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    Clinical Trial Results:
    A Phase 3, Multicenter, Double-blind, Placebo-controlled, Randomized-withdrawal Study to Evaluate the Maintenance of Efficacy of SPD489 in Adults Aged 18-55 Years with Moderate to Severe Binge Eating Disorder

    Summary
    EudraCT number
    		 2012-004457-88
    Trial protocol
    		 SE   DE   ES  
    Global end of trial date
    08 Apr 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Apr 2016
    First version publication date
    09 Apr 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SPD489-346
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02009163
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Shire Development LLC and International Affiliates
    Sponsor organisation address
    1200 Morris Drive, Wayne, United States, 19087
    Public contact
    Study Physician, Shire Development LLC and International Affiliates , +1 8668425335,
    Scientific contact
    Study Physician, Shire Development LLC and International Affiliates , +1 8668425335,
    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
    08 Apr 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Apr 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate maintenance of efficacy based on time to relapse between SPD489 (50 or 70mg) and placebo, as measured by the number of binge days (defined as days during which at least 1 binge episode occurred) per week as assessed by clinical interview based on subject diary and Clinical Global Impression – Severity (CGI-S) scores for subjects who responded to SPD489 by the end of the Open-label Treatment Phase.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation of Good Clinical Practice, the principles of the Declaration of Helsinki, as well as other applicable local ethical and legal requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Jan 2014
    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
    Spain: 15
    Country: Number of subjects enrolled
    Sweden: 24
    Country: Number of subjects enrolled
    Germany: 37
    Country: Number of subjects enrolled
    Canada: 5
    Country: Number of subjects enrolled
    United States: 337
    Worldwide total number of subjects
    418
    EEA total number of subjects
    76
    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)
    418
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were recruited to participate at 49 sites in the US (38 sites), Germany (6 sites), Sweden (2 sites), Spain (2 sites), and Canada (1 site).

    Pre-assignment
    Screening details
    		 Subjects were screened for eligibility over a period of 4 weeks

    Period 1
    Period 1 title
    Open–label Period (Non-randomized)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 SPD489 (Open-label Period)
    Arm description
    		 SPD489 treatment was taken orally once daily at approximately 7:00 AM. All participants began treatment with SPD489 at the lowest dose level (30mg) during the 4­ week open­label dose­ optimization period. After 1 week of treatment at 30mg, all participants were titrated to the next dose level (50mg). After 1 week of treatment at 50mg, all participants were titrated to the highest dose level (70mg), as tolerated and as clinically indicated. After 1 week of treatment at the highest dose, the participant could have been down­titrated to 50mg; no further dose adjustments were permitted. The optimal daily dose of 50 or 70mg achieved during dose­ optimization was maintained throughout the 8­week dose­ maintenance period. The total time of the open­label period was 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    SPD489
    Investigational medicinal product code
    Other name
    Lisdexamfetamine dimesylate
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants were administered one 30, 50, or 70mg capsule once daily.

    Number of subjects in period 1
    		SPD489 (Open-label Period)
    Started
    418
    Completed
    275
    Not completed
    143
         Adverse Event
    22
         Failure to Meet Randomization Criteria
    48
         Not specified
    13
         Pregnancy
    1
         Withdrawal by Subject
    29
         Protocol Violation
    10
         Lost to follow-up
    20
    Period 2
    Period 2 title
    Randomized-withdrawal Period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    SPD489 and placebo were identical in appearance.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo (Randomized-withdrawal Period)
    Arm description
    		 During the 26-­week double-­blind randomized­-withdrawal phase, participants randomized to placebo received matching placebo capsules daily. After the 26-­week double­-blind randomized­-withdrawal phase, participants were followed for 1 week
    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
    Participants were administered a placebo capsule once daily.

    Arm title
    		 SPD489 (Randomized-withdrawal Period)
    Arm description
    		 For participants randomized to SPD489, the optimal daily dose of 50 or 70mg was continued throughout the 26-­week double­-blind randomized­-withdrawal phase. After the 26­-week double­-blind randomized­-withdrawal phase, participants were followed for 1 week.
    Arm type
    		 Experimental

    Investigational medicinal product name
    SPD489
    Investigational medicinal product code
    Other name
    Lisdexamfetamine dimesylate
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants were administered one 50 or 70mg capsule once daily.

    Number of subjects in period 2
    		Placebo (Randomized-withdrawal Period) SPD489 (Randomized-withdrawal Period)
    Started
    138
    137
    Completed
    50
    102
    Not completed
    88
    35
         Adverse Event
    -
    6
         Not specified
    9
    5
         Pregnancy
    -
    2
         Relapse Criteria Met
    40
    5
         Withdrawal by Subject
    25
    9
         Protocol Violation
    1
    2
         Lost to follow-up
    13
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Open–label Period (Non-randomized)
    Reporting group description
    		 All participants enrolled in the open-label population.

    Reporting group values
    		 Open–label Period (Non-randomized) Total
    Number of subjects
    		 418 418
    Age categorical
    Units: Subjects
        < 40 years of age
    		 223 223
        >/= 40 years of age
    		 195 195
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 38.2 ( 10.41 ) -
    Gender categorical
    Units: Subjects
        Female
    		 363 363
        Male
    		 55 55

    End points

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    End points reporting groups
    Reporting group title
    SPD489 (Open-label Period)
    Reporting group description
    		 SPD489 treatment was taken orally once daily at approximately 7:00 AM. All participants began treatment with SPD489 at the lowest dose level (30mg) during the 4­ week open­label dose­ optimization period. After 1 week of treatment at 30mg, all participants were titrated to the next dose level (50mg). After 1 week of treatment at 50mg, all participants were titrated to the highest dose level (70mg), as tolerated and as clinically indicated. After 1 week of treatment at the highest dose, the participant could have been down­titrated to 50mg; no further dose adjustments were permitted. The optimal daily dose of 50 or 70mg achieved during dose­ optimization was maintained throughout the 8­week dose­ maintenance period. The total time of the open­label period was 12 weeks.
    Reporting group title
    Placebo (Randomized-withdrawal Period)
    Reporting group description
    		 During the 26-­week double-­blind randomized­-withdrawal phase, participants randomized to placebo received matching placebo capsules daily. After the 26-­week double­-blind randomized­-withdrawal phase, participants were followed for 1 week

    Reporting group title
    SPD489 (Randomized-withdrawal Period)
    Reporting group description
    		 For participants randomized to SPD489, the optimal daily dose of 50 or 70mg was continued throughout the 26-­week double­-blind randomized­-withdrawal phase. After the 26­-week double­-blind randomized­-withdrawal phase, participants were followed for 1 week.

    Primary: Time to Relapse From Date of Randomization to Endpoint of The Randomized-­withdrawal Period

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    End point title
    		 Time to Relapse From Date of Randomization to Endpoint of The Randomized-­withdrawal Period
    End point description
    Relapse status was assessed during the double­blind treatment phase and was defined as having 2 or more binge days per week for 2 consecutive weeks (14 consecutive days) prior to any visit and having an increase in Clinical Global Impressions­Severity (CGI­S) score of 2 or more points compared to the randomized­withdrawal baseline (date of relapse ­ date of randomization). Binge eating information was captured via a self­report paper diary. The binge diary captured the number of binges per day, total hours per day spent binging, type of binge (at mealtime or at another time other than mealtime), and a description of the binge (amounts and types of foods). Binge frequency was reviewed by the clinician with the participant to confirm reported binge episodes per day. The CGI­S was performed to rate the severity of a participant's condition using a 7-­point scale ranging from 1 (normal, not at all ill) to 7 (among the most extremely ill). This endpoint assessed the Full Analysis Set (FAS
    End point type
    Primary
    End point timeframe
    Visit 21 (26 weeks after randomization [Week 38] or Early Termination). Visit 21 could include participants who discontinued but completed a final safety and efficacy assessment.
    End point values
    		 Placebo (Randomized-withdrawal Period) SPD489 (Randomized-withdrawal Period)
    Number of subjects analysed
    131 [1]
    136 [2]
    Units: days
        median (inter-quartile range (Q1-Q3))
    99999 (55 to 99999)
    99999 (99999 to 99999)
    Notes
    [1] - Three subjects in the placebo group were randomized and included in the RSAS but not the FAS.
    [2] - For both arms, 9999 is used to indicate that the median time to relapse or range was not calculable.
    Statistical analysis title
    		 Analysis of Relapse
    Comparison groups
    Placebo (Randomized-withdrawal Period) v SPD489 (Randomized-withdrawal Period)
    Number of subjects included in analysis
    267
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [3]
    Method
    		 Logrank
    Confidence interval
    Notes
    [3] - P­value based on a log­rank test, stratified by 4­week cessation status (Yes, No). 4­week cessation was defined as a subject having no binge days during the 4 weeks prior to randomization.

    Secondary: Change From Randomized-withdrawal Baseline in The Number of Binge­Eating Days Per Week During The Randomized­-withdrawal Period

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    End point title
    		 Change From Randomized-withdrawal Baseline in The Number of Binge­Eating Days Per Week During The Randomized­-withdrawal Period
    End point description
    A binge day was defined as days during which at least 1 binge episode occurred. As assessed by clinical interview based on participant binge diary. Binge eating information was captured via a self-­report paper diary. The binge diary captured the number of binges per day, total hours per day spent binging, type of binge (at mealtime or at another time other than mealtime), and a description of the binge (amounts and types of foods). Binge frequency was reviewed by the clinician with the participant to confirm reported binge episodes per day. A negative change from Baseline indicates that binge-­related behavior decreased. The randomized­withdrawal baseline was defined as the weekly average number of binge days for the 14 days prior to the Randomization Visit (Visit 8). This endpoint assessed the FAS. Not all participants in the FAS had data collected for this outcome. Visit 21 included only participants who completed randomized treatment (placebo: n=50; SPD489: n=102).
    End point type
    Secondary
    End point timeframe
    Randomized­-withdrawal baseline (Visit 8; 12 weeks after start of open­label treatment [Week 12]), Visit 21 (26 weeks after randomization [Week 38])
    End point values
    		 Placebo (Randomized-withdrawal Period) SPD489 (Randomized-withdrawal Period)
    Number of subjects analysed
    131 [4]
    136
    Units: days
        least squares mean (standard error)
    0.63 ( 0.076 )
    0.02 ( 0.061 )
    Notes
    [4] - Three subjects in the placebo group were randomized and included in the RSAS but not the FAS.
    Statistical analysis title
    		 Analysis of Binge Eating Days
    Comparison groups
    Placebo (Randomized-withdrawal Period) v SPD489 (Randomized-withdrawal Period)
    Number of subjects included in analysis
    267
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [5]
    Method
    		 mixed­effects model for repeated measure
    Parameter type
    		 difference in LS mean
    Point estimate
    -0.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.81
         upper limit
    		 -0.42
    Notes
    [5] - Nominal P­-value not adjusted for multiplicity. MMRM over all post­randomization visits during the randomized­withdrawal phase. Value for change from baseline = outcome variable.

    Secondary: Percent of Participants Within Each Category of The Clinical Global Impression­Severity of Illness (CGI­-S) Scale at Endpoint of The Randomized-withdrawal Period

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    End point title
    		 Percent of Participants Within Each Category of The Clinical Global Impression­Severity of Illness (CGI­-S) Scale at Endpoint of The Randomized-withdrawal Period
    End point description
    The CGI-­S permits a global evaluation of a participant's condition and severity of symptoms. The CGI­-S was performed to rate the severity of a participant's condition based on a 7-­point scale ranging from 1 (normal, not at all ill) to 7 (among the most extremely ill). This endpoint assessed the FAS, defined as participants in the Randomized Safety Analysis Set (RSAS) with at least 1 post­-randomization CGI­-S assessment.
    End point type
    Secondary
    End point timeframe
    Visit 21 (26 weeks after randomization [Week 38] or Early Termination). Visit 21 could include participants who discontinued but completed a final safety and efficacy assessment.
    End point values
    		 Placebo (Randomized-withdrawal Period) SPD489 (Randomized-withdrawal Period)
    Number of subjects analysed
    131 [6]
    136
    Units: percentage of subjects
    number (not applicable)
        Normal, Not at All Ill
    45
    81.6
        Borderline Mentally Ill
    10.7
    11.8
        Mildly Ill
    14.5
    2.2
        Moderately Ill
    22.1
    2.2
        Markedly Ill
    6.9
    2.2
        Severely Ill
    0
    0
        Among the Most Extremely Ill
    0.8
    0
    Notes
    [6] - Three subjects in the placebo group were randomized and included in the RSAS but not the FAS.
    Statistical analysis title
    		 Analysis of CGI-S
    Comparison groups
    Placebo (Randomized-withdrawal Period) v SPD489 (Randomized-withdrawal Period)
    Number of subjects included in analysis
    267
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [7]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [7] - Unadjusted P­value for the difference in distribution between treatment groups in CGI­S. Cochran-Mantel­-Haenszel test with a modified ridit score, adjusting for Visit 8 (Week 12) CGI­S as the covariate.

    Secondary: Change From Randomized-withdrawal Baseline in The Total Score of The Yale-­Brown Obsessive Compulsive Scale Modified for Binge Eating (Y­-BOCS­-BE) During The Randomized-­withdrawal Period

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    End point title
    		 Change From Randomized-withdrawal Baseline in The Total Score of The Yale-­Brown Obsessive Compulsive Scale Modified for Binge Eating (Y­-BOCS­-BE) During The Randomized-­withdrawal Period
    End point description
    The Y­-BOCS-­BE measures the obsession of binge eating thoughts and compulsiveness of binge eating behaviors. The scale is a clinician rated, 10­-item scale, each item rated from 0 (no symptoms) to 4 (extreme symptoms). The scale includes questions regarding the amount of time spent on obsessions, impairment or distress experienced, and resistance and control over these thoughts. The same types of questions were asked about compulsions (ie, time spent, interference, etc.).Total scores range from 0 to 40. A total score of 0-­7 is sub­clinical, 8-­15 is mild, 16-­23 is moderate, 24­-31 is severe, and 32-­40 is extreme. A decrease from baseline in Y­-BOCS-­BE Total Score represents an improvement in obsession with binge­eating thoughts or compulsiveness of binge-­eating behaviors. The endpoint assessed the FAS. Not all participants in the FAS had data collected for this outcome. Visit 21 included only participants who completed randomized treatment (placebo: n=54; SPD489: n=107).
    End point type
    Secondary
    End point timeframe
    Randomized­withdrawal baseline (Visit 8; 12 weeks after start of open­label treatment [Week 12]), Visit 21 (26 weeks after randomization [Week 38])
    End point values
    		 Placebo (Randomized-withdrawal Period) SPD489 (Randomized-withdrawal Period)
    Number of subjects analysed
    131 [8]
    136
    Units: units on a scale
        least squares mean (standard error)
    5.5 ( 0.66 )
    0 ( 0.52 )
    Notes
    [8] - Three subjects in the placebo group were randomized and included in the RSAS but not the FAS.
    Statistical analysis title
    		 Analysis of Y-BOCS-BE
    Comparison groups
    Placebo (Randomized-withdrawal Period) v SPD489 (Randomized-withdrawal Period)
    Number of subjects included in analysis
    267
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [9]
    Method
    		 mixed­effects model for repeated measure
    Parameter type
    		 difference in LS mean
    Point estimate
    -5.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.2
         upper limit
    		 -3.9
    Notes
    [9] - Nominal P-­value not adjusted for multiplicity. MMRM over all post­randomization visits during the randomized­withdrawal phase. Value for change from baseline = outcome variable.

    Secondary: Percent of Participants Within Each Category of The Euro-Quol Group 5-­Dimension 5-­Level Self-­Report Questionnaire (EQ-­5D-­5L) For Mobility at Endpoint of the Open-label Period

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    End point title
    		 Percent of Participants Within Each Category of The Euro-Quol Group 5-­Dimension 5-­Level Self-­Report Questionnaire (EQ-­5D-­5L) For Mobility at Endpoint of the Open-label Period
    End point description
    The EuroQoL Group 5­Dimension 5­Level Self­Report Questionnaire (EQ­-5D-­5L) is a health­related quality of life (QoL) measure that assesses mobility, self­care, usual activities, pain/discomfort, and anxiety/depression as well as current overall health. It consists of a 5­item descriptive system that measures 5 dimensions of health, including mobility, self­care, usual activities, pain/discomfort, and anxiety/depression. Each dimension is represented by a single item with 5 levels of responses, from poor health to good health. This endpoint assessed the Open-label Safety Population (OSP), defined as participants who had taken at least 1 dose of SPD489 in the open­label period and who had a post­baseline safety assessment. Not all participants had data collected for this outcome.
    End point type
    Secondary
    End point timeframe
    Visit 8 (12 weeks after start of open­label treatment [Week 12] or Early Termination). Visit 8 could include participants who discontinued but completed a safety and efficacy assessment.
    End point values
    		 SPD489 (Open-label Period)
    Number of subjects analysed
    397
    Units: percentage of subjects
    number (not applicable)
        I have no problems in walking about
    87.9
        I have slight problems in walking about
    9.8
        Moderate problems in walking about
    1.5
        I have severe problems in walking about
    0.8
        I am unable to walk about
    0
    No statistical analyses for this end point

    Secondary: Percent of Participants Within Each Category of The EuroQuol Group 5­-Dimension 5­-Level Self-­Report Questionnaire (EQ-­5D-­5L) For Mobility at Endpoint of the Randomized-withdrawal Period

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    End point title
    		 Percent of Participants Within Each Category of The EuroQuol Group 5­-Dimension 5­-Level Self-­Report Questionnaire (EQ-­5D-­5L) For Mobility at Endpoint of the Randomized-withdrawal Period
    End point description
    The EuroQoL Group 5­Dimension 5­Level Self­Report Questionnaire (EQ­-5D-­5L) is a health­related quality of life (QoL) measure that assesses mobility, self­care, usual activities, pain/discomfort, and anxiety/depression as well as current overall health. It consists of a 5­item descriptive system that measures 5 dimensions of health, including mobility, self­care, usual activities, pain/discomfort, and anxiety/depression. Each dimension is represented by a single item with 5 levels of responses, from poor health to good health. This endpoint assessed the FAS. Not all participants in the FAS had data collected for this outcome.
    End point type
    Secondary
    End point timeframe
    Visit 21 (26 weeks after randomization [Week 38] or Early Termination). Visit 21 could include participants who discontinued but completed a final safety and efficacy assessment.
    End point values
    		 Placebo (Randomized-withdrawal Period) SPD489 (Randomized-withdrawal Period)
    Number of subjects analysed
    116 [10]
    127
    Units: percentage of subjects
    number (not applicable)
        I have no problems in walking about
    83.6
    91.3
        I have slight problems in walking about
    14.7
    6.3
        Moderate problems in walking about
    1.7
    1.6
        I have severe problems in walking about
    0
    0.8
        I am unable to walk about
    0
    0
    Notes
    [10] - Three subjects in the placebo group were randomized and included in the RSAS but not the FAS.
    No statistical analyses for this end point

    Secondary: Percent of Participants Within Each Category of The Euro-Quol Group 5-­Dimension 5-­Level Self-­Report Questionnaire (EQ-­5D-­5L) For Self Care at Endpoint of the Open-label Period

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    End point title
    		 Percent of Participants Within Each Category of The Euro-Quol Group 5-­Dimension 5-­Level Self-­Report Questionnaire (EQ-­5D-­5L) For Self Care at Endpoint of the Open-label Period
    End point description
    The EuroQoL Group 5­Dimension 5­Level Self­Report Questionnaire (EQ­-5D-­5L) is a health­related quality of life (QoL) measure that assesses mobility, self­care, usual activities, pain/discomfort, and anxiety/depression as well as current overall health. It consists of a 5­item descriptive system that measures 5 dimensions of health, including mobility, self­care, usual activities, pain/discomfort, and anxiety/depression. Each dimension is represented by a single item with 5 levels of responses, from poor health to good health. This endpoint assessed the Open-label Safety Population (OSP), defined as participants who had taken at least 1 dose of SPD489 in the open­label period and who had a post­baseline safety assessment. Not all participants had data collected for this outcome.
    End point type
    Secondary
    End point timeframe
    Visit 8 (12 weeks after start of open­label treatment [Week 12] or Early Termination). Visit 8 could include participants who discontinued but completed a safety and efficacy assessment.
    End point values
    		 SPD489 (Open-label Period)
    Number of subjects analysed
    397
    Units: percentage of subjects
    number (not applicable)
        I have no problems washing or dressing myself
    98.7
        I have slight problems washing or dressing myself
    0.8
        Moderate problems washing or dressing myself
    0.3
        I have severe problems washing or dressing myself
    0.3
        I am unable to wash or dress myself
    0
    No statistical analyses for this end point

    Secondary: Percent of Participants Within Each Category of The EuroQuol Group 5­-Dimension 5­-Level Self-­Report Questionnaire (EQ-­5D-­5L) For Self Care at Endpoint of the Randomized-withdrawal Period

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    End point title
    		 Percent of Participants Within Each Category of The EuroQuol Group 5­-Dimension 5­-Level Self-­Report Questionnaire (EQ-­5D-­5L) For Self Care at Endpoint of the Randomized-withdrawal Period
    End point description
    The EuroQoL Group 5­Dimension 5­Level Self­Report Questionnaire (EQ­-5D-­5L) is a health­related quality of life (QoL) measure that assesses mobility, self­care, usual activities, pain/discomfort, and anxiety/depression as well as current overall health. It consists of a 5­item descriptive system that measures 5 dimensions of health, including mobility, self­care, usual activities, pain/discomfort, and anxiety/depression. Each dimension is represented by a single item with 5 levels of responses, from poor health to good health. This endpoint assessed the FAS. Not all participants in the FAS had data collected for this outcome.
    End point type
    Secondary
    End point timeframe
    Visit 21 (26 weeks after randomization [Week 38] or Early Termination). Visit 21 could include participants who discontinued but completed a final safety and efficacy assessment.
    End point values
    		 Placebo (Randomized-withdrawal Period) SPD489 (Randomized-withdrawal Period)
    Number of subjects analysed
    116 [11]
    127
    Units: percentage of subjects
    number (not applicable)
        I have no problems washing or dressing myself
    98.3
    98.4
        I have slight problems washing or dressing myself
    0.9
    0.8
        Moderate problems washing or dressing myself
    0.9
    0.8
        I have severe problems washing or dressing myself
    0
    0
        I am unable to wash or dress myself
    0
    0
    Notes
    [11] - Three subjects in the placebo group were randomized and included in the RSAS but not the FAS
    No statistical analyses for this end point

    Secondary: Percent of Participants Within Each Category of The Euro-Quol Group 5-­Dimension 5-­Level Self-­Report Questionnaire (EQ-­5D-­5L) For Usual Activities at Endpoint of the Open-label Period

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    End point title
    		 Percent of Participants Within Each Category of The Euro-Quol Group 5-­Dimension 5-­Level Self-­Report Questionnaire (EQ-­5D-­5L) For Usual Activities at Endpoint of the Open-label Period
    End point description
    The EuroQoL Group 5­Dimension 5­Level Self­Report Questionnaire (EQ­-5D-­5L) is a health­related quality of life (QoL) measure that assesses mobility, self­care, usual activities, pain/discomfort, and anxiety/depression as well as current overall health. It consists of a 5­item descriptive system that measures 5 dimensions of health, including mobility, self­care, usual activities, pain/discomfort, and anxiety/depression. Each dimension is represented by a single item with 5 levels of responses, from poor health to good health. This endpoint assessed the Open-label Safety Population (OSP), defined as participants who had taken at least 1 dose of SPD489 in the open­label period and who had a post­baseline safety assessment. Not all participants had data collected for this outcome.
    End point type
    Secondary
    End point timeframe
    Visit 8 (12 weeks after start of open­label treatment [Week 12] or Early Termination). Visit 8 could include participants who discontinued but completed a safety and efficacy assessment.
    End point values
    		 SPD489 (Open-label Period)
    Number of subjects analysed
    397
    Units: percentage of subjects
    number (not applicable)
        I have no problems doing my usual activities
    88.9
        I have slight problems doing my usual activities
    8.1
        Moderate problems doing my usual activities
    2.3
        I have severe problems doing my usual activities
    0.8
        I am unable to do my usual activities
    0
    No statistical analyses for this end point

    Secondary: Percent of Participants Within Each Category of The EuroQuol Group 5­-Dimension 5­-Level Self-­Report Questionnaire (EQ-­5D-­5L) For Usual Activities at Endpoint of the Randomized-withdrawal Period

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    End point title
    		 Percent of Participants Within Each Category of The EuroQuol Group 5­-Dimension 5­-Level Self-­Report Questionnaire (EQ-­5D-­5L) For Usual Activities at Endpoint of the Randomized-withdrawal Period
    End point description
    The EuroQoL Group 5­Dimension 5­Level Self­Report Questionnaire (EQ­-5D-­5L) is a health­related quality of life (QoL) measure that assesses mobility, self­care, usual activities, pain/discomfort, and anxiety/depression as well as current overall health. It consists of a 5­item descriptive system that measures 5 dimensions of health, including mobility, self­care, usual activities, pain/discomfort, and anxiety/depression. Each dimension is represented by a single item with 5 levels of responses, from poor health to good health. This endpoint assessed the FAS. Not all participants in the FAS had data collected for this outcome.
    End point type
    Secondary
    End point timeframe
    Visit 21 (26 weeks after randomization [Week 38] or Early Termination). Visit 21 could include participants who discontinued but completed a final safety and efficacy assessment.
    End point values
    		 Placebo (Randomized-withdrawal Period) SPD489 (Randomized-withdrawal Period)
    Number of subjects analysed
    116 [12]
    127
    Units: percentage of subjects
    number (not applicable)
        I have no problems doing my usual activities
    79.3
    86.6
        I have slight problems doing my usual activities
    16.4
    11
        Moderate problems doing my usual activities
    2.6
    0.8
        I have severe problems doing my usual activities
    0
    1.6
        I am unable to do my usual activities
    1.7
    0
    Notes
    [12] - Three subjects in the placebo group were randomized and included in the RSAS but not the FAS.
    No statistical analyses for this end point

    Secondary: Percent of Participants Within Each Category of The Euro-Quol Group 5-­Dimension 5-­Level Self-­Report Questionnaire (EQ-­5D-­5L) For Pain And Discomfort at Endpoint of the Open-label Period

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    End point title
    		 Percent of Participants Within Each Category of The Euro-Quol Group 5-­Dimension 5-­Level Self-­Report Questionnaire (EQ-­5D-­5L) For Pain And Discomfort at Endpoint of the Open-label Period
    End point description
    The EuroQoL Group 5­Dimension 5­Level Self­Report Questionnaire (EQ­-5D-­5L) is a health­related quality of life (QoL) measure that assesses mobility, self­care, usual activities, pain/discomfort, and anxiety/depression as well as current overall health. It consists of a 5­item descriptive system that measures 5 dimensions of health, including mobility, self­care, usual activities, pain/discomfort, and anxiety/depression. Each dimension is represented by a single item with 5 levels of responses, from poor health to good health. This endpoint assessed the Open-label Safety Population (OSP), defined as participants who had taken at least 1 dose of SPD489 in the open­label period and who had a post­baseline safety assessment. Not all participants had data collected for this outcome.
    End point type
    Secondary
    End point timeframe
    Visit 8 (12 weeks after start of open­label treatment [Week 12] or Early Termination). Visit 8 could include participants who discontinued but completed a safety and efficacy assessment.
    End point values
    		 SPD489 (Open-label Period)
    Number of subjects analysed
    397
    Units: percentage of subjects
    number (not applicable)
        I have no pain or discomfort
    72.3
        I have slight pain or discomfort
    20.9
        Moderate pain or discomfort
    5.3
        I have severe pain or discomfort
    1.3
        I have extreme pain or discomfort
    0.3
    No statistical analyses for this end point

    Secondary: Percent of Participants Within Each Category of The EuroQuol Group 5­-Dimension 5­-Level Self-­Report Questionnaire (EQ-­5D-­5L) For Pain And Discomfort at Endpoint of the Randomized-withdrawal Period

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    End point title
    		 Percent of Participants Within Each Category of The EuroQuol Group 5­-Dimension 5­-Level Self-­Report Questionnaire (EQ-­5D-­5L) For Pain And Discomfort at Endpoint of the Randomized-withdrawal Period
    End point description
    The EuroQoL Group 5­Dimension 5­Level Self­Report Questionnaire (EQ­-5D-­5L) is a health­related quality of life (QoL) measure that assesses mobility, self­care, usual activities, pain/discomfort, and anxiety/depression as well as current overall health. It consists of a 5­item descriptive system that measures 5 dimensions of health, including mobility, self­care, usual activities, pain/discomfort, and anxiety/depression. Each dimension is represented by a single item with 5 levels of responses, from poor health to good health. This endpoint assessed the FAS. Not all participants in the FAS had data collected for this outcome.
    End point type
    Secondary
    End point timeframe
    Visit 21 (26 weeks after randomization [Week 38] or Early Termination). Visit 21 could include participants who discontinued but completed a final safety and efficacy assessment.
    End point values
    		 Placebo (Randomized-withdrawal Period) SPD489 (Randomized-withdrawal Period)
    Number of subjects analysed
    116 [13]
    127
    Units: percentage of subjects
    number (not applicable)
        I have no pain or discomfort
    75
    71.7
        I have slight pain or discomfort
    16.4
    18.1
        Moderate pain or discomfort
    8.6
    8.7
        I have severe pain or discomfort
    0
    0
        I have extreme pain or discomfort
    0
    1.6
    Notes
    [13] - Three subjects in the placebo group were randomized and included in the RSAS but not the FAS.
    No statistical analyses for this end point

    Secondary: Percent of Participants Within Each Category of The Euro-Quol Group 5-­Dimension 5-­Level Self-­Report Questionnaire (EQ-­5D-­5L) For Anxiety And Depression at Endpoint of the Open-label Period

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    End point title
    		 Percent of Participants Within Each Category of The Euro-Quol Group 5-­Dimension 5-­Level Self-­Report Questionnaire (EQ-­5D-­5L) For Anxiety And Depression at Endpoint of the Open-label Period
    End point description
    The EuroQoL Group 5­Dimension 5­Level Self­Report Questionnaire (EQ­-5D-­5L) is a health­related quality of life (QoL) measure that assesses mobility, self­care, usual activities, pain/discomfort, and anxiety/depression as well as current overall health. It consists of a 5­item descriptive system that measures 5 dimensions of health, including mobility, self­care, usual activities, pain/discomfort, and anxiety/depression. Each dimension is represented by a single item with 5 levels of responses, from poor health to good health. This endpoint assessed the Open-label Safety Population (OSP), defined as participants who had taken at least 1 dose of SPD489 in the open­label period and who had a post­baseline safety assessment. Not all participants had data collected for this outcome.
    End point type
    Secondary
    End point timeframe
    Visit 8 (12 weeks after start of open­label treatment [Week 12] or Early Termination). Visit 8 could include participants who discontinued but completed a safety and efficacy assessment.
    End point values
    		 SPD489 (Open-label Period)
    Number of subjects analysed
    397
    Units: percentage of subjects
    number (not applicable)
        I am not anxious or depressed
    80.9
        I am slightly anxious or depressed
    15.6
        Moderately anxious or depressed
    2.3
        I am severely anxious or depressed
    1
        I am extremely anxious or depressed
    0.3
    No statistical analyses for this end point

    Secondary: Percent of Participants Within Each Category of The EuroQuol Group 5­-Dimension 5­-Level Self-­Report Questionnaire (EQ-­5D-­5L) For Anxiety And Depression at Endpoint of the Randomized-withdrawal Period

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    End point title
    		 Percent of Participants Within Each Category of The EuroQuol Group 5­-Dimension 5­-Level Self-­Report Questionnaire (EQ-­5D-­5L) For Anxiety And Depression at Endpoint of the Randomized-withdrawal Period
    End point description
    The EuroQoL Group 5­Dimension 5­Level Self­Report Questionnaire (EQ­-5D-­5L) is a health­related quality of life (QoL) measure that assesses mobility, self­care, usual activities, pain/discomfort, and anxiety/depression as well as current overall health. It consists of a 5­item descriptive system that measures 5 dimensions of health, including mobility, self­care, usual activities, pain/discomfort, and anxiety/depression. Each dimension is represented by a single item with 5 levels of responses, from poor health to good health. This endpoint assessed the FAS. Not all participants in the FAS had data collected for this outcome.
    End point type
    Secondary
    End point timeframe
    Visit 21 (26 weeks after randomization [Week 38] or Early Termination). Visit 21 could include participants who discontinued but completed a final safety and efficacy assessment.
    End point values
    		 Placebo (Randomized-withdrawal Period) SPD489 (Randomized-withdrawal Period)
    Number of subjects analysed
    116 [14]
    127
    Units: percentage of subjects
    number (not applicable)
        I am not anxious or depressed
    66.4
    79.5
        I am slightly anxious or depressed
    26.7
    15.7
        Moderately anxious or depressed
    4.3
    3.1
        I am severely anxious or depressed
    2.6
    0.8
        I am extremely anxious or depressed
    0
    0.8
    Notes
    [14] - Three subjects in the placebo group were randomized and included in the RSAS but not the FAS.
    No statistical analyses for this end point

    Secondary: Number of Participants With a Positive Response on The Columbia Suicide Severity Rating Scale (C­-SSRS) at Endpoint of The Open-­label Period

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    End point title
    		 Number of Participants With a Positive Response on The Columbia Suicide Severity Rating Scale (C­-SSRS) at Endpoint of The Open-­label Period
    End point description
    The C­-SSRS is a semi-structured interview that captures the occurrence, severity, and frequency of suicide-­related thoughts and behaviors. It includes definitions and suggested questions to solicit the type of information needed to determine if a suicide-­related thought or behavior occurred. The interview was initiated with 5 (yes/no) questions, presented in ascending order of severity, about suicidal ideation. The most severe type of ideation was rated for frequency, duration, controllability, deterrents, and reason. "Yes" answers to the first 2 ideation questions led the clinician to ask questions 3­-5. Active suicidal ideation included any "yes" answer to questions 2-­5. If the answers to ideation questions 1 and 2 were "No," then the clinician proceeded to 5 (yes/no) questions that addressed suicidal behavior, which was categorized as actual attempt, interrupted attempt, aborted attempt, preparatory acts or behaviors, and completed suicide. This endpoint assessed the OSP.
    End point type
    Secondary
    End point timeframe
    Visit 8 (12 weeks after start of open­label treatment [Week 12]). Visit 8 included only participants who completed open-label treatment.
    End point values
    		 SPD489 (Open-label Period)
    Number of subjects analysed
    408 [15]
    Units: subjects
        Suicidal Behavior
    0
        Active Suicidal Ideation
    0
        Non-­Suicidal Self-­Injurious Behavior
    2
    Notes
    [15] - Three participants in the OSP did not have data collected for this outcome.
    No statistical analyses for this end point

    Secondary: Number of Participants With a Positive Response on The Columbia Suicide Severity Rating Scale (C­-SSRS) at Endpoint of The Randomized­-withdrawal Period

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    End point title
    		 Number of Participants With a Positive Response on The Columbia Suicide Severity Rating Scale (C­-SSRS) at Endpoint of The Randomized­-withdrawal Period
    End point description
    The C­-SSRS is a semistructured interview that captures the occurrence, severity, and frequency of suicide-­related thoughts and behaviors. It includes definitions and suggested questions to solicit the type of information needed to determine if a suicide-­related thought or behavior occurred. The interview was initiated with 5 (yes/no) questions, presented in ascending order of severity, about suicidal ideation. The most severe type of ideation was rated for frequency, duration, controllability, deterrents, and reason. "Yes" answers to the first 2 ideation questions led the clinician to ask questions 3­-5. Active suicidal ideation included any "yes" answer to questions 2-­5. If the answers to ideation questions 1 and 2 were "No," then the clinician proceeded to 5 (yes/no) questions that addressed suicidal behavior, which was categorized as actual attempt, interrupted attempt, aborted attempt, preparatory acts or behaviors, and completed suicide. This endpoint assessed the RSAS.
    End point type
    Secondary
    End point timeframe
    Visit 21 (26 weeks after randomization [Week 38] or Early Termination).
    End point values
    		 Placebo (Randomized-withdrawal Period) SPD489 (Randomized-withdrawal Period)
    Number of subjects analysed
    131 [16]
    136 [17]
    Units: subjects
        Suicidal Behavior
    0
    0
        Active Suicidal Ideation
    0
    0
        Non­-Suicidal Self­-Injurious Behavior
    0
    1
    Notes
    [16] - Four subjects were randomized but not treated and thus not included in the RSAS.
    [17] - One subject was randomized but not treated and thus not included in the RSAS.
    No statistical analyses for this end point

    Secondary: Total Scores For The Amphetamine Cessation Symptom Assessment (ACSA) Scale During Follow­up

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    End point title
    		 Total Scores For The Amphetamine Cessation Symptom Assessment (ACSA) Scale During Follow­up
    End point description
    The ACSA was used in this study to assess potential withdrawal symptoms associated with chronic use of SPD489. The ACSA is a self­completed scale used to assess withdrawal symptoms. The scale has 16 symptom items rated on a 5­point scale ranging from 0 (not at all) to 4 (extremely). The ACSA total score ranges from 0­64, where a higher score indicates greater withdrawal symptom severity. The endpoint assessed the Randomized Safety Analysis Set (RSAS), defined as participants in the SAS who were randomized and took at least 1 dose of investigational product in the randomized­withdrawal period. Not all participants had data for this or the previous outcome.
    End point type
    Secondary
    End point timeframe
    Visit 21 (26 weeks after randomization [Week 38] or Early Termination) and Visit 22 (7 days post last dose). Visits 21 and 22 could include participants who discontinued but completed a final safety and efficacy assessment.
    End point values
    		 Placebo (Randomized-withdrawal Period) SPD489 (Randomized-withdrawal Period)
    Number of subjects analysed
    134 [18]
    136 [19]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Visit 21, n=88, 94
    7.6 ( 8.33 )
    4.9 ( 7.81 )
        Visit 22 , n=75, 78
    4.6 ( 5.84 )
    5.3 ( 7.98 )
    Notes
    [18] - Four subjects were randomized but not treated and thus not included in the RSAS.
    [19] - One subject was randomized but not treated and thus not included in the RSAS.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    39 weeks
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    SPD489 (Open-label Period)
    Reporting group description
    		 SPD489 treatment was taken orally once daily at approximately 7:00 AM. All participants began treatment with SPD489 at the lowest dose level (30mg) during the 4­ week open­label dose­ optimization period. After 1 week of treatment at 30mg, all participants were titrated to the next dose level (50mg). After 1 week of treatment at 50mg, all participants were titrated to the highest dose level (70mg), as tolerated and as clinically indicated. After 1 week of treatment at the highest dose, the participant could have been down­titrated to 50mg; no further dose adjustments were permitted. The optimal daily dose of 50 or 70mg achieved during dose­ optimization was maintained throughout the 8­week dose­ maintenance period. The total time of the open­ label period was 12 weeks.

    Reporting group title
    Placebo (Randomized-withdrawal Period)
    Reporting group description
    		 During the 26-­week double-­blind randomized-­withdrawal phase, participants randomized to placebo received matching placebo capsules daily. After the 26­-week double­-blind randomized­-withdrawal phase, participants were followed for 1 week .

    Reporting group title
    SPD489 (Randomized-withdrawal Period)
    Reporting group description
    		 For participants randomized to SPD489, the optimal daily dose of 50 or 70mg was continued throughout the 26­-week double­-blind randomized­-withdrawal phase. After the 26-­week double­-blind randomized­-withdrawal phase, participants were followed for 1 week.

    Serious adverse events
    		 SPD489 (Open-label Period) Placebo (Randomized-withdrawal Period) SPD489 (Randomized-withdrawal Period)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 411 (0.73%)
    0 / 134 (0.00%)
    2 / 136 (1.47%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    0 / 411 (0.00%)
    0 / 134 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Congenital Anomaly in Offspring
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 134 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 134 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nerve root compression
         subjects affected / exposed
    0 / 411 (0.00%)
    0 / 134 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pnuemonia
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 134 (0.00%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 SPD489 (Open-label Period) Placebo (Randomized-withdrawal Period) SPD489 (Randomized-withdrawal Period)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    303 / 411 (73.72%)
    45 / 134 (33.58%)
    59 / 136 (43.38%)
    Investigations
    Blood pressure increased
         subjects affected / exposed
    15 / 411 (3.65%)
    0 / 134 (0.00%)
    1 / 136 (0.74%)
         occurrences all number
    17
    0
    1
    Heart rate increased
         subjects affected / exposed
    14 / 411 (3.41%)
    0 / 134 (0.00%)
    1 / 136 (0.74%)
         occurrences all number
    16
    0
    1
    Weight decreased
         subjects affected / exposed
    14 / 411 (3.41%)
    1 / 134 (0.75%)
    1 / 136 (0.74%)
         occurrences all number
    14
    1
    1
    Weight increased
         subjects affected / exposed
    0 / 411 (0.00%)
    1 / 134 (0.75%)
    3 / 136 (2.21%)
         occurrences all number
    0
    1
    3
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    13 / 411 (3.16%)
    0 / 134 (0.00%)
    1 / 136 (0.74%)
         occurrences all number
    13
    0
    1
    Tachycardia
         subjects affected / exposed
    17 / 411 (4.14%)
    0 / 134 (0.00%)
    2 / 136 (1.47%)
         occurrences all number
    20
    0
    3
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    10 / 411 (2.43%)
    0 / 134 (0.00%)
    1 / 136 (0.74%)
         occurrences all number
    11
    0
    4
    Headache
         subjects affected / exposed
    66 / 411 (16.06%)
    9 / 134 (6.72%)
    12 / 136 (8.82%)
         occurrences all number
    84
    9
    14
    Somnolence
         subjects affected / exposed
    1 / 411 (0.24%)
    3 / 134 (2.24%)
    5 / 136 (3.68%)
         occurrences all number
    1
    3
    5
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    18 / 411 (4.38%)
    7 / 134 (5.22%)
    4 / 136 (2.94%)
         occurrences all number
    19
    7
    4
    Feeling jittery
         subjects affected / exposed
    21 / 411 (5.11%)
    0 / 134 (0.00%)
    0 / 136 (0.00%)
         occurrences all number
    26
    0
    0
    Irritability
         subjects affected / exposed
    19 / 411 (4.62%)
    4 / 134 (2.99%)
    4 / 136 (2.94%)
         occurrences all number
    22
    5
    4
    Thirst
         subjects affected / exposed
    9 / 411 (2.19%)
    0 / 134 (0.00%)
    0 / 136 (0.00%)
         occurrences all number
    11
    0
    0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    9 / 411 (2.19%)
    1 / 134 (0.75%)
    2 / 136 (1.47%)
         occurrences all number
    10
    1
    2
    Constipation
         subjects affected / exposed
    28 / 411 (6.81%)
    1 / 134 (0.75%)
    4 / 136 (2.94%)
         occurrences all number
    29
    1
    4
    Diarrhoea
         subjects affected / exposed
    21 / 411 (5.11%)
    3 / 134 (2.24%)
    2 / 136 (1.47%)
         occurrences all number
    24
    3
    2
    Dry mouth
         subjects affected / exposed
    139 / 411 (33.82%)
    2 / 134 (1.49%)
    7 / 136 (5.15%)
         occurrences all number
    145
    2
    7
    Dyspepsia
         subjects affected / exposed
    3 / 411 (0.73%)
    1 / 134 (0.75%)
    3 / 136 (2.21%)
         occurrences all number
    3
    1
    3
    Nausea
         subjects affected / exposed
    35 / 411 (8.52%)
    3 / 134 (2.24%)
    6 / 136 (4.41%)
         occurrences all number
    37
    3
    6
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    5 / 411 (1.22%)
    2 / 134 (1.49%)
    3 / 136 (2.21%)
         occurrences all number
    6
    2
    3
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    23 / 411 (5.60%)
    0 / 134 (0.00%)
    3 / 136 (2.21%)
         occurrences all number
    24
    0
    3
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    29 / 411 (7.06%)
    2 / 134 (1.49%)
    2 / 136 (1.47%)
         occurrences all number
    32
    2
    2
    Initial insomnia
         subjects affected / exposed
    6 / 411 (1.46%)
    2 / 134 (1.49%)
    4 / 136 (2.94%)
         occurrences all number
    7
    3
    4
    Insomnia
         subjects affected / exposed
    46 / 411 (11.19%)
    2 / 134 (1.49%)
    1 / 136 (0.74%)
         occurrences all number
    46
    2
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    7 / 411 (1.70%)
    1 / 134 (0.75%)
    3 / 136 (2.21%)
         occurrences all number
    8
    1
    3
    Back pain
         subjects affected / exposed
    2 / 411 (0.49%)
    0 / 134 (0.00%)
    3 / 136 (2.21%)
         occurrences all number
    2
    0
    3
    Musculoskeletal pain
         subjects affected / exposed
    4 / 411 (0.97%)
    0 / 134 (0.00%)
    4 / 136 (2.94%)
         occurrences all number
    5
    0
    4
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    5 / 411 (1.22%)
    0 / 134 (0.00%)
    3 / 136 (2.21%)
         occurrences all number
    5
    0
    3
    Nasopharyngitis
         subjects affected / exposed
    20 / 411 (4.87%)
    9 / 134 (6.72%)
    13 / 136 (9.56%)
         occurrences all number
    20
    9
    15
    Rhinitis
         subjects affected / exposed
    0 / 411 (0.00%)
    0 / 134 (0.00%)
    3 / 136 (2.21%)
         occurrences all number
    0
    0
    3
    Upper respiratory tract infection
         subjects affected / exposed
    11 / 411 (2.68%)
    5 / 134 (3.73%)
    11 / 136 (8.09%)
         occurrences all number
    11
    7
    12
    Urinary tract infection
         subjects affected / exposed
    7 / 411 (1.70%)
    4 / 134 (2.99%)
    4 / 136 (2.94%)
         occurrences all number
    7
    4
    4
    Gastroenteritis
         subjects affected / exposed
    5 / 411 (1.22%)
    3 / 134 (2.24%)
    2 / 136 (1.47%)
         occurrences all number
    5
    3
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    38 / 411 (9.25%)
    0 / 134 (0.00%)
    0 / 136 (0.00%)
         occurrences all number
    44
    0
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Sep 2013
    This amendment included the following important changes: * Updated the number of participating sites and countries * Added region (North America, non-North America) as a stratification factor for Randomization * Added SDS and PRUQ-BED as exploratory efficacy endpoints * Clarified collection times for pharmacogenomic samples * Updated duration between study visits * Increased the number of Y-BOCS-BE assessments during the double-blind randomized withdrawal phase * Added the SDS as a health-related quality of life assessment * Added change from randomized baseline in SDS total score as an exploratory objective * Clarified that the date of relapse should be captured in the source documents and on the case report form * Added clarification for the review and documentation of contraceptive requirements for FOCPs * Added “failure to meet randomization criteria” as a reason for discontinuation * Added “met relapse criteria” as a reason for discontinuation * Added details for data input regarding stratum assignment during randomization and relapse assessment using IWRS * Clarified process for assessing abnormal ECG results * Clarified the purpose of the MINI-plus * Clarified binge frequency to be reviewed by clinician and subject to confirm reported binge episodes per day

    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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