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    Clinical Trial Results:
    The SPD489-343, 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
    2012-003309-91
    Trial protocol
    SE   DE   ES  
    Global end of trial date
    25 Sep 2013

    Results information
    Results version number
    v2(current)
    This version publication date
    24 Feb 2016
    First version publication date
    13 Mar 2015
    Other versions
    v1 (removed from public view)
    Version creation reason
    • Correction of full data set
    Updating the result in the full data set.

    Trial information

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    Trial identification
    Sponsor protocol code
    SPD489-343
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01718483
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Shire Development, LLC
    Sponsor organisation address
    725 Chesterbrook Boulevard Wayne, Pennsylvania, United States, 19087
    Public contact
    Medical Communications, Shire Pharmaceuticals Ltd, +44 8000556614, medinfoglobal@shire.com
    Scientific contact
    Medical Communications, Shire Pharmaceuticals Ltd, +44 8000556614, medinfoglobal@shire.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    25 Oct 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 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 11-12) 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
    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
    12 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
    Spain: 10
    Country: Number of subjects enrolled
    Sweden: 29
    Country: Number of subjects enrolled
    United States: 341
    Country: Number of subjects enrolled
    Germany: 3
    Worldwide total number of subjects
    383
    EEA total number of subjects
    42
    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)
    383
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Subjects were recruited between 12-Nov-2012 and 19-June-2013 and locations included medical clinics & research centers.

    Pre-assignment
    Screening details
    A total of 383 subjects were randomized to treatment. Of these, 4 subjects from the placebo arm discontinued the study prior to study drug administration (reasons for discontinuation for 4 'randomized but not treated' subjects were: 2 subjects lost to follow-up and 2 withdrew due to protocol violation). A total of 379 subjects started treatment.

    Period 1
    Period 1 title
    Double-blind Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Placebo matching SPD489 capsule administered orally, once-daily 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 matching SPD489 capsule administered orally, once-daily for up to 12 weeks.

    Arm title
    SPD489
    Arm description
    SPD489 capsule 30 (titration purpose only), 50 or 70 milligram (mg) administered orally, once-daily for up to 12 weeks once the optimal dose is reached.
    Arm type
    Experimental

    Investigational medicinal product name
    Lisdexamfetamine dimesylate
    Investigational medicinal product code
    SPD489
    Other name
    LDX, Vyvanse®, Elvanse, Tyvense, Elvanse Adult, Elvanse Vuxen, Aduvanz
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    SPD489 capsule 30 (titration purpose only), 50 or 70 milligram (mg) administered orally, once-daily for up to 12 weeks once the optimal dose is reached.

    Number of subjects in period 1 [1]
    Placebo SPD489
    Started
    187
    192
    Completed
    157
    158
    Not completed
    30
    34
         Adverse event
    5
    12
         Protocol violation
    2
    2
         Lack of efficacy
    1
    -
         Pregnancy
    1
    1
         Not specified
    1
    4
         Consent withdrawn by subject
    14
    12
         Lost to follow-up
    6
    3
    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: All enrolled subjects were not treated with study drug. Since baseline included treated subjects only, the worldwide number enrolled in the trial differs with the number of subjects reported in the baseline period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo matching SPD489 capsule administered orally, once-daily for up to 12 weeks.

    Reporting group title
    SPD489
    Reporting group description
    SPD489 capsule 30 (titration purpose only), 50 or 70 milligram (mg) administered orally, once-daily for up to 12 weeks once the optimal dose is reached.

    Reporting group values
    Placebo SPD489 Total
    Number of subjects
    187 192 379
    Age categorical
    Units: Subjects
        <40 years
    102 98 200
        >=40 years
    85 94 179
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    37.6 ± 10.21 38.5 ± 10.4 -
    Gender categorical
    Units: Subjects
        Female
    163 165 328
        Male
    24 27 51

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo matching SPD489 capsule administered orally, once-daily for up to 12 weeks.

    Reporting group title
    SPD489
    Reporting group description
    SPD489 capsule 30 (titration purpose only), 50 or 70 milligram (mg) administered orally, once-daily for up to 12 weeks once the optimal dose is reached.

    Primary: Change From Baseline in the Number of Binge Days Per Week at Visit 8 (Weeks 11-12)

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    End point title
    Change From Baseline in the Number of Binge Days Per Week at Visit 8 (Weeks 11-12)
    End point description
    Binge days defined as days during which at least 1 binge episode occurred. As assessed by clinical interview based on subject binge diary. The Full Analysis Set was defined as all randomized subjects who took at least 1 dose of investigational product and who had 1 post-baseline primary efficacy assessment (number of binge days per week calculated for at least 1 week).
    End point type
    Primary
    End point timeframe
    Baseline and Visit 8 (Weeks 11-12)
    End point values
    Placebo SPD489
    Number of subjects analysed
    184
    190
    Units: Binge days per week
    least squares mean (standard error)
        Change From Baseline in the Number of Binge Days
    -2.51 ± 0.125
    -3.87 ± 0.124
    Statistical analysis title
    Number of Binge Days Per Week at Visit 8
    Statistical analysis description
    Analysis was SPD489 vs Placebo
    Comparison groups
    Placebo v SPD489
    Number of subjects included in analysis
    374
    Analysis specification
    Pre-specified
    Analysis type
    other [1]
    P-value
    < 0.001
    Method
    Mixed Models Repeated Measures Analysis
    Parameter type
    Least squares mean difference
    Point estimate
    -1.35
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.7
         upper limit
    -1.01
    Notes
    [1] - Placebo controlled

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

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    End point title
    Percent of Subjects With Improvement on Clinical Global Impression-Improvement (CGI-I) Scores
    End point description
    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. The Full Analysis Set was defined as all randomized subjects who took at least 1 dose of investigational product and who had 1 post-baseline primary efficacy assessment (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
    Placebo SPD489
    Number of subjects analysed
    184
    190
    Units: percentage of subjects
    number (confidence interval 95%)
        Improvement on CGI-I Score
    47.3 (40.1 to 54.5)
    82.1 (76.7 to 87.6)
    Statistical analysis title
    Improvement on CGI-I Score
    Statistical analysis description
    Analysis was SPD489 vs Placebo
    Comparison groups
    Placebo v SPD489
    Number of subjects included in analysis
    374
    Analysis specification
    Pre-specified
    Analysis type
    other [2]
    P-value
    < 0.001 [3]
    Method
    Chi-squared
    Confidence interval
    Notes
    [2] - Placebo controlled
    [3] - Placebo controlled

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

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    End point title
    Percent of Subjects With a 4-Week Cessation From Binge Eating
    End point description
    4-week cessation from binge eating is defined as no binge eating episodes for 28 consecutive days prior to the last study visit. The Full Analysis Set was defined as all randomized subjects who took at least 1 dose of investigational product and who had 1 post-baseline primary efficacy assessment (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
    Placebo SPD489
    Number of subjects analysed
    184
    190
    Units: percentage of subjects
    number (confidence interval 95%)
        4-Week Cessation From Binge Eating
    14.1 (9.1 to 19.2)
    40 (33 to 47)
    Statistical analysis title
    Four-Week Cessation From Binge Eating
    Statistical analysis description
    Analysis was SPD489 vs Placebo
    Comparison groups
    Placebo v SPD489
    Number of subjects included in analysis
    374
    Analysis specification
    Pre-specified
    Analysis type
    other [4]
    P-value
    < 0.001
    Method
    Chi-squared
    Confidence interval
    Notes
    [4] - Placebo controlled

    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
    The Full Analysis Set was defined as all randomized subjects who took at least 1 dose of investigational product and who had 1 post-baseline primary efficacy assessment (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
    Placebo SPD489
    Number of subjects analysed
    184
    190
    Units: Percent change
    least squares mean (standard error)
        Percent Change in Body Weight
    0.11 ± 0.295
    -6.25 ± 0.292
    Statistical analysis title
    Percent Change in Body weight
    Statistical analysis description
    Analysis was SPD489 vs Placebo
    Comparison groups
    SPD489 v Placebo
    Number of subjects included in analysis
    374
    Analysis specification
    Pre-specified
    Analysis type
    other [5]
    P-value
    < 0.001
    Method
    Mixed Models Repeated Measures Analysis
    Parameter type
    Least squares mean difference
    Point estimate
    -6.35
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.17
         upper limit
    -5.54
    Notes
    [5] - Placebo controlled

    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. The Full Analysis Set was defined as all randomized subjects who took at least 1 dose of investigational product and who had 1 post-baseline primary efficacy assessment (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 week 12
    End point values
    Placebo SPD489
    Number of subjects analysed
    183
    188
    Units: units on a scale
    least squares mean (standard error)
        Y-BOCS-BE Total Score at Week 12
    -8.28 ± 0.55
    -15.68 ± 0.546
    Statistical analysis title
    Y-BOCS-BE Total Score at Week 12
    Statistical analysis description
    Analysis was SPD489 vs Placebo
    Comparison groups
    Placebo v SPD489
    Number of subjects included in analysis
    371
    Analysis specification
    Pre-specified
    Analysis type
    other [6]
    P-value
    < 0.001
    Method
    Mixed Models Repeated Measures Analysis
    Parameter type
    Least squares mean difference
    Point estimate
    -7.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.93
         upper limit
    -5.88
    Notes
    [6] - Placebo controlled

    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
    The Full Analysis Set was defined as all randomized subjects who took at least 1 dose of investigational product and who had 1 post-baseline primary efficacy assessment (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 Week 12/Early termination (ET)
    End point values
    Placebo SPD489
    Number of subjects analysed
    183
    190
    Units: millimole per litre (mmol/L)
    least squares mean (standard error)
        Fasting Triglyceride Levels at Up to 12 Weeks
    0.122 ± 0.0405
    -0.077 ± 0.0393
    Statistical analysis title
    Fasting Triglyceride Levels at Up to 12 Weeks
    Statistical analysis description
    Analysis was SPD489 vs Placebo
    Comparison groups
    Placebo v SPD489
    Number of subjects included in analysis
    373
    Analysis specification
    Pre-specified
    Analysis type
    other [7]
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Least squares mean difference
    Point estimate
    -0.199
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.31
         upper limit
    -0.088
    Notes
    [7] - Placebo controlled

    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
    The Full Analysis Set was defined as all randomized subjects who took at least 1 dose of investigational product and who had 1 post-baseline primary efficacy assessment (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 Week 12/ET
    End point values
    Placebo SPD489
    Number of subjects analysed
    183
    190
    Units: mmol/L
    least squares mean (standard error)
        Fasting Total Cholesterol Levels at Up to 12 Weeks
    -0.094 ± 0.0435
    -0.305 ± 0.0422
    Statistical analysis title
    Fasting Total Cholesterol Levels at Up to 12 Weeks
    Statistical analysis description
    Analysis was SPD489 vs Placebo
    Comparison groups
    Placebo v SPD489
    Number of subjects included in analysis
    373
    Analysis specification
    Pre-specified
    Analysis type
    other [8]
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Least squares mean difference
    Point estimate
    -0.211
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.33
         upper limit
    -0.092
    Notes
    [8] - Placebo controlled

    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
    The Full Analysis Set was defined as all randomized subjects who took at least 1 dose of investigational product and who had 1 post-baseline primary efficacy assessment (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 Week 12/ET
    End point values
    Placebo SPD489
    Number of subjects analysed
    181
    189
    Units: percent hemoglobin
    least squares mean (standard error)
        Hemoglobin A1c Levels at Up to 12 Weeks
    0.01 ± 0.016
    -0.02 ± 0.015
    Statistical analysis title
    Hemoglobin A1c Levels at Up to 12 Weeks
    Statistical analysis description
    Analysis was SPD489 vs Placebo
    Comparison groups
    Placebo v SPD489
    Number of subjects included in analysis
    370
    Analysis specification
    Pre-specified
    Analysis type
    other [9]
    P-value
    = 0.308
    Method
    ANCOVA
    Parameter type
    Least squares mean difference
    Point estimate
    -0.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.07
         upper limit
    0.02
    Notes
    [9] - Placebo controlled

    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. Percentage of subjects with response was reported. Responses were categorized as follows: 1-week Cessation = 100% reduction in binge episodes during the preceding 7 days. Marked Reduction = 99% to 75% reduction during the time since the previous visit. Moderate Reduction = 74% to 50% reduction during the time since the previous visit. Negative to Minimal Reduction = <50% reduction during the time since the previous visit. The Full Analysis Set was defined as all randomized subjects who took at least 1 dose of investigational product and who had 1 post-baseline primary efficacy assessment (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
    Week 12/ET
    End point values
    Placebo SPD489
    Number of subjects analysed
    184
    187
    Units: percentage of subjects
    number (not applicable)
        1-week cessation
    26.6
    47.1
        Marked Reduction
    15.2
    31.6
        Moderate Reduction
    17.9
    11.8
        Negative to Minimal Reduction
    40.2
    9.6
    Statistical analysis title
    Binge Eating Response
    Statistical analysis description
    Analysis was SPD489 vs Placebo
    Comparison groups
    Placebo v SPD489
    Number of subjects included in analysis
    371
    Analysis specification
    Pre-specified
    Analysis type
    other [10]
    P-value
    < 0.001 [11]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [10] - Placebo controlled
    [11] - Multiplicity is not adjusted for this secondary efficacy endpoint in this study.

    Secondary: Change From Baseline in the Number of Binge Episodes Per Week at Visit 8 (Weeks 11-12)

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    End point title
    Change From Baseline in the Number of Binge Episodes Per Week at Visit 8 (Weeks 11-12)
    End point description
    The Full Analysis Set was defined as all randomized subjects who took at least 1 dose of investigational product and who had 1 post-baseline primary efficacy assessment (number of binge days per week calculated for at least 1 week).
    End point type
    Secondary
    End point timeframe
    Baseline and Visit 8 (Weeks 11-12)
    End point values
    Placebo SPD489
    Number of subjects analysed
    184
    190
    Units: Binge episodes per week
    least squares mean (standard error)
        Number of Binge Episodes Per Week at Visit 8
    -3.49 ± 0.17
    -5.27 ± 0.168
    Statistical analysis title
    Number of Binge Episodes Per Week at Visit 8
    Statistical analysis description
    Analysis was SPD489 vs Placebo
    Comparison groups
    Placebo v SPD489
    Number of subjects included in analysis
    374
    Analysis specification
    Pre-specified
    Analysis type
    other [12]
    P-value
    < 0.001 [13]
    Method
    Mixed Models Repeated Measures Analysis
    Parameter type
    Least squares mean difference
    Point estimate
    -1.77
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.24
         upper limit
    -1.3
    Notes
    [12] - Placebo controlled
    [13] - Multiplicity is not adjusted for this secondary efficacy endpoint 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
    The Eating Inventory also known as the Three-Factor Eating Questionnaire is a 51-item self-reported questionnaire intended to assess 3 dimensions of eating behavior. 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. The Full Analysis Set was defined as all randomized subjects who took at least 1 dose of investigational product and who had 1 post-baseline primary efficacy assessment (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 week 12
    End point values
    Placebo SPD489
    Number of subjects analysed
    184
    188
    Units: units on a scale
    least squares mean (standard error)
        Cognitive Restraint of Eating
    1.63 ± 0.331
    3.27 ± 0.329
        Disinhibition of Eating
    -2.12 ± 0.286
    -6.31 ± 0.285
        Perceived Hunger
    -1.9 ± 0.286
    -6.6 ± 0.285
    Statistical analysis title
    Cognitive Restraint of Eating
    Statistical analysis description
    Analysis was SPD489 vs Placebo
    Comparison groups
    Placebo v SPD489
    Number of subjects included in analysis
    372
    Analysis specification
    Pre-specified
    Analysis type
    other [14]
    P-value
    < 0.001 [15]
    Method
    Mixed Models Repeated Measures Analysis
    Parameter type
    Least squares mean difference
    Point estimate
    1.65
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.72
         upper limit
    2.57
    Notes
    [14] - Placebo controlled
    [15] - Multiplicity is not adjusted for this secondary efficacy endpoint in this study.
    Statistical analysis title
    Disinhibition of Eating
    Statistical analysis description
    Analysis was SPD489 vs Placebo
    Comparison groups
    Placebo v SPD489
    Number of subjects included in analysis
    372
    Analysis specification
    Pre-specified
    Analysis type
    other [16]
    P-value
    < 0.001 [17]
    Method
    Mixed Models Repeated Measures Analysis
    Parameter type
    Least squares mean difference
    Point estimate
    -4.19
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.98
         upper limit
    -3.39
    Notes
    [16] - Placebo controlled
    [17] - Multiplicity is not adjusted for this secondary efficacy endpoint in this study.
    Statistical analysis title
    Perceived Hunger
    Statistical analysis description
    Analysis was SPD489 vs Placebo
    Comparison groups
    Placebo v SPD489
    Number of subjects included in analysis
    372
    Analysis specification
    Pre-specified
    Analysis type
    other [18]
    P-value
    < 0.001 [19]
    Method
    Mixed Models Repeated Measures Analysis
    Parameter type
    Least squares mean difference
    Point estimate
    -4.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.49
         upper limit
    -3.91
    Notes
    [18] - Placebo controlled
    [19] - Multiplicity is not adjusted for this secondary efficacy endpoint 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. The Full Analysis Set was defined as all randomized subjects who took at least 1 dose of investigational product and who had 1 post-baseline primary efficacy assessment (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 week 12
    End point values
    Placebo SPD489
    Number of subjects analysed
    184
    189
    Units: units on a scale
    least squares mean (standard error)
        BES Score at Week 12
    -8.55 ± 0.763
    -18.87 ± 0.755
    Statistical analysis title
    BES Score at Week 12
    Statistical analysis description
    Analysis was SPD489 vs Placebo
    Comparison groups
    Placebo v SPD489
    Number of subjects included in analysis
    373
    Analysis specification
    Pre-specified
    Analysis type
    other [20]
    P-value
    < 0.001
    Method
    Mixed Models Repeated Measures Analysis
    Parameter type
    Least squares mean difference
    Point estimate
    -10.32
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -12.43
         upper limit
    -8.21
    Notes
    [20] - Placebo controlled

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

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    End point title
    Change From Baseline in Frontal Systems Behavior (FrSBe) Total Score at Week 12
    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. The Full Analysis Set was 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 week 12
    End point values
    Placebo SPD489
    Number of subjects analysed
    182
    187
    Units: t-scores
    least squares mean (standard error)
        FrSBe Total Score at Week 12
    -3.09 ± 0.592
    -3.4 ± 0.572
    Statistical analysis title
    FrSBe Total Score at Week 12
    Statistical analysis description
    Analysis was SPD489 vs Placebo
    Comparison groups
    Placebo v SPD489
    Number of subjects included in analysis
    369
    Analysis specification
    Pre-specified
    Analysis type
    other [21]
    P-value
    = 0.706
    Method
    ANCOVA
    Parameter type
    Least squares mean difference
    Point estimate
    -0.31
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.93
         upper limit
    1.31
    Notes
    [21] - Placebo controlled

    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. Percentage of subjects with various mobility conditions were reported. The Full Analysis Set was defined as all randomized subjects who took at least 1 dose of investigational product and who had 1 post-baseline primary efficacy assessment (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
    Placebo SPD489
    Number of subjects analysed
    178
    187
    Units: percentage of subjects
    number (not applicable)
        No problems walking about
    82.6
    87.2
        Slight problems walking about
    14
    10.7
        Moderate problems walking about
    2.8
    2.1
        Severe problems walking about
    0.6
    0
        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. Percentage of subjects with various self-care conditions were reported. The Full Analysis Set was defined as all randomized subjects who took at least 1 dose of investigational product and who had 1 post-baseline primary efficacy assessment (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
    Placebo SPD489
    Number of subjects analysed
    178
    187
    Units: percentage of subjects
    number (not applicable)
        No problems washing or dressing
    89.3
    95.7
        Slight problems washing or dressing
    6.7
    3.2
        Moderate problems washing or dressing
    3.9
    1.1
        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. Percentage of subjects with various usual activities conditions were reported. The Full Analysis Set was defined as all randomized subjects who took at least 1 dose of investigational product and who had 1 post-baseline primary efficacy assessment (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
    Placebo SPD489
    Number of subjects analysed
    177
    186
    Units: percentage of subjects
    number (not applicable)
        No problems doing usual activities
    78
    87.1
        Slight problems doing usual activities
    14.7
    9.7
        Moderate problems doing usual activities
    6.2
    3.2
        Severe problems doing usual activities
    1.1
    0
        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. Percentage of subjects with various pain/discomfort conditions were reported. The Full Analysis Set was defined as all randomized subjects who took at least 1 dose of investigational product and who had 1 post-baseline primary efficacy assessment (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
    Placebo SPD489
    Number of subjects analysed
    178
    187
    Units: percentage of subjects
    number (not applicable)
        No pain or discomfort
    64.6
    71.1
        Slight pain or discomfort
    27.5
    20.9
        Moderate pain or discomfort
    7.3
    7.5
        Severe pain or discomfort
    0.6
    0.5
        Extreme pain or discomfort
    0
    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. Percentage of subjects with various anxiety/depression conditions were reported. The Full Analysis Set was defined as all randomized subjects who took at least 1 dose of investigational product and who had 1 post-baseline primary efficacy assessment (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
    Placebo SPD489
    Number of subjects analysed
    178
    187
    Units: percentage of subjects
    number (not applicable)
        Not anxious or depressed
    70.2
    72.2
        Slightly anxious or depressed
    19.7
    16.6
        Moderately anxious or depressed
    7.9
    9.1
        Severely anxious or depressed
    2.2
    1.6
        Extremely anxious or depressed
    0
    0.5
    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 occurrence, 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. Number of participants with suicidal ideation and suicidal behavior were reported. The Safety Analysis Set was 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. Not all subjects had data for this outcome.
    End point type
    Secondary
    End point timeframe
    Up to 12 weeks
    End point values
    Placebo SPD489
    Number of subjects analysed
    187
    191
    Units: Subjects
    number (not applicable)
        Suicidal Ideation
    3
    2
        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. The Safety Analysis Set was 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. Not all subjects had data for this outcome.
    End point type
    Secondary
    End point timeframe
    Up to 12 weeks
    End point values
    Placebo SPD489
    Number of subjects analysed
    138
    155
    Units: units on a scale
        arithmetic mean (standard deviation)
    7.3 ± 7.74
    5.7 ± 7.37
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug up to 3 days after the last dose at up to 12 weeks
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    PLACEBO
    Reporting group description
    Placebo matching SPD489 capsule administered orally, once-daily for up to 12 weeks.

    Reporting group title
    SPD489
    Reporting group description
    SPD489 capsule 30 (titration purpose only), 50 or 70 mg administered orally, once-daily for up to 12 weeks once the optimal dose is reached.

    Serious adverse events
    PLACEBO SPD489
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 187 (1.07%)
    3 / 192 (1.56%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 192 (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 / 187 (0.00%)
    2 / 192 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Conversion disorder
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 187 (0.00%)
    1 / 192 (0.52%)
         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
    PLACEBO SPD489
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    67 / 187 (35.83%)
    125 / 192 (65.10%)
    Investigations
    Heart rate increased
         subjects affected / exposed
    5 / 187 (2.67%)
    14 / 192 (7.29%)
         occurrences all number
    5
    14
    Nervous system disorders
    Headache
         subjects affected / exposed
    17 / 187 (9.09%)
    26 / 192 (13.54%)
         occurrences all number
    19
    32
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    10 / 187 (5.35%)
    7 / 192 (3.65%)
         occurrences all number
    11
    7
    Feeling jittery
         subjects affected / exposed
    2 / 187 (1.07%)
    11 / 192 (5.73%)
         occurrences all number
    3
    13
    Irritability
         subjects affected / exposed
    13 / 187 (6.95%)
    16 / 192 (8.33%)
         occurrences all number
    13
    18
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 187 (1.07%)
    13 / 192 (6.77%)
         occurrences all number
    2
    13
    Insomnia
         subjects affected / exposed
    14 / 187 (7.49%)
    34 / 192 (17.71%)
         occurrences all number
    15
    44
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    4 / 187 (2.14%)
    11 / 192 (5.73%)
         occurrences all number
    4
    11
    Dry mouth
         subjects affected / exposed
    16 / 187 (8.56%)
    76 / 192 (39.58%)
         occurrences all number
    19
    86
    Nausea
         subjects affected / exposed
    14 / 187 (7.49%)
    16 / 192 (8.33%)
         occurrences all number
    15
    19
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    1 / 187 (0.53%)
    10 / 192 (5.21%)
         occurrences all number
    1
    10
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    6 / 187 (3.21%)
    17 / 192 (8.85%)
         occurrences all number
    6
    17
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    11 / 187 (5.88%)
    8 / 192 (4.17%)
         occurrences all number
    12
    10

    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
    • Added an Overall Risk/Benefit Assessment • 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 to further describe indeterminate pregnancy test results • Clarified exclusion criterion 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 International Neuropsychiatric Interview (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 the 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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