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    Clinical Trial Results:
    A Double-blind, Placebo-Controlled Study of Cariprazine as Adjunctive Therapy in Major Depressive Disorder

    Summary
    EudraCT number
    2011-005179-18
    Trial protocol
    FI   EE   SK   SE  
    Global end of trial date
    12 Dec 2013

    Results information
    Results version number
    v1(current)
    This version publication date
    18 Apr 2018
    First version publication date
    18 Apr 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RGH-MD-75
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01469377
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Forest Laboratories, LLC, an Allergan Affiliate
    Sponsor organisation address
    5 Giralda Farms, Madison, United States, NJ 07940
    Public contact
    Clinical Trials Registry Team, Allergan plc, 001 877‐277‐8566, IR-CTRegistration@allergan.com
    Scientific contact
    Therapeutic Area Head, Allergan plc, 001 862-261-7000, IR-CTRegistration@Allergan.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
    12 Dec 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Dec 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objectives of this study were to evaluate the efficacy, safety, and tolerability of cariprazine adjunctive to antidepressant therapy (ADT) in subjects with major depressive disorder (MDD) who had an inadequate response to ADT.
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    15 Dec 2011
    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
    Estonia: 109
    Country: Number of subjects enrolled
    Finland: 76
    Country: Number of subjects enrolled
    Slovakia: 81
    Country: Number of subjects enrolled
    Sweden: 25
    Country: Number of subjects enrolled
    Ukraine: 60
    Country: Number of subjects enrolled
    United States: 468
    Worldwide total number of subjects
    819
    EEA total number of subjects
    291
    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)
    807
    From 65 to 84 years
    12
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 1248 subjects were screened for eligibility, 819 subjects were randomized to receive double-blind treatment, 812 subjects received at least 1 dose of double-blind treatment (Safety Population), and 808 subjects had at least 1 postbaseline MADRS assessment [intent to treat (ITT) Population].

    Pre-assignment period milestones
    Number of subjects started
    819
    Number of subjects completed
    812

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Randomized; Did Not Receive Study Drug: 7
    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Participants received placebo orally once a day for 8 weeks. Each participant continued to take the same dose of antidepressant therapy (bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, sertraline, venlafaxine, or vilazodone) the participant was receiving prior to entering this study throughout 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
    Subjects received matched placebo capsules, orally, once daily for 8 weeks.

    Arm title
    Cariprazine 1-2 mg
    Arm description
    Participants received cariprazine orally once a day for 8 weeks. Participants received cariprazine 0.5 mg on Days 1 and 2 and 1.0 mg on Days 3-7. At the investigator’s discretion dose levels could be increased during Week 2. Dose levels allowed during Week 2 were 1.0 or 1.5 mg. A second dose increase was allowed starting at Week 3. Dose levels allowed during Week 3 and the remainder of the treatment period were 1.0, 1.5, or 2.0 mg. Each participant continued to take the same dose of antidepressant therapy (bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, sertraline, venlafaxine, or vilazodone) the participant was receiving prior to entering this study throughout treatment.
    Arm type
    Experimental

    Investigational medicinal product name
    Cariprazine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received cariprazine (1-2 mg/day) capsules, orally, once daily for 8 weeks.

    Arm title
    Cariprazine 2-4.5 mg
    Arm description
    Participants received cariprazine orally once a day for 8 weeks. Participants received cariprazine 0.5 mg on Days 1 and 2, 1.0 mg on Day 3, 1.5 mg on Day 4, and 2.0 mg on Days 5-7. At the investigator’s discretion dose levels could be increased during Week 2. Dose levels allowed during Week 2 were 2.0 or 3.0 mg. A second dose increase was allowed starting at Week 3. Dose levels allowed during Week 3 and the remainder of the treatment period were 2.0, 3.0, or 4.5 mg. Each participant continued to take the same dose of antidepressant therapy (bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, sertraline, venlafaxine, or vilazodone) the participant was receiving prior to entering this study throughout treatment.
    Arm type
    Experimental

    Investigational medicinal product name
    Cariprazine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received cariprazine (2-4.5 mg/day) capsules, orally, once daily for 8 weeks.

    Number of subjects in period 1 [1]
    Placebo Cariprazine 1-2 mg Cariprazine 2-4.5 mg
    Started
    266
    273
    273
    Completed
    234
    226
    210
    Not completed
    32
    47
    63
         Withdrawal of Consent
    11
    13
    14
         Protocol Deviation
    6
    10
    9
         Adverse event, non-fatal
    8
    18
    36
         Lost to follow-up
    2
    2
    4
         Other Miscellaneous Reasons
    2
    -
    -
         Insufficient Therapeutic Response
    3
    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: Baseline Period is based on the Safety Population, that included all randomized participants who received at least 1 dose of investigational product. 7 participants did not receive study drug and are excluded.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants received placebo orally once a day for 8 weeks. Each participant continued to take the same dose of antidepressant therapy (bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, sertraline, venlafaxine, or vilazodone) the participant was receiving prior to entering this study throughout treatment.

    Reporting group title
    Cariprazine 1-2 mg
    Reporting group description
    Participants received cariprazine orally once a day for 8 weeks. Participants received cariprazine 0.5 mg on Days 1 and 2 and 1.0 mg on Days 3-7. At the investigator’s discretion dose levels could be increased during Week 2. Dose levels allowed during Week 2 were 1.0 or 1.5 mg. A second dose increase was allowed starting at Week 3. Dose levels allowed during Week 3 and the remainder of the treatment period were 1.0, 1.5, or 2.0 mg. Each participant continued to take the same dose of antidepressant therapy (bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, sertraline, venlafaxine, or vilazodone) the participant was receiving prior to entering this study throughout treatment.

    Reporting group title
    Cariprazine 2-4.5 mg
    Reporting group description
    Participants received cariprazine orally once a day for 8 weeks. Participants received cariprazine 0.5 mg on Days 1 and 2, 1.0 mg on Day 3, 1.5 mg on Day 4, and 2.0 mg on Days 5-7. At the investigator’s discretion dose levels could be increased during Week 2. Dose levels allowed during Week 2 were 2.0 or 3.0 mg. A second dose increase was allowed starting at Week 3. Dose levels allowed during Week 3 and the remainder of the treatment period were 2.0, 3.0, or 4.5 mg. Each participant continued to take the same dose of antidepressant therapy (bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, sertraline, venlafaxine, or vilazodone) the participant was receiving prior to entering this study throughout treatment.

    Reporting group values
    Placebo Cariprazine 1-2 mg Cariprazine 2-4.5 mg Total
    Number of subjects
    266 273 273 812
    Age categorical
    Units: Subjects
        18 - 64 years
    259 270 272 801
        65 - 84 years
    7 3 1 11
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    46.4 ± 11.6 45.5 ± 11.9 45.1 ± 11.4 -
    Gender, Male/Female
    Units: Subjects
        Female
    190 187 201 578
        Male
    76 86 72 234
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    14 17 22 53
        Not Hispanic or Latino
    252 256 251 759
        Unknown or Not Reported
    0 0 0 0
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    2 1 1 4
        Asian
    1 4 4 9
        Native Hawaiian or Other Pacific Islander
    0 0 0 0
        Black or African American
    32 31 24 87
        White
    230 234 242 706
        More than one race
    0 0 0 0
        Unknown or Not Reported
    1 3 2 6
    Body Mass Index (BMI)
    Units: kg/m^2
        arithmetic mean (standard deviation)
    28.93 ± 5.09 28.21 ± 5.51 29.05 ± 5.59 -
    Waist Circumference
    Units: cm
        arithmetic mean (standard deviation)
    94.32 ± 13.44 93.36 ± 14.20 94.91 ± 14.66 -
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    81.53 ± 16.19 79.69 ± 16.31 82.17 ± 17.37 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants received placebo orally once a day for 8 weeks. Each participant continued to take the same dose of antidepressant therapy (bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, sertraline, venlafaxine, or vilazodone) the participant was receiving prior to entering this study throughout treatment.

    Reporting group title
    Cariprazine 1-2 mg
    Reporting group description
    Participants received cariprazine orally once a day for 8 weeks. Participants received cariprazine 0.5 mg on Days 1 and 2 and 1.0 mg on Days 3-7. At the investigator’s discretion dose levels could be increased during Week 2. Dose levels allowed during Week 2 were 1.0 or 1.5 mg. A second dose increase was allowed starting at Week 3. Dose levels allowed during Week 3 and the remainder of the treatment period were 1.0, 1.5, or 2.0 mg. Each participant continued to take the same dose of antidepressant therapy (bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, sertraline, venlafaxine, or vilazodone) the participant was receiving prior to entering this study throughout treatment.

    Reporting group title
    Cariprazine 2-4.5 mg
    Reporting group description
    Participants received cariprazine orally once a day for 8 weeks. Participants received cariprazine 0.5 mg on Days 1 and 2, 1.0 mg on Day 3, 1.5 mg on Day 4, and 2.0 mg on Days 5-7. At the investigator’s discretion dose levels could be increased during Week 2. Dose levels allowed during Week 2 were 2.0 or 3.0 mg. A second dose increase was allowed starting at Week 3. Dose levels allowed during Week 3 and the remainder of the treatment period were 2.0, 3.0, or 4.5 mg. Each participant continued to take the same dose of antidepressant therapy (bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, sertraline, venlafaxine, or vilazodone) the participant was receiving prior to entering this study throughout treatment.

    Primary: Change From Baseline in the Montgomery-Åsberg Depression Rating Scale Total Score at Week 8

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    End point title
    Change From Baseline in the Montgomery-Åsberg Depression Rating Scale Total Score at Week 8
    End point description
    The Montgomery-Åsberg Depression Rating Scale is a clinician-rated scale to assess depressive symptomatology during the preceding week. Participants are rated on 10 items (feelings of sadness, lassitude, pessimism, inner tension, suicidality, reduced sleep or appetite, difficulty concentrating, and lack of interest) each on a 7-point scale from 0 (no symptoms) to 6 (symptoms of maximum severity). The total score ranges from 0 to 60 with a higher score indicating more depression. A negative change score indicates improvement.
    End point type
    Primary
    End point timeframe
    Baseline to Week 8
    End point values
    Placebo Cariprazine 1-2 mg Cariprazine 2-4.5 mg
    Number of subjects analysed
    264
    273
    271
    Units: Units on a scale
        least squares mean (standard error)
    -12.5 ± 0.5
    -13.4 ± 0.5
    -14.6 ± 0.6
    Statistical analysis title
    Cariprazine 1-2 mg vs Placebo
    Comparison groups
    Placebo v Cariprazine 1-2 mg
    Number of subjects included in analysis
    537
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.2404 [1]
    Method
    Mixed-effect model for repeated measures
    Parameter type
    Least squares mean difference
    Point estimate
    -0.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.4
         upper limit
    0.6
    Notes
    [1] - p-values were from an mixed-effects model for repeated measures with treatment group, pooled study center, visit, and treatment-group-by-visit interaction as fixed effects and the baseline value and baseline value-by-visit interaction as covariates.
    Statistical analysis title
    Cariprazine 2-4.5 mg vs Placebo
    Comparison groups
    Placebo v Cariprazine 2-4.5 mg
    Number of subjects included in analysis
    535
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.0114 [2]
    Method
    Mixed-effect model for repeated measures
    Parameter type
    Least squares mean difference
    Point estimate
    -2.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.7
         upper limit
    -0.6
    Notes
    [2] - p-values were from an mixed-effects model for repeated measures with treatment group, pooled study center, visit, and treatment-group-by-visit interaction as fixed effects and the baseline value and baseline value-by-visit interaction as covariates.

    Secondary: Change From Baseline in the Sheehan Disability Scale Total Score at Week 8

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    End point title
    Change From Baseline in the Sheehan Disability Scale Total Score at Week 8
    End point description
    The Sheehan Disability Scale measures an individual’s perception of the extent to which his or her emotional symptoms are disrupting his or her functioning in 3 domains, work/school, social life/leisure activities, and family life/home responsibilities. The participant is asked to rate the degree to which their functioning is impaired on an 11-point scale, ranging from 0 (not at all) to 10 (extremely). Scores of 0 to 3 indicate mild functional impairment, 4 to 6 indicate moderate functional impairment, and 7 to 9 indicate marked functional impairment. The scores for the 3 domains are summed into a total score that ranges from 0 (unimpaired) to 30 (highly impaired). A higher score indicates greater impairment. A negative change score indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 8
    End point values
    Placebo Cariprazine 1-2 mg Cariprazine 2-4.5 mg
    Number of subjects analysed
    264
    273
    271
    Units: Units on a scale
        least squares mean (standard error)
    -6.6 ± 0.5
    -7.7 ± 0.5
    -8.0 ± 0.5
    Statistical analysis title
    Cariprazine 1-2 mg vs Placebo
    Comparison groups
    Placebo v Cariprazine 1-2 mg
    Number of subjects included in analysis
    537
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.2404 [3]
    Method
    Mixed-effect model for repeated measures
    Parameter type
    Least squares mean difference
    Point estimate
    -1.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.5
         upper limit
    0.3
    Notes
    [3] - p-values were from an mixed-effects model for repeated measures with treatment group, pooled study center, visit, and treatment-group-by-visit interaction as fixed effects and the baseline value and baseline value-by-visit interaction as covariates.
    Statistical analysis title
    Cariprazine 2-4.5 mg vs Placebo
    Comparison groups
    Placebo v Cariprazine 2-4.5 mg
    Number of subjects included in analysis
    535
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.114 [4]
    Method
    Mixed-effect model for repeated measures
    Parameter type
    Least squares mean difference
    Point estimate
    -1.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.8
         upper limit
    0
    Notes
    [4] - p-values were from an mixed-effects model for repeated measures with treatment group, pooled study center, visit, and treatment-group-by-visit interaction as fixed effects and the baseline value and baseline value-by-visit interaction as covariates.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events were collected and recorded from the time the participant signs the informed consent form until 30 days after the last dose of treatment.
    Adverse event reporting additional description
    Safety population: All randomized participants who received at least 1 dose of treatment.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Cariprazine 1-2 mg
    Reporting group description
    Participants received cariprazine orally once a day for 8 weeks. Participants received cariprazine 0.5 mg on Days 1 and 2 and 1.0 mg on Days 3-7. At the investigator’s discretion dose levels could be increased during Week 2. Dose levels allowed during Week 2 were 1.0 or 1.5 mg. A second dose increase was allowed starting at Week 3. Dose levels allowed during Week 3 and the remainder of the treatment period were 1.0, 1.5, or 2.0 mg. Each participant continued to take the same dose of antidepressant therapy (bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, sertraline, venlafaxine, or vilazodone) the participant was receiving prior to entering this study throughout treatment.

    Reporting group title
    Placebo
    Reporting group description
    Participants received placebo orally once a day for 8 weeks. Each participant continued to take the same dose of antidepressant therapy (bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, sertraline, venlafaxine, or vilazodone) the participant was receiving prior to entering this study throughout treatment.

    Reporting group title
    Cariprazine 2-4.5 mg
    Reporting group description
    Participants received cariprazine orally once a day for 8 weeks. Participants received cariprazine 0.5 mg on Days 1 and 2, 1.0 mg on Day 3, 1.5 mg on Day 4, and 2.0 mg on Days 5-7. At the investigator’s discretion dose levels could be increased during Week 2. Dose levels allowed during Week 2 were 2.0 or 3.0 mg. A second dose increase was allowed starting at Week 3. Dose levels allowed during Week 3 and the remainder of the treatment period were 2.0, 3.0, or 4.5 mg. Each participant continued to take the same dose of antidepressant therapy (bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, sertraline, venlafaxine, or vilazodone) the participant was receiving prior to entering this study throughout treatment.

    Serious adverse events
    Cariprazine 1-2 mg Placebo Cariprazine 2-4.5 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 266 (0.38%)
    3 / 273 (1.10%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Cardiac disorders
    Myocardial ischemia
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 266 (0.00%)
    1 / 273 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 266 (0.00%)
    1 / 273 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 266 (0.00%)
    1 / 273 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 266 (0.00%)
    1 / 273 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Panic attack
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 266 (0.00%)
    1 / 273 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 266 (0.38%)
    0 / 273 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Cariprazine 1-2 mg Placebo Cariprazine 2-4.5 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    121 / 273 (44.32%)
    102 / 266 (38.35%)
    179 / 273 (65.57%)
    Nervous system disorders
    Akathisia
         subjects affected / exposed
    18 / 273 (6.59%)
    6 / 266 (2.26%)
    61 / 273 (22.34%)
         occurrences all number
    26
    6
    80
    Dizziness
         subjects affected / exposed
    10 / 273 (3.66%)
    7 / 266 (2.63%)
    14 / 273 (5.13%)
         occurrences all number
    10
    9
    17
    Headache
         subjects affected / exposed
    24 / 273 (8.79%)
    36 / 266 (13.53%)
    24 / 273 (8.79%)
         occurrences all number
    31
    45
    30
    Somnolence
         subjects affected / exposed
    24 / 273 (8.79%)
    14 / 266 (5.26%)
    27 / 273 (9.89%)
         occurrences all number
    25
    15
    28
    Tremor
         subjects affected / exposed
    13 / 273 (4.76%)
    4 / 266 (1.50%)
    21 / 273 (7.69%)
         occurrences all number
    14
    4
    23
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    18 / 273 (6.59%)
    11 / 266 (4.14%)
    27 / 273 (9.89%)
         occurrences all number
    21
    12
    28
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    6 / 273 (2.20%)
    5 / 266 (1.88%)
    14 / 273 (5.13%)
         occurrences all number
    7
    5
    18
    Diarrhoea
         subjects affected / exposed
    8 / 273 (2.93%)
    14 / 266 (5.26%)
    8 / 273 (2.93%)
         occurrences all number
    8
    16
    9
    Dry mouth
         subjects affected / exposed
    14 / 273 (5.13%)
    7 / 266 (2.63%)
    10 / 273 (3.66%)
         occurrences all number
    14
    7
    10
    Nausea
         subjects affected / exposed
    19 / 273 (6.96%)
    13 / 266 (4.89%)
    35 / 273 (12.82%)
         occurrences all number
    20
    17
    38
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    27 / 273 (9.89%)
    17 / 266 (6.39%)
    38 / 273 (13.92%)
         occurrences all number
    29
    18
    45
    Restlessness
         subjects affected / exposed
    22 / 273 (8.06%)
    7 / 266 (2.63%)
    23 / 273 (8.42%)
         occurrences all number
    22
    7
    31
    Metabolism and nutrition disorders
    Increased appetite
         subjects affected / exposed
    5 / 273 (1.83%)
    4 / 266 (1.50%)
    14 / 273 (5.13%)
         occurrences all number
    5
    4
    14

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 May 2012
    • The Antidepressant Treatment History Form (ATHF) was added for documenting the identity, dose, duration, and response to qualifying ADT at screening • The eligibility criteria was modified in accordance with the ATHF, to expand the qualifying patient pool, and to allow conformance with local standards of care (specific changes included removing Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) codes, increasing the allowed duration of the current episode to 24 months, adding fluoxetine to the allowed ADTs, removing the inclusion criterion based on SDS total score, adding an exclusion criterion for hospitalization, and expanding the allowed range of heart rate and BP measurements) • The sensitivity analysis, pattern-mixture model were modified to improve computational efficiency (change from mixed-effects model for repeated measures [MMRM] to analysis of covariance [ANCOVA])
    11 Jul 2012
    • Required washout period for fluoxetine was removed because fluoxetine was added to the allowed antidepressant treatments in Amendment 1 • The requirement for reflex collection of hemoglobin A1c was removed in subjects with elevated glucose because detectable changes occur over a duration of time that is longer than the study duration • Collection of folate and B12 to be based on the Investigator’s clinical judgment were modified • Azithromycin as a recommended macrolide antibiotic was removed

    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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