Efficacy and Safety of SPD503 in Combination With Psychostimulants

• Sponsor: Shire (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00734578
• Collaborator: (none)
• Enrollment: 461
• Locations: 61
• Arms: 3
• Actual Duration (Months): 15.2
• Patients Per Site: 7.6
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

The purpose of this study is to assess the efficacy and safety of SPD503 in subjects with ADHD when co-administered with psychostimulants in children and adolescents aged 6-17 years with a diagnosis of ADHD with a sub-optimal, partial response to stimulants.

Condition or Disease	Intervention/Treatment	Phase
ADHD	Drug: SPD503-AM; Drug: SPD503-PM; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 461 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase III, Double-Blind, Randomized, Placebo-Controlled, Multi-Center, Dose Optimization Study Evaluating the Efficacy and Safety of SPD503 in Combination With Psychostimulants in Children and Adolescents Aged 6-17 Years With a Diagnosis of Attention-Deficit/Hyperactivity Disorder (ADHD)
• Actual Study Start Date: Sep 2, 2008
• Actual Primary Completion Date: Dec 10, 2009
• Actual Study Completion Date: Dec 10, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: SPD503-AM SPD503 (Guanfacine Extended Release)	Drug: SPD503-AM; SPD503 (Guanfacine Extended Release)-AM Optimized 1-4mg; Other Names: Intuniv
Experimental: SPD503-PM SPD503 (Guanfacine Extended Release)	Drug: SPD503-PM; SPD503 (Guanfacine Extended Release)-PM Optimized 1-4mg; Other Names: Intuniv
Placebo Comparator: Placebo	Drug: Placebo; Placebo matched to Guanfacine Hydrochloride Extended Release

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Attention Deficit Hyperactivity Disorder Rating Scale-fourth Edition (ADHD-RS-IV) Total Score at Week 8 - Last Observation Carried Forward (LOCF) [Baseline and weekly up to 8 weeks]

   The ADHD-RS-IV consists of 18 items scored on a 4-point scale ranging from 0 (no symptoms) to 3 (severe symptoms) with total score ranging from 0 to 54.

Secondary Outcome Measures

1. Percentage of Participants With Improvement on Clinical Global Impression-Improvement (CGI-I) at Week 8 - LOCF [Baseline and weekly up to 8 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.

2. Assessment of Clinical Global Impression-Severity of Illness (CGI-S) at Week 8 - LOCF [Baseline and weekly up to 8 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)

3. Change From Baseline in Conners' Global Index - Parent (CGI-P) Total Score at Week 8 - LOCF: Morning Assessment (Before School) [Baseline and weekly up to 8 weeks]

   The index contains 10 items. Each item on the scale is scored from a range of 0 (reflecting never, seldom) to 3 (reflecting very often, very frequent) with total scores ranging from 0 to 30.

4. Change From Baseline in Conners' Global Index - Parent (CGI-P) Total Score at Week 8 - LOCF: Evening Assessment (Before Bedtime) [Baseline and weekly up to 8 weeks]

   The index contains 10 items. Each item on the scale is scored from a range of 0 (reflecting never, seldom) to 3 (reflecting very often, very frequent) with total scores ranging from 0 30.

5. Percentage of Participants With Improvement on Parent Global Assessment (PGA) at Week 8 - LOCF [Baseline and week 8]

   Parent Global Assessment (PGA) 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.

6. Change From Baseline in the Oppositional Subscale of the Conners' Parent Rating Scale-Revised Long Form (CPRS-R:L) Score at Week 8 - LOCF [Baseline and weekly up to 8 weeks]

   The oppositional subscale of the CPRS-R:L contains 10 items designed to reflect criteria for oppositional defiance disorder (ODD). Each item is scored on a range from 0 (not true at all) to 3 (very much true) with total scores ranging from 0 to 30. Higher scores are reflective of more severe symptoms.

7. Change From Baseline in Before School Functioning Questionnaire (BSFQ) at Week 8 - LOCF [Baseline and weekly up to 8 weeks]

   This scale was designed to assess symptoms of ADHD that typically occur in the morning. The BSFQ consists of two components. The first, a 20-item scale with ratings from 0 (none) to 3 (severe) with a range of 0-60 followed by two questions answered with duration of time (in minutes). The second, a 14-item scale with ratings from 0 (no) to 2 (a lot) with a range of 0-28. The results reported here are from the 20-item scale. Lower scores are better.

8. Post Sleep Questionnaire (PSQ) Quality of Sleep at Week 8 - LOCF [Baseline and weekly up to 8 weeks]

   Post Sleep Questionnaire (PSQ) overall rating of quality of sleep. There are 5 rating responses ranging from very poor to very good. No numbers are associated with the rating responses.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Years to 17 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Healthy subjects with ADHD currently taking a stable dose of psychostimulant for at least 4 weeks

• Aged 6-17 years with a sub-optimal

• Partial response to stimulants

• Subjects must be < 95th percentile for BMI with weight >= 55lbs and <= 176lbs

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Harmonex Neuroscience Research	Dothan	Alabama	United States	36303
2	Melmed Center	Scottsdale	Arizona	United States	85254
3	Clinical Study Centers, LLC	Little Rock	Arkansas	United States	72205
4	Valley Clinical Research, Inc.	El Centro	California	United States	92243
5	Peninsula Research Associates	Rolling Hills Estates	California	United States	90274
6	UCSD Department of Psychiatry	San Diego	California	United States	8620
7	University of California, San Francisco	San Francisco	California	United States	94143
8	Elite Clinical Trials, Inc	Wildomar	California	United States	92595
9	Florida Clinical Research Center, LLC	Bradenton	Florida	United States	32751
10	Gulfcoast Clinical Research Center	Fort Myers	Florida	United States	33912
11	Sarkis Clinical Trials	Gainesville	Florida	United States	32607
12	Clinical Neuroscience Solutions, Inc.	Jacksonville	Florida	United States	32216
13	Florida Clinical Research Center, LLC	Maitland	Florida	United States	32751
14	Miami Children's Hospital	Miami	Florida	United States	33155
15	Clinical Neuroscience Solutions, Inc.	Orlando	Florida	United States	32806
16	Janus Center for Psychiatric Research	West Palm Beach	Florida	United States	33407
17	AMR-Baber Research, Inc.	Naperville	Illinois	United States	60563
18	American Medical Research, Inc	Oak Brook	Illinois	United States	60523
19	Goldpoint Clinical Research, LLC	Indianapolis	Indiana	United States	46260
20	Pedia Research	Newburgh	Indiana	United States	47630
21	Psychiatric Associates	Overland Park	Kansas	United States	66211
22	Vince and Associates Clinical Research	Overland Park	Kansas	United States	66212
23	Pedia Research, LLC	Owensboro	Kentucky	United States	42301
24	Marc Hertzman, MD, PC	Rockville	Maryland	United States	20852
25	Delmarva Family Resources	Salisbury	Maryland	United States	21801
26	Massachussests General Hospital	Cambridge	Massachusetts	United States	02138
27	Neurobehaviorial Medicine	Bloomfield Hills	Michigan	United States	48302
28	Rochester Center for Behavioral Medicine	Rochester Hills	Michigan	United States	48307
29	Behavioral Medicine Center	Troy	Michigan	United States	48083
30	The Center for Pharmaceutical Research	Kansas City	Missouri	United States	64114
31	Midwest Research Group/St. Charles Psychiatric Associates	Saint Charles	Missouri	United States	63301
32	Premier Psychiatric Research Inst. LLC	Lincoln	Nebraska	United States	68510
33	Centers for Psychiatry and Behavioral Medicine	Las Vegas	Nevada	United States	89128
34	Children's Specialized Hospital	Toms River	New Jersey	United States	08755
35	Bioscience Research, LLC	Mount Kisco	New York	United States	10549
36	Richmond Behavioral Associates	Staten Island	New York	United States	10312
37	Duke University Medical Center ADHD Program	Durham	North Carolina	United States	27705
38	Triangle Neuropsychiatry, PLLC	Durham	North Carolina	United States	27707
39	University Hospitals Cleveland Medical Center	Cleveland	Ohio	United States	44106
40	Department of Psychiatry, The Ohio State University	Columbus	Ohio	United States	43210
41	IPS Research	Oklahoma City	Oklahoma	United States	73103
42	Oregon Center for Clinical Investigations, Inc	Eugene	Oregon	United States	97401
43	Oregon Center for Clinical Investigations, INC (OCCI, Inc.)	Portland	Oregon	United States	97210
44	Summit Research Network	Portland	Oregon	United States	97210
45	Oregon Center for Clinical Investigations, Inc	Salem	Oregon	United States	97301
46	Western Psychiatric Institute and Clinic	Pittsburgh	Pennsylvania	United States	15065
47	Peds Research Inc.	Barnwell	South Carolina	United States	29812
48	FutureSearch Trials	Austin	Texas	United States	75756
49	InSite Clinical Research	DeSoto	Texas	United States	75115
50	Claghorn-Lesem Research Clinic, Inc.	Houston	Texas	United States	77008
51	Red Oak Psychiatry Associates, PA	Houston	Texas	United States	77090
52	Western Clinical Investigations	Lubbock	Texas	United States	79423
53	Cerebral Research, LLC	San Antonio	Texas	United States	78247
54	Wharton Research Center	Wharton	Texas	United States	77488
55	Vermont Clinical Study Center	Burlington	Vermont	United States	05401
56	Psychiatric Alliance of the Blue Ridge Clinical Research	Charlottesville	Virginia	United States	22903
57	NeuroScience, Inc	Herndon	Virginia	United States	20170
58	Dominion Clinical Research	Midlothian	Virginia	United States	23112
59	Alliance Research Group	Richmond	Virginia	United States	23230
60	Bayou City Research	Richmond	Virginia	United States	23230
61	Northwest Clinical Research Center	Bellevue	Washington	United States	98004

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 Label

Publications

None provided.

• Responsible Party: Shire
• ClinicalTrials.gov Identifier: NCT00734578
• Other Study ID Numbers: SPD503-313
• First Posted: Aug 14, 2008
• Last Update Posted: Jun 14, 2021
• Last Verified: Jun 1, 2021

• Additional relevant MeSH terms: Guanfacine

Study Results

Participant Flow

Arm/Group Title	SPD503-AM + Psychostimulant	SPD503-PM + Psychostimulant	Placebo + Psychostimulant
Arm/Group Description	Guanfacine Hydrochloride Extended Release administered in the AM plus a psychostimulant (subject was on a stable dose on entry and maintained throughout) administered each morning. This group received a matching placebo in the PM. An optimal dose of Guanfacine Hydrochloride Extended Release (1-4 mg/day once-daily) is determined for each subject over 5 weeks. The subject is then maintained on this optimal dose for an additional 3 weeks.	Guanfacine Hydrochloride Extended Release administered in the PM plus a psychostimulant (subject was on a stable dose on entry and maintained throughout) administered each morning. This group received a matching placebo in the AM. An optimal dose of Guanfacine Hydrochloride Extended Release (1-4 mg/day once-daily) is determined for each subject over 5 weeks. The subject is then maintained on this optimal dose for an additional 3 weeks.	Placebo was administered in both the AM and PM plus a psychostimulant (subject was on a stable dose on entry and maintained throughout) each morning.
Period Title: Overall Study
STARTED	154	153	154
COMPLETED	121	128	129
NOT COMPLETED	33	25	25

Baseline Characteristics

Arm/Group Title	SPD503-AM + Psychostimulant	SPD503-PM + Psychostimulant	Placebo + Psychostimulant	Total
Arm/Group Description	Guanfacine Hydrochloride Extended Release administered in the AM plus a psychostimulant (subject was on a stable dose on entry and maintained throughout) administered each morning. This group received a matching placebo in the PM. An optimal dose of Guanfacine Hydrochloride Extended Release (1-4 mg/day once-daily) is determined for each subject over 5 weeks. The subject is then maintained on this optimal dose for an additional 3 weeks.	Guanfacine Hydrochloride Extended Release administered in the PM plus a psychostimulant (subject was on a stable dose on entry and maintained throughout) administered each morning. This group received a matching placebo in the AM. An optimal dose of Guanfacine Hydrochloride Extended Release (1-4 mg/day once-daily) is determined for each subject over 5 weeks. The subject is then maintained on this optimal dose for an additional 3 weeks.	Placebo was administered in both the AM and PM plus a psychostimulant (subject was on a stable dose on entry and maintained throughout) each morning.	Total of all reporting groups
Overall Participants	150	152	153	455
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	11.0 (2.6)	10.6 (2.3)	10.8 (2.3)	10.8 (2.4)
Age, Customized (Count of Participants)
6-17 years	150 100%	152 100%	153 100%	455 100%
Sex: Female, Male (Count of Participants)
Female	42 28%	46 30.3%	41 26.8%	129 28.4%
Male	108 72%	106 69.7%	112 73.2%	326 71.6%
Region of Enrollment (Count of Participants)
United States	150 100%	152 100%	153 100%	455 100%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Attention Deficit Hyperactivity Disorder Rating Scale-fourth Edition (ADHD-RS-IV) Total Score at Week 8 - Last Observation Carried Forward (LOCF)
Description	The ADHD-RS-IV consists of 18 items scored on a 4-point scale ranging from 0 (no symptoms) to 3 (severe symptoms) with total score ranging from 0 to 54.
Time Frame	Baseline and weekly up to 8 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) which includes all subjects who received at least 1 dose of any study drug during this study.

Arm/Group Title	SPD503-AM + Psychostimulant	SPD503-PM + Psychostimulant	Placebo + Psychostimulant
Arm/Group Description	Guanfacine Hydrochloride Extended Release administered in the AM plus a psychostimulant (subject was on a stable dose on entry and maintained throughout) administered each morning. This group received a matching placebo in the PM. An optimal dose of Guanfacine Hydrochloride Extended Release (1-4 mg/day once-daily) is determined for each subject over 5 weeks. The subject is then maintained on this optimal dose for an additional 3 weeks.	Guanfacine Hydrochloride Extended Release administered in the PM plus a psychostimulant (subject was on a stable dose on entry and maintained throughout) administered each morning. This group received a matching placebo in the AM. An optimal dose of Guanfacine Hydrochloride Extended Release (1-4 mg/day once-daily) is determined for each subject over 5 weeks. The subject is then maintained on this optimal dose for an additional 3 weeks.	Placebo was administered in both the AM and PM plus a psychostimulant (subject was on a stable dose on entry and maintained throughout) each morning.
Measure Participants	149	148	152
Mean (Standard Deviation) [Units on a scale]	-20.4 (12.77)	-21.0 (12.39)	-16.0 (11.77)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	SPD503-AM + Psychostimulant, Placebo + Psychostimulant
	Comments	The null hypothesis stated that there was no difference between SPD503 AM or placebo and that there was no difference between SPD503 PM or placebo. 90% power was needed to detect an effect size of at least 0.4 between either SPD503 group and placebo.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments	Both SPD503 groups were compared with placebo using Dunnett's adjustment. Each treatment comparison was evaluated at the 0.05 significance level (Dunnett's adjusted).
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Placebo-adjusted difference in LS mean
	Estimated Value	-4.5
	Confidence Interval	() 95%; -7.5 to -1.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	SPD503-PM + Psychostimulant, Placebo + Psychostimulant
	Comments	The null hypothesis stated that there was no difference between SPD503 AM or placebo and that there was no difference between SPD503 PM or placebo. 90% power was needed to detect an effect size of at least 0.4 between either SPD503 group and placebo.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Both SPD503 groups were compared with placebo using Dunnett's adjustment. Each treatment comparison was evaluated at the 0.05 significance level (Dunnett's adjusted).
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Placebo-adjusted difference in LS mean
	Estimated Value	-5.3
	Confidence Interval	() 95%; -8.3 to -2.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Percentage of Participants With Improvement on Clinical Global Impression-Improvement (CGI-I) at Week 8 - 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	Baseline and weekly up to 8 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	SPD503-AM + Psychostimulant	SPD503-PM + Psychostimulant	Placebo + Psychostimulant
Arm/Group Description	Guanfacine Hydrochloride Extended Release administered in the AM plus a psychostimulant (subject was on a stable dose on entry and maintained throughout) administered each morning. This group received a matching placebo in the PM. An optimal dose of Guanfacine Hydrochloride Extended Release (1-4 mg/day once-daily) is determined for each subject over 5 weeks. The subject is then maintained on this optimal dose for an additional 3 weeks.	Guanfacine Hydrochloride Extended Release administered in the PM plus a psychostimulant (subject was on a stable dose on entry and maintained throughout) administered each morning. This group received a matching placebo in the AM. An optimal dose of Guanfacine Hydrochloride Extended Release (1-4 mg/day once-daily) is determined for each subject over 5 weeks. The subject is then maintained on this optimal dose for an additional 3 weeks.	Placebo was administered in both the AM and PM plus a psychostimulant (subject was on a stable dose on entry and maintained throughout) each morning.
Measure Participants	149	148	152
Number [Percent of participants]	70.5 47%	74.3 48.9%	57.9 37.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	SPD503-AM + Psychostimulant, Placebo + Psychostimulant
	Comments	Not powered for secondary outcome measures.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.024
	Comments	No adjustments for multiple comparisons.
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	SPD503-PM + Psychostimulant, Placebo + Psychostimulant
	Comments	Not powered for secondary outcome measures.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments	No adjustments for multiple comparisons.
	Method	Cochran-Mantel-Haenszel
	Comments

3. Secondary Outcome

Title	Assessment of Clinical Global Impression-Severity of Illness (CGI-S) at Week 8 - LOCF
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	Baseline and weekly up to 8 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	SPD503-AM + Psychostimulant	SPD503-PM + Psychostimulant	Placebo + Psychostimulant
Arm/Group Description	Guanfacine Hydrochloride Extended Release administered in the AM plus a psychostimulant (subject was on a stable dose on entry and maintained throughout) administered each morning. This group received a matching placebo in the PM. An optimal dose of Guanfacine Hydrochloride Extended Release (1-4 mg/day once-daily) is determined for each subject over 5 weeks. The subject is then maintained on this optimal dose for an additional 3 weeks.	Guanfacine Hydrochloride Extended Release administered in the PM plus a psychostimulant (subject was on a stable dose on entry and maintained throughout) administered each morning. This group received a matching placebo in the AM. An optimal dose of Guanfacine Hydrochloride Extended Release (1-4 mg/day once-daily) is determined for each subject over 5 weeks. The subject is then maintained on this optimal dose for an additional 3 weeks.	Placebo was administered in both the AM and PM plus a psychostimulant (subject was on a stable dose on entry and maintained throughout) each morning.
Measure Participants	149	148	152
Normal, not at all ill	22.8 15.2%	25.0 16.4%	15.1 9.9%
Borderline mentally ill	19.5 13%	26.4 17.4%	17.8 11.6%
Mildly ill	34.2 22.8%	26.4 17.4%	28.9 18.9%
Moderately ill	16.1 10.7%	16.2 10.7%	27.0 17.6%
Markedly ill	6.0 4%	5.4 3.6%	9.2 6%
Severely ill	1.3 0.9%	0.7 0.5%	2.0 1.3%
Most extremely ill	0.0 0%	0.0 0%	0.0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	SPD503-AM + Psychostimulant, Placebo + Psychostimulant
	Comments	Not powered for secondary outcome measures.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.013
	Comments	No adjustments for multiple comparisons.
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	SPD503-PM + Psychostimulant, Placebo + Psychostimulant
	Comments	Not powered for secondary outcome measures.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	No adjustments for multiple comparisons.
	Method	Cochran-Mantel-Haenszel
	Comments

4. Secondary Outcome

Title	Change From Baseline in Conners' Global Index - Parent (CGI-P) Total Score at Week 8 - LOCF: Morning Assessment (Before School)
Description	The index contains 10 items. Each item on the scale is scored from a range of 0 (reflecting never, seldom) to 3 (reflecting very often, very frequent) with total scores ranging from 0 to 30.
Time Frame	Baseline and weekly up to 8 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	SPD503-AM + Psychostimulant	SPD503-PM + Psychostimulant	Placebo + Psychostimulant
Arm/Group Description	Guanfacine Hydrochloride Extended Release administered in the AM plus a psychostimulant (subject was on a stable dose on entry and maintained throughout) administered each morning. This group received a matching placebo in the PM. An optimal dose of Guanfacine Hydrochloride Extended Release (1-4 mg/day once-daily) is determined for each subject over 5 weeks. The subject is then maintained on this optimal dose for an additional 3 weeks.	Guanfacine Hydrochloride Extended Release administered in the PM plus a psychostimulant (subject was on a stable dose on entry and maintained throughout) administered each morning. This group received a matching placebo in the AM. An optimal dose of Guanfacine Hydrochloride Extended Release (1-4 mg/day once-daily) is determined for each subject over 5 weeks. The subject is then maintained on this optimal dose for an additional 3 weeks.	Placebo was administered in both the AM and PM plus a psychostimulant (subject was on a stable dose on entry and maintained throughout) each morning.
Measure Participants	149	147	153
Mean (Standard Deviation) [Units on a scale]	-8.4 (7.27)	-9.6 (7.68)	-6.9 (6.89)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	SPD503-AM + Psychostimulant, Placebo + Psychostimulant
	Comments	Not powered for secondary outcome measures.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.019
	Comments	No adjustments for multiple comparisons.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Placebo-adjusted difference in LS mean
	Estimated Value	-1.7
	Confidence Interval	() 95%; -3.2 to -0.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	SPD503-PM + Psychostimulant, Placebo + Psychostimulant
	Comments	Not powered for secondary outcome measures.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	No adjustments for multiple comparisons.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Placebo-adjusted difference in LS mean
	Estimated Value	-2.6
	Confidence Interval	() 95%; -4.0 to -1.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Change From Baseline in Conners' Global Index - Parent (CGI-P) Total Score at Week 8 - LOCF: Evening Assessment (Before Bedtime)
Description	The index contains 10 items. Each item on the scale is scored from a range of 0 (reflecting never, seldom) to 3 (reflecting very often, very frequent) with total scores ranging from 0 30.
Time Frame	Baseline and weekly up to 8 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	SPD503-AM + Psychostimulant	SPD503-PM + Psychostimulant	Placebo + Psychostimulant
Arm/Group Description	Guanfacine Hydrochloride Extended Release administered in the AM plus a psychostimulant (subject was on a stable dose on entry and maintained throughout) administered each morning. This group received a matching placebo in the PM. An optimal dose of Guanfacine Hydrochloride Extended Release (1-4 mg/day once-daily) is determined for each subject over 5 weeks. The subject is then maintained on this optimal dose for an additional 3 weeks.	Guanfacine Hydrochloride Extended Release administered in the PM plus a psychostimulant (subject was on a stable dose on entry and maintained throughout) administered each morning. This group received a matching placebo in the AM. An optimal dose of Guanfacine Hydrochloride Extended Release (1-4 mg/day once-daily) is determined for each subject over 5 weeks. The subject is then maintained on this optimal dose for an additional 3 weeks.	Placebo was administered in both the AM and PM plus a psychostimulant (subject was on a stable dose on entry and maintained throughout) each morning.
Measure Participants	149	147	153
Mean (Standard Deviation) [Units on a scale]	-8.2 (7.79)	-8.8 (7.21)	-6.0 (6.84)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	SPD503-AM + Psychostimulant, Placebo + Psychostimulant
	Comments	Not powered for secondary outcome measures.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments	No adjustments for multiple comparisons.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Placebo-adjusted difference in LS mean
	Estimated Value	-2.4
	Confidence Interval	() 95%; -4.0 to -0.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	SPD503-PM + Psychostimulant, Placebo + Psychostimulant
	Comments	Not powered for secondary outcome measures.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	No adjustments for multiple comparisons.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Placebo-adjusted difference in LS mean
	Estimated Value	-3.0
	Confidence Interval	() 95%; -4.5 to -1.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Percentage of Participants With Improvement on Parent Global Assessment (PGA) at Week 8 - LOCF
Description	Parent Global Assessment (PGA) 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	Baseline and week 8

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	SPD503-AM + Psychostimulant	SPD503-PM + Psychostimulant	Placebo + Psychostimulant
Arm/Group Description	Guanfacine Hydrochloride Extended Release administered in the AM plus a psychostimulant (subject was on a stable dose on entry and maintained throughout) administered each morning. This group received a matching placebo in the PM. An optimal dose of Guanfacine Hydrochloride Extended Release (1-4 mg/day once-daily) is determined for each subject over 5 weeks. The subject is then maintained on this optimal dose for an additional 3 weeks.	Guanfacine Hydrochloride Extended Release administered in the PM plus a psychostimulant (subject was on a stable dose on entry and maintained throughout) administered each morning. This group received a matching placebo in the AM. An optimal dose of Guanfacine Hydrochloride Extended Release (1-4 mg/day once-daily) is determined for each subject over 5 weeks. The subject is then maintained on this optimal dose for an additional 3 weeks.	Placebo was administered in both the AM and PM plus a psychostimulant (subject was on a stable dose on entry and maintained throughout) each morning.
Measure Participants	129	133	141
Number [Percent of participants]	69.8 46.5%	67.7 44.5%	47.5 31%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	SPD503-AM + Psychostimulant, Placebo + Psychostimulant
	Comments	Not powered for secondary outcome measures.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	No adjustments for multiple comparisons.
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	SPD503-PM + Psychostimulant, Placebo + Psychostimulant
	Comments	Not powered for secondary outcome measures.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	No adjustments for multiple comparisons.
	Method	Cochran-Mantel-Haenszel
	Comments

7. Secondary Outcome

Title	Change From Baseline in the Oppositional Subscale of the Conners' Parent Rating Scale-Revised Long Form (CPRS-R:L) Score at Week 8 - LOCF
Description	The oppositional subscale of the CPRS-R:L contains 10 items designed to reflect criteria for oppositional defiance disorder (ODD). Each item is scored on a range from 0 (not true at all) to 3 (very much true) with total scores ranging from 0 to 30. Higher scores are reflective of more severe symptoms.
Time Frame	Baseline and weekly up to 8 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	SPD503-AM + Psychostimulant	SPD503-PM + Psychostimulant	Placebo + Psychostimulant
Arm/Group Description	Guanfacine Hydrochloride Extended Release administered in the AM plus a psychostimulant (subject was on a stable dose on entry and maintained throughout) administered each morning. This group received a matching placebo in the PM. An optimal dose of Guanfacine Hydrochloride Extended Release (1-4 mg/day once-daily) is determined for each subject over 5 weeks. The subject is then maintained on this optimal dose for an additional 3 weeks.	Guanfacine Hydrochloride Extended Release administered in the PM plus a psychostimulant (subject was on a stable dose on entry and maintained throughout) administered each morning. This group received a matching placebo in the AM. An optimal dose of Guanfacine Hydrochloride Extended Release (1-4 mg/day once-daily) is determined for each subject over 5 weeks. The subject is then maintained on this optimal dose for an additional 3 weeks.	Placebo was administered in both the AM and PM plus a psychostimulant (subject was on a stable dose on entry and maintained throughout) each morning.
Measure Participants	129	134	141
Mean (Standard Deviation) [Units on a scale]	-6.6 (6.97)	-6.3 (7.05)	-4.2 (6.79)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	SPD503-AM + Psychostimulant, Placebo + Psychostimulant
	Comments	Not powered for secondary outcome measures.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	No adjustments for multiple comparisons.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Placebo-adjusted difference in LS mean
	Estimated Value	-2.4
	Confidence Interval	() 95%; -3.9 to -0.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	SPD503-PM + Psychostimulant, Placebo + Psychostimulant
	Comments	Not powered for secondary outcome measures.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments	No adjustments for multiple comparisons.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Placebo-adjusted difference in LS mean
	Estimated Value	-2.2
	Confidence Interval	() 95%; -3.6 to -0.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Change From Baseline in Before School Functioning Questionnaire (BSFQ) at Week 8 - LOCF
Description	This scale was designed to assess symptoms of ADHD that typically occur in the morning. The BSFQ consists of two components. The first, a 20-item scale with ratings from 0 (none) to 3 (severe) with a range of 0-60 followed by two questions answered with duration of time (in minutes). The second, a 14-item scale with ratings from 0 (no) to 2 (a lot) with a range of 0-28. The results reported here are from the 20-item scale. Lower scores are better.
Time Frame	Baseline and weekly up to 8 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	SPD503-AM + Psychostimulant	SPD503-PM + Psychostimulant	Placebo + Psychostimulant
Arm/Group Description	Guanfacine Hydrochloride Extended Release administered in the AM plus a psychostimulant (subject was on a stable dose on entry and maintained throughout) administered each morning. This group received a matching placebo in the PM. An optimal dose of Guanfacine Hydrochloride Extended Release (1-4 mg/day once-daily) is determined for each subject over 5 weeks. The subject is then maintained on this optimal dose for an additional 3 weeks.	Guanfacine Hydrochloride Extended Release administered in the PM plus a psychostimulant (subject was on a stable dose on entry and maintained throughout) administered each morning. This group received a matching placebo in the AM. An optimal dose of Guanfacine Hydrochloride Extended Release (1-4 mg/day once-daily) is determined for each subject over 5 weeks. The subject is then maintained on this optimal dose for an additional 3 weeks.	Placebo was administered in both the AM and PM plus a psychostimulant (subject was on a stable dose on entry and maintained throughout) each morning.
Measure Participants	141	141	144
Mean (Standard Deviation) [Units on a scale]	-16.7 (13.87)	-16.7 (13.45)	-11.5 (13.45)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	SPD503-AM + Psychostimulant, Placebo + Psychostimulant
	Comments	Not powered for secondary outcome measures.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	No adjustments for multiple comparisons.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Placebo-adjusted difference in LS mean
	Estimated Value	-5.1
	Confidence Interval	() 95%; -8.0 to -2.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	SPD503-PM + Psychostimulant, Placebo + Psychostimulant
	Comments	Not powered for secondary outcome measures.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments	No adjustments for multiple comparisons.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Placebo-adjusted difference in LS mean
	Estimated Value	-4.7
	Confidence Interval	() 95%; -7.6 to -1.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Post Sleep Questionnaire (PSQ) Quality of Sleep at Week 8 - LOCF
Description	Post Sleep Questionnaire (PSQ) overall rating of quality of sleep. There are 5 rating responses ranging from very poor to very good. No numbers are associated with the rating responses.
Time Frame	Baseline and weekly up to 8 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	SPD503-AM + Psychostimulant	SPD503-PM + Psychostimulant	Placebo + Psychostimulant
Arm/Group Description	Guanfacine Hydrochloride Extended Release administered in the AM plus a psychostimulant (subject was on a stable dose on entry and maintained throughout) administered each morning. This group received a matching placebo in the PM. An optimal dose of Guanfacine Hydrochloride Extended Release (1-4 mg/day once-daily) is determined for each subject over 5 weeks. The subject is then maintained on this optimal dose for an additional 3 weeks.	Guanfacine Hydrochloride Extended Release administered in the PM plus a psychostimulant (subject was on a stable dose on entry and maintained throughout) administered each morning. This group received a matching placebo in the AM. An optimal dose of Guanfacine Hydrochloride Extended Release (1-4 mg/day once-daily) is determined for each subject over 5 weeks. The subject is then maintained on this optimal dose for an additional 3 weeks.	Placebo was administered in both the AM and PM plus a psychostimulant (subject was on a stable dose on entry and maintained throughout) each morning.
Measure Participants	149	148	153
Very poor	0.7 0.5%	0.7 0.5%	0.0 0%
Poor	6.7 4.5%	6.8 4.5%	3.3 2.2%
Average	26.8 17.9%	29.7 19.5%	33.3 21.8%
Good	40.3 26.9%	41.2 27.1%	40.5 26.5%
Very good	25.5 17%	21.6 14.2%	22.9 15%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	SPD503-AM + Psychostimulant, Placebo + Psychostimulant
	Comments	Not powered for secondary outcome measures.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.971
	Comments	No adjustments for multiple comparisons.
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	SPD503-PM + Psychostimulant, Placebo + Psychostimulant
	Comments	Not powered for secondary outcome measures.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.502
	Comments	No adjustments for multiple comparisons.
	Method	Cochran-Mantel-Haenszel
	Comments

Adverse Events

Time Frame	Up to 8 weeks
Adverse Event Reporting Description	For the serious adverse events: syncope occurred in the context of nausea, vomiting and sinusitis; self-injurious behavior, aggression, homicidal ideation, and adjustment disorder with mixed disturbance of emotions and conduct in a subject with similar behaviors prior to study start; exposure to toxic agent was poison ivy.
Arm/Group Title	SPD503-AM + Psychostimulant		SPD503-PM + Psychostimulant		Placebo + Psychostimulant
Arm/Group Description	Guanfacine Hydrochloride Extended Release administered in the AM plus a psychostimulant (subject was on a stable dose on entry and maintained throughout) administered each morning. This group received a matching placebo in the PM. An optimal dose of Guanfacine Hydrochloride Extended Release (1-4 mg/day once-daily) is determined for each subject over 5 weeks. The subject is then maintained on this optimal dose for an additional 3 weeks.		Guanfacine Hydrochloride Extended Release administered in the PM plus a psychostimulant (subject was on a stable dose on entry and maintained throughout) administered each morning. This group received a matching placebo in the AM. An optimal dose of Guanfacine Hydrochloride Extended Release (1-4 mg/day once-daily) is determined for each subject over 5 weeks. The subject is then maintained on this optimal dose for an additional 3 weeks.		Placebo was administered in both the AM and PM plus a psychostimulant (subject was on a stable dose on entry and maintained throughout) each morning.
All Cause Mortality
	SPD503-AM + Psychostimulant		SPD503-PM + Psychostimulant		Placebo + Psychostimulant
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	SPD503-AM + Psychostimulant		SPD503-PM + Psychostimulant		Placebo + Psychostimulant
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/150 (0.7%)		2/152 (1.3%)		0/153 (0%)
Injury, poisoning and procedural complications
Exposure to toxic agent	0/150 (0%)		1/152 (0.7%)		0/153 (0%)
Nervous system disorders
Syncope	0/150 (0%)		1/152 (0.7%)		0/153 (0%)
Psychiatric disorders
Adjustment disorder with mixed disturbance of emotion and conduct	1/150 (0.7%)		0/152 (0%)		0/153 (0%)
Aggression	1/150 (0.7%)		0/152 (0%)		0/153 (0%)
Homicidal ideation	1/150 (0.7%)		0/152 (0%)		0/153 (0%)
Self injurious behavior	1/150 (0.7%)		0/152 (0%)		0/153 (0%)
Other (Not Including Serious) Adverse Events
	SPD503-AM + Psychostimulant		SPD503-PM + Psychostimulant		Placebo + Psychostimulant
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	116/150 (77.3%)		116/152 (76.3%)		97/153 (63.4%)
Gastrointestinal disorders
Nausea	4/150 (2.7%)		11/152 (7.2%)		5/153 (3.3%)
Abdominal pain upper	12/150 (8%)		13/152 (8.6%)		3/153 (2%)
General disorders
Fatigue	18/150 (12%)		11/152 (7.2%)		4/153 (2.6%)
Irritability	6/150 (4%)		9/152 (5.9%)		11/153 (7.2%)
Pyrexia	6/150 (4%)		8/152 (5.3%)		6/153 (3.9%)
Infections and infestations
Upper respiratory tract infection	14/150 (9.3%)		16/152 (10.5%)		12/153 (7.8%)
Metabolism and nutrition disorders
Decreased appetite	9/150 (6%)		11/152 (7.2%)		6/153 (3.9%)
Nervous system disorders
Headache	32/150 (21.3%)		32/152 (21.1%)		20/153 (13.1%)
Somnolence	21/150 (14%)		20/152 (13.2%)		7/153 (4.6%)
Dizziness	15/150 (10%)		8/152 (5.3%)		6/153 (3.9%)
Sedation	5/150 (3.3%)		8/152 (5.3%)		3/153 (2%)
Psychiatric disorders
Insomnia	8/150 (5.3%)		18/152 (11.8%)		6/153 (3.9%)
Respiratory, thoracic and mediastinal disorders
Cough	9/150 (6%)		7/152 (4.6%)		7/153 (4.6%)
Pharyngolaryngeal pain	2/150 (1.3%)		8/152 (5.3%)		5/153 (3.3%)

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.