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    Clinical Trial Results:
    The SPD489-322 Phase 3, Multicenter, Randomized, Double-blind, Parallel-group, Placebo-controlled, Flexible Dose Titration, Efficacy and Safety Study of SPD489 in Combination with an Antidepressant in the Treatment of Adults with Major Depressive Disorder with Inadequate Response to Prospective Treatment with an Antidepressant

    Summary
    EudraCT number
    2011-003018-17
    Trial protocol
    ES  
    Global end of trial date
    23 Dec 2013

    Results information
    Results version number
    v1
    This version publication date
    23 Oct 2018
    First version publication date
    08 Feb 2015
    Other versions
    v2

    Trial information

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    Trial identification
    Sponsor protocol code
    SPD489-322
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01436149
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Shire Development LLC
    Sponsor organisation address
    725 Chesterbrook Boulevard, Wayne, PA, United States, 19087
    Public contact
    Study Physician, Shire Pharmaceuticals Ltd, +1 866 842 5335,
    Scientific contact
    Study Physician, Shire Pharmaceuticals Ltd, +1 866 842 5335,
    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
    23 Dec 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Dec 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to demonstrate the efficacy of SPD489 when used as augmentation therapy in the treatment of major depressive disorder (MDD) in inadequate responders following an 8-week course of treatment with an antidepressant, as measured by the mean change in Montgomery-Asberg Depression Rating Scale (MADRS) total scores.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice, the principles of the Declaration of Helsinki, as well as other applicable local ethical and legal requirements. The subject’s informed consent was a mandatory condition for taking part in the study. It was obtained in writing at the Screening Visit (Visit 1) prior to the performance of any study-specific procedures. The subject’s informed consent was documented (on an appropriate form approved by the EC) by the dated signature of the subject and the dated signature of the investigator or investigator's delegate.
    Background therapy
    The background products provided for this study were the following selective serotonin reuptake inhibitor (SSRI) and serotonin norepinephrine reuptake inhibitor (SNRI) antidepressants: escitalopram oxalate, sertraline HCl, venlafaxine HCl extended-release, and duloxetine HCl. Randomized subjects were assigned to receive either SPD489 or placebo orally once daily in addition to their assigned background product. If not already on 1 of the 4 permitted background products at the Screening Visit (Visit 1), a subject was assigned 1 of the 4 background products, as available and provided by the sponsor, at the Lead-in Baseline Visit (Visit 2). Assignment of background product was based on investigator assessment of clinical factors, including prior antidepressant use, response, and tolerability. Investigators were to distribute background product choices equally at their site and were to have made an effort not to assign any 1 background product to more than 40% of their subjects.
    Evidence for comparator
    -
    Actual start date of recruitment
    27 Oct 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 15
    Country: Number of subjects enrolled
    Canada: 83
    Country: Number of subjects enrolled
    Croatia: 10
    Country: Number of subjects enrolled
    Mexico: 58
    Country: Number of subjects enrolled
    United States: 1096
    Worldwide total number of subjects
    1262
    EEA total number of subjects
    25
    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)
    1256
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 76 sites in 5 countries (Canada, Croatia, Mexico, Spain, United States).

    Pre-assignment
    Screening details
    Adults (18-65 years of age, inclusive) who met all study eligibility criteria, including a primary diagnosis of non-psychotic major depressive disorder (single or recurrent) as defined by the SCID-CT, that had lasted at least 8 weeks prior to the Screening Visit (Visit 1), were eligible for evaluation to participate in this study.

    Period 1
    Period 1 title
    Antidepressant Lead-in Phase
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Single blind
    Roles blinded
    Subject
    Blinding implementation details
    Placebo capsules to match the over-encapsulated SPD489.

    Arms
    Arm title
    Antidepressant + Single-blind Placebo (Lead-in Phase)
    Arm description
    Subjects received assigned, unblinded, antidepressant therapy (escitalopram oxalate, sertraline hydrochloride, venlafaxine hydrochloride extended-release, or duloxetine hydrochloride) plus placebo (matching SPD489) for 8 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 once-daily

    Number of subjects in period 1
    Antidepressant + Single-blind Placebo (Lead-in Phase)
    Started
    1262
    Completed
    896
    Not completed
    366
         Withdrawal by Subject
    61
         Met BP or Pulse Withdrawal Criteria
    22
         Protocol Violation
    29
         Adverse Event
    39
         Not Specified
    119
         Lost to Follow-up
    96
    Period 2
    Period 2 title
    Randomized Phase
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator
    Blinding implementation details
    SPD489 was over-encapsulated and appeared identical to placebo. Background product (standard antidepressant therapy) was not blinded.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Antidepressant + Single-blind Placebo (Randomized Phase)
    Arm description
    Subjects received assigned, unblinded, antidepressant therapy (escitalopram oxalate, sertraline hydrochloride, venlafaxine hydrochloride extended-release, or duloxetine hydrochloride) plus placebo (matching SPD489) for 8 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 once-daily

    Arm title
    Antidepressant + Double-blind Placebo
    Arm description
    Subjects received assigned, unblinded antidepressant therapy (escitalopram oxalate, sertraline hydrochloride, venlafaxine hydrochloride extended release, or duloxetine hydrochloride) plus placebo (matching SPD489) for 8 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 once-daily

    Arm title
    Antidepressant + Double-blind SPD489
    Arm description
    Subjects received assigned, unblinded antidepressant therapy (escitalopram oxalate, sertraline hydrochloride, venlafaxine hydrochloride extended release, or duloxetine hydrochloride) plus SPD489 for 8 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    SPD489
    Investigational medicinal product code
    Other name
    Lisdexamfetamine dimesylate, Vyvanse
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Over-encapsulated SPD489 capsules optimized among 20, 30, 50, or 70 mg dose once-daily

    Number of subjects in period 2
    Antidepressant + Single-blind Placebo (Randomized Phase) Antidepressant + Double-blind Placebo Antidepressant + Double-blind SPD489
    Started
    492
    202
    202
    Completed
    415
    164
    160
    Not completed
    77
    38
    42
         Withdrawal by Subject
    16
    10
    10
         Met BP or Pulse Withdrawal Criteria
    2
    3
    3
         Lack of Efficacy
    -
    -
    1
         Protocol Violation
    4
    5
    -
         Adverse Event
    9
    10
    11
         Not Specified
    12
    5
    11
         Lost to Follow-up
    34
    5
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Antidepressant Lead-in Phase
    Reporting group description
    Subjects received assigned, unblinded, antidepressant therapy (escitalopram oxalate, sertraline hydrochloride, venlafaxine hydrochloride extended-release, or duloxetine hydrochloride) plus placebo (matching SPD489) for 8 weeks.

    Reporting group values
    Antidepressant Lead-in Phase Total
    Number of subjects
    1262 1262
    Age categorical
    Units: Subjects
        18-55 years
    1125 1125
        56-65 years
    137 137
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    39.5 ± 12.11 -
    Gender categorical
    Units: Subjects
        Female
    806 806
        Male
    456 456

    End points

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    End points reporting groups
    Reporting group title
    Antidepressant + Single-blind Placebo (Lead-in Phase)
    Reporting group description
    Subjects received assigned, unblinded, antidepressant therapy (escitalopram oxalate, sertraline hydrochloride, venlafaxine hydrochloride extended-release, or duloxetine hydrochloride) plus placebo (matching SPD489) for 8 weeks.
    Reporting group title
    Antidepressant + Single-blind Placebo (Randomized Phase)
    Reporting group description
    Subjects received assigned, unblinded, antidepressant therapy (escitalopram oxalate, sertraline hydrochloride, venlafaxine hydrochloride extended-release, or duloxetine hydrochloride) plus placebo (matching SPD489) for 8 weeks.

    Reporting group title
    Antidepressant + Double-blind Placebo
    Reporting group description
    Subjects received assigned, unblinded antidepressant therapy (escitalopram oxalate, sertraline hydrochloride, venlafaxine hydrochloride extended release, or duloxetine hydrochloride) plus placebo (matching SPD489) for 8 weeks.

    Reporting group title
    Antidepressant + Double-blind SPD489
    Reporting group description
    Subjects received assigned, unblinded antidepressant therapy (escitalopram oxalate, sertraline hydrochloride, venlafaxine hydrochloride extended release, or duloxetine hydrochloride) plus SPD489 for 8 weeks.

    Primary: Mean Change From Baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score at 8 Weeks

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    End point title
    Mean Change From Baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score at 8 Weeks
    End point description
    MADRS is a validated, 10-item rating scale with each item being scored on a scale from 0-6 with a total score ranging from 0-60. Lower scores indicate a decreased severity of depression. This end point used the Full Analysis Set, which included subjects who took at least 1 dose of randomized investigational product and who had at least 1 valid primary efficacy measurement of the MADRS total score after the Augmentation Baseline Visit (Visit 8).
    End point type
    Primary
    End point timeframe
    8 weeks
    End point values
    Antidepressant + Double-blind Placebo Antidepressant + Double-blind SPD489
    Number of subjects analysed
    200
    200
    Units: units on a scale
        least squares mean (confidence interval 95%)
    -6.3 (-7.6 to -4.9)
    -6.1 (-7.5 to -4.8)
    Statistical analysis title
    Change From Baseline in MADRS Total Score
    Comparison groups
    Antidepressant + Double-blind Placebo v Antidepressant + Double-blind SPD489
    Number of subjects included in analysis
    400
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.883
    Method
    Mixed-effects Model for Repeat Measures
    Parameter type
    Difference in LS Mean
    Point estimate
    0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.7
         upper limit
    2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.96

    Secondary: Change From Baseline in the Sheehan Disability Scale (SDS) Total Score at 8 Weeks

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    End point title
    Change From Baseline in the Sheehan Disability Scale (SDS) Total Score at 8 Weeks
    End point description
    SDS is designed to evaluate the extent to which illness symptoms impact a subject's life in 3 areas: work/school, social, and family/home. Each area is scored on a scale from 0 (no impairment) to 10 (highly impaired) with a total score ranging from 0 (unimpaired) to 30 (highly impaired). Lower scores translate into less impairment. This end point used the Full Analysis Set, which included subjects who took at least 1 dose of randomized investigational product and who had at least 1 valid primary efficacy measurement of the MADRS total score after the Augmentation Baseline Visit (Visit 8).
    End point type
    Secondary
    End point timeframe
    8 weeks
    End point values
    Antidepressant + Double-blind Placebo Antidepressant + Double-blind SPD489
    Number of subjects analysed
    200
    200
    Units: units on a scale
        least squares mean (confidence interval 95%)
    -4.3 (-5.3 to -3.3)
    -4.7 (-5.6 to -3.7)
    Statistical analysis title
    Change From Baseline in SDS Total Score
    Comparison groups
    Antidepressant + Double-blind Placebo v Antidepressant + Double-blind SPD489
    Number of subjects included in analysis
    400
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.576
    Method
    Mixed- effects Model for Repeat Measures
    Parameter type
    Difference in LS Mean
    Point estimate
    -0.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.8
         upper limit
    1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.69

    Secondary: Percentage of Participants Achieving a 25% Response on the MADRS

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    End point title
    Percentage of Participants Achieving a 25% Response on the MADRS
    End point description
    The percentage of subjects who achieved a 25% response (i.e., ≥25% reduction in MADRS total score from Lead-in Baseline, Visit 2; Week 0). A comparison was performed at Visit 14/Early Termination (ET) (Week 16/ET). This end point used the Full Analysis Set, which included subjects who took at least 1 dose of randomized investigational product and who had at least 1 valid primary efficacy measurement of the MADRS total score after the Augmentation Baseline Visit (Visit 8).
    End point type
    Secondary
    End point timeframe
    Up to 8 weeks
    End point values
    Antidepressant + Double-blind Placebo Antidepressant + Double-blind SPD489
    Number of subjects analysed
    200
    200
    Units: percentage of subjects
        number (not applicable)
    65
    74.5
    No statistical analyses for this end point

    Secondary: Percentage of Participants Achieving a 50% Response on the MADRS

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    End point title
    Percentage of Participants Achieving a 50% Response on the MADRS
    End point description
    The percentage of subjects who achieved a 50% response (i.e., ≥50% reduction in MADRS total score from Lead-in Baseline, Visit 2; Week 0). A comparison was performed at Visit 14/ET (Week 16/ET). This end point used the Full Analysis Set, which included subjects who took at least 1 dose of randomized investigational product and who had at least 1 valid primary efficacy measurement of the MADRS total score after the Augmentation Baseline Visit (Visit 8).
    End point type
    Secondary
    End point timeframe
    Up to 8 weeks
    End point values
    Antidepressant + Double-blind Placebo Antidepressant + Double-blind SPD489
    Number of subjects analysed
    200
    200
    Units: percentage of subjects
        number (not applicable)
    38.5
    41
    No statistical analyses for this end point

    Secondary: Percentage of Participants Achieving Remission on the MADRS

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    End point title
    Percentage of Participants Achieving Remission on the MADRS
    End point description
    MADRS remission was defined as a MADRS total score of ≤10. A comparison was performed at Visit 14/ET (Week 16/ET). This end point used the Full Analysis Set, which included subjects who took at least 1 dose of randomized investigational product and who had at least 1 valid primary efficacy measurement of the MADRS total score after the Augmentation Baseline Visit (Visit 8).
    End point type
    Secondary
    End point timeframe
    Up to 8 weeks
    End point values
    Antidepressant + Double-blind Placebo Antidepressant + Double-blind SPD489
    Number of subjects analysed
    200
    200
    Units: percentage of subjects
        number (not applicable)
    22.5
    18.5
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline Over Time in the MADRS Total Score

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    End point title
    Mean Change From Baseline Over Time in the MADRS Total Score
    End point description
    MADRS is a validated, 10-item rating scale with each item being scored on a scale from 0-6 with a total score ranging from 0-60. Lower scores indicate a decreased severity of depression. This end point used the Full Analysis Set, which included subjects who took at least 1 dose of randomized investigational product and who had at least 1 valid primary efficacy measurement of the MADRS total score after the Augmentation Baseline Visit (Visit 8).
    End point type
    Secondary
    End point timeframe
    Baseline and up to 8 weeks
    End point values
    Antidepressant + Double-blind Placebo Antidepressant + Double-blind SPD489
    Number of subjects analysed
    200
    200
    Units: units on a scale
    least squares mean (confidence interval 95%)
        Visit 9 (Week 9)
    -2.2 (-3.1 to -1.2)
    -3.4 (-4.3 to -2.4)
        Visit 10 (Week 10)
    -3.8 (-4.9 to -2.7)
    -4.2 (-5.3 to -3.2)
        Visit 11 (Week 11)
    -6 (-7.2 to -4.8)
    -5.4 (-6.6 to -4.2)
        Visit 12 (Week 12)
    -6.2 (-7.4 to -5)
    -5.6 (-6.8 to -4.4)
        Visit 13 (Week 14)
    -7.4 (-8.7 to -6)
    -7.3 (-8.6 to -6)
        Visit 14 (Week 16)
    -6.3 (-7.6 to -4.9)
    -6.1 (-7.5 to -4.8)
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline in the Quick Inventory of Depressive Symptomatology - Self Report (QIDS SR)

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    End point title
    Mean Change From Baseline in the Quick Inventory of Depressive Symptomatology - Self Report (QIDS SR)
    End point description
    The QIDS-SR is a self-administered questionnaire designed to rate depressive symptoms. The scale contains 16 items, each scored using a 4-point scale ranging from 0 (representing the most favorable response [low amount of symptoms]) to 3 (representing the least favorable response [frequent/intense symptoms]). The total score could range from 0 (no depression) to 27 (very severe depression). Higher scores represent more severe depressive symptoms. This end point used the Full Analysis Set, which included subjects who took at least 1 dose of randomized investigational product and who had at least 1 valid primary efficacy measurement of the MADRS total score after the Augmentation Baseline Visit (Visit 8).
    End point type
    Secondary
    End point timeframe
    Up to 8 weeks
    End point values
    Antidepressant + Double-blind Placebo Antidepressant + Double-blind SPD489
    Number of subjects analysed
    186
    185
    Units: units on a scale
        least squares mean (confidence interval 95%)
    -2.6 (-3.2 to -1.9)
    -2.3 (-2.9 to -1.7)
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline in the Short Form-12 Health Survey V2 (SF-12V2)

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    End point title
    Mean Change From Baseline in the Short Form-12 Health Survey V2 (SF-12V2)
    End point description
    The SF-12V2 total score ranges from 0 (lowest level of health) to 100 (highest level of health) on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability (i.e. a score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability). Higher scores are associated with better quality of life. This end point used the Full Analysis Set, which included subjects who took at least 1 dose of randomized investigational product and who had at least 1 valid primary efficacy measurement of the MADRS total score after the Augmentation Baseline Visit (Visit 8).
    End point type
    Secondary
    End point timeframe
    Up to 8 weeks
    End point values
    Antidepressant + Double-blind Placebo Antidepressant + Double-blind SPD489
    Number of subjects analysed
    189
    186
    Units: units on a scale
    least squares mean (confidence interval 95%)
        Physical
    0.69 (-0.39 to 1.77)
    -0.81 (-1.89 to 0.28)
        Mental
    5.59 (3.93 to 7.25)
    6.5 (4.84 to 8.16)
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline in the Quality of Life Enjoyment Satisfaction Questionnaire Short Form (Q-LES-Q-SF)

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    End point title
    Mean Change From Baseline in the Quality of Life Enjoyment Satisfaction Questionnaire Short Form (Q-LES-Q-SF)
    End point description
    The Q-LES-Q-SF is a 16-item self-report questionnaire that evaluates general subject satisfaction with health, mood, relationships, functioning in daily life, and the treatment being taken. The overall level of satisfaction is evaluated on a 5-point scale from 1 (very poor) to 5 (very good). The total score ranges from 14-70 (the last two items on the form are not included in the total score). A higher score indicates a better quality of life. This end point used the Full Analysis Set, which included subjects who took at least 1 dose of randomized investigational product and who had at least 1 valid primary efficacy measurement of the MADRS total score after the Augmentation Baseline Visit (Visit 8).
    End point type
    Secondary
    End point timeframe
    Up to 8 weeks
    End point values
    Antidepressant + Double-blind Placebo Antidepressant + Double-blind SPD489
    Number of subjects analysed
    188
    184
    Units: units on a scale
        least squares mean (confidence interval 95%)
    7.2 (4.9 to 9.5)
    7 (4.7 to 9.3)
    No statistical analyses for this end point

    Secondary: Clinical Global Impressions - Global Improvement (CGI-I)

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    End point title
    Clinical Global Impressions - Global Improvement (CGI-I)
    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 used the Full Analysis Set, which included subjects who took at least 1 dose of randomized investigational product and who had at least 1 valid primary efficacy measurement of the MADRS total score after the Augmentation Baseline Visit (Visit 8).
    End point type
    Secondary
    End point timeframe
    Up to 8 weeks
    End point values
    Antidepressant + Double-blind Placebo Antidepressant + Double-blind SPD489
    Number of subjects analysed
    199
    199
    Units: percentage of subjects
    number (not applicable)
        Improved
    53.3
    55.3
        Not Improved
    46.2
    44.7
        Not Assessed
    0.5
    0
    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 behavior occurred. The assessment is done by the nature of the responses, not by a numbered scale. This end point used the Full Analysis Set, which included subjects who took at least 1 dose of randomized investigational product and who had at least 1 valid primary efficacy measurement of the MADRS total score after the Augmentation Baseline Visit (Visit 8).
    End point type
    Secondary
    End point timeframe
    Up to 8 weeks
    End point values
    Antidepressant + Double-blind Placebo Antidepressant + Double-blind SPD489
    Number of subjects analysed
    201
    201
    Units: percentage of subjects
    number (not applicable)
        ≥1 Positive Suicidal Ideation
    7
    7
        ≥1 Suicidal Attempt
    0.5
    0
    No statistical analyses for this end point

    Secondary: Amphetamine Cessation Symptom Assessment (ACSA)

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    End point title
    Amphetamine Cessation Symptom Assessment (ACSA)
    End point description
    The 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 used the Full Analysis Set, which included subjects who took at least 1 dose of randomized investigational product and who had at least 1 valid primary efficacy measurement of the MADRS total score after the Augmentation Baseline Visit (Visit 8).
    End point type
    Secondary
    End point timeframe
    Up to 8 weeks
    End point values
    Antidepressant + Double-blind Placebo Antidepressant + Double-blind SPD489
    Number of subjects analysed
    178
    183
    Units: units on a scale
        arithmetic mean (standard deviation)
    15.1 ± 10.71
    14.7 ± 10.94
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    17 weeks
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    Antidepressant + Double-blind Placebo
    Reporting group description
    Subjects received assigned oral, once-daily antidepressant therapy (escitalopram oxalate, sertraline hydrochloride, venlafaxine hydrochloride extended release, or duloxetine hydrochloride) plus double-blind placebo (matching SPD489) for 8 weeks.

    Reporting group title
    Antidepressant + Double-blind SPD489
    Reporting group description
    Subjects received assigned oral, once-daily antidepressant therapy (escitalopram oxalate, sertraline hydrochloride, venlafaxine hydrochloride extended release, or duloxetine hydrochloride) plus SPD489 for 8 weeks.

    Serious adverse events
    Antidepressant + Double-blind Placebo Antidepressant + Double-blind SPD489
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 201 (2.49%)
    3 / 201 (1.49%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Appendicectomy
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 201 (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
    1 / 201 (0.50%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Major depression
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Antidepressant + Double-blind Placebo Antidepressant + Double-blind SPD489
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    74 / 201 (36.82%)
    99 / 201 (49.25%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    10 / 201 (4.98%)
    9 / 201 (4.48%)
         occurrences all number
    11
    9
    Headache
         subjects affected / exposed
    21 / 201 (10.45%)
    13 / 201 (6.47%)
         occurrences all number
    28
    14
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    15 / 201 (7.46%)
    19 / 201 (9.45%)
         occurrences all number
    16
    20
    Gastrointestinal disorders
    Dry mouth
         subjects affected / exposed
    6 / 201 (2.99%)
    19 / 201 (9.45%)
         occurrences all number
    6
    19
    Nausea
         subjects affected / exposed
    10 / 201 (4.98%)
    13 / 201 (6.47%)
         occurrences all number
    11
    13
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    8 / 201 (3.98%)
    15 / 201 (7.46%)
         occurrences all number
    8
    17
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    4 / 201 (1.99%)
    11 / 201 (5.47%)
         occurrences all number
    4
    12

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Nov 2011
    1-Updated information for emergency contact, MADRS, and Q-LES-Q-SF 2-Specified that the 4 antidepressants were “as available and provided by the sponsor” 3- Revised exclusion criteria 4- Added that subjects with no improvement in depressive symptoms from Visit 2 to Visit 8 were to be discontinued 5-Qualified that subjects “whose depressive symptoms have improved, but” who did not meet randomization criteria at Visit 8 were allowed to continue in the study receiving placebo 6-Reduced the duration after the study that a subject was to use contraception. 7- Specified that the management of blood pressure and pulse during the study were to be based on an “average of 3 readings” for each respective measurement as well as on an “average” value for each respective measurement on 2 consecutive visits 8- Expanded permitted concomitant medications to include any medication not affecting blood pressure, heart rate, or the CNS. Antibiotics were excluded. 9-Specified that background product was to be taken in conjunction with investigational product 10-Defined target dose of background product 11-Titration to a target dose of the background product was clarified to be consistent with the labeling guidelines 12- Listed study assessments to be performed when background product was tapered or investigational product was down-titrated 13- Dosing and re-dispensing of background and investigational products was expanded upon 14- Specified that controlled substances were to be stored based on the label 15-Removed the following sentence: “Continued antidepressant treatment will not be provided by the sponsor” from the section describing study procedures performed during the follow-up period 16- Specified tapering of background product after the study 17- Specified that any urine drug screen at Visit 2 was to be negative 18-Listed specific items of interest on the C-SSRS for the investigator to use when evaluating a subject’s suitability to remain in the study
    12 Nov 2012
    1-Updated emergency contact information 2-Removed the secondary objective to evaluate the efficacy of SPD489 augmentation based on the CGI-S 3- Increased the number of subjects to be screened 4-Increased the number of planned sites 5-Revised exclusion criteria 6- Specified Visit 2 as the start for evaluation of additional randomization assessments 7- Specified intervals for QTcF and QTcB that would trigger discontinuation 8- Removed the following sentence from the analysis of secondary efficacy variables: “The CGI-S data at Visit 14 will be compared between augmentation treatment groups using the Wilcoxon rank sum test” 9- Specified Visit 2 as the time of enrolment 10- Specified that any Visit 1 assessment requiring a repeat measurement should be performed before confirming eligibility 11- Subject discontinuation based on laboratory or ECG results that would preclude treatment with SPD489 was to be agreed upon by the investigator in conjunction with the CRO Medical Monitor 12-Added that contraceptive requirements were to be reviewed at all study visits 13-The following (in “quotes”) was removed regarding removal of a subject from drug or therapy: the reason for withdrawal (by the sponsor or investigator) should be “discussed where possible with the contract research organization (CRO) Medical Monitor before the subject stops investigational product” 14-Added that subjects requiring a prohibited change to their treatment must be discontinued 15-Added reasons for discontinuation under the category of Other: Change in background product required Treatment with a prohibited medication required Other reasons must be specified 16-Expanded the processes for discontinuing medications 17-Prohibited “chronic” use of an herbal treatment 18- Specified that the investigator was to contact the CRO Medical Monitor as soon as possible after unblinding 19-Added the formula for medication compliance 20- Changed reporting requirements of SAEs and pregnancies

    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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