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    Clinical Trial Results:
    A Multicenter, Double-Blind, Placebo-Controlled Study of JNJ-40411813 as Adjunctive Treatment to an Antidepressant in Adults with Major Depressive Disorder with Anxiety Symptoms

    Due to a system error, the data reported in v1 is not correct and has been removed from public view.
    Summary
    EudraCT number
    2011-006121-26
    Trial protocol
    HU   BG   SK  
    Global end of trial date
    25 Nov 2013

    Results information
    Results version number
    v2(current)
    This version publication date
    15 Jul 2016
    First version publication date
    13 Aug 2015
    Other versions
    v1 (removed from public view)
    Version creation reason
    • Correction of full data set
    Review of data

    Trial information

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    Trial identification
    Sponsor protocol code
    40411813DAX2001
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01582815
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Janssen Research & Development, Division of Janssen-Cilag Ltd
    Sponsor organisation address
    Turnhoutseweg 30, 2340 Beerse, Belgium,
    Public contact
    Clinical Registry Group, Janssen Research & Development, Division of Janssen-Cilag Ltd, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Janssen Research & Development, Division of Janssen-Cilag Ltd, 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
    25 Nov 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Nov 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy, as assessed by the change from baseline on a 6-item subscale derived from the Hamilton Anxiety Scale (HAM-A6), and to evaluate overall safety and tolerability of treatment with adjunctive JNJ-40411813 (a positive allosteric modulator of the metabotropic glutamate receptor 2) compared with placebo in subjects who have MDD with anxiety symptoms being treated with a selective serotonin reuptake inhibitor (SSRI) or serotonergic/noradrenergic reuptake inhibitor (SNRI).
    Protection of trial subjects
    The safety assessments included monitoring adverse events (AEs) clinical laboratory assessments (for example hematology, serum chemistry and urinalysis), vital signs measurements (oral temperature, pulse rate, blood pressure), 12-lead electrocardiogram (ECG),and physical and neurologic examinations.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    02 Aug 2012
    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
    Bulgaria: 14
    Country: Number of subjects enrolled
    Hungary: 7
    Country: Number of subjects enrolled
    Moldova, Republic of: 7
    Country: Number of subjects enrolled
    Romania: 8
    Country: Number of subjects enrolled
    Russian Federation: 42
    Country: Number of subjects enrolled
    Ukraine: 43
    Worldwide total number of subjects
    121
    EEA total number of subjects
    29
    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)
    121
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    121 subjects were enrolled and treated with JNJ-40411813 or Placebo in Period 1 of the study. Subjects who were randomly assigned to adjunctive treatment with placebo in Period 1 who did not respond to treatment were re-randomized to adjunctive placebo or JNJ-40411813 in Period 2. A subset of 22 subjects (of 121) were re-randomized in Period 2.

    Period 1
    Period 1 title
    Period 1
    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
    Period 1: Placebo
    Arm description
    Participants received matching Placebo for 4 weeks during Period 1.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Matching Placebo orally twice daily for 4 weeks in Period 1.

    Arm title
    Period 1: JNJ-40411813
    Arm description
    Participants received JNJ-40411813 orally for 4 weeks during Period 1.
    Arm type
    Experimental

    Investigational medicinal product name
    JNJ-40411813-AAA-Capsule
    Investigational medicinal product code
    JNJ-40411813-AAA
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    JNJ-40411813 titrated from 25 mg (G029) capsules twice daily (b.i.d) to 50 mg (G025) b.i.d and later flexibly dosed in the range of 50mg b.i.d. up to 150 mg b.i.d. orally for 4 weeks during Period 1.

    Number of subjects in period 1 [1]
    Period 1: Placebo Period 1: JNJ-40411813
    Started
    58
    61
    Completed
    54
    53
    Not completed
    4
    8
         Exclusion Criteria
    -
    1
         Protocol deviation
    -
    2
         Adverse event, non-fatal
    3
    1
         Consent withdrawn by subject
    1
    4
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Not all the enrolled subjects were treated with study drugs. As baseline only included treated subjects, the worldwide number enrolled in the trial differs with the number of subjects reported in the baseline period
    Period 2
    Period 2 title
    Period 2
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Period 2: Placebo
    Arm description
    Participants who got Placebo in Period 1 and were eligible for re-randomization received matching Placebo for 4 weeks during Period 2.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Matching Placebo orally twice daily for 4 weeks in Period 2.

    Arm title
    Period 2: JNJ-40411813
    Arm description
    Participants who got Placebo in Period 1 and were eligible for re-randomization received JNJ-40411813 orally for 4 weeks during Period 2.
    Arm type
    Experimental

    Investigational medicinal product name
    JNJ-40411813-AAA-Capsule
    Investigational medicinal product code
    JNJ-40411813-AAA
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    JNJ-40411813 titrated from 25 mg (G029) capsules twice daily (b.i.d) to 50 mg (G025) b.i.d and later flexibly dosed in the range of 50mg b.i.d. up to 150 mg b.i.d. orally for 4 weeks during Period 2.

    Number of subjects in period 2
    Period 2: Placebo Period 2: JNJ-40411813
    Started
    11
    11
    Completed
    10
    11
    Not completed
    1
    0
         Consent withdrawn by subject
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Period 1: Placebo
    Reporting group description
    Participants received matching Placebo for 4 weeks during Period 1.

    Reporting group title
    Period 1: JNJ-40411813
    Reporting group description
    Participants received JNJ-40411813 orally for 4 weeks during Period 1.

    Reporting group values
    Period 1: Placebo Period 1: JNJ-40411813 Total
    Number of subjects
    58 61 119
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    58 61 119
        From 65 to 84 years
    0 0 0
        85 years and over
    0 0 0
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    44.8 ± 11.55 44 ± 12.78 -
    Title for Gender
    Units: subjects
        Female
    12 18 30
        Male
    46 43 89

    End points

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    End points reporting groups
    Reporting group title
    Period 1: Placebo
    Reporting group description
    Participants received matching Placebo for 4 weeks during Period 1.

    Reporting group title
    Period 1: JNJ-40411813
    Reporting group description
    Participants received JNJ-40411813 orally for 4 weeks during Period 1.
    Reporting group title
    Period 2: Placebo
    Reporting group description
    Participants who got Placebo in Period 1 and were eligible for re-randomization received matching Placebo for 4 weeks during Period 2.

    Reporting group title
    Period 2: JNJ-40411813
    Reporting group description
    Participants who got Placebo in Period 1 and were eligible for re-randomization received JNJ-40411813 orally for 4 weeks during Period 2.

    Subject analysis set title
    Period 1: Intent-to-treat (ITT)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    ITT population included the subjects receiving at least one dose of study medication during the Period 1, having both a baseline and at least one post-baseline primary efficacy assessment during the Period 1.

    Subject analysis set title
    Period 2: Intent-to-treat (ITT)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    ITT population included Period 1 placebo subjects who were eligible for re-randomization, receiving at least one dose of study medication during the Period 2 and having both a baseline and at least one post-baseline primary efficacy assessment during the Period 2.

    Primary: Change from Baseline to Week 4 on the Hamilton Anxiety Rating scale (HAM-A6) Score

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    End point title
    Change from Baseline to Week 4 on the Hamilton Anxiety Rating scale (HAM-A6) Score
    End point description
    The HAM-A6 is a 6-item subscale derived from the original Hamilton Anxiety scale (HAM-A). The rating scale measures the severity of anxiety symptomatology. Higher scores represent more severe anxiety symptoms.
    End point type
    Primary
    End point timeframe
    Baseline and Week 4
    End point values
    Period 1: Placebo Period 2: Placebo Period 1: JNJ-40411813 Period 2: JNJ-40411813
    Number of subjects analysed
    58 [1]
    11 [2]
    61 [3]
    11 [4]
    Units: units on a scale
        least squares mean (standard error)
    -3.7 ± 0.33
    -3 ± 0.91
    -3.5 ± 0.33
    -4.5 ± 0.89
    Notes
    [1] - Period 1: ITT
    [2] - Period 2: ITT
    [3] - Period 1: ITT
    [4] - Period 2: ITT
    Statistical analysis title
    Period 1 and 2 Combined: Placebo v JNJ-40411813
    Statistical analysis description
    Based on MMRM model with treatment, time, pooled center, and time-by treatment interaction as factors, and baseline value (for respective period) as a covariate. This was the doubly randomized design: 119 subjects from Period 1 and 22 re-randomized subjects from Period 2 contributed to the JNJ-40411813 vs Placebo comparison. Statistics defined as a weighted combination of the test statistics from both periods, where weights satisfied pre-specified power optimality criterion was used.
    Comparison groups
    Period 1: Placebo v Period 1: JNJ-40411813
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.513 [5]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [5] - One-sided p-value measured.

    Secondary: Change from Baseline to Endpoint on the SIGH-A (Structured Interview Guide of the Hamilton Anxiety Scale 14-item HAM-A) Total Score

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    End point title
    Change from Baseline to Endpoint on the SIGH-A (Structured Interview Guide of the Hamilton Anxiety Scale 14-item HAM-A) Total Score
    End point description
    The (HAM-A) is a 14-item scale designed to measure anxiety in individuals. Each question reflects a symptom of anxiety and physical as well as mental symptoms are represented. The answers range from 0 which signifies a complete lack of that symptom to 4, which indicates a very severe show of anxiety with that symptom.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 4
    End point values
    Period 1: Placebo Period 2: Placebo Period 1: JNJ-40411813 Period 2: JNJ-40411813
    Number of subjects analysed
    58 [6]
    11 [7]
    61 [8]
    11 [9]
    Units: units on a scale
        least squares mean (standard error)
    -8.8 ± 0.78
    -7.4 ± 1.96
    -8.7 ± 0.78
    -8.8 ± 1.93
    Notes
    [6] - Period 1: ITT
    [7] - Period 2: ITT
    [8] - Period 1: ITT
    [9] - Period 2: ITT
    Statistical analysis title
    Period 1 and 2 Combined: Placebo v JNJ-40411813
    Statistical analysis description
    Based on MMRM model with treatment, time, pooled center, and time-by treatment interaction as factors, and baseline value (for respective period) as a covariate. This was the doubly randomized design: 119 subjects from Period 1 and 22 re-randomized subjects from Period 2 contributed to the JNJ-40411813 vs Placebo comparison. Statistics defined as a weighted combination of the test statistics from both periods, where weights satisfied pre-specified power optimality criterion was used.
    Comparison groups
    Period 1: Placebo v Period 1: JNJ-40411813
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.453 [10]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [10] - One-sided p-value measured

    Secondary: Number of Participants at Week 4 with greater than or equal to 50 percent improvement on the SIGH-A (Structured Interview Guide of the Hamilton Anxiety Scale 14-item HAM-A) Total Score

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    End point title
    Number of Participants at Week 4 with greater than or equal to 50 percent improvement on the SIGH-A (Structured Interview Guide of the Hamilton Anxiety Scale 14-item HAM-A) Total Score
    End point description
    The (HAM-A) is a 14-item scale designed to measure anxiety in individuals. Each question reflects a symptom of anxiety and physical as well as mental symptoms are represented. The answers range from 0 which signifies a complete lack of that symptom to 4, which indicates a very severe show of anxiety with that symptom.
    End point type
    Secondary
    End point timeframe
    Week 4
    End point values
    Period 1: Placebo Period 2: Placebo Period 1: JNJ-40411813 Period 2: JNJ-40411813
    Number of subjects analysed
    58 [11]
    11 [12]
    61 [13]
    11 [14]
    Units: participants
        number (not applicable)
    16
    3
    16
    4
    Notes
    [11] - Period 1: ITT
    [12] - Period 2: ITT
    [13] - Period 1: ITT
    [14] - Period 2: ITT
    No statistical analyses for this end point

    Secondary: Change from Baseline to Endpoint on the Hamilton Depression Rating Scale (HDRS17) Total Score

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    End point title
    Change from Baseline to Endpoint on the Hamilton Depression Rating Scale (HDRS17) Total Score
    End point description
    The HDRS17 is a clinician-administered rating scale designed to assess the severity of symptoms in patients diagnosed with depression with a score range of 0 to 52. Questions are related to symptoms such as depressed mood, guilt feelings, suicide, sleep disturbances, anxiety levels and weight loss. The higher the score, the more severe the depression.
    End point type
    Secondary
    End point timeframe
    Baseline and week 4
    End point values
    Period 1: Placebo Period 2: Placebo Period 1: JNJ-40411813 Period 2: JNJ-40411813
    Number of subjects analysed
    58 [15]
    11 [16]
    61 [17]
    11 [18]
    Units: units on a scale
        least squares mean (standard error)
    -9 ± 0.72
    -7 ± 1.62
    -9.4 ± 0.72
    -9.8 ± 1.6
    Notes
    [15] - Period 1: ITT
    [16] - Period 2: ITT
    [17] - Period 1: ITT
    [18] - Period 2: ITT
    Statistical analysis title
    Period 1 and 2 Combined: Placebo v JNJ-40411813
    Statistical analysis description
    Based on MMRM model with treatment, time, pooled center, and time-by treatment interaction as factors, and baseline value (for respective period) as a covariate. This was the doubly randomized design: 119 subjects from Period 1 and 22 re-randomized subjects from Period 2 contributed to the JNJ-40411813 vs Placebo comparison. Statistics defined as a weighted combination of the test statistics from both periods, where weights satisfied pre-specified power optimality criterion was used.
    Comparison groups
    Period 1: Placebo v Period 1: JNJ-40411813
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.182 [19]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [19] - One-sided p-value measured

    Secondary: Number of Participants with Either Greater than or Equal to 50 Percent or Greater than or equal to 30 Percent Improvement on the HDRS17 Total Score at Week 4

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    End point title
    Number of Participants with Either Greater than or Equal to 50 Percent or Greater than or equal to 30 Percent Improvement on the HDRS17 Total Score at Week 4
    End point description
    The HDRS17 is a clinician-administered rating scale designed to assess the severity of symptoms in patients diagnosed with depression with a score range of 0 to 52. Questions are related to symptoms such as depressed mood, guilt feelings, suicide, sleep disturbances, anxiety levels and weight loss. The higher the score, the more severe the depression.
    End point type
    Secondary
    End point timeframe
    Week 4
    End point values
    Period 1: Placebo Period 2: Placebo Period 1: JNJ-40411813 Period 2: JNJ-40411813
    Number of subjects analysed
    58 [20]
    11 [21]
    61 [22]
    11 [23]
    Units: participants
    number (not applicable)
        Greater than or equal to 50 Percent Improvement
    14
    3
    15
    6
        Greater than or equal to 30 Percent Improvemnet
    34
    5
    37
    9
    Notes
    [20] - Period 1: ITT
    [21] - Period 2: ITT
    [22] - Period 1: ITT
    [23] - Period 2: ITT
    No statistical analyses for this end point

    Secondary: Number of Participants with Remission Rates (HDRS 17 Total Score less than or equal to 7)

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    End point title
    Number of Participants with Remission Rates (HDRS 17 Total Score less than or equal to 7)
    End point description
    Remission is defined as HDRS 17 total score ≤ 7. The HDRS17 is a clinician-administered rating scale designed to assess the severity of symptoms in patients diagnosed with depression with a score range of 0 to 52. Questions are related to symptoms such as depressed mood, guilt feelings, suicide, sleep disturbances, anxiety levels and weight loss. The higher the score, the more severe the depression.
    End point type
    Secondary
    End point timeframe
    Week 4
    End point values
    Period 1: Placebo Period 2: Placebo Period 1: JNJ-40411813 Period 2: JNJ-40411813
    Number of subjects analysed
    58 [24]
    11 [25]
    61 [26]
    11 [27]
    Units: participants
        number (not applicable)
    1
    1
    4
    2
    Notes
    [24] - Period 1: ITT
    [25] - Period 2: ITT
    [26] - Period 1: ITT
    [27] - Period 2: ITT
    No statistical analyses for this end point

    Secondary: Change from Baseline to Endpoint in the Hamilton Depression Rating Scale (HDRS17) Anxiety/Somatization Factor Total Score

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    End point title
    Change from Baseline to Endpoint in the Hamilton Depression Rating Scale (HDRS17) Anxiety/Somatization Factor Total Score
    End point description
    The anxiety/somatization factor total score derived from HDRS scale. It includes six items from the original 17-item version: psychic anxiety, somatic anxiety, gastrointestinal somatic symptoms, general somatic symptoms, hypochondriasis, and insight. The scale measures the severity of anxious depression. The higher the score, the more severe anxiety symptoms.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 4
    End point values
    Period 1: Placebo Period 2: Placebo Period 1: JNJ-40411813 Period 2: JNJ-40411813
    Number of subjects analysed
    58 [28]
    11 [29]
    61 [30]
    11 [31]
    Units: units on a scale
        least squares mean (standard error)
    -3.1 ± 0.31
    -2.9 ± 0.61
    -3.5 ± 0.31
    -4 ± 0.59
    Notes
    [28] - Period 1: ITT
    [29] - Period 2: ITT
    [30] - Period 1: ITT
    [31] - Period 2: ITT
    Statistical analysis title
    Period 1 and 2 Combined: Placebo v JNJ-40411813
    Statistical analysis description
    Based on MMRM model with treatment, time, pooled center, and time-by treatment interaction as factors, and baseline value (for respective period) as a covariate. This was the doubly randomized design: 119 subjects from Period 1 and 22 re-randomized subjects from Period 2 contributed to the JNJ-40411813 vs Placebo comparison. Statistics defined as a weighted combination of the test statistics from both periods, where weights satisfied pre-specified power optimality criterion was used.
    Comparison groups
    Period 1: Placebo v Period 1: JNJ-40411813
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.099 [32]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [32] - One-sided p-value measured

    Secondary: Number of Participants Meeting Criteria for Anxious Depression at Week 4

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    End point title
    Number of Participants Meeting Criteria for Anxious Depression at Week 4
    End point description
    The anxiety/somatization factor total score derived from HDRS scale. It includes six items from the original 17-item version: psychic anxiety, somatic anxiety, gastrointestinal somatic symptoms, general somatic symptoms, hypochondriasis, and insight. The scale measures the severity of anxious depression. The higher the score, the more severe anxiety symptoms.
    End point type
    Secondary
    End point timeframe
    Week 4
    End point values
    Period 1: Placebo Period 2: Placebo Period 1: JNJ-40411813 Period 2: JNJ-40411813
    Number of subjects analysed
    58 [33]
    11 [34]
    61 [35]
    11 [36]
    Units: participants
        number (not applicable)
    30
    5
    25
    0
    Notes
    [33] - Period 1: ITT
    [34] - Period 2: ITT
    [35] - Period 1: ITT
    [36] - Period 2: ITT
    No statistical analyses for this end point

    Secondary: Change from Baseline to Endpoint in the Hamilton Depression Rating Scale - 6-item (HAM-D6) Score

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    End point title
    Change from Baseline to Endpoint in the Hamilton Depression Rating Scale - 6-item (HAM-D6) Score
    End point description
    The HAM-D6 is a 6-item subscale derived from the Hamilton Depression Rating Scale (HDRS17). The rating scale measures the severity of depressive symptomatology. Higher scores represent more severe depressive symptoms.
    End point type
    Secondary
    End point timeframe
    Baselien and Week 4
    End point values
    Period 1: Placebo Period 2: Placebo Period 1: JNJ-40411813 Period 2: JNJ-40411813
    Number of subjects analysed
    58 [37]
    11 [38]
    61 [39]
    11 [40]
    Units: units on a scale
        least squares mean (standard error)
    -4.3 ± 0.37
    -3.1 ± 0.84
    -4.6 ± 0.37
    -5.1 ± 0.83
    Notes
    [37] - Period 1: ITT
    [38] - Period 2: ITT
    [39] - Period 1: ITT
    [40] - Period 2: ITT
    Statistical analysis title
    Period 1 and 2 Combined: Placebo v JNJ-40411813
    Statistical analysis description
    Based on MMRM model with treatment, time, pooled center, and time-by treatment interaction as factors, and baseline value (for respective period) as a covariate. This was the doubly randomized design: 119 subjects from Period 1 and 22 re-randomized subjects from Period 2 contributed to the JNJ-40411813 vs Placebo comparison. Statistics defined as a weighted combination of the test statistics from both periods, where weights satisfied pre-specified power optimality criterion was used.
    Comparison groups
    Period 1: Placebo v Period 1: JNJ-40411813
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.133 [41]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [41] - One-sided p-value measured

    Secondary: Change from Baseline to Endpoint in the Inventory of Depressive Symptomatolgy -Clinician rated (IDS-C30) Total Score

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    End point title
    Change from Baseline to Endpoint in the Inventory of Depressive Symptomatolgy -Clinician rated (IDS-C30) Total Score
    End point description
    The IDS-C30 is a clinician administered 30 item depression specific severity rating scale designed to measure specific signs and symptoms of depression including melancholic, atypical and anxious features. Scores range from 0 to 84 with higher scores representing greater severity of depressive symptoms.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 4
    End point values
    Period 1: Placebo Period 2: Placebo Period 1: JNJ-40411813 Period 2: JNJ-40411813
    Number of subjects analysed
    58 [42]
    11 [43]
    61 [44]
    11 [45]
    Units: units on a scale
        least squares mean (standard error)
    -15 ± 1.23
    -10.4 ± 2.92
    -15.8 ± 1.23
    -15.1 ± 2.89
    Notes
    [42] - Period 1: ITT
    [43] - Period 2: ITT
    [44] - Period 1: ITT
    [45] - Period 2: ITT
    Statistical analysis title
    Period 1 and 2 Combined: Placebo v JNJ-40411813
    Statistical analysis description
    Based on MMRM model with treatment, time, pooled center, and time-by treatment interaction as factors, and baseline value (for respective period) as a covariate. This was the doubly randomized design: 119 subjects from Period 1 and 22 re-randomized subjects from Period 2 contributed to the JNJ-40411813 vs Placebo comparison. Statistics defined as a weighted combination of the test statistics from both periods, where weights satisfied pre-specified power optimality criterion was used.
    Comparison groups
    Period 1: Placebo v Period 1: JNJ-40411813
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.195 [46]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [46] - One-sided p-value measured

    Secondary: Change from Baseline to Endpoint in the Inventory of Depressive Symptomatology - Clinician-Rated (IDS-C30) Anxiety Subscale Score

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    End point title
    Change from Baseline to Endpoint in the Inventory of Depressive Symptomatology - Clinician-Rated (IDS-C30) Anxiety Subscale Score
    End point description
    The IDS-C30 is a clinician administered 30 item depression specific severity rating scale designed to measure specific signs and symptoms of depression including melancholic, atypical and anxious features. The anxiety subscale includes five anxiety symptoms: anxious mood, somatic complaints, sympathetic arousal, panic, and gastrointestinal symptoms. The rating scale measures the severity of anxiety symptomatology. Higher scores represent more severe anxiety symptoms.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 4
    End point values
    Period 1: Placebo Period 2: Placebo Period 1: JNJ-40411813 Period 2: JNJ-40411813
    Number of subjects analysed
    58 [47]
    11 [48]
    61 [49]
    11 [50]
    Units: units on a scale
        least squares mean (standard error)
    -2.6 ± 0.25
    -1.9 ± 0.65
    -2.8 ± 0.25
    -2.7 ± 0.64
    Notes
    [47] - Period 1: ITT
    [48] - Period 2: ITT
    [49] - Period 1: ITT
    [50] - Period 2: ITT
    Statistical analysis title
    Period 1 and 2 Combined: Placebo v JNJ-40411813
    Statistical analysis description
    Based on MMRM model with treatment, time, pooled center, and time-by treatment interaction as factors, and baseline value (for respective period) as a covariate. This was the doubly randomized design: 119 subjects from Period 1 and 22 re-randomized subjects from Period 2 contributed to the JNJ-40411813 vs Placebo comparison. Statistics defined as a weighted combination of the test statistics from both periods, where weights satisfied pre-specified power optimality criterion was used.
    Comparison groups
    Period 1: Placebo v Period 1: JNJ-40411813
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.174 [51]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [51] - One-sided p-value measured

    Secondary: Number of participants with Clinical Global Impression - Improvement (CGI-I) score

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    End point title
    Number of participants with Clinical Global Impression - Improvement (CGI-I) score
    End point description
    The CGI-I is a 7-point scale that requires the clinician to assess how much the patient's illness has improved or worsened relative to a baseline state at the beginning of the intervention and rated as: 1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; 7=very much worse.
    End point type
    Secondary
    End point timeframe
    Week 4
    End point values
    Period 1: Placebo Period 2: Placebo Period 1: JNJ-40411813 Period 2: JNJ-40411813
    Number of subjects analysed
    58 [52]
    11 [53]
    61 [54]
    11 [55]
    Units: participants
    number (not applicable)
        Minimally Worse
    0
    0
    2
    0
        No Change
    11
    3
    7
    1
        Minimally Improved
    22
    3
    21
    3
        Much Improved
    20
    4
    26
    3
        Very Much Improved
    5
    1
    5
    4
    Notes
    [52] - Period 1: ITT
    [53] - Period 2: ITT
    [54] - Period 1: ITT
    [55] - Period 2: ITT
    No statistical analyses for this end point

    Secondary: Change from Baseline to Endpoint on the Perceived Stress Scale (PSS) Total Score

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    End point title
    Change from Baseline to Endpoint on the Perceived Stress Scale (PSS) Total Score
    End point description
    The PSS is a 10-item, self-reported unidimensional instrument developed to measure perceived stress in response to situations in a person's life. Prevalence of an item within the last month is measured on a 5 point scale, ranging from "never" to "very often". Higher scores reflect higher levels of perceived stress.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 4
    End point values
    Period 1: Placebo Period 2: Placebo Period 1: JNJ-40411813 Period 2: JNJ-40411813
    Number of subjects analysed
    58 [56]
    10 [57]
    59 [58]
    11 [59]
    Units: units on a scale
        least squares mean (standard error)
    -5.1 ± 0.64
    -4 ± 2
    -5.8 ± 0.63
    -7.1 ± 1.93
    Notes
    [56] - Period 1: ITT
    [57] - ITT population with evaluable participants for this endpoint out of 11 (full Period 2 ITT).
    [58] - ITT population with evaluable participants for this endpoint out of 61 (full Period 1 ITT).
    [59] - Period 2: ITT
    Statistical analysis title
    Period 1 and 2 Combined: Placebo v JNJ-40411813
    Statistical analysis description
    Based on ANCOVA model with treatment(placebo,JNJ-40411813) and pooled center as factors and baseline value (for respective period) as a covariate. This was the doubly randomized design: 117 subjects from Period 1 and 21 re-randomized subjects from Period 2 contributed to the JNJ-40411813 vs Placebo comparison. Statistics defined as a weighted combination of the test statistics from both periods, where weights satisfied pre-specified power optimality criterion was used.
    Comparison groups
    Period 1: Placebo v Period 1: JNJ-40411813
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.124 [60]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [60] - One-sided p-value measured

    Secondary: Change From Baseline to Endpoint in the Profile of Moods Scale-Brief Form (POMS-BF)

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    End point title
    Change From Baseline to Endpoint in the Profile of Moods Scale-Brief Form (POMS-BF)
    End point description
    The POMS-BF is a 30 item, self-report inventory in which a series of mood states (such as "Tense" or "Worn out") are rated based on how well each item describes the respondent's mood during the past week, including today. Items are rated on a 5-point scale with response options of: "Not at all", "A little", "Moderately", "Quite a bit" or "Extremely" with a global score range of 0 to 120 or individual domain scores on Tension-Anxiety, Depression-Dejection, Anger-Hostility, Vigor-Activity, Fatigue-Inertia, and Confusion-Bewilderment. Total Mood Disturbance score is calculated by summing the domains scores for Tension- Anxiety, Depression-Dejection, Anger-Hostility, Fatigue-Inertia, and Confusion-Bewilderment, then subtracting the domain score for Vigor-Activity. A higher Total Mood Disturbance score indicates worse mood state.
    End point type
    Secondary
    End point timeframe
    Baseline and week 4
    End point values
    Period 1: Placebo Period 2: Placebo Period 1: JNJ-40411813 Period 2: JNJ-40411813
    Number of subjects analysed
    58 [61]
    10 [62]
    59 [63]
    11 [64]
    Units: units on a scale
        least squares mean (standard error)
    -20 ± 2.08
    -14.7 ± 4.23
    -19.5 ± 2.04
    -18.8 ± 4.07
    Notes
    [61] - Period 1: ITT
    [62] - ITT population with evaluable subjects for this endpoint out of 11 (full Period 2 ITT).
    [63] - ITT population with evaluable participants for this endpoint out of 61 (full Period 1 ITT).
    [64] - Period 2: ITT
    Statistical analysis title
    Period 1 and 2 Combined: Placebo v JNJ-40411813
    Statistical analysis description
    Based on ANCOVA model with treatment (placebo,JNJ-40411813) and pooled center as factors and baseline value (for respective period) as a covariate. This was the doubly randomized design: 117 subjects from Period 1 and 21 re-randomized subjects from Period 2 contributed to the JNJ-40411813 vs Placebo comparison. Statistics defined as a weighted combination of the test statistics from both periods, where weights satisfied pre-specified power optimality criterion was used.
    Comparison groups
    Period 1: JNJ-40411813 v Period 1: Placebo
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.445 [65]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [65] - One-sided p-value measured

    Secondary: Change from Baseline to Endpoint on the Medical Outcomes Study-12-item Sleep Scale Acute - Revised (MOS Sleep-R)

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    End point title
    Change from Baseline to Endpoint on the Medical Outcomes Study-12-item Sleep Scale Acute - Revised (MOS Sleep-R)
    End point description
    The MOS Sleep-R is a self-reported scale containing 12 items addressing dimensions of sleep. It comprises six subscales: sleep disturbance, snoring, shortness of breath or headache, sleep adequacy, sleep somnolence, and sleep quantity. Items are answered on 5-point scales, where 1="all of the time," and 5="none of the time," 1 item (sleep latency) is answered on a 5 point scale from 1="0-15 minutes" to 5="more than 60 minutes." Score range of 0 to 100, where higher scores indicate fewer sleep-related problems. Duration of sleep is scored as the average number of hours slept per night. Here 'n' signifies number of participants who were analysed for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 4
    End point values
    Period 1: Placebo Period 2: Placebo Period 1: JNJ-40411813 Period 2: JNJ-40411813
    Number of subjects analysed
    58 [66]
    11 [67]
    61 [68]
    11 [69]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Shortness of Breath (n= 58, 59, 10, 11)
    8.3 ± 12.68
    3.5 ± 13.66
    9.4 ± 11.94
    6.4 ± 14.3
        Sleep Adequacy (n= 58, 59, 10, 11)
    9.5 ± 11.15
    8.2 ± 11.2
    8.9 ± 10.48
    7.5 ± 15.67
        Sleep Disturbance (n= 58, 59, 10, 11)
    9.2 ± 8.83
    6 ± 8
    8.6 ± 10.44
    8.4 ± 9.82
        Snoring (n= 58, 59, 10, 11)
    0.9 ± 4.29
    0.8 ± 2.4
    2.2 ± 5.48
    3.5 ± 7.87
        Somnolence (n= 58, 59, 10, 11)
    6.3 ± 9.01
    9.3 ± 4.53
    6.9 ± 8.19
    3.9 ± 8.79
        Sleep Problems Index (6 items) (n= 58, 59, 10, 11)
    11.9 ± 10.28
    7.8 ± 10.14
    10.9 ± 10.5
    8.5 ± 15.54
        Sleep Problems Index (9 items) (n= 58, 59, 10, 11)
    10.9 ± 9.68
    8.4 ± 9.86
    10.8 ± 10.07
    9.2 ± 13.33
        Sleep Quantity (n= 58, 59, 10, 11)
    1.1 ± 1.66
    0.3 ± 1.06
    0.9 ± 1.39
    0.6 ± 1.29
    Notes
    [66] - Period 1: ITT
    [67] - Period 2: ITT
    [68] - Period 1: ITT
    [69] - Period 2: ITT
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 4 in the Work Limitations Questionnaire (WLQ)

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    End point title
    Change from Baseline to Week 4 in the Work Limitations Questionnaire (WLQ)
    End point description
    The WLQ is a 25-item questionnaire self-report rating scale developed to measure the on-the-job impact of chronic health problems and/or treatment ("work limitations"), with a recall period of the previous 2 weeks. It comprises four dimensions of limitations: handling time, physical, mental-interpersonal, and output demands. Patients respond to each item with options ranging from "Almost all of the time" to "none of the time", or "Does not apply to my job". The global score ranges from 0 to 100 with lower score indicating low level of work limitations. Here 'n' signifies number of participants who were analysed for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 4
    End point values
    Period 1: Placebo Period 2: Placebo Period 1: JNJ-40411813 Period 2: JNJ-40411813
    Number of subjects analysed
    58 [70]
    11 [71]
    61 [72]
    11 [73]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Time Management (n= 42, 41, 8 , 10)
    -20.6 ± 23.61
    -7.5 ± 23.6
    -17.9 ± 21.95
    -29.5 ± 23.27
        Physical Demands (n= 42, 44, 7, 10)
    -14.6 ± 15.81
    -11.5 ± 17.76
    -14.7 ± 18.38
    -20.8 ± 18.63
        Mental-Interpersonal Demands (n= 42, 43, 8, 10)
    -15.5 ± 19.6
    -13 ± 20.93
    -16.9 ± 18.34
    -23.3 ± 22.15
        Output Demands (n= 42, 43, 8, 10)
    -17.6 ± 18.4
    -9.4 ± 20.26
    -18.2 ± 18.84
    -27 ± 23.12
        WLQ Productivity Loss Score (%) (n= 41, 40, 7, 10)
    -4.2 ± 4.18
    -3.3 ± 5.11
    -3.9 ± 3.63
    -6.4 ± 5.16
    Notes
    [70] - Period 1: ITT
    [71] - Period 2: ITT
    [72] - Period 1: ITT
    [73] - Period 2: ITT
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to Follow-up (2 weeks after the last dose of study drug administration)
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Placebo / NA
    Reporting group description
    Participants receiving matching Placebo who dropped out before or at the end of Period 1.

    Reporting group title
    JNJ-40411813 / JNJ-40411813
    Reporting group description
    Participants receiving JNJ-40411813 in Period 1, having at least one dose of JNJ-40411813 in Period 2.

    Reporting group title
    Placebo / JNJ-40411813
    Reporting group description
    Participants receiving matching Placebo in Period 1, having at least one dose of JNJ-40411813 in Period 2.

    Reporting group title
    JNJ-40411813 / NA
    Reporting group description
    Participants receiving JNJ-40411813 who dropped out before, or at the end of Period 1.

    Reporting group title
    Placebo / Placebo
    Reporting group description
    Participants receiving matching Placebo in Period 1, having at least one dose of Placebo in Period 2.

    Serious adverse events
    Placebo / NA JNJ-40411813 / JNJ-40411813 Placebo / JNJ-40411813 JNJ-40411813 / NA Placebo / Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 53 (0.00%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 43 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    Placebo / NA JNJ-40411813 / JNJ-40411813 Placebo / JNJ-40411813 JNJ-40411813 / NA Placebo / Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 5 (80.00%)
    29 / 53 (54.72%)
    8 / 11 (72.73%)
    3 / 9 (33.33%)
    20 / 43 (46.51%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 53 (3.77%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Raynaud's Phenomenon
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 53 (1.89%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Vascular Pain
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 53 (1.89%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 53 (1.89%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Hyperthermia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 53 (1.89%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Hypothermia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 53 (1.89%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Irritability
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 53 (3.77%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Psychiatric disorders
    Abnormal Dreams
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 53 (3.77%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Agitation
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 53 (0.00%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    0
    1
    Anxiety
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 53 (1.89%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    1
    0
    0
    1
    Insomnia
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 53 (3.77%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    3
    0
    0
    1
    Libido Decreased
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 53 (0.00%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Restlessness
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 53 (0.00%)
    0 / 11 (0.00%)
    1 / 9 (11.11%)
    0 / 43 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Reproductive system and breast disorders
    Amenorrhoea
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 53 (1.89%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Dysmenorrhoea
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 53 (0.00%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    0
    1
    Endometrial Hyperplasia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 53 (0.00%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    Joint Dislocation
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 53 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 53 (0.00%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 53 (0.00%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Blood Creatine Phosphokinase Increased
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 53 (0.00%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Blood Lactate Dehydrogenase Increased
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 53 (0.00%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Blood Pressure Increased
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 53 (1.89%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Heart Rate Increased
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 53 (1.89%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Urine Ketone Body Present
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 53 (0.00%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    0
    1
    Weight Decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 53 (0.00%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    0
    2
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 53 (1.89%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    1
    0
    0
    1
    Sinus Bradycardia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 53 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 53 (1.89%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 53 (1.89%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Balance Disorder
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 53 (0.00%)
    0 / 11 (0.00%)
    1 / 9 (11.11%)
    0 / 43 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Disturbance in Attention
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 53 (0.00%)
    0 / 11 (0.00%)
    1 / 9 (11.11%)
    0 / 43 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Dizziness
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 53 (1.89%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Dizziness Exertional
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 53 (0.00%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    0
    2
    Dizziness Postural
         subjects affected / exposed
    1 / 5 (20.00%)
    5 / 53 (9.43%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    2 / 43 (4.65%)
         occurrences all number
    2
    8
    1
    0
    2
    Headache
         subjects affected / exposed
    0 / 5 (0.00%)
    5 / 53 (9.43%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    5 / 43 (11.63%)
         occurrences all number
    0
    5
    1
    0
    9
    Somnolence
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 53 (0.00%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    2 / 43 (4.65%)
         occurrences all number
    0
    0
    0
    0
    2
    Eye disorders
    Accommodation Disorder
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 53 (0.00%)
    0 / 11 (0.00%)
    1 / 9 (11.11%)
    0 / 43 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 5 (20.00%)
    12 / 53 (22.64%)
    3 / 11 (27.27%)
    1 / 9 (11.11%)
    4 / 43 (9.30%)
         occurrences all number
    1
    25
    4
    1
    4
    Gastrointestinal disorders
    Abdominal Discomfort
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 53 (1.89%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Abdominal Pain Upper
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 53 (3.77%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Constipation
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 53 (1.89%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Diarrhoea
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 53 (3.77%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    3 / 43 (6.98%)
         occurrences all number
    0
    2
    0
    0
    3
    Dry Mouth
         subjects affected / exposed
    0 / 5 (0.00%)
    4 / 53 (7.55%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    3 / 43 (6.98%)
         occurrences all number
    0
    5
    0
    0
    3
    Dyspepsia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 53 (1.89%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Faecal Incontinence
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 53 (0.00%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    0
    1
    Nausea
         subjects affected / exposed
    0 / 5 (0.00%)
    3 / 53 (5.66%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    5 / 43 (11.63%)
         occurrences all number
    0
    4
    0
    0
    6
    Vomiting
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 53 (1.89%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Renal and urinary disorders
    Urinary Incontinence
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 53 (0.00%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 53 (0.00%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Pain in Extremity
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 53 (1.89%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 53 (0.00%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    0
    1
    Infections and infestations
    Cystitis
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 53 (3.77%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    2
    0
    0
    1
    Pharyngitis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 53 (1.89%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Respiratory Tract Infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 53 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Respiratory Tract Infection Viral
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 53 (3.77%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Rhinitis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 53 (1.89%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 53 (0.00%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    0
    1
    Viral Infection
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 53 (1.89%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    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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