SPD489 in Combination With an Antidepressant in the Treatment of Adults With Major Depressive Disorder

• Sponsor: Shire (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01435759
• Collaborator: (none)
• Enrollment: 1,197
• Locations: 82
• Arms: 5
• Actual Duration (Months): 31.6
• Patients Per Site: 14.6
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

This study will examine SPD489 in subjects aged 18-65 with major depressive disorder (MDD) who are taking certain types of antidepressants but continue to have residual depression symptoms. The purpose of this study is to help answer the following questions:

• How safe is SPD489 for the supplemental treatment of depression and what are the side effects that might be related to it?

• Can SPD489 help patients with depression who are also taking an antidepressant?

• How much SPD489 should be given to patients with depression who are also taking an antidepressant?

• How does SPD489 compare to placebo in depressed patients who are also taking an antidepressant?

Condition or Disease	Intervention/Treatment	Phase
Major Depressive Disorder	Drug: Antidepressant + SPD489 (Lisdexamfetamine dimesylate) 10 mg; Drug: Antidepressant + SPD489 (Lisdexamfetamine dimesylate) 30 mg; Drug: Antidepressant + SPD489 (Lisdexamfetamine dimesylate) 50 mg; Drug: Antidepressant + SPD489 (Lisdexamfetamine dimesylate) 70 mg; Drug: Antidepressant + Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 1197 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: May 31, 2011
• Actual Primary Completion Date: Jan 17, 2014
• Actual Study Completion Date: Jan 17, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Antidepressant + SPD489 10 mg	Drug: Antidepressant + SPD489 (Lisdexamfetamine dimesylate) 10 mg; Antidepressant + SPD489 oral, 10 mg, once daily for 8 weeks; Other Names: Vyvanse
Experimental: Antidepressant + SPD489 30 mg	Drug: Antidepressant + SPD489 (Lisdexamfetamine dimesylate) 30 mg; Antidepressant + SPD489 oral, 30 mg, once daily for 8 weeks; Other Names: Vyvanse
Experimental: Antidepressant + SPD489 50 mg	Drug: Antidepressant + SPD489 (Lisdexamfetamine dimesylate) 50 mg; Antidepressant + SPD489 oral, 50 mg, once daily for 8 weeks; Other Names: Vyvanse
Experimental: Antidepressant + SPD489 70 mg	Drug: Antidepressant + SPD489 (Lisdexamfetamine dimesylate) 70 mg; Antidepressant + SPD489 oral, 70 mg, once daily for 8 weeks; Other Names: Vyvanse
Placebo Comparator: Antidepressant + Placebo	Drug: Antidepressant + Placebo; oral, once daily for 8 weeks

Outcome Measures

Primary Outcome Measures

1. 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) [Augmentation Baseline (Week 8) to Week 16]

   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.

Secondary Outcome Measures

1. Change in Average Systolic Blood Pressure From Augmentation Baseline (Week 8) to Week 16 [From Augmentation Baseline (Week 8) to Week 16]

2. Change in Average Diastolic Blood Pressure From Augmentation Baseline (Week 8) to Week 16 [From Augmentation Baseline (Week 8) to Week 16]

3. Change in Average Pulse Rate From Augmentation Baseline (Week 8) to Week 16 [From Augmentation Baseline (Week 8) to Week 16]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria

1. Subject is able to provide written, personally signed and dated informed consent to participate in the study before completing any study-related procedures.

2. Subject is between 18-65 years of age.

3. Subject has a primary diagnosis of non-psychotic MDD.

4. Subject has a MADRS total score 24

5. Subject is willing and has an understanding and ability to fully comply with study procedures and restrictions defined in this protocol.

6. Subject, who is female, must have a negative serum beta human chorionic gonadotropin (HCG) pregnancy test and a negative urine pregnancy test and agrees to comply with any applicable contraceptive requirements.

7. Subject is able to swallow a capsule.

Exclusion Criteria

1. Subject whose current episode of MDD has not responded to an adequate treatment regimen.

2. Subject who has a lifetime history of treatment resistant depression, defined as having not responded to adequate treatment with 2 or more treatment regimens.

3. Subject has a current comorbid psychiatric disorder that is either controlled with medications prohibited in this study or is uncontrolled and associated with significant symptoms.

4. Subject has been hospitalized (within the last 12 months) for their current MDD episode.

5. Subject has a current or lifetime history of attention-deficit/hyperactivity disorder (ADHD).

6. Subject has a first degree relative that has been diagnosed with bipolar I disorder.

7. Subject has a recent history (within the last 6 months) of suspected substance abuse or dependence disorder.

8. Subject is considered a suicide risk, has previously made a suicide attempt within the past 3 years, or is currently demonstrating active suicidal ideation.

9. Subject has a concurrent chronic or acute illness or unstable medical condition.

10. Subject has a history of seizures (other than infantile febrile seizures), any tic disorder, or a current diagnosis and/or a known family history of Tourette's Disorder, serious neurological disease, history of significant head trauma, dementia, cerebrovascular disease, Parkinson's disease, or intracranial lesions.

11. Subject has known history of symptomatic cardiovascular disease, advanced arteriosclerosis, structural cardiac abnormality, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems that may place them at increased vulnerability to the sympathomimetic effects of a stimulant medication.

12. Subject has a history of thyroid disorder that has not been stabilized on thyroid medication or treatment within 3 months prior to the Screening Visit.

13. Subject has a known family history of sudden cardiac death or ventricular arrhythmia.

14. Subject has glaucoma.

15. Subject has any clinically significant ECG or clinical laboratory abnormalities at the Screening Visit.

16. Subject has a history of moderate to severe hypertension.

17. Current use of any other medication (including over-the-counter [OTC], herbal or homeopathic preparations) that has central nervous system effects.

18. Subject has the potential to need to initiate or modify frequency of psychotherapy or to continue or initiate other treatments for depression, outside of those allowed in this protocol.

19. Subject has had electroconvulsive therapy for the current depressive episode 3 months prior to the Lead-in Baseline Visit.

20. The subject has a known or suspected intolerance or hypersensitivity to the investigational product.

21. The subject has a known or suspected intolerance or hypersensitivity to any of the possible antidepressant treatments (escitalopram oxalate or venlafaxine HCL extended release.

22. Subject has a positive urine drug result.

23. Subject has a body mass index of <18.5 or >40.

24. Subject is female and is pregnant or nursing.

25. Subject has participated in another clinical study involving SPD489/NRP104 or has previously used commercial lisdexamfetamine dimesylate.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Arkansas Psychiatric Clinic Clinical Research Trials	Little Rock	Arkansas	United States	72223
2	South Coast Clinical Trials	Anaheim	California	United States	92804
3	Catalina Research Institute, LLC	Chino	California	United States	91710
4	Shanti Clinical Trials	Colton	California	United States	92324
5	Clinical Innovation, Inc.	Costa Mesa	California	United States	92626
6	Collaborative Neuroscience Network, Inc.	Garden Grove	California	United States	92845
7	Irvine Center for Clinical Research	Irvine	California	United States	92618
8	Omega Clinical Trials	La Habra	California	United States	90631
9	Provate Practice of Andrew Leuchter, MD	Los Angeles	California	United States	90024
10	PCSD - Feighner Research	San Diego	California	United States	92108
11	Artemis Institute for Clinical Research	San Diego	California	United States	92123
12	Neuropsychiatric Research Center of Orange County	Santa Ana	California	United States	92701
13	California Neuroscience Research Medical Group, Inc.	Sherman Oaks	California	United States	91403
14	Western Affiliated Research Institute	Denver	Colorado	United States	80209
15	Connecticut Clinical Research	Cromwell	Connecticut	United States	06416
16	Institute of Living	Hartford	Connecticut	United States	06106
17	The Hospital of Central Connecticut, Psychiatry & Behavioral Health Research	New Britain	Connecticut	United States	06050
18	Gulfcoast Clinical Research Center	Fort Myers	Florida	United States	33912
19	Sarkis Clinical Trials	Gainesville	Florida	United States	32607
20	Clinical Neuroscience Solutions, Inc.	Jacksonville	Florida	United States	32216
21	Private Practice - Amit Vijapura MD	Jacksonville	Florida	United States	32256
22	Psychiatric Associates	Lake City	Florida	United States	32025
23	Comprehensive Neuroscience, Inc.	Miramar	Florida	United States	33027
24	Fideltiy Clinical Research, Inc.	North Miami	Florida	United States	33161
25	Ali A. Kashfi, MD, PA	Orlando	Florida	United States	32839
26	Clinical Research of Central Florida	Winter Haven	Florida	United States	33880
27	Kolin Research Group	Winter Park	Florida	United States	32789
28	Institute for Behavioral Medicine, LLC	Smyrna	Georgia	United States	30080
29	Treatment Research Center, Rush University Medical Center	Chicago	Illinois	United States	60612
30	Alexian Brothers Center for Psychiatric Research	Hoffman Estates	Illinois	United States	60169
31	Psychiatric Medicine Associates, LLC	Skokie	Illinois	United States	60076
32	Sleep and Behavior Medicine Institute	Vernon Hills	Illinois	United States	60061
33	Clinical Trials Technology, Inc.	Prairie Village	Kansas	United States	66206
34	Pedia Research, LLC	Owensboro	Kentucky	United States	42301
35	Psyichatric Care and Research Center	O'Fallon	Missouri	United States	63368
36	Mid-America Clinical Research, LLC	Saint Louis	Missouri	United States	63109
37	Premier Psychiatric Research Institute, LLC.	Lincoln	Nebraska	United States	68526
38	Clinical Research Consortium	Las Vegas	Nevada	United States	89119
39	Center for Emotional Fitness	Cherry Hill	New Jersey	United States	08002
40	CRI Worldwide LLC	Willingboro	New Jersey	United States	08046
41	Albuquerque Neuroscience, Inc.	Albuquerque	New Mexico	United States	87109
42	Montefiore Medical Center	Bronx	New York	United States	10467
43	Clinlabs, Inc.	New York	New York	United States	10010
44	Mount Sinai School of Medicine	New York	New York	United States	11029
45	Private Practice - Daniel I. Rifkin MD PC	West Seneca	New York	United States	14224
46	Clinical Trials of America, Inc.	Hickory	North Carolina	United States	28601
47	North Coast Clinical Trials, Inc.	Beachwood	Ohio	United States	44122
48	Ohio State University, Dept. of Psychiatry	Columbus	Ohio	United States	43210
49	Neurology & Neuroscience Center of Ohio	Toledo	Ohio	United States	43623
50	IPS Research Company	Oklahoma City	Oklahoma	United States	73103
51	Thomas Jefferson University	Philadelphia	Pennsylvania	United States	19107
52	University Services	West Chester	Pennsylvania	United States	19380
53	Pillar Clinical Research, LLC	Dallas	Texas	United States	75243
54	Bay Area Clinical Services	Friendswood	Texas	United States	77546
55	Houston Clinical Trials, LLC	Houston	Texas	United States	77098
56	Wharton Research Center, Inc.	Wharton	Texas	United States	77488
57	Grayline Clinical Drug Trials	Wichita Falls	Texas	United States	76309
58	Alliance Research Group	Richmond	Virginia	United States	23230
59	Dean Foundation for Health, Research and Education, Inc.	Middleton	Wisconsin	United States	53562
60	Independent Psychiatric Consultants, SC, dba, IPC Research	Waukesha	Wisconsin	United States	53188
61	Instituto Nacional de Psicopatologia	Buenos Aires		Argentina	C1405BOA
62	Cervino	Buenos Aires		Argentina
63	Centro Medico de Medicina Familiar Mind Out Research	Caba		Argentina	1417
64	BA Psychiatric Research Center	Caba		Argentina	C1012AAU
65	Instituto Medico SAMIC	Cordoba		Argentina
66	Peninsula Health Mental Health Services	Frankston	Victoria	Australia	3199
67	Neurotherapy Victoria	Malvern	Victoria	Australia	3144
68	The Alfred, Monash Alfred Psychiatry Research Centre	Melbourne	Victoria	Australia	3004
69	The Melbourne Clinic	Richmond	Victoria	Australia	3121
70	Lyell McEwin Hospital, Mental Health Clinical Trials Unit	Elizabeth Vale		Australia	5112
71	Psocomed Estudios Medicos	Antofagasta	Il Region	Chile	1270244
72	Especialidades Medicas L y S	Las Condes	Santiago	Chile	7560356
73	Centro de Estudios y Tratemiento de Enfermedades Psiquiatricas	Las Condes	Santiago	Chile	7580307
74	Biomedica Research Group	Providencia	Santiago	Chile	7500710
75	Centro de Estudios Clinicos	Providencia	Santiago	Chile	7510186
76	Unidad de Salud Mental y Psiquietriea Hospital y CRS El Pino	San Bernardo	Santiago	Chile	8053095
77	Hospital Barros Luco Trudsau	San Miguel	Santiago	Chile	890085
78	Hollins Park Hospital	Winwick	Warrington Cheshire	United Kingdom	WA2 8WA
79	Radbourne Unit	Derby		United Kingdom	DE22 3NE
80	ADHD Mental Health Research Unit	Horsham		United Kingdom	RH12 1RJ
81	Newcastle University, Wolfson Research Centre	Newcastle upon Tyne		United Kingdom	NE4 5PL
82	Rushcliffe Mental Health Team	Nottingham		United Kingdom	NG2 7PG

Sponsors and Collaborators

• Shire

Investigators

• Study Director: Study Director, Takeda

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Shire
• ClinicalTrials.gov Identifier: NCT01435759
• Other Study ID Numbers: SPD489-209; 2011-003615-28
• First Posted: Sep 19, 2011
• Last Update Posted: Jun 9, 2021
• Last Verified: May 1, 2021

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

Study Results

Participant Flow

Arm/Group Title	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
Arm/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 single-blind placebo (matching SPD489).	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).	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.	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.	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.	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.
Period Title: Antidepressant Lead-in Phase
STARTED	1197	0	0	0	0	0
COMPLETED	855	0	0	0	0	0
NOT COMPLETED	342	0	0	0	0	0
Period Title: Antidepressant Lead-in Phase
STARTED	463	78	78	78	78	80
COMPLETED	397	71	71	69	69	71
NOT COMPLETED	66	7	7	9	9	9

Baseline Characteristics

Arm/Group Title	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
Arm/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).	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.	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.	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.	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.	Total of all reporting groups
Overall Participants	78	77	76	78	80	389
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	43.7 (10.48)	39.1 (11.83)	43.4 (12.06)	43.8 (12.4)	41.5 (10.81)	42.3 (11.61)
Age, Customized (Count of Participants)
18-55	69 88.5%	70 90.9%	62 81.6%	60 76.9%	71 88.8%	332 85.3%
56-65	9 11.5%	7 9.1%	14 18.4%	18 23.1%	9 11.3%	57 14.7%
Sex: Female, Male (Count of Participants)
Female	53 67.9%	53 68.8%	52 68.4%	53 67.9%	53 66.3%	264 67.9%
Male	25 32.1%	24 31.2%	24 31.6%	25 32.1%	27 33.8%	125 32.1%
Region of Enrollment (Count of Participants)
ARGENTINA	2 2.6%	3 3.9%	5 6.6%	3 3.8%	5 6.3%	18 4.6%
AUSTRALIA	0 0%	0 0%	0 0%	2 2.6%	3 3.8%	5 1.3%
CHILE	3 3.8%	6 7.8%	12 15.8%	9 11.5%	2 2.5%	32 8.2%
UNITED KINGDOM	1 1.3%	0 0%	0 0%	0 0%	0 0%	1 0.3%
UNITED STATES	72 92.3%	68 88.3%	59 77.6%	64 82.1%	70 87.5%	333 85.6%

Outcome Measures

1. Secondary Outcome

Title	Change in Average Systolic Blood Pressure From Augmentation Baseline (Week 8) to Week 16
Time Frame	From Augmentation Baseline (Week 8) to Week 16

Outcome Measure Data

Analysis Population Description

Vital Signs Evaluable Set: 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.

Arm/Group Title	Antidepressant + Double-blind Placebo	Antidepressant + Double-blind SPD489 10mg	Antidepressant + Double-blind SPD489 30mg	Antidepressant + Double-blind SPD489 50mg	Antidepressant + Double-blind SPD489 70mg
Arm/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).	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.	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.	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.	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.
Measure Participants	67	68	65	51	63
Mean (Standard Deviation) [mmHg]	-0.2 (9.55)	0.2 (8.58)	0.5 (9.17)	3.5 (7.82)	2.6 (10.55)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Antidepressant + Double-blind Placebo, Antidepressant + Double-blind SPD489 10mg, Antidepressant + Double-blind SPD489 30mg, Antidepressant + Double-blind SPD489 50mg, Antidepressant + Double-blind SPD489 70mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments
	Method	MCP-Mod Analysis
	Comments	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.
Method of Estimation	Estimation Parameter	Least Squares Mean
	Estimated Value	3.16
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.01
	Estimation Comments	The t-statistic used for this analysis, 3.14, was based on MCP-Mod Analysis for the candidate model EMax.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Antidepressant + Double-blind Placebo, Antidepressant + Double-blind SPD489 10mg, Antidepressant + Double-blind SPD489 30mg, Antidepressant + Double-blind SPD489 50mg, Antidepressant + Double-blind SPD489 70mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.032
	Comments
	Method	MCP-Mod Analysis
	Comments	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.
Method of Estimation	Estimation Parameter	Least Squares Means
	Estimated Value	2.50
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.01
	Estimation Comments	The t-statistic used for this analysis, 2.48, was based on MCP-Mod Analysis for the candidate model Exponential.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Antidepressant + Double-blind Placebo, Antidepressant + Double-blind SPD489 10mg, Antidepressant + Double-blind SPD489 30mg, Antidepressant + Double-blind SPD489 50mg, Antidepressant + Double-blind SPD489 70mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	MCP-Mod Analysis
	Comments	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.
Method of Estimation	Estimation Parameter	Least Squares Mean
	Estimated Value	3.28
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.01
	Estimation Comments	The t-statistic used for this analysis, 3.26 was based on MCP-Mod Analysis for the candidate model Linear.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Antidepressant + Double-blind Placebo, Antidepressant + Double-blind SPD489 10mg, Antidepressant + Double-blind SPD489 30mg, Antidepressant + Double-blind SPD489 50mg, Antidepressant + Double-blind SPD489 70mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.010
	Comments
	Method	MCP-Mod Analysis Method
	Comments	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.
Method of Estimation	Estimation Parameter	Least Squares Means
	Estimated Value	2.91
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.01
	Estimation Comments	The t-statistic used for this analysis, 2.88, was based on MCP-Mod Analysis for the candidate model Logistic1.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Antidepressant + Double-blind Placebo, Antidepressant + Double-blind SPD489 10mg, Antidepressant + Double-blind SPD489 30mg, Antidepressant + Double-blind SPD489 50mg, Antidepressant + Double-blind SPD489 70mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.005
	Comments
	Method	MCP-Mod Analysis
	Comments	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.
Method of Estimation	Estimation Parameter	Least Squares Means
	Estimated Value	3.15
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.01
	Estimation Comments	The t-statistic used for this analysis, 3.12, was based on MCP-Mod Analysis for the candidate model Logistic2.

2. Secondary Outcome

Title	Change in Average Diastolic Blood Pressure From Augmentation Baseline (Week 8) to Week 16
Time Frame	From Augmentation Baseline (Week 8) to Week 16

Outcome Measure Data

Analysis Population Description

Vital Signs Evaluable Set: 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.

Arm/Group Title	Antidepressant + Double-blind Placebo	Antidepressant + Double-blind SPD489 10mg	Antidepressant + Double-blind SPD489 30mg	Antidepressant + Double-blind SPD489 50mg	Antidepressant + Double-blind SPD489 70mg
Arm/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).	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.	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.	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.	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.
Measure Participants	67	68	65	51	63
Mean (Standard Deviation) [mmHg]	-0.1 (6.69)	-0.9 (6.64)	-0.1 (7.39)	2.8 (6.58)	1.9 (7.45)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Antidepressant + Double-blind Placebo, Antidepressant + Double-blind SPD489 10mg, Antidepressant + Double-blind SPD489 30mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.011
	Comments
	Method	MCP-Mod Analysis
	Comments	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.
Method of Estimation	Estimation Parameter	Least Squares Means
	Estimated Value	2.16
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.75
	Estimation Comments	The t-statistic used for this analysis, 2.86 was based on MCP-Mod Analysis for the candidate model Emax.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Antidepressant + Double-blind Placebo, Antidepressant + Double-blind SPD489 10mg, Antidepressant + Double-blind SPD489 30mg, Antidepressant + Double-blind SPD489 50mg, Antidepressant + Double-blind SPD489 70mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.023
	Comments
	Method	MCP-Mod Analysis
	Comments	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.
Method of Estimation	Estimation Parameter	Least Squares Means
	Estimated Value	1.95
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.75
	Estimation Comments	The t-statistic used for this analysis, 2.59, was based on MCP-Mod Analysis for the candidate model Exponential.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Antidepressant + Double-blind Placebo, Antidepressant + Double-blind SPD489 10mg, Antidepressant + Double-blind SPD489 30mg, Antidepressant + Double-blind SPD489 50mg, Antidepressant + Double-blind SPD489 70mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	Least Squares Means
	Comments	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.
Method of Estimation	Estimation Parameter	MCP-Mod Analysis
	Estimated Value	2.47
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.75
	Estimation Comments	The t-statistic used for this analysis, 3.28, was based on MCP-Mod Analysis for the candidate model Linear.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Antidepressant + Double-blind Placebo, Antidepressant + Double-blind SPD489 10mg, Antidepressant + Double-blind SPD489 30mg, Antidepressant + Double-blind SPD489 50mg, Antidepressant + Double-blind SPD489 70mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.009
	Comments
	Method	MCP-Mod Analysis
	Comments	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.
Method of Estimation	Estimation Parameter	Least Squares Means
	Estimated Value	2.22
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.76
	Estimation Comments	The t-statistic used for this analysis, 2.93, was based on MCP-Mod Analysis for the candidate model Logistic1.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Antidepressant + Double-blind Placebo, Antidepressant + Double-blind SPD489 10mg, Antidepressant + Double-blind SPD489 30mg, Antidepressant + Double-blind SPD489 50mg, Antidepressant + Double-blind SPD489 70mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.005
	Comments
	Method	MCP-Mod Analysis
	Comments	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.
Method of Estimation	Estimation Parameter	Least Squares Means
	Estimated Value	2.37
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.76
	Estimation Comments	The t-statistic used for this analysis, 3.13, was based on MCP-Mod Analysis for the candidate model Logistic2.

3. Secondary Outcome

Title	Change in Average Pulse Rate From Augmentation Baseline (Week 8) to Week 16
Time Frame	From Augmentation Baseline (Week 8) to Week 16

Outcome Measure Data

Analysis Population Description

Vital Signs Evaluable Set: 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.

Arm/Group Title	Antidepressant + Double-blind Placebo	Antidepressant + Double-blind SPD489 10mg	Antidepressant + Double-blind SPD489 30mg	Antidepressant + Double-blind SPD489 50mg	Antidepressant + Double-blind SPD489 70mg
Arm/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).	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.	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.	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.	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.
Measure Participants	67	68	65	51	63
Mean (Standard Deviation) [bpm]	-0.8 (9.95)	0.8 (7.32)	5.3 (8.08)	4.0 (9.80)	6.0 (11.25)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Antidepressant + Double-blind Placebo, Antidepressant + Double-blind SPD489 10mg, Antidepressant + Double-blind SPD489 30mg, Antidepressant + Double-blind SPD489 50mg, Antidepressant + Double-blind SPD489 70mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	MCP-Mod Analysis
	Comments	The pulse p-value was based on a critical value of 1.99 from a multivariate-t distribution with 341 degrees of freedom.
Method of Estimation	Estimation Parameter	Least Squares Means
	Estimated Value	4.45
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.05
	Estimation Comments	The t-statistic used for this analysis, 4.24, was based on MCP-Mod Analysis for the candidate model Emax

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Antidepressant + Double-blind Placebo, Antidepressant + Double-blind SPD489 10mg, Antidepressant + Double-blind SPD489 30mg, Antidepressant + Double-blind SPD489 50mg, Antidepressant + Double-blind SPD489 70mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	MCP-Mod Analysis
	Comments	The pulse p-value was based on a critical value of 1.99 from a multivariate-t distribution with 341 degrees of freedom.
Method of Estimation	Estimation Parameter	Least Squares Means
	Estimated Value	3.52
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.05
	Estimation Comments	The t-statistic used for this analysis, 3.36, was based on MCP-Mod Analysis for the candidate model Expontential.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Antidepressant + Double-blind Placebo, Antidepressant + Double-blind SPD489 10mg, Antidepressant + Double-blind SPD489 30mg, Antidepressant + Double-blind SPD489 50mg, Antidepressant + Double-blind SPD489 70mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	MCP-Mod Analysis
	Comments	The pulse p-value was based on a critical value of 1.99 from a multivariate-t distribution with 341 degrees of freedom.
Method of Estimation	Estimation Parameter	Least Squares Means
	Estimated Value	4.30
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.05
	Estimation Comments	The t-statistic used for this analysis, 4.10, was based on MCP-Mod Analysis for the candidate model Linear.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Antidepressant + Double-blind Placebo, Antidepressant + Double-blind SPD489 10mg, Antidepressant + Double-blind SPD489 30mg, Antidepressant + Double-blind SPD489 50mg, Antidepressant + Double-blind SPD489 70mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	MCP-Mod Analysis
	Comments	The pulse p-value was based on a critical value of 1.99 from a multivariate-t distribution with 341 degrees of freedom.
Method of Estimation	Estimation Parameter	Least Squares Means
	Estimated Value	4.63
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.05
	Estimation Comments	The t-statistic used for this analysis, 4.39, was based on MCP-Mod Analysis for the candidate model Logistic1.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Antidepressant + Double-blind Placebo, Antidepressant + Double-blind SPD489 10mg, Antidepressant + Double-blind SPD489 30mg, Antidepressant + Double-blind SPD489 50mg, Antidepressant + Double-blind SPD489 70mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	MCP-Mod Analysis
	Comments	The pulse p-value was based on a critical value of 1.99 from a multivariate-t distribution with 341 degrees of freedom.
Method of Estimation	Estimation Parameter	Least Squares Means
	Estimated Value	4.63
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.05
	Estimation Comments	The t-statistic used for this analysis, 4.39 was based on MCP-Mod Analysis for the candidate model Logistic2.

4. Primary Outcome

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)
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.
Time Frame	Augmentation Baseline (Week 8) to Week 16

Outcome Measure Data

Analysis Population Description

Dose Response Evaluable Set (DRES): 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.

Arm/Group Title	Antidepressant + Double-blind Placebo	Antidepressant + Double-blind SPD489 10mg	Antidepressant + Double-blind SPD489 30mg	Antidepressant + Double-blind SPD489 50mg	Antidepressant + Double-blind SPD489 70mg
Arm/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).	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.	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.	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.	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.
Measure Participants	72	71	69	66	71
Least Squares Mean (90% Confidence Interval) [units on a scale]	-5.4	-6.7	-5.3	-6.1	-6.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Antidepressant + Double-blind Placebo, Antidepressant + Double-blind SPD489 10mg, Antidepressant + Double-blind SPD489 30mg, Antidepressant + Double-blind SPD489 50mg, Antidepressant + Double-blind SPD489 70mg
	Comments	Analysis of Dose-Response Using the MCP-Mod Analysis Method
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments	Any p-value <=0.10 indicates successful establishment of dose-response relationship.
	Method	MCP-Mod Analysis Method
	Comments	The adjusted p-value was based on a critical value of 2.02 from a multivariate-t distribution with 341 degrees of freedom.
Method of Estimation	Estimation Parameter	Least Squares Means
	Estimated Value	-.11
	Confidence Interval	(1-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.07
	Estimation Comments	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.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Antidepressant + Double-blind Placebo, Antidepressant + Double-blind SPD489 10mg, Antidepressant + Double-blind SPD489 30mg, Antidepressant + Double-blind SPD489 50mg, Antidepressant + Double-blind SPD489 70mg
	Comments	Analysis of Dose-Response Using the MCP-Mod Analysis Method.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.942
	Comments	Any p-value <=0.10 indicates successful establishment of dose-response relationship.
	Method	MCP-Mod Analysis
	Comments	The adjusted p-value was based on a critical value of 2.02 from a multivariate-t distribution with 341 degrees of freedom.
Method of Estimation	Estimation Parameter	Least Squares Means
	Estimated Value	0.43
	Confidence Interval	(1-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.06
	Estimation Comments	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.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Antidepressant + Double-blind Placebo, Antidepressant + Double-blind SPD489 10mg, Antidepressant + Double-blind SPD489 30mg, Antidepressant + Double-blind SPD489 50mg, Antidepressant + Double-blind SPD489 70mg
	Comments	Analysis of Dose-Response Using the MCP-Mod Analysis Method.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.995
	Comments	Any p-value <=0.10 indicates successful establishment of dose-response relationship.
	Method	MCP-Mod Analysis
	Comments	The adjusted p-value was based on a critical value of 2.02 from a multivariate-t distribution with 341 degrees of freedom.
Method of Estimation	Estimation Parameter	Least Squares Means
	Estimated Value	0.21
	Confidence Interval	(1-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.06
	Estimation Comments	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.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Antidepressant + Double-blind Placebo, Antidepressant + Double-blind SPD489 10mg, Antidepressant + Double-blind SPD489 30mg, Antidepressant + Double-blind SPD489 50mg, Antidepressant + Double-blind SPD489 70mg
	Comments	Analysis of Dose-Response Using the MCP-Mod Analysis Method
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.978
	Comments	Any p-value <=0.10 indicates successful establishment of dose-response relationship.
	Method	MCP-Mod Analysis
	Comments	The adjusted p-value was based on a critical value of 2.02 from a multivariate-t distribution with 341 degrees of freedom.
Method of Estimation	Estimation Parameter	Least Squares Means
	Estimated Value	-.32
	Confidence Interval	(1-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.07
	Estimation Comments	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.

Adverse Events

Adverse Event Reporting Description	Safety Analysis Set: All subjects who took at least 1 dose of randomized investigational product and who had at least 1 post-augmentation baseline safety assessment (e.g. coming back for any visit, reporting of an AE or reporting the absence of AEs). Subjects who received only single-blind placebo were not included in this group.
Arm/Group Title	Antidepressant + Double-blind Placebo		Antidepressant + Double-blind SPD489 10mg		Antidepressant + Double-blind SPD489 30mg		Antidepressant + Double-blind SPD489 50mg		Antidepressant + Double-blind SPD489 70mg
Arm/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).		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.		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.		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.		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.
All Cause Mortality
	Antidepressant + Double-blind Placebo		Antidepressant + Double-blind SPD489 10mg		Antidepressant + Double-blind SPD489 30mg		Antidepressant + Double-blind SPD489 50mg		Antidepressant + Double-blind SPD489 70mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
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
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/78 (0%)		0/77 (0%)		0/76 (0%)		0/78 (0%)		1/80 (1.3%)
Hepatobiliary disorders
Cholecystitis	0/78 (0%)	0	0/77 (0%)	0	0/76 (0%)	0	0/78 (0%)	0	1/80 (1.3%)	1
Other (Not Including 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
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	20/78 (25.6%)		30/77 (39%)		29/76 (38.2%)		36/78 (46.2%)		44/80 (55%)
Gastrointestinal disorders
Diarrhoea	4/78 (5.1%)	5	2/77 (2.6%)	2	3/76 (3.9%)	3	2/78 (2.6%)	2	5/80 (6.3%)	5
Dry mouth	1/78 (1.3%)	1	2/77 (2.6%)	2	2/76 (2.6%)	2	10/78 (12.8%)	10	10/80 (12.5%)	10
Nausea	1/78 (1.3%)	1	5/77 (6.5%)	5	6/76 (7.9%)	6	1/78 (1.3%)	1	6/80 (7.5%)	7
General disorders
Fatigue	1/78 (1.3%)	1	0/77 (0%)	0	2/76 (2.6%)	2	1/78 (1.3%)	1	4/80 (5%)	4
Infections and infestations
Influenza	2/78 (2.6%)	3	1/77 (1.3%)	1	4/76 (5.3%)	4	4/78 (5.1%)	5	1/80 (1.3%)	1
Nasopharyngitis	0/78 (0%)	0	5/77 (6.5%)	5	4/76 (5.3%)	5	2/78 (2.6%)	2	7/80 (8.8%)	8
Upper respiratory tract infection	0/78 (0%)	0	3/77 (3.9%)	3	3/76 (3.9%)	3	4/78 (5.1%)	4	3/80 (3.8%)	3
Urinary tract infection	5/78 (6.4%)	5	1/77 (1.3%)	1	2/76 (2.6%)	2	1/78 (1.3%)	1	2/80 (2.5%)	2
Investigations
Blood pressure increased	0/78 (0%)	0	1/77 (1.3%)	1	0/76 (0%)	0	3/78 (3.8%)	3	4/80 (5%)	4
Metabolism and nutrition disorders
Decreased appetite	1/78 (1.3%)	1	4/77 (5.2%)	4	5/76 (6.6%)	6	5/78 (6.4%)	5	4/80 (5%)	6
Nervous system disorders
Dizziness	2/78 (2.6%)	2	2/77 (2.6%)	2	2/76 (2.6%)	2	5/78 (6.4%)	5	1/80 (1.3%)	1
Headache	10/78 (12.8%)	12	7/77 (9.1%)	8	5/76 (6.6%)	9	3/78 (3.8%)	5	8/80 (10%)	9
Psychiatric disorders
Bruxism	1/78 (1.3%)	1	0/77 (0%)	0	1/76 (1.3%)	1	4/78 (5.1%)	4	6/80 (7.5%)	7
Insomnia	2/78 (2.6%)	2	7/77 (9.1%)	9	2/76 (2.6%)	2	8/78 (10.3%)	10	9/80 (11.3%)	11
Skin and subcutaneous tissue disorders
Hyperhidrosis	1/78 (1.3%)	1	4/77 (5.2%)	4	0/76 (0%)	0	1/78 (1.3%)	1	3/80 (3.8%)	3

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.