Trial Outcomes & Findings for A Study to Evaluate the Efficacy, Pharmacokinetics, Safety and Tolerability of Flexible Doses of Intranasal Esketamine Plus an Oral Antidepressant in Adult Participants With Treatment-resistant Depression (NCT NCT03434041)

Last Updated: 2025-04-29

Results Overview

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

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

252 participants

Primary outcome timeframe

Baseline up to end of the double-blind treatment phase (Day 28)

Results posted on

2025-04-29

Participant Flow

Participant milestones

Participant milestones
Measure	Intranasal Esketamine + Oral Antidepressant (AD) Participants received intranasal esketamine 56 milligrams (mg) or 84 mg twice per week for 4 weeks as a flexible dose regimen. All participants started at a dose of 56 mg on Day 1. The dose could be increased to 84 mg or maintained at 56 mg per investigator's discretion. Participants simultaneously received 1 of the 4 open-label oral antidepressant treatment (duloxetine, escitalopram, sertraline, or venlafaxine extended release \[XR\]) on Day 1 that was continued for the duration of the 4-week Double-Blind Treatment Phase. The follow-up phase included participants who received at least 1 dose of intranasal study medication in the double-blind treatment phase. Participants received oral AD for 8 weeks in the follow-up phase unless it was determined not to be clinically appropriate.	Intranasal Placebo + Oral AD Participants received intranasal placebo twice per week for 4 weeks as a flexible dose regimen. Participants simultaneously received 1 of the 4 open-label oral antidepressant treatment (duloxetine, escitalopram, sertraline, or venlafaxine XR) on Day 1 that was continued for the duration of the 4-week Double-Blind Treatment Phase. The follow-up phase included participants who received at least 1 dose of intranasal study medication in the double-blind treatment phase. Participants received oral AD for 8 weeks in the follow-up phase unless it was determined not to be clinically appropriate.
Double Blind Treatment Phase (4 Weeks) STARTED	126	126
Double Blind Treatment Phase (4 Weeks) Full Analysis Set	124	126
Double Blind Treatment Phase (4 Weeks) COMPLETED	108	106
Double Blind Treatment Phase (4 Weeks) NOT COMPLETED	18	20
Follow-up Phase (Up to 8 Weeks) STARTED	106	103
Follow-up Phase (Up to 8 Weeks) COMPLETED	99	100
Follow-up Phase (Up to 8 Weeks) NOT COMPLETED	7	3

Reasons for withdrawal

Reasons for withdrawal
Measure	Intranasal Esketamine + Oral Antidepressant (AD) Participants received intranasal esketamine 56 milligrams (mg) or 84 mg twice per week for 4 weeks as a flexible dose regimen. All participants started at a dose of 56 mg on Day 1. The dose could be increased to 84 mg or maintained at 56 mg per investigator's discretion. Participants simultaneously received 1 of the 4 open-label oral antidepressant treatment (duloxetine, escitalopram, sertraline, or venlafaxine extended release \[XR\]) on Day 1 that was continued for the duration of the 4-week Double-Blind Treatment Phase. The follow-up phase included participants who received at least 1 dose of intranasal study medication in the double-blind treatment phase. Participants received oral AD for 8 weeks in the follow-up phase unless it was determined not to be clinically appropriate.	Intranasal Placebo + Oral AD Participants received intranasal placebo twice per week for 4 weeks as a flexible dose regimen. Participants simultaneously received 1 of the 4 open-label oral antidepressant treatment (duloxetine, escitalopram, sertraline, or venlafaxine XR) on Day 1 that was continued for the duration of the 4-week Double-Blind Treatment Phase. The follow-up phase included participants who received at least 1 dose of intranasal study medication in the double-blind treatment phase. Participants received oral AD for 8 weeks in the follow-up phase unless it was determined not to be clinically appropriate.
Double Blind Treatment Phase (4 Weeks) Lost to Follow-up	1	0
Double Blind Treatment Phase (4 Weeks) Withdrawal by Subject	2	1
Double Blind Treatment Phase (4 Weeks) Lack of Efficacy	3	14
Double Blind Treatment Phase (4 Weeks) Adverse Event	7	2
Double Blind Treatment Phase (4 Weeks) Death	1	0
Double Blind Treatment Phase (4 Weeks) Covid-19 related	2	2
Double Blind Treatment Phase (4 Weeks) Non-compliance with study drug	0	1
Double Blind Treatment Phase (4 Weeks) Other	2	0
Follow-up Phase (Up to 8 Weeks) Withdrawal by Subject	4	3
Follow-up Phase (Up to 8 Weeks) Adverse Event	2	0
Follow-up Phase (Up to 8 Weeks) Investigator decision to discontinue follow-up and proceed to 54135419TRD3008 (NCT02782104)	1	0

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Intranasal Esketamine + Oral Antidepressant (AD) n=126 Participants Participants received intranasal esketamine 56 milligrams (mg) or 84 mg twice per week for 4 weeks as a flexible dose regimen. All participants started at a dose of 56 mg on Day 1. The dose could be increased to 84 mg or maintained at 56 mg per investigator's discretion. Participants simultaneously received 1 of the 4 open-label oral antidepressant treatment (duloxetine, escitalopram, sertraline, or venlafaxine extended release \[XR\]) on Day 1 that was continued for the duration of the 4-week Double-Blind Treatment Phase. The follow-up phase included participants who received at least 1 dose of intranasal study medication in the double-blind treatment phase. Participants received oral AD for 8 weeks in the follow-up phase unless it was determined not to be clinically appropriate.	Intranasal Placebo + Oral AD n=126 Participants Participants received intranasal placebo twice per week for 4 weeks as a flexible dose regimen. Participants simultaneously received 1 of the 4 open-label oral antidepressant treatment (duloxetine, escitalopram, sertraline, or venlafaxine XR) on Day 1 that was continued for the duration of the 4-week Double-Blind Treatment Phase. The follow-up phase included participants who received at least 1 dose of intranasal study medication in the double-blind treatment phase. Participants received oral AD for 8 weeks in the follow-up phase unless it was determined not to be clinically appropriate.	Total n=252 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=39 Participants	0 Participants n=41 Participants	0 Participants n=35 Participants
Age, Categorical Between 18 and 65 years	126 Participants n=39 Participants	126 Participants n=41 Participants	252 Participants n=35 Participants
Age, Categorical >=65 years	0 Participants n=39 Participants	0 Participants n=41 Participants	0 Participants n=35 Participants
Age, Continuous	36.8 years STANDARD_DEVIATION 11.95 • n=39 Participants	37.8 years STANDARD_DEVIATION 12.36 • n=41 Participants	37.3 years STANDARD_DEVIATION 12.14 • n=35 Participants
Sex: Female, Male Female	58 Participants n=39 Participants	55 Participants n=41 Participants	113 Participants n=35 Participants
Sex: Female, Male Male	68 Participants n=39 Participants	71 Participants n=41 Participants	139 Participants n=35 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants n=39 Participants	1 Participants n=41 Participants	3 Participants n=35 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	121 Participants n=39 Participants	124 Participants n=41 Participants	245 Participants n=35 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	3 Participants n=39 Participants	1 Participants n=41 Participants	4 Participants n=35 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=39 Participants	0 Participants n=41 Participants	0 Participants n=35 Participants
Race (NIH/OMB) Asian	112 Participants n=39 Participants	112 Participants n=41 Participants	224 Participants n=35 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=39 Participants	0 Participants n=41 Participants	0 Participants n=35 Participants
Race (NIH/OMB) Black or African American	1 Participants n=39 Participants	4 Participants n=41 Participants	5 Participants n=35 Participants
Race (NIH/OMB) White	12 Participants n=39 Participants	9 Participants n=41 Participants	21 Participants n=35 Participants
Race (NIH/OMB) More than one race	1 Participants n=39 Participants	0 Participants n=41 Participants	1 Participants n=35 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=39 Participants	1 Participants n=41 Participants	1 Participants n=35 Participants
Region of Enrollment CHINA	112 Participants n=39 Participants	112 Participants n=41 Participants	224 Participants n=35 Participants
Region of Enrollment UNITED STATES	14 Participants n=39 Participants	14 Participants n=41 Participants	28 Participants n=35 Participants

PRIMARY outcome

Timeframe: Baseline up to end of the double-blind treatment phase (Day 28)

Population: Full analysis set included all randomized participants who received a least 1 dose of intranasal study medication and 1 dose of oral antidepressant medication during the double-blind treatment phase. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.

Outcome measures

Outcome measures
Measure	Intranasal Esketamine + Oral Antidepressant (AD) n=109 Participants Participants received intranasal esketamine 56 milligrams (mg) or 84 mg twice per week for 4 weeks as a flexible dose regimen. All participants started at a dose of 56 mg on Day 1. The dose could be increased to 84 mg or maintained at 56 mg per investigator's discretion. Participants simultaneously received 1 of the 4 open-label oral antidepressant treatment (duloxetine, escitalopram, sertraline, or venlafaxine extended release \[XR\]) on Day 1 that was continued for the duration of the 4-week Double-Blind Treatment Phase. The follow-up phase included participants who received at least 1 dose of intranasal study medication in the double-blind treatment phase. Participants received oral AD for 8 weeks in the follow-up phase unless it was determined not to be clinically appropriate.	Intranasal Placebo + Oral AD n=106 Participants Participants received intranasal placebo twice per week for 4 weeks as a flexible dose regimen. Participants simultaneously received 1 of the 4 open-label oral antidepressant treatment (duloxetine, escitalopram, sertraline, or venlafaxine XR) on Day 1 that was continued for the duration of the 4-week Double-Blind Treatment Phase. The follow-up phase included participants who received at least 1 dose of intranasal study medication in the double-blind treatment phase. Participants received oral AD for 8 weeks in the follow-up phase unless it was determined not to be clinically appropriate.
Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score to the End of Double-blind Treatment Phase (Day 28)	-10.1 Units on a Scale Standard Deviation 10.80	-8.1 Units on a Scale Standard Deviation 10.26

SECONDARY outcome

Timeframe: Baseline (Day 1: predose) to 24 hours post first dose (Day 2)

Outcome measures

Outcome measures
Measure	Intranasal Esketamine + Oral Antidepressant (AD) n=123 Participants Participants received intranasal esketamine 56 milligrams (mg) or 84 mg twice per week for 4 weeks as a flexible dose regimen. All participants started at a dose of 56 mg on Day 1. The dose could be increased to 84 mg or maintained at 56 mg per investigator's discretion. Participants simultaneously received 1 of the 4 open-label oral antidepressant treatment (duloxetine, escitalopram, sertraline, or venlafaxine extended release \[XR\]) on Day 1 that was continued for the duration of the 4-week Double-Blind Treatment Phase. The follow-up phase included participants who received at least 1 dose of intranasal study medication in the double-blind treatment phase. Participants received oral AD for 8 weeks in the follow-up phase unless it was determined not to be clinically appropriate.	Intranasal Placebo + Oral AD n=125 Participants Participants received intranasal placebo twice per week for 4 weeks as a flexible dose regimen. Participants simultaneously received 1 of the 4 open-label oral antidepressant treatment (duloxetine, escitalopram, sertraline, or venlafaxine XR) on Day 1 that was continued for the duration of the 4-week Double-Blind Treatment Phase. The follow-up phase included participants who received at least 1 dose of intranasal study medication in the double-blind treatment phase. Participants received oral AD for 8 weeks in the follow-up phase unless it was determined not to be clinically appropriate.
Change From Baseline in Depressive Symptoms as Measured by the MADRS Total Score to 24 Hours Post First Dose (Day 2)	-8.0 Units on a Scale Standard Deviation 9.01	-4.4 Units on a Scale Standard Deviation 7.66

SECONDARY outcome

Timeframe: Baseline up to end of the double-blind treatment phase (Day 28)

The SDS is a subject-reported outcome measure that consists of 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 are 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 underproductive.

Outcome measures

Outcome measures
Measure	Intranasal Esketamine + Oral Antidepressant (AD) n=99 Participants Participants received intranasal esketamine 56 milligrams (mg) or 84 mg twice per week for 4 weeks as a flexible dose regimen. All participants started at a dose of 56 mg on Day 1. The dose could be increased to 84 mg or maintained at 56 mg per investigator's discretion. Participants simultaneously received 1 of the 4 open-label oral antidepressant treatment (duloxetine, escitalopram, sertraline, or venlafaxine extended release \[XR\]) on Day 1 that was continued for the duration of the 4-week Double-Blind Treatment Phase. The follow-up phase included participants who received at least 1 dose of intranasal study medication in the double-blind treatment phase. Participants received oral AD for 8 weeks in the follow-up phase unless it was determined not to be clinically appropriate.	Intranasal Placebo + Oral AD n=98 Participants Participants received intranasal placebo twice per week for 4 weeks as a flexible dose regimen. Participants simultaneously received 1 of the 4 open-label oral antidepressant treatment (duloxetine, escitalopram, sertraline, or venlafaxine XR) on Day 1 that was continued for the duration of the 4-week Double-Blind Treatment Phase. The follow-up phase included participants who received at least 1 dose of intranasal study medication in the double-blind treatment phase. Participants received oral AD for 8 weeks in the follow-up phase unless it was determined not to be clinically appropriate.
Change From Baseline in Sheehan Disability Scale (SDS) Total Score to the End of Double-blind Treatment Phase (Day 28)	-6.3 Units on a Scale Standard Deviation 7.54	-5.3 Units on a Scale Standard Deviation 7.03

SECONDARY outcome

Timeframe: Day 2 up to Day 28

Onset of clinical response is defined as greater than or equal to (\>=) 50 percent (%) improvement from baseline in MADRS total score with onset by Day 2 that was maintained through Day 28. The MADRS scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, inability to feel (interest level), pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), summed for a total possible score range of 0 to 60. Higher scores represent a more severe condition. Negative change in score indicates improvement.

Outcome measures

Outcome measures
Measure	Intranasal Esketamine + Oral Antidepressant (AD) n=124 Participants Participants received intranasal esketamine 56 milligrams (mg) or 84 mg twice per week for 4 weeks as a flexible dose regimen. All participants started at a dose of 56 mg on Day 1. The dose could be increased to 84 mg or maintained at 56 mg per investigator's discretion. Participants simultaneously received 1 of the 4 open-label oral antidepressant treatment (duloxetine, escitalopram, sertraline, or venlafaxine extended release \[XR\]) on Day 1 that was continued for the duration of the 4-week Double-Blind Treatment Phase. The follow-up phase included participants who received at least 1 dose of intranasal study medication in the double-blind treatment phase. Participants received oral AD for 8 weeks in the follow-up phase unless it was determined not to be clinically appropriate.	Intranasal Placebo + Oral AD n=126 Participants Participants received intranasal placebo twice per week for 4 weeks as a flexible dose regimen. Participants simultaneously received 1 of the 4 open-label oral antidepressant treatment (duloxetine, escitalopram, sertraline, or venlafaxine XR) on Day 1 that was continued for the duration of the 4-week Double-Blind Treatment Phase. The follow-up phase included participants who received at least 1 dose of intranasal study medication in the double-blind treatment phase. Participants received oral AD for 8 weeks in the follow-up phase unless it was determined not to be clinically appropriate.
Percentage of Participants With Onset of Clinical Response	6.5 Percentage of participants	1.6 Percentage of participants

SECONDARY outcome

Timeframe: Day 28

Percentage of responders at the end of double-blind treatment phase (Day 28) were assessed. A participant was defined as a responder at a given time point if the percent improvement from baseline in MADRS total score is at least 50%. The MADRS scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, inability to feel (interest level), pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), summed for a total possible score range of 0 to 60. Higher scores represent a more severe condition. Negative change in score indicates improvement.

Outcome measures

Outcome measures
Measure	Intranasal Esketamine + Oral Antidepressant (AD) n=109 Participants Participants received intranasal esketamine 56 milligrams (mg) or 84 mg twice per week for 4 weeks as a flexible dose regimen. All participants started at a dose of 56 mg on Day 1. The dose could be increased to 84 mg or maintained at 56 mg per investigator's discretion. Participants simultaneously received 1 of the 4 open-label oral antidepressant treatment (duloxetine, escitalopram, sertraline, or venlafaxine extended release \[XR\]) on Day 1 that was continued for the duration of the 4-week Double-Blind Treatment Phase. The follow-up phase included participants who received at least 1 dose of intranasal study medication in the double-blind treatment phase. Participants received oral AD for 8 weeks in the follow-up phase unless it was determined not to be clinically appropriate.	Intranasal Placebo + Oral AD n=106 Participants Participants received intranasal placebo twice per week for 4 weeks as a flexible dose regimen. Participants simultaneously received 1 of the 4 open-label oral antidepressant treatment (duloxetine, escitalopram, sertraline, or venlafaxine XR) on Day 1 that was continued for the duration of the 4-week Double-Blind Treatment Phase. The follow-up phase included participants who received at least 1 dose of intranasal study medication in the double-blind treatment phase. Participants received oral AD for 8 weeks in the follow-up phase unless it was determined not to be clinically appropriate.
Percentage of Responders at the End of Double-blind Treatment Phase (Day 28)	19.3 Percentage of Responders	16.0 Percentage of Responders

SECONDARY outcome

Timeframe: Day 28

Percentage of participants in remission at the end of double-blind treatment phase (Day 28) were assessed. A participant was considered as a remitter if participant had a MADRS total score of less than or equal to \[\<=\] 12 at a visit. MADRS scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, inability to feel (interest level), pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), summed for a total possible score range of 0 to 60. Higher scores represent a more severe condition. Negative change in score indicates improvement.

Outcome measures

Outcome measures
Measure	Intranasal Esketamine + Oral Antidepressant (AD) n=109 Participants Participants received intranasal esketamine 56 milligrams (mg) or 84 mg twice per week for 4 weeks as a flexible dose regimen. All participants started at a dose of 56 mg on Day 1. The dose could be increased to 84 mg or maintained at 56 mg per investigator's discretion. Participants simultaneously received 1 of the 4 open-label oral antidepressant treatment (duloxetine, escitalopram, sertraline, or venlafaxine extended release \[XR\]) on Day 1 that was continued for the duration of the 4-week Double-Blind Treatment Phase. The follow-up phase included participants who received at least 1 dose of intranasal study medication in the double-blind treatment phase. Participants received oral AD for 8 weeks in the follow-up phase unless it was determined not to be clinically appropriate.	Intranasal Placebo + Oral AD n=106 Participants Participants received intranasal placebo twice per week for 4 weeks as a flexible dose regimen. Participants simultaneously received 1 of the 4 open-label oral antidepressant treatment (duloxetine, escitalopram, sertraline, or venlafaxine XR) on Day 1 that was continued for the duration of the 4-week Double-Blind Treatment Phase. The follow-up phase included participants who received at least 1 dose of intranasal study medication in the double-blind treatment phase. Participants received oral AD for 8 weeks in the follow-up phase unless it was determined not to be clinically appropriate.
Percentage of Participants in Remission at the End of Double-blind Treatment Phase (Day 28)	12.8 Percentage of Participants	10.4 Percentage of Participants

SECONDARY outcome

Timeframe: Up to Day 28

Sustained remission is defined as the first occurrence of remission (MADRS Total score \<=12) that was maintained through the Day 28 assessment with one excursion prior to Day 28. The MADRS scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, inability to feel (interest level), pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), summed for a total possible score range of 0 to 60. Higher scores represent a more severe condition. Negative change in score indicates improvement.

Outcome measures

Outcome measures
Measure	Intranasal Esketamine + Oral Antidepressant (AD) n=124 Participants Participants received intranasal esketamine 56 milligrams (mg) or 84 mg twice per week for 4 weeks as a flexible dose regimen. All participants started at a dose of 56 mg on Day 1. The dose could be increased to 84 mg or maintained at 56 mg per investigator's discretion. Participants simultaneously received 1 of the 4 open-label oral antidepressant treatment (duloxetine, escitalopram, sertraline, or venlafaxine extended release \[XR\]) on Day 1 that was continued for the duration of the 4-week Double-Blind Treatment Phase. The follow-up phase included participants who received at least 1 dose of intranasal study medication in the double-blind treatment phase. Participants received oral AD for 8 weeks in the follow-up phase unless it was determined not to be clinically appropriate.	Intranasal Placebo + Oral AD n=126 Participants Participants received intranasal placebo twice per week for 4 weeks as a flexible dose regimen. Participants simultaneously received 1 of the 4 open-label oral antidepressant treatment (duloxetine, escitalopram, sertraline, or venlafaxine XR) on Day 1 that was continued for the duration of the 4-week Double-Blind Treatment Phase. The follow-up phase included participants who received at least 1 dose of intranasal study medication in the double-blind treatment phase. Participants received oral AD for 8 weeks in the follow-up phase unless it was determined not to be clinically appropriate.
Percentage of Participants With Sustained Remission	5.6 Percentage of Participants	6.3 Percentage of Participants

SECONDARY outcome

Timeframe: Baseline up to Double-blind Endpoint (Day 28)

The CGI-S provides an overall clinician-determined summary measure of the severity of the participant's illness that takes into account all available information, including knowledge of the participant's history, psychosocial circumstances, symptoms, behavior, and the impact of the symptoms on the participant's ability to function. The CGI-S evaluates the severity of psychopathology on a scale of 1 to 7. Considering total clinical experience, a participant is assessed on severity of mental illness at the time of rating according to: 1=normal (not at all ill); 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=among the most extremely ill patients. The CGI-S permits a global evaluation of the participant's condition at a given time. Negative change in score indicates improvement. The last post-baseline observation during the double-blind phase was carried forward as Endpoint.

Outcome measures

Outcome measures
Measure	Intranasal Esketamine + Oral Antidepressant (AD) n=121 Participants Participants received intranasal esketamine 56 milligrams (mg) or 84 mg twice per week for 4 weeks as a flexible dose regimen. All participants started at a dose of 56 mg on Day 1. The dose could be increased to 84 mg or maintained at 56 mg per investigator's discretion. Participants simultaneously received 1 of the 4 open-label oral antidepressant treatment (duloxetine, escitalopram, sertraline, or venlafaxine extended release \[XR\]) on Day 1 that was continued for the duration of the 4-week Double-Blind Treatment Phase. The follow-up phase included participants who received at least 1 dose of intranasal study medication in the double-blind treatment phase. Participants received oral AD for 8 weeks in the follow-up phase unless it was determined not to be clinically appropriate.	Intranasal Placebo + Oral AD n=126 Participants Participants received intranasal placebo twice per week for 4 weeks as a flexible dose regimen. Participants simultaneously received 1 of the 4 open-label oral antidepressant treatment (duloxetine, escitalopram, sertraline, or venlafaxine XR) on Day 1 that was continued for the duration of the 4-week Double-Blind Treatment Phase. The follow-up phase included participants who received at least 1 dose of intranasal study medication in the double-blind treatment phase. Participants received oral AD for 8 weeks in the follow-up phase unless it was determined not to be clinically appropriate.
Change From Baseline in Clinical Global Impression Severity (CGI-S) Scale Score up to the Endpoint (Double-blind Treatment Phase [Day 28])	-1.0 Units on a Scale Interval -5.0 to 1.0	-1.0 Units on a Scale Interval -5.0 to 1.0

SECONDARY outcome

Timeframe: Baseline up to Endpoint (double-blind treatment phase [Day 28])

The GAD-7 is a brief and validated 7-item self-reported 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 double-blind phase was carried forward as the "Endpoint".

Outcome measures

Outcome measures
Measure	Intranasal Esketamine + Oral Antidepressant (AD) n=118 Participants Participants received intranasal esketamine 56 milligrams (mg) or 84 mg twice per week for 4 weeks as a flexible dose regimen. All participants started at a dose of 56 mg on Day 1. The dose could be increased to 84 mg or maintained at 56 mg per investigator's discretion. Participants simultaneously received 1 of the 4 open-label oral antidepressant treatment (duloxetine, escitalopram, sertraline, or venlafaxine extended release \[XR\]) on Day 1 that was continued for the duration of the 4-week Double-Blind Treatment Phase. The follow-up phase included participants who received at least 1 dose of intranasal study medication in the double-blind treatment phase. Participants received oral AD for 8 weeks in the follow-up phase unless it was determined not to be clinically appropriate.	Intranasal Placebo + Oral AD n=120 Participants Participants received intranasal placebo twice per week for 4 weeks as a flexible dose regimen. Participants simultaneously received 1 of the 4 open-label oral antidepressant treatment (duloxetine, escitalopram, sertraline, or venlafaxine XR) on Day 1 that was continued for the duration of the 4-week Double-Blind Treatment Phase. The follow-up phase included participants who received at least 1 dose of intranasal study medication in the double-blind treatment phase. Participants received oral AD for 8 weeks in the follow-up phase unless it was determined not to be clinically appropriate.
Change From Baseline in Generalized Anxiety Disorder 7-item (GAD-7) Scale Score up to the Endpoint (Double-blind Treatment Phase [Day 28])	-4.3 Units on a Scale Standard Deviation 5.65	-2.9 Units on a Scale Standard Deviation 5.28

SECONDARY outcome

Timeframe: Baseline up to Double-blind Endpoint (Day 28)

The EQ-5D-5L is a standardized 2-part instrument for use as a measure of health outcome, primarily designed for self-completion by respondents. It essentially consists of the EQ-5D-5L descriptive system and the EQ Visual Analogue Scale (EQ-VAS). The EQ-5D-5L descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each of the 5 dimensions is divided into 5 levels of perceived problems (Level 1 indicating no problem, Level 2 indicating slight problems, Level 3 indicating moderate problems, Level 4 indicating severe problems, and Level 5 indicating 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 HSI. Health Status Index ranges from -0.148 to 0.949, and is anchored at 0 (dead) and 1 (full health), a lower score indicates worse health.

Outcome measures

Outcome measures
Measure	Intranasal Esketamine + Oral Antidepressant (AD) n=120 Participants Participants received intranasal esketamine 56 milligrams (mg) or 84 mg twice per week for 4 weeks as a flexible dose regimen. All participants started at a dose of 56 mg on Day 1. The dose could be increased to 84 mg or maintained at 56 mg per investigator's discretion. Participants simultaneously received 1 of the 4 open-label oral antidepressant treatment (duloxetine, escitalopram, sertraline, or venlafaxine extended release \[XR\]) on Day 1 that was continued for the duration of the 4-week Double-Blind Treatment Phase. The follow-up phase included participants who received at least 1 dose of intranasal study medication in the double-blind treatment phase. Participants received oral AD for 8 weeks in the follow-up phase unless it was determined not to be clinically appropriate.	Intranasal Placebo + Oral AD n=123 Participants Participants received intranasal placebo twice per week for 4 weeks as a flexible dose regimen. Participants simultaneously received 1 of the 4 open-label oral antidepressant treatment (duloxetine, escitalopram, sertraline, or venlafaxine XR) on Day 1 that was continued for the duration of the 4-week Double-Blind Treatment Phase. The follow-up phase included participants who received at least 1 dose of intranasal study medication in the double-blind treatment phase. Participants received oral AD for 8 weeks in the follow-up phase unless it was determined not to be clinically appropriate.
Change From Baseline in Participant-Reported Health-Related Quality of Life as Assessed by EuroQol-5 Dimension-5 Level (EQ-5D-5L) Score up to the Endpoint (Double-blind Treatment Phase [Day 28]): Health Status Index	0.152 Units on a Scale Standard Deviation 0.2294	0.103 Units on a Scale Standard Deviation 0.2084

SECONDARY outcome

Timeframe: Baseline up to Double-blind Endpoint (Day 28)

The EQ-5D-5L is a standardized 2-part instrument for use as a measure of health outcome, primarily designed for self-completion by respondents. It essentially consists of the EQ-5D-5L descriptive system and the EQ-VAS. 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). Positive change in score indicates improvement.

Outcome measures

Outcome measures
Measure	Intranasal Esketamine + Oral Antidepressant (AD) n=120 Participants Participants received intranasal esketamine 56 milligrams (mg) or 84 mg twice per week for 4 weeks as a flexible dose regimen. All participants started at a dose of 56 mg on Day 1. The dose could be increased to 84 mg or maintained at 56 mg per investigator's discretion. Participants simultaneously received 1 of the 4 open-label oral antidepressant treatment (duloxetine, escitalopram, sertraline, or venlafaxine extended release \[XR\]) on Day 1 that was continued for the duration of the 4-week Double-Blind Treatment Phase. The follow-up phase included participants who received at least 1 dose of intranasal study medication in the double-blind treatment phase. Participants received oral AD for 8 weeks in the follow-up phase unless it was determined not to be clinically appropriate.	Intranasal Placebo + Oral AD n=123 Participants Participants received intranasal placebo twice per week for 4 weeks as a flexible dose regimen. Participants simultaneously received 1 of the 4 open-label oral antidepressant treatment (duloxetine, escitalopram, sertraline, or venlafaxine XR) on Day 1 that was continued for the duration of the 4-week Double-Blind Treatment Phase. The follow-up phase included participants who received at least 1 dose of intranasal study medication in the double-blind treatment phase. Participants received oral AD for 8 weeks in the follow-up phase unless it was determined not to be clinically appropriate.
Change From Baseline in Participant-Reported Health Status as Assessed by EuroQol-5 Dimension-5 Level (EQ-5D-5L) Score up to the Endpoint (Double-blind Treatment Phase [Day 28]): Visual Analogue Scale (VAS)	16.7 Units on a Scale Standard Deviation 20.47	11.9 Units on a Scale Standard Deviation 25.21

SECONDARY outcome

Timeframe: Baseline up to Double-blind Endpoint (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). HSI ranges from -0.148 to 0.949 and is anchored at 0 (health state value equal to 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.

Outcome measures

Outcome measures
Measure	Intranasal Esketamine + Oral Antidepressant (AD) n=120 Participants Participants received intranasal esketamine 56 milligrams (mg) or 84 mg twice per week for 4 weeks as a flexible dose regimen. All participants started at a dose of 56 mg on Day 1. The dose could be increased to 84 mg or maintained at 56 mg per investigator's discretion. Participants simultaneously received 1 of the 4 open-label oral antidepressant treatment (duloxetine, escitalopram, sertraline, or venlafaxine extended release \[XR\]) on Day 1 that was continued for the duration of the 4-week Double-Blind Treatment Phase. The follow-up phase included participants who received at least 1 dose of intranasal study medication in the double-blind treatment phase. Participants received oral AD for 8 weeks in the follow-up phase unless it was determined not to be clinically appropriate.	Intranasal Placebo + Oral AD n=123 Participants Participants received intranasal placebo twice per week for 4 weeks as a flexible dose regimen. Participants simultaneously received 1 of the 4 open-label oral antidepressant treatment (duloxetine, escitalopram, sertraline, or venlafaxine XR) on Day 1 that was continued for the duration of the 4-week Double-Blind Treatment Phase. The follow-up phase included participants who received at least 1 dose of intranasal study medication in the double-blind treatment phase. Participants received oral AD for 8 weeks in the follow-up phase unless it was determined not to be clinically appropriate.
Change From Baseline in Participant-Reported Health Status as Assessed by EuroQol-5 Dimension-5 Level (EQ-5D-5L) up to the Endpoint (Double-blind Treatment Phase [Day 28]): Sum Score	-13.4 Units on a Scale Standard Deviation 18.83	-9.5 Units on a Scale Standard Deviation 16.95

Adverse Events

Double-blind: Intranasal Esketamine+ Oral Antidepressant (AD)

Serious events: 3 serious events

Other events: 118 other events

Deaths: 1 deaths

Double-blind: Oral AD + Intranasal Placebo

Serious events: 3 serious events

Other events: 61 other events

Deaths: 0 deaths

Follow-up: Intranasal Esketamine+ Oral AD

Serious events: 2 serious events

Other events: 10 other events

Deaths: 0 deaths

Follow-up: Oral AD + Intranasal Placebo

Serious events: 2 serious events

Other events: 13 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Double-blind: Intranasal Esketamine+ Oral Antidepressant (AD) n=126 participants at risk Participants received intranasal esketamine 56 milligrams (mg) or 84 mg twice per week for 4 weeks as a flexible dose regimen. All participants started at a dose of 56 mg on Day 1. The dose could be increased to 84 mg or maintained at 56 mg per investigator's discretion. Participants simultaneously received 1 of the 4 open-label oral antidepressant treatment (duloxetine, escitalopram, sertraline, or venlafaxine extended release \[XR\]) on Day 1 that was continued for the duration of the 4-week Double-Blind Treatment Phase.	Double-blind: Oral AD + Intranasal Placebo n=126 participants at risk Participants received intranasal placebo twice per week for 4 weeks as a flexible dose regimen. Participants simultaneously received 1 of the 4 open-label oral antidepressant treatment (duloxetine, escitalopram, sertraline, or venlafaxine XR) on Day 1 that was continued for the duration of the 4-week Double-Blind Treatment Phase.	Follow-up: Intranasal Esketamine+ Oral AD n=106 participants at risk The follow-up phase included participants who received at least 1 dose of intranasal study medication in the double-blind treatment phase. Participants received oral AD for 8 weeks of the follow-up phase unless it was determined to not be clinically appropriate. No intranasal study medication was administered during this phase.	Follow-up: Oral AD + Intranasal Placebo n=103 participants at risk The follow-up phase included participants who received at least 1 dose of intranasal study medication in the double-blind treatment phase. Participants received oral AD for 8 weeks of the follow-up phase unless it was determined to not be clinically appropriate. No intranasal study medication was administered during this phase.
Hepatobiliary disorders Cholecystitis Acute	0.00% 0/126 • Up to 16 weeks The safety analysis set (SAS) 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 treatment phase. The Follow-up analysis set included all subjects who entered the follow-up phase. Safety analysis was done on SAS for double-blind phase and Follow-up analysis set for follow-up phase.	0.00% 0/126 • Up to 16 weeks The safety analysis set (SAS) 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 treatment phase. The Follow-up analysis set included all subjects who entered the follow-up phase. Safety analysis was done on SAS for double-blind phase and Follow-up analysis set for follow-up phase.	0.00% 0/106 • Up to 16 weeks The safety analysis set (SAS) 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 treatment phase. The Follow-up analysis set included all subjects who entered the follow-up phase. Safety analysis was done on SAS for double-blind phase and Follow-up analysis set for follow-up phase.	0.97% 1/103 • Up to 16 weeks The safety analysis set (SAS) 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 treatment phase. The Follow-up analysis set included all subjects who entered the follow-up phase. Safety analysis was done on SAS for double-blind phase and Follow-up analysis set for follow-up phase.
Psychiatric disorders Completed Suicide	0.79% 1/126 • Up to 16 weeks The safety analysis set (SAS) 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 treatment phase. The Follow-up analysis set included all subjects who entered the follow-up phase. Safety analysis was done on SAS for double-blind phase and Follow-up analysis set for follow-up phase.	0.00% 0/126 • Up to 16 weeks The safety analysis set (SAS) 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 treatment phase. The Follow-up analysis set included all subjects who entered the follow-up phase. Safety analysis was done on SAS for double-blind phase and Follow-up analysis set for follow-up phase.	0.00% 0/106 • Up to 16 weeks The safety analysis set (SAS) 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 treatment phase. The Follow-up analysis set included all subjects who entered the follow-up phase. Safety analysis was done on SAS for double-blind phase and Follow-up analysis set for follow-up phase.	0.00% 0/103 • Up to 16 weeks The safety analysis set (SAS) 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 treatment phase. The Follow-up analysis set included all subjects who entered the follow-up phase. Safety analysis was done on SAS for double-blind phase and Follow-up analysis set for follow-up phase.
Psychiatric disorders Depression	0.79% 1/126 • Up to 16 weeks The safety analysis set (SAS) 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 treatment phase. The Follow-up analysis set included all subjects who entered the follow-up phase. Safety analysis was done on SAS for double-blind phase and Follow-up analysis set for follow-up phase.	2.4% 3/126 • Up to 16 weeks The safety analysis set (SAS) 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 treatment phase. The Follow-up analysis set included all subjects who entered the follow-up phase. Safety analysis was done on SAS for double-blind phase and Follow-up analysis set for follow-up phase.	0.94% 1/106 • Up to 16 weeks The safety analysis set (SAS) 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 treatment phase. The Follow-up analysis set included all subjects who entered the follow-up phase. Safety analysis was done on SAS for double-blind phase and Follow-up analysis set for follow-up phase.	0.97% 1/103 • Up to 16 weeks The safety analysis set (SAS) 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 treatment phase. The Follow-up analysis set included all subjects who entered the follow-up phase. Safety analysis was done on SAS for double-blind phase and Follow-up analysis set for follow-up phase.
Psychiatric disorders Suicide Attempt	0.79% 1/126 • Up to 16 weeks The safety analysis set (SAS) 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 treatment phase. The Follow-up analysis set included all subjects who entered the follow-up phase. Safety analysis was done on SAS for double-blind phase and Follow-up analysis set for follow-up phase.	0.00% 0/126 • Up to 16 weeks The safety analysis set (SAS) 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 treatment phase. The Follow-up analysis set included all subjects who entered the follow-up phase. Safety analysis was done on SAS for double-blind phase and Follow-up analysis set for follow-up phase.	0.94% 1/106 • Up to 16 weeks The safety analysis set (SAS) 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 treatment phase. The Follow-up analysis set included all subjects who entered the follow-up phase. Safety analysis was done on SAS for double-blind phase and Follow-up analysis set for follow-up phase.	0.00% 0/103 • Up to 16 weeks The safety analysis set (SAS) 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 treatment phase. The Follow-up analysis set included all subjects who entered the follow-up phase. Safety analysis was done on SAS for double-blind phase and Follow-up analysis set for follow-up phase.

Other adverse events

Additional Information

DIRECTOR CLINICAL LEADER

Janssen Research & Development, LLC

Phone: 844-434-4210

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee If an investigator wishes to publish information from 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 by the sponsor in writing, the investigator will with hold such publication for up to an additional 60 days.
Publication restrictions are in place

Restriction type: OTHER