day 28	-0.073 (0.5071)	-0.247 (0.5428)
Change from Baseline at Follow-up Day 35	-0.153 (0.4178)	-0.209 (0.5137)
Change from Baseline at Follow-up Day 42	-0.168 (0.4661)	-0.133 (0.4544)

64. Secondary Outcome

Title	Change From Baseline in Lymphocytes to Leukocytes Ratio (%) - Part B
Description	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes, reticulocytes to erythrocytes ratio and leukocytes. The analysis was performed in participants included in Part B of the study. ET = Early Termination. The blood cell differential (ratio) data are presented as SI unit, percentage (%).
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Baseline	33.06 (7.144)	33.87 (10.189)
Change from Baseline at Day 8	-0.43 (6.613)	1.86 (7.057)
Change from Baseline at Day 15/ET	1.25 (7.203)	1.96 (8.304)
Change from Baseline at Follow-up Day 21	0.04 (7.177)	-0.13 (9.353)
Change from Baseline at Follow-up Day 28	0.61 (9.038)	-0.61 (9.527)
Change from Baseline at Follow-up Day 35	-0.75 (7.861)	-0.02 (8.937)
Change from Baseline at Follow-up Day 42	0.91 (6.960)	0.30 (8.641)

65. Secondary Outcome

Title	Change From Baseline in Monocytes - Part B
Description	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes, reticulocytes to erythrocytes ratio and leukocytes. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Baseline	0.442 (0.1206)	0.438 (0.1339)
Change from Baseline at Day 8	0.003 (0.1209)	0.035 (0.1631)
Change from Baseline at Day 15/ET	0.017 (0.1253)	0.028 (0.1185)
Change from Baseline at Follow-up Day 21	0.007 (0.1063)	0.025 (0.1333)
Change from Baseline at Follow-up Day 28	0.045 (0.1415)	-0.010 (0.1523)
Change from Baseline at Follow-up Day 35	0.024 (0.1364)	0.002 (0.1381)
Change from Baseline at Follow-up Day 42	0.011 (0.1050)	0.004 (0.1313)

66. Secondary Outcome

Title	Change From Baseline in Monocytes to Leukocytes Ratio (%) - Part B
Description	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes, reticulocytes to erythrocytes ratio and leukocytes. The analysis was performed in participants included in Part B of the study. ET = Early Termination. The blood cell differential (ratio) data are presented as SI unit, percentage (%).
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Baseline	6.33 (1.760)	6.78 (1.970)
Change from Baseline at Day 8	0.20 (1.430)	0.98 (1.661)
Change from Baseline at Day 15/ET	0.40 (1.942)	0.79 (1.617)
Change from Baseline at Follow-up Day 21	0.57 (1.473)	0.90 (2.030)
Change from Baseline at Follow-up Day 28	0.97 (1.869)	0.77 (2.562)
Change from Baseline at Follow-up Day 35	0.66 (1.546)	0.78 (2.374)
Change from Baseline at Follow-up Day 42	0.94 (1.270)	0.74 (2.076)

67. Secondary Outcome

Title	Change From Baseline in Neutrophils - Part B
Description	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes, reticulocytes to erythrocytes ratio and leukocytes. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Baseline	4.174 (1.4046)	3.852 (1.5129)
Change from Baseline at Day 8	-0.100 (1.1146)	-0.399 (1.7192)
Change from Baseline at Day 15/ET	-0.389 (1.2882)	-0.406 (1.2479)
Change from Baseline at Follow-up Day 21	-0.354 (1.0854)	-0.280 (1.3687)
Change from Baseline at Follow-up Day 28	-0.363 (1.2994)	-0.454 (1.3814)
Change from Baseline at Follow-up Day 35	-0.209 (1.3250)	-0.494 (1.0343)
Change from Baseline at Follow-up Day 42	-0.584 (1.2204)	-0.323 (1.4669)

68. Secondary Outcome

Title	Change From Baseline in Neutrophils to Leukocytes Ratio (%) - Part B
Description	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes, reticulocytes to erythrocytes ratio and leukocytes. The analysis was performed in participants included in Part B of the study. ET = Early Termination. The blood cell differential (ratio) data are presented as SI unit, percentage (%).
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Baseline	58.03 (7.850)	56.76 (10.809)
Change from Baseline at Day 8	-0.03 (7.549)	-3.32 (8.015)
Change from Baseline at Day 15/ET	-2.23 (8.600)	-3.46 (9.345)
Change from Baseline at Follow-up Day 21	-1.15 (8.173)	-1.32 (10.154)
Change from Baseline at Follow-up Day 28	-2.11 (10.514)	-0.63 (11.160)
Change from Baseline at Follow-up Day 35	-0.38 (9.087)	-1.22 (9.600)
Change from Baseline at Follow-up Day 42	-2.50 (7.678)	-1.58 (9.818)

69. Secondary Outcome

Title	Change From Baseline in Platelets - Part B
Description	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes, reticulocytes to erythrocytes ratio and leukocytes. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	44
Baseline	287.0 (74.33)	272.2 (60.08)
Change from Baseline at Day 8	-8.5 (42.93)	-0.9 (36.43)
Change from Baseline at Day 15/ET	6.8 (39.39)	3.7 (36.16)
Change from Baseline at Follow-up Day 21	4.7 (32.94)	7.4 (29.01)
Change from Baseline at Follow-up Day 28	3.5 (40.30)	5.0 (31.48)
Change from Baseline at Follow-up Day 35	-4.9 (43.23)	-1.7 (31.25)
Change from Baseline at Follow-up Day 42	-1.8 (48.71)	-2.7 (33.61)

70. Secondary Outcome

Title	Change From Baseline in Erythrocytes - Part B
Description	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes, reticulocytes to erythrocytes ratio and leukocytes. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Baseline	4.811 (0.4827)	4.902 (0.4956)
Change from Baseline at Day 8	-0.041 (0.2802)	-0.074 (0.2889)
Change from Baseline at Day 15/ET	-0.069 (0.2436)	-0.128 (0.2714)
Change from Baseline at Follow-up Day 21	-0.182 (0.2841)	-0.225 (0.2794)
Change from Baseline at Follow-up Day 28	-0.176 (0.2599)	-0.172 (0.2684)
Change from Baseline at Follow-up Day 35	-0.134 (0.3050)	-0.189 (0.2675)
Change from Baseline at Follow-up Day 42	-0.161 (0.2365)	-0.202 (0.3181)

71. Secondary Outcome

Title	Change From Baseline in Reticulocytes - Part B
Description	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes, reticulocytes to erythrocytes ratio and leukocytes. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Overall number of participants analyzed: Number of participants analyzed in this outcome measure. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	3	2
Baseline	32.313 (19.0547)	78.735 (58.5272)
Change from Baseline at Day 8	-19.035 (12.9613)
Change from Baseline at Day 15/ET	9.240 (NA)

72. Secondary Outcome

Title	Change From Baseline in Reticulocytes to Erythrocytes Ratio (%) - Part B
Description	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes, reticulocytes to erythrocytes ratio and leukocytes. The analysis was performed in participants included in Part B of the study. ET = Early Termination. The blood cell differential (ratio) data are presented as SI unit, percentage (%).
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	42	43
Baseline	1.32 (0.360)	1.40 (0.517)
Change from Baseline at Day 8	-0.02 (0.290)	-0.07 (0.363)
Change from Baseline at Day 15/ET	-0.03 (0.310)	0.00 (0.372)
Change from Baseline at Follow-up Day 21	0.14 (0.352)	0.05 (0.359)
Change from Baseline at Follow-up Day 28	0.17 (0.289)	0.03 (0.296)
Change from Baseline at Follow-up Day 35	0.15 (0.254)	0.07 (0.320)
Change from Baseline at Follow-up Day 42	0.12 (0.227)	0.03 (0.312)

73. Secondary Outcome

Title	Change From Baseline in Leukocytes - Part B
Description	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes, reticulocytes to erythrocytes ratio and leukocytes. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Baseline	7.08 (1.778)	6.63 (1.688)
Change from Baseline at Day 8	-0.11 (1.324)	-0.40 (1.913)
Change from Baseline at Day 15/ET	-0.27 (1.435)	-0.34 (1.241)
Change from Baseline at Follow-up Day 21	-0.41 (1.258)	-0.35 (1.410)
Change from Baseline at Follow-up Day 28	-0.34 (1.266)	-0.70 (1.348)
Change from Baseline at Follow-up Day 35	-0.32 (1.355)	-0.70 (0.993)
Change from Baseline at Follow-up Day 42	-0.69 (1.421)	-0.45 (1.443)

74. Secondary Outcome

Title	Change From Baseline in Albumin - Part B
Description	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium, chloride, carbon dioxide, creatinine, glucose, potassium, magnesium, phosphate, protein, sodium, thyrotropin, and urea nitrogen. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Baseline	44.6 (2.69)	44.6 (3.30)
Change from Baseline at Day 8	-1.1 (2.66)	-0.8 (3.24)
Change from Baseline at Day 15/ET	-0.8 (2.73)	-0.9 (3.23)
Change from Baseline at Follow-up Day 21	-1.1 (2.72)	-1.4 (3.40)
Change from Baseline at Follow-up Day 28	-0.2 (3.01)	-0.9 (3.07)
Change from Baseline at Follow-up Day 35	-0.5 (2.90)	-1.0 (3.40)
Change from Baseline at Follow-up Day 42	-0.5 (2.30)	-0.7 (3.43)

75. Secondary Outcome

Title	Change From Baseline in Alkaline Phosphatase - Part B
Description	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium, chloride, carbon dioxide, creatinine, glucose, potassium, magnesium, phosphate, protein, sodium, thyrotropin, and urea nitrogen. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Baseline	80.9 (19.18)	85.5 (27.97)
Change from Baseline at Day 8	-0.1 (8.95)	1.3 (14.37)
Change from Baseline at Day 15/ET	1.6 (10.39)	3.1 (17.84)
Change from Baseline at Follow-up Day 21	-0.9 (7.66)	-2.9 (13.64)
Change from Baseline at Follow-up Day 28	-0.8 (8.50)	-2.5 (11.01)
Change from Baseline at Follow-up Day 35	1.0 (8.28)	-4.3 (8.87)
Change from Baseline at Follow-up Day 42	-0.4 (12.97)	-4.4 (9.26)

76. Secondary Outcome

Title	Change From Baseline in Alanine Aminotransferase - Part B
Description	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium, chloride, carbon dioxide, creatinine, glucose, potassium, magnesium, phosphate, protein, sodium, thyrotropin, and urea nitrogen. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Baseline	22.9 (11.09)	22.2 (9.43)
Change from Baseline at Day 8	4.1 (13.09)	11.0 (28.79)
Change from Baseline at Day 15/ET	7.3 (22.23)	9.1 (32.27)
Change from Baseline at Follow-up Day 21	3.4 (22.86)	0.1 (6.50)
Change from Baseline at Follow-up Day 28	1.6 (9.57)	-0.8 (6.21)
Change from Baseline at Follow-up Day 35	0.5 (8.55)	0.5 (10.11)
Change from Baseline at Follow-up Day 42	-0.2 (10.12)	-1.0 (6.30)

77. Secondary Outcome

Title	Change From Baseline in Aspartate Aminotransferase - Part B
Description	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium, chloride, carbon dioxide, creatinine, glucose, potassium, magnesium, phosphate, protein, sodium, thyrotropin, and urea nitrogen. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Baseline	23.0 (5.19)	23.5 (6.49)
Change from Baseline at Day 8	-0.5 (6.31)	10.0 (43.42)
Change from Baseline at Day 15/ET	2.2 (12.54)	5.0 (27.21)
Change from Baseline at Follow-up Day 21	1.4 (11.60)	-0.1 (6.79)
Change from Baseline at Follow-up Day 28	-0.5 (4.89)	-0.3 (7.62)
Change from Baseline at Follow-up Day 35	-1.2 (5.43)	-0.5 (7.36)
Change from Baseline at Follow-up Day 42	0.1 (7.03)	-0.1 (6.40)

78. Secondary Outcome

Title	Change From Baseline in Bilirubin - Part B
Description	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium, chloride, carbon dioxide, creatinine, glucose, potassium, magnesium, phosphate, protein, sodium, thyrotropin, and urea nitrogen. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Baseline	8.157 (3.5160)	9.422 (7.5457)
Change from Baseline at Day 8	-1.095 (2.7830)	-1.670 (4.7335)
Change from Baseline at Day 15/ET	-0.652 (3.3092)	-1.673 (3.1661)
Change from Baseline at Follow-up Day 21	-0.453 (3.7470)	-0.978 (3.0372)
Change from Baseline at Follow-up Day 28	-1.049 (3.0737)	0.162 (3.7768)
Change from Baseline at Follow-up Day 35	-0.945 (3.6470)	-1.170 (4.3101)
Change from Baseline at Follow-up Day 42	-0.708 (3.9947)	-0.526 (4.4450)

79. Secondary Outcome

Title	Change From Baseline in Calcium - Part B
Description	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium, chloride, carbon dioxide, creatinine, glucose, potassium, magnesium, phosphate, protein, sodium, thyrotropin, and urea nitrogen. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Baseline	2.359 (0.0909)	2.364 (0.1517)
Change from Baseline at Day 8	-0.021 (0.0911)	-0.033 (0.1220)
Change from Baseline at Day 15/ET	-0.019 (0.1083)	-0.041 (0.1171)
Change from Baseline at Follow-up Day 21	-0.038 (0.0900)	-0.065 (0.1120)
Change from Baseline at Follow-up Day 28	-0.035 (0.1138)	-0.044 (0.0961)
Change from Baseline at Follow-up Day 35	-0.038 (0.1024)	-0.048 (0.1201)
Change from Baseline at Follow-up Day 42	-0.041 (0.0954)	-0.041 (0.1290)

80. Secondary Outcome

Title	Change From Baseline in Chloride - Part B
Description	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium, chloride, carbon dioxide, creatinine, glucose, potassium, magnesium, phosphate, protein, sodium, thyrotropin, and urea nitrogen. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Baseline	104.7 (1.87)	104.4 (2.53)
Change from Baseline at Day 8	-0.2 (2.49)	-0.2 (2.86)
Change from Baseline at Day 15/ET	-0.4 (2.10)	-0.1 (2.83)
Change from Baseline at Follow-up Day 21	0.8 (2.59)	0.5 (2.37)
Change from Baseline at Follow-up Day 28	0.6 (2.47)	0.3 (3.27)
Change from Baseline at Follow-up Day 35	0.0 (2.50)	1.1 (2.49)
Change from Baseline at Follow-up Day 42	0.4 (2.39)	0.8 (2.75)

81. Secondary Outcome

Title	Change From Baseline in Carbon Dioxide - Part B
Description	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium, chloride, carbon dioxide, creatinine, glucose, potassium, magnesium, phosphate, protein, sodium, thyrotropin, and urea nitrogen. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Baseline	29.3 (2.32)	28.8 (2.25)
Change from Baseline at Day 8	-1.1 (2.87)	0.0 (2.61)
Change from Baseline at Day 15/ET	-0.3 (2.41)	0.7 (2.32)
Change from Baseline at Follow-up Day 21	-1.1 (2.31)	0.2 (2.50)
Change from Baseline at Follow-up Day 28	-1.0 (2.84)	-0.5 (2.69)
Change from Baseline at Follow-up Day 35	-1.0 (2.56)	-0.1 (2.68)
Change from Baseline at Follow-up Day 42	-0.8 (2.86)	-0.8 (2.70)

82. Secondary Outcome

Title	Change From Baseline in Creatinine - Part B
Description	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium, chloride, carbon dioxide, creatinine, glucose, potassium, magnesium, phosphate, protein, sodium, thyrotropin, and urea nitrogen. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Baseline	76.363 (16.0294)	77.894 (14.1946)
Change from Baseline at Day 8	0.036 (7.6537)	-1.710 (8.0850)
Change from Baseline at Day 15/ET	1.028 (9.1198)	0.566 (7.9601)
Change from Baseline at Follow-up Day 21	0.632 (8.8186)	1.495 (9.8651)
Change from Baseline at Follow-up Day 28	4.462 (7.4979)	2.614 (6.6486)
Change from Baseline at Follow-up Day 35	2.300 (9.0428)	1.263 (14.2508)
Change from Baseline at Follow-up Day 42	1.949 (8.5582)	0.852 (9.5738)

83. Secondary Outcome

Title	Change From Baseline in Glucose - Part B
Description	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium, chloride, carbon dioxide, creatinine, glucose, potassium, magnesium, phosphate, protein, sodium, thyrotropin, and urea nitrogen. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Baseline	5.438 (1.8453)	5.114 (0.9726)
Change from Baseline at Day 8	0.103 (1.4778)	0.045 (1.4529)
Change from Baseline at Day 15/ET	0.203 (1.5462)	0.390 (1.5054)
Change from Baseline at Follow-up Day 21	-0.031 (1.2125)	-0.308 (1.3738)
Change from Baseline at Follow-up Day 28	-0.053 (1.1142)	0.166 (1.3791)
Change from Baseline at Follow-up Day 35	-0.094 (1.5798)	0.355 (1.6032)
Change from Baseline at Follow-up Day 42	0.114 (1.3631)	0.059 (1.1655)

84. Secondary Outcome

Title	Change From Baseline in Potassium - Part B
Description	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium, chloride, carbon dioxide, creatinine, glucose, potassium, magnesium, phosphate, protein, sodium, thyrotropin, and urea nitrogen. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Baseline	4.33 (0.362)	4.36 (0.442)
Change from Baseline at Day 8	0.05 (0.432)	0.09 (0.517)
Change from Baseline at Day 15/ET	0.05 (0.402)	0.03 (0.408)
Change from Baseline at Follow-up Day 21	0.01 (0.371)	-0.01 (0.467)
Change from Baseline at Follow-up Day 28	0.05 (0.342)	0.00 (0.581)
Change from Baseline at Follow-up Day 35	0.07 (0.351)	-0.04 (0.468)
Change from Baseline at Follow-up Day 42	0.04 (0.420)	-0.06 (0.491)

85. Secondary Outcome

Title	Change From Baseline in Magnesium - Part B
Description	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium, chloride, carbon dioxide, creatinine, glucose, potassium, magnesium, phosphate, protein, sodium, thyrotropin, and urea nitrogen. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	42	45
Baseline	0.891 (0.0772)	0.879 (0.0977)
Change from Baseline at Day 8	-0.020 (0.0911)	-0.011 (0.0950)
Change from Baseline at Day 15/ET	-0.025 (0.0980)	-0.014 (0.1095)
Change from Baseline at Follow-up Day 21	-0.023 (0.0864)	-0.025 (0.0998)
Change from Baseline at Follow-up Day 28	-0.009 (0.0996)	-0.030 (0.0804)
Change from Baseline at Follow-up Day 35	-0.033 (0.0981)	-0.033 (0.1046)
Change from Baseline at Follow-up Day 42	-0.012 (0.1070)	-0.025 (0.0929)

86. Secondary Outcome

Title	Change From Baseline in Phosphate - Part B
Description	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium, chloride, carbon dioxide, creatinine, glucose, potassium, magnesium, phosphate, protein, sodium, thyrotropin, and urea nitrogen. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	42	45
Baseline	1.245 (0.1623)	1.212 (0.1359)
Change from Baseline at Day 8	0.053 (0.2050)	0.048 (0.2078)
Change from Baseline at Day 15/ET	0.019 (0.1969)	0.010 (0.1798)
Change from Baseline at Follow-up Day 21	-0.015 (0.1609)	-0.102 (0.1652)
Change from Baseline at Follow-up Day 28	-0.022 (0.1657)	-0.084 (0.2291)
Change from Baseline at Follow-up Day 35	-0.108 (0.1761)	-0.120 (0.2033)
Change from Baseline at Follow-up Day 42	-0.102 (0.1600)	-0.089 (0.1941)

87. Secondary Outcome

Title	Change From Baseline in Protein - Part B
Description	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium, chloride, carbon dioxide, creatinine, glucose, potassium, magnesium, phosphate, protein, sodium, thyrotropin, and urea nitrogen. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Baseline	75.0 (5.02)	76.0 (5.90)
Change from Baseline at Day 8	-2.1 (4.47)	-1.3 (5.47)
Change from Baseline at Day 15/ET	-1.3 (4.45)	-1.6 (5.90)
Change from Baseline at Follow-up Day 21	-2.1 (4.05)	-2.5 (5.77)
Change from Baseline at Follow-up Day 28	-0.9 (5.05)	-1.9 (5.58)
Change from Baseline at Follow-up Day 35	-1.2 (4.61)	-2.3 (5.72)
Change from Baseline at Follow-up Day 42	-1.4 (4.01)	-2.1 (5.73)

88. Secondary Outcome

Title	Change From Baseline in Sodium - Part B
Description	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium, chloride, carbon dioxide, creatinine, glucose, potassium, magnesium, phosphate, protein, sodium, thyrotropin, and urea nitrogen. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Baseline	140.8 (1.78)	140.5 (1.82)
Change from Baseline at Day 8	-0.7 (1.74)	0.1 (2.08)
Change from Baseline at Day 15/ET	-0.6 (1.94)	0.0 (2.60)
Change from Baseline at Follow-up Day 21	0.3 (2.00)	0.0 (2.33)
Change from Baseline at Follow-up Day 28	-0.1 (2.14)	-0.1 (2.68)
Change from Baseline at Follow-up Day 35	-0.8 (2.20)	0.3 (2.26)
Change from Baseline at Follow-up Day 42	-0.6 (2.10)	-0.1 (2.28)

89. Secondary Outcome

Title	Change From Baseline in Thyrotropin - Part B
Description	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium, chloride, carbon dioxide, creatinine, glucose, potassium, magnesium, phosphate, protein, sodium, thyrotropin, and urea nitrogen. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Baseline	1.328 (0.7996)	1.398 (0.9451)
Change from Baseline at Day 8	0.464 (0.8096)	0.445 (0.7181)
Change from Baseline at Day 15/ET	0.668 (1.5106)	0.315 (0.6782)
Change from Baseline at Follow-up Day 21	-0.011 (0.7579)	-0.014 (0.7316)
Change from Baseline at Follow-up Day 28	0.218 (0.8047)	0.099 (0.6297)
Change from Baseline at Follow-up Day 35	0.156 (0.7314)	0.103 (0.5723)
Change from Baseline at Follow-up Day 42	0.156 (1.0520)	0.124 (0.5530)

90. Secondary Outcome

Title	Change From Baseline in Urea Nitrogen - Part B
Description	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium, chloride, carbon dioxide, creatinine, glucose, potassium, magnesium, phosphate, protein, sodium, thyrotropin, and urea nitrogen. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Baseline	4.186 (1.4151)	4.644 (2.0582)
Change from Baseline at Day 8	0.322 (1.0179)	0.334 (1.6435)
Change from Baseline at Day 15/ET	0.330 (1.2817)	0.189 (1.6860)
Change from Baseline at Follow-up Day 21	-0.096 (1.1059)	0.196 (1.0191)
Change from Baseline at Follow-up Day 28	0.057 (1.2372)	0.186 (1.0919)
Change from Baseline at Follow-up Day 35	0.138 (1.0796)	0.078 (1.4422)
Change from Baseline at Follow-up Day 42	0.057 (1.2051)	-0.275 (1.1708)

91. Secondary Outcome

Title	Change From Baseline in Activated Partial Thromboplastin Time - Part B
Description	Coagulation measures included activated partial thromboplastin time, prothrombin international normalized ratio, and prothrombin time. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Baseline	27.60	27.80
Change from Baseline at Day 8	0.20	-0.20
Change from Baseline at Day 15/ET	0.10	0.40
Change from Baseline at Follow-up Day 21	0.40	0.05
Change from Baseline at Follow-up Day 28	0.40	0.30
Change from Baseline at Follow-up Day 35	0.10	-0.25
Change from Baseline at Follow-up Day 42	0.30	0.20

92. Secondary Outcome

Title	Change From Baseline in Prothrombin International Normalized Ratio (%) - Part B
Description	Coagulation measures included activated partial thromboplastin time, prothrombin international normalized ratio, and prothrombin time. The analysis was performed in participants included in Part B of the study. ET = Early Termination. The data for prothrombin international normalized ratio are presented as SI unit, percentage (%).
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Baseline	1.006 (0.0394)	1.032 (0.0527)
Change from Baseline at Day 8	0.011 (0.0466)	-0.016 (0.0436)
Change from Baseline at Day 15/ET	-0.003 (0.0426)	-0.010 (0.0628)
Change from Baseline at Follow-up Day 21	0.002 (0.0380)	-0.003 (0.0372)
Change from Baseline at Follow-up Day 28	-0.007 (0.0337)	0.002 (0.0440)
Change from Baseline at Follow-up Day 35	-0.002 (0.0439)	-0.005 (0.0384)
Change from Baseline at Follow-up Day 42	0.002 (0.0390)	0.003 (0.0420)

93. Secondary Outcome

Title	Change From Baseline in Prothrombin Time - Part B
Description	Coagulation measures included activated partial thromboplastin time, prothrombin international normalized ratio, and prothrombin time. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Baseline	10.40	10.60
Change from Baseline at Day 8	0.00	-0.20
Change from Baseline at Day 15/ET	0.00	-0.20
Change from Baseline at Follow-up Day 21	0.10	-0.10
Change from Baseline at Follow-up Day 28	-0.10	0.10
Change from Baseline at Follow-up Day 35	0.00	0.05
Change from Baseline at Follow-up Day 42	0.10	0.00

94. Secondary Outcome

Title	Change From Baseline in pH - Part B
Description	Urinalysis measures included pH and specific gravity. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Baseline	6.22 (0.879)	6.23 (0.857)
Change from Baseline at Day 8	-0.32 (0.923)	-0.16 (1.169)
Change from Baseline at Day 15/ET	-0.37 (0.877)	-0.23 (0.909)
Change from Baseline at Follow-up Day 21	-0.32 (0.940)	-0.15 (0.852)
Change from Baseline at Follow-up Day 28	-0.27 (0.945)	-0.31 (1.065)
Change from Baseline at Follow-up Day 35	-0.01 (1.275)	-0.17 (0.933)
Change from Baseline at Follow-up Day 42	-0.12 (1.109)	-0.42 (0.962)

95. Secondary Outcome

Title	Change From Baseline in Specific Gravity - Part B
Description	Urinalysis measures included pH and specific gravity. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Time Frame	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Baseline	1.016 (0.0086)	1.018 (0.0092)
Change from Baseline at Day 8	0.002 (0.0092)	0.000 (0.0090)
Change from Baseline at Day 15/ET	0.003 (0.0092)	-0.001 (0.0106)
Change from Baseline at Follow-up Day 21	0.003 (0.0101)	0.000 (0.0094)
Change from Baseline at Follow-up Day 28	0.004 (0.0093)	0.002 (0.0087)
Change from Baseline at Follow-up Day 35	0.001 (0.0096)	0.001 (0.0099)
Change from Baseline at Follow-up Day 42	0.004 (0.0086)	0.002 (0.0112)

96. Secondary Outcome

Title	Change From Baseline (CFB) in Supine Systolic Blood Pressure - Part B
Description	Vital signs measures included supine systolic blood pressure, supine diastolic blood pressure, standing systolic blood pressure, standing diastolic blood pressure, heart rate, respiratory rate, oral temperature, and oxygen saturation. The analysis was performed in participants included in Part B of the study. H = Hour(s). ET = Early Termination.
Time Frame	Baseline, Day 1 (0.25, 0.5, 1, 2, 12 hours postdose), Days 2, 3, 4, 5, 6 and 7 (predose, 0.25, 0.5, 1, 2, 12 hours postdose), Days 8, 9, 10, 11, 12, 13 and 14 (predose, 1 hour postdose), Day 15/ET, follow-up Days 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Baseline	120.5 (15.41)	120.6 (13.95)
CFB at Day 1: 0.25 H Postdose	1.7 (9.33)	0.6 (9.57)
CFB at Day 1: 0.5 H Postdose	1.3 (8.38)	0.7 (10.38)
CFB at Day 1: 1 H Postdose	1.1 (8.63)	-0.3 (11.09)
CFB at Day 1: 2 H Postdose	2.3 (11.51)	-0.5 (11.92)
CFB at Day 1: 12 H Postdose	0.0 (12.72)	-1.5 (10.58)
CFB at Day 2: Predose	-0.3 (10.62)	-0.9 (10.72)
CFB at Day 2: 0.25 H Postdose	2.7 (12.88)	0.9 (12.39)
CFB at Day 2: 0.5 H Postdose	1.9 (9.49)	0.2 (13.18)
CFB at Day 2: 1 H Postdose	2.2 (10.83)	-0.5 (11.19)
CFB at Day 2: 2 H Postdose	1.7 (11.72)	-0.2 (12.39)
CFB at Day 2: 12 H Postdose	-1.2 (11.11)	-1.4 (12.55)
CFB at Day 3: Predose	1.3 (10.50)	-0.1 (12.61)
CFB at Day 3: 0.25 H Postdose	2.4 (10.49)	0.4 (12.37)
CFB at Day 3: 0.5 H Postdose	3.4 (13.80)	-0.9 (13.55)
CFB at Day 3: 1 H Postdose	2.2 (10.18)	-0.3 (12.76)
CFB at Day 3: 2 H Postdose	1.5 (12.35)	-0.2 (14.21)
CFB at Day 3: 12 H Postdose	-2.7 (13.22)	-3.9 (12.84)
CFB at Day 4: Predose	1.1 (13.77)	0.6 (12.38)
CFB at Day 4: 0.25 H Postdose	1.3 (11.83)	2.8 (11.28)
CFB at Day 4: 0.5 H Postdose	2.2 (12.29)	0.7 (10.42)
CFB at Day 4: 1 H Postdose	-0.5 (11.88)	0.4 (11.41)
CFB at Day 4: 2 H Postdose	-1.4 (13.06)	0.3 (12.84)
CFB at Day 4: 12 H Postdose	-2.8 (14.65)	-0.1 (14.51)
CFB at Day 5: Predose	-1.9 (12.82)	1.0 (13.67)
CFB at Day 5: 0.25 H Postdose	-0.8 (11.60)	2.6 (11.60)
CFB at Day 5: 0.5 H Postdose	0.3 (14.05)	1.2 (9.26)
CFB at Day 5: 1 H Postdose	-0.4 (10.26)	2.3 (11.04)
CFB at Day 5: 2 H Postdose	0.8 (10.42)	-2.4 (10.78)
CFB at Day 5: 12 H Postdose	-1.7 (13.79)	-1.8 (12.13)
CFB at Day 6: Predose	0.5 (13.69)	5.3 (13.08)
CFB at Day 6: 0.25 H Postdose	0.9 (12.24)	6.3 (10.66)
CFB at Day 6: 0.5 H Postdose	-0.4 (13.01)	4.3 (12.23)
CFB at Day 6: 1 H Postdose	0.5 (12.91)	4.7 (12.07)
CFB at Day 6: 2 H Postdose	2.6 (16.10)	3.9 (14.18)
CFB at Day 6: 12 H Postdose	-1.6 (11.10)	-0.2 (12.90)
CFB at Day 7: Predose	-1.0 (12.54)	3.2 (11.76)
CFB at Day 7: 0.25 H Postdose	0.5 (14.43)	1.8 (10.44)
CFB at Day 7: 0.5 H Postdose	0.4 (14.04)	2.4 (11.22)
CFB at Day 7: 1 H Postdose	-0.7 (13.83)	3.0 (11.35)
CFB at Day 7: 2 H Postdose	0.2 (15.73)	0.8 (12.29)
CFB at Day 7: 12 H Postdose	-3.4 (11.68)	0.5 (12.11)
CFB at Day 8: Predose	-0.8 (13.53)	2.3 (12.96)
CFB at Day 8: 1 H Postdose	1.6 (12.35)	1.6 (14.27)
CFB at Day 9: Predose	0.5 (14.43)	1.7 (11.76)
CFB at Day 9: 1 H Postdose	2.8 (16.01)	-0.1 (14.04)
CFB at Day 10: Predose	0.0 (14.32)	-0.2 (12.08)
CFB at Day 10: 1 H Postdose	0.0 (16.48)	0.2 (11.39)
CFB at Day 11: Predose	-2.5 (16.30)	4.4 (13.67)
CFB at Day 11: 1 H Postdose	-3.6 (16.84)	3.1 (13.00)
CFB at Day 12: Predose	-2.2 (11.70)	1.7 (12.05)
CFB at Day 12: 1 H Postdose	0.4 (11.64)	2.0 (12.33)
CFB at Day 13: Predose	-0.2 (13.23)	1.4 (11.04)
CFB at Day 13: 1 H Postdose	2.3 (13.27)	-0.2 (10.27)
CFB at Day 14: Predose	-2.7 (14.09)	2.4 (12.12)
CFB at Day 14: 1 H Postdose	0.1 (14.54)	2.9 (12.28)
CFB at Day 15/ET	0.0 (14.14)	5.8 (12.10)
CFB at Follow-up Day 21	2.4 (13.92)	6.2 (14.18)
CFB at Follow-up Day 28	1.0 (13.83)	5.5 (11.63)
CFB at Follow-up Day 35	2.9 (15.58)	7.8 (13.89)
CFB at Follow-up Day 42	-0.9 (15.02)	8.3 (13.06)

97. Secondary Outcome

Title	Change From Baseline (CFB) in Supine Diastolic Blood Pressure - Part B
Description	Vital signs measures included supine systolic blood pressure, supine diastolic blood pressure, standing systolic blood pressure, standing diastolic blood pressure, heart rate, respiratory rate, oral temperature, and oxygen saturation. The analysis was performed in participants included in Part B of the study. H = Hour(s). ET = Early Termination.
Time Frame	Baseline, Day 1 (0.25, 0.5, 1, 2, 12 hours postdose), Days 2, 3, 4, 5, 6 and 7 (predose, 0.25, 0.5, 1, 2, 12 hours postdose), Days 8, 9, 10, 11, 12, 13 and 14 (predose, 1 hour postdose), Day 15/ET, follow-up Days 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Baseline	76.1 (10.10)	75.2 (7.91)
CFB at Day 1: 0.25 H Postdose	0.8 (5.04)	1.0 (7.26)
CFB at Day 1: 0.5 H Postdose	-0.1 (6.38)	0.6 (7.09)
CFB at Day 1: 1 H Postdose	0.6 (6.40)	0.3 (8.43)
CFB at Day 1: 2 H Postdose	0.8 (7.32)	-0.2 (8.16)
CFB at Day 1: 12 H Postdose	1.7 (9.22)	0.2 (7.98)
CFB at Day 2: Predose	-0.5 (8.77)	0.3 (7.21)
CFB at Day 2: 0.25 H Postdose	1.8 (8.23)	0.8 (9.53)
CFB at Day 2: 0.5 H Postdose	1.6 (7.86)	0.2 (9.30)
CFB at Day 2: 1 H Postdose	2.2 (8.74)	-0.3 (7.97)
CFB at Day 2: 2 H Postdose	0.8 (7.88)	1.3 (10.10)
CFB at Day 2: 12 H Postdose	-0.1 (7.15)	-0.5 (10.11)
CFB at Day 3: Predose	1.7 (7.35)	0.1 (9.03)
CFB at Day 3: 0.25 H Postdose	3.4 (8.57)	0.6 (8.99)
CFB at Day 3: 0.5 H Postdose	3.0 (7.96)	-0.4 (9.78)
CFB at Day 3: 1 H Postdose	1.3 (8.29)	0.0 (10.69)
CFB at Day 3: 2 H Postdose	1.3 (7.97)	-0.7 (10.86)
CFB at Day 3: 12 H Postdose	-0.5 (7.14)	-1.7 (10.42)
CFB at Day 4: Predose	1.9 (9.49)	1.5 (9.23)
CFB at Day 4: 0.25 H Postdose	1.8 (9.53)	0.3 (10.77)
CFB at Day 4: 0.5 H Postdose	0.9 (10.07)	0.6 (10.50)
CFB at Day 4: 1 H Postdose	1.3 (9.83)	0.4 (9.16)
CFB at Day 4: 2 H Postdose	0.3 (9.61)	0.9 (10.25)
CFB at Day 4: 12 H Postdose	-0.1 (9.06)	-1.3 (9.86)
CFB at Day 5: Predose	-1.5 (9.88)	0.0 (8.94)
CFB at Day 5: 0.25 H Postdose	0.8 (9.99)	0.1 (8.78)
CFB at Day 5: 0.5 H Postdose	1.3 (9.75)	0.7 (9.12)
CFB at Day 5: 1 H Postdose	0.3 (9.49)	0.3 (9.45)
CFB at Day 5: 2 H Postdose	0.8 (10.59)	-1.3 (9.92)
CFB at Day 5: 12 H Postdose	0.0 (9.72)	-1.3 (8.16)
CFB at Day 6: Predose	1.4 (10.96)	2.1 (9.04)
CFB at Day 6: 0.25 H Postdose	0.6 (10.12)	2.7 (7.23)
CFB at Day 6: 0.5 H Postdose	1.3 (11.29)	2.0 (8.85)
CFB at Day 6: 1 H Postdose	1.5 (9.74)	0.9 (10.62)
CFB at Day 6: 2 H Postdose	2.9 (11.43)	2.7 (11.00)
CFB at Day 6: 12 H Postdose	-1.0 (8.30)	0.4 (10.66)
CFB at Day 7: Predose	0.0 (8.25)	0.5 (8.78)
CFB at Day 7: 0.25 H Postdose	1.4 (10.33)	1.5 (9.49)
CFB at Day 7: 0.5 H Postdose	0.2 (10.10)	2.3 (9.66)
CFB at Day 7: 1 H Postdose	0.1 (9.03)	2.0 (9.14)
CFB at Day 7: 2 H Postdose	1.3 (11.20)	2.1 (9.90)
CFB at Day 7: 12 H Postdose	-0.4 (8.09)	2.0 (10.00)
CFB at Day 8: Predose	-0.1 (9.22)	0.6 (7.76)
CFB at Day 8: 1 H Postdose	0.9 (9.85)	1.9 (9.92)
CFB at Day 9: Predose	-0.1 (9.03)	1.0 (8.18)
CFB at Day 9: 1 H Postdose	0.4 (9.87)	-0.5 (10.18)
CFB at Day 10: Predose	-0.5 (10.94)	0.7 (10.23)
CFB at Day 10: 1 H Postdose	0.8 (9.97)	-0.5 (9.14)
CFB at Day 11: Predose	-0.5 (11.53)	0.6 (8.57)
CFB at Day 11: 1 H Postdose	-2.1 (10.72)	2.2 (9.15)
CFB at Day 12: Predose	-1.0 (8.94)	1.1 (7.98)
CFB at Day 12: 1 H Postdose	-0.5 (9.17)	0.0 (9.06)
CFB at Day 13: Predose	0.7 (11.64)	0.5 (9.33)
CFB at Day 13: 1 H Postdose	2.7 (10.42)	-0.1 (8.04)
CFB at Day 14: Predose	-3.3 (9.52)	1.6 (9.68)
CFB at Day 14: 1 H Postdose	1.3 (9.96)	2.1 (8.38)
CFB at Day 15/ET	2.4 (10.00)	4.1 (8.94)
CFB at Follow-up Day 21	2.8 (9.47)	3.9 (9.13)
CFB at Follow-up Day 28	2.9 (9.73)	3.4 (8.42)
CFB at Follow-up Day 35	-0.4 (11.31)	4.3 (9.86)
CFB at Follow-up Day 42	0.5 (10.98)	4.6 (10.46)

98. Secondary Outcome

Title	Change From Baseline (CFB) in Standing Systolic Blood Pressure - Part B
Description	Vital signs measures included supine systolic blood pressure, supine diastolic blood pressure, standing systolic blood pressure, standing diastolic blood pressure, heart rate, respiratory rate, oral temperature, and oxygen saturation. The analysis was performed in participants included in Part B of the study. H = Hour(s). ET = Early Termination.
Time Frame	Baseline, Day 1 (0.25, 0.5, 1, 2, 12 hours postdose), Days 2, 3, 4, 5, 6 and 7 (predose, 0.25, 0.5, 1, 2, 12 hours postdose), Days 8, 9, 10, 11, 12, 13 and 14 (predose, 1 hour postdose), Day 15/ET, follow-up Days 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Baseline	125.9 (14.19)	125.1 (14.00)
CFB at Day 1: 0.25 H Postdose	0.3 (8.48)	0.8 (8.20)
CFB at Day 1: 0.5 H Postdose	-0.7 (8.88)	-1.7 (12.05)
CFB at Day 1: 1 H Postdose	-0.7 (9.44)	-0.3 (12.46)
CFB at Day 1: 2 H Postdose	0.2 (11.68)	-2.6 (10.56)
CFB at Day 1: 12 H Postdose	-3.8 (13.79)	-4.5 (11.27)
CFB at Day 2: Predose	-1.3 (9.20)	-0.3 (14.50)
CFB at Day 2: 0.25 H Postdose	1.1 (10.10)	-3.9 (15.98)
CFB at Day 2: 0.5 H Postdose	-0.2 (10.16)	0.4 (11.25)
CFB at Day 2: 1 H Postdose	-0.7 (11.01)	-1.8 (10.26)
CFB at Day 2: 2 H Postdose	-1.5 (11.38)	-2.7 (12.51)
CFB at Day 2: 12 H Postdose	-5.5 (11.62)	-2.4 (12.67)
CFB at Day 3: Predose	-3.0 (10.48)	0.1 (13.03)
CFB at Day 3: 0.25 H Postdose	-0.1 (11.97)	-0.2 (12.78)
CFB at Day 3: 0.5 H Postdose	-1.0 (12.26)	-2.1 (10.83)
CFB at Day 3: 1 H Postdose	-0.7 (12.22)	-1.7 (13.34)
CFB at Day 3: 2 H Postdose	-1.9 (11.45)	-1.4 (14.55)
CFB at Day 3: 12 H Postdose	-4.3 (8.94)	-3.4 (11.42)
CFB at Day 4: Predose	-1.2 (16.11)	-0.2 (10.91)
CFB at Day 4: 0.25 H Postdose	-1.3 (13.21)	1.6 (11.83)
CFB at Day 4: 0.5 H Postdose	-1.9 (10.60)	-0.4 (9.38)
CFB at Day 4: 1 H Postdose	-3.1 (13.79)	1.2 (10.70)
CFB at Day 4: 2 H Postdose	-2.5 (13.34)	-1.8 (13.77)
CFB at Day 4: 12 H Postdose	-5.5 (13.01)	-4.5 (11.79)
CFB at Day 5: Predose	-1.3 (12.57)	1.3 (13.70)
CFB at Day 5: 0.25 H Postdose	-0.5 (11.86)	1.4 (13.22)
CFB at Day 5: 0.5 H Postdose	-1.0 (11.04)	1.3 (11.90)
CFB at Day 5: 1 H Postdose	-2.4 (10.89)	1.8 (11.63)
CFB at Day 5: 2 H Postdose	-1.6 (13.12)	-2.2 (12.56)
CFB at Day 5: 12 H Postdose	-5.5 (14.11)	-3.5 (13.36)
CFB at Day 6: Predose	-4.2 (14.69)	3.2 (13.50)
CFB at Day 6: 0.25 H Postdose	-1.6 (11.52)	2.8 (12.65)
CFB at Day 6: 0.5 H Postdose	-3.6 (12.23)	1.7 (14.73)
CFB at Day 6: 1 H Postdose	-1.9 (12.98)	2.3 (14.61)
CFB at Day 6: 2 H Postdose	-2.9 (12.89)	2.2 (13.98)
CFB at Day 6: 12 H Postdose	-5.7 (11.59)	-1.6 (13.21)
CFB at Day 7: Predose	-2.8 (14.48)	4.3 (15.71)
CFB at Day 7: 0.25 H Postdose	-2.6 (15.62)	1.2 (13.56)
CFB at Day 7: 0.5 H Postdose	-2.6 (15.42)	1.0 (11.22)
CFB at Day 7: 1 H Postdose	-1.5 (15.18)	1.5 (12.20)
CFB at Day 7: 2 H Postdose	-2.9 (16.37)	-1.9 (10.48)
CFB at Day 7: 12 H Postdose	-6.9 (12.84)	-3.2 (11.19)
CFB at Day 8: Predose	-2.2 (13.37)	1.9 (10.57)
CFB at Day 8: 1 H Postdose	-0.9 (10.82)	0.6 (11.49)
CFB at Day 9: Predose	-3.9 (13.94)	1.5 (13.77)
CFB at Day 9: 1 H Postdose	-2.6 (14.50)	0.8 (11.08)
CFB at Day 10: Predose	-2.1 (16.07)	-0.7 (11.64)
CFB at Day 10: 1 H Postdose	-1.2 (16.73)	-0.6 (16.41)
CFB at Day 11: Predose	-4.8 (16.81)	2.0 (17.24)
CFB at Day 11: 1 H Postdose	-6.1 (16.18)	-0.1 (12.09)
CFB at Day 12: Predose	-2.3 (13.70)	2.4 (12.20)
CFB at Day 12: 1 H Postdose	-2.5 (13.80)	3.1 (14.10)
CFB at Day 13: Predose	-4.1 (12.65)	0.6 (11.69)
CFB at Day 13: 1 H Postdose	-1.6 (10.92)	1.8 (11.83)
CFB at Day 14: Predose	-4.4 (12.31)	2.3 (11.60)
CFB at Day 14: 1 H Postdose	-1.2 (13.75)	3.1 (13.90)
CFB at Day 15/ET	-2.8 (13.56)	-0.3 (11.32)
CFB at Follow-up Day 21	-1.7 (14.21)	1.7 (12.63)
CFB at Follow-up Day 28	-3.2 (12.13)	-1.9 (11.32)
CFB at Follow-up Day 35	-1.0 (13.00)	2.6 (12.04)
CFB at Follow-up Day 42	-2.5 (14.02)	0.8 (9.94)

99. Secondary Outcome

Title	Change From Baseline (CFB) in Standing Diastolic Blood Pressure - Part B
Description	Vital signs measures included supine systolic blood pressure, supine diastolic blood pressure, standing systolic blood pressure, standing diastolic blood pressure, heart rate, respiratory rate, oral temperature, and oxygen saturation. The analysis was performed in participants included in Part B of the study. H = Hour(s). ET = Early Termination.
Time Frame	Baseline, Day 1 (0.25, 0.5, 1, 2, 12 hours postdose), Days 2, 3, 4, 5, 6 and 7 (predose, 0.25, 0.5, 1, 2, 12 hours postdose), Days 8, 9, 10, 11, 12, 13 and 14 (predose, 1 hour postdose), Day 15/ET, follow-up Days 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Baseline	81.9 (9.32)	80.1 (8.26)
CFB at Day 1: 0.25 H Postdose	1.0 (7.45)	2.6 (6.06)
CFB at Day 1: 0.5 H Postdose	0.7 (7.24)	1.5 (7.30)
CFB at Day 1: 1 H Postdose	-0.7 (7.75)	0.8 (9.09)
CFB at Day 1: 2 H Postdose	1.5 (7.41)	0.4 (8.13)
CFB at Day 1: 12 H Postdose	-0.1 (9.77)	0.0 (7.96)
CFB at Day 2: Predose	-1.5 (8.02)	0.9 (8.07)
CFB at Day 2: 0.25 H Postdose	1.7 (6.86)	-1.2 (11.02)
CFB at Day 2: 0.5 H Postdose	-0.2 (7.06)	0.1 (8.21)
CFB at Day 2: 1 H Postdose	0.8 (6.27)	-1.8 (8.47)
CFB at Day 2: 2 H Postdose	0.0 (7.65)	0.6 (8.05)
CFB at Day 2: 12 H Postdose	-0.1 (7.87)	1.1 (9.87)
CFB at Day 3: Predose	-1.5 (7.83)	-0.4 (8.08)
CFB at Day 3: 0.25 H Postdose	1.0 (8.05)	0.4 (8.02)
CFB at Day 3: 0.5 H Postdose	1.3 (8.28)	-0.4 (8.11)
CFB at Day 3: 1 H Postdose	0.3 (8.17)	-0.7 (9.97)
CFB at Day 3: 2 H Postdose	-0.4 (8.57)	-0.1 (10.06)
CFB at Day 3: 12 H Postdose	-0.5 (6.72)	-0.4 (8.59)
CFB at Day 4: Predose	-0.7 (9.70)	2.4 (9.41)
CFB at Day 4: 0.25 H Postdose	0.1 (9.23)	2.2 (9.94)
CFB at Day 4: 0.5 H Postdose	0.3 (8.49)	0.2 (9.36)
CFB at Day 4: 1 H Postdose	0.2 (8.06)	0.3 (10.05)
CFB at Day 4: 2 H Postdose	0.6 (9.46)	-0.8 (10.84)
CFB at Day 4: 12 H Postdose	0.0 (8.35)	-0.6 (9.38)
CFB at Day 5: Predose	-1.1 (8.74)	-0.2 (8.65)
CFB at Day 5: 0.25 H Postdose	0.2 (8.12)	0.6 (9.08)
CFB at Day 5: 0.5 H Postdose	-1.1 (10.02)	0.8 (9.19)
CFB at Day 5: 1 H Postdose	-0.7 (8.56)	1.3 (10.24)
CFB at Day 5: 2 H Postdose	-1.3 (9.05)	-0.5 (9.62)
CFB at Day 5: 12 H Postdose	-2.1 (8.54)	-0.3 (11.77)
CFB at Day 6: Predose	-0.9 (9.09)	1.8 (11.79)
CFB at Day 6: 0.25 H Postdose	-0.6 (10.69)	3.0 (8.78)
CFB at Day 6: 0.5 H Postdose	0.0 (10.09)	1.3 (12.70)
CFB at Day 6: 1 H Postdose	1.2 (9.07)	2.3 (11.84)
CFB at Day 6: 2 H Postdose	1.0 (9.85)	1.7 (9.93)
CFB at Day 6: 12 H Postdose	-0.7 (7.21)	1.6 (12.66)
CFB at Day 7: Predose	-0.6 (9.33)	-0.5 (8.27)
CFB at Day 7: 0.25 H Postdose	2.3 (8.89)	0.2 (9.03)
CFB at Day 7: 0.5 H Postdose	0.1 (11.03)	0.7 (11.28)
CFB at Day 7: 1 H Postdose	0.8 (10.89)	0.8 (10.27)
CFB at Day 7: 2 H Postdose	-0.2 (9.69)	0.6 (8.90)
CFB at Day 7: 12 H Postdose	-2.7 (7.17)	0.4 (9.28)
CFB at Day 8: Predose	-0.3 (9.52)	0.7 (9.77)
CFB at Day 8: 1 H Postdose	-0.4 (7.18)	2.3 (8.57)
CFB at Day 9: Predose	-1.5 (9.64)	0.5 (7.27)
CFB at Day 9: 1 H Postdose	0.6 (9.66)	1.7 (8.83)
CFB at Day 10: Predose	0.2 (8.57)	2.0 (10.21)
CFB at Day 10: 1 H Postdose	0.0 (10.47)	1.7 (12.59)
CFB at Day 11: Predose	-2.3 (12.73)	1.6 (13.81)
CFB at Day 11: 1 H Postdose	-4.3 (12.66)	0.0 (10.73)
CFB at Day 12: Predose	2.1 (9.35)	1.2 (10.41)
CFB at Day 12: 1 H Postdose	-1.4 (11.63)	2.0 (12.93)
CFB at Day 13: Predose	0.0 (9.92)	2.1 (8.87)
CFB at Day 13: 1 H Postdose	0.7 (7.60)	-0.8 (9.39)
CFB at Day 14: Predose	-2.8 (9.26)	2.5 (9.59)
CFB at Day 14: 1 H Postdose	1.2 (10.72)	1.8 (8.36)
CFB at Day 15/ET	0.8 (9.09)	1.5 (8.41)
CFB at Follow-up Day 21	1.7 (8.65)	2.3 (8.58)
CFB at Follow-up Day 28	-0.3 (7.05)	1.9 (9.00)
CFB at Follow-up Day 35	-0.4 (8.34)	3.5 (9.60)
CFB at Follow-up Day 42	0.3 (9.61)	2.5 (7.69)

100. Secondary Outcome

Title	Change From Baseline (CFB) in Heart Rate - Part B
Description	Vital signs measures included supine systolic blood pressure, supine diastolic blood pressure, standing systolic blood pressure, standing diastolic blood pressure, heart rate, respiratory rate, oral temperature, and oxygen saturation. The analysis was performed in participants included in Part B of the study. H = Hour(s). ET = Early Termination.
Time Frame	Baseline, Day 1 (0.25, 0.5, 1, 2, 12 hours postdose), Days 2, 3, 4, 5, 6 and 7 (predose, 0.25, 0.5, 1, 2, 12 hours postdose), Days 8, 9, 10, 11, 12, 13 and 14 (predose, 1 hour postdose), Day 15/ET, follow-up Days 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Baseline	74.3 (12.80)	76.8 (12.33)
CFB at Day 1: 0.25 H Postdose	-1.9 (9.96)	-2.8 (8.50)
CFB at Day 1: 0.5 H Postdose	-2.1 (10.77)	-2.5 (9.26)
CFB at Day 1: 1 H Postdose	-1.8 (11.14)	-4.6 (9.13)
CFB at Day 1: 2 H Postdose	-0.8 (12.63)	-1.1 (9.30)
CFB at Day 1: 12 H Postdose	-1.0 (11.53)	-4.3 (12.18)
CFB at Day 2: Predose	2.5 (11.80)	-1.8 (11.47)
CFB at Day 2: 0.25 H Postdose	-0.2 (10.75)	-1.8 (11.79)
CFB at Day 2: 0.5 H Postdose	-1.0 (10.98)	-2.4 (10.50)
CFB at Day 2: 1 H Postdose	-0.2 (11.79)	-3.0 (11.15)
CFB at Day 2: 2 H Postdose	-1.7 (8.50)	-1.3 (11.50)
CFB at Day 2: 12 H Postdose	-2.3 (11.09)	-4.0 (11.51)
CFB at Day 3: Predose	2.5 (12.40)	-0.7 (13.35)
CFB at Day 3: 0.25 H Postdose	0.0 (9.56)	-1.4 (10.93)
CFB at Day 3: 0.5 H Postdose	-0.5 (10.82)	-1.8 (11.57)
CFB at Day 3: 1 H Postdose	0.8 (10.24)	-1.2 (11.03)
CFB at Day 3: 2 H Postdose	0.4 (12.45)	-0.5 (11.19)
CFB at Day 3: 12 H Postdose	-3.0 (10.46)	-4.2 (11.62)
CFB at Day 4: Predose	4.9 (10.28)	2.0 (10.30)
CFB at Day 4: 0.25 H Postdose	2.8 (9.06)	3.5 (15.13)
CFB at Day 4: 0.5 H Postdose	1.9 (10.43)	-1.4 (10.73)
CFB at Day 4: 1 H Postdose	1.4 (9.75)	-0.8 (10.63)
CFB at Day 4: 2 H Postdose	1.1 (11.94)	1.6 (12.66)
CFB at Day 4: 12 H Postdose	-0.6 (11.36)	-3.6 (11.76)
CFB at Day 5: Predose	4.3 (11.14)	1.9 (9.70)
CFB at Day 5: 0.25 H Postdose	2.4 (11.59)	0.3 (12.44)
CFB at Day 5: 0.5 H Postdose	3.7 (11.81)	0.0 (9.57)
CFB at Day 5: 1 H Postdose	0.6 (10.52)	2.0 (12.34)
CFB at Day 5: 2 H Postdose	1.5 (11.68)	2.5 (10.62)
CFB at Day 5: 12 H Postdose	-0.2 (14.80)	-1.4 (12.45)
CFB at Day 6: Predose	4.7 (10.64)	3.9 (8.00)
CFB at Day 6: 0.25 H Postdose	3.1 (11.30)	0.7 (9.81)
CFB at Day 6: 0.5 H Postdose	2.5 (11.80)	0.4 (10.44)
CFB at Day 6: 1 H Postdose	3.2 (12.71)	0.4 (8.54)
CFB at Day 6: 2 H Postdose	2.6 (9.70)	0.5 (11.53)
CFB at Day 6: 12 H Postdose	1.4 (12.65)	-2.3 (12.57)
CFB at Day 7: Predose	3.7 (10.26)	3.0 (11.63)
CFB at Day 7: 0.25 H Postdose	3.9 (12.00)	1.5 (11.16)
CFB at Day 7: 0.5 H Postdose	3.7 (12.25)	-0.4 (11.19)
CFB at Day 7: 1 H Postdose	5.5 (13.30)	1.4 (11.25)
CFB at Day 7: 2 H Postdose	0.9 (10.64)	2.2 (13.04)
CFB at Day 7: 12 H Postdose	-0.4 (11.53)	-1.3 (13.75)
CFB at Day 8: Predose	10.1 (14.90)	6.9 (14.46)
CFB at Day 8: 1 H Postdose	8.5 (12.78)	6.9 (12.02)
CFB at Day 9: Predose	7.7 (10.64)	7.5 (12.00)
CFB at Day 9: 1 H Postdose	5.9 (10.94)	4.4 (12.05)
CFB at Day 10: Predose	6.4 (11.40)	8.9 (13.59)
CFB at Day 10: 1 H Postdose	4.0 (12.11)	6.1 (13.09)
CFB at Day 11: Predose	6.2 (15.10)	4.6 (11.26)
CFB at Day 11: 1 H Postdose	4.3 (14.76)	4.5 (11.22)
CFB at Day 12: Predose	4.4 (11.99)	3.8 (13.85)
CFB at Day 12: 1 H Postdose	4.8 (13.56)	2.1 (13.19)
CFB at Day 13: Predose	3.1 (12.72)	4.1 (11.22)
CFB at Day 13: 1 H Postdose	2.9 (10.46)	5.0 (11.53)
CFB at Day 14: Predose	6.4 (12.18)	4.6 (10.91)
CFB at Day 14: 1 H Postdose	3.6 (10.21)	2.8 (9.96)
CFB at Day 15/ET	-1.6 (12.73)	-0.1 (10.78)
CFB at Follow-up Day 21	0.1 (10.32)	-5.9 (10.54)
CFB at Follow-up Day 28	-0.5 (13.06)	-5.3 (15.54)
CFB at Follow-up Day 35	-3.8 (11.13)	-3.9 (13.47)
CFB at Follow-up Day 42	-3.7 (11.93)	-6.0 (12.73)

101. Secondary Outcome

Title	Change From Baseline (CFB) in Respiratory Rate - Part B
Description	Vital signs measures included supine systolic blood pressure, supine diastolic blood pressure, standing systolic blood pressure, standing diastolic blood pressure, heart rate, respiratory rate, oral temperature, and oxygen saturation. The analysis was performed in participants included in Part B of the study. H = Hour(s). ET = Early Termination.
Time Frame	Baseline, Day 1 (0.25, 0.5, 1, 2, 12 hours postdose), Days 2, 3, 4, 5, 6 and 7 (predose, 0.25, 0.5, 1, 2, 12 hours postdose), Days 8, 9, 10, 11, 12, 13 and 14 (predose, 1 hour postdose), Day 15/ET, follow-up Days 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Baseline	16.7 (1.72)	16.8 (1.41)
CFB at Day 1: 0.25 H Postdose	0.2 (1.24)	-0.1 (1.05)
CFB at Day 1: 0.5 H Postdose	0.4 (1.08)	0.0 (0.71)
CFB at Day 1: 1 H Postdose	0.3 (1.76)	0.1 (1.00)
CFB at Day 1: 2 H Postdose	0.4 (1.66)	-0.1 (0.98)
CFB at Day 1: 12 H Postdose	-0.3 (1.99)	0.2 (1.65)
CFB at Day 2: Predose	-0.1 (2.36)	0.0 (1.48)
CFB at Day 2: 0.25 H Postdose	0.0 (1.86)	0.0 (1.41)
CFB at Day 2: 0.5 H Postdose	0.4 (1.94)	0.1 (1.59)
CFB at Day 2: 1 H Postdose	0.1 (1.89)	-0.2 (1.40)
CFB at Day 2: 2 H Postdose	0.3 (1.88)	0.0 (1.45)
CFB at Day 2: 12 H Postdose	-0.2 (2.14)	0.0 (1.83)
CFB at Day 3: Predose	0.0 (1.88)	0.1 (2.07)
CFB at Day 3: 0.25 H Postdose	0.0 (1.87)	0.0 (1.52)
CFB at Day 3: 0.5 H Postdose	0.0 (2.00)	0.0 (1.45)
CFB at Day 3: 1 H Postdose	0.2 (2.14)	0.2 (1.51)
CFB at Day 3: 2 H Postdose	0.4 (1.94)	0.3 (1.63)
CFB at Day 3: 12 H Postdose	0.0 (2.33)	0.2 (1.82)
CFB at Day 4: Predose	0.3 (1.92)	-0.1 (1.75)
CFB at Day 4: 0.25 H Postdose	0.4 (1.94)	-0.1 (2.03)
CFB at Day 4: 0.5 H Postdose	0.2 (2.12)	0.2 (1.90)
CFB at Day 4: 1 H Postdose	0.3 (1.71)	0.4 (2.01)
CFB at Day 4: 2 H Postdose	0.2 (1.80)	0.1 (1.90)
CFB at Day 4: 12 H Postdose	0.2 (2.46)	0.2 (2.43)
CFB at Day 5: Predose	0.3 (2.23)	0.0 (1.82)
CFB at Day 5: 0.25 H Postdose	0.0 (2.10)	0.1 (1.87)
CFB at Day 5: 0.5 H Postdose	0.1 (2.10)	0.0 (1.82)
CFB at Day 5: 1 H Postdose	0.2 (2.16)	0.2 (1.66)
CFB at Day 5: 2 H Postdose	0.2 (2.13)	0.1 (1.90)
CFB at Day 5: 12 H Postdose	0.1 (2.24)	0.4 (2.01)
CFB at Day 6: Predose	0.5 (2.02)	0.6 (2.56)
CFB at Day 6: 0.25 H Postdose	0.6 (2.11)	0.2 (1.85)
CFB at Day 6: 0.5 H Postdose	0.3 (1.95)	0.2 (1.81)
CFB at Day 6: 1 H Postdose	0.3 (1.71)	0.2 (2.00)
CFB at Day 6: 2 H Postdose	0.5 (2.18)	0.4 (1.84)
CFB at Day 6: 12 H Postdose	0.1 (1.92)	1.4 (8.64)
CFB at Day 7: Predose	0.8 (2.70)	0.7 (1.91)
CFB at Day 7: 0.25 H Postdose	1.0 (2.71)	0.0 (2.01)
CFB at Day 7: 0.5 H Postdose	1.1 (2.28)	0.3 (1.48)
CFB at Day 7: 1 H Postdose	0.8 (2.48)	0.4 (1.99)
CFB at Day 7: 2 H Postdose	0.5 (2.26)	0.5 (1.91)
CFB at Day 7: 12 H Postdose	-0.2 (1.96)	0.1 (1.73)
CFB at Day 8: Predose	0.5 (2.05)	0.4 (1.88)
CFB at Day 8: 1 H Postdose	1.0 (2.26)	0.4 (1.65)
CFB at Day 9: Predose	0.7 (2.22)	0.3 (1.81)
CFB at Day 9: 1 H Postdose	0.4 (1.91)	0.1 (1.82)
CFB at Day 10: Predose	0.5 (1.60)	0.5 (2.05)
CFB at Day 10: 1 H Postdose	0.5 (2.21)	0.6 (1.67)
CFB at Day 11: Predose	0.3 (1.97)	0.5 (1.99)
CFB at Day 11: 1 H Postdose	0.3 (2.18)	0.3 (2.04)
CFB at Day 12: Predose	0.7 (2.27)	0.5 (1.93)
CFB at Day 12: 1 H Postdose	0.6 (2.05)	0.4 (1.83)
CFB at Day 13: Predose	1.0 (1.94)	0.4 (1.96)
CFB at Day 13: 1 H Postdose	1.0 (2.18)	0.3 (1.79)
CFB at Day 14: Predose	0.8 (2.08)	0.1 (2.89)
CFB at Day 14: 1 H Postdose	0.9 (1.98)	0.4 (1.61)
CFB at Day 15/ET	1.2 (8.39)	-0.4 (1.59)
CFB at Follow-up Day 21	0.1 (2.21)	0.2 (1.70)
CFB at Follow-up Day 28	0.0 (2.15)	0.0 (1.88)
CFB at Follow-up Day 35	0.0 (2.40)	0.1 (1.64)
CFB at Follow-up Day 42	-0.2 (2.48)	0.1 (1.50)

102. Secondary Outcome

Title	Change From Baseline (CFB) in Oral Temperature - Part B
Description	Vital signs measures included supine systolic blood pressure, supine diastolic blood pressure, standing systolic blood pressure, standing diastolic blood pressure, heart rate, respiratory rate, oral temperature, and oxygen saturation. The analysis was performed in participants included in Part B of the study. H = Hour(s). ET = Early Termination.
Time Frame	Baseline, Day 1 (0.25, 0.5, 1, 2, 12 hours postdose), Days 2, 3, 4, 5, 6 and 7 (predose, 0.25, 0.5, 1, 2, 12 hours postdose), Days 8, 9, 10, 11, 12, 13 and 14 (predose, 1 hour postdose), Day 15/ET, follow-up Days 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Baseline	36.72 (0.298)	36.72 (0.324)
CFB at Day 1: 0.25 H Postdose	0.03 (0.309)	0.03 (0.374)
CFB at Day 1: 0.5 H Postdose	0.03 (0.315)	0.05 (0.367)
CFB at Day 1: 1 H Postdose	0.05 (0.311)	-0.02 (0.414)
CFB at Day 1: 2 H Postdose	0.03 (0.360)	-0.05 (0.384)
CFB at Day 1: 12 H Postdose	-0.09 (0.328)	-0.10 (0.382)
CFB at Day 2: Predose	-0.04 (0.250)	-0.01 (0.283)
CFB at Day 2: 0.25 H Postdose	-0.03 (0.330)	-0.04 (0.421)
CFB at Day 2: 0.5 H Postdose	0.01 (0.284)	-0.06 (0.539)
CFB at Day 2: 1 H Postdose	-0.05 (0.242)	-0.02 (0.371)
CFB at Day 2: 2 H Postdose	-0.06 (0.257)	-0.05 (0.327)
CFB at Day 2: 12 H Postdose	-0.13 (0.307)	-0.06 (0.397)
CFB at Day 3: Predose	-0.03 (0.403)	-0.02 (0.321)
CFB at Day 3: 0.25 H Postdose	-0.06 (0.417)	-0.05 (0.332)
CFB at Day 3: 0.5 H Postdose	0.08 (0.408)	-0.03 (0.361)
CFB at Day 3: 1 H Postdose	0.03 (0.430)	-0.04 (0.330)
CFB at Day 3: 2 H Postdose	-0.03 (0.353)	0.00 (0.380)
CFB at Day 3: 12 H Postdose	-0.13 (0.269)	-0.08 (0.339)
CFB at Day 4: Predose	-0.14 (0.421)	-0.03 (0.348)
CFB at Day 4: 0.25 H Postdose	-0.07 (0.335)	-0.04 (0.343)
CFB at Day 4: 0.5 H Postdose	-0.03 (0.414)	-0.04 (0.333)
CFB at Day 4: 1 H Postdose	-0.11 (0.310)	0.01 (0.392)
CFB at Day 4: 2 H Postdose	-0.02 (0.458)	-0.04 (0.367)
CFB at Day 4: 12 H Postdose	-0.07 (0.370)	0.01 (0.586)
CFB at Day 5: Predose	0.01 (0.414)	-0.01 (0.343)
CFB at Day 5: 0.25 H Postdose	0.01 (0.376)	-0.03 (0.349)
CFB at Day 5: 0.5 H Postdose	0.07 (0.359)	-0.08 (0.359)
CFB at Day 5: 1 H Postdose	-0.01 (0.345)	-0.01 (0.354)
CFB at Day 5: 2 H Postdose	-0.04 (0.301)	-0.08 (0.349)
CFB at Day 5: 12 H Postdose	-0.09 (0.322)	-0.12 (0.277)
CFB at Day 6: Predose	0.06 (0.381)	0.07 (0.428)
CFB at Day 6: 0.25 H Postdose	0.01 (0.381)	0.04 (0.523)
CFB at Day 6: 0.5 H Postdose	0.04 (0.401)	0.00 (0.376)
CFB at Day 6: 1 H Postdose	0.04 (0.373)	-0.05 (0.392)
CFB at Day 6: 2 H Postdose	0.05 (0.405)	0.01 (0.452)
CFB at Day 6: 12 H Postdose	-0.10 (0.341)	-0.10 (0.366)
CFB at Day 7: Predose	0.02 (0.386)	0.02 (0.430)
CFB at Day 7: 0.25 H Postdose	-0.04 (0.341)	-0.02 (0.358)
CFB at Day 7: 0.5 H Postdose	0.05 (0.402)	0.00 (0.390)
CFB at Day 7: 1 H Postdose	0.05 (0.388)	0.06 (0.444)
CFB at Day 7: 2 H Postdose	0.01 (0.489)	0.01 (0.387)
CFB at Day 7: 12 H Postdose	-0.06 (0.350)	-0.10 (0.353)
CFB at Day 8: Predose	0.05 (0.350)	0.02 (0.388)
CFB at Day 8: 1 H Postdose	0.11 (0.372)	0.02 (0.355)
CFB at Day 9: Predose	0.04 (0.421)	0.04 (0.414)
CFB at Day 9: 1 H Postdose	0.09 (0.404)	0.05 (0.389)
CFB at Day 10: Predose	-0.01 (0.409)	-0.04 (0.402)
CFB at Day 10: 1 H Postdose	0.06 (0.454)	0.01 (0.412)
CFB at Day 11: Predose	-0.02 (0.536)	-0.06 (0.382)
CFB at Day 11: 1 H Postdose	-0.05 (0.374)	-0.10 (0.387)
CFB at Day 12: Predose	0.01 (0.422)	-0.06 (0.358)
CFB at Day 12: 1 H Postdose	0.01 (0.364)	-0.12 (0.359)
CFB at Day 13: Predose	-0.01 (0.348)	0.04 (0.353)
CFB at Day 13: 1 H Postdose	0.03 (0.449)	0.02 (0.418)
CFB at Day 14: Predose	0.06 (0.416)	-0.01 (0.315)
CFB at Day 14: 1 H Postdose	0.06 (0.378)	0.00 (0.419)
CFB at Day 15/ET	-0.09 (0.320)	-0.03 (0.391)
CFB at Follow-up Day 21	-0.12 (0.281)	-0.03 (0.314)
CFB at Follow-up Day 28	-0.04 (0.321)	-0.07 (0.352)
CFB at Follow-up Day 35	-0.05 (0.324)	-0.05 (0.359)
CFB at Follow-up Day 42	0.03 (0.338)	-0.08 (0.389)

103. Secondary Outcome

Title	Change From Baseline (CFB) in Oxygen Saturation - Part B
Description	Vital signs measures included supine systolic blood pressure, supine diastolic blood pressure, standing systolic blood pressure, standing diastolic blood pressure, heart rate, respiratory rate, oral temperature, and oxygen saturation. The analysis was performed in participants included in Part B of the study. H = Hour(s). ET = Early Termination.
Time Frame	Baseline, Day 1 (0.25, 0.5, 1, 2, 12 hours postdose), Days 2, 3, 4, 5, 6 and 7 (predose, 0.25, 0.5, 1, 2, 12 hours postdose), Day 8 (predose, 1 hour postdose)

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Baseline	97.95 (1.509)	98.02 (1.485)
CFB at Day 1: 0.25 H Postdose	-0.11 (1.768)	-0.02 (1.502)
CFB at Day 1: 0.5 H Postdose	0.12 (1.384)	0.00 (1.510)
CFB at Day 1: 1 H Postdose	0.02 (1.470)	-0.39 (1.401)
CFB at Day 1: 2 H Postdose	0.11 (1.513)	-0.32 (1.459)
CFB at Day 1: 12 H Postdose	0.09 (1.789)	-0.24 (1.827)
CFB at Day 2: Predose	-0.23 (1.939)	-0.29 (1.576)
CFB at Day 2: 0.25 H Postdose	-0.23 (1.915)	-0.22 (1.475)
CFB at Day 2: 0.5 H Postdose	-0.20 (2.041)	-0.44 (1.726)
CFB at Day 2: 1 H Postdose	-0.09 (1.902)	-0.38 (1.762)
CFB at Day 2: 2 H Postdose	-0.11 (1.907)	-0.36 (1.654)
CFB at Day 2: 12 H Postdose	-0.34 (5.278)	-0.47 (2.599)
CFB at Day 3: Predose	-0.32 (1.827)	-0.29 (1.766)
CFB at Day 3: 0.25 H Postdose	-0.09 (1.789)	-0.32 (1.695)
CFB at Day 3: 0.5 H Postdose	-0.11 (1.742)	-0.42 (1.712)
CFB at Day 3: 1 H Postdose	-0.27 (1.860)	-0.44 (1.902)
CFB at Day 3: 2 H Postdose	-0.32 (2.340)	-0.78 (1.894)
CFB at Day 3: 12 H Postdose	0.14 (1.959)	-0.24 (1.824)
CFB at Day 4: Predose	-0.20 (1.579)	-0.27 (1.643)
CFB at Day 4: 0.25 H Postdose	0.09 (1.709)	-0.24 (1.667)
CFB at Day 4: 0.5 H Postdose	-0.20 (1.720)	-0.33 (1.581)
CFB at Day 4: 1 H Postdose	-0.41 (1.933)	-0.29 (1.646)
CFB at Day 4: 2 H Postdose	-0.70 (2.018)	-1.16 (2.667)
CFB at Day 4: 12 H Postdose	0.00 (2.000)	-1.31 (4.986)
CFB at Day 5: Predose	-0.16 (1.539)	-0.36 (2.165)
CFB at Day 5: 0.25 H Postdose	0.20 (1.407)	-0.58 (2.179)
CFB at Day 5: 0.5 H Postdose	-0.09 (1.736)	-0.49 (2.564)
CFB at Day 5: 1 H Postdose	-0.07 (2.161)	-0.61 (2.895)
CFB at Day 5: 2 H Postdose	-0.05 (1.765)	-0.62 (2.338)
CFB at Day 5: 12 H Postdose	0.11 (1.979)	0.09 (1.856)
CFB at Day 6: Predose	-0.02 (1.933)	-0.13 (1.424)
CFB at Day 6: 0.25 H Postdose	0.09 (1.525)	-0.02 (1.631)
CFB at Day 6: 0.5 H Postdose	0.12 (1.749)	0.16 (1.147)
CFB at Day 6: 1 H Postdose	0.09 (1.849)	-0.22 (1.820)
CFB at Day 6: 2 H Postdose	-0.07 (1.920)	0.16 (1.492)
CFB at Day 6: 12 H Postdose	0.37 (1.852)	0.02 (1.672)
CFB at Day 7: Predose	-0.31 (1.932)	-0.16 (1.656)
CFB at Day 7: 0.25 H Postdose	0.05 (2.129)	0.07 (1.516)
CFB at Day 7: 0.5 H Postdose	-0.21 (2.007)	-0.16 (1.928)
CFB at Day 7: 1 H Postdose	-0.05 (1.987)	-0.45 (1.663)
CFB at Day 7: 2 H Postdose	0.17 (1.987)	-0.55 (2.757)
CFB at Day 7: 12 H Postdose	0.31 (2.089)	-0.11 (1.833)
CFB at Day 8: Predose	0.21 (1.510)	-0.26 (1.499)
CFB at Day 8: 1 H Postdose	0.08 (2.005)	-0.67 (1.789)

104. Secondary Outcome

Title	Change From Baseline in QT Interval - Part B
Description	ECG measures included QT interval, QTcF interval, ECG mean heart rate, RR interval, PR interval, and QRS duration. The analysis was performed in participants included in Part B of the study.
Time Frame	Baseline, Days 1, 2, 7, 14 and follow-up Day 21

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Baseline	403.5	398.0
Change from Baseline at Day 1	-9.0	-7.0
Change from Baseline at Day 2	-12.0	-15.0
Change from Baseline at Day 7	-22.0	-25.5
Change from Baseline at Day 14	-23.0	-25.5
Change from Baseline at Follow-up Day 21	-12.5	-7.5

105. Secondary Outcome

Title	Change From Baseline in QTcF Interval - Part B
Description	ECG measures included QT interval, QTcF interval, ECG mean heart rate, RR interval, PR interval, and QRS duration. The analysis was performed in participants included in Part B of the study.
Time Frame	Baseline, Days 1, 2, 7, 14 and follow-up Day 21

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Baseline	406.0	410.0
Change from Baseline at Day 1	0.0	-2.0
Change from Baseline at Day 2	-2.5	-4.0
Change from Baseline at Day 7	-5.0	-7.5
Change from Baseline at Day 14	-8.0	-3.0
Change from Baseline at Follow-up Day 21	-2.0	0.5

106. Secondary Outcome

Title	Change From Baseline in ECG Mean Heart Rate - Part B
Description	ECG measures included QT interval, QTcF interval, ECG mean heart rate, RR interval, PR interval, and QRS duration. The analysis was performed in participants included in Part B of the study.
Time Frame	Baseline, Days 1, 2, 7, 14 and follow-up Day 21

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Baseline	65.0 (11.17)	64.8 (10.06)
Change from Baseline at Day 1	3.2 (8.74)	4.5 (10.25)
Change from Baseline at Day 2	6.0 (9.58)	4.7 (10.91)
Change from Baseline at Day 7	8.3 (9.67)	7.2 (10.37)
Change from Baseline at Day 14	7.1 (9.22)	11.0 (11.23)
Change from Baseline at Follow-up Day 21	5.1 (9.22)	-0.5 (15.10)

107. Secondary Outcome

Title	Change From Baseline in RR Interval - Part B
Description	ECG measures included QT interval, QTcF interval, ECG mean heart rate, RR interval, PR interval, and QRS duration. The analysis was performed in participants included in Part B of the study.
Time Frame	Baseline, Days 1, 2, 7, 14 and follow-up Day 21

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Baseline	952.0	938.0
Change from Baseline at Day 1	-50.0	-52.5
Change from Baseline at Day 2	-46.0	-51.0
Change from Baseline at Day 7	-115.5	-92.0
Change from Baseline at Day 14	-111.0	-142.0
Change from Baseline at Follow-up Day 21	-68.5	-32.0

108. Secondary Outcome

Title	Change From Baseline in PR Interval - Part B
Description	ECG measures included QT interval, QTcF interval, ECG mean heart rate, RR interval, PR interval, and QRS duration. The analysis was performed in participants included in Part B of the study.
Time Frame	Baseline, Days 1, 2, 7, 14 and follow-up Day 21

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Baseline	149.5	162.0
Change from Baseline at Day 1	1.0	2.0
Change from Baseline at Day 2	1.5	4.0
Change from Baseline at Day 7	3.5	1.5
Change from Baseline at Day 14	4.0	3.0
Change from Baseline at Follow-up Day 21	0.0	0.5

109. Secondary Outcome

Title	Change From Baseline in QRS Duration - Part B
Description	ECG measures included QT interval, QTcF interval, ECG mean heart rate, RR interval, PR interval, and QRS duration. The analysis was performed in participants included in Part B of the study.
Time Frame	Baseline, Days 1, 2, 7, 14 and follow-up Day 21

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Baseline	88.0	89.0
Change from Baseline at Day 1	0.5	0.5
Change from Baseline at Day 2	1.0	1.0
Change from Baseline at Day 7	-0.5	-1.5
Change from Baseline at Day 14	0.0	0.0
Change from Baseline at Follow-up Day 21	-0.5	0.0

110. Secondary Outcome

Title	Percentage of Participants With a Response of "Yes" to Any C-SSRS Suicidal Ideation (SI) Item - Part B
Description	The C-SSRS scale consisted of a baseline evaluation (at screening) that assessed the lifetime experience of participants with suicidal ideation and behavior and a postbaseline evaluation that focused on suicidality since the last study visit. The C-SSRS included "yes" or "no"' responses for assessment of suicidal ideation and behavior as well as numeric ratings for severity of ideation, if present (from 1 to 5, with 5 being the most severe). The C-SSRS SI items involved wish to be dead, non-specific active suicidal thoughts, active SI with any methods, active SI with some intent and active SI with specific plan. The analysis was performed in participants included in Part B of the study. SCLR = screening: lifetime recall.
Time Frame	Screening, Days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug. Number analyzed: Number of participants in the safety set with a non-missing value at the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
SCLR: Wish to be Dead	11 84.6%	8 18.2%
SCLR: Non-specific Active Suicidal Thoughts	3 23.1%	0 0%
SCLR: Active SI with Any Methods	1 7.7%	0 0%
SCLR: Active SI with Some Intent	1 7.7%	0 0%
Day 1: Wish to be Dead	9.1 70%	2.2 5%
Day 2: Wish to be Dead	2.3 17.7%	2.2 5%
Day 3: Wish to be Dead	2.3 17.7%	2.2 5%
Day 4: Wish to be Dead	2.3 17.7%	2.2 5%
Day 5: Wish to be Dead	2.3 17.7%	2.2 5%
Day 6: Wish to be Dead	2.3 17.7%	2.2 5%
Day 7: Wish to be Dead	2.3 17.7%	0 0%
Day 8: Wish to be Dead	2.4 18.5%	0 0%
Day 9: Wish to be Dead	2.4 18.5%	0 0%
Day 11: Wish to be Dead	2.4 18.5%	0 0%
Day 12: Wish to be Dead	2.4 18.5%	0 0%
Day 13: Wish to be Dead	2.5 19.2%	0 0%
Day 15: Wish to be Dead	2.4 18.5%	0 0%
Day 21: Wish to be Dead	2.6 20%	0 0%
Day 28: Wish to be Dead	2.6 20%	0 0%
Day 35: Wish to be Dead	2.5 19.2%	0 0%
Day 42: Wish to be Dead	2.6 20%	0 0%

111. Secondary Outcome

Title	Percentage of Participants With HAM-D Response - Part A
Description	HAM-D response was defined as having a 50% or greater reduction from baseline in HAM-D total score. The HAM-D total score comprised a sum of 17 individual item scores. Items scored in a range of 0 to 2 included: insomnia (early, middle, late), somatic symptoms (gastrointestinal and general), genital symptoms, loss of weight, and insight. The following items were scored in a range of 0 to 4: agitation, depressed mood, feelings of guilt, suicide, work and activities, retardation, anxiety (psychic and somatic), and hypochondriasis. The total score could range from 0 to 52. Higher scores indicate a greater degree of depression. A negative change from baseline indicated less depression. A positive change from baseline indicated more depression. The analysis was performed in participants included in Part A of the study. Data is reported for participants who had HAM-D response.
Time Frame	Days 2, 3, 4, 5, 6, 7, 8, 15, 21 and 28

Outcome Measure Data

Analysis Population Description

The efficacy set included all participants who were randomized and received at least 1 dose of the double-blind study drug and had a baseline and at least 1 post-baseline efficacy evaluation.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Day 2	15.4 118.5%
Day 3	15.4 118.5%
Day 4	30.8 236.9%
Day 5	53.8 413.8%
Day 6	61.5 473.1%
Day 7	61.5 473.1%
Day 8	84.6 650.8%
Day 15	84.6 650.8%
Day 21	76.9 591.5%
Day 28	76.9 591.5%

112. Secondary Outcome

Title	Percentage of Participants With HAM-D Remission - Part A
Description	HAM-D remission was defined as having a HAM-D total score of ≤7. The HAM-D total score comprised a sum of the 17 individual item scores. Items scored in a range of 0 to 2 included: insomnia (early, middle, late), somatic symptoms (gastrointestinal and general), genital symptoms, loss of weight, and insight. The following items were scored in a range of 0 to 4: agitation, depressed mood, feelings of guilt, suicide, work and activities, retardation, anxiety (psychic and somatic), and hypochondriasis. The total score could range from 0 to 52. Higher scores indicated a greater degree of depression. A negative change from baseline indicated less depression. A positive change from baseline indicated more depression. The analysis was performed in participants included in Part A of the study.
Time Frame	Days 2, 3, 4, 5, 6, 7, 8, 15, 21 and 28

Outcome Measure Data

Analysis Population Description

The efficacy set included all participants who were randomized and received at least 1 dose of the double-blind study drug and had a baseline and at least 1 post-baseline efficacy evaluation.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 milligrams (mg), oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Day 2	0 0%
Day 3	0 0%
Day 4	15.4 118.5%
Day 5	15.4 118.5%
Day 6	38.5 296.2%
Day 7	38.5 296.2%
Day 8	46.2 355.4%
Day 15	61.5 473.1%
Day 21	69.2 532.3%
Day 28	69.2 532.3%

113. Secondary Outcome

Title	Change From Baseline in the Montgomery and Åsberg Depression Rating Scale (MADRS) Total Score at Day 15 and All Other Time Points - Part A
Description	The MADRS was a ten-item diagnostic questionnaire which psychiatrists used to measure the severity of depressive episodes in participants with mood disorders. It was designed as an adjunct to the HAM-D, to be more sensitive than the Hamilton Scale to the changes brought on by antidepressants and other forms of treatment. Each item yielded a score of 0 to 6. The MADRS total score was calculated as the sum of the 10 individual item scores, which ranged from 0 to 60. Higher MADRS scores indicated more severe depression. A negative change from baseline indicated less severe depression. A positive change from baseline indicated more severe depression. The analysis was performed in participants included in Part A of the study.
Time Frame	Baseline, Days 2, 3, 4, 5, 6, 7, 8, 15, 21 and 28

Outcome Measure Data

Analysis Population Description

The efficacy set included all participants who were randomized and received at least 1 dose of the double-blind study drug and had a baseline and at least 1 post-baseline efficacy evaluation.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Baseline	36.9 (5.22)
Change from Baseline at Day 2	-6.4 (5.72)
Change from Baseline at Day 3	-9.6 (7.05)
Change from Baseline at Day 4	-14.2 (8.85)
Change from Baseline at Day 5	-16.2 (9.38)
Change from Baseline at Day 6	-18.9 (9.84)
Change from Baseline at Day 7	-19.3 (9.28)
Change from Baseline at Day 8	-22.8 (9.71)
Change from Baseline at Day 15	-26.4 (9.30)
Change from Baseline at Day 21	-26.1 (11.15)
Change from Baseline at Day 28	-25.0 (12.77)

114. Secondary Outcome

Title	Change From Baseline in HAM-D Subscale Scores at Day 15 and All Other Time Points - Part A
Description	HAM-D subscales were: Core, symptoms: depressed mood (DM), feelings of guilt (FG), suicide, work and activities (WA), and retardation (RE); Anxiety, symptoms: anxiety (psychic and somatic), somatic symptoms (SS) (gastrointestinal and general), hypochondriasis, and loss of weight; Bech-6, symptoms: DM, FG, WA, RE, anxiety psychic (AP), and SS general; and Maier, symptoms: DM, FG, WA, RE, agitation, and AP. Each item was scored in a range of 0 to 2 or 0 to 4. Higher scores indicated a greater degree of depression. Subscale scores were calculated as sum of individual rating scores related to each subscale, divided by total possible score within subscale, multiplied by 100, and rounded to a whole number. Therefore, subscale scores would be within range of 0-100 and might be larger than total score. A negative change from baseline indicated less depression. A positive change from baseline indicated more depression. The analysis was performed in participants included in Part A of study.
Time Frame	Baseline, Days 2, 3, 4, 5, 6, 7, 8, 15, 21 and 28

Outcome Measure Data

Analysis Population Description

The efficacy set included all participants who were randomized and received at least 1 dose of the double-blind study drug and had a baseline and at least 1 post-baseline efficacy evaluation.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Core: Baseline	45.0 (5.77)
Core: Change from Baseline at Day 2	-5.4 (8.03)
Core: Change from Baseline at Day 3	-12.3 (11.48)
Core: Change from Baseline at Day 4	-18.5 (13.90)
Core: Change from Baseline at Day 5	-21.9 (14.22)
Core: Change from Baseline at Day 6	-25.4 (11.27)
Core: Change from Baseline at Day 7	-25.4 (15.06)
Core: Change from Baseline at Day 8	-28.8 (14.88)
Core: Change from Baseline at Day 15	-34.6 (12.98)
Core: Change from Baseline at Day 21	-35.0 (15.68)
Core: Change from Baseline at Day 28	-33.5 (16.88)
Anxiety: Baseline	50.1 (10.52)
Anxiety: Change from Baseline at Day 2	-10.4 (8.89)
Anxiety: Change from Baseline at Day 3	-15.4 (9.79)
Anxiety: Change from Baseline at Day 4	-21.8 (12.16)
Anxiety: Change from Baseline at Day 5	-24.9 (14.23)
Anxiety: Change from Baseline at Day 6	-29.1 (13.70)
Anxiety: Change from Baseline at Day 7	-29.2 (13.44)
Anxiety: Change from Baseline at Day 8	-32.5 (15.86)
Anxiety: Change from Baseline at Day 15	-34.2 (14.73)
Anxiety: Change from Baseline at Day 21	-34.2 (14.62)
Anxiety: Change from Baseline at Day 28	-34.2 (15.79)
Bech-6: Baseline	61.6 (7.38)
Bech-6: Change from Baseline at Day 2	-8.2 (11.02)
Bech-6: Change from Baseline at Day 3	-16.6 (14.52)
Bech-6: Change from Baseline at Day 4	-25.5 (17.43)
Bech-6: Change from Baseline at Day 5	-29.4 (16.94)
Bech-6: Change from Baseline at Day 6	-34.0 (16.80)
Bech-6: Change from Baseline at Day 7	-34.4 (17.82)
Bech-6: Change from Baseline at Day 8	-38.9 (18.23)
Bech-6: Change from Baseline at Day 15	-45.4 (16.04)
Bech-6: Change from Baseline at Day 21	-44.5 (20.11)
Bech-6: Change from Baseline at Day 28	-42.2 (22.12)
Meier: Baseline	54.2 (8.57)
Meier: Change from Baseline at Day 2	-7.1 (8.80)
Meier: Change from Baseline at Day 3	-16.1 (10.87)
Meier: Change from Baseline at Day 4	-23.6 (11.99)
Meier: Change from Baseline at Day 5	-27.2 (12.55)
Meier: Change from Baseline at Day 6	-31.6 (12.13)
Meier: Change from Baseline at Day 7	-31.7 (14.49)
Meier: Change from Baseline at Day 8	-35.7 (14.57)
Meier: Change from Baseline at Day 15	-40.4 (13.78)
Meier: Change from Baseline at Day 21	-40.5 (17.23)
Meier: Change from Baseline at Day 28	-38.2 (18.78)

115. Secondary Outcome

Title	Change From Baseline (CFB) in HAM-D Individual Item Scores at Day 15 and All Other Time Points - Part A
Description	The HAM-D comprised individual ratings of the following symptoms scored in a range of 0 to 2: insomnia (early, middle, late), somatic symptoms [gastrointestinal (GI) and general], genital symptoms, loss of weight, and insight. The following symptoms were scored in a range of 0 to 4: agitation, depressed mood, feelings of guilt, suicide, work and activities, retardation, anxiety (psychic and somatic), and hypochondriasis. Higher scores indicated a greater degree of depression. A negative change from baseline indicated less depression. A positive change from baseline indicated more depression. The analysis was performed in participants included in Part A of the study.
Time Frame	Baseline, Days 2, 3, 4, 5, 6, 7, 8, 15, 21 and 28

Outcome Measure Data

Analysis Population Description

The efficacy set included all participants who were randomized and received at least 1 dose of the double-blind study drug and had a baseline and at least 1 post-baseline efficacy evaluation.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Depressed Mood: Baseline	3.2 (0.55)
Depressed Mood: CFB at Day 2	-0.2 (0.60)
Depressed Mood: CFB at Day 3	-0.8 (0.83)
Depressed Mood: CFB at Day 4	-1.3 (1.18)
Depressed Mood: CFB at Day 5	-1.4 (1.33)
Depressed Mood: CFB at Day 6	-1.6 (1.19)
Depressed Mood: CFB at Day 7	-1.6 (1.19)
Depressed Mood: CFB at Day 8	-1.8 (1.14)
Depressed Mood: CFB at Day 15	-2.2 (1.07)
Depressed Mood: CFB at Day 21	-2.2 (1.24)
Depressed Mood: CFB at Day 28	-2.0 (1.29)
Work and Activities: Baseline	3.1 (0.28)
Work and Activities: CFB at Day 2	-0.3 (0.48)
Work and Activities: CFB at Day 3	-0.7 (0.85)
Work and Activities: CFB at Day 4	-0.9 (0.86)
Work and Activities: CFB at Day 5	-1.4 (0.87)
Work and Activities: CFB at Day 6	-1.4 (0.96)
Work and Activities: CFB at Day 7	-1.5 (1.13)
Work and Activities: CFB at Day 8	-1.8 (1.21)
Work and Activities: CFB at Day 15	-2.5 (0.78)
Work and Activities: CFB at Day 21	-2.3 (1.11)
Work and Activities: CFB at Day 28	-2.2 (1.30)
Insomnia Early: Baseline	1.8 (0.55)
Insomnia Early: CFB at Day 2	-0.9 (0.86)
Insomnia Early: CFB at Day 3	-1.2 (0.90)
Insomnia Early: CFB at Day 4	-1.5 (0.88)
Insomnia Early: CFB at Day 5	-1.5 (0.78)
Insomnia Early: CFB at Day 6	-1.6 (0.77)
Insomnia Early: CFB at Day 7	-1.5 (0.78)
Insomnia Early: CFB at Day 8	-1.8 (0.55)
Insomnia Early: CFB at Day 15	-1.8 (0.55)
Insomnia Early: CFB at Day 21	-1.8 (0.60)
Insomnia Early: CFB at Day 28	-1.5 (0.88)
Insomnia Middle: Baseline	2.0 (0.00)
Insomnia Middle: CFB at Day 2	-0.9 (0.95)
Insomnia Middle: CFB at Day 3	-1.1 (0.76)
Insomnia Middle: CFB at Day 4	-1.2 (0.80)
Insomnia Middle: CFB at Day 5	-1.4 (0.65)
Insomnia Middle: CFB at Day 6	-1.4 (0.65)
Insomnia Middle: CFB at Day 7	-1.5 (0.78)
Insomnia Middle: CFB at Day 8	-1.6 (0.65)
Insomnia Middle: CFB at Day 15	-1.7 (0.48)
Insomnia Middle: CFB at Day 21	-1.5 (0.66)
Insomnia Middle: CFB at Day 28	-1.5 (0.66)
Insomnia Late: Baseline	1.8 (0.38)
Insomnia Late: CFB at Day 2	-0.8 (0.93)
Insomnia Late: CFB at Day 3	-0.8 (0.80)
Insomnia Late: CFB at Day 4	-1.0 (0.82)
Insomnia Late: CFB at Day 5	-1.3 (0.85)
Insomnia Late: CFB at Day 6	-1.2 (0.93)
Insomnia Late: CFB at Day 7	-1.3 (0.85)
Insomnia Late: CFB at Day 8	-1.3 (0.85)
Insomnia Late: CFB at Day 15	-1.5 (0.78)
Insomnia Late: CFB at Day 21	-1.5 (0.78)
Insomnia Late: CFB at Day 28	-1.4 (0.96)
Genital Symptoms: Baseline	2.0 (0.00)
Genital Symptoms: CFB at Day 2	-0.1 (0.28)
Genital Symptoms: CFB at Day 3	-0.1 (0.28)
Genital Symptoms: CFB at Day 4	-0.2 (0.60)
Genital Symptoms: CFB at Day 5	-0.3 (0.63)
Genital Symptoms: CFB at Day 6	-0.5 (0.66)
Genital Symptoms: CFB at Day 7	-0.5 (0.78)
Genital Symptoms: CFB at Day 8	-0.6 (0.77)
Genital Symptoms: CFB at Day 15	-0.8 (0.73)
Genital Symptoms: CFB at Day 21	-1.3 (0.85)
Genital Symptoms: CFB at Day 28	-1.3 (0.85)
Somatic Symptoms GI: Baseline	1.3 (0.75)
Somatic Symptoms GI: CFB at Day 2	-0.3 (0.63)
Somatic Symptoms GI: CFB at Day 3	-0.7 (0.63)
Somatic Symptoms GI: CFB at Day 4	-0.8 (0.60)
Somatic Symptoms GI: CFB at Day 5	-0.8 (0.73)
Somatic Symptoms GI: CFB at Day 6	-0.9 (0.64)
Somatic Symptoms GI: CFB at Day 7	-0.8 (0.69)
Somatic Symptoms GI: CFB at Day 8	-0.9 (0.76)
Somatic Symptoms GI: CFB at Day 15	-1.0 (0.82)
Somatic Symptoms GI: CFB at Day 21	-1.1 (0.76)
Somatic Symptoms GI: CFB at Day 28	-1.0 (0.82)
Loss of Weight: Baseline	0.5 (0.78)
Loss of Weight: CFB at Day 2	-0.5 (0.78)
Loss of Weight: CFB at Day 3	-0.4 (0.77)
Loss of Weight: CFB at Day 4	-0.4 (0.87)
Loss of Weight: CFB at Day 5	-0.4 (0.87)
Loss of Weight: CFB at Day 6	-0.5 (0.78)
Loss of Weight: CFB at Day 7	-0.5 (0.78)
Loss of Weight: CFB at Day 8	-0.4 (0.77)
Loss of Weight: CFB at Day 15	-0.3 (0.85)
Loss of Weight: CFB at Day 21	-0.5 (0.78)
Loss of Weight: CFB at Day 28	-0.5 (0.78)
Somatic Symptoms General: Baseline	1.9 (0.28)
Somatic Symptoms General: CFB at Day 2	-0.3 (0.63)
Somatic Symptoms General: CFB at Day 3	-0.4 (0.77)
Somatic Symptoms General: CFB at Day 4	-0.7 (0.85)
Somatic Symptoms General: CFB at Day 5	-0.8 (0.83)
Somatic Symptoms General: CFB at Day 6	-0.7 (0.95)
Somatic Symptoms General: CFB at Day 7	-0.8 (0.80)
Somatic Symptoms General: CFB at Day 8	-1.0 (0.82)
Somatic Symptoms General: CFB at Day 15	-1.2 (0.73)
Somatic Symptoms General: CFB at Day 21	-1.2 (0.80)
Somatic Symptoms General: CFB at Day 28	-1.2 (0.90)
Feelings of Guilt: Baseline	1.7 (0.63)
Feelings of Guilt: CFB at Day 2	-0.1 (0.49)
Feelings of Guilt: CFB at Day 3	-0.3 (1.03)
Feelings of Guilt: CFB at Day 4	-0.8 (0.83)
Feelings of Guilt: CFB at Day 5	-0.8 (0.99)
Feelings of Guilt: CFB at Day 6	-1.1 (0.86)
Feelings of Guilt: CFB at Day 7	-1.0 (0.91)
Feelings of Guilt: CFB at Day 8	-1.2 (0.80)
Feelings of Guilt: CFB at Day 15	-1.3 (0.75)
Feelings of Guilt: CFB at Day 21	-1.4 (0.77)
Feelings of Guilt: CFB at Day 28	-1.4 (0.77)
Suicide: Baseline	0.1 (0.28)
Suicide: CFB at Day 2	-0.1 (0.28)
Suicide: CFB at Day 3	-0.1 (0.28)
Suicide: CFB at Day 4	-0.1 (0.28)
Suicide: CFB at Day 5	-0.1 (0.28)
Suicide: CFB at Day 6	-0.1 (0.28)
Suicide: CFB at Day 7	-0.1 (0.28)
Suicide: CFB at Day 8	-0.1 (0.28)
Suicide: CFB at Day 15	-0.1 (0.28)
Suicide: CFB at Day 21	-0.1 (0.28)
Suicide: CFB at Day 28	-0.1 (0.28)
Anxiety Psychic: Baseline	2.7 (0.63)
Anxiety Psychic: CFB at Day 2	-0.5 (0.52)
Anxiety Psychic: CFB at Day 3	-0.8 (0.55)
Anxiety Psychic: CFB at Day 4	-1.3 (0.85)
Anxiety Psychic: CFB at Day 5	-1.4 (0.87)
Anxiety Psychic: CFB at Day 6	-1.8 (1.09)
Anxiety Psychic: CFB at Day 7	-1.7 (1.03)
Anxiety Psychic: CFB at Day 8	-1.8 (0.99)
Anxiety Psychic: CFB at Day 15	-1.9 (0.95)
Anxiety Psychic: CFB at Day 21	-1.7 (0.95)
Anxiety Psychic: CFB at Day 28	-1.5 (0.97)
Anxiety Somatic: Baseline	1.5 (0.66)
Anxiety Somatic: CFB at Day 2	-0.2 (0.55)
Anxiety Somatic: CFB at Day 3	-0.2 (0.73)
Anxiety Somatic: CFB at Day 4	-0.5 (0.78)
Anxiety Somatic: CFB at Day 5	-0.8 (0.60)
Anxiety Somatic: CFB at Day 6	-0.8 (0.60)
Anxiety Somatic: CFB at Day 7	-0.8 (0.69)
Anxiety Somatic: CFB at Day 8	-0.8 (0.80)
Anxiety Somatic: CFB at Day 15	-1.1 (0.64)
Anxiety Somatic: CFB at Day 21	-1.1 (0.86)
Anxiety Somatic: CFB at Day 28	-1.2 (0.69)
Hypochondriasis: Baseline	1.1 (0.76)
Hypochondriasis: CFB at Day 2	-0.2 (0.90)
Hypochondriasis: CFB at Day 3	-0.2 (0.60)
Hypochondriasis: CFB at Day 4	-0.3 (0.48)
Hypochondriasis: CFB at Day 5	-0.4 (0.51)
Hypochondriasis: CFB at Day 6	-0.6 (0.51)
Hypochondriasis: CFB at Day 7	-0.5 (0.52)
Hypochondriasis: CFB at Day 8	-0.8 (0.55)
Hypochondriasis: CFB at Day 15	-0.6 (0.51)
Hypochondriasis: CFB at Day 21	-0.7 (0.75)
Hypochondriasis: CFB at Day 28	-0.8 (0.80)
Insight: Baseline	0.2 (0.38)
Insight: CFB at Day 2	-0.1 (0.28)
Insight: CFB at Day 3	-0.1 (0.28)
Insight: CFB at Day 4	-0.2 (0.38)
Insight: CFB at Day 5	-0.2 (0.38)
Insight: CFB at Day 6	-0.2 (0.38)
Insight: CFB at Day 7	-0.2 (0.38)
Insight: CFB at Day 8	-0.2 (0.38)
Insight: CFB at Day 15	-0.2 (0.38)
Insight: CFB at Day 21	-0.2 (0.38)
Insight: CFB at Day 28	-0.2 (0.38)
Agitation: Baseline	1.4 (0.87)
Agitation: CFB at Day 2	-0.2 (0.44)
Agitation: CFB at Day 3	-0.6 (0.87)
Agitation: CFB at Day 4	-0.8 (0.83)
Agitation: CFB at Day 5	-0.8 (0.90)
Agitation: CFB at Day 6	-0.8 (0.69)
Agitation: CFB at Day 7	-0.9 (0.64)
Agitation: CFB at Day 8	-1.0 (0.71)
Agitation: CFB at Day 15	-0.9 (0.76)
Agitation: CFB at Day 21	-1.1 (0.76)
Agitation: CFB at Day 28	-1.0 (0.91)
Retardation: Baseline	1.0 (0.71)
Retardation: CFB at Day 2	-0.4 (0.65)
Retardation: CFB at Day 3	-0.6 (0.65)
Retardation: CFB at Day 4	-0.6 (0.65)
Retardation: CFB at Day 5	-0.7 (0.63)
Retardation: CFB at Day 6	-0.9 (0.76)
Retardation: CFB at Day 7	-0.8 (0.69)
Retardation: CFB at Day 8	-0.8 (0.69)
Retardation: CFB at Day 15	-0.9 (0.64)
Retardation: CFB at Day 21	-1.0 (0.71)
Retardation: CFB at Day 28	-1.0 (0.71)

116. Secondary Outcome

Title	Change From Baseline in Hamilton Anxiety Rating Scale (HAM-A) Total Score at All Time Points - Part A
Description	The 14-item HAM-A was used to rate the severity of symptoms of anxiety. Each of the 14 items was defined by a series of symptoms, and measured both psychic anxiety (mental agitation and psychological distress) and somatic anxiety (physical complaints related to anxiety). Scoring for HAM-A was calculated by assigning scores of 0 (not present) to 4 (very severe), with a total score range of 0 to 56, where 0-13=Normal, 14-17 Mild Anxiety, 18-24 Moderate Anxiety, >=25 Severe Anxiety, per the Psych Congress Network. The HAM-A total score was calculated as the sum of the 14 individual item scores. A negative change from baseline indicated less anxiety. A positive change from baseline indicated more anxiety. The analysis was performed in participants included in Part A of the study.
Time Frame	Baseline, Days 2, 3, 8, 15, 21 and 28

Outcome Measure Data

Analysis Population Description

The efficacy set included all participants who were randomized and received at least 1 dose of the double-blind study drug and had a baseline and at least 1 post-baseline efficacy evaluation.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Baseline	23.2 (5.65)
Change from Baseline at Day 2	-2.8 (3.44)
Change from Baseline at Day 3	-5.6 (3.59)
Change from Baseline at Day 8	-13.3 (6.25)
Change from Baseline at Day 15	-15.5 (6.19)
Change from Baseline at Day 21	-15.6 (7.05)
Change from Baseline at Day 28	-15.5 (7.22)

117. Secondary Outcome

Title	Percentage of Participants With Clinical Global Impression - Improvement (CGI-I) Response - Part A
Description	The CGI-I item employed a 7-point Likert scale to measure the overall improvement in the participant's condition post-treatment. The investigator rated the participant's total improvement whether or not it was due entirely to drug treatment. Response choices included: 0 = not assessed, 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse. The CGI-I was only rated at post-treatment assessments. By definition, all CGI-I assessments were evaluated against baseline conditions. CGI-I response was defined as having a CGI-I global improvement score of 1 (very much improved) or 2 (much improved). The analysis was performed in participants included in Part A of the study. Data is reported for participants who had CGI-I response.
Time Frame	Days 2, 3, 8, 15, 21 and 28

Outcome Measure Data

Analysis Population Description

The efficacy set included all participants who were randomized and received at least 1 dose of the double-blind study drug and had a baseline and at least 1 post-baseline efficacy evaluation.

Arm/Group Title	Part A: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.
Measure Participants	13
Day 2	7.7 59.2%
Day 3	15.4 118.5%
Day 8	84.6 650.8%
Day 15	92.3 710%
Day 21	84.6 650.8%
Day 28	76.9 591.5%

118. Secondary Outcome

Title	Change From Baseline (CFB) in the SSS Score - Part B
Description	The SSS was participant-rated scale designed to quickly assess how alert a participant was feeling. Degrees of sleepiness and alertness were rated on a scale of one to seven, where the lowest score of 'one' indicated the participant was 'feeling active, vital, alert, or wide awake' and the highest score of 'seven' indicated the participant was 'no longer fighting sleep, sleep onset soon; having dream-like thoughts'. A negative change from baseline indicated less sleepiness. A positive change from baseline indicated more sleepiness. The analysis was performed in participants included in Part B of the study. H = Hour(s).
Time Frame	Baseline, Day 1 (0.25, 0.5, 1, 2 hours postdose), Days 2, 3, 4, 5, 6 and 7 (predose, 0.25, 0.5, 1, 2 hours postdose), Days 8, 9, 10, 11, 12, 13 and 14 (predose, 1 hour postdose), Day 15

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least 1 dose of the double-blind study drug. Number analyzed: Number of participants in the safety set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral solution, once daily for 14 days.
Measure Participants	44	45
Baseline	2.7 (1.47)	2.6 (1.31)
CFB at Day 1: 0.25 H Postdose	0.0 (0.94)	0.0 (0.82)
CFB at Day 1: 0.5 H Postdose	-0.1 (0.73)	0.0 (1.20)
CFB at Day 1: 1 H Postdose	-0.1 (0.84)	0.2 (1.54)
CFB at Day 1: 2 H Postdose	-0.1 (1.26)	0.6 (1.70)
CFB at Day 2: Predose	-0.6 (1.19)	-0.1 (1.39)
CFB at Day 2: 0.25 H Postdose	-0.5 (1.28)	0.1 (1.59)
CFB at Day 2: 0.5 H Postdose	-0.5 (1.13)	0.2 (1.62)
CFB at Day 2: 1 H Postdose	-0.3 (1.06)	0.5 (1.75)
CFB at Day 2: 2 H Postdose	0.1 (1.29)	0.4 (1.73)
CFB at Day 3: Predose	-0.6 (1.14)	-0.4 (1.11)
CFB at Day 3: 0.25 H Postdose	-0.7 (1.20)	-0.2 (1.45)
CFB at Day 3: 0.5 H Postdose	-0.5 (1.05)	-0.1 (1.50)
CFB at Day 3: 1 H Postdose	-0.3 (1.06)	0.1 (1.55)
CFB at Day 3: 2 H Postdose	0.0 (1.21)	0.5 (1.53)
CFB at Day 4: Predose	-0.7 (1.22)	-0.3 (1.39)
CFB at Day 4: 0.25 H Postdose	-0.7 (1.16)	-0.2 (1.37)
CFB at Day 4: 0.5 H Postdose	-0.5 (1.19)	0.0 (1.42)
CFB at Day 4: 1 H Postdose	-0.4 (1.19)	0.0 (1.44)
CFB at Day 4: 2 H Postdose	-0.3 (1.21)	0.4 (1.53)
CFB at Day 5: Predose	-1.0 (1.49)	-0.5 (1.32)
CFB at Day 5: 0.25 H Postdose	-0.8 (1.41)	-0.3 (1.44)
CFB at Day 5: 0.5 H Postdose	-0.8 (1.31)	-0.2 (1.29)
CFB at Day 5: 1 H Postdose	-0.6 (1.35)	0.2 (1.50)
CFB at Day 5: 2 H Postdose	-0.3 (1.37)	0.4 (1.49)
CFB at Day 6: Predose	-0.8 (1.15)	-0.5 (1.39)
CFB at Day 6: 0.25 H Postdose	-0.7 (1.20)	-0.2 (1.40)
CFB at Day 6: 0.5 H Postdose	-0.6 (1.18)	-0.2 (1.39)
CFB at Day 6: 1 H Postdose	-0.4 (1.03)	0.1 (1.45)
CFB at Day 6: 2 H Postdose	-0.2 (1.17)	0.2 (1.49)
CFB at Day 7: Predose	-0.8 (1.26)	-0.6 (1.31)
CFB at Day 7: 0.25 H Postdose	-0.8 (1.25)	-0.5 (1.47)
CFB at Day 7: 0.5 H Postdose	-0.6 (1.23)	-0.3 (1.30)
CFB at Day 7: 1 H Postdose	-0.4 (1.25)	-0.2 (1.36)
CFB at Day 7: 2 H Postdose	-0.2 (1.25)	0.1 (1.40)
CFB at Day 8: Predose	-0.8 (1.34)	-0.7 (1.36)
CFB at Day 8: 1 H Postdose	-0.6 (1.38)	-0.2 (1.65)
CFB at Day 9: Predose	-0.9 (1.38)	-0.6 (1.35)
CFB at Day 9: 1 H Postdose	-0.6 (1.23)	-0.3 (1.42)
CFB at Day 10: Predose	-1.0 (1.32)	-0.6 (1.38)
CFB at Day 10: 1 H Postdose	-0.7 (1.28)	-0.3 (1.55)
CFB at Day 11: Predose	-0.7 (1.23)	-0.6 (1.36)
CFB at Day 11: 1 H Postdose	-0.6 (1.31)	-0.3 (1.68)
CFB at Day 12: Predose	-0.9 (1.25)	-0.7 (1.44)
CFB at Day 12: 1 H Postdose	-0.7 (1.30)	-0.4 (1.76)
CFB at Day 13: Predose	-0.8 (1.30)	-0.8 (1.50)
CFB at Day 13: 1 H Postdose	-0.6 (1.34)	-0.4 (1.50)
CFB at Day 14: Predose	-0.7 (1.27)	-0.7 (1.35)
CFB at Day 14: 1 H Postdose	-0.5 (1.31)	-0.3 (1.46)
CFB at Day 15	-0.6 (1.50)	-0.8 (1.61)

119. Secondary Outcome

Title	Change From Baseline in the 17-item HAM-D Total Score at All Time Points - Part B
Description	The HAM-D total score comprised a sum of 17 individual item scores. Items scored in a range of 0 to 2 included: insomnia (early, middle, late), somatic symptoms (gastrointestinal and general), genital symptoms, loss of weight, and insight. The following items were scored in a range of 0 to 4: agitation, depressed mood, feelings of guilt, suicide, work and activities, retardation, anxiety (psychic and somatic), and hypochondriasis. The total score could range from 0 to 52. Higher scores indicated a greater degree of depression. A negative change from baseline indicated less depression. A positive change from baseline indicated more depression. The analysis was performed in participants included in Part B of the study.
Time Frame	Baseline, Days 2, 3, 4, 5, 6, 7, 8, 15, 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The efficacy set included all participants who were randomized and received at least 1 dose of the double-blind study drug and had a baseline and at least 1 post-baseline efficacy evaluation.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Change from Baseline at Day 2	-3.5 (0.98)	-5.8 (0.97)
Change from Baseline at Day 3	-5.2 (1.09)	-9.3 (1.07)
Change from Baseline at Day 4	-7.7 (1.13)	-10.6 (1.11)
Change from Baseline at Day 5	-8.5 (1.19)	-12.3 (1.17)
Change from Baseline at Day 6	-9.1 (1.21)	-13.6 (1.19)
Change from Baseline at Day 7	-9.2 (1.29)	-13.7 (1.27)
Change from Baseline at Day 8	-11.0 (1.29)	-14.4 (1.27)
Change from Baseline at Day 15	-10.3 (1.33)	-17.4 (1.31)
Change from Baseline at Day 21	-11.3 (1.43)	-16.3 (1.40)
Change from Baseline at Day 28	-11.3 (1.44)	-15.4 (1.41)
Change from Baseline at Day 35	-12.6 (1.49)	-14.9 (1.47)
Change from Baseline at Day 42	-12.3 (1.49)	-14.6 (1.46)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part A: SAGE-217, Part B: SAGE-217
	Comments	Day 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0223
	Comments
	Method	Mixed Effect Model for Repeated Measures
	Comments	The MMRM included the change from baseline in HAM-D total score at each visit as the dependent variables.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-2.3
	Confidence Interval	(2-Sided) 95%; -4.3 to -0.3
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.99
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Part A: SAGE-217, Part B: SAGE-217
	Comments	Day 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0010
	Comments
	Method	Mixed Effect Model for Repeated Measures
	Comments	The MMRM included the change from baseline in HAM-D total score at each visit as the dependent variables.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-4.1
	Confidence Interval	(2-Sided) 95%; -6.4 to -1.7
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.18
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Part A: SAGE-217, Part B: SAGE-217
	Comments	Day 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0233
	Comments
	Method	Mixed Effect Model for Repeated Measures
	Comments	The MMRM included the change from baseline in HAM-D total score at each visit as the dependent variables.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-2.9
	Confidence Interval	(2-Sided) 95%; -5.5 to -0.4
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.27
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Part A: SAGE-217, Part B: SAGE-217
	Comments	Day 5
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0066
	Comments
	Method	Mixed Effect Model for Repeated Measures
	Comments	The MMRM included the change from baseline in HAM-D total score at each visit as the dependent variables.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-3.8
	Confidence Interval	(2-Sided) 95%; -6.6 to -1.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.37
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Part A: SAGE-217, Part B: SAGE-217
	Comments	Day 6
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0019
	Comments
	Method	Mixed Effect Model for Repeated Measures
	Comments	The MMRM included the change from baseline in HAM-D total score at each visit as the dependent variables.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-4.5
	Confidence Interval	(2-Sided) 95%; -7.3 to -1.7
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.40
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Part A: SAGE-217, Part B: SAGE-217
	Comments	Day 7
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0043
	Comments
	Method	Mixed Effect Model for Repeated Measures
	Comments	The MMRM included the change from baseline in HAM-D total score at each visit as the dependent variables.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-4.5
	Confidence Interval	(2-Sided) 95%; -7.6 to -1.5
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.53
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Part A: SAGE-217, Part B: SAGE-217
	Comments	Day 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0318
	Comments
	Method	Mixed Effect Model for Repeated Measures
	Comments	The MMRM included the change from baseline in HAM-D total score at each visit as the dependent variables.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-3.4
	Confidence Interval	(2-Sided) 95%; -6.4 to -0.3
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.54
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Part A: SAGE-217, Part B: SAGE-217
	Comments	Day 15
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments
	Method	Mixed Effect Model for Repeated Measures
	Comments	The MMRM included the change from baseline in HAM-D total score at each visit as the dependent variables.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-7.0
	Confidence Interval	(2-Sided) 95%; -10.2 to -3.9
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.60
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Part A: SAGE-217, Part B: SAGE-217
	Comments	Day 21
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0064
	Comments
	Method	Mixed Effect Model for Repeated Measures
	Comments	The MMRM included the change from baseline in HAM-D total score at each visit as the dependent variables.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-4.9
	Confidence Interval	(2-Sided) 95%; -8.4 to -1.4
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.76
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Part A: SAGE-217, Part B: SAGE-217
	Comments	Day 28
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0243
	Comments
	Method	Mixed Effect Model for Repeated Measures
	Comments	The MMRM included the change from baseline in HAM-D total score at each visit as the dependent variables.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-4.1
	Confidence Interval	(2-Sided) 95%; -7.6 to -0.5
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.77
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Part A: SAGE-217, Part B: SAGE-217
	Comments	Day 35
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2285
	Comments
	Method	Mixed Effect Model for Repeated Measures
	Comments	The MMRM included the change from baseline in HAM-D total score at each visit as the dependent variables.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-2.3
	Confidence Interval	(2-Sided) 95%; -6.0 to 1.4
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.86
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Part A: SAGE-217, Part B: SAGE-217
	Comments	Day 42
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2120
	Comments
	Method	Mixed Effect Model for Repeated Measures
	Comments	The MMRM included the change from baseline in HAM-D total score at each visit as the dependent variables.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-2.3
	Confidence Interval	(2-Sided) 95%; -6.0 to 1.4
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.86
	Estimation Comments

120. Secondary Outcome

Title	Percentage of Participants With HAM-D Response - Part B
Description	HAM-D response was defined as having a 50% or greater reduction from baseline in HAM-D total score. The HAM-D total score comprised a sum of 17 individual item scores. Items scored in a range of 0 to 2 included: insomnia (early, middle, late), somatic symptoms (gastrointestinal and general), genital symptoms, loss of weight, and insight. The following items were scored in a range of 0 to 4: agitation, depressed mood, feelings of guilt, suicide, work and activities, retardation, anxiety (psychic and somatic), and hypochondriasis. The total score could range from 0 to 52. Higher scores indicated a greater degree of depression. A negative change from baseline indicated less depression. A positive change from baseline indicated more depression. The analysis was performed in participants included in Part B of the study. Data is reported for participants who had HAM-D response.
Time Frame	Days 2, 8, 15, 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The efficacy set included all participants who were randomized and received at least 1 dose of the double-blind study drug and had a baseline and at least 1 post-baseline efficacy evaluation. Number analyzed: Number of participants in the efficacy set ith a non-missing value at the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Day 2	4.5 34.6%	15.6 35.5%
Day 8	47.6 366.2%	59.1 134.3%
Day 15	40.5 311.5%	78.6 178.6%
Day 21	42.1 323.8%	73.8 167.7%
Day 28	46.2 355.4%	61.9 140.7%
Day 35	50.0 384.6%	65.9 149.8%
Day 42	56.4 433.8%	61.9 140.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part A: SAGE-217, Part B: SAGE-217
	Comments	Day 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0884
	Comments
	Method	Generalized Estimating Equation
	Comments	Statistics are from a generalized estimating equation (GEE) method including the HAM-D response at each visit as the dependent variables.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	4.4
	Confidence Interval	(2-Sided) 95%; 0.8 to 24.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	For the model parameters estimation, the exchangeable working correlation structure was used.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Part A: SAGE-217, Part B: SAGE-217
	Comments	Day 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0732
	Comments
	Method	Generalized Estimating Equation
	Comments	Statistics are from a GEE method including the HAM-D response at each visit as the dependent variables.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.4
	Confidence Interval	(2-Sided) 95%; 0.9 to 6.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	For the model parameters estimation, the exchangeable working correlation structure was used.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Part A: SAGE-217, Part B: SAGE-217
	Comments	Day 15
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	Generalized Estimating Equation
	Comments	Statistics are from a GEE method including the HAM-D response at each visit as the dependent variables.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	9.6
	Confidence Interval	(2-Sided) 95%; 2.9 to 31.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	For the model parameters estimation, the exchangeable working correlation structure was used.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Part A: SAGE-217, Part B: SAGE-217
	Comments	Day 21
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0006
	Comments
	Method	Generalized Estimating Equation
	Comments	Statistics are from a GEE method including the HAM-D response at each visit as the dependent variables.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	6.7
	Confidence Interval	(2-Sided) 95%; 2.3 to 19.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	For the model parameters estimation, the exchangeable working correlation structure was used.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Part A: SAGE-217, Part B: SAGE-217
	Comments	Day 28
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0379
	Comments
	Method	Generalized Estimating Equation
	Comments	Statistics are from a GEE method including the HAM-D response at each visit as the dependent variables.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.1
	Confidence Interval	(2-Sided) 95%; 1.1 to 8.9
	Parameter Dispersion	Type: Value:
	Estimation Comments	For the model parameters estimation, the exchangeable working correlation structure was used.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Part A: SAGE-217, Part B: SAGE-217
	Comments	Day 35
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0468
	Comments
	Method	Generalized Estimating Equation
	Comments	Statistics are from a GEE method including the HAM-D response at each visit as the dependent variables.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.0
	Confidence Interval	(2-Sided) 95%; 1.0 to 9.0
	Parameter Dispersion	Type: Value:
	Estimation Comments	For the model parameters estimation, the exchangeable working correlation structure was used.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Part A: SAGE-217, Part B: SAGE-217
	Comments	Day 42
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2208
	Comments
	Method	Generalized Estimating Equation
	Comments	Statistics are from a GEE method including the HAM-D response at each visit as the dependent variables.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.9
	Confidence Interval	(2-Sided) 95%; 0.7 to 5.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	For the model parameters estimation, the exchangeable working correlation structure was used.

121. Secondary Outcome

Title	Percentage of Participants With HAM-D Remission - Part B
Description	HAM-D remission was defined as having a HAM-D total score of ≤7. The HAM-D total score comprised a sum of the 17 individual item scores. Items scored in a range of 0 to 2 included: insomnia (early, middle, late), somatic symptoms (gastrointestinal and general), genital symptoms, loss of weight, and insight. The following items were scored in a range of 0 to 4: agitation, depressed mood, feelings of guilt, suicide, work and activities, retardation, anxiety (psychic and somatic), and hypochondriasis. The total score could range from 0 to 52. Higher scores indicated a greater degree of depression. A negative change from baseline indicated less depression. A positive change from baseline indicated more depression. The analysis was performed in participants included in Part B of the study.
Time Frame	Days 2, 8, 15, 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The efficacy set included all participants who were randomized and received at least 1 dose of the double-blind study drug and had a baseline and at least 1 post-baseline efficacy evaluation. Number analyzed: Number of participants in efficacy set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Day 2	0 0%	2.2 5%
Day 8	28.6 220%	36.4 82.7%
Day 15	26.2 201.5%	64.3 146.1%
Day 21	26.3 202.3%	52.4 119.1%
Day 28	28.2 216.9%	52.4 119.1%
Day 35	35.0 269.2%	43.9 99.8%
Day 42	33.3 256.2%	45.2 102.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part A: SAGE-217, Part B: SAGE-217
	Comments	Day 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4300
	Comments
	Method	Generalized Estimating Equation
	Comments	Statistics are from a GEE method including the HAM-D remission at each visit as the dependent variables.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.5
	Confidence Interval	(2-Sided) 95%; 0.6 to 3.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	For the model parameters estimation, the exchangeable working correlation structure was used.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Part A: SAGE-217, Part B: SAGE-217
	Comments	Day 15
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0005
	Comments
	Method	Generalized Estimating Equation
	Comments	Statistics are from a GEE method including the HAM-D remission at each visit as the dependent variables.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	5.3
	Confidence Interval	(2-Sided) 95%; 2.1 to 13.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	For the model parameters estimation, the exchangeable working correlation structure was used.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Part A: SAGE-217, Part B: SAGE-217
	Comments	Day 21
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0172
	Comments
	Method	Generalized Estimating Equation
	Comments	Statistics are from a GEE method including the HAM-D remission at each visit as the dependent variables.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.1
	Confidence Interval	(2-Sided) 95%; 1.2 to 8.0
	Parameter Dispersion	Type: Value:
	Estimation Comments	For the model parameters estimation, the exchangeable working correlation structure was used.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Part A: SAGE-217, Part B: SAGE-217
	Comments	Day 28
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0221
	Comments
	Method	Generalized Estimating Equation
	Comments	Statistics are from a GEE method including the HAM-D remission at each visit as the dependent variables.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.9
	Confidence Interval	(2-Sided) 95%; 1.2 to 7.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	For the model parameters estimation, the exchangeable working correlation structure was used.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Part A: SAGE-217, Part B: SAGE-217
	Comments	Day 35
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4139
	Comments
	Method	Generalized Estimating Equation
	Comments	Statistics are from a GEE method including the HAM-D remission at each visit as the dependent variables.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.4
	Confidence Interval	(2-Sided) 95%; 0.6 to 3.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	For the model parameters estimation, the exchangeable working correlation structure was used.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Part A: SAGE-217, Part B: SAGE-217
	Comments	Day 42
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2332
	Comments
	Method	Generalized Estimating Equation
	Comments	Statistics are from a GEE method including the HAM-D remission at each visit as the dependent variables.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.7
	Confidence Interval	(2-Sided) 95%; 0.7 to 4.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	For the model parameters estimation, the exchangeable working correlation structure was used.

122. Secondary Outcome

Title	Change From Baseline in the MADRS Total Score at Day 15 and All Other Time Points - Part B
Description	The MADRS was a ten-item diagnostic questionnaire which psychiatrists used to measure the severity of depressive episodes in participants with mood disorders. It was designed as an adjunct to the HAM-D, to be more sensitive than the Hamilton Scale to the changes brought on by antidepressants and other forms of treatment. Each item yielded a score of 0 to 6. The MADRS total score was calculated as the sum of the 10 individual item scores, which ranged from 0 to 60. Higher MADRS scores indicated more severe depression. A negative change from baseline indicated less severe depression. A positive change from baseline indicated more severe depression. The analysis was performed in participants included in Part B of the study.
Time Frame	Baseline, Days 2, 8, 15, 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The efficacy set included all participants who were randomized and received at least 1 dose of the double-blind study drug and had a baseline and at least 1 post-baseline efficacy evaluation.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Change from Baseline at Day 2	-4.5 (1.36)	-6.9 (1.35)
Change from Baseline at Day 8	-15.4 (1.90)	-19.4 (1.88)
Change from Baseline at Day 15	-15.0 (1.94)	-22.5 (1.92)
Change from Baseline at Day 21	-15.2 (2.14)	-21.9 (2.11)
Change from Baseline at Day 28	-14.8 (2.14)	-20.1 (2.11)
Change from Baseline at Day 35	-16.4 (2.25)	-19.4 (2.23)
Change from Baseline at Day 42	-17.2 (2.15)	-19.1 (2.11)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part A: SAGE-217, Part B: SAGE-217
	Comments	Day 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0836
	Comments
	Method	Mixed Effect Model for Repeated Measures
	Comments	The MMRM included the change from baseline in MADRS total score at each visit as the dependent variable.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-2.4
	Confidence Interval	(2-Sided) 95%; -5.1 to 0.3
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.38
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Part A: SAGE-217, Part B: SAGE-217
	Comments	Day 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0864
	Comments
	Method	Mixed Effect Model for Repeated Measures
	Comments	The MMRM included the change from baseline in MADRS total score at each visit as the dependent variable.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-4.0
	Confidence Interval	(2-Sided) 95%; -8.6 to 0.6
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.32
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Part A: SAGE-217, Part B: SAGE-217
	Comments	Day 15
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0021
	Comments
	Method	Mixed Effect Model for Repeated Measures
	Comments	The MMRM included the change from baseline in MADRS total score at each visit as the dependent variable.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-7.6
	Confidence Interval	(2-Sided) 95%; -12.3 to -2.8
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.38
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Part A: SAGE-217, Part B: SAGE-217
	Comments	Day 21
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0157
	Comments
	Method	Mixed Effect Model for Repeated Measures
	Comments	The MMRM included the change from baseline in MADRS total score at each visit as the dependent variable.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-6.6
	Confidence Interval	(2-Sided) 95%; -12.0 to -1.3
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.69
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Part A: SAGE-217, Part B: SAGE-217
	Comments	Day 28
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0533
	Comments
	Method	Mixed Effect Model for Repeated Measures
	Comments	The MMRM included the change from baseline in MADRS total score at each visit as the dependent variable.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-5.3
	Confidence Interval	(2-Sided) 95%; -10.6 to 0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.69
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Part A: SAGE-217, Part B: SAGE-217
	Comments	Day 35
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2878
	Comments
	Method	Mixed Effect Model for Repeated Measures
	Comments	The MMRM included the change from baseline in MADRS total score at each visit as the dependent variable.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-3.1
	Confidence Interval	(2-Sided) 95%; -8.8 to 2.6
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.87
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Part A: SAGE-217, Part B: SAGE-217
	Comments	Day 42
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4664
	Comments
	Method	Mixed Effect Model for Repeated Measures
	Comments	The MMRM included the change from baseline in MADRS total score at each visit as the dependent variable.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-2.0
	Confidence Interval	(2-Sided) 95%; -7.4 to 3.4
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.70
	Estimation Comments

123. Secondary Outcome

Title	Change From Baseline in HAM-D Subscale Scores at All Time Points - Part B
Description	HAM-D subscales were: Core, symptoms: depressed mood (DM), feelings of guilt (FG), suicide, work and activities (WA), and retardation (RE); Anxiety, symptoms: anxiety (psychic and somatic), somatic symptoms (SS) (gastrointestinal and general), hypochondriasis, and loss of weight; Bech-6, symptoms: DM, FG, WA, RE, anxiety psychic (AP), and SS general; and Maier, symptoms: DM, FG, WA, RE, agitation, and AP. Each item was scored in a range of 0 to 2 or 0 to 4. Higher scores indicated a greater degree of depression. Subscale scores were calculated as sum of individual rating scores related to each subscale, divided by total possible score within subscale, multiplied by 100, and rounded to a whole number. Therefore, subscale scores would be within range of 0-100 and might be larger than total score. A negative change from baseline indicated less depression. A positive change from baseline indicated more depression. The analysis was performed in participants included in Part B of study.
Time Frame	Baseline, Days 2, 3, 4, 5, 6, 7, 8, 15, 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The efficacy set included all participants who were randomized and received at least 1 dose of the double-blind study drug and had a baseline and at least 1 post-baseline efficacy evaluation. Number analyzed: Number of participants in efficacy set with a non-missing value at both baseline and visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Core: Baseline	47.3 (6.86)	46.9 (7.01)
Core: Change from Baseline at Day 2	-5.9 (6.84)	-7.2 (12.04)
Core: Change from Baseline at Day 3	-9.4 (9.16)	-14.1 (14.31)
Core: Change from Baseline at Day 4	-13.3 (10.85)	-18.3 (14.92)
Core: Change from Baseline at Day 5	-15.8 (12.39)	-21.2 (15.45)
Core: Change from Baseline at Day 6	-17.5 (14.04)	-25.6 (15.20)
Core: Change from Baseline at Day 7	-18.0 (15.97)	-24.8 (15.74)
Core: Change from Baseline at Day 8	-22.5 (16.28)	-26.6 (16.35)
Core: Change from Baseline at Day 15	-21.9 (17.94)	-33.1 (14.73)
Core: Change from Baseline at Day 21	-22.9 (17.77)	-30.7 (16.10)
Core: Change from Baseline at Day 28	-22.1 (17.42)	-29.3 (17.89)
Core: Change from Baseline at Day 35	-24.3 (17.34)	-28.2 (17.20)
Core: Change from Baseline at Day 42	-25.8 (17.79)	-28.0 (18.41)
Anxiety: Baseline	48.1 (13.28)	48.8 (11.46)
Anxiety: Change from Baseline at Day 2	-8.4 (10.51)	-12.8 (12.63)
Anxiety: Change from Baseline at Day 3	-12.5 (10.21)	-18.9 (15.03)
Anxiety: Change from Baseline at Day 4	-17.5 (17.17)	-21.8 (16.33)
Anxiety: Change from Baseline at Day 5	-18.5 (18.72)	-24.1 (15.83)
Anxiety: Change from Baseline at Day 6	-18.8 (18.30)	-26.5 (17.21)
Anxiety: Change from Baseline at Day 7	-19.5 (17.65)	-25.4 (17.66)
Anxiety: Change from Baseline at Day 8	-21.5 (18.32)	-27.9 (17.96)
Anxiety: Change from Baseline at Day 15	-20.5 (17.11)	-34.1 (16.27)
Anxiety: Change from Baseline at Day 21	-23.6 (18.67)	-32.7 (17.85)
Anxiety: Change from Baseline at Day 28	-23.1 (20.34)	-30.8 (16.95)
Anxiety: Change from Baseline at Day 35	-24.9 (20.74)	-30.0 (17.75)
Anxiety: Change from Baseline at Day 42	-22.9 (21.60)	-29.7 (16.57)
Bech-6: Baseline	60.1 (7.12)	59.8 (7.23)
Bech-6: Change from Baseline at Day 2	-6.8 (9.71)	-10.2 (14.55)
Bech-6: Change from Baseline at Day 3	-11.3 (9.38)	-18.8 (17.93)
Bech-6: Change from Baseline at Day 4	-17.0 (13.92)	-23.8 (19.11)
Bech-6: Change from Baseline at Day 5	-19.5 (16.61)	-26.8 (19.32)
Bech-6: Change from Baseline at Day 6	-21.4 (16.76)	-32.0 (20.13)
Bech-6: Change from Baseline at Day 7	-22.8 (18.88)	-31.4 (19.69)
Bech-6: Change from Baseline at Day 8	-27.5 (19.47)	-33.0 (20.08)
Bech-6: Change from Baseline at Day 15	-26.3 (21.07)	-41.8 (17.78)
Bech-6: Change from Baseline at Day 21	-27.9 (20.69)	-38.8 (20.80)
Bech-6: Change from Baseline at Day 28	-27.7 (21.02)	-36.1 (21.86)
Bech-6: Change from Baseline at Day 35	-29.3 (22.03)	-35.0 (21.51)
Bech-6: Change from Baseline at Day 42	-30.2 (22.34)	-34.7 (22.35)
Meier: Baseline	51.1 (6.56)	49.4 (5.58)
Meier: Change from Baseline at Day 2	-6.3 (8.68)	-7.8 (12.10)
Meier: Change from Baseline at Day 3	-9.6 (8.54)	-16.0 (15.18)
Meier: Change from Baseline at Day 4	-14.1 (12.47)	-20.4 (16.38)
Meier: Change from Baseline at Day 5	-17.3 (13.74)	-23.2 (15.88)
Meier: Change from Baseline at Day 6	-18.2 (14.24)	-27.5 (16.95)
Meier: Change from Baseline at Day 7	-19.4 (16.85)	-26.3 (16.90)
Meier: Change from Baseline at Day 8	-24.6 (16.85)	-27.9 (16.72)
Meier: Change from Baseline at Day 15	-22.6 (17.15)	-35.1 (14.55)
Meier: Change from Baseline at Day 21	-23.8 (18.08)	-32.5 (16.88)
Meier: Change from Baseline at Day 28	-24.2 (17.57)	-30.8 (17.36)
Meier: Change from Baseline at Day 35	-25.5 (17.89)	-29.5 (18.24)
Meier: Change from Baseline at Day 42	-26.7 (18.21)	-29.1 (18.27)

124. Secondary Outcome

Title	Change From Baseline (CFB) in HAM-D Individual Item Scores at All Time Points - Part B
Description	The HAM-D comprised individual ratings of the following symptoms scored in a range of 0 to 2: insomnia (early, middle, late), somatic symptoms (GI and general), genital symptoms, loss of weight, and insight. The following symptoms were scored in a range of 0 to 4: agitation, depressed mood, feelings of guilt, suicide, work and activities, retardation, anxiety (psychic and somatic), and hypochondriasis. Higher scores indicated a greater degree of depression. A negative change from baseline indicated less depression. A positive change from baseline indicated more depression. The analysis was performed in participants included in Part B of the study.
Time Frame	Baseline, Days 2, 3, 4, 5, 6, 7, 8, 15, 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The efficacy set included all participants who were randomized and received at least 1 dose of the double-blind study drug and had a baseline and at least 1 post-baseline efficacy evaluation. Number analyzed: Number of participants in efficacy set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Depressed Mood: Baseline	3.1 (0.56)	3.1 (0.32)
Depressed Mood: CFB at Day 2	-0.3 (0.54)	-0.5 (0.84)
Depressed Mood: CFB at Day 3	-0.5 (0.63)	-0.8 (0.90)
Depressed Mood: CFB at Day 4	-0.7 (0.77)	-1.2 (1.09)
Depressed Mood: CFB at Day 5	-1.0 (0.86)	-1.2 (1.10)
Depressed Mood: CFB at Day 6	-1.0 (0.99)	-1.6 (1.12)
Depressed Mood: CFB at Day 7	-1.1 (1.14)	-1.4 (1.16)
Depressed Mood: CFB at Day 8	-1.4 (1.25)	-1.7 (1.14)
Depressed Mood: CFB at Day 15	-1.3 (1.23)	-2.0 (1.07)
Depressed Mood: CFB at Day 21	-1.3 (1.34)	-1.8 (1.09)
Depressed Mood: CFB at Day 28	-1.3 (1.31)	-1.7 (1.22)
Depressed Mood: CFB at Day 35	-1.3 (1.31)	-1.7 (1.15)
Depressed Mood: CFB at Day 42	-1.4 (1.29)	-1.7 (1.20)
Work and Activities: Baseline	3.1 (0.42)	3.1 (0.33)
Work and Activities: CFB at Day 2	-0.3 (0.56)	-0.5 (0.89)
Work and Activities: CFB at Day 3	-0.5 (0.59)	-1.0 (1.18)
Work and Activities: CFB at Day 4	-0.9 (0.77)	-1.1 (1.12)
Work and Activities: CFB at Day 5	-1.0 (0.88)	-1.3 (1.28)
Work and Activities: CFB at Day 6	-1.2 (0.99)	-1.4 (1.27)
Work and Activities: CFB at Day 7	-1.1 (1.05)	-1.4 (1.20)
Work and Activities: CFB at Day 8	-1.4 (1.15)	-1.6 (1.22)
Work and Activities: CFB at Day 15	-1.5 (1.09)	-2.1 (1.18)
Work and Activities: CFB at Day 21	-1.5 (1.22)	-1.9 (1.09)
Work and Activities: CFB at Day 28	-1.6 (1.27)	-1.8 (1.22)
Work and Activities: CFB at Day 35	-1.7 (1.26)	-1.8 (1.31)
Work and Activities: CFB at Day 42	-1.8 (1.29)	-1.7 (1.29)
Insomnia Early: Baseline	1.7 (0.71)	1.7 (0.65)
Insomnia Early: CFB at Day 2	0.0 (0.82)	-0.5 (1.08)
Insomnia Early: CFB at Day 3	-0.2 (0.92)	-0.8 (1.07)
Insomnia Early: CFB at Day 4	-0.3 (0.80)	-0.7 (1.16)
Insomnia Early: CFB at Day 5	-0.3 (0.88)	-1.0 (1.13)
Insomnia Early: CFB at Day 6	-0.5 (1.00)	-1.0 (1.02)
Insomnia Early: CFB at Day 7	-0.3 (0.94)	-1.0 (1.02)
Insomnia Early: CFB at Day 8	-0.4 (1.01)	-1.2 (0.90)
Insomnia Early: CFB at Day 15	-0.2 (0.96)	-1.3 (1.00)
Insomnia Early: CFB at Day 21	-0.3 (1.14)	-1.2 (0.94)
Insomnia Early: CFB at Day 28	-0.5 (1.17)	-1.0 (0.96)
Insomnia Early: CFB at Day 35	-0.5 (1.13)	-1.0 (1.04)
Insomnia Early: CFB at Day 42	-0.7 (1.13)	-0.9 (0.98)
Insomnia Middle: Baseline	1.8 (0.51)	1.7 (0.64)
Insomnia Middle: CFB at Day 2	-0.4 (0.87)	-0.5 (0.99)
Insomnia Middle: CFB at Day 3	-0.5 (0.79)	-1.0 (0.93)
Insomnia Middle: CFB at Day 4	-0.6 (0.95)	-0.9 (0.97)
Insomnia Middle: CFB at Day 5	-0.6 (0.87)	-0.9 (1.07)
Insomnia Middle: CFB at Day 6	-0.8 (1.05)	-0.9 (1.06)
Insomnia Middle: CFB at Day 7	-0.7 (0.99)	-1.0 (0.95)
Insomnia Middle: CFB at Day 8	-0.9 (1.01)	-1.1 (0.93)
Insomnia Middle: CFB at Day 15	-0.6 (0.99)	-1.2 (0.95)
Insomnia Middle: CFB at Day 21	-0.8 (0.90)	-1.2 (0.86)
Insomnia Middle: CFB at Day 28	-0.8 (0.98)	-0.9 (0.96)
Insomnia Middle: CFB at Day 35	-0.9 (1.00)	-0.9 (0.98)
Insomnia Middle: CFB at Day 42	-0.8 (0.94)	-1.0 (0.94)
Insomnia Late: Baseline	1.6 (0.70)	1.5 (0.82)
Insomnia Late: CFB at Day 2	-0.5 (0.95)	-0.6 (1.05)
Insomnia Late: CFB at Day 3	-0.6 (1.00)	-0.7 (1.24)
Insomnia Late: CFB at Day 4	-0.7 (1.09)	-0.7 (1.18)
Insomnia Late: CFB at Day 5	-0.8 (1.06)	-0.8 (1.24)
Insomnia Late: CFB at Day 6	-0.8 (1.06)	-0.9 (1.22)
Insomnia Late: CFB at Day 7	-0.9 (1.10)	-0.8 (1.31)
Insomnia Late: CFB at Day 8	-0.9 (1.05)	-0.9 (1.18)
Insomnia Late: CFB at Day 15	-0.7 (1.04)	-1.1 (1.13)
Insomnia Late: CFB at Day 21	-0.8 (1.05)	-1.0 (1.22)
Insomnia Late: CFB at Day 28	-0.8 (1.14)	-1.0 (1.19)
Insomnia Late: CFB at Day 35	-1.0 (1.11)	-0.9 (1.21)
Insomnia Late: CFB at Day 42	-0.9 (1.09)	-1.1 (1.01)
Genital Symptoms: Baseline	1.7 (0.60)	1.6 (0.68)
Genital Symptoms: CFB at Day 2	-0.1 (0.50)	-0.1 (0.50)
Genital Symptoms: CFB at Day 3	-0.1 (0.42)	-0.1 (0.42)
Genital Symptoms: CFB at Day 4	-0.2 (0.57)	-0.1 (0.67)
Genital Symptoms: CFB at Day 5	-0.2 (0.51)	-0.4 (0.69)
Genital Symptoms: CFB at Day 6	-0.3 (0.61)	-0.3 (0.56)
Genital Symptoms: CFB at Day 7	-0.3 (0.58)	-0.6 (0.72)
Genital Symptoms: CFB at Day 8	-0.4 (0.67)	-0.5 (0.66)
Genital Symptoms: CFB at Day 15	-0.6 (0.79)	-0.8 (0.78)
Genital Symptoms: CFB at Day 21	-0.6 (0.89)	-0.9 (0.80)
Genital Symptoms: CFB at Day 28	-0.6 (0.78)	-0.8 (0.87)
Genital Symptoms: CFB at Day 35	-0.7 (0.86)	-0.8 (0.90)
Genital Symptoms: CFB at Day 42	-0.6 (0.88)	-0.7 (0.86)
Somatic Symptoms GI: Baseline	1.3 (0.79)	1.5 (0.76)
Somatic Symptoms GI: CFB at Day 2	-0.1 (0.69)	-0.4 (0.62)
Somatic Symptoms GI: CFB at Day 3	-0.2 (0.64)	-0.6 (0.77)
Somatic Symptoms GI: CFB at Day 4	-0.4 (0.82)	-0.7 (0.73)
Somatic Symptoms GI: CFB at Day 5	-0.5 (0.98)	-0.8 (0.77)
Somatic Symptoms GI: CFB at Day 6	-0.5 (0.95)	-0.8 (0.85)
Somatic Symptoms GI: CFB at Day 7	-0.4 (1.00)	-0.9 (0.89)
Somatic Symptoms GI: CFB at Day 8	-0.5 (0.94)	-0.9 (0.95)
Somatic Symptoms GI: CFB at Day 15	-0.4 (1.01)	-1.1 (0.86)
Somatic Symptoms GI: CFB at Day 21	-0.6 (0.95)	-1.1 (0.89)
Somatic Symptoms GI: CFB at Day 28	-0.6 (0.91)	-1.0 (0.92)
Somatic Symptoms GI: CFB at Day 35	-0.7 (0.94)	-1.0 (0.89)
Somatic Symptoms GI: CFB at Day 42	-0.7 (0.77)	-0.9 (0.84)
Loss of Weight: Baseline	0.9 (0.87)	1.1 (0.86)
Loss of Weight: CFB at Day 2	-0.5 (0.73)	-0.5 (0.79)
Loss of Weight: CFB at Day 3	-0.5 (0.90)	-0.7 (0.88)
Loss of Weight: CFB at Day 4	-0.5 (0.91)	-0.7 (1.00)
Loss of Weight: CFB at Day 5	-0.6 (0.97)	-0.7 (0.86)
Loss of Weight: CFB at Day 6	-0.6 (0.90)	-0.8 (0.93)
Loss of Weight: CFB at Day 7	-0.7 (0.87)	-0.7 (0.94)
Loss of Weight: CFB at Day 8	-0.6 (0.94)	-0.8 (0.91)
Loss of Weight: CFB at Day 15	-0.7 (0.93)	-0.8 (0.88)
Loss of Weight: CFB at Day 21	-0.7 (0.93)	-0.9 (0.88)
Loss of Weight: CFB at Day 28	-0.6 (0.97)	-1.0 (0.88)
Loss of Weight: CFB at Day 35	-0.7 (0.97)	-0.9 (0.90)
Loss of Weight: CFB at Day 42	-0.6 (0.88)	-0.9 (0.95)
Somatic Symptoms General: Baseline	1.7 (0.50)	1.7 (0.46)
Somatic Symptoms General: CFB at Day 2	-0.1 (0.55)	-0.3 (0.60)
Somatic Symptoms General: CFB at Day 3	-0.3 (0.47)	-0.4 (0.66)
Somatic Symptoms General: CFB at Day 4	-0.5 (0.74)	-0.5 (0.73)
Somatic Symptoms General: CFB at Day 5	-0.5 (0.85)	-0.5 (0.89)
Somatic Symptoms General: CFB at Day 6	-0.6 (0.70)	-0.7 (0.89)
Somatic Symptoms General: CFB at Day 7	-0.6 (0.72)	-0.9 (0.76)
Somatic Symptoms General: CFB at Day 8	-0.6 (0.79)	-0.8 (0.86)
Somatic Symptoms General: CFB at Day 15	-0.7 (0.91)	-1.1 (0.78)
Somatic Symptoms General: CFB at Day 21	-0.8 (0.88)	-1.0 (0.90)
Somatic Symptoms General: CFB at Day 28	-0.8 (0.96)	-0.9 (0.87)
Somatic Symptoms General: CFB at Day 35	-0.9 (0.94)	-1.0 (0.89)
Somatic Symptoms General: CFB at Day 42	-0.8 (0.92)	-0.9 (0.89)
Feelings of Guilt: Baseline	2.1 (0.70)	1.9 (0.83)
Feelings of Guilt: CFB at Day 2	-0.3 (0.69)	-0.4 (0.68)
Feelings of Guilt: CFB at Day 3	-0.5 (0.73)	-0.5 (0.82)
Feelings of Guilt: CFB at Day 4	-0.6 (0.87)	-0.7 (0.84)
Feelings of Guilt: CFB at Day 5	-0.7 (0.76)	-1.0 (0.93)
Feelings of Guilt: CFB at Day 6	-0.8 (0.97)	-1.2 (0.96)
Feelings of Guilt: CFB at Day 7	-0.9 (0.99)	-1.2 (1.04)
Feelings of Guilt: CFB at Day 8	-1.2 (0.91)	-1.2 (1.12)
Feelings of Guilt: CFB at Day 15	-1.0 (1.15)	-1.4 (1.01)
Feelings of Guilt: CFB at Day 21	-1.1 (1.04)	-1.2 (1.12)
Feelings of Guilt: CFB at Day 28	-1.0 (1.03)	-1.3 (1.05)
Feelings of Guilt: CFB at Day 35	-1.2 (1.00)	-1.1 (1.14)
Feelings of Guilt: CFB at Day 42	-1.3 (0.95)	-1.2 (1.09)
Suicide: Baseline	0.3 (0.51)	0.1 (0.29)
Suicide: CFB at Day 2	-0.2 (0.46)	0.0 (0.15)
Suicide: CFB at Day 3	-0.2 (0.46)	0.0 (0.15)
Suicide: CFB at Day 4	-0.2 (0.45)	0.0 (0.21)
Suicide: CFB at Day 5	-0.2 (0.45)	0.0 (0.26)
Suicide: CFB at Day 6	-0.2 (0.48)	0.0 (0.21)
Suicide: CFB at Day 7	-0.2 (0.48)	-0.1 (0.25)
Suicide: CFB at Day 8	-0.2 (0.51)	-0.1 (0.29)
Suicide: CFB at Day 15	-0.2 (0.52)	-0.1 (0.30)
Suicide: CFB at Day 21	-0.2 (0.54)	-0.1 (0.30)
Suicide: CFB at Day 28	-0.2 (0.52)	-0.1 (0.30)
Suicide: CFB at Day 35	-0.2 (0.52)	-0.1 (0.26)
Suicide: CFB at Day 42	-0.2 (0.52)	-0.1 (0.30)
Anxiety Psychic: Baseline	2.3 (0.67)	2.1 (0.49)
Anxiety Psychic: CFB at Day 2	-0.3 (0.78)	-0.4 (0.75)
Anxiety Psychic: CFB at Day 3	-0.5 (0.66)	-0.8 (0.94)
Anxiety Psychic: CFB at Day 4	-0.7 (1.05)	-1.0 (1.16)
Anxiety Psychic: CFB at Day 5	-0.8 (1.05)	-1.1 (0.98)
Anxiety Psychic: CFB at Day 6	-0.8 (0.91)	-1.2 (1.13)
Anxiety Psychic: CFB at Day 7	-0.9 (1.01)	-1.1 (1.25)
Anxiety Psychic: CFB at Day 8	-1.1 (0.97)	-1.2 (1.01)
Anxiety Psychic: CFB at Day 15	-0.9 (0.93)	-1.5 (0.86)
Anxiety Psychic: CFB at Day 21	-1.0 (0.90)	-1.4 (0.97)
Anxiety Psychic: CFB at Day 28	-1.0 (1.00)	-1.2 (0.92)
Anxiety Psychic: CFB at Day 35	-0.9 (1.13)	-1.1 (1.04)
Anxiety Psychic: CFB at Day 42	-0.9 (1.08)	-1.2 (0.83)
Anxiety Somatic: Baseline	1.4 (0.78)	1.4 (0.75)
Anxiety Somatic: CFB at Day 2	-0.3 (0.61)	-0.4 (0.81)
Anxiety Somatic: CFB at Day 3	-0.4 (0.75)	-0.6 (0.84)
Anxiety Somatic: CFB at Day 4	-0.5 (0.88)	-0.5 (0.84)
Anxiety Somatic: CFB at Day 5	-0.4 (0.87)	-0.6 (0.81)
Anxiety Somatic: CFB at Day 6	-0.4 (0.87)	-0.6 (0.69)
Anxiety Somatic: CFB at Day 7	-0.4 (0.91)	-0.5 (0.87)
Anxiety Somatic: CFB at Day 8	-0.6 (0.99)	-0.7 (0.87)
Anxiety Somatic: CFB at Day 15	-0.6 (0.80)	-0.8 (0.83)
Anxiety Somatic: CFB at Day 21	-0.7 (0.92)	-0.8 (0.87)
Anxiety Somatic: CFB at Day 28	-0.7 (0.90)	-0.7 (0.94)
Anxiety Somatic: CFB at Day 35	-0.8 (0.80)	-0.8 (0.86)
Anxiety Somatic: CFB at Day 42	-0.6 (1.02)	-0.8 (0.85)
Hypochondriasis: Baseline	1.1 (0.85)	1.0 (0.83)
Hypochondriasis: CFB at Day 2	-0.2 (0.76)	-0.2 (0.67)
Hypochondriasis: CFB at Day 3	-0.3 (0.74)	-0.3 (0.84)
Hypochondriasis: CFB at Day 4	-0.5 (0.83)	-0.5 (0.82)
Hypochondriasis: CFB at Day 5	-0.5 (0.90)	-0.6 (0.78)
Hypochondriasis: CFB at Day 6	-0.5 (1.02)	-0.6 (0.80)
Hypochondriasis: CFB at Day 7	-0.5 (1.03)	-0.5 (0.84)
Hypochondriasis: CFB at Day 8	-0.5 (1.02)	-0.6 (0.87)
Hypochondriasis: CFB at Day 15	-0.5 (0.77)	-0.7 (0.91)
Hypochondriasis: CFB at Day 21	-0.5 (0.73)	-0.7 (0.81)
Hypochondriasis: CFB at Day 28	-0.5 (0.91)	-0.7 (0.92)
Hypochondriasis: CFB at Day 35	-0.6 (0.87)	-0.7 (0.94)
Hypochondriasis: CFB at Day 42	-0.6 (0.96)	-0.7 (0.92)
Insight: Baseline	0.1 (0.25)	0.1 (0.25)
Insight: CFB at Day 2	0.0 (0.15)	0.0 (0.21)
Insight: CFB at Day 3	0.0 (0.21)	0.0 (0.26)
Insight: CFB at Day 4	0.0 (0.21)	0.0 (0.26)
Insight: CFB at Day 5	0.0 (0.21)	0.0 (0.26)
Insight: CFB at Day 6	0.0 (0.21)	0.0 (0.26)
Insight: CFB at Day 7	0.0 (0.21)	0.0 (0.26)
Insight: CFB at Day 8	0.0 (0.22)	0.0 (0.26)
Insight: CFB at Day 15	0.0 (0.22)	0.0 (0.22)
Insight: CFB at Day 21	-0.1 (0.23)	0.0 (0.22)
Insight: CFB at Day 28	-0.1 (0.22)	0.0 (0.15)
Insight: CFB at Day 35	-0.1 (0.22)	0.0 (0.16)
Insight: CFB at Day 42	-0.1 (0.22)	0.0 (0.22)
Agitation: Baseline	0.8 (0.88)	0.5 (0.63)
Agitation: CFB at Day 2	-0.2 (0.73)	0.0 (0.52)
Agitation: CFB at Day 3	-0.2 (0.87)	-0.2 (0.53)
Agitation: CFB at Day 4	-0.2 (0.97)	-0.2 (0.53)
Agitation: CFB at Day 5	-0.4 (0.76)	-0.2 (0.61)
Agitation: CFB at Day 6	-0.3 (0.87)	-0.3 (0.60)
Agitation: CFB at Day 7	-0.3 (0.86)	-0.3 (0.60)
Agitation: CFB at Day 8	-0.5 (0.92)	-0.3 (0.64)
Agitation: CFB at Day 15	-0.4 (0.99)	-0.4 (0.66)
Agitation: CFB at Day 21	-0.4 (0.79)	-0.3 (0.65)
Agitation: CFB at Day 28	-0.6 (1.04)	-0.4 (0.59)
Agitation: CFB at Day 35	-0.6 (0.96)	-0.4 (0.63)
Agitation: CFB at Day 42	-0.6 (0.88)	-0.3 (0.68)
Retardation: Baseline	0.8 (0.89)	1.2 (0.97)
Retardation: CFB at Day 2	-0.1 (0.63)	-0.2 (0.83)
Retardation: CFB at Day 3	-0.2 (0.67)	-0.5 (0.87)
Retardation: CFB at Day 4	-0.3 (0.85)	-0.7 (0.95)
Retardation: CFB at Day 5	-0.3 (0.82)	-0.8 (0.96)
Retardation: CFB at Day 6	-0.3 (0.86)	-0.9 (0.99)
Retardation: CFB at Day 7	-0.4 (0.88)	-0.8 (0.90)
Retardation: CFB at Day 8	-0.4 (0.93)	-0.8 (0.93)
Retardation: CFB at Day 15	-0.4 (0.96)	-1.0 (0.91)
Retardation: CFB at Day 21	-0.4 (0.86)	-1.1 (0.93)
Retardation: CFB at Day 28	-0.4 (0.75)	-1.0 (1.02)
Retardation: CFB at Day 35	-0.5 (0.85)	-1.0 (0.94)
Retardation: CFB at Day 42	-0.5 (0.79)	-0.9 (0.99)

125. Secondary Outcome

Title	Change From Baseline in HAM-A Total Score at Day 15 and All Other Time Points - Part B
Description	The 14-item HAM-A was used to rate the severity of symptoms of anxiety. Each of the 14 items was defined by a series of symptoms, and measured both psychic anxiety (mental agitation and psychological distress) and somatic anxiety (physical complaints related to anxiety). Scoring for HAM-A was calculated by assigning scores of 0 (not present) to 4 (very severe), with a total score range of 0 to 56, where 0-13=Normal, 14-17 Mild Anxiety, 18-24 Moderate Anxiety, >=25 Severe Anxiety, per the Psych Congress Network. The HAM-A total score was calculated as the sum of the 14 individual item scores. A negative change from baseline indicated less anxiety. A positive change from baseline indicated more anxiety. The analysis was performed in participants included in Part B of the study.
Time Frame	Baseline, Days 2, 8, 15, 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The efficacy set included all participants who were randomized and received at least 1 dose of the double-blind study drug and had a baseline and at least 1 post-baseline efficacy evaluation.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Change from Baseline at Day 2	-3.7 (0.86)	-5.5 (0.83)
Change from Baseline at Day 8	-8.9 (1.09)	-11.4 (1.06)
Change from Baseline at Day 15	-8.6 (1.11)	-13.2 (1.08)
Change from Baseline at Day 21	-9.5 (1.25)	-12.9 (1.21)
Change from Baseline at Day 28	-10.0 (1.26)	-12.2 (1.22)
Change from Baseline at Day 35	-9.9 (1.38)	-12.0 (1.35)
Change from Baseline at Day 42	-9.6 (1.39)	-11.8 (1.35)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part A: SAGE-217, Part B: SAGE-217
	Comments	Day 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0391
	Comments
	Method	Mixed Effect Model for Repeated Measures
	Comments	The MMRM included the change from baseline in HAM-A total score at each visit as the dependent variable.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-1.8
	Confidence Interval	(2-Sided) 95%; -3.6 to -0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.87
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Part A: SAGE-217, Part B: SAGE-217
	Comments	Day 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0516
	Comments
	Method	Mixed Effect Model for Repeated Measures
	Comments	The MMRM included the change from baseline in HAM-A total score at each visit as the dependent variable.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-2.5
	Confidence Interval	(2-Sided) 95%; -5.1 to 0.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.29
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Part A: SAGE-217, Part B: SAGE-217
	Comments	Day 15
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0008
	Comments
	Method	Mixed Effect Model for Repeated Measures
	Comments	The MMRM included the change from baseline in HAM-A total score at each visit as the dependent variable.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-4.6
	Confidence Interval	(2-Sided) 95%; -7.3 to -2.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.32
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Part A: SAGE-217, Part B: SAGE-217
	Comments	Day 21
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0282
	Comments
	Method	Mixed Effect Model for Repeated Measures
	Comments	The MMRM included the change from baseline in HAM-A total score at each visit as the dependent variable.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-3.4
	Confidence Interval	(2-Sided) 95%; -6.5 to -0.4
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.54
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Part A: SAGE-217, Part B: SAGE-217
	Comments	Day 28
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1686
	Comments
	Method	Mixed Effect Model for Repeated Measures
	Comments	The MMRM included the change from baseline in HAM-A total score at each visit as the dependent variable.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-2.2
	Confidence Interval	(2-Sided) 95%; -5.3 to 0.9
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.56
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Part A: SAGE-217, Part B: SAGE-217
	Comments	Day 35
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2488
	Comments
	Method	Mixed Effect Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-2.0
	Confidence Interval	(2-Sided) 95%; -5.5 to 1.5
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.75
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Part A: SAGE-217, Part B: SAGE-217
	Comments	Day 42
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2037
	Comments
	Method	Mixed Effect Model for Repeated Measures
	Comments	The MMRM included the change from baseline in HAM-A total score at each visit as the dependent variable.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-2.3
	Confidence Interval	(2-Sided) 95%; -5.7 to 1.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.76
	Estimation Comments

126. Secondary Outcome

Title	Percentage of Participants With CGI-I Response - Part B
Description	The CGI-I item employed a 7-point Likert scale to measure the overall improvement in the participant's condition post-treatment. The investigator rated the participant's total improvement whether or not it was due entirely to drug treatment. Response choices included: 0 = not assessed, 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse. The CGI-I was only rated at post-treatment assessments. By definition, all CGI-I assessments were evaluated against baseline conditions. CGI-I response was defined as having a score of 1 (very much improved) or 2 (much improved). The analysis was performed in participants included in Part B of the study. Data is reported for participants who had CGI-I response.
Time Frame	Days 2, 8, 15, 21, 28, 35 and 42

Outcome Measure Data

Analysis Population Description

The efficacy set included all participants who were randomized and received at least 1 dose of the double-blind study drug and had a baseline and at least 1 post-baseline efficacy evaluation. Number analyzed: Number of participants in efficacy set with a non-missing value at both baseline and the visit within each treatment group.

Arm/Group Title	Part B: Placebo	Part B: SAGE-217
Arm/Group Description	Eligible participants received matching placebo capsules once daily for 14 days.	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
Measure Participants	44	45
Day 2	0 0%	15.6 35.5%
Day 8	45.2 347.7%	70.5 160.2%
Day 15	45.2 347.7%	78.6 178.6%
Day 21	50.0 384.6%	71.4 162.3%
Day 28	46.2 355.4%	66.7 151.6%
Day 35	55.0 423.1%	63.4 144.1%
Day 42	59.0 453.8%	69.0 156.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part A: SAGE-217, Part B: SAGE-217
	Comments	Day 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0048
	Comments
	Method	Generalized Estimating Equation
	Comments	Statistics are from a GEE method including the CGI-I response at each visit as the dependent variable.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	5.5
	Confidence Interval	(2-Sided) 95%; 1.7 to 17.9
	Parameter Dispersion	Type: Value:
	Estimation Comments	For the model parameters estimation, the exchangeable working correlation structure was used.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Part A: SAGE-217, Part B: SAGE-217
	Comments	Day 15
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0007
	Comments
	Method	Generalized Estimating Equation
	Comments	Statistics are from a GEE method including the CGI-I response at each visit as the dependent variable.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	8.6
	Confidence Interval	(2-Sided) 95%; 2.5 to 29.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	For the model parameters estimation, the exchangeable working correlation structure was used.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Part A: SAGE-217, Part B: SAGE-217
	Comments	Day 21
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0113
	Comments
	Method	Generalized Estimating Equation
	Comments	Statistics are from a GEE method including the CGI-I response at each visit as the dependent variable.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	4.4
	Confidence Interval	(2-Sided) 95%; 1.4 to 13.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	For the model parameters estimation, the exchangeable working correlation structure was used.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Part A: SAGE-217, Part B: SAGE-217
	Comments	Day 28
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0227
	Comments
	Method	Generalized Estimating Equation
	Comments	Statistics are from a GEE method including the CGI-I response at each visit as the dependent variable.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.9
	Confidence Interval	(2-Sided) 95%; 1.2 to 12.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	For the model parameters estimation, the exchangeable working correlation structure was used.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Part A: SAGE-217, Part B: SAGE-217
	Comments	Day 35
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1516
	Comments
	Method	Generalized Estimating Equation
	Comments	Statistics are from a GEE method including the CGI-I response at each visit as the dependent variable.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.3
	Confidence Interval	(2-Sided) 95%; 0.7 to 7.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	For the model parameters estimation, the exchangeable working correlation structure was used.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Part A: SAGE-217, Part B: SAGE-217
	Comments	Day 42
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0793
	Comments
	Method	Generalized Estimating Equation
	Comments	Statistics are from a GEE method including the CGI-I response at each visit as the dependent variable.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.7
	Confidence Interval	(2-Sided) 95%; 0.9 to 8.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	For the model parameters estimation, the exchangeable working correlation structure was used.

Adverse Events

Time Frame	Part A: Up to Day 21; Part B: Up to Day 21 and from Day 21 up to Day 42
Adverse Event Reporting Description	AEs included TEAEs and AEs that occurred during post-TEAE period. TEAE was defined as adverse event with onset after the start of study drug, or any worsening of a pre-existing medical condition/adverse event with onset after the start of study drug and until 7 days after the last dose. Post-TEAE period was defined as 7 days after final study drug dose through last follow-up. The safety set included all participants who received at least one dose of the study drug.
Arm/Group Title	Part A: SAGE-217		Part B: Placebo		Part B: SAGE-217
Arm/Group Description	Participants received SAGE-217, 30 mg, oral solution, once daily for 14 days, as tolerated.		Eligible participants received matching placebo capsules once daily for 14 days.		Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.
All Cause Mortality
	Part A: SAGE-217		Part B: Placebo		Part B: SAGE-217
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/44 (0%)		0/45 (0%)
Serious Adverse Events
	Part A: SAGE-217		Part B: Placebo		Part B: SAGE-217
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/44 (0%)		0/45 (0%)
Other (Not Including Serious) Adverse Events
	Part A: SAGE-217		Part B: Placebo		Part B: SAGE-217
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/13 (92.3%)		12/44 (27.3%)		15/45 (33.3%)
Ear and labyrinth disorders
Ear pain	1/13 (7.7%)		0/44 (0%)		0/45 (0%)
Gastrointestinal disorders
Dyspepsia	1/13 (7.7%)		1/44 (2.3%)		1/45 (2.2%)
Diarrhoea	0/13 (0%)		4/44 (9.1%)		0/45 (0%)
Nausea	0/13 (0%)		3/44 (6.8%)		5/45 (11.1%)
General disorders
Fatigue	1/13 (7.7%)		0/44 (0%)		2/45 (4.4%)
Investigations
Alanine aminotransferase increased	1/13 (7.7%)		0/44 (0%)		1/45 (2.2%)
Aspartate aminotransferase increased	1/13 (7.7%)		0/44 (0%)		1/45 (2.2%)
Blood alkaline phosphatase increased	1/13 (7.7%)		0/44 (0%)		1/45 (2.2%)
Musculoskeletal and connective tissue disorders
Myalgia	3/13 (23.1%)		1/44 (2.3%)		0/45 (0%)
Flank pain	1/13 (7.7%)		1/44 (2.3%)		0/45 (0%)
Nervous system disorders
Sedation	6/13 (46.2%)		2/44 (4.5%)		2/45 (4.4%)
Headache	4/13 (30.8%)		8/44 (18.2%)		9/45 (20%)
Somnolence	3/13 (23.1%)		1/44 (2.3%)		3/45 (6.7%)
Dysgeusia	1/13 (7.7%)		0/44 (0%)		0/45 (0%)
Muscle contractions involuntary	1/13 (7.7%)		0/44 (0%)		0/45 (0%)
Dizziness	3/13 (23.1%)		1/44 (2.3%)		5/45 (11.1%)
Psychiatric disorders
Euphoric mood	1/13 (7.7%)		0/44 (0%)		1/45 (2.2%)
Libido increased	1/13 (7.7%)		0/44 (0%)		0/45 (0%)
Irritability	0/13 (0%)		3/44 (6.8%)		0/45 (0%)
Renal and urinary disorders
Chromaturia	0/13 (0%)		4/44 (9.1%)		1/45 (2.2%)
Reproductive system and breast disorders
Vaginal discharge	1/13 (7.7%)		0/44 (0%)		0/45 (0%)
Respiratory, thoracic and mediastinal disorders
Nasal congestion	2/13 (15.4%)		0/44 (0%)		0/45 (0%)
Skin and subcutaneous tissue disorders
Pruritus	1/13 (7.7%)		2/44 (4.5%)		1/45 (2.2%)
Vascular disorders
Hot flush	1/13 (7.7%)		0/44 (0%)		1/45 (2.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The PI can either be a party and subject to the same restrictions as the institution, or if not a party, the restrictions are described on the face of the contract (i.e., PI is a contractor of the institution; PI is part of a larger group of study personnel; institution has contracted with or otherwise bound all study personnel under confidentiality obligations and requirements to vest intellectual property to the institution).