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    Clinical Trial Results:
    A Phase 3, Open-label, Multicenter, 12-month Extension Safety and Tolerability Study of SPD489 in Combination With an Antidepressant in the Treatment of Adults With Major Depressive Disorder With Residual Symptoms or Inadequate Response Following Treatment With an Antidepressant

    Summary
    EudraCT number
    		 2011-003019-47
    Trial protocol
    		 DE   HU   PL   CZ   ES   BE   EE   FI   SE   GB  
    Global end of trial date
    27 Mar 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Sep 2018
    First version publication date
    21 Feb 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SPD489-329
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01436175
    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 0800 0556614, medinfoglobal@shire.com
    Scientific contact
    Medical Communications, Shire Pharmaceuticals Ltd, +44 0800 0556614, 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
    27 Mar 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Mar 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective was to evaluate the long-term safety and tolerability of SPD489 administered as a daily morning dose (20, 30, 50, and 70 milligram per day [mg/day]) as adjunctive therapy to an antidepressant for the treatment of major depressive disorder (MDD) in adults (18-65 years of age inclusive at the time of consent for the respective short-term antecedent SPD489 MDD study). Long-term safety was described using: • Occurrence of treatment-emergent adverse events (TEAEs), • Responses to the Columbia Suicide Severity Rating Scale (C-SSRS), and • Specific evaluation of blood pressure and pulse rate, clinical laboratory evaluations, and electrocardiogram (ECG) results.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation (ICH) of Good Clinical Practice (GCP), the principles of the Declaration of Helsinki, as well as other applicable local ethical and legal requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Feb 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
    Poland: 20
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    Czech Republic: 83
    Country: Number of subjects enrolled
    Estonia: 24
    Country: Number of subjects enrolled
    Finland: 8
    Country: Number of subjects enrolled
    Germany: 69
    Country: Number of subjects enrolled
    Hungary: 4
    Country: Number of subjects enrolled
    United States: 1190
    Country: Number of subjects enrolled
    Mexico: 27
    Country: Number of subjects enrolled
    Canada: 36
    Country: Number of subjects enrolled
    Romania: 8
    Country: Number of subjects enrolled
    South Africa: 5
    Country: Number of subjects enrolled
    Chile: 33
    Country: Number of subjects enrolled
    Argentina: 27
    Country: Number of subjects enrolled
    Australia: 13
    Country: Number of subjects enrolled
    Croatia: 5
    Worldwide total number of subjects
    1559
    EEA total number of subjects
    228
    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)
    1559
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study enrolled eligible adults with MDD who had completed treatment in a short-term antecedent SPD489 (lisdexamfetamine dimesylate) MDD study (SPD489-209 [2011-003615-28], SPD489-322 [2011-003018-17], and SPD489-323 [2011-003006-25]).

    Pre-assignment
    Screening details
    		 A total of 1570 subjects were enrolled. Of these, 11 subjects excluded from the Safety Analysis Set (reasons for discontinuation were 3 subjects lost to follow up, 3 subject withdrew and 5 subjects were without a post-Visit 0 safety assessment). A total of 1559 subjects were included in Safety Analysis Set.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 SPD489 + Antidepressant
    Arm description
    		 SPD489 20, 30, 50 or 70 mg once daily orally for 52 weeks along with the assigned background product that subject had received during the antecedent study (antidepressant: either escitalopram oxalate, sertraline hydrochloride [HCl], venlafaxine HCl extended-release, or duloxetine HCl) at a dose consistent with applicable local labeling guidelines.
    Arm type
    		 Experimental

    Investigational medicinal product name
    lisdexamfetamine dimesylate (LDX)
    Investigational medicinal product code
    SPD489
    Other name
    Vyvanse, Venvanse, Elvanse, Tyvense
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    SPD489 20, 30, 50 or 70 mg once daily orally for 52 weeks along with the assigned background product that subject had received during the antecedent study.

    Number of subjects in period 1
    		SPD489 + Antidepressant
    Started
    1559
    Completed
    300
    Not completed
    1259
         Consent withdrawn by subject
    105
         Adverse Event
    111
         Protocol Violation
    44
         Lost to follow-up
    86
         'Unspecified '
    826
         Met blood pressure or pulse withdrawal
    63
         Lack of efficacy
    24

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    SPD489 + Antidepressant
    Reporting group description
    		 SPD489 20, 30, 50 or 70 mg once daily orally for 52 weeks along with the assigned background product that subject had received during the antecedent study (antidepressant: either escitalopram oxalate, sertraline hydrochloride [HCl], venlafaxine HCl extended-release, or duloxetine HCl) at a dose consistent with applicable local labeling guidelines.

    Reporting group values
    		 SPD489 + Antidepressant Total
    Number of subjects
    		 1559 1559
    Age categorical
    Safety Analysis Set consisted of all subjects who took at least 1 dose of investigational product and had at least 1 post-Visit 0 safety assessment.
    Units: Subjects
        18-55 Years
    		 1333 1333
        56-65 Years
    		 226 226
    Age continuous
    Safety Analysis Set.
    Units: years
        arithmetic mean (standard deviation)
    		 41.9 ± 11.89 -
    Gender categorical
    Safety Analysis Set.
    Units: Subjects
        Female
    		 1056 1056
        Male
    		 503 503

    End points

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    End points reporting groups
    Reporting group title
    SPD489 + Antidepressant
    Reporting group description
    		 SPD489 20, 30, 50 or 70 mg once daily orally for 52 weeks along with the assigned background product that subject had received during the antecedent study (antidepressant: either escitalopram oxalate, sertraline hydrochloride [HCl], venlafaxine HCl extended-release, or duloxetine HCl) at a dose consistent with applicable local labeling guidelines.

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

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    End point title
    		 Columbia-Suicide Severity Rating Scale (C-SSRS) [1]
    End point description
    C-SSRS is a semi-structured interview that captures the occurrence, severity, and frequency of suicide-related thoughts and behaviour 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. Safety analysis set included all subjects who took at least 1 dose of investigational product and had at least 1 post-Visit 0 (Week 0) safety assessment in this study.
    End point type
    Primary
    End point timeframe
    Week 5 up to Week 52/Early Termination(ET)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Since this is a single arm study, no statistical analysis was planned.
    End point values
    		 SPD489 + Antidepressant
    Number of subjects analysed
    1559
    Units: subjects
        Positive Suicidal Ideation
    68
        Suicidal Attempt
    4
    No statistical analyses for this end point

    Primary: Change From Baseline in Systolic Blood Pressure at Week 52

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    End point title
    		 Change From Baseline in Systolic Blood Pressure at Week 52 [2]
    End point description
    Baseline was defined as the Augmentation Baseline Visit of the antecedent study (SPD489-209 [2011-003615-28], SPD489-322 [2011-003018-17], and SPD489-323 [2011-003006-25]). Safety Analysis Set. Here n = subjects evaluable at specified time-points.
    End point type
    Primary
    End point timeframe
    Baseline, Week 52/ET
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Since this is a single arm study, no statistical analysis was planned.
    End point values
    		 SPD489 + Antidepressant
    Number of subjects analysed
    1559
    Units: millimeter of mercury (mmHg)
    arithmetic mean (standard deviation)
        Baseline (n = 1559)
    117.6 ± 11.13
        Change at Week 52/ET (n = 1558)
    2.4 ± 10.37
    No statistical analyses for this end point

    Primary: Change From Baseline in Diastolic Blood Pressure at Week 52

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    End point title
    		 Change From Baseline in Diastolic Blood Pressure at Week 52 [3]
    End point description
    Baseline was defined as the Augmentation Baseline Visit of the antecedent study (SPD489-209 [2011-003615-28], SPD489-322 [2011-003018-17], and SPD489-323 [2011-003006-25]). Safety Analysis Set. Here n = subjects evaluable at specified time-points.
    End point type
    Primary
    End point timeframe
    Baseline, Week 52/ET
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Since this is a single arm study, no statistical analysis was planned.
    End point values
    		 SPD489 + Antidepressant
    Number of subjects analysed
    1559
    Units: mmHg
    arithmetic mean (standard deviation)
        Baseline (n = 1559)
    75.4 ± 8.15
        Change at Week 52/ET (n = 1558)
    1.2 ± 7.94
    No statistical analyses for this end point

    Primary: Change From Baseline in Pulse Rate at Week 52

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    End point title
    		 Change From Baseline in Pulse Rate at Week 52 [4]
    End point description
    Baseline was defined as the Augmentation Baseline Visit of the antecedent study (SPD489-209 [2011-003615-28], SPD489-322 [2011-003018-17], and SPD489-323 [2011-003006-25]). Safety Analysis Set. Here n = subjects evaluable at specified time-points.
    End point type
    Primary
    End point timeframe
    Baseline, Week 52/ET
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Since this is a single arm study, no statistical analysis was planned.
    End point values
    		 SPD489 + Antidepressant
    Number of subjects analysed
    1559
    Units: beats per minute(bpm)
    arithmetic mean (standard deviation)
        Baseline (n = 1559)
    72.7 ± 9.9
        Change at Week 52/ET (n = 1558)
    5.2 ± 10.58
    No statistical analyses for this end point

    Secondary: Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Week 52/ET

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    End point title
    		 Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Week 52/ET
    End point description
    Designed to evaluate the extent to which illness symptoms impact a subject's life in 3 areas: work, 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. Baseline was defined as the Augmentation Baseline Visit of the antecedent study (SPD489-209 [2011-003615-28], SPD489-322 [2011-003018-17], and SPD489-323 [2011-003006-25]). Full Analysis Set (FAS) included all subjects in the Safety Analysis Set who had at least 1 clinical experience outcome assessment in the study. Here n = subjects evaluable at specified time-points.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52/ET
    End point values
    		 SPD489 + Antidepressant
    Number of subjects analysed
    1556
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=1548)
    12.7 ± 7.06
        Change at Week 52/ET (n = 1530)
    -4.3 ± 7.77
    No statistical analyses for this end point

    Secondary: Number of Subjects With Improvement on Clinical Global Impressions - Global Improvement (CGI-I)

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    End point title
    		 Number of Subjects With Improvement on Clinical Global Impressions - Global Improvement (CGI-I)
    End point description
    Subjects who did not have Clinical Global Impressions - Severity of Illness (CGI-S) assessed at Week 8 in the antecedent study should not have had CGI-I assessed in this study and were excluded from the summary of CGI-I. CGI-I consists of a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). Improvement includes a score of 1 (very much improved) or 2 (much improved) on the scale. FAS. Here, Number of Subjects Analyzed = subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Week 52/ET
    End point values
    		 SPD489 + Antidepressant
    Number of subjects analysed
    1345
    Units: subjects
        Number of Subjects With Improvement on CGI-I
    1021
    No statistical analyses for this end point

    Secondary: Short Form-12 Health Survey Version 2 (SF-12V2)

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    End point title
    		 Short Form-12 Health Survey Version 2 (SF-12V2)
    End point description
    SF-12V2 is a multi-purpose, 7-item survey that measures 8 domains of health: physical functioning, role limitations due to physical health, bodily pain, general health perceptions, vitality, social functioning, role limitations due to emotional problems, and mental health. It is expressed by two summary measures (Aggregate Physical and Aggregate Mental) for which values can range from 0 to 100. A higher score is indicative of a better health state. FAS. Here, Number of Subjects Analyzed = subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Week 52/ET
    End point values
    		 SPD489 + Antidepressant
    Number of subjects analysed
    1531
    Units: units on a scale
    arithmetic mean (standard deviation)
        Aggregate Physical
    49.1 ± 9.67
        Aggregate Mental
    42.7 ± 11.55
    No statistical analyses for this end point

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

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    End point title
    		 EuroQoL Group 5-Dimension 5-Level Self Report Questionnaire (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. Each dimension is represented by a single item with 5 levels of responses. FAS. Here, Number of Subjects Analyzed = subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Week 52/ET
    End point values
    		 SPD489 + Antidepressant
    Number of subjects analysed
    1537
    Units: subjects
        No problems in walking about
    1193
        Slight problems in walking about
    237
        Moderate problems in walking about
    82
        Severe problems in walking about
    24
        Unable to walk about
    1
    No statistical analyses for this end point

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

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    End point title
    		 EuroQoL Group 5-Dimension 5-Level Self Report Questionnaire (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. Each dimension is represented by a single item with 5 levels of responses. FAS. Here, Number of Subjects Analyzed = subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Week 52/ET
    End point values
    		 SPD489 + Antidepressant
    Number of subjects analysed
    1537
    Units: subjects
        No problems washing or dressing myself
    1304
        Slight problems washing or dressing myself
    174
        Moderate problems washing or dressing myself
    49
        Severe problems washing or dressing myself
    9
        Unable to wash or dress myself
    1
    No statistical analyses for this end point

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

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    End point title
    		 EuroQoL Group 5-Dimension 5-Level Self Report Questionnaire (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. Each dimension is represented by a single item with 5 levels of responses. FAS. Here, Number of Subjects Analyzed = subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Week 52/ET
    End point values
    		 SPD489 + Antidepressant
    Number of subjects analysed
    1537
    Units: subjects
        No problems doing my usual activities
    800
        Slight problems doing my usual activities
    475
        Moderate problems doing my usual activities
    197
        Severe problems doing my usual activities
    55
        Unable to do my usual activities
    10
    No statistical analyses for this end point

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

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    End point title
    		 EuroQoL Group 5-Dimension 5-Level Self Report Questionnaire (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. Each dimension is represented by a single item with 5 levels of responses. FAS. Here, Number of Subjects Analyzed = subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Week 52/ET
    End point values
    		 SPD489 + Antidepressant
    Number of subjects analysed
    1537
    Units: subjects
        No pain or discomfort
    715
        Slight pain or discomfort
    536
        Moderate pain or discomfort
    208
        Severe pain or discomfort
    68
        Extreme pain or discomfort
    10
    No statistical analyses for this end point

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

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    End point title
    		 EuroQoL Group 5-Dimension 5-Level Self Report Questionnaire (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. Each dimension is represented by a single item with 5 levels of responses. FAS. Here, Number of Subjects Analyzed = subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Week 52/ET
    End point values
    		 SPD489 + Antidepressant
    Number of subjects analysed
    1537
    Units: subjects
        Not anxious or depressed
    461
        Slightly anxious or depressed
    687
        Moderately anxious or depressed
    289
        Severely anxious or depressed
    73
        Extremely anxious or depressed
    27
    No statistical analyses for this end point

    Secondary: EuroQoL Group 5-Dimension 5-Level Self Report Questionnaire (EQ-5D-5L): Visual Analog Scale

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    End point title
    		 EuroQoL Group 5-Dimension 5-Level Self Report Questionnaire (EQ-5D-5L): Visual Analog Scale
    End point description
    EQ-5D-5L is one of the most widely used generic index measures of health-related quality of life. EQ-5D-5L Visual Analog Scale score is numbered from 0 to 100, where a score of 100 is the best health a subject can imagine. FAS. Here, Number of Subjects Analyzed = subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Week 52/ET
    End point values
    		 SPD489 + Antidepressant
    Number of subjects analysed
    1537
    Units: units on a scale
        arithmetic mean (standard deviation)
    75.7 ± 18.35
    No statistical analyses for this end point

    Secondary: Quick Inventory of Depressive Symptomatology - Self Report (QIDS-SR)

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    End point title
    		 Quick Inventory of Depressive Symptomatology - Self Report (QIDS-SR)
    End point description
    QIDS-SR is a validated, self-reported rating scale that contains 16 items scored on a scale from 0-3 with total scores ranging from 0 (no depression) to 27 (very severe depression). Lower scores indicate less depression. The QIDS-SR was only assessed in the SPD489-322 antecedent study. The QIDS-SR total score is calculated as the sum of the highest score on any 1 of Items 1-4, Item 5, the highest score on any 1 of Items 6-9, Items 10-14, the highest score on either Item 15 or 16. FAS. Here, Number of Subjects Analyzed = subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Week 52/ET
    End point values
    		 SPD489 + Antidepressant
    Number of subjects analysed
    506
    Units: units on a scale
    arithmetic mean (standard deviation)
        QIDS-SR
    6.9 ± 4.48
    No statistical analyses for this end point

    Secondary: Quality of Life Enjoyment Satisfaction Questionnaire Short Form (Q-LES-Q-SF)

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    End point title
    		 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 which evaluates general subject satisfaction with health, mood, relationships, functioning in daily life, and their treatment. Each item is rated on a 5-point scale from 1 (very poor) to 5 (very good). The total raw score (summary scale score) was calculated by summing item scores 1 to 14 (total raw score range: 14 to 70). Item 15 (satisfaction with medication, raw score range: 1 to 5) and Item 16 (overall satisfaction and contentment; raw score range: 1 to 5) were stand-alone items. For reporting, summary scale, Item 15 and Item 16 raw scores were transformed into percentage maximum possible score which ranged from 0 to 100, where higher scores are indicative of greater enjoyment or satisfaction. FAS. Here, Number of Subjects Analyzed = subjects who were evaluable for this endpoint, n = subjects evaluable for specified categories.
    End point type
    Secondary
    End point timeframe
    Week 52/ET
    End point values
    		 SPD489 + Antidepressant
    Number of subjects analysed
    506
    Units: units on a scale
    arithmetic mean (standard deviation)
        Summary Scale (n = 506)
    61.5 ± 17.22
        Satisfaction with Medication (n = 478)
    68.6 ± 19.66
        Overall Satisfaction and Contentment (n = 506)
    63.2 ± 21.58
    No statistical analyses for this end point

    Secondary: Change From Baseline in Sexual Functioning Questionnaire - 14 Item Scale (CSFQ-14) Total Score at Week 52/ET

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    End point title
    		 Change From Baseline in Sexual Functioning Questionnaire - 14 Item Scale (CSFQ-14) Total Score at Week 52/ET
    End point description
    CSFQ-14 is a 14 item self-report tool that evaluates sexual functioning. Each item is scored on a 5-point Likert scale ranging from 1 (never) to 5 (always) with total scores ranging from 14 to 70. Higher scores reflect better sexual functioning. Baseline was defined as the Augmentation Baseline Visit of the antecedent study (SPD489-209 [2011-003615-28], SPD489-322 [2011-003018-17], and SPD489-323 [2011-003006-25]). FAS. Here, Number of Subjects Analyzed = subjects who were evaluable for this endpoint, n = subjects evaluable for specified categories.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52/ET
    End point values
    		 SPD489 + Antidepressant
    Number of subjects analysed
    508
    Units: units on a scale
    arithmetic mean (standard deviation)
        Male: Baseline (n=167)
    46.6 ± 9.17
        Male: Change at Week 52/ET (n=164)
    1.7 ± 7.16
        Female: Baseline (n=341)
    37.2 ± 9.65
        Female: Change at Week 52/ET (n=330)
    2.8 ± 8.33
    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. FAS. Here, Number of Subjects Analyzed = subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Week 53
    End point values
    		 SPD489 + Antidepressant
    Number of subjects analysed
    1349
    Units: units on a scale
    arithmetic mean (standard deviation)
        ACSA Total Score
    14.3 ± 10.59
    No statistical analyses for this end point

    Secondary: Patient Resource Utilization Questionnaire - Major Depressive Disorder (PRUQ-MDD)

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    End point title
    		 Patient Resource Utilization Questionnaire - Major Depressive Disorder (PRUQ-MDD)
    End point description
    The PRUQ-MDD assessed the long term economic outcomes. It collects utilization of healthcare resources reported by the study subjects. Subjects answered the following questions: 1. Were you hospitalized in the past month, 2. Do you work for pay, 3. If you missed time at work last week, please note all the reasons why, 4. Would you say that the past week was typical, like the rest of the 3 weeks this month, in terms of your working hours, 5. Do you do volunteer work (VW), and 6. If you do not receive money for your work and do not participate in volunteer work, the reason is. Number of subjects with response is reported. FAS. Here, Number of Subjects Analyzed = subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Week 52/ET
    End point values
    		 SPD489 + Antidepressant
    Number of subjects analysed
    482
    Units: subjects
        Hospitalized in Past Month
    4
        Work for Pay
    337
        Reason Missing Work Time: Had a Day Off
    24
        Reason Missing Work Time: Physically Ill
    10
        Reason Missing Work Time: Upset/Depressed/Nervous
    15
        Reason Missing Work Time: Other
    36
        Past Week Was Typical: Yes
    249
        Past Week Was Typical: No, Worked More Hours
    43
        Past Week Was Typical: No, Worked Less Hours
    45
        Volunteer Work
    86
        Reason no Money/VW: Physically Ill
    6
        Reason no Money/VW: Upset/Depressed/Nervous
    30
        Reason no Money/VW: Cannot Find Work
    39
        Reason no Money/VW: Other
    48
        Reason no Money/VW: Not Applicable
    348
    No statistical analyses for this end point

    Secondary: PRUQ-MDD – Number of Days of Resource Utilization

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    End point title
    		 PRUQ-MDD – Number of Days of Resource Utilization
    End point description
    The PRUQ-MDD assessed the long term economic outcomes. It collects utilization of healthcare resources reported by the study subjects. Number of nights in medical/surgical ward, number of nights in ICU, and number of days a subject received home care in the past month are reported. FAS. Here, Number of Subjects Analyzed = subjects who were evaluable for this endpoint, n = subjects evaluable for specified categories.
    End point type
    Secondary
    End point timeframe
    Week 52/ET
    End point values
    		 SPD489 + Antidepressant
    Number of subjects analysed
    482
    Units: days
    arithmetic mean (standard deviation)
        Number of nights in medical/surgical ward (n=4)
    1.3 ± 0.5
        Number of nights in ICU (n=4)
    0 ± 0
        Number of days received home care in past month
    0 ± 0
    No statistical analyses for this end point

    Secondary: PRUQ-MDD – Number of Events (Visit to Health Care Provider/Visit to Hospital Facilities/Number of Times a Test Was Performed)

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    End point title
    		 PRUQ-MDD – Number of Events (Visit to Health Care Provider/Visit to Hospital Facilities/Number of Times a Test Was Performed)
    End point description
    The PRUQ-MDD assessed the long term economic outcomes. It collects utilization of healthcare resources reported by the study subjects. Subjects answered following questions - 1. How many times did you visit the following healthcare providers in the past month: Family doctor/primary care, Non-physician healthcare practitioner (NPHP), Psychiatrist/Psychologist/Counselor (PPC); 2. How many times did you take one of the tests, mentioned below, during the past month: Blood test, CT Scan, X Ray, Renal function, Thyroid function; and 3. How many times did you visit the hospital emergency room (ER), urgent care facility (UCF) or an after-hours clinic (AHC) in the past month. Number of events (visit to health care provider, visit to hospital facilities, number of times a test was performed) are reported. FAS. Here, Number of Subjects Analyzed = subjects who were evaluable for this endpoint, n = subjects evaluable for specified categories.
    End point type
    Secondary
    End point timeframe
    Week 52/ET
    End point values
    		 SPD489 + Antidepressant
    Number of subjects analysed
    482
    Units: events
    arithmetic mean (standard deviation)
        Visit to Family doctor/primary care (n=481)
    0.2 ± 0.58
        Visit to NPHP(n=480)
    0.1 ± 0.43
        Visit to PPC(n=481)
    0.1 ± 0.86
        Test performed: Blood Test (n=480)
    0.2 ± 2.3
        Test performed: CT Scan (n=480)
    0 ± 0.08
        Test performed: X Ray (n=480)
    0 ± 0.2
        Test performed: Renal function (n=480)
    0 ± 0
        Test performed: Thyroid function (n=480)
    0 ± 0.09
        Test performed: Other test (n=479)
    0.1 ± 0.49
        Visit to Hospital ER, UCF or AHC (n=482)
    0 ± 0.23
    No statistical analyses for this end point

    Secondary: PRUQ-MDD – Number of Hours

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    End point title
    		 PRUQ-MDD – Number of Hours
    End point description
    The PRUQ-MDD assessed the long term economic outcomes. It collects utilization of healthcare resources reported by the study subjects. Subjects answered following questions - 1. How many hours do you usually work or would you usually be expected to work (hrs/week); 2. How many hours did you actually work last week; 3. On average, how many hours do you volunteer per week. Number of hours are reported. FAS. Here, Number of Subjects Analyzed = subjects who were evaluable for this endpoint, n = subjects evaluable for specified categories.
    End point type
    Secondary
    End point timeframe
    Week 52/ET
    End point values
    		 SPD489 + Antidepressant
    Number of subjects analysed
    482
    Units: hours
    arithmetic mean (standard deviation)
        Work or usually expect to work (n=337)
    34 ± 11.85
        Actual work (n=337)
    31.2 ± 15.13
        Average volunteer per week (n=86)
    8.6 ± 8.94
    No statistical analyses for this end point

    Secondary: PRUQ-MDD – Effect of Depressive Symptoms

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    End point title
    		 PRUQ-MDD – Effect of Depressive Symptoms
    End point description
    The PRUQ-MDD assessed the long term economic outcomes. It collects utilization of healthcare resources reported by the study subjects. Subjects answered following questions on a 0 to 10 point scale - 1. During past week, how much did depressive symptoms affect work productivity; 2. During past week, how much did depressive symptoms affect regular non-work daily activities. Higher scores indicates more effect of depressive symptoms on work productivity and non-work daily activities. FAS. Here, Number of Subjects Analyzed = subjects who were evaluable for this endpoint, n = subjects evaluable for specified categories
    End point type
    Secondary
    End point timeframe
    Week 52/ET
    End point values
    		 SPD489 + Antidepressant
    Number of subjects analysed
    482
    Units: units on scale
    arithmetic mean (standard deviation)
        Affected work productivity (n= 335)
    2.1 ± 2.37
        Affected regular non work daily activities (n=482)
    2.5 ± 2.43
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Week 53
    Adverse event reporting additional description
    TEAEs were defined as Adverse Events (AEs) that started or deteriorated on or after the date of the first dose of investigational product and no later than 3 days after the last dose of investigational product.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    SPD489 + Antidepressant
    Reporting group description
    		 SPD489 20, 30, 50 or 70 mg once daily orally for 52 weeks along with the assigned background product that subject had received during the antecedent study (antidepressant: either escitalopram oxalate, sertraline hydrochloride [HCl], venlafaxine HCl extended-release, or duloxetine HCl) at a dose consistent with applicable local labeling guidelines.

    Serious adverse events
    		 SPD489 + Antidepressant
    Total subjects affected by serious adverse events
         subjects affected / exposed
    33 / 1559 (2.12%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Angiomyolipoma
         subjects affected / exposed
    1 / 1559 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ovarian fibroma
         subjects affected / exposed
    1 / 1559 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    2 / 1559 (0.13%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 1559 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Non-Cardiac chest pain
         subjects affected / exposed
    2 / 1559 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    1 / 1559 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 1559 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    1 / 1559 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 1559 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumomediastinum
         subjects affected / exposed
    1 / 1559 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 1559 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    2 / 1559 (0.13%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Depressive symptom
         subjects affected / exposed
    1 / 1559 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hallucination, auditory
         subjects affected / exposed
    1 / 1559 (0.06%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Major depression
         subjects affected / exposed
    1 / 1559 (0.06%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    3 / 1559 (0.19%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    1 / 1559 (0.06%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Suicide attempt
         subjects affected / exposed
    3 / 1559 (0.19%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Blood pressure increased
         subjects affected / exposed
    1 / 1559 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Head injury
         subjects affected / exposed
    1 / 1559 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gun shot wound
         subjects affected / exposed
    1 / 1559 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 1559 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 1559 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 1559 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Migraine
         subjects affected / exposed
    1 / 1559 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 1559 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 1559 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Small intestinal obstruction
         subjects affected / exposed
    1 / 1559 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intestinal strangulation
         subjects affected / exposed
    1 / 1559 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 1559 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 1559 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Renal mass
         subjects affected / exposed
    1 / 1559 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal cyst
         subjects affected / exposed
    1 / 1559 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Costochondritis
         subjects affected / exposed
    1 / 1559 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 1559 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    1 / 1559 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 1559 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 1559 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 1559 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 SPD489 + Antidepressant
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    921 / 1559 (59.08%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    91 / 1559 (5.84%)
         occurrences all number
    102
    Headache
         subjects affected / exposed
    241 / 1559 (15.46%)
         occurrences all number
    347
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    80 / 1559 (5.13%)
         occurrences all number
    82
    Feeling jittery
         subjects affected / exposed
    82 / 1559 (5.26%)
         occurrences all number
    89
    Irritability
         subjects affected / exposed
    79 / 1559 (5.07%)
         occurrences all number
    87
    Gastrointestinal disorders
    Dry mouth
         subjects affected / exposed
    212 / 1559 (13.60%)
         occurrences all number
    233
    Nausea
         subjects affected / exposed
    116 / 1559 (7.44%)
         occurrences all number
    132
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    83 / 1559 (5.32%)
         occurrences all number
    94
    Bruxism
         subjects affected / exposed
    89 / 1559 (5.71%)
         occurrences all number
    97
    Insomnia
         subjects affected / exposed
    204 / 1559 (13.09%)
         occurrences all number
    235
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    137 / 1559 (8.79%)
         occurrences all number
    156
    Upper respiratory tract infection
         subjects affected / exposed
    100 / 1559 (6.41%)
         occurrences all number
    117
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    189 / 1559 (12.12%)
         occurrences all number
    210

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Nov 2011
    Specified that the 4 antidepressants (background product) were to be provided by the sponsor. Clarified psychiatric disorders that were exclusionary to study participation. Specified that the systolic and diastolic blood pressure readings were based on an average of 3 readings. Included medications having Central Nervous System (CNS) effects as being exclusionary to study participation. Clarified prior use of investigational product, participation in a previous clinical study, and use of commercial LDX as being exclusionary to study participation. Reduced the duration after the study that a subject was to take contraception from 30 days after the last dose of investigational product to 7 (+2) days. 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. Updated excluded treatments to describe excluded investigational compounds and to add LDX as being an excluded treatment. Expanded permitted concomitant medications during the study to include any medication (not just over the counter medications or antibiotics) not affecting blood pressure, heart rate, or the CNS and that were considered necessary for the subject’s welfare. Specified that background product was to be taken in conjunction with investigational product. Noted which study assessments were to be performed when background product was tapered or investigational product was down-titrated. Noted that investigational product was to be stored based on the temperature range specified on the label. Added that eligible subjects who declined participation were not permitted to enroll in the study at a later date. Updated specific items of interest on the C-SSRS for the investigator to use when evaluating a subject’s suitability to remain in the study. Updated Q-LES-Q-SF version and date.
    15 Nov 2012
    Female subjects must “not have a positive beta-human chorionic gonadotropin (β-hCG)” rather than “must have a negative β-hCG.” Specified that a female subject’s pregnancy was to be reported within 24 hours. Updated to include requirements regarding malignancy and skin cancer history exclusion. Specified that an average QT interval calculated using Fridericia’s formula (QTcF) or QT interval calculated using Bazett’s formula (QTcB) interval greater than (>) 450 millisecond (msec) (males) or >470msec (females) was exclusionary to study participation. Limited use of prohibited medications to “current use” rather than “current use or prior use (during the antecedent study).” Removed the requirement that the investigator contact the contract research organization (CRO) medical monitor prior to withdrawal of the subject from investigational product. Added that, in the opinion of the investigator, changes in physical examination, clinical laboratory, or ECG results precluding treatment with SPD489 would require the subject to discontinue from the study. Specified that subjects requiring a change in MDD treatment prohibited by the protocol were discontinued from the study. Specified intervals for QTcF and QTcB for which a subject would be excluded. The following reasons for discontinuation were added under the category of “other”: – Change in background product for MDD treatment required, Treatment for MDD, or any other condition, by a prohibited medication, Other reasons for discontinuation (must be specified) Added that occasional non-chronic use of sedatives and anxiolytics was permitted. Updated window for Visit 0 (Dose Optimization) study assessments for subjects not entering this study directly from the pre-defined antecedent study. Also specified that these subjects must have signed informed consent prior to these assessments being done.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    11 Feb 2014
    The study was terminated as SPD489 failed to demonstrate a benefit as adjunctive treatment to antidepressants in two Phase 3 studies (SPD489-322 [2011-003018-17] and SPD489-323 [2011-003006-25]) . Termination was not related to any new safety findings.
    -

    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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