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    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

    Summary
    EudraCT number
    2014-005206-37
    Trial protocol
    PL   GB  
    Global end of trial date
    22 May 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    06 Jun 2019
    First version publication date
    06 Jun 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CNTO136MDD2001
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02473289
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Janssen Research & Development, LLC
    Sponsor organisation address
    920 Route, New Jersey, United States, 08869
    Public contact
    Clinical Registry Group, Janssen Research & Development, LLC, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Janssen Research & Development, LLC, ClinicalTrialsEU@its.jnj.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    22 May 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 May 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    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).
    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.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    03 Aug 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 7
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    Poland: 40
    Country: Number of subjects enrolled
    Russian Federation: 95
    Country: Number of subjects enrolled
    United States: 48
    Worldwide total number of subjects
    193
    EEA total number of subjects
    43
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    193
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    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.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    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
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received placebo on Day 1, Day 28 and Day 56, while continuing their baseline oral monoaminergic antidepressant(s).

    Arm title
    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
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    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).

    Number of subjects in period 1
    Placebo Sirukumab 50 mg
    Started
    99
    94
    Completed
    88
    81
    Not completed
    11
    13
         Protocol deviation
    -
    1
         Treatment unblinded + Adverse event
    -
    1
         Adverse event, non-fatal
    2
    3
         Unspecified
    2
    -
         Consent withdrawn by subject
    6
    7
         Lost to follow-up
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    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
    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).

    Reporting group values
    Placebo Sirukumab 50 mg Total
    Number of subjects
    99 94 193
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    99 94 193
        From 65 to 84 years
    0 0 0
        85 years and over
    0 0 0
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    44.1 ± 11.73 45.4 ± 10.83 -
    Title for Gender
    Units: subjects
        Female
    75 74 149
        Male
    24 20 44

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    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
    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).

    Primary: Change From Baseline in Hamilton Depression Rating Scale (HDRS-17) Total Score at Week 12

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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.
    End point type
    Primary
    End point timeframe
    Baseline and Week 12
    End point values
    Placebo Sirukumab 50 mg
    Number of subjects analysed
    42
    44
    Units: Units on a scale
        least squares mean (standard error)
    -10.6 ± 1.43
    -11.4 ± 1.52
    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.
    Comparison groups
    Sirukumab 50 mg v Placebo
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.31 [1]
    Method
    MMRM
    Parameter type
    Difference of Least Square (LS) Means
    Point estimate
    -0.8
    Confidence interval
         level
    75%
         sides
    2-sided
         lower limit
    -2.77
         upper limit
    1.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.67
    Notes
    [1] - 1-sided

    Secondary: Change From Baseline in HDRS-17 Total Score at Weeks 1, 4 and 8

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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.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 1, 4 and 8
    End point values
    Placebo Sirukumab 50 mg
    Number of subjects analysed
    47
    47
    Units: Units on a scale
    least squares mean (standard error)
        Change at Week 1 (n= 46, 47)
    -5.1 ± 1.03
    -4.6 ± 1.15
        Change at Week 4 (n= 46, 45)
    -7.5 ± 1.21
    -7.8 ± 1.33
        Change at Week 8 (n= 42, 45)
    -7.9 ± 1.29
    -11.0 ± 1.39
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Remission as Assessed by HDRS-17 Total Score at Week 12

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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.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    Placebo Sirukumab 50 mg
    Number of subjects analysed
    42
    44
    Units: Percentage of subjects
        number (not applicable)
    19.0
    15.9
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Response as Assessed by HDRS-17 Total Score at Week 12

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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.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    Placebo Sirukumab 50 mg
    Number of subjects analysed
    42
    44
    Units: Percentage of subjects
        number (not applicable)
    33.3
    34.1
    No statistical analyses for this end point

    Secondary: Change From Baseline in Clinical Global Impression - Severity (CGI-S) Total Score at Weeks 1, 4, 8, 12, 16, and 22

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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.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 1, 4, 8, 12, 16, and 22
    End point values
    Placebo Sirukumab 50 mg
    Number of subjects analysed
    47
    47
    Units: Units on a scale
    least squares mean (standard error)
        Change at Week 1 (n=46, 47)
    -0.6 ± 0.14
    -0.7 ± 0.15
        Change at Week 4 (n=46, 45)
    -1.1 ± 0.16
    -1.0 ± 0.17
        Change at Week 8 (n=42, 45)
    -1.4 ± 0.18
    -1.5 ± 0.19
        Change at Week 12 (n=44, 44)
    -1.5 ± 0.21
    -1.9 ± 0.22
        Change at Week 16 (n=42, 44)
    -1.9 ± 0.23
    -2.1 ± 0.24
        Change at Week 22 (n=42, 43)
    -2.0 ± 0.24
    -2.3 ± 0.25
    No statistical analyses for this end point

    Secondary: Change From Baseline in Patient Health Questionnaire (PHQ-9) Total Score at Weeks 1, 4, 8, 12, 16, and 22

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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.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 1, 4, 8, 12, 16, and 22
    End point values
    Placebo Sirukumab 50 mg
    Number of subjects analysed
    47
    47
    Units: Units on a scale
    least squares mean (standard error)
        Change at Week 1 (n= 45, 47)
    -2.5 ± 0.58
    -3.1 ± 0.61
        Change at Week 4 (n= 45, 45)
    -4.4 ± 0.75
    -5.3 ± 0.79
        Change at Week 8 (n= 41, 45)
    -5.6 ± 0.86
    -7.6 ± 0.87
        Change at Week 12 (n= 43, 44)
    -7.5 ± 0.98
    -8.9 ± 1.00
        Change at Week 16 (n= 42, 44)
    -8.2 ± 0.98
    -9.6 ± 1.00
        Change at Week 22 (n= 41, 43)
    -9.1 ± 1.04
    -10.7 ± 1.05
    No statistical analyses for this end point

    Secondary: Change From Baseline in Snaith Hamilton Pleasure Scale (SHAPS) Total Score (Definition 1) at Weeks 1, 4, 8, 12, 16, and 22

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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.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 1, 4, 8, 12, 16, and 22
    End point values
    Placebo Sirukumab 50 mg
    Number of subjects analysed
    47
    47
    Units: Units on a scale
    least squares mean (standard error)
        Change at Week 1 (n= 45, 47)
    -1.4 ± 0.72
    -3.3 ± 0.74
        Change at Week 4 (n= 45, 45)
    -3.9 ± 0.75
    -5.1 ± 0.78
        Change at Week 8 (n= 41, 45)
    -5.8 ± 0.87
    -7.0 ± 0.88
        Change at Week 12 (n= 43, 44)
    -5.9 ± 1.00
    -8.9 ± 1.02
        Change at Week 16 (n= 42, 44)
    -7.0 ± 1.11
    -8.8 ± 1.12
        Change at Week 22 (n= 41, 43)
    -7.8 ± 1.11
    -10.6 ± 1.12
    No statistical analyses for this end point

    Secondary: Change From Baseline in Snaith Hamilton Pleasure Scale (SHAPS) Total Score (Definition 2) at Weeks 1, 4, 8, 12, 16, and 22

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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.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 1, 4, 8, 12, 16, and 22
    End point values
    Placebo Sirukumab 50 mg
    Number of subjects analysed
    47
    47
    Units: Units on a scale
    least squares mean (standard error)
        Change at Week 1 (n= 45, 47)
    -1.2 ± 0.45
    -2.0 ± 0.47
        Change at Week 4 (n= 45, 45)
    -2.2 ± 0.49
    -3.3 ± 0.51
        Change at Week 8 (n= 41, 45)
    -3.6 ± 0.57
    -4.4 ± 0.57
        Change at Week 12 (n= 43, 44)
    -3.7 ± 0.64
    -5.4 ± 0.66
        Change at Week 16 (n= 42, 44)
    -4.1 ± 0.69
    -5.6 ± 0.70
        Change at Week 22 (n= 41, 43)
    -4.6 ± 0.71
    -6.8 ± 0.72
    No statistical analyses for this end point

    Secondary: Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)- Fatigue Total Score at Weeks 1, 4, 8, 12, 16, and 22

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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.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 1, 4, 8, 12, 16, and 22
    End point values
    Placebo Sirukumab 50 mg
    Number of subjects analysed
    47
    47
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Change at Week 1 (n= 45, 47)
    1.75 ± 4.671
    4.91 ± 10.097
        Change at Week 4 (n= 45, 45)
    6.87 ± 10.119
    6.44 ± 9.633
        Change at Week 8 (n= 41, 45)
    8.93 ± 9.913
    10.09 ± 10.346
        Change at Week 12 (n= 43, 44)
    11.65 ± 13.476
    13.82 ± 11.486
        Change at Week 16 (n= 42, 44)
    13.55 ± 12.029
    13.95 ± 12.066
        Change at Week 22 (n= 41, 43)
    14.54 ± 13.585
    17.23 ± 12.051
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Approximately 26 weeks
    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.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Sirukumab 50 mg
    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
    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).

    Serious adverse events
    Sirukumab 50 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 94 (3.19%)
    2 / 99 (2.02%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Investigations
    Transaminases Increased
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Myocardial Infarction
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression Suicidal
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide Attempt
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Sirukumab 50 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 94 (20.21%)
    13 / 99 (13.13%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 94 (5.32%)
    12 / 99 (12.12%)
         occurrences all number
    5
    19
    General disorders and administration site conditions
    Injection Site Pain
         subjects affected / exposed
    5 / 94 (5.32%)
    1 / 99 (1.01%)
         occurrences all number
    8
    2
    Injection Site Erythema
         subjects affected / exposed
    11 / 94 (11.70%)
    0 / 99 (0.00%)
         occurrences all number
    15
    0

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    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.
    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.

    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.
    None reported
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