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    Clinical Trial Results:
    A Phase 2, Multicenter, Double-blind, Parallel-group, Randomized, Placebo-controlled, Forced-dose Titration, Dose-ranging 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
    		 2011-003615-28
    Trial protocol
    		 GB  
    Global end of trial date
    17 Jan 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Oct 2018
    First version publication date
    25 Mar 2015
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    SPD489-209
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01435759
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Shire Development LLC
    Sponsor organisation address
    725 Chesterbrook Boulevard, Wayne, United States, 19087
    Public contact
    Study Physician, Shire Development LLC, +1 866 842 5335, medinfoglobal@shire.com
    Scientific contact
    Study Physician, Shire Development LLC, +1 866 842 5335, 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
    17 Jan 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Jan 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the dose-response relationship of SPD489 (10, 30, 50, and 70mg) and placebo 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 Montgomery-Asberg Depression Rating Scale (MADRS) total score, using a pre-specified set of candidate dose-response curves.
    Protection of trial subjects
    The study protocol, any protocol amendments, the final approved informed consent document, relevant supporting information, and all types of subject recruitment information were submitted by the investigator to the ethics committee (EC) and approved by the EC and regulatory agency (as appropriate) prior to study initiation. This study was conducted in accordance with International Conference on Harmonisation's principles of 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 used in this study were provided as commercially available (in manageable container counts) by the sponsor. Investigators were responsible for dispensing the assigned background product to each subject at each visit as well as for monitoring drug accountability. The background products used in this study were Escitalopram oxalate (a selective serotonin reuptake inhibitor) and Venlafaxine HCl extended-release (a serotonin-norepinephrine reuptake inhibitor). Background product strengths may have varied based on commercial availability and was managed according to applicable requirements. Subjects either entered the study on 1 of the 2 allowed background products or were assigned 1 of the 2 allowed background products at study entry. For subjects who were assigned a background product at study entry, dosing began at the lowest allowed dose level. All subjects took a single dose of background product on the morning following the Lead-in Baseline Visit (Week 0). The background product was subsequently titrated to a target dose (i.e., the maximum tolerated dose) by the end of the fourth week of treatment (i.e., by Visit 6); dose adjustments of background product were not permitted after Week 4. For all subjects, weekly dose increases were made by the clinician according to the labeled guidelines for their respective background product. If a subject required a dose decrease in their respective background product or if the subject needed to be discontinued from their respective background product, the dose was tapered according to the labeled guidelines; individualized tapering was permitted. Assessments of vital signs (blood pressure, pulse, and respiratory rate), adverse events, and Columbia-Suicide Severity Rating Scale were made in conjunction with dose decreases in background product.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 May 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 1 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 36
    Country: Number of subjects enrolled
    Australia: 19
    Country: Number of subjects enrolled
    Chile: 81
    Country: Number of subjects enrolled
    United States: 1058
    Country: Number of subjects enrolled
    United Kingdom: 3
    Worldwide total number of subjects
    1197
    EEA total number of subjects
    3
    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)
    1191
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 This multicenter study was conducted globally at 76 sites in 5 countries (United States, Argentina, Chile, Australia, and United Kingdom).

    Pre-assignment
    Screening details
    		 Adults (18-65 years of age, inclusive [or age of majority if >18 years of age, as defined by local regulations]) who met all study eligibility criteria including a primary diagnosis of non-psychotic MDD (single or recurrent), as defined by the SCID-CT, that had lasted at least 8 weeks prior to screening were eligible 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

    Arms
    Arm title
    		 Lead-in Antidepressant + Single-blind Placebo
    Arm description
    		 Subjects received unblinded standard antidepressant therapy (either escitalopram oxalate or venlafaxine hydrochloride extended-release titrated to the maximum tolerated dose) plus oral, once daily (QD) placebo (matching SPD489).
    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 capsules QD upon awakening at approximately 07:00 (±2 hours) in conjunction with reference product, for 8 weeks

    Number of subjects in period 1
    		Lead-in Antidepressant + Single-blind Placebo
    Started
    1197
    Completed
    855
    Not completed
    342
         Adverse Event
    40
         Lost to Follow-up
    83
         Not Specified
    119
         Withdrawal by Subject
    74
         Protocol Violation
    16
         Met BP or Pulse Withdrawal Criteria
    10
    Period 2
    Period 2 title
    Double-blind Phase
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor
    Blinding implementation details
    SPD489 was over-encapsulated and appeared identical to matching placebo.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Antidepressant + Single-blind Placebo
    Arm description
    		 Subjects whose depressive symptoms improved but who did not meet the randomization criteria were not randomized and continued to receive unblinded standard antidepressant therapy (either escitalopram oxalate or venlafaxine hydrochloride extended-release titrated to the maximum tolerated dose) plus oral, once daily (QD) single-blind placebo (matching SPD489).
    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 capsules QD upon awakening at approximately 07:00 (±2 hours) in conjunction with reference product, for 8 weeks

    Arm title
    		 Antidepressant + Double-blind Placebo
    Arm description
    		 Subjects received unblinded standard antidepressant therapy (either escitalopram oxalate or venlafaxine hydrochloride extended-release titrated to the maximum tolerated dose) plus oral, QD placebo (matching SPD489).
    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 capsules QD upon awakening at approximately 07:00 (±2 hours) in conjunction with reference product, for 8 weeks

    Arm title
    		 Antidepressant + Double-blind SPD489 10mg
    Arm description
    		 Subjects received unblinded standard antidepressant therapy (either escitalopram oxalate or venlafaxine hydrochloride extended-release titrated to the maximum tolerated dose) plus oral, QD over-encapsulated SPD489 as a 10mg dose.
    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
    One over-encapsulated SPD489 capsule, 10mg, QD upon awakening at approximately 07:00 (±2 hours) in conjunction with reference product, for 8 weeks

    Arm title
    		 Antidepressant + Double-blind SPD489 30mg
    Arm description
    		 Subjects received unblinded standard antidepressant therapy (either escitalopram oxalate or venlafaxine hydrochloride extended-release titrated to the maximum tolerated dose) plus oral, QD over-encapsulated SPD489 as a 30mg dose.
    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
    One over-encapsulated SPD489 capsule, 30mg, QD upon awakening at approximately 07:00 (±2 hours) in conjunction with reference product, for 8 weeks

    Arm title
    		 Antidepressant + Double-blind SPD489 50mg
    Arm description
    		 Subjects received unblinded standard antidepressant therapy (either escitalopram oxalate or venlafaxine hydrochloride extended-release titrated to the maximum tolerated dose) plus oral, QD over-encapsulated SPD489 as a 50mg dose.
    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
    One over-encapsulated SPD489 capsule, 50mg, QD upon awakening at approximately 07:00 (±2 hours) in conjunction with reference product, for 8 weeks

    Arm title
    		 Antidepressant + Double-blind SPD489 70mg
    Arm description
    		 Subjects received unblinded standard antidepressant therapy (either escitalopram oxalate or venlafaxine hydrochloride extended-release titrated to the maximum tolerated dose) plus oral, QD over-encapsulated SPD489 as a 70mg dose.
    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
    One over-encapsulated SPD489 capsule, 70mg, QD upon awakening at approximately 07:00 (±2 hours) in conjunction with reference product, for 8 weeks

    Number of subjects in period 2
    		Antidepressant + Single-blind Placebo Antidepressant + Double-blind Placebo Antidepressant + Double-blind SPD489 10mg Antidepressant + Double-blind SPD489 30mg Antidepressant + Double-blind SPD489 50mg Antidepressant + Double-blind SPD489 70mg
    Started
    463
    78
    78
    78
    78
    80
    Completed
    397
    71
    71
    69
    69
    71
    Not completed
    66
    7
    7
    9
    9
    9
         Adverse Event
    7
    -
    1
    1
    1
    3
         Lost to Follow-up
    31
    1
    2
    -
    3
    3
         Not Specified
    8
    2
    -
    2
    -
    -
         Withdrawal by Subject
    17
    4
    3
    4
    2
    2
         Protocol Violation
    2
    -
    1
    2
    -
    1
         Met BP or Pulse Withdrawal Criteria
    1
    -
    -
    -
    3
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lead-in Antidepressant + Single-blind Placebo
    Reporting group description
    		 Subjects received unblinded standard antidepressant therapy (either escitalopram oxalate or venlafaxine hydrochloride extended-release titrated to the maximum tolerated dose) plus oral, once daily (QD) placebo (matching SPD489).

    Reporting group values
    		 Lead-in Antidepressant + Single-blind Placebo Total
    Number of subjects
    		 1197 1197
    Age categorical
    Units: Subjects
        18-55 years
    		 1053 1053
        56-65 years
    		 144 144
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 40.6 ± 11.81 -
    Gender categorical
    Units: Subjects
        Female
    		 790 790
        Male
    		 407 407
    Region of Enrollment
    Units: Subjects
        United States
    		 1058 1058
        United Kingdom
    		 3 3
        Chile
    		 81 81
        Argentina
    		 36 36
        Australia
    		 19 19

    End points

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    End points reporting groups
    Reporting group title
    Lead-in Antidepressant + Single-blind Placebo
    Reporting group description
    		 Subjects received unblinded standard antidepressant therapy (either escitalopram oxalate or venlafaxine hydrochloride extended-release titrated to the maximum tolerated dose) plus oral, once daily (QD) placebo (matching SPD489).
    Reporting group title
    Antidepressant + Single-blind Placebo
    Reporting group description
    		 Subjects whose depressive symptoms improved but who did not meet the randomization criteria were not randomized and continued to receive unblinded standard antidepressant therapy (either escitalopram oxalate or venlafaxine hydrochloride extended-release titrated to the maximum tolerated dose) plus oral, once daily (QD) single-blind placebo (matching SPD489).

    Reporting group title
    Antidepressant + Double-blind Placebo
    Reporting group description
    		 Subjects received unblinded standard antidepressant therapy (either escitalopram oxalate or venlafaxine hydrochloride extended-release titrated to the maximum tolerated dose) plus oral, QD placebo (matching SPD489).

    Reporting group title
    Antidepressant + Double-blind SPD489 10mg
    Reporting group description
    		 Subjects received unblinded standard antidepressant therapy (either escitalopram oxalate or venlafaxine hydrochloride extended-release titrated to the maximum tolerated dose) plus oral, QD over-encapsulated SPD489 as a 10mg dose.

    Reporting group title
    Antidepressant + Double-blind SPD489 30mg
    Reporting group description
    		 Subjects received unblinded standard antidepressant therapy (either escitalopram oxalate or venlafaxine hydrochloride extended-release titrated to the maximum tolerated dose) plus oral, QD over-encapsulated SPD489 as a 30mg dose.

    Reporting group title
    Antidepressant + Double-blind SPD489 50mg
    Reporting group description
    		 Subjects received unblinded standard antidepressant therapy (either escitalopram oxalate or venlafaxine hydrochloride extended-release titrated to the maximum tolerated dose) plus oral, QD over-encapsulated SPD489 as a 50mg dose.

    Reporting group title
    Antidepressant + Double-blind SPD489 70mg
    Reporting group description
    		 Subjects received unblinded standard antidepressant therapy (either escitalopram oxalate or venlafaxine hydrochloride extended-release titrated to the maximum tolerated dose) plus oral, QD over-encapsulated SPD489 as a 70mg dose.

    Primary: Change in Montgomery-Ǻsberg Depression Rating Scale (MADRS) Total Score From Augmentation Baseline (Week 8) to Week 16 (Double-blind Phase, Dose Response Evaluable Set)

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    End point title
    		 Change in Montgomery-Ǻsberg Depression Rating Scale (MADRS) Total Score From Augmentation Baseline (Week 8) to Week 16 (Double-blind Phase, Dose Response Evaluable Set)
    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. Change in MADRS total score in Augmentsion Baseline to Week 16. This end point used the Dose Response Evaluable Set (DRES), which included all randomized subjects who had at least 1 valid primary efficacy measurement (MADRS total score) during the Dose Maintenance Period (Weeks 11-16) while on the target dose level of investigational product.
    End point type
    Primary
    End point timeframe
    Augmentation baseline (Week 8) to Week 16
    End point values
    		 Antidepressant + Double-blind Placebo Antidepressant + Double-blind SPD489 10mg Antidepressant + Double-blind SPD489 30mg Antidepressant + Double-blind SPD489 50mg Antidepressant + Double-blind SPD489 70mg
    Number of subjects analysed
    72
    71
    69
    66
    71
    Units: units on a scale
        least squares mean (confidence interval 90%)
    -5.4 (-7.2 to -3.5)
    -6.7 (-8.6 to -4.9)
    -5.3 (-7.1 to -3.4)
    -6.1 (-8.1 to -4.1)
    -6.3 (-8.2 to -4.4)
    Statistical analysis title
    		 Dose Response Analysis-MADRS
    Statistical analysis description
    Analysis of Dose Response Using the MCP-Mod Analysis Method
    Comparison groups
    Antidepressant + Double-blind SPD489 10mg v Antidepressant + Double-blind SPD489 30mg v Antidepressant + Double-blind SPD489 50mg v Antidepressant + Double-blind SPD489 70mg v Antidepressant + Double-blind Placebo
    Number of subjects included in analysis
    349
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 1 [2]
    Method
    		 MCP-Mod Analysis Method
    Confidence interval
    Notes
    [1] - For the method of estimation, the t-statistic used for this analysis, 0.10, was based on MCP-Mod Analysis from the linear contrast using optimal coefficients for the pre-specified candidate model Betamod.
    [2] - The adjusted p-value was based on a critical value of 2.02 from a multivariate-t distribution with 341 degrees of freedom. Any p-value <=0.10 indicates successful establishment of dose-response relationship.
    Statistical analysis title
    		 Dose Response Analysis-MADRS #2
    Statistical analysis description
    Analysis of Dose Response Using the MCP-Mod Analysis Method
    Comparison groups
    Antidepressant + Double-blind SPD489 30mg v Antidepressant + Double-blind SPD489 70mg v Antidepressant + Double-blind SPD489 50mg v Antidepressant + Double-blind SPD489 10mg v Antidepressant + Double-blind Placebo
    Number of subjects included in analysis
    349
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.942 [4]
    Method
    		 MCP-Mod Analysis
    Confidence interval
    Notes
    [3] - For the method of estimation, the t-statistic used for this analysis, 0.41, was based on MCP-Mod Analysis from the linear contrast using optimal coefficients for the pre-specified candidate model Emax.
    [4] - The adjusted p-value is based on a critical value of 2.02 from a multivariate-t distribution with 341 degrees of freedom. Any p-value <=0.10 indicates successful establishment of dose-response relationship.
    Statistical analysis title
    		 Dose Response Analysis-MADRS #3
    Statistical analysis description
    Analysis of Dose Response Using the MCP-Mod Analysis Method
    Comparison groups
    Antidepressant + Double-blind SPD489 10mg v Antidepressant + Double-blind SPD489 30mg v Antidepressant + Double-blind SPD489 50mg v Antidepressant + Double-blind SPD489 70mg v Antidepressant + Double-blind Placebo
    Number of subjects included in analysis
    349
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.995 [6]
    Method
    		 MCP-Mod Analysis
    Confidence interval
    Notes
    [5] - For the method of estimation, the t-statistic used for this analysis, 0.20, was based on MCP-Mod Analysis from the linear contrast using optimal coefficients for the pre-specified candidate model Linear.
    [6] - The adjusted p-value is based on a critical value of 2.02 from a multivariate-t distribution with 341 degrees of freedom. Any p-value <=0.10 indicates successful establishment of dose-response relationship.
    Statistical analysis title
    		 Dose Response Analysis-MADRS #4
    Statistical analysis description
    Analysis of Dose Response Using the MCP-Mod Analysis Method
    Comparison groups
    Antidepressant + Double-blind SPD489 10mg v Antidepressant + Double-blind SPD489 30mg v Antidepressant + Double-blind SPD489 50mg v Antidepressant + Double-blind SPD489 70mg v Antidepressant + Double-blind Placebo
    Number of subjects included in analysis
    349
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 = 0.978 [8]
    Method
    		 MCP-Mod Analysis
    Confidence interval
    Notes
    [7] - For the method of estimation, the t-statistic used for this analysis, 0.30, was based on MCP-Mod Analysis from the linear contrast using optimal coefficients for the pre-specified candidate model Logistic.
    [8] - The adjusted p-value is based on a critical value of 2.02 from a multivariate-t distribution with 341 degrees of freedom. Any p-value <=0.10 indicates successful establishment of dose-response relationship.

    Secondary: Change in Average Systolic Blood Pressure From Augmentation Baseline (Week 8) to Week 16

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    End point title
    		 Change in Average Systolic Blood Pressure From Augmentation Baseline (Week 8) to Week 16
    End point description
    This end point used the Vital Signs Evaluable Set, which included all randomized subjects who had at least 1 valid vital signs measurement during the Dose Maintenance Period while on the target dose level of investigational product.
    End point type
    Secondary
    End point timeframe
    From Augmentation Baseline (Week 8) to Week 16
    End point values
    		 Antidepressant + Double-blind Placebo Antidepressant + Double-blind SPD489 10mg Antidepressant + Double-blind SPD489 30mg Antidepressant + Double-blind SPD489 50mg Antidepressant + Double-blind SPD489 70mg
    Number of subjects analysed
    67
    68
    65
    51
    63
    Units: mmHg
        arithmetic mean (standard deviation)
    -0.2 ± 9.55
    0.2 ± 8.58
    0.5 ± 9.17
    3.5 ± 7.82
    2.6 ± 10.55
    Statistical analysis title
    		 Dose Response Analysis-Systolic Blood Pressure
    Statistical analysis description
    Analysis of Dose Response Using the MCP-Mod Analysis Method
    Comparison groups
    Antidepressant + Double-blind Placebo v Antidepressant + Double-blind SPD489 10mg v Antidepressant + Double-blind SPD489 30mg v Antidepressant + Double-blind SPD489 50mg v Antidepressant + Double-blind SPD489 70mg
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 = 0.004 [10]
    Method
    		 MCP-Mod Analysis
    Confidence interval
    Notes
    [9] - For the method of estimation, the t-statistic used for this analysis, 3.14, was based on MCP-Mod Analysis for the candidate model EMax.
    [10] - The systolic blood pressure p-value was based on a critical value of 1.99 from a multivariate-t distribution with 341 degrees of freedom.
    Statistical analysis title
    		 Dose Response Analysis-Systolic Blood Pressure #2
    Statistical analysis description
    Analysis of Dose Response Using the MCP-Mod Analysis Method
    Comparison groups
    Antidepressant + Double-blind Placebo v Antidepressant + Double-blind SPD489 10mg v Antidepressant + Double-blind SPD489 30mg v Antidepressant + Double-blind SPD489 50mg v Antidepressant + Double-blind SPD489 70mg
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    P-value
    		 = 0.032 [12]
    Method
    		 MCP-Mod Analysis
    Confidence interval
    Notes
    [11] - For the method of estimation, the t-statistic used for this analysis, 2.48, was based on MCP-Mod Analysis for the candidate model Exponential.
    [12] - The systolic blood pressure p-value was based on a critical value of 1.99 from a multivariate-t distribution with 341 degrees of freedom.
    Statistical analysis title
    		 Dose Response Analysis-Systolic Blood Pressure #3
    Statistical analysis description
    Analysis of Dose Response Using the MCP-Mod Analysis Method
    Comparison groups
    Antidepressant + Double-blind Placebo v Antidepressant + Double-blind SPD489 10mg v Antidepressant + Double-blind SPD489 30mg v Antidepressant + Double-blind SPD489 50mg v Antidepressant + Double-blind SPD489 70mg
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 other [13]
    P-value
    		 = 0.003 [14]
    Method
    		 MCP-Mod Analysis
    Confidence interval
    Notes
    [13] - For the method of estimation, the t-statistic used for this analysis, 3.26 was based on MCP-Mod Analysis for the candidate model Linear.
    [14] - The systolic blood pressure p-value was based on a critical value of 1.99 from a multivariate-t distribution with 341 degrees of freedom.
    Statistical analysis title
    		 Dose Response Analysis-Systolic Blood Pressure #4
    Statistical analysis description
    Analysis of Dose Response Using the MCP-Mod Analysis Method
    Comparison groups
    Antidepressant + Double-blind Placebo v Antidepressant + Double-blind SPD489 10mg v Antidepressant + Double-blind SPD489 30mg v Antidepressant + Double-blind SPD489 50mg v Antidepressant + Double-blind SPD489 70mg
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 other [15]
    P-value
    		 = 0.01 [16]
    Method
    		 MCP-Mod Analysis
    Confidence interval
    Notes
    [15] - For the method of estimation, the t-statistic used for this analysis, 2.88, was based on MCP-Mod Analysis for the candidate model Logistic1.
    [16] - The systolic blood pressure p-value was based on a critical value of 1.99 from a multivariate-t distribution with 341 degrees of freedom
    Statistical analysis title
    		 Dose Response Analysis-Systolic Blood Pressure #5
    Statistical analysis description
    Analysis of Dose Response Using the MCP-Mod Analysis Method
    Comparison groups
    Antidepressant + Double-blind Placebo v Antidepressant + Double-blind SPD489 10mg v Antidepressant + Double-blind SPD489 30mg v Antidepressant + Double-blind SPD489 50mg v Antidepressant + Double-blind SPD489 70mg
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 other [17]
    P-value
    		 = 0.005 [18]
    Method
    		 MCP-Mod Analysis
    Confidence interval
    Notes
    [17] - For the method of estimation, the t-statistic used for this analysis, 3.12, was based on MCP-Mod Analysis for the candidate model Logistic2.
    [18] - The systolic blood pressure p-value was based on a critical value of 1.99 from a multivariate-t distribution with 341 degrees of freedom.

    Secondary: Change in Average Diastolic Blood Pressure From Augmentation Baseline (Week 8) to Week 16

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    End point title
    		 Change in Average Diastolic Blood Pressure From Augmentation Baseline (Week 8) to Week 16
    End point description
    This endpoint used the Vital Signs Evaluable Set, which included all randomized subjects who had at least 1 valid vital signs measurement during the Dose Maintenance Period while on the target dose level of investigational product.
    End point type
    Secondary
    End point timeframe
    From Augmentation Baseline (Week 8) to Week 16
    End point values
    		 Antidepressant + Double-blind Placebo Antidepressant + Double-blind SPD489 10mg Antidepressant + Double-blind SPD489 30mg Antidepressant + Double-blind SPD489 50mg Antidepressant + Double-blind SPD489 70mg
    Number of subjects analysed
    67
    68
    65
    51
    63
    Units: mmHg
        arithmetic mean (standard deviation)
    -0.1 ± 6.69
    -0.9 ± 6.64
    -0.1 ± 7.39
    2.8 ± 6.58
    1.9 ± 7.45
    Statistical analysis title
    		 Dose Response Analysis-Diastolic Blood Pressure
    Statistical analysis description
    Analysis of Dose Response Using the MCP-Mod Analysis Method
    Comparison groups
    Antidepressant + Double-blind Placebo v Antidepressant + Double-blind SPD489 10mg v Antidepressant + Double-blind SPD489 30mg v Antidepressant + Double-blind SPD489 50mg v Antidepressant + Double-blind SPD489 70mg
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 other [19]
    P-value
    		 = 0.011 [20]
    Method
    		 MCP-Mod Analysis
    Confidence interval
    Notes
    [19] - For the method of estimation, the t-statistic used for this analysis, 2.86 was based on MCP-Mod Analysis for the candidate model Emax
    [20] - The diastolic blood pressure p-value was based on a critical value of 1.99 from a multivariate-t distribution with 341 degrees of freedom.
    Statistical analysis title
    		 Dose Response Analysis-Diastolic Blood Pressure #2
    Statistical analysis description
    Analysis of Dose Response Using the MCP-Mod Analysis Method
    Comparison groups
    Antidepressant + Double-blind Placebo v Antidepressant + Double-blind SPD489 10mg v Antidepressant + Double-blind SPD489 30mg v Antidepressant + Double-blind SPD489 50mg v Antidepressant + Double-blind SPD489 70mg
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 other [21]
    P-value
    		 = 0.023 [22]
    Method
    		 MCP-Mod Analysis
    Confidence interval
    Notes
    [21] - For the method of estimation, the t-statistic used for this analysis, 2.59, was based on MCP-Mod Analysis for the candidate model Exponential.
    [22] - The diastolic blood pressure p-value was based on a critical value of 1.99 from a multivariate-t distribution with 341 degrees of freedom.
    Statistical analysis title
    		 Dose Response Analysis-Diastolic Blood Pressure #3
    Statistical analysis description
    Analysis of Dose Response Using the MCP-Mod Analysis Method
    Comparison groups
    Antidepressant + Double-blind Placebo v Antidepressant + Double-blind SPD489 10mg v Antidepressant + Double-blind SPD489 30mg v Antidepressant + Double-blind SPD489 50mg v Antidepressant + Double-blind SPD489 70mg
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 other [23]
    P-value
    		 = 0.003 [24]
    Method
    		 MCP-Mod Analysis
    Confidence interval
    Notes
    [23] - For the method of estimation, the t-statistic used for this analysis, 3.28, was based on MCP-Mod Analysis for the candidate model Linear.
    [24] - The diastolic blood pressure p-value was based on a critical value of 1.99 from a multivariate-t distribution with 341 degrees of freedom.
    Statistical analysis title
    		 Dose Response Analysis-Diastolic Blood Pressure #4
    Statistical analysis description
    Analysis of Dose Response Using the MCP-Mod Analysis Method
    Comparison groups
    Antidepressant + Double-blind Placebo v Antidepressant + Double-blind SPD489 10mg v Antidepressant + Double-blind SPD489 30mg v Antidepressant + Double-blind SPD489 50mg v Antidepressant + Double-blind SPD489 70mg
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 other [25]
    P-value
    		 = 0.009 [26]
    Method
    		 MCP-Mod Analysis
    Confidence interval
    Notes
    [25] - For the method of estimation, the t-statistic used for this analysis, 2.93, was based on MCP-Mod Analysis for the candidate model Logistic1.
    [26] - The diastolic blood pressure p-value was based on a critical value of 1.99 from a multivariate-t distribution with 341 degrees of freedom.
    Statistical analysis title
    		 Dose Response Analysis-Diastolic Blood Pressure #5
    Statistical analysis description
    Analysis of Dose Response Using the MCP-Mod Analysis Method
    Comparison groups
    Antidepressant + Double-blind Placebo v Antidepressant + Double-blind SPD489 10mg v Antidepressant + Double-blind SPD489 30mg v Antidepressant + Double-blind SPD489 50mg v Antidepressant + Double-blind SPD489 70mg
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 other [27]
    P-value
    		 = 0.005 [28]
    Method
    		 MCP-Mod Analysis
    Confidence interval
    Notes
    [27] - For the method of estimation, the t-statistic used for this analysis, 3.13, was based on MCP-Mod Analysis for the candidate model Logistic2.
    [28] - The diastolic blood pressure p-value was based on a critical value of 1.99 from a multivariate-t distribution with 341 degrees of freedom.

    Secondary: Change in Average Pulse Rate From Augmentation Baseline (Week 8) to Week 16

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    End point title
    		 Change in Average Pulse Rate From Augmentation Baseline (Week 8) to Week 16
    End point description
    This end point used the Vital Signs Evaluable Set, which included all randomized subjects who had at least 1 valid vital signs measurement during the Dose Maintenance Period while on the target dose level of investigational product.
    End point type
    Secondary
    End point timeframe
    From Augmentation Baseline (Week 8) to Week 16
    End point values
    		 Antidepressant + Double-blind Placebo Antidepressant + Double-blind SPD489 10mg Antidepressant + Double-blind SPD489 30mg Antidepressant + Double-blind SPD489 50mg Antidepressant + Double-blind SPD489 70mg
    Number of subjects analysed
    67
    68
    65
    51
    63
    Units: bpm
        arithmetic mean (standard deviation)
    -0.8 ± 9.95
    0.8 ± 7.32
    5.3 ± 8.08
    4 ± 9.8
    6 ± 11.25
    Statistical analysis title
    		 Dose Response Analysis-Pulse
    Statistical analysis description
    Analysis of Dose Response Using the MCP-Mod Analysis Method
    Comparison groups
    Antidepressant + Double-blind Placebo v Antidepressant + Double-blind SPD489 10mg v Antidepressant + Double-blind SPD489 30mg v Antidepressant + Double-blind SPD489 50mg v Antidepressant + Double-blind SPD489 70mg
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 other [29]
    P-value
    		 < 0.001 [30]
    Method
    		 MCP-Mod Analysis
    Confidence interval
    Notes
    [29] - For the method of estimation, the t-statistic used for this analysis, 4.24, was based on MCP-Mod Analysis for the candidate model Emax
    [30] - The pulse p-value was based on a critical value of 1.99 from a multivariate-t distribution with 341 degrees of freedom.
    Statistical analysis title
    		 Dose Response Analysis-Pulse #2
    Statistical analysis description
    Analysis of Dose Response Using the MCP-Mod Analysis Method
    Comparison groups
    Antidepressant + Double-blind Placebo v Antidepressant + Double-blind SPD489 10mg v Antidepressant + Double-blind SPD489 30mg v Antidepressant + Double-blind SPD489 50mg v Antidepressant + Double-blind SPD489 70mg
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 other [31]
    P-value
    		 = 0.002 [32]
    Method
    		 MCP-Mod Analysis
    Confidence interval
    Notes
    [31] - For the method of estimation, the t-statistic used for this analysis, 3.36, was based on MCP-Mod Analysis for the candidate model Expontential.
    [32] - The pulse p-value was based on a critical value of 1.99 from a multivariate-t distribution with 341 degrees of freedom.
    Statistical analysis title
    		 Dose Response Analysis-Pulse #3
    Statistical analysis description
    Analysis of Dose Response Using the MCP-Mod Analysis Method
    Comparison groups
    Antidepressant + Double-blind Placebo v Antidepressant + Double-blind SPD489 10mg v Antidepressant + Double-blind SPD489 30mg v Antidepressant + Double-blind SPD489 50mg v Antidepressant + Double-blind SPD489 70mg
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 other [33]
    P-value
    		 < 0.001 [34]
    Method
    		 MCP-Mod Analysis
    Confidence interval
    Notes
    [33] - For the method of estimation, the t-statistic used for this analysis, 4.10, was based on MCP-Mod Analysis for the candidate model Linear.
    [34] - The pulse p-value was based on a critical value of 1.99 from a multivariate-t distribution with 341 degrees of freedom.
    Statistical analysis title
    		 Dose Response Analysis-Pulse #4
    Statistical analysis description
    Analysis of Dose Response Using the MCP-Mod Analysis Method
    Comparison groups
    Antidepressant + Double-blind Placebo v Antidepressant + Double-blind SPD489 10mg v Antidepressant + Double-blind SPD489 30mg v Antidepressant + Double-blind SPD489 50mg v Antidepressant + Double-blind SPD489 70mg
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 other [35]
    P-value
    		 < 0.001 [36]
    Method
    		 MCP-Mod Analysis
    Confidence interval
    Notes
    [35] - For the method of estimation, the t-statistic used for this analysis, 4.39, was based on MCP-Mod Analysis for the candidate model Logistic1.
    [36] - The pulse p-value was based on a critical value of 1.99 from a multivariate-t distribution with 341 degrees of freedom.
    Statistical analysis title
    		 Dose Response Analysis-Pulse #5
    Statistical analysis description
    Analysis of Dose Response Using the MCP-Mod Analysis Method
    Comparison groups
    Antidepressant + Double-blind Placebo v Antidepressant + Double-blind SPD489 10mg v Antidepressant + Double-blind SPD489 30mg v Antidepressant + Double-blind SPD489 50mg v Antidepressant + Double-blind SPD489 70mg
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 other [37]
    P-value
    		 < 0.001 [38]
    Method
    		 MCP-Mod Analysis
    Confidence interval
    Notes
    [37] - For the method of estimation, the t-statistic used for this analysis, 4.39 was based on MCP-Mod Analysis for the candidate model Logistic2.
    [38] - The pulse p-value was based on a critical value of 1.99 from a multivariate-t distribution with 341 degrees of freedom.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 21 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 unblinded standard antidepressant therapy (either escitalopram oxalate or venlafaxine hydrochloride extended-release titrated to the maximum tolerated dose) plus oral, once daily double-blind placebo (matching SPD489).

    Reporting group title
    Antidepressant + Double-blind SPD489 10mg
    Reporting group description
    		 Subjects received unblinded standard antidepressant therapy (either escitalopram oxalate or venlafaxine hydrochloride extended-release titrated to the maximum tolerated dose) plus oral, once daily over-encapsulated SPD489 as a 10mg dose.

    Reporting group title
    Antidepressant + Double-blind SPD489 30mg
    Reporting group description
    		 Subjects received unblinded standard antidepressant therapy (either escitalopram oxalate or venlafaxine hydrochloride extended-release titrated to the maximum tolerated dose) plus oral, once daily over-encapsulated SPD489 as a 30mg dose.

    Reporting group title
    Antidepressant + Double-blind SPD489 50mg
    Reporting group description
    		 Subjects received unblinded standard antidepressant therapy (either escitalopram oxalate or venlafaxine hydrochloride extended-release titrated to the maximum tolerated dose) plus oral, once daily over-encapsulated SPD489 as a 50mg dose.

    Reporting group title
    Antidepressant + Double-blind SPD489 70mg
    Reporting group description
    		 Subjects received unblinded standard antidepressant therapy (either escitalopram oxalate or venlafaxine hydrochloride extended-release titrated to the maximum tolerated dose) plus oral, once daily over-encapsulated SPD489 as a 70mg dose.

    Serious adverse events
    		 Antidepressant + Double-blind Placebo Antidepressant + Double-blind SPD489 10mg Antidepressant + Double-blind SPD489 30mg Antidepressant + Double-blind SPD489 50mg Antidepressant + Double-blind SPD489 70mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    1 / 80 (1.25%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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 10mg Antidepressant + Double-blind SPD489 30mg Antidepressant + Double-blind SPD489 50mg Antidepressant + Double-blind SPD489 70mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 78 (25.64%)
    30 / 77 (38.96%)
    29 / 76 (38.16%)
    36 / 78 (46.15%)
    44 / 80 (55.00%)
    Investigations
    Blood pressure increased
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 77 (1.30%)
    0 / 76 (0.00%)
    3 / 78 (3.85%)
    4 / 80 (5.00%)
         occurrences all number
    0
    1
    0
    3
    4
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 78 (2.56%)
    2 / 77 (2.60%)
    2 / 76 (2.63%)
    5 / 78 (6.41%)
    1 / 80 (1.25%)
         occurrences all number
    2
    2
    2
    5
    1
    Headache
         subjects affected / exposed
    10 / 78 (12.82%)
    7 / 77 (9.09%)
    5 / 76 (6.58%)
    3 / 78 (3.85%)
    8 / 80 (10.00%)
         occurrences all number
    12
    8
    9
    5
    9
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 77 (0.00%)
    2 / 76 (2.63%)
    1 / 78 (1.28%)
    4 / 80 (5.00%)
         occurrences all number
    1
    0
    2
    1
    4
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    4 / 78 (5.13%)
    2 / 77 (2.60%)
    3 / 76 (3.95%)
    2 / 78 (2.56%)
    5 / 80 (6.25%)
         occurrences all number
    5
    2
    3
    2
    5
    Dry mouth
         subjects affected / exposed
    1 / 78 (1.28%)
    2 / 77 (2.60%)
    2 / 76 (2.63%)
    10 / 78 (12.82%)
    10 / 80 (12.50%)
         occurrences all number
    1
    2
    2
    10
    10
    Nausea
         subjects affected / exposed
    1 / 78 (1.28%)
    5 / 77 (6.49%)
    6 / 76 (7.89%)
    1 / 78 (1.28%)
    6 / 80 (7.50%)
         occurrences all number
    1
    5
    6
    1
    7
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    1 / 78 (1.28%)
    4 / 77 (5.19%)
    0 / 76 (0.00%)
    1 / 78 (1.28%)
    3 / 80 (3.75%)
         occurrences all number
    1
    4
    0
    1
    3
    Psychiatric disorders
    Bruxism
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 77 (0.00%)
    1 / 76 (1.32%)
    4 / 78 (5.13%)
    6 / 80 (7.50%)
         occurrences all number
    1
    0
    1
    4
    7
    Insomnia
         subjects affected / exposed
    2 / 78 (2.56%)
    7 / 77 (9.09%)
    2 / 76 (2.63%)
    8 / 78 (10.26%)
    9 / 80 (11.25%)
         occurrences all number
    2
    9
    2
    10
    11
    Infections and infestations
    Influenza
         subjects affected / exposed
    2 / 78 (2.56%)
    1 / 77 (1.30%)
    4 / 76 (5.26%)
    4 / 78 (5.13%)
    1 / 80 (1.25%)
         occurrences all number
    3
    1
    4
    5
    1
    Nasopharyngitis
         subjects affected / exposed
    0 / 78 (0.00%)
    5 / 77 (6.49%)
    4 / 76 (5.26%)
    2 / 78 (2.56%)
    7 / 80 (8.75%)
         occurrences all number
    0
    5
    5
    2
    8
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 78 (0.00%)
    3 / 77 (3.90%)
    3 / 76 (3.95%)
    4 / 78 (5.13%)
    3 / 80 (3.75%)
         occurrences all number
    0
    3
    3
    4
    3
    Urinary tract infection
         subjects affected / exposed
    5 / 78 (6.41%)
    1 / 77 (1.30%)
    2 / 76 (2.63%)
    1 / 78 (1.28%)
    2 / 80 (2.50%)
         occurrences all number
    5
    1
    2
    1
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 78 (1.28%)
    4 / 77 (5.19%)
    5 / 76 (6.58%)
    5 / 78 (6.41%)
    4 / 80 (5.00%)
         occurrences all number
    1
    4
    6
    5
    6

    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
    • Updated emergency contact information • Removed the Probabilistic Reward Task • Specified that the 2 antidepressants were “as provided by the sponsor” • Revised exclusion criteria • Clarified that subjects with no improvement in or a worsening of depressive symptoms at Visit 8 were to be discontinued and that average readings were to be used when referring to the management of blood pressure and pulse • Reduced the requirement for post-study contraception • Updated withdrawal criteria with respect to additional vital signs collected at Visits 8, 10, 12, and 14 • Added commercial lisdexamfetamine dimesylate as being excluded • Clarified that medications not affecting blood pressure, heart rate, or the CNS, and necessary for the subject’s welfare were not restricted • Specified assessments to be conducted if background product was tapered • Defined target dose of background product and re-dispensing procedures for background products and investigational product • Clarified assessments to be carried out if down-titration of investigational product occurred and that for subjects who discontinued early, the Visit 14 procedures would be performed and dosing • Qualified that subjects “whose depressive symptoms have improved based on MADRS total score, but” who did not meet randomization criteria at Visit 8 were allowed to continue receiving placebo • Specified that Visit 8 is the beginning of the Forced-dose Titration Period • Increased duration of Forced-dose Titration Period • Added a collection of additional vital signs measurements at specified visits • Revised language to include necessary tapering of background product for subjects who terminated early or who completed but did not enter the long-term safety study • Clarified pharmacokinetic sample collection and processing procedures • Updated criteria on the C-SSRS for evaluating suitability to remain in the study • Updated the MADRS version and date and language on product storage
    01 Oct 2012
    • Increased the number of screened subjects • Increased the number of planned sites • Clarified the use of background product containers • Specified that any down titration of antidepressant should be managed by the investigator • Changed the level of significance for “other” efficacy assessments from a 0.05 to a 0.10 level and 95% CI coverage to 90%. • Added 2 exploratory objectives to summarize efficacy of SPD489 • Revised exclusion criteria • Added the CGI-I and CGI-S as efficacy assessments • Clarified that clinical laboratory tests and ECGs were to be repeated prior to Visit 2 and the results verified before enrollment. • Removed the suggestion for the investigator to contact the CRO medical monitor prior to subject withdrawal • Specified that, in determining whether a subject should be discontinued from study, the investigator was to consult with the CRO medical monitor. • Added that contraceptive requirements were to be reviewed with subjects at all visits • Added that a subject who required a change to their MDD treatment that was prohibited by the protocol must be discontinued from the study • The following reasons for discontinuation were added under the category of Other: _ Change in background product for MDD treatment required _ Treatment for MDD by a prohibited medication required _ Other reasons for discontinuation (must be specified) • Specified that the investigator was to contact the CRO medical monitor as soon as possible after becoming unblinded • Removed the requirement to report in the IV/WRS any investigational or background product that had been damaged after a temperature excursion and the requirement to discard these products • Added the formula to calculate medication compliance • Clarified that the discontinuation of prohibited medications that were used prior to Visit 2 was at the discretion of the investigator and that subjects who discontinued these were to have a negative urine drug screen prior to Visit 2

    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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