Dose-optimization in Adolescents Aged 13-17 Diagnosed With Attention-deficit/Hyperactivity Disorder (ADHD) Using Extended-release Guanfacine HCl

• Sponsor: Shire (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01081132
• Collaborator: (none)
• Enrollment: 314
• Locations: 54
• Arms: 2
• Actual Duration (Months): 19.9
• Patients Per Site: 5.8
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

To assess the efficacy of optimized Extended-release Guanfacine Hydrochloride compared with placebo in the treatment of adolescents aged 13-17 years with a diagnosis of ADHD as measured by the ADHD-RS-IV

Condition or Disease	Intervention/Treatment	Phase
Attention-Deficit/Hyperactivity Disorder	Drug: Extended-release Guanfacine Hydrochloride; Other: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 314 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Double-blind, Randomized, Multi-center, Placebo Controlled, Dose-optimization Study Evaluating the Safety, Efficacy, and Tolerability of Once Daily Dosing With Extended-release Guanfacine Hydrochloride in Adolescents Aged 13-17 Years Diagnosed With Attention-deficit/Hyperactivity Disorder (ADHD)
• Actual Study Start Date: Sep 19, 2011
• Actual Primary Completion Date: May 16, 2013
• Actual Study Completion Date: May 16, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Extended-release Guanfacine HCl	Drug: Extended-release Guanfacine Hydrochloride; The test product will be provided as 1, 2, 3, and 4mg tablets. Subjects will be administered a once-daily dose between 1-7mg/day depending on weight.; Other Names: Intuniv
Placebo Comparator: Placebo	Other: Placebo; Matching placebo will be provided as 1,2,3, and 4mg tablets. Subjects will be administered a once-daily dose of placebo between 1-7mg/day depending on weight.

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 13 [Baseline through week 13]

   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. Percent of Subjects With an Assessment of Normal/Borderline Mentally Ill on Clinical Global Impression-Severity of Illness (CGI-S) Scale at the Last On-Treatment Assessment [Baseline through week 13]

   CGI-S assesses the severity of the subject's condition on a 7-point scale: 1 (normal, not at all ill), 2 (borderline mentally ill), 3 (mildly ill), 4 (moderately ill), 5 (markedly ill), 6 (severely ill), 7 (among the most extremely ill)

2. Change From Baseline in the Weiss Functional Impairment Rating Scale - Parent Report (WFIRS-P) Learning and School Domain Scores at Week 13 [Baseline and week 13]

   The WFIRS-P is a 50-item scale with each item scored from 0 (never/not at all) to 3 (very often/very much). The Learning and School Domain consists of 10-items. Mean scores range from 0 to 3. Higher scores indicate greater functional impairment.

3. Change From Baseline in the WFIRS-P Family Domain Score at Week 13 [Baseline and week 13]

   The WFIRS-P is a 50-item scale with each item scored from 0 (never/not at all) to 3 (very often/very much). The Family Domain consists of 10-items. Mean scores range from 0 to 3. Higher scores indicate greater functional impairment.

4. Change From Baseline in the WFIRS-P Behavior in School Domain Score at Week 13 [Baseline and week 13]

   The WFIRS-P is a 50-item scale with each item scored from 0 (never/not at all) to 3 (very often/very much). Mean scores range from 0 to 3. Higher scores indicate greater functional impairment.

5. Change From Baseline in the WFIRS-P Global Domain Score at Week 13 [Baseline and week 13]

   The WFIRS-P is a 50-item scale with each item scored from 0 (never/not at all) to 3 (very often/very much). Mean scores range from 0 to 3. Higher scores indicate greater functional impairment.

6. Change From Baseline in the WFIRS-P Risk Domain Score at Week 13 [Baseline and week 13]

   The WFIRS-P is a 50-item scale with each item scored from 0 (never/not at all) to 3 (very often/very much). The Risk Domain consists of 10-items. Mean scores range from 0 to 3. Higher scores indicate greater functional impairment.

7. Change From Baseline in the WFIRS-P Social Domain Score at Week 13 [Baseline and week 13]

   The WFIRS-P is a 50-item scale with each item scored from 0 (never/not at all) to 3 (very often/very much). The Social Domain consists of 7-items. Mean scores range from 0 to 3. Higher scores indicate greater functional impairment.

8. Change From Baseline in the WFIRS-P Child Self-Concept Domain Score at Week 13 [Baseline and week 13]

   The WFIRS-P is a 50-item scale with each item scored from 0 (never/not at all) to 3 (very often/very much). The Child Self-Concept Domain consists of 3-items. Mean scores range from 0 to 3. Higher scores indicate greater functional impairment.

9. Change From Baseline in the WFIRS-P Life Skills Domain Score at Week 13 [Baseline and week 13]

   The WFIRS-P is a 50-item scale with each item scored from 0 (never/not at all) to 3 (very often/very much). The Life Skills Domain consists of 10-items. Mean scores range from 0 to 3. Higher scores indicate greater functional impairment.

10. Change From Baseline in the WFIRS-P Academic Performance Domain Score at Week 13 [Baseline and week 13]

    The WFIRS-P is a 50-item scale with each item scored from 0 (never/not at all) to 3 (very often/very much). Mean scores range from 0 to 3. Higher scores indicate greater functional impairment.

11. Percent of Subjects With Improvement on Clinical Global Impression-Improvement (CGI-I) Scores at the Last On-Treatment Assessment [weeks 1 through 13]

    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.

12. Changes From Baseline in Behavior Rating Inventory of Executive Function (BRIEF) Scores at Week 13 [Baseline and week 13]

    Behavior Rating Inventory of Executive Function (BRIEF) is a questionnaire composed of three indices: Global Executive Composite, Behavioral Regulation Index, and Metacognition Index. Items are rated 1 (never), 2 (sometimes), and 3 (often). The Global Executive Composite consists of 72 items with scoring ranging from 72 to 216. The Behavioral Regulation Index score is the total of 28 items and ranges from 28 to 84. The Metacognition Index score is the total of 44 items and ranges from 44 to 132. Lower scores reflect better functioning.

13. Change From Baseline in Pediatric Daytime Sleepiness Scale (PDSS) Total Score at Week 13 [Baseline through week 13]

    The Pediatric Daytime Sleepiness Scale (PDSS) is an 8 item questionnaire scored on a scale from 0 (never) to 4 (always/very often). Total scores range from 0 to 32, with increasing score reflecting greater sleepiness.

14. Change From Baseline in Brief Psychiatric Rating Scale for Children (BPRS-C) Total Score at Last On-Treatment Assessment [Baseline and week 13]

    The BPRS-C characterizes childhood behavioral and emotional symptomatology. A total of 21 items are rated on a scale from 0 (not present) to 6 (extremely severe) with a total score ranging from 0 to 126. A decrease in score indicates a reduction in psychopathology.

15. Structure Side-Effect Questionnaire (SSEQ) [Through week 16]

    The Structured Side-effect Questionnaire is a simple checklist of 17 side effects. The subject indicates whether a side effect has occurred since the last visit by marking 'yes' or 'no' on the checklist for each of the events listed.

16. Columbia-Suicide Severity Rating Scale (C-SSRS) [Through week 16]

    C-SSRS is a semi-structured interview that captures the occurence, severity, and frequency of suicide-related thoughts and behaviors during the assessment period. The interview includes definitions and suggested questions to solicit the type of information needed to determine if a suicide-related thought or behaviour occurred. The assessment is done by the nature of the responses, not by a numbered scale.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 13 Years to 17 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Male or female, aged 13-17 years at the time of consent/assent (screening only).

2. Subject's parent or legally authorized representative (LAR) must provide signature of informed consent, and there must be documentation of assent by the subject indicating that the subject is aware of the investigational nature of the study and the required procedures and restrictions in accordance with the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Guidance E6 (1996) and applicable regulations before completing any study-related procedures at screening.

3. Subject meets Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-Text Revision (DSM-IV-TR) criteria for a primary diagnosis of ADHD, combined subtype, or hyperactive/impulsive subtype, based on a detailed psychiatric evaluation using the Kiddie Schedule for Affective Disorders and Schizophrenia - Present and Lifetime version (K SADS PL) at screening (re-confirm if baseline visit is >35 days from screening).

4. Subject has a minimum ADHD-RS-IV total score of 32 at baseline.

5. Subject has a minimum CGI-S score of 4 at baseline.

6. Subject is functioning at an age-appropriate level intellectually, as deemed by the Investigator.

7. Subject and parent/LAR understand, are able, willing and likely to fully comply with the study procedures and restrictions defined in this protocol.

8. Subject is able to swallow intact tablets.

9. All females must have a negative serum beta human Chorionic Gonadotropin (hCG) pregnancy test at screening and a negative urine pregnancy test at baseline. Female subjects must abstain from sexual activity that could result in pregnancy or agree to use acceptable methods of contraception.

10. Subject has a supine and standing blood pressure (BP) measurement within the 95th percentile for age, gender, and height.

Exclusion Criteria:

1. Subject has a current, controlled (requiring a prohibited medication or behavioral modification program) or uncontrolled, comorbid psychiatric diagnosis [except Oppositional Defiant Disorder (ODD), but including all anxiety disorders (except simple phobias)], all major depressive disorders (dysthymia allowed unless medication required), and any severe comorbid Axis II disorders or severe Axis I disorders such as post traumatic stress disorder, bipolar illness, psychosis, pervasive developmental disorder, obsessive-compulsive disorder, substance abuse disorder, or other symptomatic manifestations that, in the opinion of the Investigator, contraindicate SPD503 treatment or confound efficacy or safety assessments.

2. Subject has any condition or illness including clinically significant abnormal screening laboratory values which, in the opinion of the Investigator, represents an inappropriate risk to the subject and/or could confound the interpretation of the study.

3. Subject has a known history or presence of structural cardiac abnormalities, serious heart rhythm abnormalities, syncope, cardiac conduction problems (e.g., clinically significant heart block), exercise-related cardiac events including syncope and pre-syncope, or clinically significant bradycardia.

4. Subject has any abnormal or clinically significant ECG findings as judged by the Investigator with consideration of the central ECG interpretation.

5. Subject with orthostatic hypotension or a known history of controlled or uncontrolled hypertension.

6. Current use of any prohibited medication, including herbal supplements that affect blood pressure, heart rate, have central nervous system (CNS) effects, or affect cognitive performance, such as sedating antihistamines and decongestant sympathomimetics (inhaled bronchodilators are permitted) or a history of chronic use of sedating medications (i.e., antihistamines) at baseline.

7. Subject has a history of alcohol or other substance abuse or dependence, as defined by DSM IV-TR (with the exceptions of nicotine) within the last six months.

8. Subject has taken another investigational product within 30 days prior to baseline.

9. Subject is significantly overweight based on Center for Disease Control and Prevention Body Mass Index (BMI)-for-age gender specific charts at screening. Significantly overweight is defined as a BMI >95th percentile for this study.

10. Body weight of less than 34.0kg or greater than 91.0kg at screening.

11. Subject has a known or suspected allergy, hypersensitivity, or clinically significant intolerance to guanfacine hydrochloride or any components found in SPD503.

12. Clinically important abnormality on urine drug and/or alcohol screen (excluding the subject's current ADHD stimulant if applicable).

13. Subject is female and is pregnant or currently lactating.

14. Subject failed screening or was previously enrolled in this study.

15. Subject who is currently considered a suicide risk, has previously made a suicide attempt, or has a prior history of, or is currently demonstrating suicidal ideation.

16. History of failure to respond to an adequate trial (consisting of an appropriate dose and adequate duration of therapy), in the opinion of the Investigator, of an α2-agonist for the treatment of ADHD.

17. Subject has a history of a seizure disorder (other than a single childhood febrile seizure occurring before the age of 3 years) or a history of a tic disorder (including Tourette's syndrome).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Harmonex Neuroscience Research	Dothan	Alabama	United States	36303
2	Clinical Study Centers, LLC	Little Rock	Arkansas	United States	72211
3	Peninsula Research Associates	Rolling Hills Estates	California	United States	90274
4	Psychiatric Centers at San Diego (PCSD-Feighner Research Institute)	San Diego	California	United States	92108
5	Encompass Clinical Research	Spring Valley	California	United States	91978
6	Elite Clinical Trials, Inc.	Wildomar	California	United States	92595
7	IMMUNO International Research Centers	Centennial	Colorado	United States	80112
8	Coastal Connecticut Research LLC	New London	Connecticut	United States	06320
9	Florida Clinical Research Center, LLC	Bradenton	Florida	United States	34201
10	Sarkis Clinical Trials	Gainesville	Florida	United States	32607
11	Amedica Research Institute, Inc.	Hialeah	Florida	United States	33013
12	George M. Joseph, MD, PA	Jacksonville Beach	Florida	United States	32250
13	Clinical Neuroscience Solutions, Inc.	Jacksonville	Florida	United States	32216
14	Morteza Nadjafi, MD, FAPA	Orlando	Florida	United States	32803
15	Clinical Neuroscience Solutions, Inc.	Orlando	Florida	United States	32806
16	Miami Research Associates	South Miami	Florida	United States	33143
17	Janus Center for Psychiatric Research	West Palm Beach	Florida	United States	33407
18	Northwest Behavioral Research Center	Roswell	Georgia	United States	30076
19	Institute for Behavioral Medicine	Smyrna	Georgia	United States	30080
20	Capstone Clinical Research	Libertyville	Illinois	United States	60048
21	AMR-Baber Research Inc.	Naperville	Illinois	United States	60563
22	Goldpoint Clinical Research, LLC	Indianapolis	Indiana	United States	46260
23	Clinco, Inc.	Terre Haute	Indiana	United States	47802
24	Psychiatric Associates	Overland Park	Kansas	United States	66211
25	Four Rivers Clinical Research, Inc.	Paducah	Kentucky	United States	42003
26	Rochester Center for Behavioral Medicine	Rochester Hills	Michigan	United States	48307
27	Clinical Neurophysiology Services, PC	Sterling Heights	Michigan	United States	48314
28	Comprehensive Psychiatric Associates	Gladstone	Missouri	United States	64118
29	St Charles Psychiatric Associates - Midwest Research Group	Saint Charles	Missouri	United States	63301
30	Center for Psychiatry and Behavioral Medicine, Inc.	Las Vegas	Nevada	United States	89128
31	Albuquerque Neuroscience Inc.	Albuquerque	New Mexico	United States	87109
32	Finger Lakes Clinical Research	Rochester	New York	United States	14618
33	Richmond Behavioral Associates	Staten Island	New York	United States	10312
34	Triangle Neuropsychiatry	Durham	North Carolina	United States	27707
35	NorthCoast Clinical Trials	Beachwood	Ohio	United States	44122
36	The Ohio State University	Columbus	Ohio	United States	43210
37	IPS Research Company	Oklahoma City	Oklahoma	United States	73103
38	Tulsa Clinical Research, LLC	Tulsa	Oklahoma	United States	74104
39	OCCI, Inc.	Portland	Oregon	United States	97210
40	Oregon Center for Clinical Investigations, Inc.	Salem	Oregon	United States	97301
41	CRI Worldwide	Philadelphia	Pennsylvania	United States	19139
42	University Services Sleep Diagnostic and Treatment Centers	West Chester	Pennsylvania	United States	19380
43	Rainbow Research	Barnwell	South Carolina	United States	29812
44	The Jackson Clinic	Jackson	Tennessee	United States	38305
45	Clinical Neuroscience Solutions, Inc.	Memphis	Tennessee	United States	38119
46	Research Strategies of Memphis, LLC	Memphis	Tennessee	United States	38119
47	FutureSearch Trials	Austin	Texas	United States	78731
48	InSite Clinical Research	DeSoto	Texas	United States	75115
49	R/D Clinical Research, Inc.	Lake Jackson	Texas	United States	77566
50	Westex Clinical Investigations	Lubbock	Texas	United States	79423
51	Neuroscience, Inc.	Herndon	Virginia	United States	20170
52	Alliance Research Group	Richmond	Virginia	United States	23230
53	Northwest Clinical Research Center	Bellevue	Washington	United States	98007
54	East Side Therapeutic Resource	Kirkland	Washington	United States	98033

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: NCT01081132
• Other Study ID Numbers: SPD503-312; 2011-002221-21
• First Posted: Mar 5, 2010
• Last Update Posted: Jun 28, 2021
• Last Verified: Jun 1, 2021

• Additional relevant MeSH terms: Hyperkinesis; Attention Deficit Disorder with Hyperactivity; Guanfacine

Study Results

Participant Flow

Arm/Group Title	PLACEBO	SPD503
Arm/Group Description	Orally administered a once-daily dose	Orally administered a once-daily optimal dose between 0.05 mg/kg/day - 0.12 mg/kg/day (up to 7 mg/day depending on weight).
Period Title: Overall Study
STARTED	157	157
COMPLETED	102	105
NOT COMPLETED	55	52

Baseline Characteristics

Arm/Group Title	PLACEBO	SPD503	Total
Arm/Group Description	Orally administered a once-daily dose	Orally administered a once-daily optimal dose between 0.05 mg/kg/day - 0.12 mg/kg/day (up to 7 mg/day depending on weight).	Total of all reporting groups
Overall Participants	155	157	312
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	14.6 (1.44)	14.5 (1.35)	14.5 (1.39)
Age, Customized (Count of Participants)
<18 years	155 100%	157 100%	312 100%
Sex: Female, Male (Count of Participants)
Female	56 36.1%	54 34.4%	110 35.3%
Male	99 63.9%	103 65.6%	202 64.7%
Region of Enrollment (Count of Participants)
UNITED STATES	155 100%	157 100%	312 100%

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 13
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 through week 13

Outcome Measure Data

Analysis Population Description

The Full Analysis Set consisted of all randomized subjects who took at least 1 dose of investigational product. A mixed model repeated measures (MMRM) was used to analyze the observed change from the Baseline Visit scores at all post-baseline, pre-taper, on-treatment visits.

Arm/Group Title	PLACEBO	SPD503
Arm/Group Description	Orally administered a once-daily dose	Orally administered a once-daily optimal dose between 0.05 mg/kg/day - 0.12 mg/kg/day (up to 7 mg/day depending on weight).
Measure Participants	106	109
Least Squares Mean (Standard Error) [units on a scale]	-18.527 (1.0841)	-24.552 (1.0625)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	PLACEBO, SPD503
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Repeated Measures Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-6.026
	Confidence Interval	(2-Sided) 95%; -8.865 to -3.187
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Percent of Subjects With an Assessment of Normal/Borderline Mentally Ill on Clinical Global Impression-Severity of Illness (CGI-S) Scale at the Last On-Treatment Assessment
Description	CGI-S assesses the severity of the subject's condition on a 7-point scale: 1 (normal, not at all ill), 2 (borderline mentally ill), 3 (mildly ill), 4 (moderately ill), 5 (markedly ill), 6 (severely ill), 7 (among the most extremely ill)
Time Frame	Baseline through week 13

Outcome Measure Data

Analysis Population Description

Full Analysis Set consisted of all randomized subjects who took at least 1 dose of investigational product.

Arm/Group Title	PLACEBO	SPD503
Arm/Group Description	Orally administered a once-daily dose	Orally administered a once-daily optimal dose between 0.05 mg/kg/day - 0.12 mg/kg/day (up to 7 mg/day depending on weight).
Measure Participants	155	154
Number [percentage of subjects]	36.1	50.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	PLACEBO, SPD503
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.010
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

3. Secondary Outcome

Title	Change From Baseline in the Weiss Functional Impairment Rating Scale - Parent Report (WFIRS-P) Learning and School Domain Scores at Week 13
Description	The WFIRS-P is a 50-item scale with each item scored from 0 (never/not at all) to 3 (very often/very much). The Learning and School Domain consists of 10-items. Mean scores range from 0 to 3. Higher scores indicate greater functional impairment.
Time Frame	Baseline and week 13

Outcome Measure Data

Analysis Population Description

Full Analysis Set consisted of all randomized subjects who took at least 1 dose of investigational product.

Arm/Group Title	PLACEBO	SPD503
Arm/Group Description	Orally administered a once-daily dose	Orally administered a once-daily optimal dose between 0.05 mg/kg/day - 0.12 mg/kg/day (up to 7 mg/day depending on weight).
Measure Participants	101	97
Least Squares Mean (Standard Error) [units on a scale]	-0.457 (0.058)	-0.572 (0.058)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	PLACEBO, SPD503
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.104
	Comments
	Method	Mixed Models Repeated Measures Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.115
	Confidence Interval	(2-Sided) 95%; -0.254 to 0.024
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline in the WFIRS-P Family Domain Score at Week 13
Description	The WFIRS-P is a 50-item scale with each item scored from 0 (never/not at all) to 3 (very often/very much). The Family Domain consists of 10-items. Mean scores range from 0 to 3. Higher scores indicate greater functional impairment.
Time Frame	Baseline and week 13

Outcome Measure Data

Analysis Population Description

Full Analysis Set consisted of all randomized subjects who took at least 1 dose of investigational product.

Arm/Group Title	PLACEBO	SPD503
Arm/Group Description	Orally administered a once-daily dose	Orally administered a once-daily optimal dose between 0.05 mg/kg/day - 0.12 mg/kg/day (up to 7 mg/day depending on weight).
Measure Participants	101	105
Least Squares Mean (Standard Error) [units on a scale]	-0.314 (0.055)	-0.371 (0.054)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	PLACEBO, SPD503
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.408
	Comments
	Method	Mixed Models Repeated Measures Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.057
	Confidence Interval	(2-Sided) 95%; -0.192 to 0.078
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Change From Baseline in the WFIRS-P Behavior in School Domain Score at Week 13
Description	The WFIRS-P is a 50-item scale with each item scored from 0 (never/not at all) to 3 (very often/very much). Mean scores range from 0 to 3. Higher scores indicate greater functional impairment.
Time Frame	Baseline and week 13

Outcome Measure Data

Analysis Population Description

Full Analysis Set consisted of all randomized subjects who took at least 1 dose of investigational product.

Arm/Group Title	PLACEBO	SPD503
Arm/Group Description	Orally administered a once-daily dose	Orally administered a once-daily optimal dose between 0.05 mg/kg/day - 0.12 mg/kg/day (up to 7 mg/day depending on weight).
Measure Participants	101	97
Least Squares Mean (Standard Error) [units on a scale]	-0.376 (0.051)	-0.459 (0.050)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	PLACEBO, SPD503
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.176
	Comments
	Method	Mixed Models Repeated Measures Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.083
	Confidence Interval	(2-Sided) 95%; -0.203 to 0.037
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Change From Baseline in the WFIRS-P Global Domain Score at Week 13
Description	The WFIRS-P is a 50-item scale with each item scored from 0 (never/not at all) to 3 (very often/very much). Mean scores range from 0 to 3. Higher scores indicate greater functional impairment.
Time Frame	Baseline and week 13

Outcome Measure Data

Analysis Population Description

Full Analysis Set consisted of all randomized subjects who took at least 1 dose of investigational product.

Arm/Group Title	PLACEBO	SPD503
Arm/Group Description	Orally administered a once-daily dose	Orally administered a once-daily optimal dose between 0.05 mg/kg/day - 0.12 mg/kg/day (up to 7 mg/day depending on weight).
Measure Participants	105	108
Least Squares Mean (Standard Error) [units on a scale]	-0.296 (0.036)	-0.347 (0.035)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	PLACEBO, SPD503
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.253
	Comments
	Method	Mixed Models Repeated Measures Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.050
	Confidence Interval	(2-Sided) 95%; -0.136 to -0.036
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Change From Baseline in the WFIRS-P Risk Domain Score at Week 13
Description	The WFIRS-P is a 50-item scale with each item scored from 0 (never/not at all) to 3 (very often/very much). The Risk Domain consists of 10-items. Mean scores range from 0 to 3. Higher scores indicate greater functional impairment.
Time Frame	Baseline and week 13

Outcome Measure Data

Analysis Population Description

Full Analysis Set consisted of all randomized subjects who took at least 1 dose of investigational product.

Arm/Group Title	PLACEBO	SPD503
Arm/Group Description	Orally administered a once-daily dose	Orally administered a once-daily optimal dose between 0.05 mg/kg/day - 0.12 mg/kg/day (up to 7 mg/day depending on weight).
Measure Participants	105	107
Least Squares Mean (Standard Error) [units on a scale]	-0.194 (0.027)	-0.191 (0.026)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	PLACEBO, SPD503
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.912
	Comments
	Method	Mixed Models Repeated Measures Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.004
	Confidence Interval	(2-Sided) 95%; -0.061 to 0.068
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Change From Baseline in the WFIRS-P Social Domain Score at Week 13
Description	The WFIRS-P is a 50-item scale with each item scored from 0 (never/not at all) to 3 (very often/very much). The Social Domain consists of 7-items. Mean scores range from 0 to 3. Higher scores indicate greater functional impairment.
Time Frame	Baseline and week 13

Outcome Measure Data

Analysis Population Description

Full Analysis Set consisted of all randomized subjects who took at least 1 dose of investigational product.

Arm/Group Title	PLACEBO	SPD503
Arm/Group Description	Orally administered a once-daily dose	Orally administered a once-daily optimal dose between 0.05 mg/kg/day - 0.12 mg/kg/day (up to 7 mg/day depending on weight).
Measure Participants	105	108
Least Squares Mean (Standard Error) [units on a scale]	-0.234 (0.046)	-0.263 (0.045)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	PLACEBO, SPD503
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.606
	Comments
	Method	Mixed Models Repeated Measures Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.029
	Confidence Interval	(2-Sided) 95%; -0.139 to 0.081
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Change From Baseline in the WFIRS-P Child Self-Concept Domain Score at Week 13
Description	The WFIRS-P is a 50-item scale with each item scored from 0 (never/not at all) to 3 (very often/very much). The Child Self-Concept Domain consists of 3-items. Mean scores range from 0 to 3. Higher scores indicate greater functional impairment.
Time Frame	Baseline and week 13

Outcome Measure Data

Analysis Population Description

Full Analysis Set consisted of all randomized subjects who took at least 1 dose of investigational product.

Arm/Group Title	PLACEBO	SPD503
Arm/Group Description	Orally administered a once-daily dose	Orally administered a once-daily optimal dose between 0.05 mg/kg/day - 0.12 mg/kg/day (up to 7 mg/day depending on weight).
Measure Participants	104	106
Least Squares Mean (Standard Error) [units on a scale]	-0.376 (0.067)	-0.275 (0.066)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	PLACEBO, SPD503
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.228
	Comments
	Method	Mixed Models Repeated Measures Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.102
	Confidence Interval	(2-Sided) 95%; -0.064 to 0.268
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Change From Baseline in the WFIRS-P Life Skills Domain Score at Week 13
Description	The WFIRS-P is a 50-item scale with each item scored from 0 (never/not at all) to 3 (very often/very much). The Life Skills Domain consists of 10-items. Mean scores range from 0 to 3. Higher scores indicate greater functional impairment.
Time Frame	Baseline and week 13

Outcome Measure Data

Analysis Population Description

Full Analysis Set consisted of all randomized subjects who took at least 1 dose of investigational product.

Arm/Group Title	PLACEBO	SPD503
Arm/Group Description	Orally administered a once-daily dose	Orally administered a once-daily optimal dose between 0.05 mg/kg/day - 0.12 mg/kg/day (up to 7 mg/day depending on weight).
Measure Participants	105	107
Least Squares Mean (Standard Error) [units on a scale]	-0.328 (0.046)	-0.375 (0.045)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	PLACEBO, SPD503
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.410
	Comments
	Method	Mixed Models Repeated Measures Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.047
	Confidence Interval	(2-Sided) 95%; -0.159 to 0.065
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Change From Baseline in the WFIRS-P Academic Performance Domain Score at Week 13
Description	The WFIRS-P is a 50-item scale with each item scored from 0 (never/not at all) to 3 (very often/very much). Mean scores range from 0 to 3. Higher scores indicate greater functional impairment.
Time Frame	Baseline and week 13

Outcome Measure Data

Analysis Population Description

Full Analysis Set consisted of all randomized subjects who took at least 1 dose of investigational product.

Arm/Group Title	PLACEBO	SPD503
Arm/Group Description	Orally administered a once-daily dose	Orally administered a once-daily optimal dose between 0.05 mg/kg/day - 0.12 mg/kg/day (up to 7 mg/day depending on weight).
Measure Participants	104	96
Least Squares Mean (Standard Error) [units on a scale]	-0.632 (0.096)	-0.841 (0.096)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	PLACEBO, SPD503
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.082
	Comments
	Method	Mixed Models Repeated Measures Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.208
	Confidence Interval	(2-Sided) 95%; -0.443 to 0.026
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Secondary Outcome

Title	Percent of Subjects With Improvement on Clinical Global Impression-Improvement (CGI-I) Scores at the Last On-Treatment Assessment
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	weeks 1 through 13

Outcome Measure Data

Analysis Population Description

Full Analysis Set consisted of all randomized subjects who took at least 1 dose of investigational product.

Arm/Group Title	PLACEBO	SPD503
Arm/Group Description	Orally administered a once-daily dose	Orally administered a once-daily optimal dose between 0.05 mg/kg/day - 0.12 mg/kg/day (up to 7 mg/day depending on weight).
Measure Participants	155	154
Number [percentage of subjects]	45.8	67.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	PLACEBO, SPD503
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

13. Secondary Outcome

Title	Changes From Baseline in Behavior Rating Inventory of Executive Function (BRIEF) Scores at Week 13
Description	Behavior Rating Inventory of Executive Function (BRIEF) is a questionnaire composed of three indices: Global Executive Composite, Behavioral Regulation Index, and Metacognition Index. Items are rated 1 (never), 2 (sometimes), and 3 (often). The Global Executive Composite consists of 72 items with scoring ranging from 72 to 216. The Behavioral Regulation Index score is the total of 28 items and ranges from 28 to 84. The Metacognition Index score is the total of 44 items and ranges from 44 to 132. Lower scores reflect better functioning.
Time Frame	Baseline and week 13

Outcome Measure Data

Analysis Population Description

Full Analysis Set consisted of all randomized subjects who took at least 1 dose of investigational product.

Arm/Group Title	PLACEBO	SPD503
Arm/Group Description	Orally administered a once-daily dose	Orally administered a once-daily optimal dose between 0.05 mg/kg/day - 0.12 mg/kg/day (up to 7 mg/day depending on weight).
Measure Participants	82	88
Global Executive Composite	-10.6 (1.23)	-12.9 (1.19)
Behavioral Regulation Index	-11.5 (1.29)	-12.4 (1.25)
Metacognition Index	-8.9 (1.18)	-11.6 (1.14)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	PLACEBO, SPD503
	Comments	Global Executive Composite
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.134
	Comments
	Method	Mixed Models Repeated Measures Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.3
	Confidence Interval	(2-Sided) 95%; -5.3 to 0.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	PLACEBO, SPD503
	Comments	Behavioral Regulation Index
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.579
	Comments
	Method	Mixed Models Repeated Measures Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.9
	Confidence Interval	(2-Sided) 95%; -4.0 to 2.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	PLACEBO, SPD503
	Comments	Metacognition Index
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.072
	Comments
	Method	Mixed Models Repeated Measures Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.7
	Confidence Interval	(2-Sided) 95%; -5.6 to 0.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. Secondary Outcome

Title	Change From Baseline in Pediatric Daytime Sleepiness Scale (PDSS) Total Score at Week 13
Description	The Pediatric Daytime Sleepiness Scale (PDSS) is an 8 item questionnaire scored on a scale from 0 (never) to 4 (always/very often). Total scores range from 0 to 32, with increasing score reflecting greater sleepiness.
Time Frame	Baseline through week 13

Outcome Measure Data

Analysis Population Description

Safety Population consisted of all randomized subjects who took at least 1 dose of investigational product.

Arm/Group Title	PLACEBO	SPD503
Arm/Group Description	Orally administered a once-daily dose	Orally administered a once-daily optimal dose between 0.05 mg/kg/day - 0.12 mg/kg/day (up to 7 mg/day depending on weight).
Measure Participants	105	108
Least Squares Mean (Standard Error) [units on a scale]	-3.7 (0.52)	-4.2 (0.51)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	PLACEBO, SPD503
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.465
	Comments
	Method	Mixed Models Repeated Measures Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.5
	Confidence Interval	(2-Sided) 95%; -1.8 to 0.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

15. Secondary Outcome

Title	Change From Baseline in Brief Psychiatric Rating Scale for Children (BPRS-C) Total Score at Last On-Treatment Assessment
Description	The BPRS-C characterizes childhood behavioral and emotional symptomatology. A total of 21 items are rated on a scale from 0 (not present) to 6 (extremely severe) with a total score ranging from 0 to 126. A decrease in score indicates a reduction in psychopathology.
Time Frame	Baseline and week 13

Outcome Measure Data

Analysis Population Description

Safety Population consisted of all randomized subjects who took at least 1 dose of investigational product.

Arm/Group Title	PLACEBO	SPD503
Arm/Group Description	Orally administered a once-daily dose	Orally administered a once-daily optimal dose between 0.05 mg/kg/day - 0.12 mg/kg/day (up to 7 mg/day depending on weight).
Measure Participants	151	151
Mean (Standard Deviation) [units on a scale]	-7.0 (9.85)	-9.1 (8.11)

16. Secondary Outcome

Title	Structure Side-Effect Questionnaire (SSEQ)
Description	The Structured Side-effect Questionnaire is a simple checklist of 17 side effects. The subject indicates whether a side effect has occurred since the last visit by marking 'yes' or 'no' on the checklist for each of the events listed.
Time Frame	Through week 16

Outcome Measure Data

Analysis Population Description

Safety Population consisted of all randomized subjects who took at least 1 dose of investigational product.

Arm/Group Title	PLACEBO	SPD503
Arm/Group Description	Orally administered a once-daily dose	Orally administered a once-daily optimal dose between 0.05 mg/kg/day - 0.12 mg/kg/day (up to 7 mg/day depending on weight).
Measure Participants	155	157
Nausea	33 21.3%	37 23.6%
Vomiting	17 11%	18 11.5%
Diarrhea	24 15.5%	29 18.5%
Abdominal pain	28 18.1%	30 19.1%
Decreased appetite	42 27.1%	48 30.6%
Increased appetite	47 30.3%	42 26.8%
Headache	53 34.2%	76 48.4%
Dizziness	31 20%	49 31.2%
Fatigue	43 27.7%	65 41.4%
Nervousness/anxiety	23 14.8%	30 19.1%
Insomnia	25 16.1%	28 17.8%
Somnolence	26 16.8%	41 26.1%
Depression	17 11%	14 8.9%
Itching	9 5.8%	11 7%
Rash	7 4.5%	6 3.8%
Missed menses	1 0.6%	4 2.5%

17. Secondary Outcome

Title	Columbia-Suicide Severity Rating Scale (C-SSRS)
Description	C-SSRS is a semi-structured interview that captures the occurence, severity, and frequency of suicide-related thoughts and behaviors during the assessment period. The interview includes definitions and suggested questions to solicit the type of information needed to determine if a suicide-related thought or behaviour occurred. The assessment is done by the nature of the responses, not by a numbered scale.
Time Frame	Through week 16

Outcome Measure Data

Analysis Population Description

Safety Population consisted of all randomized subjects who took at least 1 dose of investigational product.

Arm/Group Title	PLACEBO	SPD503
Arm/Group Description	Orally administered a once-daily dose	Orally administered a once-daily optimal dose between 0.05 mg/kg/day - 0.12 mg/kg/day (up to 7 mg/day depending on weight).
Measure Participants	155	154
Suicidal ideation	4 2.6%	5 3.2%
Suicidal behavior	0 0%	0 0%

Adverse Events

Adverse Event Reporting Description	Safety Population defined as all randomized subjects who took at least 1 dose of investigational product. Two subjects did not take investigational product, therefore n = 312 (Placebo = 155, SPD503 = 157).
Arm/Group Title	PLACEBO		SPD503
Arm/Group Description	Orally administered a once-daily dose		Orally administered a once-daily optimal dose between 0.05 mg/kg/day - 0.12 mg/kg/day (up to 7 mg/day depending on weight).
All Cause Mortality
	PLACEBO		SPD503
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	PLACEBO		SPD503
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/155 (1.3%)		4/157 (2.5%)
Gastrointestinal disorders
Abdominal pain	0/155 (0%)	0	1/157 (0.6%)	1
Vomiting	0/155 (0%)	0	1/157 (0.6%)	1
Hepatobiliary disorders
Cholecystitis chronic	0/155 (0%)	0	1/157 (0.6%)	1
Injury, poisoning and procedural complications
Clavicle fracture	1/155 (0.6%)	1	0/157 (0%)	0
Concussion	0/155 (0%)	0	1/157 (0.6%)	1
Pelvic fracture	1/155 (0.6%)	1	0/157 (0%)	0
Nervous system disorders
Loss of consciousness	0/155 (0%)	0	1/157 (0.6%)	1
Psychiatric disorders
Homicidal ideation	0/155 (0%)	0	1/157 (0.6%)	1
Reproductive system and breast disorders
Ovarian cyst ruptured	1/155 (0.6%)	1	0/157 (0%)	0
Vascular disorders
Withdrawal hypertension	0/155 (0%)	0	1/157 (0.6%)	1
Other (Not Including Serious) Adverse Events
	PLACEBO		SPD503
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	120/155 (77.4%)		147/157 (93.6%)
Gastrointestinal disorders
Abdominal pain	6/155 (3.9%)	7	9/157 (5.7%)	10
Abdominal pain upper	7/155 (4.5%)	7	10/157 (6.4%)	11
Diarrhoea	13/155 (8.4%)	15	12/157 (7.6%)	17
Dry mouth	0/155 (0%)	0	12/157 (7.6%)	12
Nausea	21/155 (13.5%)	22	19/157 (12.1%)	22
Vomiting	10/155 (6.5%)	12	9/157 (5.7%)	9
General disorders
Fatigue	19/155 (12.3%)	21	35/157 (22.3%)	41
Irritability	6/155 (3.9%)	6	11/157 (7%)	13
Infections and infestations
Nasopharyngitis	9/155 (5.8%)	9	18/157 (11.5%)	20
Upper respiratory tract infection	12/155 (7.7%)	14	14/157 (8.9%)	15
Metabolism and nutrition disorders
Decreased appetite	21/155 (13.5%)	24	23/157 (14.6%)	27
Increased appetite	13/155 (8.4%)	15	14/157 (8.9%)	15
Nervous system disorders
Dizziness	16/155 (10.3%)	17	25/157 (15.9%)	32
Dizziness postural	3/155 (1.9%)	3	8/157 (5.1%)	8
Headache	28/155 (18.1%)	43	42/157 (26.8%)	64
Sedation	3/155 (1.9%)	3	18/157 (11.5%)	21
Somnolence	33/155 (21.3%)	39	69/157 (43.9%)	102
Psychiatric disorders
Insomnia	6/155 (3.9%)	7	14/157 (8.9%)	16
Respiratory, thoracic and mediastinal disorders
Cough	8/155 (5.2%)	8	3/157 (1.9%)	4

Limitations/Caveats

For the secondary outcomes, the p-values are not controlled for multiplicity, therefore they should be considered as descriptive not inferential.

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.