Exploratory Study of SPD489 in Adults With Major Depressive Disorder (MDD) as Augmentation Therapy to an Antidepressant

• Sponsor: Shire (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00905424
• Collaborator: (none)
• Enrollment: 246
• Locations: 15
• Arms: 2
• Actual Duration (Months): 12.2
• Patients Per Site: 16.4
• Patients Per Site Per Month: 1.3

Study Details

Study Description

Brief Summary

To evaluate the efficacy of SPD489 when used as augmentation to an antidepressant in the treatment of major depressive disorder (MDD) as measured by mean change in total Montgomery-Ǻsberg Depression Rating Scale (MADRS) scores.

Condition or Disease	Intervention/Treatment	Phase
Major Depressive Disorder	Drug: Antidepressant + SPD489 (lisdexamfetamine dimesylate); Drug: Antidepressant + placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 246 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Multicenter, Randomized, Double-blind, Parallel-group, Placebo Controlled Exploratory Efficacy and Safety Study of SPD489 in Adults 18-55 Years With Major Depressive Disorder (MDD) as Augmentation Therapy to an Antidepressant
• Actual Study Start Date: Jul 30, 2009
• Actual Primary Completion Date: Aug 4, 2010
• Actual Study Completion Date: Aug 4, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Active Antidepressant + SPD489	Drug: Antidepressant + SPD489 (lisdexamfetamine dimesylate); Escitalopram oxalate (antidepressant) 20 mg/day oral + 20, 30, or 50 mg SPD489 oral once daily for 6 weeks; Other Names: LDX, Vyvanse
Placebo Comparator: Placebo Antidepressant + placebo	Drug: Antidepressant + placebo; Escitalopram oxalate (antidepressant) 20 mg/day oral + placebo oral once daily for 6 weeks

Outcome Measures

Primary Outcome Measures

1. Change From Augmentation Baseline for Non-Remitters in Montgomery-Ǻsberg Depression Rating Scale (MADRS) Total Score at Week 6 - Last Observation Carried Forward (LOCF) [Augmentation Baseline, 6 weeks]

   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.

Secondary Outcome Measures

1. Change From Augmentation Baseline for Non-Remitters in the Hamilton Depression Scale (HAM-D) Total Score at Week 6 - LOCF [Augmentation Baseline, 6 weeks]

   The HAM-D is a validated rating scale which consists of 17 items. Nine of the items are scored on a scale of 0-4 and 8 items are scored on a scale of 0-2 for a total scoring range of 0-52. A score of 0-7 is generally accepted to be within the normal range (or in clinical remission), while a score of 20 or higher indicates increased severity of depression. In general, the lower the total score the less severe the depression.

2. Change From Augmentation Baseline for Non-Remitters in the Sheehan Disability Scale (SDS) Total Score at Week 6 [Augmentation Baseline, 6 weeks]

   Designed to evaluate the extent to which illness symptoms impact a subject's life in 3 areas: work/school, social, and family/home. Each area is scored on a scale from 0 (no impairment) to 10 (highly impaired) with a total score ranging from 0 (unimpaired) to 30 (highly impaired). Lower scores translate into less impairment.

3. Percentage of Non-Remitters With Improvement on Clinical Global Impression-Improvement (CGI-I) at Week 6 - LOCF [6 weeks]

   Clinical Global Impression-Improvement (CGI-I) consists of a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). Improvement is defined as a score of 1 (very much improved) or 2 (much improved) on the scale.

4. Assessment in Non-Remitters of Clinical Global Impression-Severity of Illness (CGI-S) at Augmentation Baseline [Augmentation baseline]

   CGI-S assesses the severity of the subject's condition on a 7-point scale ranging from 1 (normal, not at all ill) to 7 (among the most extremely ill)

5. Assessment in Non-Remitters of Clinical Global Impression-Severity of Illness (CGI-S) at Week 6 [6 weeks]

   CGI-S assesses the severity of the subject's condition on a 7-point scale ranging from 1 (normal, not at all ill) to 7 (among the most extremely ill)

6. Change From Augmentation Baseline for Non-Remitters in the Behavior Rating Inventory of Executive Function - Adult Version (BRIEF-A) Scale Total Score at Week 6 [Augmentation Baseline and 6 weeks]

   BRIEF-A is a validated 75-item questionnaire composed of three scales (Global Executive Composite, Behavioral Recognition Index, and Metacognition Index). Items are rated 1 (never), 2 (sometimes), and 3 (often). There is no range for a total score. Raw scale scores are used to develop interpretive reports. Lower scores reflect better functioning.

7. Change From Augmentation Baseline for Non-Remitters in the Multidimensional Assessment of Fatigue (MAF) Scale Total Score at Week 6 [Augmentation Baseline and 6 weeks]

   MAF contains 16 items scored on a scale from 1 (not at all) to 10 (a great deal). Answers are converted to a Global Fatigue Index with total scores ranging from 1 (no fatigue) to 50 (severe fatigue). Lower scores indicate less fatigue.

8. Change From Augmentation Baseline for Non-Remitters in the Quick Inventory of Depressive Symptomatology - Self-Report (QIDS-SR) Scale Total Score at Week 6 [Augmentation Baseline and 6 weeks]

   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.

9. Change From Augmentation Baseline for Remitters in MADRS Total Score at Week 6 - LOCF [Augmentation Baseline and 6 weeks]

   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.

10. Change From Augmentation Baseline for Remitters in the HAM-D Total Score at Week 6 - LOCF [Augmentation Baseline and 6 weeks]

    The HAM-D is a validated rating scale which consists of 17 items. Nine of the items are scored on a scale of 0-4 and 8 items are scored on a scale of 0-2 for a total scoring range of 0-52. A score of 0-7 is generally accepted to be within the normal range (or in clinical remission), while a score of 20 or higher indicates increased severity of depression. In general, the lower the total score the less severe the depression.

11. Change From Augmentation Baseline for Remitters in the SDS Total Score at Week 6 [Augmentation Baseline and 6 weeks]

    Designed to evaluate the extent to which illness symptoms impact a subject's life in 3 areas: work/school, social, and family/home. Each area is scored on a scale from 0 (no impairment) to 10 (highly impaired) with a total score ranging from 0 (unimpaired) to 30 (highly impaired). Lower scores translate into less impairment.

12. Percentage of Remitters With Improvement on CGI-I at Week 6 - LOCF [6 weeks]

    Clinical Global Impression-Improvement (CGI-I) consists of a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). Improvement is defined as a score of 1 (very much improved) or 2 (much improved) on the scale.

13. Assessment in Remitters of CGI-S at Augmentation Baseline [Augmentation Baseline]

    CGI-S assesses the severity of the subject's condition on a 7-point scale ranging from 1 (normal, not at all ill) to 7 (among the most extremely ill)

14. Assessment in Remitters of CGI-S at Week 6 [6 weeks]

    CGI-S assesses the severity of the subject's condition on a 7-point scale ranging from 1 (normal, not at all ill) to 7 (among the most extremely ill)

15. Change From Augmentation Baseline for Remitters in the BRIEF-A Scale Total Score at Week 6 [Augmentation baseline and 6 weeks]

    BRIEF-A is a validated 86-item questionnaire composed of three scales (Global Executive Composite, Behavioral Recognition Index, and Metacognition Index). Items are rated 1 (never), 2 (sometimes), and 3 (often). Lower scores reflect better functioning.

16. Change From Augmentation Baseline for Remitters in the MAF Scale Total Score at Week 6 [Augmentation baseline and 6 weeks]

    MAF contains 16 items scored on a scale from 1 (not at all) to 10 (a great deal). Answers are converted to a Global Fatigue Index with total scores ranging from 1 (no fatigue) to 50 (severe fatigue). Lower scores indicate less fatigue.

17. Change From Augmentation Baseline for Remitters in the QIDS-SR Scale Total Score at Week 6 [Augmentation baseline and 6 weeks]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Adults aged 18-55 with a primary diagnosis of nonpsychotic MDD

Exclusion Criteria:

• History of non-response to multiple antidepressants

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Pharmacology Research Institute (PRI)	Newport Beach	California	United States	92660
2	Affiliated Research Institute	San Diego	California	United States	92108
3	Florida Clinical Research Center, LLC	Bradenton	Florida	United States	34208
4	Gulfcoast Clinical Research Center	Fort Myers	Florida	United States	33912
5	Clinical Neuroscience Solutions, Inc.	Orlando	Florida	United States	32809
6	Atlanta Institute of Medicine & Research	Atlanta	Georgia	United States	30328
7	Carman Research	Smyrna	Georgia	United States	30080
8	Vince & Associates Clinical Research	Overland Park	Kansas	United States	66212
9	Duke University Medical Center	Durham	North Carolina	United States	27705
10	North Star Medical Research, LLC	Middleburg Heights	Ohio	United States	44130
11	IPS Research Company	Oklahoma City	Oklahoma	United States	73103
12	Summit Research Network	Portland	Oregon	United States	97210
13	FutureSearch Clinical Trials, LP	Austin	Texas	United States	78756
14	Northwest Clinical Research Center	Bellevue	Washington	United States	98007
15	Summit Research Network (Seattle), LLC	Seattle	Washington	United States	98104

Sponsors and Collaborators

• Shire

Investigators

• Study Director: Study Director, Takeda

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• FDA Recall Information
• FDA-approved Labelling

Publications

None provided.

• Responsible Party: Shire
• ClinicalTrials.gov Identifier: NCT00905424
• Other Study ID Numbers: SPD489-203
• First Posted: May 20, 2009
• Last Update Posted: Jun 14, 2021
• Last Verified: Jun 1, 2021

• Additional relevant MeSH terms: Depressive Disorder; Depression; Depressive Disorder, Major; Lisdexamfetamine Dimesylate; Antidepressive Agents

Study Results

Participant Flow

Pre-assignment Detail	246 subjects entered the antidepressant lead-in phase receiving escitalopram oxalate (antidepressant) 20 mg/day for 8 weeks. After 8 weeks, subjects with residual depressive symptoms (n = 177) were randomly assigned (stratified by remission, either remitters or non-remitters) to receive augmentation therapy (either SPD489 or placebo).

Arm/Group Title	Antidepressant + SPD489	Antidepressant + Placebo .
Arm/Group Description	Subjects with residual depressive symptoms (symptoms of depression that remain after initial antidepressant treatment) after the 8-week lead-in period with antidepressant (escitalopram @ 20 mg/day) were randomly assigned to receive augmentation therapy (antidepressant @ 20 mg/day + SPD489 @ either 20, 30, or 50 mg/day) for 6 weeks. This includes both non-remitters (Montgomery-Ǻsberg Depression Rating Scale [MADRS] total score greater than 10 at augmentation baseline) and remitters (MADRS total score of less than or equal to 10 at augmentation baseline).	Subjects with residual depressive symptoms after the 8-week lead-in period with antidepressant were randomly assigned to receive augmentation therapy (antidepressant @ 20 mg/day + placebo) for 6 weeks. This includes both non-remitters and remitters.
Period Title: Overall Study
STARTED	89	88
COMPLETED	78	79
NOT COMPLETED	11	9

Baseline Characteristics

Arm/Group Title	Antidepressant + SPD489	Antidepressant + Placebo .	Total
Arm/Group Description	Subjects with residual depressive symptoms (symptoms of depression that remain after initial antidepressant treatment) after the 8-week lead-in period with antidepressant (escitalopram @ 20 mg/day) were randomly assigned to receive augmentation therapy (antidepressant @ 20 mg/day + SPD489 @ either 20, 30, or 50 mg/day) for 6 weeks. This includes both non-remitters (Montgomery-Ǻsberg Depression Rating Scale [MADRS] total score greater than 10 at augmentation baseline) and remitters (MADRS total score of less than or equal to 10 at augmentation baseline).	Subjects with residual depressive symptoms after the 8-week lead-in period with antidepressant were randomly assigned to receive augmentation therapy (antidepressant @ 20 mg/day + placebo) for 6 weeks. This includes both non-remitters and remitters.	Total of all reporting groups
Overall Participants	88	85	173
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	39.4 (9.65)	38.6 (10.38)	39.0 (9.99)
Age, Customized (Count of Participants)
18-40 years	44 50%	49 57.6%	93 53.8%
41-55 years	44 50%	36 42.4%	80 46.2%
Sex: Female, Male (Count of Participants)
Female	53 60.2%	54 63.5%	107 61.8%
Male	35 39.8%	31 36.5%	66 38.2%
Region of Enrollment (Count of Participants)
United States	88 100%	85 100%	173 100%

Outcome Measures

1. Primary Outcome

Title	Change From Augmentation Baseline for Non-Remitters in Montgomery-Ǻsberg Depression Rating Scale (MADRS) Total Score at Week 6 - Last Observation Carried Forward (LOCF)
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.
Time Frame	Augmentation Baseline, 6 weeks

Outcome Measure Data

Analysis Population Description

Primary Efficacy Analysis Set defined as all non-remitters (MADRS total score greater than 10 at augmentation baseline) who take at least 1 dose of randomized augmentation treatment and have at least 1 primary efficacy measurement after randomization.

Arm/Group Title	Antidepressant + SPD489 (Non-remitters)	Antidepressant + Placebo (Non-remitters)
Arm/Group Description	Subjects with residual depressive symptoms after the 8-week lead-in period with antidepressant were randomly assigned to receive augmentation therapy (SPD489). At augmentation baseline, randomization was stratified by Non-remitters and remitters. Non-remitters were defined as subjects who had an MADRS total score of greater than 10 at augmentation baseline. Subjects received antidepressant (escitalopram @ 20 mg/day) + an optimal dose of SPD489 (either 20, 30, or 50 mg/day) for 6 weeks.	Subjects with residual depressive symptoms after the 8-week lead-in period with antidepressant were randomly assigned to receive augmentation therapy (placebo). At augmentation baseline, randomization was stratified by Non-remitters and remitters. Non-remitters were defined as subjects who had an MADRS total score of greater than 10 at augmentation baseline. Subjects received antidepressant (escitalopram @ 20 mg/day) + placebo for 6 weeks.
Measure Participants	65	64
Least Squares Mean (Standard Error) [Units on a scale]	-7.1 (0.93)	-4.9 (0.94)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Antidepressant + SPD489 (Non-remitters), Antidepressant + Placebo (Non-remitters)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0902
	Comments	The test was performed a priori at the significance level of 0.10
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.3
	Confidence Interval	(2-Sided) 90%; -4.5 to -0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From Augmentation Baseline for Non-Remitters in the Hamilton Depression Scale (HAM-D) Total Score at Week 6 - LOCF
Description	The HAM-D is a validated rating scale which consists of 17 items. Nine of the items are scored on a scale of 0-4 and 8 items are scored on a scale of 0-2 for a total scoring range of 0-52. A score of 0-7 is generally accepted to be within the normal range (or in clinical remission), while a score of 20 or higher indicates increased severity of depression. In general, the lower the total score the less severe the depression.
Time Frame	Augmentation Baseline, 6 weeks

Outcome Measure Data

Analysis Population Description

Primary Efficacy Analysis Set

Arm/Group Title	Antidepressant + SPD489 (Non-remitters)	Antidepressant + Placebo (Non-remitters)
Arm/Group Description	Subjects with residual depressive symptoms after the 8-week lead-in period with antidepressant were randomly assigned to receive augmentation therapy (SPD489). At augmentation baseline, randomization was stratified by Non-remitters and remitters. Non-remitters were defined as subjects who had an MADRS total score of greater than 10 at augmentation baseline. Subjects received antidepressant (escitalopram @ 20 mg/day) + an optimal dose of SPD489 (either 20, 30, or 50 mg/day) for 6 weeks.	Subjects with residual depressive symptoms after the 8-week lead-in period with antidepressant were randomly assigned to receive augmentation therapy (placebo). At augmentation baseline, randomization was stratified by Non-remitters and remitters. Non-remitters were defined as subjects who had an MADRS total score of greater than 10 at augmentation baseline. Subjects received antidepressant (escitalopram @ 20 mg/day) + placebo for 6 weeks.
Measure Participants	65	64
Least Squares Mean (Standard Error) [Units on a scale]	-4.9 (0.64)	-4.0 (0.65)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Antidepressant + SPD489 (Non-remitters), Antidepressant + Placebo (Non-remitters)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.3091
	Comments	The test was performed a priori at the significance level of 0.10
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.9
	Confidence Interval	(2-Sided) 90%; -2.4 to 0.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change From Augmentation Baseline for Non-Remitters in the Sheehan Disability Scale (SDS) Total Score at Week 6
Description	Designed to evaluate the extent to which illness symptoms impact a subject's life in 3 areas: work/school, social, and family/home. Each area is scored on a scale from 0 (no impairment) to 10 (highly impaired) with a total score ranging from 0 (unimpaired) to 30 (highly impaired). Lower scores translate into less impairment.
Time Frame	Augmentation Baseline, 6 weeks

Outcome Measure Data

Analysis Population Description

Primary Efficacy Analysis Set

Arm/Group Title	Antidepressant + SPD489 (Non-remitters)	Antidepressant + Placebo (Non-remitters)
Arm/Group Description	Subjects with residual depressive symptoms after the 8-week lead-in period with antidepressant were randomly assigned to receive augmentation therapy (SPD489). At augmentation baseline, randomization was stratified by Non-remitters and remitters. Non-remitters were defined as subjects who had an MADRS total score of greater than 10 at augmentation baseline. Subjects received antidepressant (escitalopram @ 20 mg/day) + an optimal dose of SPD489 (either 20, 30, or 50 mg/day) for 6 weeks.	Subjects with residual depressive symptoms after the 8-week lead-in period with antidepressant were randomly assigned to receive augmentation therapy (placebo). At augmentation baseline, randomization was stratified by Non-remitters and remitters. Non-remitters were defined as subjects who had an MADRS total score of greater than 10 at augmentation baseline. Subjects received antidepressant (escitalopram @ 20 mg/day) + placebo for 6 weeks.
Measure Participants	63	62
Least Squares Mean (Standard Error) [Units on a scale]	-3.7 (0.73)	-1.7 (0.74)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Antidepressant + SPD489 (Non-remitters), Antidepressant + Placebo (Non-remitters)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0573
	Comments	The test was performed a priori at the significance level of 0.10
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.0
	Confidence Interval	(2-Sided) 90%; -3.7 to -0.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Percentage of Non-Remitters With Improvement on Clinical Global Impression-Improvement (CGI-I) at Week 6 - LOCF
Description	Clinical Global Impression-Improvement (CGI-I) consists of a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). Improvement is defined as a score of 1 (very much improved) or 2 (much improved) on the scale.
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

Primary Efficacy Analysis Set

Arm/Group Title	Antidepressant + SPD489 (Non-remitters)	Antidepressant + Placebo (Non-remitters)
Arm/Group Description	Subjects with residual depressive symptoms after the 8-week lead-in period with antidepressant were randomly assigned to receive augmentation therapy (SPD489). At augmentation baseline, randomization was stratified by Non-remitters and remitters. Non-remitters were defined as subjects who had an MADRS total score of greater than 10 at augmentation baseline. Subjects received antidepressant (escitalopram @ 20 mg/day) + an optimal dose of SPD489 (either 20, 30, or 50 mg/day) for 6 weeks.	Subjects with residual depressive symptoms after the 8-week lead-in period with antidepressant were randomly assigned to receive augmentation therapy (placebo). At augmentation baseline, randomization was stratified by Non-remitters and remitters. Non-remitters were defined as subjects who had an MADRS total score of greater than 10 at augmentation baseline. Subjects received antidepressant (escitalopram @ 20 mg/day) + placebo for 6 weeks.
Measure Participants	65	64
Number [Percent of Participants]	60.0 68.2%	45.3 53.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Antidepressant + SPD489 (Non-remitters), Antidepressant + Placebo (Non-remitters)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.2368
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

5. Secondary Outcome

Title	Assessment in Non-Remitters of Clinical Global Impression-Severity of Illness (CGI-S) at Augmentation Baseline
Description	CGI-S assesses the severity of the subject's condition on a 7-point scale ranging from 1 (normal, not at all ill) to 7 (among the most extremely ill)
Time Frame	Augmentation baseline

Outcome Measure Data

Analysis Population Description

Primary Efficacy Analysis Set

Arm/Group Title	Antidepressant + SPD489 (Non-remitters)	Antidepressant + Placebo (Non-remitters)
Arm/Group Description	Subjects with residual depressive symptoms after the 8-week lead-in period with antidepressant were randomly assigned to receive augmentation therapy (SPD489). At augmentation baseline, randomization was stratified by Non-remitters and remitters. Non-remitters were defined as subjects who had an MADRS total score of greater than 10 at augmentation baseline. Subjects received antidepressant (escitalopram @ 20 mg/day) + an optimal dose of SPD489 (either 20, 30, or 50 mg/day) for 6 weeks.	Subjects with residual depressive symptoms after the 8-week lead-in period with antidepressant were randomly assigned to receive augmentation therapy (placebo). At augmentation baseline, randomization was stratified by Non-remitters and remitters. Non-remitters were defined as subjects who had an MADRS total score of greater than 10 at augmentation baseline. Subjects received antidepressant (escitalopram @ 20 mg/day) + placebo for 6 weeks.
Measure Participants	64	64
Normal, not at all ill	1.5 1.7%	1.6 1.9%
Borderline mentally ill	20.0 22.7%	12.5 14.7%
Mildly ill	40.0 45.5%	34.4 40.5%
Moderately ill	32.3 36.7%	48.4 56.9%
Markedly ill	6.2 7%	3.1 3.6%
Severely ill	0 0%	0 0%
Among the most extremely ill	0 0%	0 0%

6. Secondary Outcome

Title	Assessment in Non-Remitters of Clinical Global Impression-Severity of Illness (CGI-S) at Week 6
Description	CGI-S assesses the severity of the subject's condition on a 7-point scale ranging from 1 (normal, not at all ill) to 7 (among the most extremely ill)
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

Primary Efficacy Analysis Set

Arm/Group Title	Antidepressant + SPD489 (Non-remitters)	Antidepressant + Placebo (Non-remitters)
Arm/Group Description	Subjects with residual depressive symptoms after the 8-week lead-in period with antidepressant were randomly assigned to receive augmentation therapy (SPD489). At augmentation baseline, randomization was stratified by Non-remitters and remitters. Non-remitters were defined as subjects who had an MADRS total score of greater than 10 at augmentation baseline. Subjects received antidepressant (escitalopram @ 20 mg/day) + an optimal dose of SPD489 (either 20, 30, or 50 mg/day) for 6 weeks.	Subjects with residual depressive symptoms after the 8-week lead-in period with antidepressant were randomly assigned to receive augmentation therapy (placebo). At augmentation baseline, randomization was stratified by Non-remitters and remitters. Non-remitters were defined as subjects who had an MADRS total score of greater than 10 at augmentation baseline. Subjects received antidepressant (escitalopram @ 20 mg/day) + placebo for 6 weeks.
Measure Participants	63	62
Normal, not at all ill	27.0 30.7%	14.5 17.1%
Borderline mentally ill	31.7 36%	24.2 28.5%
Mildly ill	30.2 34.3%	22.6 26.6%
Moderately ill	9.5 10.8%	29.0 34.1%
Markedly ill	1.6 1.8%	9.7 11.4%
Severely ill	0 0%	0 0%
Among the most extremely ill	0 0%	0 0%

7. Secondary Outcome

Title	Change From Augmentation Baseline for Non-Remitters in the Behavior Rating Inventory of Executive Function - Adult Version (BRIEF-A) Scale Total Score at Week 6
Description	BRIEF-A is a validated 75-item questionnaire composed of three scales (Global Executive Composite, Behavioral Recognition Index, and Metacognition Index). Items are rated 1 (never), 2 (sometimes), and 3 (often). There is no range for a total score. Raw scale scores are used to develop interpretive reports. Lower scores reflect better functioning.
Time Frame	Augmentation Baseline and 6 weeks

Outcome Measure Data

Analysis Population Description

Primary Efficacy Analysis Set

Arm/Group Title	Antidepressant + SPD489 (Non-remitters)	Antidepressant + Placebo (Non-remitters)
Arm/Group Description	Subjects with residual depressive symptoms after the 8-week lead-in period with antidepressant were randomly assigned to receive augmentation therapy (SPD489). At augmentation baseline, randomization was stratified by Non-remitters and remitters. Non-remitters were defined as subjects who had an MADRS total score of greater than 10 at augmentation baseline. Subjects received antidepressant (escitalopram @ 20 mg/day) + an optimal dose of SPD489 (either 20, 30, or 50 mg/day) for 6 weeks.	Subjects with residual depressive symptoms after the 8-week lead-in period with antidepressant were randomly assigned to receive augmentation therapy (placebo). At augmentation baseline, randomization was stratified by Non-remitters and remitters. Non-remitters were defined as subjects who had an MADRS total score of greater than 10 at augmentation baseline. Subjects received antidepressant (escitalopram @ 20 mg/day) + placebo for 6 weeks.
Measure Participants	62	60
Global Executive Composite	-4.7 (1.03)	-1.7 (1.04)
Behavioral Regulation Index	-3.7 (0.97)	-1.7 (0.99)
Metacognition Index	-4.8 (1.04)	-1.5 (1.06)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Antidepressant + SPD489 (Non-remitters), Antidepressant + Placebo (Non-remitters)
	Comments	Global Executive Composite
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0463
	Comments	The test was performed a priori at the significance level of 0.10
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.0
	Confidence Interval	(2-Sided) 90%; -5.4 to -0.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Antidepressant + SPD489 (Non-remitters), Antidepressant + Placebo (Non-remitters)
	Comments	Behavioral Regulation Index
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.1431
	Comments	The test was performed a priori at the significance level of 0.10
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.0
	Confidence Interval	(2-Sided) 90%; -4.3 to 0.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Antidepressant + SPD489 (Non-remitters), Antidepressant + Placebo (Non-remitters)
	Comments	Metacognition Index
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0281
	Comments	The test was performed a priori at the significance level of 0.10
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.3
	Confidence Interval	(2-Sided) 90%; -5.8 to -0.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Change From Augmentation Baseline for Non-Remitters in the Multidimensional Assessment of Fatigue (MAF) Scale Total Score at Week 6
Description	MAF contains 16 items scored on a scale from 1 (not at all) to 10 (a great deal). Answers are converted to a Global Fatigue Index with total scores ranging from 1 (no fatigue) to 50 (severe fatigue). Lower scores indicate less fatigue.
Time Frame	Augmentation Baseline and 6 weeks

Outcome Measure Data

Analysis Population Description

Primary Efficacy Analysis Set

Arm/Group Title	Antidepressant + SPD489 (Non-remitters)	Antidepressant + Placebo (Non-remitters)
Arm/Group Description	Subjects with residual depressive symptoms after the 8-week lead-in period with antidepressant were randomly assigned to receive augmentation therapy (SPD489). At augmentation baseline, randomization was stratified by Non-remitters and remitters. Non-remitters were defined as subjects who had an MADRS total score of greater than 10 at augmentation baseline. Subjects received antidepressant (escitalopram @ 20 mg/day) + an optimal dose of SPD489 (either 20, 30, or 50 mg/day) for 6 weeks.	Subjects with residual depressive symptoms after the 8-week lead-in period with antidepressant were randomly assigned to receive augmentation therapy (placebo). At augmentation baseline, randomization was stratified by Non-remitters and remitters. Non-remitters were defined as subjects who had an MADRS total score of greater than 10 at augmentation baseline. Subjects received antidepressant (escitalopram @ 20 mg/day) + placebo for 6 weeks.
Measure Participants	63	62
Least Squares Mean (Standard Error) [Units on a scale]	-5.3 (1.25)	-2.3 (1.26)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Antidepressant + SPD489 (Non-remitters), Antidepressant + Placebo (Non-remitters)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0920
	Comments	The test was performed a priori at the significance level of 0.10
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.0
	Confidence Interval	(2-Sided) 90%; -6.0 to -0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Change From Augmentation Baseline for Non-Remitters in the Quick Inventory of Depressive Symptomatology - Self-Report (QIDS-SR) Scale Total Score at Week 6
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.
Time Frame	Augmentation Baseline and 6 weeks

Outcome Measure Data

Analysis Population Description

Primary Efficacy Analysis Set

Arm/Group Title	Antidepressant + SPD489 (Non-remitters)	Antidepressant + Placebo (Non-remitters)
Arm/Group Description	Subjects with residual depressive symptoms after the 8-week lead-in period with antidepressant were randomly assigned to receive augmentation therapy (SPD489). At augmentation baseline, randomization was stratified by Non-remitters and remitters. Non-remitters were defined as subjects who had an MADRS total score of greater than 10 at augmentation baseline. Subjects received antidepressant (escitalopram @ 20 mg/day) + an optimal dose of SPD489 (either 20, 30, or 50 mg/day) for 6 weeks.	Subjects with residual depressive symptoms after the 8-week lead-in period with antidepressant were randomly assigned to receive augmentation therapy (placebo). At augmentation baseline, randomization was stratified by Non-remitters and remitters. Non-remitters were defined as subjects who had an MADRS total score of greater than 10 at augmentation baseline. Subjects received antidepressant (escitalopram @ 20 mg/day) + placebo for 6 weeks.
Measure Participants	63	62
Least Squares Mean (Standard Error) [Units on a scale]	-2.4 (0.45)	-1.2 (0.46)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Antidepressant + SPD489 (Non-remitters), Antidepressant + Placebo (Non-remitters)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0774
	Comments	The test was performed a priori at the significance level of 0.10
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.2
	Confidence Interval	(2-Sided) 90%; -2.2 to -0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Change From Augmentation Baseline for Remitters in MADRS Total Score at Week 6 - LOCF
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.
Time Frame	Augmentation Baseline and 6 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) defined as all subjects who take at least 1 dose of randomized augmentation treatment and have at least 1 primary efficacy measurement after randomization.

Arm/Group Title	Antidepressant + SPD489 (Remitters)	Antidepressant + Placebo (Remitters)
Arm/Group Description	Subjects with residual depressive symptoms after the 8-week lead-in period with antidepressant were randomly assigned to receive augmentation therapy (SPD489). At augmentation baseline, randomization was stratified by non-remitters and remitters. Remitters were defined as subjects who had an MADRS total score of less than or equal to 10 at augmentation baseline. Subjects received antidepressant (escitalopram @ 20 mg/day) + an optimal dose of SPD489 (either 20, 30, or 50 mg/day) for 6 weeks.	Subjects with residual depressive symptoms after the 8-week lead-in period with antidepressant were randomly assigned to receive augmentation therapy (placebo). At augmentation baseline, randomization was stratified by non-remitters and remitters. Remitters were defined as subjects who had an MADRS total score of less than or equal to 10 at augmentation baseline. Subjects received antidepressant (escitalopram @ 20 mg/day) + placebo for 6 weeks.
Measure Participants	23	21
Least Squares Mean (Standard Error) [Units on a scale]	0.1 (1.13)	-1.1 (1.18)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Antidepressant + SPD489 (Non-remitters), Antidepressant + Placebo (Non-remitters)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.4726
	Comments	The test was performed a priori at the significance level of 0.10
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.2
	Confidence Interval	(2-Sided) 90%; -1.6 to 4.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Change From Augmentation Baseline for Remitters in the HAM-D Total Score at Week 6 - LOCF
Description	The HAM-D is a validated rating scale which consists of 17 items. Nine of the items are scored on a scale of 0-4 and 8 items are scored on a scale of 0-2 for a total scoring range of 0-52. A score of 0-7 is generally accepted to be within the normal range (or in clinical remission), while a score of 20 or higher indicates increased severity of depression. In general, the lower the total score the less severe the depression.
Time Frame	Augmentation Baseline and 6 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Antidepressant + SPD489 (Remitters)	Antidepressant + Placebo (Remitters)
Arm/Group Description	Subjects with residual depressive symptoms after the 8-week lead-in period with antidepressant were randomly assigned to receive augmentation therapy (SPD489). At augmentation baseline, randomization was stratified by non-remitters and remitters. Remitters were defined as subjects who had an MADRS total score of less than or equal to 10 at augmentation baseline. Subjects received antidepressant (escitalopram @ 20 mg/day) + an optimal dose of SPD489 (either 20, 30, or 50 mg/day) for 6 weeks.	Subjects with residual depressive symptoms after the 8-week lead-in period with antidepressant were randomly assigned to receive augmentation therapy (placebo). At augmentation baseline, randomization was stratified by non-remitters and remitters. Remitters were defined as subjects who had an MADRS total score of less than or equal to 10 at augmentation baseline. Subjects received antidepressant (escitalopram @ 20 mg/day) + placebo for 6 weeks.
Measure Participants	23	21
Least Squares Mean (Standard Error) [Units on a scale]	-0.8 (0.92)	-1.6 (0.96)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Antidepressant + SPD489 (Non-remitters), Antidepressant + Placebo (Non-remitters)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.5182
	Comments	The test was performed a priori at the significance level of 0.10
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.9
	Confidence Interval	(2-Sided) 90%; -1.4 to 3.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Secondary Outcome

Title	Change From Augmentation Baseline for Remitters in the SDS Total Score at Week 6
Description	Designed to evaluate the extent to which illness symptoms impact a subject's life in 3 areas: work/school, social, and family/home. Each area is scored on a scale from 0 (no impairment) to 10 (highly impaired) with a total score ranging from 0 (unimpaired) to 30 (highly impaired). Lower scores translate into less impairment.
Time Frame	Augmentation Baseline and 6 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Antidepressant + SPD489 (Remitters)	Antidepressant + Placebo (Remitters)
Arm/Group Description	Subjects with residual depressive symptoms after the 8-week lead-in period with antidepressant were randomly assigned to receive augmentation therapy (SPD489). At augmentation baseline, randomization was stratified by non-remitters and remitters. Remitters were defined as subjects who had an MADRS total score of less than or equal to 10 at augmentation baseline. Subjects received antidepressant (escitalopram @ 20 mg/day) + an optimal dose of SPD489 (either 20, 30, or 50 mg/day) for 6 weeks.	Subjects with residual depressive symptoms after the 8-week lead-in period with antidepressant were randomly assigned to receive augmentation therapy (placebo). At augmentation baseline, randomization was stratified by non-remitters and remitters. Remitters were defined as subjects who had an MADRS total score of less than or equal to 10 at augmentation baseline. Subjects received antidepressant (escitalopram @ 20 mg/day) + placebo for 6 weeks.
Measure Participants	22	21
Least Squares Mean (Standard Error) [Units on a scale]	-1.6 (0.89)	-0.6 (0.91)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Antidepressant + SPD489 (Non-remitters), Antidepressant + Placebo (Non-remitters)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.4630
	Comments	The test was performed a priori at the significance level of 0.10
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.9
	Confidence Interval	(2-Sided) 90%; -3.1 to 1.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

13. Secondary Outcome

Title	Percentage of Remitters With Improvement on CGI-I at Week 6 - LOCF
Description	Clinical Global Impression-Improvement (CGI-I) consists of a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). Improvement is defined as a score of 1 (very much improved) or 2 (much improved) on the scale.
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Antidepressant + SPD489 (Remitters)	Antidepressant + Placebo (Remitters)
Arm/Group Description	Subjects with residual depressive symptoms after the 8-week lead-in period with antidepressant were randomly assigned to receive augmentation therapy (SPD489). At augmentation baseline, randomization was stratified by non-remitters and remitters. Remitters were defined as subjects who had an MADRS total score of less than or equal to 10 at augmentation baseline. Subjects received antidepressant (escitalopram @ 20 mg/day) + an optimal dose of SPD489 (either 20, 30, or 50 mg/day) for 6 weeks.	Subjects with residual depressive symptoms after the 8-week lead-in period with antidepressant were randomly assigned to receive augmentation therapy (placebo). At augmentation baseline, randomization was stratified by non-remitters and remitters. Remitters were defined as subjects who had an MADRS total score of less than or equal to 10 at augmentation baseline. Subjects received antidepressant (escitalopram @ 20 mg/day) + placebo for 6 weeks.
Measure Participants	23	21
Number [Percent of participants]	65.2 74.1%	52.4 61.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Antidepressant + SPD489 (Non-remitters), Antidepressant + Placebo (Non-remitters)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.5230
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

14. Secondary Outcome

Title	Assessment in Remitters of CGI-S at Augmentation Baseline
Description	CGI-S assesses the severity of the subject's condition on a 7-point scale ranging from 1 (normal, not at all ill) to 7 (among the most extremely ill)
Time Frame	Augmentation Baseline

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Antidepressant + SPD489 (Remitters)	Antidepressant + Placebo (Remitters)
Arm/Group Description	Subjects with residual depressive symptoms after the 8-week lead-in period with antidepressant were randomly assigned to receive augmentation therapy (SPD489). At augmentation baseline, randomization was stratified by non-remitters and remitters. Remitters were defined as subjects who had an MADRS total score of less than or equal to 10 at augmentation baseline. Subjects received antidepressant (escitalopram @ 20 mg/day) + an optimal dose of SPD489 (either 20, 30, or 50 mg/day) for 6 weeks.	Subjects with residual depressive symptoms after the 8-week lead-in period with antidepressant were randomly assigned to receive augmentation therapy (placebo). At augmentation baseline, randomization was stratified by non-remitters and remitters. Remitters were defined as subjects who had an MADRS total score of less than or equal to 10 at augmentation baseline. Subjects received antidepressant (escitalopram @ 20 mg/day) + placebo for 6 weeks.
Measure Participants	23	21
Normal, not at all ill	26.1 29.7%	23.8 28%
Borderline mentally ill	47.8 54.3%	71.4 84%
Mildly ill	21.7 24.7%	4.8 5.6%
Moderately ill	4.3 4.9%	0 0%
Markedly ill	0 0%	0 0%
Severely ill	0 0%	0 0%
Among the most extremely ill	0 0%	0 0%

15. Secondary Outcome

Title	Assessment in Remitters of CGI-S at Week 6
Description	CGI-S assesses the severity of the subject's condition on a 7-point scale ranging from 1 (normal, not at all ill) to 7 (among the most extremely ill)
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Antidepressant + SPD489 (Remitters)	Antidepressant + Placebo (Remitters)
Arm/Group Description	Subjects with residual depressive symptoms after the 8-week lead-in period with antidepressant were randomly assigned to receive augmentation therapy (SPD489). At augmentation baseline, randomization was stratified by non-remitters and remitters. Remitters were defined as subjects who had an MADRS total score of less than or equal to 10 at augmentation baseline. Subjects received antidepressant (escitalopram @ 20 mg/day) + an optimal dose of SPD489 (either 20, 30, or 50 mg/day) for 6 weeks.	Subjects with residual depressive symptoms after the 8-week lead-in period with antidepressant were randomly assigned to receive augmentation therapy (placebo). At augmentation baseline, randomization was stratified by non-remitters and remitters. Remitters were defined as subjects who had an MADRS total score of less than or equal to 10 at augmentation baseline. Subjects received antidepressant (escitalopram @ 20 mg/day) + placebo for 6 weeks.
Measure Participants	22	21
Normal, not at all ill	50.0 56.8%	61.9 72.8%
Borderline mentally ill	36.4 41.4%	23.8 28%
Mildly ill	13.6 15.5%	9.5 11.2%
Moderately ill	0 0%	4.8 5.6%
Markedly ill	0 0%	0 0%
Severely ill	0 0%	0 0%
Among the most extremely ill	0 0%	0 0%

16. Secondary Outcome

Title	Change From Augmentation Baseline for Remitters in the BRIEF-A Scale Total Score at Week 6
Description	BRIEF-A is a validated 86-item questionnaire composed of three scales (Global Executive Composite, Behavioral Recognition Index, and Metacognition Index). Items are rated 1 (never), 2 (sometimes), and 3 (often). Lower scores reflect better functioning.
Time Frame	Augmentation baseline and 6 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Antidepressant + SPD489 (Remitters)	Antidepressant + Placebo (Remitters)
Arm/Group Description	Subjects with residual depressive symptoms after the 8-week lead-in period with antidepressant were randomly assigned to receive augmentation therapy (SPD489). At augmentation baseline, randomization was stratified by non-remitters and remitters. Remitters were defined as subjects who had an MADRS total score of less than or equal to 10 at augmentation baseline. Subjects received antidepressant (escitalopram @ 20 mg/day) + an optimal dose of SPD489 (either 20, 30, or 50 mg/day) for 6 weeks.	Subjects with residual depressive symptoms after the 8-week lead-in period with antidepressant were randomly assigned to receive augmentation therapy (placebo). At augmentation baseline, randomization was stratified by non-remitters and remitters. Remitters were defined as subjects who had an MADRS total score of less than or equal to 10 at augmentation baseline. Subjects received antidepressant (escitalopram @ 20 mg/day) + placebo for 6 weeks.
Measure Participants	21	21
Global Executive Composite	-0.9 (1.21)	-2.7 (1.21)
Behavioral Regulation Index	-0.4 (1.37)	-1.5 (1.37)
Metacognition Index	-1.1 (1.24)	-3.4 (1.24)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Antidepressant + SPD489 (Non-remitters), Antidepressant + Placebo (Non-remitters)
	Comments	Global Executive Composite
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.2876
	Comments	The test was performed a priori at the significance level of 0.10
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.8
	Confidence Interval	(2-Sided) 90%; -1.0 to 4.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Antidepressant + SPD489 (Non-remitters), Antidepressant + Placebo (Non-remitters)
	Comments	Behavioral Regulation Index
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.5590
	Comments	The test was performed a priori at the significance level of 0.10
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.1
	Confidence Interval	(2-Sided) 90%; -2.1 to 4.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Antidepressant + SPD489 (Non-remitters), Antidepressant + Placebo (Non-remitters)
	Comments	Metacognition Index
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.2079
	Comments	The test was performed a priori at the significance level of 0.10
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.3
	Confidence Interval	(2-Sided) 90%; -0.7 to 5.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

17. Secondary Outcome

Title	Change From Augmentation Baseline for Remitters in the MAF Scale Total Score at Week 6
Description	MAF contains 16 items scored on a scale from 1 (not at all) to 10 (a great deal). Answers are converted to a Global Fatigue Index with total scores ranging from 1 (no fatigue) to 50 (severe fatigue). Lower scores indicate less fatigue.
Time Frame	Augmentation baseline and 6 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Antidepressant + SPD489 (Remitters)	Antidepressant + Placebo (Remitters)
Arm/Group Description	Subjects with residual depressive symptoms after the 8-week lead-in period with antidepressant were randomly assigned to receive augmentation therapy (SPD489). At augmentation baseline, randomization was stratified by non-remitters and remitters. Remitters were defined as subjects who had an MADRS total score of less than or equal to 10 at augmentation baseline. Subjects received antidepressant (escitalopram @ 20 mg/day) + an optimal dose of SPD489 (either 20, 30, or 50 mg/day) for 6 weeks.	Subjects with residual depressive symptoms after the 8-week lead-in period with antidepressant were randomly assigned to receive augmentation therapy (placebo). At augmentation baseline, randomization was stratified by non-remitters and remitters. Remitters were defined as subjects who had an MADRS total score of less than or equal to 10 at augmentation baseline. Subjects received antidepressant (escitalopram @ 20 mg/day) + placebo for 6 weeks.
Measure Participants	22	21
Least Squares Mean (Standard Error) [Units on a scale]	-4.0 (1.77)	-0.2 (1.81)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Antidepressant + SPD489 (Non-remitters), Antidepressant + Placebo (Non-remitters)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.1489
	Comments	The test was performed a priori at the significance level of 0.10
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.7
	Confidence Interval	(2-Sided) 90%; -8.0 to 0.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

18. Secondary Outcome

Title	Change From Augmentation Baseline for Remitters in the QIDS-SR Scale Total Score at Week 6
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.
Time Frame	Augmentation baseline and 6 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Antidepressant + SPD489 (Remitters)	Antidepressant + Placebo (Remitters)
Arm/Group Description	Subjects with residual depressive symptoms after the 8-week lead-in period with antidepressant were randomly assigned to receive augmentation therapy (SPD489). At augmentation baseline, randomization was stratified by non-remitters and remitters. Remitters were defined as subjects who had an MADRS total score of less than or equal to 10 at augmentation baseline. Subjects received antidepressant (escitalopram @ 20 mg/day) + an optimal dose of SPD489 (either 20, 30, or 50 mg/day) for 6 weeks.	Subjects with residual depressive symptoms after the 8-week lead-in period with antidepressant were randomly assigned to receive augmentation therapy (placebo). At augmentation baseline, randomization was stratified by non-remitters and remitters. Remitters were defined as subjects who had an MADRS total score of less than or equal to 10 at augmentation baseline. Subjects received antidepressant (escitalopram @ 20 mg/day) + placebo for 6 weeks.
Measure Participants	22	21
Least Squares Mean (Standard Error) [Units on a scale]	-1.9 (0.57)	-0.4 (0.58)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Antidepressant + SPD489 (Non-remitters), Antidepressant + Placebo (Non-remitters)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0852
	Comments	The test was performed a priori at the significance level of 0.10
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.4
	Confidence Interval	(2-Sided) 90%; -2.8 to -0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Adverse Event Reporting Description	Randomized Safety Analysis Set (RSAS) defined as all subjects who take at least 1 dose of randomized augmentation treatment and at least 1 follow-up safety assessment.
Arm/Group Title	Antidepressant + SPD489		Antidepressant + Placebo .
Arm/Group Description	Subjects with residual depressive symptoms (symptoms of depression that remain after initial antidepressant treatment) after the 8-week lead-in period with antidepressant (escitalopram @ 20 mg/day) were randomly assigned to receive augmentation therapy (antidepressant @ 20 mg/day + SPD489 @ either 20, 30, or 50 mg/day) for 6 weeks. This includes both non-remitters (Montgomery-Ǻsberg Depression Rating Scale [MADRS] total score greater than 10 at augmentation baseline) and remitters (MADRS total score of less than or equal to 10 at augmentation baseline).		Subjects with residual depressive symptoms after the 8-week lead-in period with antidepressant were randomly assigned to receive augmentation therapy (antidepressant @ 20 mg/day + placebo) for 6 weeks. This includes both non-remitters and remitters.
All Cause Mortality
	Antidepressant + SPD489		Antidepressant + Placebo .
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Antidepressant + SPD489		Antidepressant + Placebo .
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/88 (0%)		1/85 (1.2%)
Musculoskeletal and connective tissue disorders
Rhabdomyolysis	0/88 (0%)		1/85 (1.2%)
Other (Not Including Serious) Adverse Events
	Antidepressant + SPD489		Antidepressant + Placebo .
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	35/88 (39.8%)		15/85 (17.6%)
Gastrointestinal disorders
Dry mouth	10/88 (11.4%)		0/85 (0%)
Infections and infestations
Nasopharyngitis	5/88 (5.7%)		3/85 (3.5%)
Metabolism and nutrition disorders
Decreased appetite	6/88 (6.8%)		2/85 (2.4%)
Nervous system disorders
Headache	10/88 (11.4%)		4/85 (4.7%)
Psychiatric disorders
Insomnia	4/88 (4.5%)		6/85 (7.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

If a multicenter publication is not submitted within twelve (12) months after conclusion, abandonment or termination of the Study at all sites, or after Sponsor confirms there shall be no multicenter Study publication, the Institution and/or such Principal Investigator may publish the results from the Institution site individually.