TRANSFORM-2: A Study to Evaluate the Efficacy, Safety, and Tolerability of Flexible Doses of Intranasal Esketamine Plus an Oral Antidepressant in Adult Participants With Treatment-resistant Depression

• Sponsor: Janssen Research & Development, LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02418585
• Collaborator: (none)
• Enrollment: 236
• Locations: 50
• Arms: 2
• Actual Duration (Months): 27
• Patients Per Site: 4.7
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to compare the efficacy and safety of switching treatment-resistant depression (TRD) subjects from a prior antidepressant treatment (to which they have not responded) to either intranasal esketamine plus a new oral antidepressant or switching to a new oral antidepressant plus intranasal placebo.

Condition or Disease	Intervention/Treatment	Phase
Treatment-resistant Depression	Drug: Esketamine; Drug: Placebo; Drug: Duloxetine (Oral Antidepressant); Drug: Escitalopram (Oral antidepressant); Drug: Sertraline (Oral Antidepressant); Drug: Venlafaxine Extended Release (XR) (Oral Antidepressant)	Phase 3

Detailed Description

This is a randomized, double-blind (neither the researchers nor the subjects know what treatment the subject is receiving), active-controlled, multicenter study (more than 1 study site) in subjects with TRD to assess the efficacy, safety, and tolerability of flexible doses of intranasal esketamine plus a newly initiated oral antidepressant compared with a newly initiated oral antidepressant (active comparator) plus intranasal placebo. The study will consist of 3 phases: Screening/Prospective Observational Phase (4-7 weeks), Double-blind Induction Phase (4-weeks), Follow-up Phase (24-weeks). Subjects who rollover into a long-term maintenance study will not participate in the Follow-up Phase. The antidepressant treatment, as well as any other ongoing medications being taken for depression at screening (including adjunctive/ augmentation therapies), will continue unchanged, at the same dosage, from the start of Week 1 through the end of Week 4 of the screening/prospective observational phase. Subjects' safety will be monitored throughout the study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 236 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Multicenter, Active-controlled Study to Evaluate the Efficacy, Safety, and Tolerability of Flexible Doses of Intranasal Esketamine Plus an Oral Antidepressant in Adult Subjects With Treatment-resistant Depression
• Actual Study Start Date: Aug 7, 2015
• Actual Primary Completion Date: Jun 1, 2017
• Actual Study Completion Date: Nov 6, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Intranasal Esketamine plus oral antidepressant Participants will self-administer esketamine intranasally twice per week for 4 weeks as a flexible dose regimen in the Double-Blind Induction Phase. All participants will start at a dose of 56 mg on Day 1. On Day 4, the dose may be increased to 84 mg or remain at 56 mg per investigator's discretion. On Days 8 and 11 the dose may be increased to 84 mg (from 56 mg), remain same, or be reduced to 56 mg (from 84 mg) per investigator's discretion. On Day 15, a dose reduction from 84 mg to 56 mg is permitted, if required for tolerability; no dose increase permitted. After Day 15, dose must remain stable (unchanged). In addition participants will simultaneously initiate a new, open-label oral antidepressant (duloxetine, escitalopram, sertraline, or venlafaxine extended release [XR]) on Day 1 that will be continued for the duration of Double-Blind Induction Phase.	Drug: Esketamine; Participants will self-administer either 56 mg or 84 mg of esketamine, intranasally, twice per week as a flexible dose regimen in the Double-Blind Induction Phase.; Drug: Duloxetine (Oral Antidepressant); Duloxetine could be selected as the oral antidepressant medication by the investigator based on review of Massachusetts General Hospital - Antidepressant Treatment Response Questionnaire (MGH-ATRQ) and relevant prior antidepressant medication information. The minimum therapeutic dose is 60 milligram per day (mg/day).; Drug: Escitalopram (Oral antidepressant); Escitalopram could be selected as the oral antidepressant medication by the investigator based on review of MGH-ATRQ and relevant prior antidepressant medication information. Escitalopram will be titrated upto a dose of 20 mg/day, but if not tolerated the dose can be reduced to the minimum therapeutic dose of 10 mg/day.; Drug: Sertraline (Oral Antidepressant); Sertraline could be selected as the oral antidepressant medication by the investigator based on review of MGH-ATRQ and relevant prior antidepressant medication information. Sertraline will be titrated upto a dose of 150 mg/day, but if not tolerated the dose can be reduced to the minimum therapeutic dose of 50 mg/day.; Drug: Venlafaxine Extended Release (XR) (Oral Antidepressant); Venlafaxine Extended Release could be selected as the oral antidepressant medication by the investigator based on review of MGH-ATRQ and relevant prior antidepressant medication information. Venlafaxine Extended Release will be titrated upto a dose of 225 mg/day, but if not tolerated the dose can be reduced to the minimum therapeutic dose of 150 mg/day.
Active Comparator: Placebo plus oral antidepressant Participants will self-administer matching placebo, intranasally, twice per week for 4 weeks as a flexible dose regimen in Double-Blind Induction Phase. In addition participants will simultaneously initiate a new, open-label oral antidepressant (ie, duloxetine, escitalopram, sertraline, or venlafaxine extended release [XR]) on Day 1 that will be continued for the duration of Double-Blind Induction Phase.	Drug: Placebo; Participants will self-administer matching placebo, intranasally, twice per week for 4 weeks as a flexible dose regimen in the Double-Blind Induction Phase.; Drug: Duloxetine (Oral Antidepressant); Duloxetine could be selected as the oral antidepressant medication by the investigator based on review of Massachusetts General Hospital - Antidepressant Treatment Response Questionnaire (MGH-ATRQ) and relevant prior antidepressant medication information. The minimum therapeutic dose is 60 milligram per day (mg/day).; Drug: Escitalopram (Oral antidepressant); Escitalopram could be selected as the oral antidepressant medication by the investigator based on review of MGH-ATRQ and relevant prior antidepressant medication information. Escitalopram will be titrated upto a dose of 20 mg/day, but if not tolerated the dose can be reduced to the minimum therapeutic dose of 10 mg/day.; Drug: Sertraline (Oral Antidepressant); Sertraline could be selected as the oral antidepressant medication by the investigator based on review of MGH-ATRQ and relevant prior antidepressant medication information. Sertraline will be titrated upto a dose of 150 mg/day, but if not tolerated the dose can be reduced to the minimum therapeutic dose of 50 mg/day.; Drug: Venlafaxine Extended Release (XR) (Oral Antidepressant); Venlafaxine Extended Release could be selected as the oral antidepressant medication by the investigator based on review of MGH-ATRQ and relevant prior antidepressant medication information. Venlafaxine Extended Release will be titrated upto a dose of 225 mg/day, but if not tolerated the dose can be reduced to the minimum therapeutic dose of 150 mg/day.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score up to Day 28 in the Double-blind Induction Phase- Mixed-Effects Model Using Repeated Measures (MMRM) Analysis [Baseline up to Day 28 of Double-blind Induction Phase]

   MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition.

2. Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- Analysis of Covariance (ANCOVA) Analysis [Baseline up to Endpoint (Double-blind Induction Phase [Day 28])]

   MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition. The last post baseline observation during the phase was carried forward as "End Point" for that phase.

Secondary Outcome Measures

1. Percentage of Participants With Onset of Clinical Response on Day 2 and Day 8 [Day 2 up to Day 28 and Day 8 up to Day 28]

   A participant was defined as having a clinical response if there is at least 50 percent (%) improvement from baseline in the MADRS total score with onset by Day 2 and Day 8 that was maintained to Day 28. MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition. Participants who did not meet such criterion or discontinue during the study before Day 28 for any reason were considered as non-responders.

2. Change From Baseline in Sheehan Disability Scale (SDS) Total Score up to Day 28 of Double-blind Induction Phase- MMRM Analysis [Baseline up to Day 28 of Double-blind Induction phase]

   The SDS is a participant-reported outcome measure and 5 item questionnaire used for assessment of functional impairment and associated disability. First three items assess disruption of 1 work/school, 2 social life, 3 family life/home responsibilities using a 0(no impairment)-10 (most severe impairment). Score for first 3 items are summed to create total score of 0-30 where higher score indicates greater impairment and a negative change in score indicates improvement. It also has one item on days lost from school or work and one item on days when under productive.

3. Change From Baseline in Sheehan Disability Scale (SDS) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis [Baseline up to Endpoint (Double-blind Induction Phase [Day 28])]

   The SDS is a participant-reported outcome measure and 5 item questionnaire used for assessment of functional impairment and associated disability. First three items assess disruption of 1 work/school, 2 social life, 3 family life/home responsibilities using a 0(no impairment)-10 (most severe impairment). Score for first 3 items are summed to create total score of 0-30 where higher score indicates greater impairment and a negative change in score indicates improvement. It also has one item on days lost from school or work and one item on days when under productive. The last post baseline observation during the phase was carried forward as "End Point" for that phase.

4. Change From Baseline in Patient Health Questionnaire - 9-Item Depression Module (PHQ-9) Total Score up to Day 28 of Double-blind Induction Phase- MMRM Analysis [Baseline up to Day 28 of Double-blind Induction phase]

   PHQ-9 is 9-item, self-report scale assessing depressive symptoms. Each item is rated on 4-point scale (0=Not at all, 1=Several Days, 2=More than half days, 3=Nearly every day. Scale scores each of 9 symptom domains of Diagnostic and Statistical Manual of Mental Disorders, Major Depressive Disorder criteria and it has been used both as screening tool and measure of response to treatment for depression. The participant's item responses are summed to provide a total score (range of 0 to 27) with higher scores indicating greater severity of depressive symptoms. Severity of PHQ-9 categorized as follows: None-minimal (0-4), Mild (5-9), Moderate (10-14), Moderately Severe (15-19), Severe (20-27).

5. Change From Baseline in Patient Health Questionnaire - 9-Item Depression Module (PHQ-9) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis [Baseline up to Endpoint (Double-blind Induction Phase [Day 28])]

   PHQ-9 is 9-item, self-report scale assessing depressive symptoms. Each item is rated on 4-point scale (0=Not at all, 1=Several Days, 2=More than half days, 3=Nearly every day). Scale scores each of 9 symptom domains of Diagnostic and Statistical Manual of Mental Disorders, Major Depressive Disorder criteria and it has been used both as screening tool and measure of response to treatment for depression. The participant's item responses are summed to provide a total score (range of 0 to 27) with higher scores indicating greater severity of depressive symptoms. Severity of PHQ-9 categorized as follows: None-minimal (0-4), Mild (5-9), Moderate (10-14), Moderately Severe (15-19), Severe (20-27). The last post baseline observation during the phase was carried forward as "End Point" for that phase.

6. Percentage of Participants Who Achieved >=50% Reduction From Baseline in MADRS Total Score at the Endpoint (Double-blind Induction Phase [Day 28]) [At Endpoint (Double-blind Induction Phase [Day 28])]

   MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition. The percentage of participants with greater than or equal to (>=) 50 % reduction from baseline in MADRS total score was reported. The last post baseline observation during the phase was carried forward as "End Point" for that phase.

7. Percentage of Participants in Remission (MADRS<=12) at the Endpoint (Double-blind Induction Phase [Day 28]) [At Endpoint (Double-blind Induction Phase [Day 28])]

   Remission was defined as participants who had a MADRS total score of less than or equal to (=<) 12. MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition. The last post baseline observation during the phase was carried forward as "End Point" for that phase.

8. Percentage of Participants in Response (SDS Total Score <=12 and Individual Item Scores Each <=4) at the End of 4-Week Double-blind Induction Phase (Day 28) [At Day 28 [end of Double-blind Induction Phase]]

   Response defined as SDS total score <= 12 and individual item scores each <= 4. SDS is a participant-reported outcome measure and 5 item questionnaire used for assessment of functional impairment and associated disability. First three items assess disruption of 1 work/school, 2 social life, 3 family life/home responsibilities using a 0(no impairment)-10 (most severe impairment). Score for first 3 items are summed to create total score of 0-30 where higher score indicates greater impairment and a negative change in score indicates improvement. It also has one item on days lost from school or work and one item on days when under productive.

9. Percentage of Participants in Remission (SDS Total Score <=6 and Individual Item Scores Each <=2) at the End of 4-Week Double-blind Induction Phase (Day 28) [At Day 28 (End of Double-blind Induction Phase)]

   Remission defined as SDS total score <= 6 and individual item scores each <= 2. SDS is a participant reported outcome measure and is a 5-item questionnaire which has been widely used and accepted for assessment of functional impairment and associated disability. The first three items assess disruption of (1) work/school, (2) social life, and (3) family life/home responsibilities using a 0-10 rating scale. The score for the first three items were summed to create a total score of 0-30 where a higher score indicates greater impairment. It also has one item on days lost from school or work and one item on days when under productive.

10. Change From Baseline in Clinical Global Impression-Severity (CGI-S) Total Score up to Endpoint (Double-blind Induction Phase [Day 28]) [Baseline up to Endpoint (Double-blind Induction Phase [Day 28])]

    CGI-S provides measure of severity of participant's illness including participant's history, psychosocial circumstances, symptoms, behavior and impact of symptoms on ability to function. CGI-S evaluates severity of psychopathology on scale of 0 to 7. Considering total clinical experience, participant is assessed on severity of mental illness according to: 0=not assessed; 1=normal (not at all ill); 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=among most extremely ill patients. CGI-S permits global evaluation of participant's condition at given time. The last post baseline observation during the phase was carried forward as "End Point" for that phase.

11. Change From Baseline in Generalized Anxiety Disorder (GAD-7) Total Score up to Endpoint (Double-blind Induction Phase [Day 28]) [Baseline up to Endpoint (Double-blind Induction Phase [Day 28])]

    GAD-7 is a brief and validated 7-item self-report assessment of overall anxiety. Participants respond to each item using a 4-point scale with response categories of 0=not at all, 1=several days, 2=more than half the days, and 3=nearly every day. Item responses are summed to yield a total score with a range of 0 to 21, where higher scores indicate more anxiety. The recall period is 2 weeks. The severity of the GAD-7 is categorized as follows: None (0-4), Mild (5-9), Moderate (10-14) and Severe (15 -21). The last post baseline observation during the phase was carried forward as "End Point" for that phase.

12. Change From Baseline in EQ 5D-5L-Health Status Index to End of Double-blind Induction Phase (Day 28) [Baseline up to End of Double-blind Induction Phase (Day 28)]

    European Quality of Life Group-5 Dimension-5-Level (EQ-5D-5L) is a 2-part instrument for use as a measure of health outcome, designed for self-completion by respondents. It consists of EQ-5D-5L descriptive system and EQ VAS. EQ-5D-5L descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each has 5 levels of perceived problems (1-no problem, 2-slight problems, 3-moderate problems, 4-severe problems, 5-extreme problems). Participant selects answer for each of 5 dimensions considering response that best matches his/her health "today". Responses were used to generate a Health Status Index (HSI). Health Status Index range is -0.148 - 0.949, is anchored at 0 (dead) and 1 (full health).

13. Change From Baseline in EQ 5D-5L- European Quality of Life - Visual Analogue Scale (EQ-VAS) to End of Double-blind Induction Phase (Day 28) [Baseline up to End of Double-blind Induction Phase (Day 28)]

    EQ-5D-5L is a 2-part instrument for use as a measure of health outcome, designed for self-completion by respondents. It consists of EQ-5D-5L descriptive system and EQ VAS. The EQ VAS self-rating records the respondent's own assessment of his or her overall health status at the time of completion, on a scale of 0 (the worst health you can imagine) to 100 (the best health you can imagine).

14. Change From Baseline in EQ 5D-5L- Sum Score to End of Double-blind Induction Phase (Day 28) [Baseline up to End of Double-blind Induction Phase (Day 28)]

    EQ-5D-5L consists of EQ-5D-5L descriptive system and EQ visual analogue scale (EQ VAS). EQ-5D-5L descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each has 5 levels of perceived problems (1-no problem, 2-slight problems, 3-moderate problems, 4-severe problems, 5-extreme problems). Participant selects answer for each of 5 dimensions considering response that best matches his/her health "today". Responses were used to generate a Health Status Index (HSI). Health Status Index range is -0.148 - 0.949, is anchored at 0 (dead) and 1 (full health). EQ VAS self-rating records the respondent's own assessment of his/her overall health status at time of completion, on a scale of 0 (worst health you can imagine) to 100 (best health you can imagine). Sum score ranges from 0 to 100 where, sum score = (sum of the scores from the 5 dimensions minus 5) *5. Higher score indicates worst health state.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 64 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• At the time of signing the informed consent form (ICF), participant must be a man or woman 18 (or older if the minimum legal age of consent in the country in which the study is taking place is greater than [>]18) to 64 years of age, inclusive

• At the start of the screening/prospective observational phase, participant must meet the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) diagnostic criteria for single-episode major depressive disorder (MDD) (if single-episode MDD, the duration must be greater than or equal to [>=] 2 years) or recurrent MDD, without psychotic features, based upon clinical assessment and confirmed by the Mini-International Neuropsychiatric Interview (MINI)

• At the start of the screening/prospective observational phase, participant must have an Inventory of Depressive Symptomatology-Clinician rated ( IDS-C30) total score of greater than or equal to (>=) 34

• At the start of the screening/prospective observational phase, participant must have had non-response (greater than or equal to [<=25] percent [%] improvement) to ≥1 but less than or equal to (<=) 5 (if current episode is >2 years, upper limit is applicable to only the last 2 years) oral antidepressant treatments in the current episode of depression, assessed using the Massachusetts General Hospital - Antidepressant Treatment Response Questionnaire (MGH-ATRQ) and documented by medical history and pharmacy/prescription records, for the current episode of depression. In addition, the participant is taking a different oral antidepressant treatment (on the MGH-ATRQ) for at least the previous 2 weeks at or above the minimum therapeutic dose

• The participant's current major depressive episode, depression symptom severity (Week 1 MADRS total score >=28 required), and antidepressant treatment response in the current depressive episode, must be confirmed using a Site Independent Qualification Assessment

Exclusion Criteria:

• Participants who have previously demonstrated nonresponse of depressive symptoms to esketamine or ketamine in the current major depressive episode, to all 4 of the oral antidepressant treatment options available for the double-blind induction phase (ie, duloxetine, escitalopram, sertraline, and venlafaxine extended release [XR]) in the current major depressive episode (based on MGH-ATRQ), or an adequate course of treatment with electroconvulsive therapy (ECT) in the current major depressive episode, defined as at least 7 treatments with unilateral/bilateral ECT

• Participant has received vagal nerve stimulation (VNS) or has received deep brain stimulation (DBS) in the current episode of depression

• Participant has a current or prior DSM-5 diagnosis of a psychotic disorder or MDD with psychosis, bipolar or related disorders (confirmed by the MINI), comorbid obsessive compulsive disorder, intellectual disability (DSM-5 diagnostic codes 317, 318.0, 318.1, 318.2, 315.8, and 319), borderline personality disorder, antisocial personality disorder, histrionic personality disorder, or narcissistic personality disorder

• Participant has homicidal ideation/intent, per the investigator's clinical judgment, or has suicidal ideation with some intent to act within 6 months prior to the start of the screening/prospective observational phase, per the investigator's clinical judgment or based on the Columbia Suicide Severity Rating Scale (C-SSRS)

• Participants with history of moderate or severe substance or alcohol use disorder according to DSM-5 criteria

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Birmingham	Alabama	United States
2		Orange	California	United States
3		San Rafael	California	United States
4		Maitland	Florida	United States
5		Atlanta	Georgia	United States
6		Chicago	Illinois	United States
7		Gaithersburg	Maryland	United States
8		Boston	Massachusetts	United States
9		Philadelphia	Pennsylvania	United States
10		Dallas	Texas	United States
11		Klecany		Czechia
12		Litomerice		Czechia
13		Plzen		Czechia
14		Prague		Czechia
15		Praha 10		Czechia
16		Praha 6		Czechia
17		Prerov		Czechia
18		Berlin		Germany
19		Cham		Germany
20		Dresden		Germany
21		Gelsenkirchen		Germany
22		Halle (Saale)		Germany
23		Leipzig		Germany
24		Mainz		Germany
25		Mannheim		Germany
26		Mittweida		Germany
27		Pfaffenhofen		Germany
28		Prien		Germany
29		Tübingen		Germany
30		Bialystok		Poland
31		Bydgoszcz		Poland
32		Gdansk		Poland
33		Krakow		Poland
34		Myslowice		Poland
35		Pruszkow		Poland
36		Torun		Poland
37		Tuszyn		Poland
38		Warszawa		Poland
39		Alcorcón		Spain
40		Barcelona		Spain
41		Córdoba		Spain
42		Mostoles		Spain
43		Murcia		Spain
44		Málaga		Spain
45		Palma		Spain
46		Pamplona		Spain
47		Sabadell		Spain
48		Salamanca		Spain
49		Santa Coloma De Gramanet		Spain
50		Vitoria-Gasteiz		Spain

Sponsors and Collaborators

• Janssen Research & Development, LLC

Investigators

• Study Director: Janssen Research & Development, LLC Clinical Trial, Janssen Research & Development, LLC

Study Documents (Full-Text)

• Study Protocol - Jun 3, 2016
• Statistical Analysis Plan - Jun 15, 2017

More Information

Additional Information:

• A Randomized, Double-blind, Multicenter, Active-controlled Study to Evaluate the Efficacy, Safety, and Tolerability of Flexible Doses of Intranasal Esketamine Plus an Oral Antidepressant in Adult Subjects with Treatment-resistant Depression

Publications

None provided.

• Responsible Party: Janssen Research & Development, LLC
• ClinicalTrials.gov Identifier: NCT02418585
• Other Study ID Numbers: CR107147; ESKETINTRD3002; 2014-004585-22
• First Posted: Apr 16, 2015
• Last Update Posted: Jun 2, 2020
• Last Verified: May 1, 2020

• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Janssen Research & Development, LLC: Treatment-resistant Depression; Esketamine; Placebo; Oral Antidepressant
• Additional relevant MeSH terms: Depression; Depressive Disorder; Depressive Disorder, Treatment-Resistant; Duloxetine Hydrochloride; Citalopram; Venlafaxine Hydrochloride; Sertraline; Antidepressive Agents; Esketamine

Study Results

Participant Flow

Pre-assignment Detail	Total 236 participants were enrolled, out of which 227 were randomized and 9 participants were excluded due to Good Clinical Practice (GCP) violations.

Arm/Group Title	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)	Intranasal Placebo Plus Oral AD
Arm/Group Description	Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003[NCT02493868]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 [NCT02493868]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Period Title: Double Blind (DB) Phase (4 Weeks)
STARTED	116	111
Safety Analysis Set	115	109
Full Analysis Set	114	109
COMPLETED	98	99
NOT COMPLETED	18	12
Period Title: Double Blind (DB) Phase (4 Weeks)
STARTED	34	52
COMPLETED	16	27
NOT COMPLETED	18	25

Baseline Characteristics

Arm/Group Title	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)	Intranasal Placebo Plus Oral AD	Total
Arm/Group Description	Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003[NCT02493868]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 [NCT02493868]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Total of all reporting groups
Overall Participants	115	109	224
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	115 100%	109 100%	224 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	45 (12.56)	46.4 (11.14)	45.7 (11.89)
Sex: Female, Male (Count of Participants)
Female	76 66.1%	63 57.8%	139 62.1%
Male	39 33.9%	46 42.2%	85 37.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	5 4.3%	7 6.4%	12 5.4%
Not Hispanic or Latino	109 94.8%	99 90.8%	208 92.9%
Unknown or Not Reported	1 0.9%	3 2.8%	4 1.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 0.9%	1 0.9%	2 0.9%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	6 5.2%	5 4.6%	11 4.9%
White	107 93%	102 93.6%	209 93.3%
More than one race	1 0.9%	1 0.9%	2 0.9%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
CZECH REPUBLIC	30 26.1%	28 25.7%	58 25.9%
GERMANY	10 8.7%	10 9.2%	20 8.9%
POLAND	20 17.4%	18 16.5%	38 17%
SPAIN	9 7.8%	9 8.3%	18 8%
UNITED STATES	46 40%	44 40.4%	90 40.2%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score up to Day 28 in the Double-blind Induction Phase- Mixed-Effects Model Using Repeated Measures (MMRM) Analysis
Description	MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition.
Time Frame	Baseline up to Day 28 of Double-blind Induction Phase

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) defined as all randomized participants who received at least 1 dose of intranasal study medication, 1 dose of oral antidepressant (AD) medication during double-blind induction phase (D-BIP). Here 'N' (overall number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.

Arm/Group Title	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)	Intranasal Placebo Plus Oral AD
Arm/Group Description	Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003[NCT02493868]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 [NCT02493868]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Measure Participants	101	100
Mean (Standard Deviation) [Units on a scale]	-21.4 (12.32)	-17.0 (13.88)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD), Intranasal Placebo Plus Oral AD
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.020
	Comments
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	Difference of Least Square (LS) Means
	Estimated Value	-4.0
	Confidence Interval	(2-Sided) 95%; -7.31 to -0.64
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.69
	Estimation Comments

2. Primary Outcome

Title	Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- Analysis of Covariance (ANCOVA) Analysis
Description	MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition. The last post baseline observation during the phase was carried forward as "End Point" for that phase.
Time Frame	Baseline up to Endpoint (Double-blind Induction Phase [Day 28])

Outcome Measure Data

Analysis Population Description

FAS defined as all randomized participants who received at least 1 dose of intranasal study medication, 1 dose of AD medication during double-blind induction phase (D-BIP). Here 'N' (overall number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.

Arm/Group Title	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)	Intranasal Placebo Plus Oral AD
Arm/Group Description	Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003[NCT02493868]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 [NCT02493868]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Measure Participants	112	109
Mean (Standard Deviation) [Units on a scale]	-19.6 (13.58)	-16.3 (14.24)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD), Intranasal Placebo Plus Oral AD
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.034
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference of Least Square (LS) Means
	Estimated Value	-3.5
	Confidence Interval	(2-Sided) 95%; -6.67 to -0.26
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Percentage of Participants With Onset of Clinical Response on Day 2 and Day 8
Description	A participant was defined as having a clinical response if there is at least 50 percent (%) improvement from baseline in the MADRS total score with onset by Day 2 and Day 8 that was maintained to Day 28. MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition. Participants who did not meet such criterion or discontinue during the study before Day 28 for any reason were considered as non-responders.
Time Frame	Day 2 up to Day 28 and Day 8 up to Day 28

Outcome Measure Data

Analysis Population Description

FAS is defined as all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral AD medication during the double-blind induction phase.

Arm/Group Title	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)	Intranasal Placebo Plus Oral AD
Arm/Group Description	Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003[NCT02493868]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 [NCT02493868]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Measure Participants	114	109
Onset of Clinical response on Day 2	7.9 6.9%	4.6 4.2%
Onset of Clinical response on Day 8	10.5 9.1%	6.4 5.9%

4. Secondary Outcome

Title	Change From Baseline in Sheehan Disability Scale (SDS) Total Score up to Day 28 of Double-blind Induction Phase- MMRM Analysis
Description	The SDS is a participant-reported outcome measure and 5 item questionnaire used for assessment of functional impairment and associated disability. First three items assess disruption of 1 work/school, 2 social life, 3 family life/home responsibilities using a 0(no impairment)-10 (most severe impairment). Score for first 3 items are summed to create total score of 0-30 where higher score indicates greater impairment and a negative change in score indicates improvement. It also has one item on days lost from school or work and one item on days when under productive.
Time Frame	Baseline up to Day 28 of Double-blind Induction phase

Outcome Measure Data

Analysis Population Description

FAS is defined as all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral AD medication during double-blind induction phase. Here 'N' (overall number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.

Arm/Group Title	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)	Intranasal Placebo Plus Oral AD
Arm/Group Description	Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003[NCT02493868]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 [NCT02493868]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Measure Participants	86	85
Mean (Standard Deviation) [Units on a scale]	-13.6 (8.31)	-9.4 (8.43)

5. Secondary Outcome

Title	Change From Baseline in Sheehan Disability Scale (SDS) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis
Description	The SDS is a participant-reported outcome measure and 5 item questionnaire used for assessment of functional impairment and associated disability. First three items assess disruption of 1 work/school, 2 social life, 3 family life/home responsibilities using a 0(no impairment)-10 (most severe impairment). Score for first 3 items are summed to create total score of 0-30 where higher score indicates greater impairment and a negative change in score indicates improvement. It also has one item on days lost from school or work and one item on days when under productive. The last post baseline observation during the phase was carried forward as "End Point" for that phase.
Time Frame	Baseline up to Endpoint (Double-blind Induction Phase [Day 28])

Outcome Measure Data

Analysis Population Description

FAS is defined as all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral AD medication during double-blind induction phase. Here 'N' (overall number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.

Arm/Group Title	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)	Intranasal Placebo Plus Oral AD
Arm/Group Description	Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003[NCT02493868]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 [NCT02493868]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Measure Participants	95	89
Mean (Standard Deviation) [Units on a scale]	-12.5 (8.85)	-9.3 (8.39)

6. Secondary Outcome

Title	Change From Baseline in Patient Health Questionnaire - 9-Item Depression Module (PHQ-9) Total Score up to Day 28 of Double-blind Induction Phase- MMRM Analysis
Description	PHQ-9 is 9-item, self-report scale assessing depressive symptoms. Each item is rated on 4-point scale (0=Not at all, 1=Several Days, 2=More than half days, 3=Nearly every day. Scale scores each of 9 symptom domains of Diagnostic and Statistical Manual of Mental Disorders, Major Depressive Disorder criteria and it has been used both as screening tool and measure of response to treatment for depression. The participant's item responses are summed to provide a total score (range of 0 to 27) with higher scores indicating greater severity of depressive symptoms. Severity of PHQ-9 categorized as follows: None-minimal (0-4), Mild (5-9), Moderate (10-14), Moderately Severe (15-19), Severe (20-27).
Time Frame	Baseline up to Day 28 of Double-blind Induction phase

Outcome Measure Data

Analysis Population Description

FAS is defined as all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral AD medication during double-blind induction phase. Here 'N' signifies overall number of participants who were evaluable for this outcome measure.

Arm/Group Title	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)	Intranasal Placebo Plus Oral AD
Arm/Group Description	Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003[NCT02493868]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 [NCT02493868]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Measure Participants	104	100
Mean (Standard Deviation) [Units on a scale]	-13.0 (6.42)	-10.2 (7.80)

7. Secondary Outcome

Title	Change From Baseline in Patient Health Questionnaire - 9-Item Depression Module (PHQ-9) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis
Description	PHQ-9 is 9-item, self-report scale assessing depressive symptoms. Each item is rated on 4-point scale (0=Not at all, 1=Several Days, 2=More than half days, 3=Nearly every day). Scale scores each of 9 symptom domains of Diagnostic and Statistical Manual of Mental Disorders, Major Depressive Disorder criteria and it has been used both as screening tool and measure of response to treatment for depression. The participant's item responses are summed to provide a total score (range of 0 to 27) with higher scores indicating greater severity of depressive symptoms. Severity of PHQ-9 categorized as follows: None-minimal (0-4), Mild (5-9), Moderate (10-14), Moderately Severe (15-19), Severe (20-27). The last post baseline observation during the phase was carried forward as "End Point" for that phase.
Time Frame	Baseline up to Endpoint (Double-blind Induction Phase [Day 28])

Outcome Measure Data

Analysis Population Description

FAS is defined as all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral AD medication during double-blind induction phase. Here 'N' signifies overall number of participants who were evaluable for this outcome measure.

Arm/Group Title	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)	Intranasal Placebo Plus Oral AD
Arm/Group Description	Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003[NCT02493868]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 [NCT02493868]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Measure Participants	111	105
Mean (Standard Deviation) [Units on a scale]	-12.2 (6.87)	-10.1 (7.87)

8. Secondary Outcome

Title	Percentage of Participants Who Achieved >=50% Reduction From Baseline in MADRS Total Score at the Endpoint (Double-blind Induction Phase [Day 28])
Description	MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition. The percentage of participants with greater than or equal to (>=) 50 % reduction from baseline in MADRS total score was reported. The last post baseline observation during the phase was carried forward as "End Point" for that phase.
Time Frame	At Endpoint (Double-blind Induction Phase [Day 28])

Outcome Measure Data

Analysis Population Description

FAS is defined as all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral AD medication during the double-blind induction phase. Here 'N' (overall number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.

Arm/Group Title	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)	Intranasal Placebo Plus Oral AD
Arm/Group Description	Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003[NCT02493868]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 [NCT02493868]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Measure Participants	112	109
Number [Percentage of participants]	63.4 55.1%	49.5 45.4%

9. Secondary Outcome

Title	Percentage of Participants in Remission (MADRS<=12) at the Endpoint (Double-blind Induction Phase [Day 28])
Description	Remission was defined as participants who had a MADRS total score of less than or equal to (=<) 12. MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition. The last post baseline observation during the phase was carried forward as "End Point" for that phase.
Time Frame	At Endpoint (Double-blind Induction Phase [Day 28])

Outcome Measure Data

Analysis Population Description

FAS is defined as all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral AD medication during the double-blind induction phase. Here 'N' (overall number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.

Arm/Group Title	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)	Intranasal Placebo Plus Oral AD
Arm/Group Description	Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003[NCT02493868]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 [NCT02493868]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Measure Participants	112	109
Number [Percentage of participants]	48.2 41.9%	30.3 27.8%

10. Secondary Outcome

Title	Percentage of Participants in Response (SDS Total Score <=12 and Individual Item Scores Each <=4) at the End of 4-Week Double-blind Induction Phase (Day 28)
Description	Response defined as SDS total score <= 12 and individual item scores each <= 4. SDS is a participant-reported outcome measure and 5 item questionnaire used for assessment of functional impairment and associated disability. First three items assess disruption of 1 work/school, 2 social life, 3 family life/home responsibilities using a 0(no impairment)-10 (most severe impairment). Score for first 3 items are summed to create total score of 0-30 where higher score indicates greater impairment and a negative change in score indicates improvement. It also has one item on days lost from school or work and one item on days when under productive.
Time Frame	At Day 28 [end of Double-blind Induction Phase]

Outcome Measure Data

Analysis Population Description

FAS is defined as all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral AD medication during the double-blind induction phase. Here 'N' (overall number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.

Arm/Group Title	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)	Intranasal Placebo Plus Oral AD
Arm/Group Description	Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003[NCT02493868]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 [NCT02493868]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Measure Participants	86	86
Number [Percentage of participants]	57.0 49.6%	39.5 36.2%

11. Secondary Outcome

Title	Percentage of Participants in Remission (SDS Total Score <=6 and Individual Item Scores Each <=2) at the End of 4-Week Double-blind Induction Phase (Day 28)
Description	Remission defined as SDS total score <= 6 and individual item scores each <= 2. SDS is a participant reported outcome measure and is a 5-item questionnaire which has been widely used and accepted for assessment of functional impairment and associated disability. The first three items assess disruption of (1) work/school, (2) social life, and (3) family life/home responsibilities using a 0-10 rating scale. The score for the first three items were summed to create a total score of 0-30 where a higher score indicates greater impairment. It also has one item on days lost from school or work and one item on days when under productive.
Time Frame	At Day 28 (End of Double-blind Induction Phase)

Outcome Measure Data

Analysis Population Description

FAS is defined as all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral AD medication during the double-blind induction phase. Here 'N' (overall number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.

Arm/Group Title	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)	Intranasal Placebo Plus Oral AD
Arm/Group Description	Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003[NCT02493868]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 [NCT02493868]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Measure Participants	86	86
Number [Percentage of participants]	39.5 34.3%	20.9 19.2%

12. Secondary Outcome

Title	Change From Baseline in Clinical Global Impression-Severity (CGI-S) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])
Description	CGI-S provides measure of severity of participant's illness including participant's history, psychosocial circumstances, symptoms, behavior and impact of symptoms on ability to function. CGI-S evaluates severity of psychopathology on scale of 0 to 7. Considering total clinical experience, participant is assessed on severity of mental illness according to: 0=not assessed; 1=normal (not at all ill); 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=among most extremely ill patients. CGI-S permits global evaluation of participant's condition at given time. The last post baseline observation during the phase was carried forward as "End Point" for that phase.
Time Frame	Baseline up to Endpoint (Double-blind Induction Phase [Day 28])

Outcome Measure Data

Analysis Population Description

FAS defined as all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral AD medication during the double-blind induction phase. Here 'N' (overall number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.

Arm/Group Title	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)	Intranasal Placebo Plus Oral AD
Arm/Group Description	Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003[NCT02493868]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 [NCT02493868]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Measure Participants	111	109
Median (Full Range) [Units on a scale]	-2.0	-2.0

13. Secondary Outcome

Title	Change From Baseline in Generalized Anxiety Disorder (GAD-7) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])
Description	GAD-7 is a brief and validated 7-item self-report assessment of overall anxiety. Participants respond to each item using a 4-point scale with response categories of 0=not at all, 1=several days, 2=more than half the days, and 3=nearly every day. Item responses are summed to yield a total score with a range of 0 to 21, where higher scores indicate more anxiety. The recall period is 2 weeks. The severity of the GAD-7 is categorized as follows: None (0-4), Mild (5-9), Moderate (10-14) and Severe (15 -21). The last post baseline observation during the phase was carried forward as "End Point" for that phase.
Time Frame	Baseline up to Endpoint (Double-blind Induction Phase [Day 28])

Outcome Measure Data

Analysis Population Description

FAS is defined as all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral AD medication during the double-blind induction phase. Here 'N' (overall number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.

Arm/Group Title	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)	Intranasal Placebo Plus Oral AD
Arm/Group Description	Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003[NCT02493868]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 [NCT02493868]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Measure Participants	110	102
Mean (Standard Deviation) [Units on a scale]	-7.9 (6.12)	-6.8 (5.75)

14. Secondary Outcome

Title	Change From Baseline in EQ 5D-5L-Health Status Index to End of Double-blind Induction Phase (Day 28)
Description	European Quality of Life Group-5 Dimension-5-Level (EQ-5D-5L) is a 2-part instrument for use as a measure of health outcome, designed for self-completion by respondents. It consists of EQ-5D-5L descriptive system and EQ VAS. EQ-5D-5L descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each has 5 levels of perceived problems (1-no problem, 2-slight problems, 3-moderate problems, 4-severe problems, 5-extreme problems). Participant selects answer for each of 5 dimensions considering response that best matches his/her health "today". Responses were used to generate a Health Status Index (HSI). Health Status Index range is -0.148 - 0.949, is anchored at 0 (dead) and 1 (full health).
Time Frame	Baseline up to End of Double-blind Induction Phase (Day 28)

Outcome Measure Data

Analysis Population Description

FAS is defined as all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral AD medication during the double-blind induction phase. Here 'N' (overall number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.

Arm/Group Title	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)	Intranasal Placebo Plus Oral AD
Arm/Group Description	Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003[NCT02493868]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 [NCT02493868]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Measure Participants	111	105
Mean (Standard Deviation) [Units on a Scale]	0.288 (0.2317)	0.231 (0.2506)

15. Secondary Outcome

Title	Change From Baseline in EQ 5D-5L- European Quality of Life - Visual Analogue Scale (EQ-VAS) to End of Double-blind Induction Phase (Day 28)
Description	EQ-5D-5L is a 2-part instrument for use as a measure of health outcome, designed for self-completion by respondents. It consists of EQ-5D-5L descriptive system and EQ VAS. The EQ VAS self-rating records the respondent's own assessment of his or her overall health status at the time of completion, on a scale of 0 (the worst health you can imagine) to 100 (the best health you can imagine).
Time Frame	Baseline up to End of Double-blind Induction Phase (Day 28)

Outcome Measure Data

Analysis Population Description

FAS is defined as all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral AD medication during the double blind induction phase. Here 'N' (overall number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.

Arm/Group Title	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)	Intranasal Placebo Plus Oral AD
Arm/Group Description	Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003[NCT02493868]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 [NCT02493868]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Measure Participants	111	105
Mean (Standard Deviation) [Units on a scale]	29.1 (26.32)	20.9 (26.60)

16. Secondary Outcome

Title	Change From Baseline in EQ 5D-5L- Sum Score to End of Double-blind Induction Phase (Day 28)
Description	EQ-5D-5L consists of EQ-5D-5L descriptive system and EQ visual analogue scale (EQ VAS). EQ-5D-5L descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each has 5 levels of perceived problems (1-no problem, 2-slight problems, 3-moderate problems, 4-severe problems, 5-extreme problems). Participant selects answer for each of 5 dimensions considering response that best matches his/her health "today". Responses were used to generate a Health Status Index (HSI). Health Status Index range is -0.148 - 0.949, is anchored at 0 (dead) and 1 (full health). EQ VAS self-rating records the respondent's own assessment of his/her overall health status at time of completion, on a scale of 0 (worst health you can imagine) to 100 (best health you can imagine). Sum score ranges from 0 to 100 where, sum score = (sum of the scores from the 5 dimensions minus 5) *5. Higher score indicates worst health state.
Time Frame	Baseline up to End of Double-blind Induction Phase (Day 28)

Outcome Measure Data

Analysis Population Description

FAS is defined as all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral AD medication during the double-blind induction phase. Here 'N' (overall number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.

Arm/Group Title	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)	Intranasal Placebo Plus Oral AD
Arm/Group Description	Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003[NCT02493868]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 [NCT02493868]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Measure Participants	111	105
Mean (Standard Deviation) [Units on a scale]	-23.2 (16.64)	-17.1 (19.66)

Adverse Events

Time Frame	Approximately up to 2.2 Years
Adverse Event Reporting Description	The safety analysis set included all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during the double-blind induction phase. The follow-up analysis set included all participants who entered the follow-up phase.
Arm/Group Title	DB Phase: Intranasal Esk + Oral AD		DB Phase: Oral AD + Intranasal Placebo		FU Phase: Intranasal Esk + Oral AD		FU Phase: Oral AD + Intranasal Placebo
Arm/Group Description	Participants self-administered (under direct supervision by health care professional [HCP]) esketamine either 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1, 4, 8, 11, 15, 18, 22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral antidepressant (AD) with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase.		Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1, 4, 8, 11, 15, 18, 22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase.		Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 [NCT02493868]) and had received at least 1 dose of intranasal Esk+ Oral AD in DB induction phase were followed in posttreatment follow-up (FU) phase for up to 24 weeks.		Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 [NCT02493868]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
All Cause Mortality
	DB Phase: Intranasal Esk + Oral AD		DB Phase: Oral AD + Intranasal Placebo		FU Phase: Intranasal Esk + Oral AD		FU Phase: Oral AD + Intranasal Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/115 (0.9%)		0/109 (0%)		0/34 (0%)		0/52 (0%)
Serious Adverse Events
	DB Phase: Intranasal Esk + Oral AD		DB Phase: Oral AD + Intranasal Placebo		FU Phase: Intranasal Esk + Oral AD		FU Phase: Oral AD + Intranasal Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/115 (0.9%)		1/109 (0.9%)		1/34 (2.9%)		0/52 (0%)
Ear and labyrinth disorders
Vertigo Positional	0/115 (0%)		1/109 (0.9%)		0/34 (0%)		0/52 (0%)
Injury, poisoning and procedural complications
Multiple Injuries	1/115 (0.9%)		0/109 (0%)		0/34 (0%)		0/52 (0%)
Road Traffic Accident	1/115 (0.9%)		0/109 (0%)		0/34 (0%)		0/52 (0%)
Nervous system disorders
Cerebral Haemorrhage	0/115 (0%)		0/109 (0%)		1/34 (2.9%)		0/52 (0%)
Other (Not Including Serious) Adverse Events
	DB Phase: Intranasal Esk + Oral AD		DB Phase: Oral AD + Intranasal Placebo		FU Phase: Intranasal Esk + Oral AD		FU Phase: Oral AD + Intranasal Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	90/115 (78.3%)		53/109 (48.6%)		7/34 (20.6%)		6/52 (11.5%)
Ear and labyrinth disorders
Vertigo	30/115 (26.1%)		3/109 (2.8%)		0/34 (0%)		0/52 (0%)
Eye disorders
Vision Blurred	14/115 (12.2%)		3/109 (2.8%)		0/34 (0%)		0/52 (0%)
Gastrointestinal disorders
Diarrhoea	10/115 (8.7%)		10/109 (9.2%)		1/34 (2.9%)		2/52 (3.8%)
Dry Mouth	9/115 (7.8%)		3/109 (2.8%)		1/34 (2.9%)		0/52 (0%)
Hypoaesthesia Oral	9/115 (7.8%)		1/109 (0.9%)		0/34 (0%)		0/52 (0%)
Nausea	30/115 (26.1%)		7/109 (6.4%)		1/34 (2.9%)		0/52 (0%)
Paraesthesia Oral	9/115 (7.8%)		1/109 (0.9%)		0/34 (0%)		0/52 (0%)
Vomiting	11/115 (9.6%)		2/109 (1.8%)		0/34 (0%)		0/52 (0%)
General disorders
Fatigue	5/115 (4.3%)		6/109 (5.5%)		0/34 (0%)		0/52 (0%)
Feeling Drunk	9/115 (7.8%)		1/109 (0.9%)		0/34 (0%)		0/52 (0%)
Infections and infestations
Upper Respiratory Tract Infection	0/115 (0%)		1/109 (0.9%)		3/34 (8.8%)		0/52 (0%)
Investigations
Blood Pressure Increased	11/115 (9.6%)		0/109 (0%)		0/34 (0%)		0/52 (0%)
Metabolism and nutrition disorders
Decreased Appetite	2/115 (1.7%)		3/109 (2.8%)		2/34 (5.9%)		0/52 (0%)
Nervous system disorders
Dizziness	24/115 (20.9%)		5/109 (4.6%)		1/34 (2.9%)		2/52 (3.8%)
Dizziness Postural	8/115 (7%)		1/109 (0.9%)		0/34 (0%)		0/52 (0%)
Dysgeusia	28/115 (24.3%)		13/109 (11.9%)		0/34 (0%)		0/52 (0%)
Headache	23/115 (20%)		19/109 (17.4%)		2/34 (5.9%)		1/52 (1.9%)
Hypoaesthesia	8/115 (7%)		1/109 (0.9%)		0/34 (0%)		0/52 (0%)
Paraesthesia	13/115 (11.3%)		1/109 (0.9%)		1/34 (2.9%)		0/52 (0%)
Somnolence	15/115 (13%)		7/109 (6.4%)		0/34 (0%)		0/52 (0%)
Psychiatric disorders
Anxiety	12/115 (10.4%)		5/109 (4.6%)		1/34 (2.9%)		1/52 (1.9%)
Dissociation	30/115 (26.1%)		4/109 (3.7%)		0/34 (0%)		0/52 (0%)
Insomnia	11/115 (9.6%)		5/109 (4.6%)		0/34 (0%)		1/52 (1.9%)
Respiratory, thoracic and mediastinal disorders
Nasal Discomfort	8/115 (7%)		2/109 (1.8%)		0/34 (0%)		0/52 (0%)
Throat Irritation	9/115 (7.8%)		5/109 (4.6%)		0/34 (0%)		0/52 (0%)

Limitations/Caveats

As this was a flexible-dose study, dose-response relationships could not be evaluated because direct comparisons between dose groups could not be made.

More Information

Certain Agreements

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

A copy of the manuscript must be provided to the sponsor for review at least 60 days before submission for publication or presentation. If requested in writing, such publication will be withheld for up to an additional 60 days.