Clinical Trial Results:
A Double-blind, Randomized, Placebo-controlled Study to Evaluate the Efficacy and Safety of Intranasal Esketamine in Addition to Comprehensive Standard of Care for the Rapid Reduction of the Symptoms of Major Depressive Disorder, Including Suicidal Ideation, in Adult Subjects Assessed to be at Imminent Risk for Suicide
Summary
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EudraCT number |
2016-003990-17 |
Trial protocol |
SK DE HU ES BG |
Global end of trial date |
18 Dec 2018
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Results information
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Results version number |
v2(current) |
This version publication date |
14 Oct 2020
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First version publication date |
03 Jan 2020
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Other versions |
v1 |
Version creation reason |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
54135419SUI3001
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03039192 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Janssen Research & Development, LLC
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Sponsor organisation address |
920 US Route 202, Raritan,, United States, NJ 08869-0602
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Public contact |
Clinical Registry Group, Janssen Research & Development, LLC, ClinicalTrialsEU@its.jnj.com
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Scientific contact |
Clinical Registry Group, Janssen Research & Development, LLC, ClinicalTrialsEU@its.jnj.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
18 Dec 2018
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
18 Dec 2018
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary objective of this study was to evaluate the efficacy of intranasal esketamine 84 milligram (mg) compared with intranasal placebo in addition to comprehensive standard of care in reducing the symptoms of major depressive disorder (MDD), including suicidal ideation, in subjects who are assessed to be at imminent risk for suicide, as measured by the change from baseline on the Montgomery Asberg Depression Rating Scale (MADRS) total score at 24 hours post first dose.
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Protection of trial subjects |
This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements. Safety was evaluated based on the following variables: Adverse events, Clinical laboratory tests (hematology, serum chemistry, and urinalysis), Vital sign measurements, Physical examinations, electrocardiogram (ECG), Nasal examinations, Suicide Ideation and Behavior Assessment Tool (SIBAT), Dosing day assessments (pulse oximetry, MOAA/S, CADSS).
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
29 Jun 2017
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Bulgaria: 19
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Country: Number of subjects enrolled |
Germany: 18
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Country: Number of subjects enrolled |
Spain: 45
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Country: Number of subjects enrolled |
Estonia: 4
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Country: Number of subjects enrolled |
Hungary: 15
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Country: Number of subjects enrolled |
Korea, Republic of: 20
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Country: Number of subjects enrolled |
Malaysia: 16
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Country: Number of subjects enrolled |
Taiwan: 17
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Country: Number of subjects enrolled |
United States: 57
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Country: Number of subjects enrolled |
South Africa: 15
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Worldwide total number of subjects |
226
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EEA total number of subjects |
101
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
226
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
A total of 226 subjects were enrolled and treated. Of the 226 subjects, 114 enrolled in the esketamine nasal spray 84 mg + standard of care (SOC) antidepressant treatment group and 112 enrolled in the placebo nasal spray + SOC antidepressant treatment group. | ||||||||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator | ||||||||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Placebo Plus SOC Antidepressant treatment | ||||||||||||||||||||||||||||||||||||
Arm description |
Subjects self-administered placebo matched to esketamine intranasally (1 spray of placebo to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) plus received standard of care (SOC) antidepressant treatment which was initiated or optimized on Day 1. | ||||||||||||||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Nasal spray, solution
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Routes of administration |
Nasal use
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Dosage and administration details |
Subjects self-administered placebo intranasally (1 spray of placebo to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25).
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Arm title
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Esketamine 84 mg Plus SOC Antidepressant Treatment | ||||||||||||||||||||||||||||||||||||
Arm description |
Subjects self-administered esketamine 84 milligram (mg) intranasally (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) plus received SOC antidepressant treatment which was initiated or optimized on Day 1. | ||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Esketamine
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Investigational medicinal product code |
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Other name |
JNJ-54135419
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Pharmaceutical forms |
Nasal spray, solution
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Routes of administration |
Nasal use
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Dosage and administration details |
Subjects self-administered esketamine 84 milligram (mg) intranasally (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25)
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Baseline characteristics reporting groups
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Reporting group title |
Placebo Plus SOC Antidepressant treatment
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Reporting group description |
Subjects self-administered placebo matched to esketamine intranasally (1 spray of placebo to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) plus received standard of care (SOC) antidepressant treatment which was initiated or optimized on Day 1. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Esketamine 84 mg Plus SOC Antidepressant Treatment
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Reporting group description |
Subjects self-administered esketamine 84 milligram (mg) intranasally (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) plus received SOC antidepressant treatment which was initiated or optimized on Day 1. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Placebo Plus SOC Antidepressant treatment
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Reporting group description |
Subjects self-administered placebo matched to esketamine intranasally (1 spray of placebo to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) plus received standard of care (SOC) antidepressant treatment which was initiated or optimized on Day 1. | ||
Reporting group title |
Esketamine 84 mg Plus SOC Antidepressant Treatment
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Reporting group description |
Subjects self-administered esketamine 84 milligram (mg) intranasally (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) plus received SOC antidepressant treatment which was initiated or optimized on Day 1. |
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End point title |
Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score at 24 hours after the first dose (Day 2) During Double-blind Phase | ||||||||||||
End point 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. A negative change in score indicates improvement. Full efficacy analysis set included all randomized subjects who received at least 1 dose of intranasal study agent during the double-blind phase and have had both a baseline and a postbaseline evaluation for the MADRS total score or Clinical Global Impression –Severity of Suicidality - Revised (CGI-SS-R). Here, N (number of subjects analyzed) signifies number of subjects evaluable for this endpoint.
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End point type |
Primary
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End point timeframe |
Baseline (Day 1, predose) and 24 hours first post dose (Day 2)
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Comparison groups |
Placebo Plus SOC Antidepressant treatment v Esketamine 84 mg Plus SOC Antidepressant Treatment
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Number of subjects included in analysis |
223
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
P-value |
= 0.006 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Difference of Least Square Means | ||||||||||||
Point estimate |
-3.8
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-6.56 | ||||||||||||
upper limit |
-1.09 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
1.39
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End point title |
Change From Baseline in Clinical Global Impression of Severity of Suicidality- Revised (CGI-SS-R) Score at 24 hours after the first dose (Day 2) During Double-blind Phase | ||||||||||||
End point description |
CGI-SS-R was derived from the Clinical Global Impression Severity Scale (CGI-S), a global rating scale that gives an overall measure of the severity of a subjects illness. The CGI-SS-R rating is scored on a 7-point scale from 0 (normal, not at all suicidal) to 6 (among the most extremely suicidal subjects) a higher score indicates a more severe condition and a reduction in score indicates improvement (that is, lower severity of suicidality). Full efficacy analysis set included all randomized subjects who received at least 1 dose of intranasal study agent during the double-blind phase and have had both a baseline and a postbaseline evaluation for the MADRS total score or CGI-SS-R. Here, N (number of subjects analyzed) signifies number of subjects evaluable for this endpoint.
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End point type |
Secondary
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End point timeframe |
Baseline (Day 1, predose) and 24 hours first post dose (Day 2)
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No statistical analyses for this end point |
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End point title |
Number of Subjects Who Achieved Remission (MADRS Total Score Less Than or Equal to [<=] 12) Through the Double-blind Phase | |||||||||||||||||||||||||||||||||||||||
End point description |
Subjects who had a MADRS total score of <=12 were considered remitters. 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 and a negative change in score indicates improvement. Full efficacy analysis set included all randomized subjects who received at least 1 dose of intranasal study agent during the double-blind phase and have had both a baseline and a post-baseline evaluation for the MADRS total score or CGI-SS-R.
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End point type |
Secondary
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End point timeframe |
Days 1, 2, 4, 8, 11, 15, 18, 22 and Day 25 (predose and 4 hours postdose)
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No statistical analyses for this end point |
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End point title |
Change From Baseline in Montgomery Asberg Depression Rating Scale Total Score During Double-blind Phase | ||||||||||||||||||||||||||||||||||||||||||
End point 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 and a negative change in score indicates improvement. Full efficacy analysis set included all randomized subjects who received at least 1 dose of intranasal study agent during the double-blind phase and have had both a baseline and a post-baseline evaluation for the MADRS total score or CGI-SS-R. Here, 'n' (number analyzed) signifies number of subjects who were evaluable at specified time points.
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End point type |
Secondary
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End point timeframe |
Baseline and Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 (predose and 4 hours postdose)
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No statistical analyses for this end point |
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End point title |
Change From Baseline in Clinical Global Impression- Severity of Suicidality-Revised (CGI-SS-R) Through the Double-blind Phase | |||||||||||||||||||||||||||||||||||||||
End point description |
CGI-SS-R was derived from the Clinical Global Impression Severity Scale (CGI-S), a global rating scale that gives an overall measure of the severity of a subjects illness. The CGI-SS-R rating is scored on a 7-point scale from 0 (normal, not at all suicidal) to 6 (among the most extremely suicidal subjects). A higher score indicates a more severe condition. Negative change in score indicates improvement. Full efficacy analysis set included all randomized subjects who received at least 1 dose of intranasal study agent during the double-blind phase and have had both a baseline and a post-baseline evaluation for the MADRS total score or CGI-SS-R. Here, 'n' (number analyzed) signifies number of subjects who were evaluable at specified time points.
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End point type |
Secondary
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End point timeframe |
Baseline and Days 1, 2, 4, 8, 11, 15, 18, 22 and 25
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No statistical analyses for this end point |
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End point title |
Number of Subjects Who Achieved Resolution of Suicidality (CGI-SS-R Score of 0 or 1) Total score Through Double-blind Phase | ||||||||||||||||||||||||||||||||||||
End point description |
CGI-SS-R was derived from the Clinical Global Impression Severity Scale (CGI-S), a global rating scale that gives an overall measure of the severity of a subjects illness. The CGI-SS-R rating is scored on a 7-point scale from 0 (normal, not at all suicidal) to 6 (among the most extremely suicidal subjects). A higher score indicates a more severe condition. Negative change in score indicates improvement. A subject was considered to achieve resolution of suicidality at a given time point if the CGI-SS-R score was 0 (normal, not at all suicidal) or 1 (questionably suicidal). Full efficacy analysis set included all randomized subjects who received at least 1 dose of intranasal study agent during the double-blind phase and have had both a baseline and a post-baseline evaluation for the MADRS total score or CGI-SS-R.
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End point type |
Secondary
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End point timeframe |
Days 1, 2, 4, 8, 11, 15, 18, 22 and 25
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No statistical analyses for this end point |
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End point title |
Change From Baseline in Clinical Global Impression of Imminent Suicide Risk (CGI-SR-I) Scale Total Score Through Double-blind Phase | |||||||||||||||||||||||||||||||||||||||
End point description |
The CGI-SR-I is a scale summarizing the clinician’s best assessment of the likelihood that the subject will attempt suicide in the next 7 days. The CGI-SR-I rating is scored on a 7-point scale from 0 (no imminent suicide risk) to 6 (extreme imminent suicide risk). Score ranges from 0-6. A higher score indicates a more severe condition. Negative change in score indicates improvement. Full efficacy analysis set included all randomized subjects who received at least 1 dose of intranasal study agent during the double-blind phase and have had both a baseline and a post-baseline evaluation for the MADRS total score or CGI-SS-R. Here, 'n' (number analyzed) signifies number of subjects who were evaluable at specified time points.
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End point type |
Secondary
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End point timeframe |
Baseline and Days 1, 2, 4, 8, 11, 15, 18, 22 and 25
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No statistical analyses for this end point |
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End point title |
Change From Baseline in Beck Hopelessness Scale (BHS) Total Score at Day 8 and 25 During Double-blind Phase | ||||||||||||||||||
End point description |
BHS is a self-reported measure consists of 20 true-false items. 9 are keyed false and 11 are keyed true. These items fall within 3 domains: feelings about the future; loss of motivation; future expectations. For every statement, each response was assigned a score of 0 or 1. Total score is a sum of item responses. Ranges from 0-20. Total scores 0-3 are normal range, 4-8 identify mild hopelessness, 9-14 identify moderate hopelessness, greater than 14 identify severe hopelessness. Full efficacy analysis set included all randomized subjects who received at least 1 dose of intranasal study agent during double-blind phase and have had both a baseline and a post-baseline evaluation for MADRS total score or CGI-SS-R. Here, 'n' (number analyzed) signifies number of subjects who were evaluable at specified time points.
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End point type |
Secondary
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End point timeframe |
Baseline, Day 8 and 25
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No statistical analyses for this end point |
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End point title |
Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) Through Double-blind Phase: Health Status Index | |||||||||||||||||||||
End point description |
EQ-5D-5L measures health outcome. It consists of EQ-5D-5L descriptive system and EQ visual analogue scale (EQ-VAS). EQ-5D-5L system comprises following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each of 5 dimensions is divided into 5 levels of perceived problems (Level 1-no problem, Level 2-slight problems, Level 3-moderate problems, Level 4-severe problems, Level 5-extreme problems). Health Status Index ranges from 0.148 - 0.949, anchored at 0 (dead) and 1 (full health), a lower score indicates worse health. Full efficacy analysis set included all randomized subjects who received at least 1 dose of intranasal study agent during double-blind phase, have had both a baseline and a post-baseline evaluation for MADRS total score or CGI-SS-R. Here, 'n' (number analyzed) signifies number of subjects who were evaluable at specified time points.
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End point type |
Secondary
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End point timeframe |
Baseline and Days 2, 11 and 25
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No statistical analyses for this end point |
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End point title |
Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) Through Double-blind Phase: EQ-VAS | |||||||||||||||||||||
End point description |
EQ-5D-5L measures health outcome. It consists of EQ-5D-5L descriptive system and the EQ visual analogue scale (EQ-VAS). EQ-5D-5L system comprises following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each of 5 dimensions is divided into 5 levels of perceived problems (Level 1-no problem, Level 2-slight problems, Level 3-moderate problems, Level 4-severe problems, and Level 5-extreme problems). EQ-VAS score from 0 (worst health) to 100 (best health), positive change in score indicates improvement. Full efficacy analysis set included all randomized subjects who received at least 1 dose of intranasal study agent during double-blind phase, have had both a baseline and a post-baseline evaluation for MADRS total score or CGI-SS-R. Here, 'n' (number analyzed) signifies number of subjects who were evaluable at specified time points.
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End point type |
Secondary
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End point timeframe |
Baseline, Days 2, 11 and 25
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No statistical analyses for this end point |
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End point title |
Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) Through Double-blind Phase: Sum Score | |||||||||||||||||||||
End point description |
EQ-5D-5L measures health outcome. It consists of EQ-5D-5L system and EQ-VAS. EQ-5D-5L system comprises following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each of 5 dimensions is divided into 5 levels of perceived problems (Level 1-no problem, Level 2-slight problems, Level 3-moderate problems, Level 4-severe problems, and Level 5-extreme problems). Sum score=(sum of the scores from the 5 dimensions minus 5)*5”. Higher score indicates a more severe problem. Negative change in score indicates improvement. Full efficacy analysis set included all randomized subjects who received at least 1 dose of intranasal study agent during double-blind phase, have had both a baseline and a post-baseline evaluation for MADRS total score or CGI-SS-R. Here, 'n' (number analyzed) signifies number of subjects who were evaluable at specified time points.
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End point type |
Secondary
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End point timeframe |
Baseline, Days 2, 11 and 25
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No statistical analyses for this end point |
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End point title |
Change From Baseline in Quality of Life in Depression Scale (QLDS) Total Score Through Double-blind Phase | |||||||||||||||||||||
End point description |
The QLDS is a disease specific patient-reported outcome designed to assess health related quality of life in subjects with major depressive disorder (MDD). The instrument has a recall period of "at the moment", contains 34-items with "yes"/"no" or “true”/“not true” response options and takes approximately 5-10 minutes to complete. The score range is from 0 (good quality of life) to 34 (very poor quality of life). A higher score indicates a more severe condition. Negative change indicates improvement. Full efficacy analysis set included all randomized subjects who received at least 1 dose of intranasal study agent during the double-blind phase and have had both a baseline and a post-baseline evaluation for the MADRS total score or CGI-SS-R. Here, 'n' (number analyzed) signifies number of subjects who were evaluable at specified time points.
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End point type |
Secondary
|
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End point timeframe |
Baseline and Days 2, 11 and 25
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No statistical analyses for this end point |
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End point title |
Treatment Satisfaction Questionnaire for Medication (TSQM-9) Total Score Through Double-blind Phase | ||||||||||||||||||||||||||||||
End point description |
The TSQM-9 is a 9-item generic patient-reported outcome instrument to assess subject’s satisfaction with medication. It covers three domains (effectiveness, convenience, and global satisfaction) were each scored from 0 to 100 with a higher score indicating higher satisfaction and a lower score indicates lower satisfaction. Full efficacy analysis set included all randomized subjects who received at least 1 dose of intranasal study agent during the double-blind phase and have had both a baseline and a post-baseline evaluation for the MADRS total score or CGI-SS-R. Here, 'n' (number analyzed) signifies number of subjects who were evaluable at specified time points.
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End point type |
Secondary
|
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End point timeframe |
Days 15 and 25
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No statistical analyses for this end point |
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End point title |
Change From Baseline in Suicide Ideation and Behavior Assessment Tool (SIBAT) Module 5 (My Risk) Question 3 (Patient-reported FoST) Total Score Through Double-blind Phase | |||||||||||||||||||||||||||||||||||||||
End point description |
SIBAT Module 5 (My Risk) Question 3, Assessment of Frequency of Suicidal Thinking (FoST), asks patients to describe their thinking about suicide right now. There are 5 response options ranging from “I have no suicidal thoughts” to “I have suicidal thoughts all of the time” and ranges from 0 to 4. A higher score indicates a more severe condition. Negative change in score indicates improvement. Full efficacy analysis set included all randomized subjects who received at least 1 dose of intranasal study agent during the double-blind phase and have had both a baseline and a post-baseline evaluation for the MADRS total score or CGI-SS-R. Here, 'n' (number analyzed) signifies number of subjects who were evaluable at specified time points.
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End point type |
Secondary
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End point timeframe |
Baseline, Days 1, 2, 4, 8, 11, 15, 18, 22 and 25
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No statistical analyses for this end point |
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End point title |
Change From Baseline in Suicide Ideation and Behavior Assessment Tool (SIBAT) Module 7 – Clinician-rated FoST Total Score During Double-blind Phase | |||||||||||||||||||||||||||||||||||||||
End point description |
SIBAT Module 7 Assessment of frequency of suicidal thinking (FoST) is a clinician-reported global impression with response options of “Never”, “Rarely”, “Sometimes”, “Often”, “Most of the time”, and “All of the time.” The score ranges from 0 to 5. A higher score indicates a more severe condition. Negative change in score indicates improvement. Full efficacy analysis set included all randomized subjects who received at least 1 dose of intranasal study agent during the double-blind phase and have had both a baseline and a post-baseline evaluation for the MADRS total score or CGI-SS-R. Here, 'n' (number analyzed) signifies number of subjects who were evaluable at specified time points.
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End point type |
Secondary
|
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End point timeframe |
Baseline and Days 1, 2, 4, 8, 11, 15, 18, 22 and 25
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No statistical analyses for this end point |
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End point title |
Number of Subjects with Treatment Emergent Adverse events (TEAEs): DB Treatment Phase | |||||||||
End point description |
An adverse event (AE) is any untoward medical occurrence in a clinical study subject administered a medicinal (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal finding), symptom, or disease temporally associated with the use of a medicinal (investigational or non investigational) product, whether or not related to that medicinal (investigational or non-investigational) product. A TEAE is categorized as related if assessed by the investigator as possibly, probably, or very likely related to study agent. Safety analysis set included all randomized subjects who received at least 1 dose of study drug in the DB treatment phase.
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
Up to Day 25
|
|||||||||
|
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No statistical analyses for this end point |
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End point title |
Number of Subjects With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Low and high abnormal values are as follows: ALT-high=200 Units per liter(U/L); ALP-high=250U/L; aspartate aminotransferase(AST)-high=250U/L; gamma glutamyl transferase(GGT)=300U/L; Albumin(24-60 g/L); Bicarbonate(15.1-34.9 millimoles per liter [mmol/L]); Bilirubin(high=51.3micromol/L[mcm/L]); calcium(1.5-3mmol/L);Chloride(94-112mmol/L); CK(high=990U/L); Creatinine(high=265.2 mcm/L); Eosinophils(high=10%); Erythrocytes(3.0*10^12/L-6.4*10^12/L); Glucose(2.2-16.7mmol/L); Hemoglobin(80-190g/L);Hematocrit(0.28-0.55 fraction); LD(high=500U/L); Leukocytes(2.5*10^9/L-15.5*10^9/L); Lymphocytes(10-60%); Monocytes(high=20%); Neutrophils(low-high: 30-90%); Phosphate(0.7-2.6mmol/L); Platelet count(100*10^9/L-600*10^9/L]; Potassium(3.0-5.8 mmol/L]; Protein(low=50 g/L); Sodium(125-155 mmol/L); Urate(89.2-594.8 mcm/L); Urine(high=8.0 pH). Analysis was done on safety analysis set. ‘n’ (number analyzed)= subjects evaluable for each category.
|
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End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Up to Day 25
|
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No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Number of Subjects With Abnormal Nasal Examinations at Day 25: DB Treatment Phase | |||||||||||||||||||||||||||||||||||||||||||||
End point description |
Number of subjects with abnormal nasal examination were reported. Nasal examination of visual inspection of the epistaxis, nasal crusts, nasal discharge, and nasal erythema was performed. Safety analysis set included all randomized subjects who received at least 1 dose of study drug in the DB treatment phase. Here, ‘n’ (number analyzed) signifies number of subjects analyzed for each specified category.
|
|||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
At Day 25
|
|||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||
End point title |
Number of Subjects With Treatment Emergent Abnormal Electrocardiogram (ECG) Values at Any Time: DB Treatment Phase | ||||||||||||||||||||||||||||||
End point description |
Number of subjects with treatment emergent abnormal ECG values for variables including heart rate (abnormally low refers to less than or equal to [<=] 50 beats per minute [bpm] , abnormally high refers greater than or equal to [>=] 100 bpm), pulse rate (PR) interval (abnormally high refers to >= 210 milliseconds [msec]), QRS interval (abnormally Low refers to <= 50, abnormally high refers to >= 120 msec) and QT interval (abnormally low refers to <= 200, abnormally high >= 500 msec) were reported. Safety analysis set included all randomized subjects who received at least 1 dose of study drug in the DB treatment phase.
|
||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||
End point timeframe |
Up to Day 25
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||
End point title |
Number of Subjects with Abnormal Arterial Oxygen Saturation (SpO2) Levels (less than [<] 93%) as Assessed by Pulse Oximetry at Any Time: DB Treatment Phase | |||||||||
End point description |
Pulse oximetry was used to measure arterial SpO2 levels. On each dosing day, the device was attached to the finger, toe, or ear, and SpO2 was monitored and documented. If oxygen saturation levels were less than (<) 93% at any time during the 1.5 hours postdose interval, pulse oximetry was recorded every 5 minutes until levels return to >= 93% or until the participant is referred for appropriate medical care, if clinically indicated. Participants with at least 2 consecutive postdose oxygen saturation below 93% during the DB treatment phase were reported. Safety analysis set included all randomized participants who received at least 1 dose of study drug in the DB treatment phase.
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
Up to Day 25
|
|||||||||
|
||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||
End point title |
Number of Subjects With Treatment Emergent Vital Signs Abnormalities: DB Treatment Phase | |||||||||||||||||||||||||||
End point description |
Number of participants with treatment emergent vital signs abnormalities (pulse rate in bpm [abnormally low = a decrease from baseline of >= 15 to a value <= 50; abnormally high = an increase from baseline of >=15 to a value >=100] , systolic blood pressure [SBP] in mmHg [abnormally low = a decrease from baseline of >= 20 to a value <= 90; abnormally high = an increase from baseline of >= 20 to a value >= 180], and diastolic blood pressure [DBP] in mmHg [abnormally low= a decrease from baseline of >=15 to a value <= 50; abnormally high = an increase from baseline of >= 15 to a value >= 105) were reported. Safety analysis set included all randomized subjects who received at least 1 dose of study drug in the DB treatment phase.
|
|||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||
End point timeframe |
Up to Day 25
|
|||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||
End point title |
Number of Sedated Subjects as Assessed by Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) Score at any Time: DB Treatment Phase | ||||||||||||||||||
End point description |
MOAA/S was used to measure treatment-emergent sedation with correlation to levels of sedation defined by the American society of anesthesiologists (ASA) continuum. The MOAA/S scores range from 0 to 5 where,0 = no response to painful stimulus; ASA continuum = general anesthesia, 1 = responds to trapezius squeeze; ASA continuum = deep sedation, 2 = purposeful response to mild prodding or mild shaking; ASA continuum = moderate sedation, 3 = responds after name called loudly or repeatedly; ASA continuum = moderate sedation, 4 = lethargic response to name spoken in normal tone; ASA continuum = moderate sedation and 5 = readily responds to name spoken in normal tone (awake); ASA continuum = minimal sedation. Safety analysis set included all randomized subjects who received at least 1 dose of study drug in the DB treatment phase.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Up to Day 25
|
||||||||||||||||||
|
|||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||
End point title |
Number of Subjects With an Increase in Clinician-administered Dissociative States Scale (CADSS) Total Score: DB Treatment Phase | |||||||||||||||||||||||||||||||||
End point description |
The CADSS used to measure present-state dissociative symptoms, and to assess treatment-emergent dissociative symptoms. It comprises 23 subjective items divided into 3 components: depersonalization (with score range from 0 to 28), derealization (with score range from 0 to 52), and amnesia (with score range from 0 to 8). Subjects responses are coded on a 5-point scale (0 = "Not at all", 1 = "Mild", 2 = "Moderate", 3 = 'Severe" and 4 = "Extreme"). The total score is sum of the 23 items and range from 0 to 92, where 0 (best) and 92 (worst). A higher score indicates a more severe condition. Number of subjects with an increase in CADSS total score (increase based on maximum CADSS total score change from predose of > 0) was reported. Safety analysis set included all randomized subjects who received at least 1 dose of study drug in the DB treatment phase. Here, 'n' (number analyzed) signifies the number of subjects analyzed for each specified time point.
|
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End point type |
Secondary
|
|||||||||||||||||||||||||||||||||
End point timeframe |
Days 1, 4, 8, 11, 15, 18, 22 and 25
|
|||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
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Timeframe for reporting adverse events |
Up to Day 25
|
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Adverse event reporting additional description |
Safety analysis set included all randomized subjects who received at least 1 dose of study agent in the double-blind treatment phase.
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Assessment type |
Non-systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
21.1
|
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Reporting groups
|
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Reporting group title |
Placebo Plus SOC Antidepressant treatment (Placebo)
|
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Reporting group description |
Subjects self-administered placebo intranasally (1 spray of placebo to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) plus standard of care (SOC) antidepressant treatment which was initiated on Day 1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Esketamine 84 mg Plus SOC Antidepressant Treatment
|
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Reporting group description |
Subjects self-administered esketamine 84 milligram (mg) intranasally (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) plus SOC antidepressant treatment which was initiated on Day 1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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|
|||
Substantial protocol amendments (globally) |
|||
Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
07 Apr 2017 |
The overall reason for the amendment was to revise based on comments received during an initial Voluntary Harmonisation Procedure (VHP) assessment; the following changes are included: Duration of hospitalization without the need for discussion with the Sponsor updated, A remote contact at Day 35 was added to the Time and Events Schedule, Exclusion criteria were revised to explicitly specify a detailed list of important medical conditions which are exclusionary, Text was added to emphasize that subjects may participate in the study only if they have adequate capacity to give consent and after fully understanding the potential risks, benefits, and potential adverse events of the study. |
||
20 Apr 2017 |
The overall reason for the amendment was to update and/or clarify protocol content based on feedback received during study initiation activities. Exclusion criterion was revised to clarify which potential subjects are excluded from participation in the study due to substance or alcohol use disorder, a positive urine test result; to clarify that subjects who were previously enrolled in this study or the Sponsor’s other studies in this population (54135419SUI3002 and ESKETINSUI2001) are excluded from participation in this study. |
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08 Feb 2018 |
The overall reason for the amendment was to remove the interim analysis from the 54135419SUI3001 protocol; to clarify that Module 3 Suicide Ideation and Behavior Assessment Tool (SIBAT) was an exploratory objective; to modify the timing of screening procedures to be consistent with the Time and Events Schedule; to clarify which potential subjects were not excluded from participation in the 54135419SUI3001 study due to having a positive screening test for prescribed psychostimulants that are permitted during the study; and updated text regarding the presentation of nasal examination data. |
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Interruptions (globally) |
|||
Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
Esketamine has known effects that may impact blinding, these treatment-emergent events potentially could have biased research staff. To minimize this bias, protocol specified that different raters perform efficacy, safety assessments. |