Clinical Trial Results:
A Double-blind, Placebo-controlled, Multicenter Study of Sirukumab as Adjunctive Treatment to a Monoaminergic Antidepressant in Adults with Major Depressive Disorder
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Summary
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EudraCT number |
2014-005206-37 |
Trial protocol |
PL GB |
Global end of trial date |
22 May 2018
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Results information
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Results version number |
v1(current) |
This version publication date |
06 Jun 2019
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First version publication date |
06 Jun 2019
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Other versions |
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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 |
CNTO136MDD2001
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02473289 | ||
WHO universal trial number (UTN) |
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Sponsors
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Sponsor organisation name |
Janssen Research & Development, LLC
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Sponsor organisation address |
920 Route, New Jersey, United States, 08869
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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 |
22 May 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 |
22 May 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 main objective of this study was to evaluate the efficacy of sirukumab as adjunctive treatment to monoaminergic antidepressant therapy where sirukumab (administered as a 50 milligram [mg] subcutaneous [SC] injection at Day 1, Day 28 and Day 56 during the 12 week double-blind treatment period) was compared to adjunctive placebo (placebo) based on the change from baseline to 12 week in the depressive symptoms as measured by the total score on the Hamilton Depression Rating Scale (HDRS-17), in subjects diagnosed with Major Depressive Disorder (MDD) who have had a suboptimal response to the current standard oral antidepressant therapy and had a screening and baseline high sensitivity C-Reactive Protein (hsCRP) greater than or equal to (>=) 0.300 milligrams per deciliter (mg/dL) (International system of units [SI] 3.00 mg/L).
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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 evaluations included monitoring of adverse events (AEs), clinical laboratory tests (hsCRP), hematology, serum chemistry, lipids, and urinalysis), electrocardiograms (ECGs), vital sign measurements (oral temperature, pulse/heart rate, blood pressure), physical examinations, suicidal risk (closely monitored throughout the study for clinical worsening, suicidality, and/or unusual changes in behavior), suicidal ideation and behavior (assessed via Columbia Suicide Severity Rating Scale [C-SSRS]), allergic reactions, injection-site reactions, hepatobiliary abnormalities and early detection of active tuberculosis (TB) and hepatobiliary abnormalities.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
03 Aug 2015
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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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 |
Canada: 7
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Country: Number of subjects enrolled |
United Kingdom: 3
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Country: Number of subjects enrolled |
Poland: 40
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Country: Number of subjects enrolled |
Russian Federation: 95
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Country: Number of subjects enrolled |
United States: 48
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Worldwide total number of subjects |
193
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EEA total number of subjects |
43
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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) |
193
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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 |
- | ||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
A total of 193 subjects were randomized to one of the two treatment groups: sirukumab 50 milligram (mg) (94 subjects) or placebo (99 subjects) group, out of which 169 subjects completed the study. | ||||||||||||||||||||||||||||||
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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 | ||||||||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Placebo | ||||||||||||||||||||||||||||||
Arm description |
Subjects received placebo subcutaneous (SC) injection on Day 1, Day 28 and Day 56, while continuing their baseline oral monoaminergic antidepressant(s). | ||||||||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||||||||
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 |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Subjects received placebo on Day 1, Day 28 and Day 56, while continuing their baseline oral monoaminergic antidepressant(s).
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Arm title
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Sirukumab 50 mg | ||||||||||||||||||||||||||||||
Arm description |
Subjects received sirukumab 50 milligram (mg) on Day 1, Day 28 and Day 56, while continuing their baseline oral monoaminergic antidepressant(s). | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Sirukumab
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Subjects received sirukumab 50 milligram (mg) on Day 1, Day 28 and Day 56, while continuing their baseline oral monoaminergic antidepressant(s).
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Baseline characteristics reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Subjects received placebo subcutaneous (SC) injection on Day 1, Day 28 and Day 56, while continuing their baseline oral monoaminergic antidepressant(s). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Sirukumab 50 mg
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Reporting group description |
Subjects received sirukumab 50 milligram (mg) on Day 1, Day 28 and Day 56, while continuing their baseline oral monoaminergic antidepressant(s). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Subjects received placebo subcutaneous (SC) injection on Day 1, Day 28 and Day 56, while continuing their baseline oral monoaminergic antidepressant(s). | ||
Reporting group title |
Sirukumab 50 mg
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Reporting group description |
Subjects received sirukumab 50 milligram (mg) on Day 1, Day 28 and Day 56, while continuing their baseline oral monoaminergic antidepressant(s). | ||
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End point title |
Change From Baseline in Hamilton Depression Rating Scale (HDRS-17) Total Score at Week 12 | ||||||||||||
End point description |
HDRS-17 is a clinician-administered rating scale designed to assess severity of symptoms in subjects with depression with score range of 0 to 52. Each of the 17 items is rated by clinician on either 3-point (0 to 2) or 5-point scale (0 to 4). The point scale used a rating of 0 (absent), 1 (doubtful to mild), 2 (mild to moderate), 3 (moderate to severe), and 4 (very severe). A total score (0 to 52) was calculated by adding the scores of all 17 items. For each item as well as the total score, a higher score represents a more severe condition. Modified Intent-to-treat 1 (mITT1) analysis set: all randomized subjects with high sensitivity c-reactive protein (hsCRP) >= 3.00 milligram per liter (mg/L) at screening and baseline who receive at least 1 dose of study drug and have both baseline and at least one postbaseline HDRS-17 total score in double-blind (DB) treatment period. Here 'N' (number of subjects analyzed) signifies number of subjects who were evaluable for this endpoint.
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End point type |
Primary
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End point timeframe |
Baseline and Week 12
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
Total 44 subjects were included in this statistical analysis. Here 'MMRM' refers to Mixed-effect Model Using Repeated Measures.
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Comparison groups |
Sirukumab 50 mg v Placebo
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Number of subjects included in analysis |
86
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.31 [1] | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Difference of Least Square (LS) Means | ||||||||||||
Point estimate |
-0.8
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Confidence interval |
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75% | ||||||||||||
sides |
2-sided
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lower limit |
-2.77 | ||||||||||||
upper limit |
1.1 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
1.67
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End point title |
Change From Baseline in HDRS-17 Total Score at Weeks 1, 4 and 8 | |||||||||||||||||||||
End point description |
The HDRS-17 is a clinician-administered rating scale designed to assess the severity of symptoms in subjects diagnosed with depression with a score range of 0 to 52. Each of the 17 items is rated by the clinician on either a 3-point (0 to 2) or a 5-point scale (0 to 4). The point scale used a rating of 0 (absent), 1 (doubtful to mild), 2 (mild to moderate), 3 (moderate to severe), and 4 (very severe). A total score (0 to 52) was calculated by adding the scores of all 17 items. For each item as well as the total score, a higher score represents a more severe condition. mITT1 analysis set: all randomized participants with hsCRP >= 3.00 mg/L at screening and baseline who receive at least 1 dose of study drug and have both baseline and at least one postbaseline HDRS-17 total score in DB treatment period. 'n' (number of subjects analyzed)- number of subjects analyzed at each specified timepoint, for each arm.
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End point type |
Secondary
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End point timeframe |
Baseline, Weeks 1, 4 and 8
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| No statistical analyses for this end point | ||||||||||||||||||||||
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End point title |
Percentage of Subjects with Remission as Assessed by HDRS-17 Total Score at Week 12 | ||||||||||||
End point description |
Remission- Percentage of subjects with HDRS-17 total score less than or equal to (<=) 7 were considered as remitters. HDRS-17 defined as clinician-administered rating scale designed to assess severity of symptoms in subjects diagnosed with depression with score range of 0 to 52. Each of 17 items is rated by clinician on either a 3-point (0 to 2) or a 5-point scale (0 to 4). The point scale used a rating of 0 (absent), 1 (doubtful to mild), 2 (mild to moderate), 3 (moderate to severe), and 4 (very severe). A total score (0 to 52) was calculated by adding scores of all 17 items. For each item as well as total score, a higher score represents a more severe condition. mITT1 analysis set: all randomized subjects with hsCRP >=3.00 mg/L at screening and baseline who receive at least 1 dose of study drug and have both baseline and at least one postbaseline HDRS-17 total score in DB treatment period. 'N' (number of subjects analyzed)- number of subjects who were evaluable for this endpoint.
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End point type |
Secondary
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End point timeframe |
Week 12
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Percentage of Subjects with Response as Assessed by HDRS-17 Total Score at Week 12 | ||||||||||||
End point description |
Response- Percentage of subjects with greater than or equal to (>=) 50 percent (%) improvement on HDRS-17 total score from baseline at Week 12 were considered as responders. HDRS-17 is clinician-administered rating scale designed to assess severity of symptoms in subjects with depression with score range 0-52. Each of 17 items rated by clinician either 3-point (0-2) or 5-point scale (0-4). Point scale used rating of 0 (absent), 1 (doubtful to mild), 2 (mild to moderate), 3 (moderate to severe), and 4 (very severe). Total score (0-52) was calculated by adding scores of all 17 items. For each item as well as total score, higher score represents more severe condition. mITT1 analysis set: all randomized subjects with hsCRP >= 3.00 mg/L at screening and baseline who receive at least 1 dose of study drug and have both baseline and at least one postbaseline HDRS-17 total score in DB treatment period. 'N' (number of subjects analyzed)- number of subjects who were evaluable for this endpoint.
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End point type |
Secondary
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End point timeframe |
Week 12
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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 (CGI-S) Total Score at Weeks 1, 4, 8, 12, 16, and 22 | ||||||||||||||||||||||||||||||
End point description |
CGI-S defined as clinician-rated scale that assesses the severity of mental illness on a scale of 0 to 7. Considering total clinical experience, a subject was 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. A higher score implies a more severe condition. mITT1 analysis set: all randomized subjects with hsCRP >= 3.00 mg/L at screening and baseline who receive at least 1 dose of study drug and have both baseline and at least one postbaseline HDRS-17 total score in DB treatment period. 'n' (number of subjects analyzed)- number of subjects analyzed at each specified timepoint, for each arm.
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End point type |
Secondary
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End point timeframe |
Baseline and Weeks 1, 4, 8, 12, 16, and 22
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
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End point title |
Change From Baseline in Patient Health Questionnaire (PHQ-9) Total Score at Weeks 1, 4, 8, 12, 16, and 22 | ||||||||||||||||||||||||||||||
End point description |
The PHQ-9 used as a subject-reported measure of depressive symptomatology. The PHQ-9 is 9-item scale, where each item is rated on a 4-point scale (0=Not at all, 1=Several Days, 2=More than half the days, and 3=Nearly every day). The subject's item responses were summed to provide a total score range of 0 to 27. Higher scores indicates greater severity of depressive symptoms. The recall period is 2 weeks. mITT1 analysis set: all randomized participants with hsCRP >= 3.00 mg/L at screening and baseline who receive at least 1 dose of study drug and have both baseline and at least one postbaseline HDRS-17 total score in DB treatment period. 'n' (number of subjects analyzed)- number of subjects analyzed at each specified timepoint, for each arm.
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End point type |
Secondary
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End point timeframe |
Baseline and Weeks 1, 4, 8, 12, 16, and 22
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
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End point title |
Change From Baseline in Snaith Hamilton Pleasure Scale (SHAPS) Total Score (Definition 1) at Weeks 1, 4, 8, 12, 16, and 22 | ||||||||||||||||||||||||||||||
End point description |
The Snaith–Hamilton Pleasure Scale (SHAPS) is short, 14-item instrument to measure anhedonia. Each of the 14 items has a set of four response categories (Definition 1): Definitely Agree (=1), Agree (= 2), Disagree (= 3), and Definitely Disagree (= 4). A SHAPS total score was calculated as the sum of the 14 item scores with a total score range from 14 to 56. A higher total score indicates higher levels of state anhedonia. mITT1 analysis set: all randomized subjects with hsCRP >= 3.00 mg/L at screening and baseline who receive at least 1 dose of study drug and have both baseline and at least one postbaseline HDRS-17 total score in DB treatment period. 'n' (number of subjects analyzed)- number of subjects analyzed at each specified timepoint, for each arm.
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End point type |
Secondary
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End point timeframe |
Baseline and Weeks 1, 4, 8, 12, 16, and 22
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
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End point title |
Change From Baseline in Snaith Hamilton Pleasure Scale (SHAPS) Total Score (Definition 2) at Weeks 1, 4, 8, 12, 16, and 22 | ||||||||||||||||||||||||||||||
End point description |
The Snaith–Hamilton Pleasure Scale (SHAPS) is short, 14-item instrument to measure anhedonia. Each of the 14 items has a set of four response categories (Definition 2): Definitely Agree (= 0), Agree (= 0), Disagree (= 1), and Definitely Disagree (= 1). A SHAPS total score was calculated as the sum of the 14 item scores with a score range from 0 to 14. A higher total score indicates higher levels of state anhedonia. mITT1 analysis set: all randomized subjects with hsCRP >= 3.00 mg/L at screening and baseline who receive at least 1 dose of study drug and have both baseline and at least one postbaseline HDRS-17 total score in DB treatment period. 'n' (number of subjects analyzed)- number of subjects analyzed at each specified timepoint, for each arm.
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End point type |
Secondary
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End point timeframe |
Baseline and Weeks 1, 4, 8, 12, 16, and 22
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
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End point title |
Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)- Fatigue Total Score at Weeks 1, 4, 8, 12, 16, and 22 | ||||||||||||||||||||||||||||||
End point description |
The FACIT-Fatigue is a questionnaire that assesses self-reported tiredness, weakness, and difficulty conducting usual activities due to fatigue. The subscale consists 13-item instrument to measure fatigue. Each of the 13 items has a set of five response categories: Not at all (=0), A little bit (=1), Somewhat (=2), Quite a bit (=3) and Very much (=4). A total FACIT-Fatigue subscale score was calculated as the sum of the 13 item scores (reserved scores [4 – score] for all except for 2 items: “I have energy” and “I am able to do my usual activities”), and ranges from 0 to 52, with a higher score indicating less fatigue. mITT1 analysis set: all randomized subjects with hsCRP >= 3.00 mg/L at screening and baseline who receive at least 1 dose of study drug and have both baseline and at least one postbaseline HDRS-17 total score in DB treatment period. 'n' (number of subjects analyzed)- number of subjects analyzed at each specified timepoint, for each arm.
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End point type |
Secondary
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End point timeframe |
Baseline and Weeks 1, 4, 8, 12, 16, and 22
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Approximately 26 weeks
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Adverse event reporting additional description |
The safety analysis set included all randomized subjects who received at least 1 dose of study agent in the double-blind phase.
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Assessment type |
Non-systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
20.0
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Reporting groups
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Reporting group title |
Sirukumab 50 mg
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Reporting group description |
Subjects received sirukumab 50 milligram (mg) on Day 1, Day 28 and Day 56, while continuing on their baseline oral monoaminergic antidepressant(s). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Subjects received placebo subcutaneous (SC) injection on Day 1, Day 28 and Day 56, while continuing their baseline oral monoaminergic antidepressant(s). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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13 May 2015 |
Amendment INT-2 included following changes: Additional clinical laboratory assessment (neutrophils, platelets, and liver enzymes) at the Week 4 visit were added in response to feedback received from Food and Drug Administration (FDA); Clarification was made that the Structured Interview Guide for the Hamilton Depression Scale (SIGH-D) scale will be used for the Hamilton Depression Rating Scale (HDRS-17) assessment. |
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03 Feb 2016 |
Amendment INT-4 included following changes: List of allowed antidepressants, concomitant therapies and comorbidities in subjects with Major Depressive Disorder (MDD) was updated to include subjects who may be more reflective of the general population of subjects with MDD; Screening assessments of the first screening visit were divided over 2 days to stage the screening assessments in order of priority and allow more flexibility to the sites and the study subjects. However, it was clarified that Columbia Suicide Severity Rating Scale (C-SSRS), Inventory of Depressive Symptomatology-Clinician Rated 30 Item Scale (IDS-C30) total score and HDRS17 were to be performed on the same day; Acceptable improvement on HDRS17 total score from the screening to baseline visit was increased from less than (<) 20 percent (%) to less than or equal to (=<) 25% to reflect the most commonly used criteria for minimal response; Orthostatic vital sign evaluation was removed as study agent has no effect on blood pressure; Inclusion criteria, exclusion criteria and prestudy and concomitant therapy criteria were updated to have a better reflection of the general population of subjects with MDD. To achieve better understanding of the relationship between C-reactive protein (CRP) (and potentially other inflammatory biomarkers) and clinical response, additional 50 subjects with screening hsCRP levels <0.300 mg/dL and a 4th stratum of hsCRP level 0.000 to <0.300 milligrams per deciliter (mg/dL) (International system of units [SI] 3.00 mg/L) were added. Related secondary objectives were also added and analyses were updated. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
