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    Clinical Trial Results:
    The SPD489-344, Phase 3, Multicenter, Randomized, Double-blind, Parallel-group, Placebo-controlled, Dose-optimization Study to Evaluate the Efficacy, Safety, and Tolerability of SPD489 in Adults Aged 18-55 Years with Moderate to Severe Binge Eating Disorder

    Summary
    EudraCT number
    		 2012-003310-14
    Trial protocol
    		 ES   IT  
    Global end of trial date
    20 Sep 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Sep 2018
    First version publication date
    01 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SPD489-344
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01718509
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Shire Development, LLC
    Sponsor organisation address
    725 Chesterbrook Boulevard, Wayne, United States, 19087
    Public contact
    Study Physician, Shire Development LLC, +1 8668425335,
    Scientific contact
    Study Physician, Shire Development LLC, +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
    20 Sep 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Sep 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the efficacy of SPD489 compared with placebo in adults (18-55 years of age inclusive) with moderate to severe binge eating disorder (BED) at Visit 8 (Weeks 11 and 12) as measured by the number of binge days (defined as days during which at least 1 binge episode occurs) per week as assessed by clinical interview based on subject diary.
    Protection of trial subjects
    The subject’s informed consent was a mandatory condition for taking part in the study. It was obtained in writing prior to the performance of any study-specific procedures.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Nov 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
    Germany: 20
    Country: Number of subjects enrolled
    United States: 370
    Worldwide total number of subjects
    390
    EEA total number of subjects
    20
    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)
    390
    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 41 sites in the United States and 2 sites in Germany.

    Pre-assignment
    Screening details
    		 A total of 390 subjects were randomized to treatment. Of these, 4 subjects in the placebo arm and 8 subjects in the SPD489 arm did not receive study drug. A total of 378 subjects started treatment.

    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
    Blinding implementation details
    Both investigational products (SPD489 and placebo) were identical in appearance in order to protect the study blind.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 SPD489
    Arm description
    		 Subjects received SPD489 for up to 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
    30, 50, or 70mg capsules administered once-daily. The starting dose was 30mg/day with subjects being individually titrated, based on efficacy and tolerability, to achieve an optimized dose (50 or 70mg/day) during the Dose-optimization Period. Following the Dose-optimization Period, subjects continued on their optimized dose for the duration of the 8-week Dose-maintenance Period.

    Arm title
    		 Placebo
    Arm description
    		 Subjects received placebo for up to 12 weeks
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo capsule administered once-daily

    Number of subjects in period 1 [1]
    		SPD489 Placebo
    Started
    181
    185
    Completed
    147
    145
    Not completed
    34
    40
         Protocol violation
    1
    4
         Adverse event
    7
    5
         Other reasons
    4
    7
         Lost to follow-up
    11
    16
         Withdrawal by subject
    11
    7
         Lack of efficacy
    -
    1
    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: The numbers started represents the Safety Analysis Set, which included all randomized subjects who took at least 1 dose of investigational product and who had at least 1 follow-up safety assessment completed.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    SPD489
    Reporting group description
    		 Subjects received SPD489 for up to 12 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo for up to 12 weeks

    Reporting group values
    		 SPD489 Placebo Total
    Number of subjects
    		 181 185 366
    Age categorical
    Units: Subjects
        < 40 years
    		 108 90 198
        > = 40 years
    		 73 95 168
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 37.1 ( 10 ) 38.7 ( 10.01 ) -
    Gender categorical
    Units: Subjects
        Female
    		 159 153 312
        Male
    		 22 32 54
    Region of enrollment
    Units: Subjects
        Germany
    		 11 9 20
        United States
    		 170 176 346

    End points

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    End points reporting groups
    Reporting group title
    SPD489
    Reporting group description
    		 Subjects received SPD489 for up to 12 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo for up to 12 weeks

    Primary: Change From Baseline in the Number of Binge Days Per Week at Visit 8 Which Spans Weeks 11/12

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    End point title
    		 Change From Baseline in the Number of Binge Days Per Week at Visit 8 Which Spans Weeks 11/12
    End point description
    Binge days were defined as days during which at least 1 binge episode occurred. As assessed by clinical interview based on subject binge diary. The end point analyzed the Full Analysis Set (FAS), defined as all randomized subjects who took at least 1 dose of investigational product and who had 1 post-baseline primary efficacy assessment (i.e., number of binge days per week calculated for at least 1 week).
    End point type
    Primary
    End point timeframe
    Baseline and Visit 8 Which Spans Weeks 11/12
    End point values
    		 SPD489 Placebo
    Number of subjects analysed
    174
    176
    Units: Binge days per week
        least squares mean (standard error)
    -3.92 ( 0.135 )
    -2.26 ( 0.137 )
    Statistical analysis title
    		 Analysis of the number of binge days
    Comparison groups
    SPD489 v Placebo
    Number of subjects included in analysis
    350
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed Models Repeated Measures Analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -1.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.04
         upper limit
    		 -1.28

    Secondary: Percent of Participants With Improvement on Clinical Global Impression-Improvement (CGI-I) Scores

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    End point title
    		 Percent of Participants With Improvement on Clinical Global Impression-Improvement (CGI-I) Scores
    End point description
    Clinical Global Impression-Improvement (CGI-I) consists of a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). Improvement is defined as a score of 1 (very much improved) or 2 (much improved) on the scale. This end point analyzed the FAS, defined as all randomized subjects who took at least 1 dose of investigational product and who had 1 post-baseline primary efficacy assessment (i.e., number of binge days per week calculated for at least 1 week).
    End point type
    Secondary
    End point timeframe
    Up to 12 weeks
    End point values
    		 SPD489 Placebo
    Number of subjects analysed
    174
    176
    Units: percent of subjects
        number (confidence interval 95%)
    86.2 (81.1 to 91.3)
    42.9 (35.5 to 50.2)
    Statistical analysis title
    		 Analysis of CGI-I scores
    Comparison groups
    SPD489 v Placebo
    Number of subjects included in analysis
    350
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Percent of Participants With a 4-Week Cessation From Binge Eating

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    End point title
    		 Percent of Participants With a 4-Week Cessation From Binge Eating
    End point description
    Four-week cessation from binge eating is defined as no binge eating episodes for 28 consecutive days prior to the last study visit. This end point analyzed the FAS, defined as all randomized subjects who took at least 1 dose of investigational product and who had 1 post-baseline primary efficacy assessment (i.e., number of binge days per week calculated for at least 1 week).
    End point type
    Secondary
    End point timeframe
    Up to 12 weeks
    End point values
    		 SPD489 Placebo
    Number of subjects analysed
    174
    176
    Units: percent of subjects
        number (confidence interval 95%)
    36.2 (29.1 to 43.3)
    13.1 (8.1 to 18)
    Statistical analysis title
    		 Analysis of 4-Week cessation from binge eating
    Comparison groups
    SPD489 v Placebo
    Number of subjects included in analysis
    350
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Percent Change From Baseline in Body Weight at Week 12

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    End point title
    		 Percent Change From Baseline in Body Weight at Week 12
    End point description
    This end point analyzed the FAS, defined as all randomized subjects who took at least 1 dose of investigational product and who had 1 post-baseline primary efficacy assessment (i.e., number of binge days per week calculated for at least 1 week).
    End point type
    Secondary
    End point timeframe
    Baseline and week 12
    End point values
    		 SPD489 Placebo
    Number of subjects analysed
    174
    176
    Units: percent change
        least squares mean (standard error)
    -5.57 ( 0.35 )
    -0.15 ( 0.353 )
    Statistical analysis title
    		 Analysis of body weight
    Comparison groups
    SPD489 v Placebo
    Number of subjects included in analysis
    350
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed Models Repeated Measures Analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -5.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.39
         upper limit
    		 -4.44

    Secondary: Change From Baseline in Yale-Brown Obsessive Compulsive Scale Modified for Binge Eating (Y-BOCS-BE) Total Score at Week 12

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    End point title
    		 Change From Baseline in Yale-Brown Obsessive Compulsive Scale Modified for Binge Eating (Y-BOCS-BE) Total Score at Week 12
    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). Total scores range from 0 to 40. Reduction in total score indicates improvement. This end point analyzed the FAS, defined as all randomized subjects who took at least 1 dose of investigational product and who had 1 post-baseline primary efficacy assessment (i.e., number of binge days per week calculated for at least 1 week).
    End point type
    Secondary
    End point timeframe
    Baseline and week 12
    End point values
    		 SPD489 Placebo
    Number of subjects analysed
    174
    176
    Units: units on a scale
        least squares mean (standard error)
    -15.36 ( 0.563 )
    -7.42 ( 0.571 )
    Statistical analysis title
    		 Analysis of Y-BOCS-BE total score
    Comparison groups
    SPD489 v Placebo
    Number of subjects included in analysis
    350
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed Models Repeated Measures Analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -7.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.51
         upper limit
    		 -6.36

    Secondary: Change From Baseline in Fasting Triglyceride Levels at Up to 12 Weeks

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    End point title
    		 Change From Baseline in Fasting Triglyceride Levels at Up to 12 Weeks
    End point description
    This end point analyzed the FAS, defined as all randomized subjects who took at least 1 dose of investigational product and who had 1 post-baseline primary efficacy assessment (i.e., number of binge days per week calculated for at least 1 week). Not all subjects had data for this outcome.
    End point type
    Secondary
    End point timeframe
    Baseline and up to 12 weeks
    End point values
    		 SPD489 Placebo
    Number of subjects analysed
    156
    153
    Units: mmol/L
        least squares mean (standard error)
    -0.133 ( 0.0449 )
    0.062 ( 0.0453 )
    Statistical analysis title
    		 Analysis of fasting triglyceride levels
    Comparison groups
    SPD489 v Placebo
    Number of subjects included in analysis
    309
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 ANCOVA
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.196
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.321
         upper limit
    		 -0.07

    Secondary: Change From Baseline in Fasting Total Cholesterol Levels at Up to 12 Weeks

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    End point title
    		 Change From Baseline in Fasting Total Cholesterol Levels at Up to 12 Weeks
    End point description
    This end point analyzed the FAS, defined as all randomized subjects who took at least 1 dose of investigational product and who had 1 post-baseline primary efficacy assessment (i.e., number of binge days per week calculated for at least 1 week). Not all subjects had data for this outcome.
    End point type
    Secondary
    End point timeframe
    Baseline and up to 12 weeks
    End point values
    		 SPD489 Placebo
    Number of subjects analysed
    156
    153
    Units: mmol/L
        least squares mean (standard error)
    -0.204 ( 0.0456 )
    -0.126 ( 0.046 )
    Statistical analysis title
    		 Analysis of fasting total cholesterol levels
    Comparison groups
    SPD489 v Placebo
    Number of subjects included in analysis
    309
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.234
    Method
    		 ANCOVA
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.077
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.205
         upper limit
    		 0.05

    Secondary: Change From Baseline in Hemoglobin A1c Levels at Up to 12 Weeks

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    End point title
    		 Change From Baseline in Hemoglobin A1c Levels at Up to 12 Weeks
    End point description
    This end point analyzed the FAS, defined as all randomized subjects who took at least 1 dose of investigational product and who had 1 post-baseline primary efficacy assessment (i.e., number of binge days per week calculated for at least 1 week). Not all subjects had data for this outcome.
    End point type
    Secondary
    End point timeframe
    Baseline and up to 12 weeks
    End point values
    		 SPD489 Placebo
    Number of subjects analysed
    156
    154
    Units: percent
        least squares mean (standard error)
    0.01 ( 0.017 )
    -0.02 ( 0.017 )
    Statistical analysis title
    		 Analysis of hemoglobin A1c levels
    Comparison groups
    SPD489 v Placebo
    Number of subjects included in analysis
    310
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.185
    Method
    		 ANCOVA
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.02
         upper limit
    		 0.08

    Secondary: Binge Eating Response

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    End point title
    		 Binge Eating Response
    End point description
    Response is based on the reduction in the number of binge eating episodes. Responses were categorized as follows: 1) 1-week Cessation = 100% reduction in binge episodes during the preceding 7 days 2) Marked Reduction = 99% to 75% reduction during the time since the previous visit 3) Moderate Reduction = 74% to 50% reduction during the time since the previous visit 4) Negative to Minimal Reduction = <50% reduction during the time since the previous visit This end point analyzed the FAS, defined as all randomized subjects who took at least 1 dose of investigational product and who had 1 post-baseline primary efficacy assessment (i.e., number of binge days per week calculated for at least 1 week). Not all subjects had data for this outcome.
    End point type
    Secondary
    End point timeframe
    Up to 12 weeks
    End point values
    		 SPD489 Placebo
    Number of subjects analysed
    145
    142
    Units: percent of subjects
    number (not applicable)
        1-week cessation
    55.9
    23.9
        Marked reduction
    22.8
    13.4
        Moderate reduction
    16.6
    19.7
        Negative to minimal reduction
    4.8
    43
    Statistical analysis title
    		 Analysis of binge eating response
    Comparison groups
    SPD489 v Placebo
    Number of subjects included in analysis
    287
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [1]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [1] - Multiplicity is not adjusted for this secondary efficacy end point in this study.

    Secondary: Change From Baseline in the Number of Binge Episodes Per Week at Visit 8 Which Spans Weeks 11/12

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    End point title
    		 Change From Baseline in the Number of Binge Episodes Per Week at Visit 8 Which Spans Weeks 11/12
    End point description
    This end point analyzed the FAS, defined as all randomized subjects who took at least 1 dose of investigational product and who had 1 post-baseline primary efficacy assessment (i.e., number of binge days per week calculated for at least 1 week).
    End point type
    Secondary
    End point timeframe
    Baseline and Visit 8 Which Spans Weeks 11/12
    End point values
    		 SPD489 Placebo
    Number of subjects analysed
    174
    176
    Units: binge episodes per week
        least squares mean (standard error)
    -5.54 ( 0.193 )
    -3.31 ( 0.194 )
    Statistical analysis title
    		 Analysis of binge episodes per week
    Comparison groups
    SPD489 v Placebo
    Number of subjects included in analysis
    350
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [2]
    Method
    		 Mixed Models Repeated Measures Analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -2.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.77
         upper limit
    		 -1.69
    Notes
    [2] - Multiplicity is not adjusted for this secondary efficacy end point in this study.

    Secondary: Change From Baseline in Eating Inventory Scores at Week 12

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    End point title
    		 Change From Baseline in Eating Inventory Scores at Week 12
    End point description
    There are 36 true/false items, 14 items on a 4-point Likert scale (1=eat rarely to 4=always), and 1 item on a 6-point Likert scale (1=eat whatever you want to 6=constantly limiting food intake). Cognitive Restraint score ranges from 0-21. Hunger score ranges from 0-14. Disinhibition score ranges from 0-16. Higher scores denote higher levels of restrained eating, disinhibited eating and predisposition to hunger. This end point analyzed the FAS, defined as all randomized subjects who took at least 1 dose of investigational product and who had 1 post-baseline primary efficacy assessment (i.e., number of binge days per week calculated for at least 1 week).
    End point type
    Secondary
    End point timeframe
    Baseline and week 12
    End point values
    		 SPD489 Placebo
    Number of subjects analysed
    174
    176
    Units: units on a scale
    least squares mean (standard error)
        Cognitive restraint of eating
    3.71 ( 0.347 )
    2.44 ( 0.352 )
        Disinhibition of eating
    -5.61 ( 0.3 )
    -2.01 ( 0.305 )
        Perceived hunger
    -6.14 ( 0.313 )
    -1.93 ( 0.318 )
    Statistical analysis title
    		 Analysis of cognitive restraint of eating
    Comparison groups
    SPD489 v Placebo
    Number of subjects included in analysis
    350
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.011 [3]
    Method
    		 Mixed Models Repeated Measures Analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    1.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.29
         upper limit
    		 2.24
    Notes
    [3] - Multiplicity is not adjusted for this secondary efficacy end point in this study.
    Statistical analysis title
    		 Analysis of disinhibition of eating
    Comparison groups
    SPD489 v Placebo
    Number of subjects included in analysis
    350
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [4]
    Method
    		 Mixed Models Repeated Measures Analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -3.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.44
         upper limit
    		 -2.76
    Notes
    [4] - Multiplicity is not adjusted for this secondary efficacy end point in this study.
    Statistical analysis title
    		 Analysis of perceived hunger
    Comparison groups
    SPD489 v Placebo
    Number of subjects included in analysis
    350
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [5]
    Method
    		 Mixed Models Repeated Measures Analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -4.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.09
         upper limit
    		 -3.33
    Notes
    [5] - Multiplicity is not adjusted for this secondary efficacy end point in this study.

    Secondary: Change From Baseline in Binge Eating Scale (BES) Score at Week 12

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    End point title
    		 Change From Baseline in Binge Eating Scale (BES) Score at Week 12
    End point description
    The BES is a self-reported questionnaire containing 16 items designed to assess behavioral, affective, and attitudinal components of the subjective experience of binge eating. Each item is assessed based on 1 of 4 responses, with 1 denoting that a subject has greater control over eating behavior and 4 denoting that a subject had less control over eating behavior. A total score (sum of the 16 items) may range from 16-64. A lower score indicates greater control over eating behavior. This end point analyzed the FAS, defined as all randomized subjects who took at least 1 dose of investigational product and who had 1 post-baseline primary efficacy assessment (i.e., number of binge days per week calculated for at least 1 week).
    End point type
    Secondary
    End point timeframe
    Baseline and week 12
    End point values
    		 SPD489 Placebo
    Number of subjects analysed
    174
    176
    Units: units on a scale
        least squares mean (standard error)
    -17.52 ( 0.771 )
    -8.24 ( 0.781 )
    Statistical analysis title
    		 Analysis of BES score
    Comparison groups
    SPD489 v Placebo
    Number of subjects included in analysis
    350
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [6]
    Method
    		 Mixed Models Repeated Measures Analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -9.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.44
         upper limit
    		 -7.12
    Notes
    [6] - Multiplicity is not adjusted for this secondary efficacy end point in this study.

    Secondary: Change From Baseline in Frontal Systems Behavior (FrSBe) Total Score at Up to 12 Weeks

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    End point title
    		 Change From Baseline in Frontal Systems Behavior (FrSBe) Total Score at Up to 12 Weeks
    End point description
    The FrSBe is a 46-item self-rating scale designed to measure the neurobehavioral traits associated with the 3 primary regions of the prefrontal cortex. Subjects were asked to indicate the frequency with which they have engaged in certain behaviors using a rating scale from “1” (almost never) to “5” (almost always). Summary scores were calculated and converted to t-score. A decrease from baseline in FrSBe total score represents improvement. This end point analyzed the FAS, defined as all randomized subjects who took at least 1 dose of investigational product and who had 1 post-baseline primary efficacy assessment (i.e., number of binge days per week calculated for at least 1 week). Not all subjects had data for this outcome.
    End point type
    Secondary
    End point timeframe
    Baseline and up to 12 weeks
    End point values
    		 SPD489 Placebo
    Number of subjects analysed
    158
    153
    Units: T-score
        least squares mean (standard error)
    -4.05 ( 0.644 )
    -3.09 ( 0.655 )
    Statistical analysis title
    		 Analysis of FrSBe Total Score
    Comparison groups
    SPD489 v Placebo
    Number of subjects included in analysis
    311
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.298 [7]
    Method
    		 ANCOVA
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.77
         upper limit
    		 0.85
    Notes
    [7] - Multiplicity is not adjusted for this secondary efficacy end point in this study.

    Secondary: EuroQoL Group 5-Dimension 5-Level Self-Report (EQ-5D-5L): Mobility

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    End point title
    		 EuroQoL Group 5-Dimension 5-Level Self-Report (EQ-5D-5L): Mobility
    End point description
    Quality of life was assessed using the EQ-5D-5L, which is one of the most widely used generic index measures of health-related quality of life. It consists of a 5-item descriptive system that measures 5 dimensions of health, including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. This end point analyzed the FAS, defined as all randomized subjects who took at least 1 dose of investigational product and who had 1 post-baseline primary efficacy assessment (i.e., number of binge days per week calculated for at least 1 week). Not all subjects had data for this outcome.
    End point type
    Secondary
    End point timeframe
    Up to 12 weeks
    End point values
    		 SPD489 Placebo
    Number of subjects analysed
    169
    168
    Units: percent of subjects
    number (not applicable)
        No problems in walking about
    91.7
    86.9
        Slight problems in walking about
    7.1
    8.9
        Moderate problems walking about
    0.6
    3
        Severe problems walking about
    0.6
    1.2
        Unable to walk about
    0
    0
    No statistical analyses for this end point

    Secondary: EuroQoL Group 5-Dimension 5-Level Self-Report (EQ-5D-5L): Self-Care

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    End point title
    		 EuroQoL Group 5-Dimension 5-Level Self-Report (EQ-5D-5L): Self-Care
    End point description
    Quality of life was assessed using the EQ-5D-5L, which is one of the most widely used generic index measures of health-related quality of life. It consists of a 5-item descriptive system that measures 5 dimensions of health, including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. This end point analyzed the FAS, defined as all randomized subjects who took at least 1 dose of investigational product and who had 1 post-baseline primary efficacy assessment (i.e., number of binge days per week calculated for at least 1 week). Not all subjects had data for this outcome.
    End point type
    Secondary
    End point timeframe
    Up to 12 weeks
    End point values
    		 SPD489 Placebo
    Number of subjects analysed
    169
    168
    Units: percent of subjects
    number (not applicable)
        No problems washing or dressing
    97
    97
        Slight problems washing or dressing
    3
    2.4
        Moderate problems washing or dressing
    0
    0.6
        Severe problems washing or dressing
    0
    0
        Unable to wash or dress
    0
    0
    No statistical analyses for this end point

    Secondary: EuroQoL Group 5-Dimension 5-Level Self-Report (EQ-5D-5L): Usual Activities

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    End point title
    		 EuroQoL Group 5-Dimension 5-Level Self-Report (EQ-5D-5L): Usual Activities
    End point description
    Quality of life was assessed using the EQ-5D-5L, which is one of the most widely used generic index measures of health-related quality of life. It consists of a 5-item descriptive system that measures 5 dimensions of health, including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. This end point analyzed the FAS, defined as all randomized subjects who took at least 1 dose of investigational product and who had 1 post-baseline primary efficacy assessment (i.e., number of binge days per week calculated for at least 1 week). Not all subjects had data for this outcome.
    End point type
    Secondary
    End point timeframe
    Up to 12 weeks
    End point values
    		 SPD489 Placebo
    Number of subjects analysed
    169
    168
    Units: percent of subjects
    number (not applicable)
        No problems doing usual activities
    89.9
    82.1
        Slight problems doing usual activities
    8.3
    14.3
        Moderate problems doing usual activities
    1.2
    3
        Severe problems doing usual activities
    0.6
    0.6
        Unable to do usual activities
    0
    0
    No statistical analyses for this end point

    Secondary: EuroQoL Group 5-Dimension 5-Level Self-Report (EQ-5D-5L): Pain/Discomfort

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    End point title
    		 EuroQoL Group 5-Dimension 5-Level Self-Report (EQ-5D-5L): Pain/Discomfort
    End point description
    Quality of life was assessed using the EQ-5D-5L, which is one of the most widely used generic index measures of health-related quality of life. It consists of a 5-item descriptive system that measures 5 dimensions of health, including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. This end point analyzed the FAS, defined as all randomized subjects who took at least 1 dose of investigational product and who had 1 post-baseline primary efficacy assessment (i.e., number of binge days per week calculated for at least 1 week). Not all subjects had data for this outcome.
    End point type
    Secondary
    End point timeframe
    Up to 12 weeks
    End point values
    		 SPD489 Placebo
    Number of subjects analysed
    169
    168
    Units: percent of subjects
    number (not applicable)
        No pain or discomfort
    76.3
    75.6
        Slight pain or discomfort
    20.1
    18.5
        Moderate pain or discomfort
    3
    3
        Severe pain or discomfort
    0
    3
        Extreme pain or discomfort
    0.6
    0
    No statistical analyses for this end point

    Secondary: EuroQoL Group 5-Dimension 5-Level Self-Report (EQ-5D-5L): Anxiety/Depression

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    End point title
    		 EuroQoL Group 5-Dimension 5-Level Self-Report (EQ-5D-5L): Anxiety/Depression
    End point description
    Quality of life was assessed using the EQ-5D-5L, which is one of the most widely used generic index measures of health-related quality of life. It consists of a 5-item descriptive system that measures 5 dimensions of health, including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. This end point analyzed the FAS, defined as all randomized subjects who took at least 1 dose of investigational product and who had 1 post-baseline primary efficacy assessment (i.e., number of binge days per week calculated for at least 1 week). Not all subjects had data for this outcome.
    End point type
    Secondary
    End point timeframe
    Up to 12 weeks
    End point values
    		 SPD489 Placebo
    Number of subjects analysed
    169
    168
    Units: percent of subjects
    number (not applicable)
        Not anxious or depressed
    76.3
    69.6
        Slightly anxious or depressed
    20.7
    23.2
        Moderately anxious or depressed
    2.4
    4.8
        Severely anxious or depressed
    0
    1.2
        Extremely anxious or depressed
    0.6
    1.2
    No statistical analyses for this end point

    Secondary: Columbia-Suicide Severity Rating Scale (C-SSRS)

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    End point title
    		 Columbia-Suicide Severity Rating Scale (C-SSRS)
    End point description
    C-SSRS is a semi-structured interview that captures the occurence, severity, and frequency of suicide-related thoughts and behaviors during the assessment period. The interview includes definitions and suggested questions to solicit the type of information needed to determine if a suicide-related thought or behaviour occurred. The assessment is done by the nature of the responses, not by a numbered scale. This end point analyzed the Safety Analysis Set (SAS), defined as all randomized subjects who took at least 1 dose of investigational product and who had at least 1 post-baseline safety assessment completed. All subjects from Site 015 were excluded from the Safety Analysis Set.
    End point type
    Secondary
    End point timeframe
    Up to 12 weeks
    End point values
    		 SPD489 Placebo
    Number of subjects analysed
    179
    183
    Units: subjects
        Suicidal ideation
    0
    0
        Suicidal behavior
    0
    0
    No statistical analyses for this end point

    Secondary: Amphetamine Cessation Symptom Assessment (ACSA) Total Score

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    End point title
    		 Amphetamine Cessation Symptom Assessment (ACSA) Total Score
    End point description
    ACSA scale has 16 symptom items rated on a scale from 0 (not at all) to 4 (extremely) with a possible total score range of 0 to 64. Higher scores indicate greater withdrawal symptom severity. This end point analyzed the SAS, defined as all randomized subjects who took at least 1 dose of investigational product and who had at least 1 post-baseline safety assessment completed. All subjects from Site 015 were excluded from the Safety Analysis Set.
    End point type
    Secondary
    End point timeframe
    Up to 12 weeks
    End point values
    		 SPD489 Placebo
    Number of subjects analysed
    135
    142
    Units: units on a scale
        arithmetic mean (standard deviation)
    4.6 ( 5.83 )
    7 ( 7.69 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    13 weeks
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    SPD489
    Reporting group description
    		 Subjects received SPD489 for up to 12 weeks

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo for up to 12 weeks

    Serious adverse events
    		 SPD489 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 181 (0.55%)
    2 / 185 (1.08%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Fibula fracture
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 185 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 185 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 185 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 185 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 185 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 SPD489 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    100 / 181 (55.25%)
    43 / 185 (23.24%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    32 / 181 (17.68%)
    16 / 185 (8.65%)
         occurrences all number
    37
    19
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    17 / 181 (9.39%)
    9 / 185 (4.86%)
         occurrences all number
    21
    12
    Feeling jittery
         subjects affected / exposed
    10 / 181 (5.52%)
    0 / 185 (0.00%)
         occurrences all number
    10
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    10 / 181 (5.52%)
    1 / 185 (0.54%)
         occurrences all number
    10
    1
    Diarrhoea
         subjects affected / exposed
    11 / 181 (6.08%)
    3 / 185 (1.62%)
         occurrences all number
    12
    3
    Dry mouth
         subjects affected / exposed
    60 / 181 (33.15%)
    11 / 185 (5.95%)
         occurrences all number
    60
    11
    Nausea
         subjects affected / exposed
    16 / 181 (8.84%)
    8 / 185 (4.32%)
         occurrences all number
    17
    9
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    19 / 181 (10.50%)
    6 / 185 (3.24%)
         occurrences all number
    19
    6
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    11 / 181 (6.08%)
    3 / 185 (1.62%)
         occurrences all number
    11
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Nov 2012
    This amendment included the following important changes: * Added an Overall Risk/Benefit Assessment to Section 1 * Changed comparison of the Y-BOCS-BE total score to a key secondary objective * Added assessments of the EQ-5D-5L at Weeks 4, 6, 8, and 10 (Visits 4, 5, 6, and 7) * Clarified inclusion criterion #7 to further describe indeterminate pregnancy test results * Clarified exclusion criterion #1 to state a current diagnosis, rather than concurrent symptoms, of bulimia nervosa, or anorexia nervosa was exclusionary * Added language regarding contraception requirements being reviewed at every study visit and document in source document * Clarified language regarding use of psychoactive medications during the study and before study entry, and changed the language of the permitted window for psychotherapy * Clarified that the MINI-Plus was to be used to exclude comorbid Axis I disorders rather than confirm diagnosis of BED * Added further language addressing the management of positive responses on the C-SSRS * Clarified that ACSA was to be collected at the Baseline Visit (Visit 0) * Added a ±2-hour window to the 7:00 AM dosing instructions * Added smoking status to items collected as part of medical history.

    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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