Safety, Tolerability, PK Profile, and Symptom Response of a 7-Day Dosing With 25 mg or 50 mg Daily of REL-1017 in MDD

• Sponsor: Relmada Therapeutics, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03051256
• Collaborator: Syneos Health (Other)
• Enrollment: 62
• Locations: 10
• Arms: 3
• Actual Duration (Months): 16.7
• Patients Per Site: 6.2
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

This a Phase 2a, multicenter, randomized, double-blind, placebo controlled 3 arm study to assess the safety and tolerability of multiple oral doses of REL-1017 25 mg and 50 mg as adjunctive therapy in the treatment of patients diagnosed with major depressive disorder (MDD). The patients will be adults with MDD who are diagnosed with a current MDE who have experienced an inadequate response to 1 to 3 courses of treatment with an antidepressant medication. This population will provide the opportunity to compare the safety and efficacy effects of treatment with an approved antidepressant in conjunction with REL-1017 versus the effects of an antidepressant alone. This study includes in-patient and out-patient periods.

Condition or Disease	Intervention/Treatment	Phase
Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant	Drug: REL-1017; Drug: Placebo	Phase 2

Detailed Description

Currently available medications have proven to be useful for the treatment of depression, but also have limitations including low response rates, a significant number of treatment resistant patients, and time-lag for response, which emphasizes a major unmet need for more efficacious and faster-acting antidepressants. Recent studies have demonstrated that ketamine, a non-competitive glutamate-N-methyl-D-Aspartate (NMDA) receptor antagonist, produces rapid onset (2 hours) and long-lasting (7 days) antidepressant actions in treatment resistant patients. This rapid action, by a mechanism completely different from typical monoamine reuptake inhibitors, represents a significant finding in the field of depression.

Racemic methadone, the 50/50 combination of d-methadone and l-methadone, has been in widespread use for decades and has been studied extensively. Methadone is currently approved for use in the management of severe pain, detoxification treatment of opioid addiction, and maintenance treatment of opioid addiction.

The results of a study evaluating the receptor binding profiles of racemic methadone and its stereoisomers suggest that d-methadone does not essentially contribute to the opioid effect of racemic methadone and that it has a 10 times lower affinity for the mu1, mu2, and delta opioid receptors compared to l-methadone. Racemic methadone and its d- and l isomers exhibit similar affinities for the non-competitive binding site of the NMDA receptor and are non-competitive NMDA receptor antagonists.

In the forced swim test, a rodent behavioral model of antidepressant activity, both ketamine and d-methadone at all doses tested significantly decreased the immobility of the rats compared to the vehicle suggesting antidepressant like activity. Neither drug increased spontaneous locomotor activity.

Relmada has conducted 2 clinical studies to identify the dose levels of REL-1017 (d-methadone) that have little to no opioid effects and that are expected to possess NMDA antagonistic properties for the evaluation of oral REL-1017 in the treatment of MDD and neuropathic pain conditions. Initial Phase 1 single ascending dose and multiple ascending dose clinical studies of REL-1017 were designed to evaluate the safety and tolerance of the pure d methadone isomer in healthy opioid-naïve subjects and identify a safe and potentially effective dose range in this population. These studies showed that REL-1017 was safe and well-tolerated at single oral doses up to 150 mg (maximum tolerated dose) and up to 75 mg administered once daily for 10 days in healthy opioid-naïve subjects.

The pre-clinical and previous clinical experience with REL-1017 (d-methadone) provided the basis for the initiation of the present study, which will extend the evaluation of the safety, tolerability, and PK of REL-1017 at 2 doses with repeated administration to depressed patients. Since REL-1017 is proposed for use as adjunctive therapy in the treatment of patients diagnosed with major depressive disorder (MDD), the patients will be male adults with MDD who are diagnosed with a current depressive episode who have experienced an inadequate response to 1 to 3 courses of treatment with an antidepressant medication.

Based on the safety data from Protocol REL-1017-111, single doses of 5 mg, 20 mg, 60 mg, 100 mg, and 150 mg of REL-1017 or placebo were well tolerated. The results of Protocol REL-1017-112 evaluated 10 days of dosing with 25 mg, 50 mg and 75 mg of REL-1017 or placebo, and no impact on safety was observed. In spite of the confirmed dose proportionality, the comparison of concentration and exposure between the 50 mg and 75 mg REL-1017 treatment groups demonstrated only slight differences. Consequently, 25 mg and 50 mg doses were chosen for administration in Protocol REL-1017-202 as single daily doses over a period of 7 days.

Thus, as a single isomer of racemic methadone, d-methadone has been shown to possess NMDA antagonist properties with virtually no opioid activity or ketamine-like toxicities at the expected therapeutic doses.

In this study, adult male patients with MDD who are diagnosed with a current MDE and who have experienced an inadequate response to 1 to 3 courses of treatment with an antidepressant medication will be randomized to study drug in a 1:1:1 ratio. Approximately 15 patients each will receive REL-1017 25 mg, REL-1017 50 mg, or placebo once daily for 7 days. Endpoints include assessments of safety, tolerability, efficacy and pharmacokinetics of REL-1017. Patients will be required to stay in the clinic for 10 days and will then be followed as an outpatient for 12 additional days.

Study Design

• Study Type: Interventional
• Actual Enrollment: 62 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Phase 2a Multicenter Randomized Double-Blind Placebo-Controlled Study to Assess the Safety, Tolerability, PK Profile, and Symptom Response of a 7-Day Dosing of REL-1017 as Adjunctive Therapy in the Treatment of Pts Diagnosed With MDD
• Actual Study Start Date: May 11, 2018
• Actual Primary Completion Date: Jul 30, 2019
• Actual Study Completion Date: Sep 30, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: REL-1017 25 mg REL-1017 75 mg of powder in 100 mL of Ocean Spray® Diet Cranberry Juice daily on Day 1, 25 mg of powder in 100 mL Ocean Spray® Diet Cranberry Juice daily on Day 2-7.	Drug: REL-1017; REL-1017 will be administered as an oral solution. Patients will continue to take the same, stabilized antidepressant medication that they were taking at screening throughout the course of the study.; Other Names: d-Methadone
Experimental: REL-1017 50 mg REL-1017 100 mg of powder in 100 mL of Ocean Spray® Diet Cranberry Juice daily on Day 1, 50 mg of powder in 100 mL Ocean Spray® Diet Cranberry Juice daily on Day 2-7.	Drug: REL-1017; REL-1017 will be administered as an oral solution. Patients will continue to take the same, stabilized antidepressant medication that they were taking at screening throughout the course of the study.; Other Names: d-Methadone
Placebo Comparator: Placebo 100 mL Ocean Spray® Diet Cranberry Juice will be administered as a single oral dose daily for 7 days.	Drug: Placebo; Placebo will be administered as an oral solution. Patients will continue to take the same, stabilized antidepressant medication that they were taking at screening throughout the course of the study.

Outcome Measures

Primary Outcome Measures

1. Incidence of Treatment Emergent Adverse Events (AEs) [Safety and Tolerability] [21 days]

   Spontaneously reported or observed AEs will be recorded and reported throughout the study, and AEs will be elicited using a non-leading question at every visit from Screening through the Day 21 assessment. An AE was any untoward medical occurrence in a patient or clinical investigation patient administered a pharmaceutical product and may not necessarily have a causal relationship with the administered treatment. An AE could therefore be any unfavorable and unintended sign (including a clinically significant laboratory abnormality, for example), symptom, or disease temporally associated with the use of a medicinal (investigational) product, regardless of relationship to the medicinal (investigational) product. During the study, an AE could also occur outside the time that the investigational product(s) was given (e.g., during the time from discontinuation of prohibited medications).

Secondary Outcome Measures

1. ECG Parameters [Safety] [Screening, Day -1, Day 1 hour 2, 8, Day 2 hour 2, 8, Day 3-7 hour 2, Day 8, Day 9, and Day 14]

   12-Lead ECGs will be performed and reported at Screening; at Check In (Day -1); Days 1 through 9; and at Day 14.

2. Columbia Suicide Severity Rating Scale (C-SSRS) [Safety and Tolerability] [Day -1, Day 1, Day 2, Day 8, Day 9 and Day 14]

   The C-SSRS will be administered and reported at Screening and Check In (Day -1); and at Days 1, 2, 8, 9 and 14. The C-SSRS is routinely used to quantify the severity of suicidal ideation and behavior. Both the ideation and behavior subscales are sensitive to change over time. The scale identifies behaviors that may be indicative of an individual's intent to commit suicide. This measure contains 6 "yes" or "no" questions in which respondents are asked to indicate whether they have experienced several thoughts or feelings relating to suicide over the past month. Each question addresses a different component of the respondent's suicide ideation severity: (1) Desire to be dead; (2) Suicidal thoughts; (3) Consideration of suicide methods; (4) Formed intent to commit suicide; (5) Completed suicide plan; and (6) Initiated suicide plan. A higher score indicates a higher intensity of suicidal ideation.

3. Montgomery-Asberg Depression Scale (MADRS) [Change from Baseline to Day 7]

   Montgomery-Asberg Depression Scale (MADRS) will be administered and reported on Days 4, 7, and 14. The MADRS questionnaire includes questions on the following symptoms: (1) Apparent sadness; (2) Reported sadness; (3) Inner tension; (4) Reduced sleep; (5) Reduced appetite; (6) Concentration difficulties; (7) Lassitude; (8) Inability to feel; (9) Pessimistic thoughts; (10) Suicidal thoughts. A higher MADRS score indicates more severe depression, and each item yields a score of 0 to 6. The overall score ranges from 0 to 60 with scores above 34 indicating severe depression. In Study REL-1017-202, the MADRS was administered using the Structured Interview Guide for the MADRS (SIGMA). A negative change from baseline indicates improvement.

4. Montgomery-Asberg Depression Scale (MADRS) [Change from Baseline to Day 14]

   Montgomery-Asberg Depression Scale (MADRS) will be administered and reported on Days 4, 7, and 14. The MADRS questionnaire includes questions on the following symptoms: (1) Apparent sadness; (2) Reported sadness; (3) Inner tension; (4) Reduced sleep; (5) Reduced appetite; (6) Concentration difficulties; (7) Lassitude; (8) Inability to feel; (9) Pessimistic thoughts; (10) Suicidal thoughts. A higher MADRS score indicates more severe depression, and each item yields a score of 0 to 6. The overall score ranges from 0 to 60 with scores above 34 indicating severe depression. In Study REL-1017-202, the MADRS was administered using the Structured Interview Guide for the MADRS (SIGMA). A negative change from baseline indicates improvement.

5. Symptoms of Depression Questionnaire (SDQ) [Change from Baseline to Day 7]

   Symptoms of Depression Questionnaire (SDQ) will be administered and reported on Days 4, 7, and 14. The SDQ is a 44-item, self-report scale designed to measure the severity of symptoms across several subtypes of depression. The SDQ was developed to more fully capture the heterogeneity of symptom presentations of depressive disorders than current, widely used scales for MDD. The SDQ includes items that inquire about an extensive number of depressive symptoms beyond the ones included in other commonly used scales. The 44 SDQ items are rated on a 6-point scale. The total score is the sum of 44 items and can range from 44 to 264. A negative change from baseline indicates improvement. 1 = Better than Normal; 2= Normal; 3= Minimally Sad; 4= Moderately Sad; 5= Markedly Sad; 6= Extremely Sad

6. Symptoms of Depression Questionnaire (SDQ) [Change from Baseline to Day 14]

   Symptoms of Depression Questionnaire (SDQ) will be administered and reported on Days 4, 7, and 14. The SDQ is a 44-item, self-report scale designed to measure the severity of symptoms across several subtypes of depression. The SDQ was developed to more fully capture the heterogeneity of symptom presentations of depressive disorders than current, widely used scales for MDD. The SDQ includes items that inquire about an extensive number of depressive symptoms beyond the ones included in other commonly used scales. The 44 SDQ items are rated on a 6-point scale. The total score is the sum of 44 items and can range from 44 to 264. A negative change from baseline indicates improvement. 1 = Better than Normal; 2= Normal; 3= Minimally Sad; 4= Moderately Sad; 5= Markedly Sad; 6= Extremely Sad

7. Clinical Global Impressions of Severity (CGI-S) [Change from Baseline to Day 7]

   Clinical Global Impressions of Severity (CGI-S) will be administered and reported on Days 4, 7, and 14. The CGI-S is a standard method used in clinical studies to quantify and track patient progress and treatment response over time. The scale is composed of 7 ratings: 1 = normal, not at all ill; 2 = borderline ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill patients. The score ranges from 1 to 7, and a lower CGI-S score indicates lower levels of depression.

8. Clinical Global Impressions of Severity (CGI-S) [Change from Baseline to Day 14]

   Clinical Global Impressions of Severity (CGI-S) will be administered and reported on Days 4, 7, and 14. The CGI-S is a standard method used in clinical studies to quantify and track patient progress and treatment response over time. The scale is composed of 7 ratings: 1 = normal, not at all ill; 2 = borderline ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill patients. The score ranges from 1 to 7, and a lower CGI-S score indicates lower levels of depression.

9. Clinical Global Impressions of Improvement (CGI-I) [Change from Baseline to Day 7]

   Clinical Global Impressions of Improvement (CGI-I) will be administered and reported at Days 4, 7 and 14. The CGI-I is a standard method used in clinical studies to quantify and track patient change over time. The scale is composed of 7 ratings: 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 score ranges from 1 to 7, and a lower CGI-I score indicates greater improvement in symptoms.

10. Clinical Global Impressions of Improvement (CGI-I) [Change from Baseline to Day 14]

    Clinical Global Impressions of Improvement (CGI-I) will be administered and reported at Days 4, 7 and 14. The CGI-I is a standard method used in clinical studies to quantify and track patient change over time. The scale is composed of 7 ratings: 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 score ranges from 1 to 7, and a lower CGI-I score indicates greater improvement in symptoms.

11. Maximum Observed Plasma Concentration (Cmax) [Pharmacokinetic] [Day 1 (hour -1, 1, 2, 4, 6, 8, 12, and 24)]

    The pharmacokinetic parameters of REL-1017 25 mg and 50 mg will be evaluated on Day 1 through Day 7, Day 8, Day 9, and Day 14 where the data allow.

12. Area Under the Plasma Concentration-time Curve From Time Zero Until the Dosing Interval of 24 Hours (AUCtau) [Pharmacokinetic] [Day 1 (hour -1, 1, 2, 4, 6, 8, 12, and 24)]

    The pharmacokinetic parameters of REL-1017 25 mg and 50 mg will be evaluated on Day 1 through Day 7, Day 8, Day 9, and Day 14 where the data allow.

13. Time to Maximum Observed Plasma Concentration (Tmax) [Pharmacokinetic] [Day 1 (hour -1, 1, 2, 4, 6, 8, 12, and 24)]

    The pharmacokinetic parameters of REL-1017 25 mg and 50 mg will be evaluated on Day 1 through Day 7, Day 8, Day 9, and Day 14 where the data allow.

14. Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) [Pharmacokinetic] [Day 1 (hour -1, 1, 2, 4, 6, 8, 12, and 24)]

    The pharmacokinetic parameters of REL-1017 25 mg and 50 mg will be evaluated on Day 1 through Day 7, Day 8, Day 9, and Day 14 where the data allow.

15. Apparent Terminal Elimination Half-life (t½) [Pharmacokinetic] [Day 1 (hour -1, 1, 2, 4, 6, 8, 12, and 24) and Day 7 (hour 24, 48, and 168 post last dose)]

    The pharmacokinetic parameters of REL-1017 25 mg and 50 mg will be evaluated on Day 1 through Day 7, Day 8, Day 9, and Day 14 where the data allow.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Males between 18 and 65 years of age, inclusive; and females between 18 and 65 years of age, inclusive, who are >1 year postmenopausal.

2. Diagnosed with recurrent MDD as defined by the Diagnostic and Statistical Manual, Fifth Edition (DSM-5), and confirmed by the Mini International Neuropsychiatric Interview, Version 7.0.2 (MINI).

3. Diagnosed with a current MDE lasting 8 weeks to 36 months as defined by the DSM-5 and confirmed by the MINI.

4. Treated with an adequate dosage of a SSRI, SNRI, or bupropion during the current MDE for at least 8 weeks prior to Screening with the same, adequate dosage for the last 4 weeks. Minimum adequate doses are defined in the (ATRQ). The maximum dose allowed for paroxetine is 40 mg QD, for fluoxetine is 60 mg QD, and for sertraline is 200 mg QD.

5. Have experienced an inadequate response to 1 to 3 courses of treatment with an antidepressant medication in the current episode, as defined as <50% improvement with an antidepressant medication at doses listed on the SAFER Interview Criteria: State versus trait; Assessability; Face validity; Ecological validity; and Rule of three Ps (pervasive, persistent, and pathological).

6. Hamilton Depression Rating Scale-17 (HAM-D-17) ≥19 at Screening and Check-in (Day -1).

7. BMI between 18.0 and 35.0 kg/m2, inclusive, and a minimum weight of 50.0 kg.

8. Per the Investigator's judgment, able to meet all study requirements, including the confined/inpatient portion of the study, adherence with both approved ADT and study drug regimen, and completion of all assessments and all scheduled visits.

9. Male patients of reproductive potential must be using and willing to continue using medically acceptable contraception, from Screening and for at least 2 months after the last study drug administration.

10. Must be able to read, speak, and understand English and must provide written informed consent prior to the initiation of any protocol-specific procedures.

Exclusion Criteria:

1. History or presence of clinically significant abnormality as assessed by physical examination, medical history, 12-lead ECG, vital signs, or laboratory values, which in the opinion of the Investigator would jeopardize the safety of the patient or the validity of the study results, including torsades de pointes, any bradyarrhythmias, or uncompensated heart failure.

2. Chronic use of prescribed opioids (i.e., >120 days in a 6-month period) up to 6 months prior to Screening or any recreational use of opioids.

3. Evidence of clinically significant hepatic or renal impairment, including ALT or AST

1.5 x upper limit of normal (ULN), bilirubin >1 x ULN, or endocrine laboratory values (including clinically significant thyroid parameters, i.e., thyroid stimulating hormone [TSH], triiodothyronine [T3], and thyroxine [T4]).

1. History or family history of sudden unexplained death or long QT syndrome (measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle).

2. Any 12-lead ECG with repeated demonstration of QTc ≥450 msec or a QRS interval >120 msec at Screening.

3. History of clinically diagnosed hypotension requiring treatment.

4. History or presence of any condition in which an opioid is contraindicated (e.g., significant respiratory depression, acute or severe bronchial asthma or hypercarbia, bronchitis, or has/is suspected of having paralytic ileus).

5. No more than 3 prescribed doses of an opioid within the 6 months prior to Screening and no use at all within the last month.

6. Use of an antipsychotic, anticonvulsant, or mood stabilizer, regardless of indication, within the 3 months prior to Screening.

7. History of allergy or hypersensitivity to methadone or related drugs (e.g., opioids).

8. Positive test for hepatitis B or HIV. Patients with a positive hepatitis C test may be considered for inclusion with approval from the Medical Monitor.

9. Any current and primary psychiatric disorder, as defined as a condition that is the primary focus of distress and/or treatment, other than MDD.

10. Any lifetime history of bipolar I or II disorder, any psychotic disorder, post-traumatic stress disorder, borderline personality disorder, antisocial personality disorder, obsessive compulsive disorder, eating disorder, intellectual disability, or pervasive developmental disorder.

11. History in the past 12 months of a primary diagnosis of anxiety disorder or panic disorder not related to the current MDE.

12. Current diagnosis of alcohol or substance use disorder, as defined by DSM-5, at Screening or within the 12 months prior to Screening. Patients with the following diagnoses within the past 12 months, however, may be included at the Investigator's discretion: mild alcohol use disorder, mild cannabis use disorder, and any severity tobacco use disorder.

13. A confirmed positive result on the urine drug/alcohol screen at Screening or Check-in. If the urine drug/alcohol screen is positive at Screening, retesting or rescreening may be scheduled with prior approval from the Medical Monitor.

14. Patients who, in the Investigator's judgment, are at significant risk for suicide. A patient with a Columbia-Suicide Severity Rating Scale (C-SSRS) ideation score of 4 or 5 within the last 6 months or any suicide attempt within the past year must be excluded, as should a patient with an ideation score of 4 or 5 or any suicide attempt at the Check-in or Baseline Visit.

15. Patients with a 20% improvement between Screening and Check-in (Day -1) on the HAM-D-17.

16. Patients who did not safely discontinue medications prohibited.

17. Patients receiving new onset psychotherapy (individual, group, marriage, or family therapy) within 2 months prior to Screening or plans to start at any time during participation in the study.

18. Patients who have received electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), or vagus nerve stimulation (VNS) or who have participated in a ketamine study within the last 6 months.

19. Patients with any clinically significant neurological, hepatic, renal, metabolic, hematological, immunological, cardiovascular, pulmonary, chronic pain, or gastrointestinal disorder. Medical conditions that are minor or well-controlled may be permitted if they will not increase the safety risk to the patient or compromise interpretation of the safety or efficacy endpoints.

20. Patients taking fluvoxamine or St. John's Wort.

21. Patients who have participated in a clinical study with an investigational medication in the past 6 months, or who have participated in more than 4 clinical studies with investigational medications in the past 2 years.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Woodland International Research Group	Little Rock	Arkansas	United States	72211
2	Collaborative Neuroscience Network, LLC	Garden Grove	California	United States	92845-2506
3	Artemis Institute for Clinical Research	San Diego	California	United States	92103
4	Innovative Clinical Research, Inc	Hialeah	Florida	United States	33012
5	Atlanta Center for Medical Research	Atlanta	Georgia	United States	30331
6	iResearch Atlanta, LLC	Decatur	Georgia	United States	30030
7	St. Louis Clinical Trials, LLC	Saint Louis	Missouri	United States	63141
8	Hassman Research Institute	Berlin	New Jersey	United States	08009
9	Midwest Clinical Research Center	Dayton	Ohio	United States	45417-3445
10	Pillar Clinical Research, LLC	Richardson	Texas	United States	75080

Sponsors and Collaborators

• Relmada Therapeutics, Inc.
• Syneos Health

Investigators

• Study Chair: Maurizio Fava, MD, KOL / Advisor

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 7, 2019

More Information

Publications

None provided.

• Responsible Party: Relmada Therapeutics, Inc.
• ClinicalTrials.gov Identifier: NCT03051256
• Other Study ID Numbers: REL-1017-202
• First Posted: Feb 13, 2017
• Last Update Posted: Mar 17, 2021
• Last Verified: Mar 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Relmada Therapeutics, Inc.: REL-1017; d-Methadone; Methadone; Depression; Refractory Depression; Antidepressant; Adjunctive Treatment; NMDA Receptor Antagonist; Excitatory Amino Acid Antagonist; Glutamate Antagonist
• Additional relevant MeSH terms: Disease; Depressive Disorder; Depression; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant; Methadone; D-methadone

Study Results

Participant Flow

Arm/Group Title	REL-1017 25 mg	REL-1017 50 mg	Placebo
Arm/Group Description	Loading dose of REL-1017 75 mg of powder in 100 mL of cranberry juice on Day 1, Maintenance dose of REL-1017 25 mg of powder in 100 mL cranberry juice daily on Days 2-7. REL-1017: REL-1017 administered as an oral solution. Patients continued to take the first line stable dose of antidepressant medication.	Loading dose of REL-1017 100 mg of powder in 100 mL of cranberry juice on Day 1, Maintenance dose of REL-1017 50 mg of powder in 100 mL cranberry juice daily on Days 2-7. REL-1017: REL-1017 administered as an oral solution. Patients continued to take the first line stable dose of antidepressant medication.	100 mL cranberry juice was administered as a single oral dose daily for 7 days. Placebo: Placebo was administered as an oral solution. Patients continued to take the first line stable dose of antidepressant medication.
Period Title: Overall Study
STARTED	19	21	22
COMPLETED	19	21	21
NOT COMPLETED	0	0	1

Baseline Characteristics

Arm/Group Title	REL-1017 25 mg	REL-1017 50 mg	Placebo	Total
Arm/Group Description	Loading dose of REL-1017 75 mg of powder in 100 mL of cranberry juice on Day 1, Maintenance dose of REL-1017 25 mg of powder in 100 mL cranberry juice daily on Days 2-7. REL-1017: REL-1017 administered as an oral solution. Patients continued to take the first line stable dose of antidepressant medication.	Loading dose of REL-1017 100 mg of powder in 100 mL of cranberry juice on Day 1, Maintenance dose of REL-1017 50 mg of powder in 100 mL cranberry juice daily on Days 2-7. REL-1017: REL-1017 administered as an oral solution. Patients continued to take the first line stable dose of antidepressant medication.	100 mL cranberry juice was administered as a single oral dose daily for 7 days. Placebo: Placebo was administered as an oral solution. Patients continued to take the first line stable dose of antidepressant medication.	Total of all reporting groups
Overall Participants	19	21	22	62
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	19 100%	21 100%	22 100%	62 100%
>=65 years	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	49.4 (12.4)	48.6 (10.9)	49.7 (11.1)	49.2 (11.3)
Sex: Female, Male (Count of Participants)
Female	8 42.1%	9 42.9%	11 50%	28 45.2%
Male	11 57.9%	12 57.1%	11 50%	34 54.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	1 4.8%	0 0%	1 1.6%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	13 68.4%	13 61.9%	13 59.1%	39 62.9%
White	6 31.6%	7 33.3%	9 40.9%	22 35.5%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	19 100%	21 100%	22 100%	62 100%
BMI (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	27.66 (3.33)	27.66 (5)	29.02 (4.27)	28.15 (4.26)

Outcome Measures

1. Primary Outcome

Title	Incidence of Treatment Emergent Adverse Events (AEs) [Safety and Tolerability]
Description	Spontaneously reported or observed AEs will be recorded and reported throughout the study, and AEs will be elicited using a non-leading question at every visit from Screening through the Day 21 assessment. An AE was any untoward medical occurrence in a patient or clinical investigation patient administered a pharmaceutical product and may not necessarily have a causal relationship with the administered treatment. An AE could therefore be any unfavorable and unintended sign (including a clinically significant laboratory abnormality, for example), symptom, or disease temporally associated with the use of a medicinal (investigational) product, regardless of relationship to the medicinal (investigational) product. During the study, an AE could also occur outside the time that the investigational product(s) was given (e.g., during the time from discontinuation of prohibited medications).
Time Frame	21 days

Outcome Measure Data

Analysis Population Description

Safety population: All randomized patients who received any study treatment (REL-1017 or placebo).

Arm/Group Title	REL-1017 25 mg	REL-1017 50 mg	Placebo
Arm/Group Description	Loading dose of REL-1017 75 mg of powder in 100 mL of cranberry juice on Day 1, Maintenance dose of REL-1017 25 mg of powder in 100 mL cranberry juice daily on Days 2-7. REL-1017: REL-1017 administered as an oral solution. Patients continued to take the first line stable dose of antidepressant medication.	Loading dose of REL-1017 100 mg of powder in 100 mL of cranberry juice on Day 1, Maintenance dose of REL-1017 50 mg of powder in 100 mL cranberry juice daily on Days 2-7. REL-1017: REL-1017 administered as an oral solution. Patients continued to take the first line stable dose of antidepressant medication.	100 mL cranberry juice was administered as a single oral dose daily for 7 days. Placebo: Placebo was administered as an oral solution. Patients continued to take the first line stable dose of antidepressant medication.
Measure Participants	19	21	22
All-causality TEAEs	9 47.4%	15 71.4%	12 54.5%
All-causality SAEs	0 0%	0 0%	0 0%

2. Secondary Outcome

Title	ECG Parameters [Safety]
Description	12-Lead ECGs will be performed and reported at Screening; at Check In (Day -1); Days 1 through 9; and at Day 14.
Time Frame	Screening, Day -1, Day 1 hour 2, 8, Day 2 hour 2, 8, Day 3-7 hour 2, Day 8, Day 9, and Day 14

Outcome Measure Data

Analysis Population Description

Safety population: All randomized patients who received any study treatment (REL-1017 or placebo).

Arm/Group Title	REL-1017 25 mg	REL-1017 50 mg	Placebo
Arm/Group Description	Loading dose of REL-1017 75 mg of powder in 100 mL of cranberry juice on Day 1, Maintenance dose of REL-1017 25 mg of powder in 100 mL cranberry juice daily on Days 2-7. REL-1017: REL-1017 administered as an oral solution. Patients continued to take the first line stable dose of antidepressant medication.	Loading dose of REL-1017 100 mg of powder in 100 mL of cranberry juice on Day 1, Maintenance dose of REL-1017 50 mg of powder in 100 mL cranberry juice daily on Days 2-7. REL-1017: REL-1017 administered as an oral solution. Patients continued to take the first line stable dose of antidepressant medication.	100 mL cranberry juice was administered as a single oral dose daily for 7 days. Placebo: Placebo was administered as an oral solution. Patients continued to take the first line stable dose of antidepressant medication.
Measure Participants	19	21	22
Normal	14 73.7%	19 90.5%	16 72.7%
Abnormal (not clinically significant)	5 26.3%	2 9.5%	6 27.3%
Abnormal (clinically significant)	0 0%	0 0%	0 0%
Normal	17 89.5%	19 90.5%	20 90.9%
Abnormal (not clinically significant)	2 10.5%	2 9.5%	2 9.1%
Abnormal (clinically significant)	0 0%	0 0%	0 0%
Normal	16 84.2%	18 85.7%	20 90.9%
Abnormal (not clinically significant)	3 15.8%	3 14.3%	2 9.1%
Abnormal (clinically significant)	0 0%	0 0%	0 0%
Normal	15 78.9%	18 85.7%	20 90.9%
Abnormal (not clinically significant)	4 21.1%	3 14.3%	2 9.1%
Abnormal (clinically significant)	0 0%	0 0%	0 0%
Normal	15 78.9%	19 90.5%	20 90.9%
Abnormal (not clinically significant)	4 21.1%	2 9.5%	2 9.1%
Abnormal (clinically significant)	0 0%	0 0%	0 0%
Normal	15 78.9%	19 90.5%	19 86.4%
Abnormal (not clinically significant)	4 21.1%	2 9.5%	2 9.1%
Abnormal (clinically significant)	0 0%	0 0%	0 0%
Normal	14 73.7%	19 90.5%	18 81.8%
Abnormal (not clinically significant)	5 26.3%	2 9.5%	3 13.6%
Abnormal (clinically significant)	0 0%	0 0%	0 0%
Normal	15 78.9%	19 90.5%	19 86.4%
Abnormal (not clinically significant)	4 21.1%	2 9.5%	2 9.1%
Abnormal (clinically significant)	0 0%	0 0%	0 0%
Normal	13 68.4%	19 90.5%	17 77.3%
Abnormal (not clinically significant)	6 31.6%	2 9.5%	4 18.2%
Abnormal (clinically significant)	0 0%	0 0%	0 0%
Normal	15 78.9%	18 85.7%	18 81.8%
Abnormal (not clinically significant)	4 21.1%	3 14.3%	3 13.6%
Abnormal (clinically significant)	0 0%	0 0%	0 0%
Normal	15 78.9%	16 76.2%	19 86.4%
Abnormal (not clinically significant)	4 21.1%	5 23.8%	2 9.1%
Abnormal (clinically significant)	0 0%	0 0%	0 0%
Normal	15 78.9%	17 81%	19 86.4%
Abnormal (not clinically significant)	4 21.1%	4 19%	2 9.1%
Abnormal (clinically significant)	0 0%	0 0%	0 0%
Normal	14 73.7%	18 85.7%	19 86.4%
Abnormal (not clinically significant)	5 26.3%	3 14.3%	2 9.1%
Abnormal (clinically significant)	0 0%	0 0%	0 0%
Normal	15 78.9%	17 81%	18 81.8%
Abnormal (not clinically significant)	3 15.8%	2 9.5%	3 13.6%
Abnormal (clinically significant)	0 0%	0 0%	0 0%

3. Secondary Outcome

Title	Columbia Suicide Severity Rating Scale (C-SSRS) [Safety and Tolerability]
Description	The C-SSRS will be administered and reported at Screening and Check In (Day -1); and at Days 1, 2, 8, 9 and 14. The C-SSRS is routinely used to quantify the severity of suicidal ideation and behavior. Both the ideation and behavior subscales are sensitive to change over time. The scale identifies behaviors that may be indicative of an individual's intent to commit suicide. This measure contains 6 "yes" or "no" questions in which respondents are asked to indicate whether they have experienced several thoughts or feelings relating to suicide over the past month. Each question addresses a different component of the respondent's suicide ideation severity: (1) Desire to be dead; (2) Suicidal thoughts; (3) Consideration of suicide methods; (4) Formed intent to commit suicide; (5) Completed suicide plan; and (6) Initiated suicide plan. A higher score indicates a higher intensity of suicidal ideation.
Time Frame	Day -1, Day 1, Day 2, Day 8, Day 9 and Day 14

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	REL-1017 25 mg	REL-1017 50 mg	Placebo
Arm/Group Description	Loading dose of REL-1017 75 mg of powder in 100 mL of cranberry juice on Day 1, Maintenance dose of REL-1017 25 mg of powder in 100 mL cranberry juice daily on Days 2-7. REL-1017: REL-1017 administered as an oral solution. Patients continued to take the first line stable dose of antidepressant medication.	Loading dose of REL-1017 100 mg of powder in 100 mL of cranberry juice on Day 1, Maintenance dose of REL-1017 50 mg of powder in 100 mL cranberry juice daily on Days 2-7. REL-1017: REL-1017 administered as an oral solution. Patients continued to take the first line stable dose of antidepressant medication.	100 mL cranberry juice was administered as a single oral dose daily for 7 days. Placebo: Placebo will be administered as an oral solution. Patients continued to take the first line stable dose of antidepressant medication.
Measure Participants	19	21	22
Participants with Suicidal Ideation (Any Score 1-5) : Day -1 (Check-in)	1 5.3%	0 0%	5 22.7%
Participants with Suicidal Ideation (Any Score 1-5) : Day 1 (Baseline)	1 5.3%	0 0%	5 22.7%
Participants with Suicidal Ideation (Any Score 1-5) : Day 2	0 0%	0 0%	0 0%
Participants with Suicidal Ideation (Any Score 1-5) : Day 8	0 0%	1 4.8%	1 4.5%
Participants with Suicidal Ideation (Any Score 1-5) : Day 9 (Discharge)	0 0%	1 4.8%	1 4.5%
Participants with Suicidal Ideation (Any Score 1-5) : Day 14	1 5.3%	1 4.8%	1 4.5%
Participants with Suicidal Behavior (any) : Day -1 (Check-in)	0 0%	0 0%	0 0%
Participants with Suicidal Behavior (any) : Day 1 (Baseline)	0 0%	0 0%	0 0%
Participants with Suicidal Behavior (any) : Day 2	0 0%	0 0%	0 0%
Participants with Suicidal Behavior (any) : Day 8	0 0%	0 0%	0 0%
Participants with Suicidal Behavior (any) : Day 9 (Discharge)	0 0%	0 0%	0 0%
Participants with Suicidal Behavior (any) : Day 14	0 0%	0 0%	0 0%

4. Secondary Outcome

Title	Montgomery-Asberg Depression Scale (MADRS)
Description	Montgomery-Asberg Depression Scale (MADRS) will be administered and reported on Days 4, 7, and 14. The MADRS questionnaire includes questions on the following symptoms: (1) Apparent sadness; (2) Reported sadness; (3) Inner tension; (4) Reduced sleep; (5) Reduced appetite; (6) Concentration difficulties; (7) Lassitude; (8) Inability to feel; (9) Pessimistic thoughts; (10) Suicidal thoughts. A higher MADRS score indicates more severe depression, and each item yields a score of 0 to 6. The overall score ranges from 0 to 60 with scores above 34 indicating severe depression. In Study REL-1017-202, the MADRS was administered using the Structured Interview Guide for the MADRS (SIGMA). A negative change from baseline indicates improvement.
Time Frame	Change from Baseline to Day 7

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	REL-1017 25 mg	REL-1017 50 mg	Placebo
Arm/Group Description	Loading dose of REL-1017 75 mg of powder in 100 mL of cranberry juice on Day 1, Maintenance dose of REL-1017 25 mg of powder in 100 mL cranberry juice daily on Days 2-7. REL-1017: REL-1017 administered as an oral solution. Patients continued to take the first line stable dose of antidepressant medication.	Loading dose of REL-1017 100 mg of powder in 100 mL of cranberry juice on Day 1, Maintenance dose of REL-1017 50 mg of powder in 100 mL cranberry juice daily on Days 2-7. REL-1017: REL-1017 administered as an oral solution. Patients continued to take the first line stable dose of antidepressant medication.	100 mL cranberry juice was administered as a single oral dose daily for 7 days. Placebo: Placebo was administered as an oral solution. Patients continued to take the first line stable dose of antidepressant medication.
Measure Participants	19	21	21
Least Squares Mean (Standard Error) [score on a scale]	-17.4 (2.5)	-15.9 (2.4)	-8.7 (2.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	REL-1017 25 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0122
	Comments
	Method	Mixed Models Analysis
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	REL-1017 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0308
	Comments
	Method	Mixed Models Analysis
	Comments

5. Secondary Outcome

Title	Montgomery-Asberg Depression Scale (MADRS)
Description	Montgomery-Asberg Depression Scale (MADRS) will be administered and reported on Days 4, 7, and 14. The MADRS questionnaire includes questions on the following symptoms: (1) Apparent sadness; (2) Reported sadness; (3) Inner tension; (4) Reduced sleep; (5) Reduced appetite; (6) Concentration difficulties; (7) Lassitude; (8) Inability to feel; (9) Pessimistic thoughts; (10) Suicidal thoughts. A higher MADRS score indicates more severe depression, and each item yields a score of 0 to 6. The overall score ranges from 0 to 60 with scores above 34 indicating severe depression. In Study REL-1017-202, the MADRS was administered using the Structured Interview Guide for the MADRS (SIGMA). A negative change from baseline indicates improvement.
Time Frame	Change from Baseline to Day 14

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	REL-1017 25 mg	REL-1017 50 mg	Placebo
Arm/Group Description	Loading dose of REL-1017 75 mg of powder in 100 mL of cranberry juice on Day 1, Maintenance dose of REL-1017 25 mg of powder in 100 mL cranberry juice daily on Days 2-7. REL-1017: REL-1017 administered as an oral solution. Patients continued to take the first line stable dose of antidepressant medication.	Loading dose of REL-1017 100 mg of powder in 100 mL of cranberry juice on Day 1, Maintenance dose of REL-1017 50 mg of powder in 100 mL cranberry juice daily on Days 2-7. REL-1017: REL-1017 administered as an oral solution. Patients continued to take the first line stable dose of antidepressant medication.	100 mL cranberry juice was administered as a single oral dose daily for 7 days. Placebo: Placebo was administered as an oral solution. Patients continued to take the first line stable dose of antidepressant medication.
Measure Participants	16	18	20
Least Squares Mean (Standard Error) [score on a scale]	-16.8 (2.7)	-17.8 (2.6)	-7.4 (2.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	REL-1017 25 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0103
	Comments
	Method	Mixed Models Analysis
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	REL-1017 50 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0039
	Comments
	Method	Mixed Models Analysis
	Comments

6. Secondary Outcome

Title	Symptoms of Depression Questionnaire (SDQ)
Description	Symptoms of Depression Questionnaire (SDQ) will be administered and reported on Days 4, 7, and 14. The SDQ is a 44-item, self-report scale designed to measure the severity of symptoms across several subtypes of depression. The SDQ was developed to more fully capture the heterogeneity of symptom presentations of depressive disorders than current, widely used scales for MDD. The SDQ includes items that inquire about an extensive number of depressive symptoms beyond the ones included in other commonly used scales. The 44 SDQ items are rated on a 6-point scale. The total score is the sum of 44 items and can range from 44 to 264. A negative change from baseline indicates improvement. 1 = Better than Normal; 2= Normal; 3= Minimally Sad; 4= Moderately Sad; 5= Markedly Sad; 6= Extremely Sad
Time Frame	Change from Baseline to Day 7

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	REL-1017 25 mg	REL-1017 50 mg	Placebo
Arm/Group Description	Loading dose of REL-1017 75 mg of powder in 100 mL of cranberry juice on Day 1, Maintenance dose of REL-1017 25 mg of powder in 100 mL cranberry juice daily on Days 2-7. REL-1017: REL-1017 administered as an oral solution. Patients continued to take the first line stable dose of antidepressant medication.	Loading dose of REL-1017 100 mg of powder in 100 mL of cranberry juice on Day 1, Maintenance dose of REL-1017 50 mg of powder in 100 mL cranberry juice daily on Days 2-7. REL-1017: REL-1017 administered as an oral solution. Patients continued to take the first line stable dose of antidepressant medication.	100 mL cranberry juice was administered as a single oral dose daily for 7 days. Placebo: Placebo was administered as an oral solution. Patients continued to take the first line stable dose of antidepressant medication.
Measure Participants	19	21	21
Least Squares Mean (Standard Error) [score on a scale]	-52.4 (7.1)	-52.9 (6.6)	-37.9 (6.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	REL-1017 25 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1237
	Comments
	Method	Mixed Models Analysis
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	REL-1017 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1017
	Comments
	Method	Mixed Models Analysis
	Comments

7. Secondary Outcome

Title	Symptoms of Depression Questionnaire (SDQ)
Description	Symptoms of Depression Questionnaire (SDQ) will be administered and reported on Days 4, 7, and 14. The SDQ is a 44-item, self-report scale designed to measure the severity of symptoms across several subtypes of depression. The SDQ was developed to more fully capture the heterogeneity of symptom presentations of depressive disorders than current, widely used scales for MDD. The SDQ includes items that inquire about an extensive number of depressive symptoms beyond the ones included in other commonly used scales. The 44 SDQ items are rated on a 6-point scale. The total score is the sum of 44 items and can range from 44 to 264. A negative change from baseline indicates improvement. 1 = Better than Normal; 2= Normal; 3= Minimally Sad; 4= Moderately Sad; 5= Markedly Sad; 6= Extremely Sad
Time Frame	Change from Baseline to Day 14

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	REL-1017 25 mg	REL-1017 50 mg	Placebo
Arm/Group Description	Loading dose of REL-1017 75 mg of powder in 100 mL of cranberry juice on Day 1, Maintenance dose of REL-1017 25 mg of powder in 100 mL cranberry juice daily on Days 2-7. REL-1017: REL-1017 administered as an oral solution. Patients continued to take the first line stable dose of antidepressant medication.	Loading dose of REL-1017 100 mg of powder in 100 mL of cranberry juice on Day 1, Maintenance dose of REL-1017 50 mg of powder in 100 mL cranberry juice daily on Days 2-7. REL-1017: REL-1017 administered as an oral solution. Patients continued to take the first line stable dose of antidepressant medication.	100 mL cranberry juice was administered as a single oral dose daily for 7 days. Placebo: Placebo was administered as an oral solution. Patients continued to take the first line stable dose of antidepressant medication.
Measure Participants	16	18	20
Least Squares Mean (Standard Error) [score on a scale]	-55.0 (6.4)	-58.6 (6.0)	-31.8 (5.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	REL-1017 25 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0066
	Comments
	Method	Mixed Models Analysis
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	REL-1017 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0014
	Comments
	Method	Mixed Models Analysis
	Comments

8. Secondary Outcome

Title	Clinical Global Impressions of Severity (CGI-S)
Description	Clinical Global Impressions of Severity (CGI-S) will be administered and reported on Days 4, 7, and 14. The CGI-S is a standard method used in clinical studies to quantify and track patient progress and treatment response over time. The scale is composed of 7 ratings: 1 = normal, not at all ill; 2 = borderline ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill patients. The score ranges from 1 to 7, and a lower CGI-S score indicates lower levels of depression.
Time Frame	Change from Baseline to Day 7

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	REL-1017 25 mg	REL-1017 50 mg	Placebo
Arm/Group Description	Loading dose of REL-1017 75 mg of powder in 100 mL of cranberry juice on Day 1, Maintenance dose of REL-1017 25 mg of powder in 100 mL cranberry juice daily on Days 2-7. REL-1017: REL-1017 administered as an oral solution. Patients continued to take the first line stable dose of antidepressant medication.	Loading dose of REL-1017 100 mg of powder in 100 mL of cranberry juice on Day 1, Maintenance dose of REL-1017 50 mg of powder in 100 mL cranberry juice daily on Days 2-7. REL-1017: REL-1017 administered as an oral solution. Patients continued to take the first line stable dose of antidepressant medication.	100 mL cranberry juice was administered as a single oral dose daily for 7 days. Placebo: Placebo was administered as an oral solution. Patients continued to take the first line stable dose of antidepressant medication.
Measure Participants	19	21	21
Least Squares Mean (Standard Error) [score on a scale]	-1.7 (0.3)	-1.7 (0.3)	-0.8 (0.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	REL-1017 25 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0245
	Comments
	Method	Mixed Models Analysis
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	REL-1017 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0253
	Comments
	Method	Mixed Models Analysis
	Comments

9. Secondary Outcome

Title	Clinical Global Impressions of Severity (CGI-S)
Description	Clinical Global Impressions of Severity (CGI-S) will be administered and reported on Days 4, 7, and 14. The CGI-S is a standard method used in clinical studies to quantify and track patient progress and treatment response over time. The scale is composed of 7 ratings: 1 = normal, not at all ill; 2 = borderline ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill patients. The score ranges from 1 to 7, and a lower CGI-S score indicates lower levels of depression.
Time Frame	Change from Baseline to Day 14

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	REL-1017 25 mg	REL-1017 50 mg	Placebo
Arm/Group Description	Loading dose of REL-1017 75 mg of powder in 100 mL of cranberry juice on Day 1, Maintenance dose of REL-1017 25 mg of powder in 100 mL cranberry juice daily on Days 2-7. REL-1017: REL-1017 administered as an oral solution. Patients continued to take the first line stable dose of antidepressant medication.	Loading dose of REL-1017 100 mg of powder in 100 mL of cranberry juice on Day 1, Maintenance dose of REL-1017 50 mg of powder in 100 mL cranberry juice daily on Days 2-7. REL-1017: REL-1017 administered as an oral solution. Patients continued to take the first line stable dose of antidepressant medication.	100 mL cranberry juice was administered as a single oral dose daily for 7 days. Placebo: Placebo was administered as an oral solution. Patients continued to take the first line stable dose of antidepressant medication.
Measure Participants	16	18	20
Least Squares Mean (Standard Error) [score on a scale]	-1.6 (0.3)	-2.0 (0.3)	-0.7 (0.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	REL-1017 25 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0454
	Comments
	Method	Mixed Models Analysis
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	REL-1017 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0043
	Comments
	Method	Mixed Models Analysis
	Comments

10. Secondary Outcome

Title	Clinical Global Impressions of Improvement (CGI-I)
Description	Clinical Global Impressions of Improvement (CGI-I) will be administered and reported at Days 4, 7 and 14. The CGI-I is a standard method used in clinical studies to quantify and track patient change over time. The scale is composed of 7 ratings: 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 score ranges from 1 to 7, and a lower CGI-I score indicates greater improvement in symptoms.
Time Frame	Change from Baseline to Day 7

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	REL-1017 25 mg	REL-1017 50 mg	Placebo
Arm/Group Description	Loading dose of REL-1017 75 mg of powder in 100 mL of cranberry juice on Day 1, Maintenance dose of REL-1017 25 mg of powder in 100 mL cranberry juice daily on Days 2-7. REL-1017: REL-1017 administered as an oral solution. Patients continued to take the first line stable dose of antidepressant medication.	Loading dose of REL-1017 100 mg of powder in 100 mL of cranberry juice on Day 1, Maintenance dose of REL-1017 50 mg of powder in 100 mL cranberry juice daily on Days 2-7. REL-1017: REL-1017 administered as an oral solution. Patients continued to take the first line stable dose of antidepressant medication.	100 mL cranberry juice was administered as a single oral dose daily for 7 days. Placebo: Placebo was administered as an oral solution. Patients continued to take the first line stable dose of antidepressant medication.
Measure Participants	19	21	21
Least Squares Mean (Standard Error) [score on a scale]	2.4 (0.2)	2.3 (0.2)	3.2 (0.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	REL-1017 25 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0177
	Comments
	Method	Mixed Models Analysis
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	REL-1017 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0072
	Comments
	Method	Mixed Models Analysis
	Comments

11. Secondary Outcome

Title	Clinical Global Impressions of Improvement (CGI-I)
Description	Clinical Global Impressions of Improvement (CGI-I) will be administered and reported at Days 4, 7 and 14. The CGI-I is a standard method used in clinical studies to quantify and track patient change over time. The scale is composed of 7 ratings: 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 score ranges from 1 to 7, and a lower CGI-I score indicates greater improvement in symptoms.
Time Frame	Change from Baseline to Day 14

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	REL-1017 25 mg	REL-1017 50 mg	Placebo
Arm/Group Description	Loading dose of REL-1017 75 mg of powder in 100 mL of cranberry juice on Day 1, Maintenance dose of REL-1017 25 mg of powder in 100 mL cranberry juice daily on Days 2-7. REL-1017: REL-1017 administered as an oral solution. Patients continued to take the first line stable dose of antidepressant medication.	Loading dose of REL-1017 100 mg of powder in 100 mL of cranberry juice on Day 1, Maintenance dose of REL-1017 50 mg of powder in 100 mL cranberry juice daily on Days 2-7. REL-1017: REL-1017 administered as an oral solution. Patients continued to take the first line stable dose of antidepressant medication.	100 mL cranberry juice was administered as a single oral dose daily for 7 days. Placebo: Placebo was administered as an oral solution. Patients continued to take the first line stable dose of antidepressant medication.
Measure Participants	16	18	20
Least Squares Mean (Standard Error) [score on a scale]	2.6 (0.3)	2.3 (0.3)	3.3 (0.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	REL-1017 25 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0895
	Comments
	Method	Mixed Models Analysis
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	REL-1017 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0109
	Comments
	Method	Mixed Models Analysis
	Comments

12. Secondary Outcome

Title	Maximum Observed Plasma Concentration (Cmax) [Pharmacokinetic]
Description	The pharmacokinetic parameters of REL-1017 25 mg and 50 mg will be evaluated on Day 1 through Day 7, Day 8, Day 9, and Day 14 where the data allow.
Time Frame	Day 1 (hour -1, 1, 2, 4, 6, 8, 12, and 24)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic population: All patients who received REL-1017, with at least 1 post-dose blood draw to determine plasma concentration of d-methadone.

Arm/Group Title	REL-1017 25 mg	REL-1017 50 mg
Arm/Group Description	Loading dose of REL-1017 75 mg of powder in 100 mL of cranberry juice on Day 1, Maintenance dose of REL-1017 25 mg of powder in 100 mL cranberry juice daily on Days 2-7. REL-1017: REL-1017 administered as an oral solution. Patients continued to take the first line stable dose of antidepressant medication.	Loading dose of REL-1017 100 mg of powder in 100 mL of cranberry juice on Day 1, Maintenance dose of REL-1017 50 mg of powder in 100 mL cranberry juice daily on Days 2-7. REL-1017: REL-1017 administered as an oral solution. Patients continued to take the first line stable dose of antidepressant medication.
Measure Participants	16	21
Mean (Standard Deviation) [ng/mL]	254.5 (60.864)	343.9 (112.36)

13. Secondary Outcome

Title	Area Under the Plasma Concentration-time Curve From Time Zero Until the Dosing Interval of 24 Hours (AUCtau) [Pharmacokinetic]
Description	The pharmacokinetic parameters of REL-1017 25 mg and 50 mg will be evaluated on Day 1 through Day 7, Day 8, Day 9, and Day 14 where the data allow.
Time Frame	Day 1 (hour -1, 1, 2, 4, 6, 8, 12, and 24)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic population: All patients who received REL-1017, with at least 1 post-dose blood draw to determine plasma concentration of d-methadone.

Arm/Group Title	REL-1017 25 mg	REL-1017 50 mg
Arm/Group Description	Loading dose of REL-1017 75 mg of powder in 100 mL of cranberry juice on Day 1, Maintenance dose of REL-1017 25 mg of powder in 100 mL cranberry juice daily on Days 2-7. REL-1017: REL-1017 administered as an oral solution. Patients continued to take the first line stable dose of antidepressant medication.	Loading dose of REL-1017 100 mg of powder in 100 mL of cranberry juice on Day 1, Maintenance dose of REL-1017 50 mg of powder in 100 mL cranberry juice daily on Days 2-7. REL-1017: REL-1017 administered as an oral solution. Patients continued to take the first line stable dose of antidepressant medication.
Measure Participants	16	20
Mean (Standard Deviation) [h*ng/mL]	3533 (1082.2)	4531 (1344.7)

14. Secondary Outcome

Title	Time to Maximum Observed Plasma Concentration (Tmax) [Pharmacokinetic]
Description	The pharmacokinetic parameters of REL-1017 25 mg and 50 mg will be evaluated on Day 1 through Day 7, Day 8, Day 9, and Day 14 where the data allow.
Time Frame	Day 1 (hour -1, 1, 2, 4, 6, 8, 12, and 24)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic population: All patients who received REL-1017, with at least 1 post-dose blood draw to determine plasma concentration of d-methadone.

Arm/Group Title	REL-1017 25 mg	REL-1017 50 mg
Arm/Group Description	Loading dose of REL-1017 75 mg of powder in 100 mL of cranberry juice on Day 1, Maintenance dose of REL-1017 25 mg of powder in 100 mL cranberry juice daily on Days 2-7. REL-1017: REL-1017 administered as an oral solution. Patients continued to take the first line stable dose of antidepressant medication.	Loading dose of REL-1017 100 mg of powder in 100 mL of cranberry juice on Day 1, Maintenance dose of REL-1017 50 mg of powder in 100 mL cranberry juice daily on Days 2-7. REL-1017: REL-1017 administered as an oral solution. Patients continued to take the first line stable dose of antidepressant medication.
Measure Participants	16	21
Median (Full Range) [hours]	1.917	2.250

15. Secondary Outcome

Title	Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) [Pharmacokinetic]
Description	The pharmacokinetic parameters of REL-1017 25 mg and 50 mg will be evaluated on Day 1 through Day 7, Day 8, Day 9, and Day 14 where the data allow.
Time Frame	Day 1 (hour -1, 1, 2, 4, 6, 8, 12, and 24)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic population: All patients who received REL-1017, with at least 1 post-dose blood draw to determine plasma concentration of d-methadone.

Arm/Group Title	REL-1017 25 mg	REL-1017 50 mg
Arm/Group Description	Loading dose of REL-1017 75 mg of powder in 100 mL of cranberry juice on Day 1, Maintenance dose of REL-1017 25 mg of powder in 100 mL cranberry juice daily on Days 2-7. REL-1017: REL-1017 administered as an oral solution. Patients continued to take the first line stable dose of antidepressant medication.	Loading dose of REL-1017 100 mg of powder in 100 mL of cranberry juice on Day 1, Maintenance dose of REL-1017 50 mg of powder in 100 mL cranberry juice daily on Days 2-7. REL-1017: REL-1017 administered as an oral solution. Patients continued to take the first line stable dose of antidepressant medication.
Measure Participants	11	15
Mean (Standard Deviation) [h*ng/mL]	7114 (2685.2)	10190 (5627.6)

16. Secondary Outcome

Title	Apparent Terminal Elimination Half-life (t½) [Pharmacokinetic]
Description	The pharmacokinetic parameters of REL-1017 25 mg and 50 mg will be evaluated on Day 1 through Day 7, Day 8, Day 9, and Day 14 where the data allow.
Time Frame	Day 1 (hour -1, 1, 2, 4, 6, 8, 12, and 24) and Day 7 (hour 24, 48, and 168 post last dose)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic population: All patients who received REL-1017, with at least 1 post-dose blood draw to determine plasma concentration of d-methadone.

Arm/Group Title	REL-1017 25 mg	REL-1017 50 mg
Arm/Group Description	Loading dose of REL-1017 75 mg of powder in 100 mL of cranberry juice on Day 1, Maintenance dose of REL-1017 25 mg of powder in 100 mL cranberry juice daily on Days 2-7. REL-1017: REL-1017 administered as an oral solution. Patients continued to take the first line stable dose of antidepressant medication.	Loading dose of REL-1017 100 mg of powder in 100 mL of cranberry juice on Day 1, Maintenance dose of REL-1017 50 mg of powder in 100 mL cranberry juice daily on Days 2-7. REL-1017: REL-1017 administered as an oral solution. Patients continued to take the first line stable dose of antidepressant medication.
Measure Participants	16	20
Day 1	30.60 (18.739)	31.74 (18.888)
Day 7	43.88 (11.621)	38.16 (3.9399)

Adverse Events

Time Frame	21 days
Arm/Group Title	REL-1017 25 mg		REL-1017 50 mg		Placebo
Arm/Group Description	Loading dose of REL-1017 75 mg of powder in 100 mL of cranberry juice on Day 1, Maintenance dose of REL-1017 25 mg of powder in 100 mL cranberry juice daily on Days 2-7. REL-1017: REL-1017 administered as an oral solution. Patients continued to take the first line stable dose of antidepressant medication.		Loading dose of REL-1017 100 mg of powder in 100 mL of cranberry juice on Day 1, Maintenance dose of REL-1017 50 mg of powder in 100 mL cranberry juice daily on Days 2-7. REL-1017: REL-1017 administered as an oral solution. Patients continued to take the first line stable dose of antidepressant medication.		100 mL cranberry juice was administered as a single oral dose daily for 7 days. Placebo: Placebo will be administered as an oral solution. Patients continued to take the first line stable dose of antidepressant medication.
All Cause Mortality
	REL-1017 25 mg		REL-1017 50 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/19 (0%)		0/21 (0%)		0/22 (0%)
Serious Adverse Events
	REL-1017 25 mg		REL-1017 50 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/19 (0%)		0/21 (0%)		0/22 (0%)
Other (Not Including Serious) Adverse Events
	REL-1017 25 mg		REL-1017 50 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/19 (47.4%)		15/21 (71.4%)		12/22 (54.5%)
Cardiac disorders
Palpitations	1/19 (5.3%)	1	0/21 (0%)	0	0/22 (0%)	0
Gastrointestinal disorders
Constipation	1/19 (5.3%)	1	3/21 (14.3%)	3	3/22 (13.6%)	3
Nausea	1/19 (5.3%)	1	2/21 (9.5%)	2	2/22 (9.1%)	2
Diarrhea	0/19 (0%)	0	0/21 (0%)	0	3/22 (13.6%)	3
Abdominal Discomfort	0/19 (0%)	0	0/21 (0%)	0	2/22 (9.1%)	2
Dyspepsia	2/19 (10.5%)	2	0/21 (0%)	0	0/22 (0%)	0
Flatulence	1/19 (5.3%)	1	0/21 (0%)	0	0/22 (0%)	0
Vomiting	1/19 (5.3%)	1	0/21 (0%)	0	0/22 (0%)	0
Gastroesophageal Reflux Disease	0/19 (0%)	0	0/21 (0%)	0	1/22 (4.5%)	1
General disorders
Fatigue	1/19 (5.3%)	1	0/21 (0%)	0	0/22 (0%)	0
Application Site Erosion	0/19 (0%)	0	1/21 (4.8%)	1	0/22 (0%)	0
Feeling of Relaxation	0/19 (0%)	0	1/21 (4.8%)	1	0/22 (0%)	0
Hepatobiliary disorders
Drug-Induced Liver Injury	0/19 (0%)	0	1/21 (4.8%)	1	0/22 (0%)	0
Infections and infestations
Upper Respiratory Infection	0/19 (0%)	0	0/21 (0%)	0	2/22 (9.1%)	2
Urinary Tract Infection	1/19 (5.3%)	1	0/21 (0%)	0	0/22 (0%)	0
Influenza	0/19 (0%)	0	1/21 (4.8%)	1	0/22 (0%)	0
Investigations
Weight Decrease	0/19 (0%)	0	2/21 (9.5%)	2	0/22 (0%)	0
Blood Pressure Increases	0/19 (0%)	0	1/21 (4.8%)	1	0/22 (0%)	0
Metabolism and nutrition disorders
Hypocalcaemia	0/19 (0%)	0	1/21 (4.8%)	1	0/22 (0%)	0
Musculoskeletal and connective tissue disorders
Back Pain	1/19 (5.3%)	1	2/21 (9.5%)	2	0/22 (0%)	0
Limb Discomfort	0/19 (0%)	0	1/21 (4.8%)	1	0/22 (0%)	0
Nervous system disorders
Headache	2/19 (10.5%)	2	3/21 (14.3%)	3	3/22 (13.6%)	3
Somnolence	1/19 (5.3%)	1	1/21 (4.8%)	1	2/22 (9.1%)	2
Dizziness	1/19 (5.3%)	1	1/21 (4.8%)	1	1/22 (4.5%)	1
Sedation	1/19 (5.3%)	1	0/21 (0%)	0	1/22 (4.5%)	1
Presyncope	0/19 (0%)	0	1/21 (4.8%)	1	0/22 (0%)	0
Tremor	0/19 (0%)	0	1/21 (4.8%)	1	0/22 (0%)	0
Psychiatric disorders
Abnormal Dreams	0/19 (0%)	0	0/21 (0%)	0	1/22 (4.5%)	1
Restlessness	0/19 (0%)	0	1/21 (4.8%)	1	0/22 (0%)	0
Renal and urinary disorders
Pollakiuria	1/19 (5.3%)	1	0/21 (0%)	0	0/22 (0%)	0
Skin and subcutaneous tissue disorders
Pruritius	1/19 (5.3%)	1	0/21 (0%)	0	0/22 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Sponsor requests an opportunity to review any proposed publication prior to public release to ensure against inadvertent release of confidential information or unprotected inventions. Sponsor has 12 months from the completion or termination of the trial to publish a joint manuscript with all participating sites.