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    Clinical Trial Results:
    A Phase 2a Randomized, Double-blind, Placebo-Controlled, Parallel-Group, Multi-center Study Investigating the Efficacy, Safety, Tolerability and Pharmacokinetics of JNJ-67953964 in Subjects with Major Depressive Disorder

    Summary
    EudraCT number
    		 2019-000695-41
    Trial protocol
    		 GB  
    Global end of trial date
    06 May 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 May 2021
    First version publication date
    21 May 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    67953964MDD2001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03559192
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Janssen Research & Development, LLC
    Sponsor organisation address
    920 Route 202, Raritan, United States, NJ 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
    06 May 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 May 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of this study was to evaluate the efficacy of JNJ-67953964 (aticaprant) compared to placebo when administered as adjunctive treatment in subjects with major depressive disorder (MDD) partially responsive to selective serotonin reuptake inhibitor (SSRI) / serotonin-norepinephrine reuptake inhibitor (SNRI) treatment in terms of reduction of symptoms of depression, as assessed by the change from baseline on the Montgomery Asberg Depression Rating Scale (MADRS) in non-responders during the placebo lead-in period.
    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 Practice (GCP) and applicable regulatory requirements. Safety was evaluated during the study through assessments: physical examination, neurological examination, vital signs, body weight, body temperature, clinical laboratory assessments, 12-lead electrocardiogram (ECG), urine drug screen, alcohol screening test, pregnancy testing, columbia suicide severity rating scale (C-SSRS) assessments, arizona sexual experiences scale (ASEX) assessment, karolinska sleepiness scale (KSS) assessment, and evaluation of adverse events (AEs) and concomitant medications.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Jul 2018
    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
    Germany: 9
    Country: Number of subjects enrolled
    United Kingdom: 27
    Country: Number of subjects enrolled
    Moldova, Republic of: 29
    Country: Number of subjects enrolled
    Russian Federation: 47
    Country: Number of subjects enrolled
    Ukraine: 17
    Country: Number of subjects enrolled
    United States: 52
    Worldwide total number of subjects
    181
    EEA total number of subjects
    9
    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)
    181
    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 181 subjects were enrolled in this study.

    Period 1
    Period 1 title
    Lead-in Period (3 Weeks)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Arm title
    		 Placebo
    Arm description
    		 Subjects with major depressive disorder (MDD) who had inadequate response to selective serotonin reuptake inhibitor /serotonin-norepinephrine reuptake inhibitor (SSRI/SNRI) treatment received JNJ-67953964 matching placebo capsules (2*1 placebo capsules) once daily starting from Day 2 to 3 weeks in lead-in period in addition to SSRI/SNRI treatment.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo capsules (2*1 placebo capsules) were administered orally up to 3 weeks in lead-in period.

    Number of subjects in period 1
    		Placebo
    Started
    181
    Completed
    169
    Not completed
    12
         Consent withdrawn by subject
    6
         Adverse event, non-fatal
    4
         Serious Adverse Event, Non-Fatal
    1
         Protocol deviation
    1
    Period 2
    Period 2 title
    Double-Blind Treatment Period (6 Weeks)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Subjects who were responders or non-responders to lead-in placebo group were re-randomized to receive JNJ-67953964 matching placebo capsules (2*1 placebo capsules) once daily during double-blind treatment period (up to 6 weeks after lead-in period) in addition to SSRI/SNRI treatment.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo capsules (2*1 placebo capsules) were administered orally up to 6 weeks after lead-in period.

    Arm title
    		 JNJ-67953964 10 milligrams (mg)
    Arm description
    		 Subjects who were responders or non-responders to lead-in placebo group were re-randomized to receive 10 mg JNJ-67953964 capsules (2*5 mg JNJ-67953964 capsules) once daily during double-blind treatment period (up to 6 weeks after lead-in period) in addition to SSRI/SNRI treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    JNJ-67953964
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg JNJ-67953964 capsules (2*5 mg JNJ-67953964 capsules) were administered orally up to 6 weeks after lead-in period.

    Number of subjects in period 2
    		Placebo JNJ-67953964 10 milligrams (mg)
    Started
    84
    85
    Placebo Lead-in Responders
    22 [1]
    23 [2]
    Placebo Lead-In Non-Responder
    62 [3]
    62 [4]
    Completed
    81
    80
    Not completed
    3
    5
         Consent withdrawn by subject
    1
    -
         Adverse event, non-fatal
    -
    1
         Other
    1
    1
         Non-compliance with study drug
    -
    1
         Serious Adverse Event-Non Fatal
    1
    -
         Protocol deviation
    -
    1
         Lack of efficacy
    -
    1
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Out of 84 subjects in Placebo arm, 22 were Placebo Lead-in Responders and 62 were Placebo Lead-In Non-Responders. For JNJ-67953964 arm, out of 85 subjects: 23 were Placebo Lead-in Responders and 62 were Placebo Lead-In Non-responders.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Out of 84 subjects in Placebo arm, 22 were Placebo Lead-in Responders and 62 were Placebo Lead-In Non-Responders. For JNJ-67953964 arm, out of 85 subjects: 23 were Placebo Lead-in Responders and 62 were Placebo Lead-In Non-responders.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Out of 84 subjects in Placebo arm, 22 were Placebo Lead-in Responders and 62 were Placebo Lead-In Non-Responders. For JNJ-67953964 arm, out of 85 subjects: 23 were Placebo Lead-in Responders and 62 were Placebo Lead-In Non-responders.
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Out of 84 subjects in Placebo arm, 22 were Placebo Lead-in Responders and 62 were Placebo Lead-In Non-Responders. For JNJ-67953964 arm, out of 85 subjects: 23 were Placebo Lead-in Responders and 62 were Placebo Lead-In Non-responders.
    Period 3
    Period 3 title
    Withdrawal Period (2 Weeks)
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Arm title
    		 Placebo
    Arm description
    		 Subjects who completed the double-blind treatment period continued to receive JNJ-67953964 matching placebo capsules (2*1 placebo capsules) once daily during the withdrawal period for up to 2 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo capsules (2*1 placebo capsules) were administered orally up to 2 weeks in withdrawal period.

    Number of subjects in period 3
    		Placebo
    Started
    161
    Completed
    160
    Not completed
    1
         Lack of efficacy
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects with major depressive disorder (MDD) who had inadequate response to selective serotonin reuptake inhibitor /serotonin-norepinephrine reuptake inhibitor (SSRI/SNRI) treatment received JNJ-67953964 matching placebo capsules (2*1 placebo capsules) once daily starting from Day 2 to 3 weeks in lead-in period in addition to SSRI/SNRI treatment.

    Reporting group values
    		 Placebo Total
    Number of subjects
    		 181 181
    Title for AgeCategorical
    Units: subjects
        Adults (18-64 years)
    		 181 181
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    		 42.5 ( 12.91 ) -
    Title for Gender
    Units: subjects
        Female
    		 131 131
        Male
    		 50 50

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects with major depressive disorder (MDD) who had inadequate response to selective serotonin reuptake inhibitor /serotonin-norepinephrine reuptake inhibitor (SSRI/SNRI) treatment received JNJ-67953964 matching placebo capsules (2*1 placebo capsules) once daily starting from Day 2 to 3 weeks in lead-in period in addition to SSRI/SNRI treatment.
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects who were responders or non-responders to lead-in placebo group were re-randomized to receive JNJ-67953964 matching placebo capsules (2*1 placebo capsules) once daily during double-blind treatment period (up to 6 weeks after lead-in period) in addition to SSRI/SNRI treatment.

    Reporting group title
    JNJ-67953964 10 milligrams (mg)
    Reporting group description
    		 Subjects who were responders or non-responders to lead-in placebo group were re-randomized to receive 10 mg JNJ-67953964 capsules (2*5 mg JNJ-67953964 capsules) once daily during double-blind treatment period (up to 6 weeks after lead-in period) in addition to SSRI/SNRI treatment.
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects who completed the double-blind treatment period continued to receive JNJ-67953964 matching placebo capsules (2*1 placebo capsules) once daily during the withdrawal period for up to 2 weeks.

    Primary: Change from Treatment Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score at Treatment Week 6 in Non-Responders during Placebo Lead-in Period

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    End point title
    		 Change from Treatment Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score at Treatment Week 6 in Non-Responders during Placebo Lead-in Period
    End point description
    The MADRS is a clinician-rated scale designed to measure depression severity and detects changes due to antidepressant treatment. The scale consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), summed for a total possible score of 60. Higher scores represent a more severe condition. The MADRS evaluates apparent sadness, reported sadness, inner tension, sleep appetite, concentration, lassitude, inability to feel (interest level), pessimistic thoughts, and suicidal thoughts. Negative change from baseline indicates improvement. The enriched intent-to-treat (eITT) analysis set included all enrolled lead-in placebo non-responders who were randomized into a treatment period, received at least 1 dose of study medication, and had at least 1 post-baseline MADRS assessment during the treatment period. Here 'N' (number of subjects analyzed) includes the number of subjects evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Treatment Baseline and Treatment Week 6
    End point values
    		 Placebo JNJ-67953964 10 milligrams (mg)
    Number of subjects analysed
    59
    59
    Units: score on a scale
        least squares mean (standard error)
    -8.0 ( 0.92 )
    -10.1 ( 0.93 )
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Placebo v JNJ-67953964 10 milligrams (mg)
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0443
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -2.1
    Confidence interval
         level
    		 80%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 -1.09
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.25

    Secondary: Change from Treatment Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score at Treatment Week 6 in Both Responders and Non-Responders during Placebo Lead-in Period

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    End point title
    		 Change from Treatment Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score at Treatment Week 6 in Both Responders and Non-Responders during Placebo Lead-in Period
    End point description
    The MADRS is a clinician-rated scale designed to measure depression severity and detects changes due to antidepressant treatment. The scale consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), summed for a total possible score of 60. Higher scores represent a more severe condition. The MADRS evaluates apparent sadness, reported sadness, inner tension, sleep appetite, concentration, lassitude, inability to feel (interest level), pessimistic thoughts, and suicidal thoughts. Negative change from baseline indicates improvement. The full intent-to-treat (fITT) analysis set included all enrolled subjects who were randomized into a treatment period, received at least 1 dose of study medication, and had at least 1 post-treatment baseline assessment of MADRS during the treatment period. Here 'N' (number of subjects analyzed) includes the number of subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Treatment Baseline and Treatment Week 6
    End point values
    		 Placebo JNJ-67953964 10 milligrams (mg)
    Number of subjects analysed
    81
    77
    Units: score on a scale
        least squares mean (standard error)
    -6.5 ( 0.78 )
    -9.6 ( 0.79 )
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Placebo v JNJ-67953964 10 milligrams (mg)
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0017
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -3.1
    Confidence interval
         level
    		 80%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 -2.21
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.05

    Secondary: Number of Subjects with Treatment-emergent Adverse Events (TEAEs) during Treatment Period

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    End point title
    		 Number of Subjects with Treatment-emergent Adverse Events (TEAEs) during Treatment Period
    End point description
    An AE can 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. TEAEs were AEs with onset during the treatment phase that has worsened since baseline. The full safety analysis set included all enrolled subjects who received at least 1 dose of study medication in the treatment period.
    End point type
    Secondary
    End point timeframe
    Up to Week 9
    End point values
    		 Placebo JNJ-67953964 10 milligrams (mg)
    Number of subjects analysed
    84
    85
    Units: Subjects
    30
    40
    No statistical analyses for this end point

    Secondary: Change from Treatment Baseline in Snaith-Hamilton Pleasure Scale (SHAPS) Total Score at Treatment Week 6

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    End point title
    		 Change from Treatment Baseline in Snaith-Hamilton Pleasure Scale (SHAPS) Total Score at Treatment Week 6
    End point description
    The SHAPS is a self-reported 14-item, instrument, developed for the assessment of hedonic capacity. Subjects score whether they experience pleasure in performing a list of activities or experiences. Subjects can rate the answers as 1-4 where 1 indicates “Definitely agree”, 2 indicates “Agree”, 3 indicates “Disagree” and 4 indicates “Definitely disagree”. The subject's item responses are summed to provide a total score ranging from 14 to 56. A higher total SHAPS score indicates higher levels of current anhedonia. Negative change from baseline indicates improvement. The eITT analysis set included all enrolled lead-in placebo non-responders who were randomized into a treatment period, received at least 1 dose of study medication, and had at least 1 post-baseline MADRS assessment during the treatment period. Here 'N' (number of subjects analyzed) includes the number of subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Treatment Baseline and Treatment Week 6
    End point values
    		 Placebo JNJ-67953964 10 milligrams (mg)
    Number of subjects analysed
    59
    59
    Units: scores on a scale
        least squares mean (standard error)
    -3.7 ( 0.64 )
    -4.4 ( 0.64 )
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Placebo v JNJ-67953964 10 milligrams (mg)
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4188
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Confidence interval
         level
    		 80%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 0.41
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.87

    Secondary: Change from Treatment Baseline in Clinical Global Impression - Severity (CGI-S) Total Score at Treatment Week 6

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    End point title
    		 Change from Treatment Baseline in Clinical Global Impression - Severity (CGI-S) Total Score at Treatment Week 6
    End point description
    CGI-S provides an overall clinician-determined summary measure of severity of subject’s illness that considers all available information, including knowledge of subject’s history, psychosocial circumstances, symptoms, behavior, and impact of symptoms on subject’s ability to function. CGI-S evaluates severity of psychopathology on scale of 0 to 7. Subject is assessed on severity of mental illness at time of rating according to: 0=not assessed; 1=normal (not at all ill); 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=among most extremely ill patients. Negative change in score indicates improvement. eITT analysis set included all enrolled lead-in placebo non-responders who were randomized into a treatment period, received at least 1 dose of study medication, had at least 1 post-baseline MADRS assessment during treatment period. Here 'N' (number of subjects analyzed) includes number of subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Treatment Baseline and Treatment Week 6
    End point values
    		 Placebo JNJ-67953964 10 milligrams (mg)
    Number of subjects analysed
    59
    59
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    -0.76 ( 0.858 )
    -0.92 ( 1.039 )
    No statistical analyses for this end point

    Secondary: Change from Treatment Baseline in Symptoms of Major Depressive Disorder Scale (SMDDS) Total Score at Treatment Week 6

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    End point title
    		 Change from Treatment Baseline in Symptoms of Major Depressive Disorder Scale (SMDDS) Total Score at Treatment Week 6
    End point description
    The SMDDS is a 16-item patient reported outcome (PRO) measure. Each item was rated by the subject according to a 5-point Likert scale. Subjects respond to each question using a rating scale between 0 ("Not at all" or "Never") to 4 ("Extremely" or "Always"). The total score ranges from 0 to 60. The SMDDS uses a 7-day recall period and verbal rating scales. Higher score indicates more severe depressive symptomatology. Negative change from baseline indicates improvement. The eITT analysis set included all enrolled lead-in placebo non-responders who were randomized into a treatment period, received at least 1 dose of study medication, and had at least 1 post-baseline MADRS assessment during the treatment period. Here 'N' (number of subjects analyzed) includes the number of subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Treatment Baseline and Treatment Week 6
    End point values
    		 Placebo JNJ-67953964 10 milligrams (mg)
    Number of subjects analysed
    59
    59
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    -8.49 ( 9.567 )
    -8.03 ( 9.957 )
    No statistical analyses for this end point

    Secondary: Number of Subjects with Self-Assessment of Treatment Experience (SATE) Score at Treatment Week 6

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    End point title
    		 Number of Subjects with Self-Assessment of Treatment Experience (SATE) Score at Treatment Week 6
    End point description
    SATE questionnaire is a 1- or 2-item self-reported scale designed to provide additional information regarding subject’s subjective experience while taking treatment. This was internal Janssen questionnaire and questions were asked to subject weekly by the Q1.6-app. For rating overall depression, subject selected one option out of Improved, not changed or got worse; for depression improvement, subject selected one option out of slightly improved, much improved, very much improved and for depression worsen subject selected slightly worse, much worse, very much worse. The eITT analysis set included all enrolled lead-in placebo non-responders who were randomized into a treatment period, received at least 1 dose of study medication, and had at least 1 post-baseline MADRS assessment during the treatment period. Here 'n' (number analyzed) included all subjects evaluable for specified categories.
    End point type
    Secondary
    End point timeframe
    Week 6
    End point values
    		 Placebo JNJ-67953964 10 milligrams (mg)
    Number of subjects analysed
    61
    60
    Units: subjects
        Overall Depression (Got worse) (n= 40, 30)
    1
    0
        Overall Depression (Not changed) (n= 40, 30)
    12
    9
        Overall Depression (Improved) (n= 40, 30)
    27
    21
        Depression Worsened (Slightly worse) (n= 1, 0)
    1
    0
        Depression Worsened (Much worse) (n= 1, 0)
    0
    0
        Depression Worsened (Very much worse) (n=1,0)
    0
    0
        Depression Slightly improved (n=27, 21)
    13
    15
        Depression Much improved (n=27, 21)
    11
    6
        Depression Very Much Improved (n=27, 21)
    3
    0
    No statistical analyses for this end point

    Secondary: Change from Treatment Baseline in Hamilton Anxiety Scale 6 (HAM-A6) Total Score at Treatment Week 6

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    End point title
    		 Change from Treatment Baseline in Hamilton Anxiety Scale 6 (HAM-A6) Total Score at Treatment Week 6
    End point description
    HAM-A scale assesses severity of different anxiety-related symptoms with a score range of 0 to 52. Higher score indicated severity in anxiety symptoms. Each of the 14 items is rated by clinician on a 5-point scale ranging from 0 (not present) to 4 (maximum degree). HAM-A6 is a uni-dimensional, 6-item subscale derived from HAM-A. HAM-A6 comprises of five psychic anxiety symptoms: anxious mood, psychic tension, fears, intellectual disturbances, and anxious behaviour observed at the interview, as well as one somatic item, muscular tension. HAM-A6 Subscale Score ranges from 0 to 24, with higher scores indicating greater severity of core symptoms. eITT analysis set included all enrolled lead-in placebo non-responders who were randomized into a treatment period, received at least 1 dose of study medication, and had at least 1 post-baseline MADRS assessment during the treatment period. Here 'N' (number of subjects analyzed) includes number of subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Treatment Baseline and Treatment Week 6
    End point values
    		 Placebo JNJ-67953964 10 milligrams (mg)
    Number of subjects analysed
    59
    59
    Units: scores on a scale
        arithmetic mean (standard deviation)
    -2.19 ( 2.837 )
    -2.73 ( 2.651 )
    No statistical analyses for this end point

    Secondary: Change from Treatment Baseline in Structured Interview Guide for the Hamilton Anxiety Rating Scale (SIGH-A) Score at Treatment Week 6

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    End point title
    		 Change from Treatment Baseline in Structured Interview Guide for the Hamilton Anxiety Rating Scale (SIGH-A) Score at Treatment Week 6
    End point description
    SIGH-A is a 14-item scale to measure severity of different anxiety-related symptoms in subjects. Each of the 14 items is rated by the clinician on a 5-point scale ranging from 0 (not present) to 4 (maximum degree) with a total score range of 0 to 56 where higher score indicates worsening. The eITT analysis set included all enrolled lead-in placebo non-responders who were randomized into a treatment period, received at least 1 dose of study medication, and had at least 1 post-baseline MADRS assessment during the treatment period. Here 'N' (number of subjects analyzed) includes the number of subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Treatment Baseline and Treatment Week 6
    End point values
    		 Placebo JNJ-67953964 10 milligrams (mg)
    Number of subjects analysed
    59
    59
    Units: scores on a scale
        arithmetic mean (standard deviation)
    -5.37 ( 6.549 )
    -5.85 ( 5.369 )
    No statistical analyses for this end point

    Secondary: Maximum Plasma Concentration (Cmax) of JNJ-67953964

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    End point title
    		 Maximum Plasma Concentration (Cmax) of JNJ-67953964
    End point description
    Cmax is defined as maximum plasma concentration of JNJ-67953964. eITT population included all enrolled lead-in placebo non-responders who were randomized into a treatment period, received at least 1 dose of study medication, and had at least 1 post-baseline MADRS assessment during the treatment period. Here 'N' (number of subjects analyzed) includes the number of subjects evaluable for this endpoint. Here 'n' (number analyzed) included all subjects evaluable for specified time point categories.
    End point type
    Secondary
    End point timeframe
    Week 1, 3 and 6
    End point values
    		 JNJ-67953964 10 milligrams (mg)
    Number of subjects analysed
    58
    Units: nanograms per milliliter (ng/ml)
    arithmetic mean (standard deviation)
        Week 1 (n=58)
    32.7 ( 10.9 )
        Week 3 (n=58)
    33.5 ( 11.1 )
        Week 6 (n=56)
    34.3 ( 11.1 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Week 9
    Adverse event reporting additional description
    Safety analysis set included all enrolled subjects who received at least 1 dose of study drug in treatment period. As planned, AEs were collected only during double blind treatment phase when study drug JNJ-67953964 was administered to randomized subjects. No AEs collected during Lead-in and Withdrawal period as subjects received only placebo.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects who were responders or non-responders to lead-in placebo group were re-randomized to receive JNJ-67953964 matching placebo capsules (2*1 placebo capsules) once daily during double blind treatment period (up to 6 weeks after lead-in period) in addition to SSRI/SNRI treatment.

    Reporting group title
    JNJ-67953964 10 milligrams (mg)
    Reporting group description
    		 Subjects who were responders or non-responders to lead-in placebo group were re-randomized to receive 10 mg JNJ-67953964 capsules (2*5 mg JNJ-67953964 capsules) once daily during double-blind treatment period (up to 6 weeks after lead-in period) in addition to SSRI/SNRI treatment.

    Serious adverse events
    		 Placebo JNJ-67953964 10 milligrams (mg)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 85 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Hepatobiliary disorders
    Cholecystitis Acute
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 85 (0.00%)
         occurrences causally related to treatment / all
    0 / 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
    		 Placebo JNJ-67953964 10 milligrams (mg)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 84 (10.71%)
    23 / 85 (27.06%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 84 (7.14%)
    10 / 85 (11.76%)
         occurrences all number
    6
    11
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 84 (2.38%)
    7 / 85 (8.24%)
         occurrences all number
    2
    7
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    0 / 84 (0.00%)
    5 / 85 (5.88%)
         occurrences all number
    0
    5
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    2 / 84 (2.38%)
    5 / 85 (5.88%)
         occurrences all number
    2
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Jun 2018
    Amendment INT-1 was substantial amendment and the overall reason for the amendment was to harmonize with procedures of some vendors, to update dosing instructions, and to correct typographical errors.
    26 Feb 2019
    Amendment INT-2 was substantial amendment and the overall reason for the amendment was to add the EudraCT number, to change inclusion criterion on female sterilization, to change exclusion criteria on concomitant medication (due to reconsideration of current clinical practices), and to implement a few changes requested by clinical sites.
    28 Aug 2019
    Amendment INT-3 was substantial amendment and the overall reason for the amendment was to harmonize aspects of local amendments (GBR-1 and GER-1) into one common protocol, to include corrections already documented in note-to-files, and to include some administrative corrections.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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