Efficacy and Safety of Extended-release Guanfacine Hydrochloride in Children and Adolescents Aged 6-17 Years With Attention-Deficit/Hyperactivity Disorder (ADHD)

• Sponsor: Shire (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01244490
• Collaborator: (none)
• Enrollment: 338
• Locations: 66
• Arms: 3
• Actual Duration (Months): 27.4
• Patients Per Site: 5.1
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

For children and adolescents, how does SPD503 compare to placebo for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD).

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 338 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Randomised, Double-blind, Multicentre, Parallel-group, Placebo- and Active-reference, Dose-optimisation Efficacy and Safety Study of Extended-release Guanfacine Hydrochloride in Children and Adolescents Aged 6-17 Years With Attention-Deficit/Hyperactivity Disorder
• Actual Study Start Date: Jan 17, 2011
• Actual Primary Completion Date: May 1, 2013
• Actual Study Completion Date: May 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Extended-release Guanfacine Hydrochloride	Drug: Extended-release Guanfacine Hydrochloride; Tablet, once daily, optimised dose (1mg to 7mg based on age and weight), 6-week maintenance duration on optimised dose.; Other Names: Intuniv
Other: Atomoxetine Hydrochloride Active Reference	Drug: Atomoxetine Hydrochloride; Capsule, once daily, optimised dose (10mg to 100mg based on weight), 8-9-weeks maintenance duration on optimised dose; Other Names: Strattera
Placebo Comparator: Placebo	Drug: Placebo Comparator; Placebo

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 10/13 - Last Observation Carried Forward (LOCF) [Baseline and Up to 10 weeks for children aged 6-12 years and up to 13 weeks for adolescents aged 13-17 years]

   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. Outcome measure is at 10 weeks for ages 6-12 years and at 13 weeks for ages 13-17 years.

Secondary Outcome Measures

1. Percentage of Participants With Improvement on Clinical Global Impression-Improvement (CGI-I) Scores [Up to 10 weeks for children aged 6-12 years and up to 13 weeks for adolescents aged 13-17 years]

   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. Outcome measure is at 10 weeks for ages 6-12 years and at 13 weeks for ages 13-17 years.

2. Change From Baseline in the Weiss Functional Impairment Rating Scale - Parent Report (WFIRS-P) Learning and School Domain Scores at Week 10/13 - LOCF [Baseline and Up to 10 weeks for children aged 6-12 years and up to 13 weeks for adolescents aged 13-17 years]

   The WFIRS-P Learning in School Domain is the mean of 10 items, ranging from 0 (never/not at all) to 3 (very often/very much). Higher scores indicate greater functional impairment. Outcome measure is at 10 weeks for ages 6-12 years and at 13 weeks for ages 13-17 years.

3. Change From Baseline in the WFIRS-P Family Domain Score at Week 10/13 - LOCF [Baseline and Up to 10 weeks for children aged 6-12 years and up to 13 weeks for adolescents aged 13-17 years]

   The WFIRS-P Family Domain is the mean of 10 items, ranging from 0 (never/not at all) to 3 (very often/very much). Higher scores indicate greater functional impairment. Outcome measure is at 10 weeks for ages 6-12 years and at 13 weeks for ages 13-17 years.

4. Clinical Global Impression-Severity of Illness (CGI-S) - LOCF [Up to 10 weeks for children aged 6-12 years and up to 13 weeks for adolescents aged 13-17 years]

   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). Outcome measure is at 10 weeks for ages 6-12 years and at 13 weeks for ages 13-17 years.

5. Health Utilities Index-2/3 (HUI 2/3) Scores - LOCF [Up to 10 weeks for children aged 6-12 years and up to 13 weeks for adolescents aged 13-17 years]

   HUI is used to describe health status and to obtain utility scores by collecting data using one or more questionnaires in formats selected to match the specific study design criteria. Scoring ranges from 0.00 (dead) to 1.00 (perfect health). Higher scores represent better health status. Outcome measure is at 10 weeks for ages 6-12 years and at 13 weeks for ages 13-17 years.

6. Change From Baseline in the WFIRS-P Global Score at Week 10/13 - LOCF [Baseline and Up to 10 weeks for children aged 6-12 years and up to 13 weeks for adolescents aged 13-17 years]

   The WFIRS-P Global Score is the mean of 50 items, ranging from 0 (never/not at all) to 3 (very often/very much). Higher scores indicate greater functional impairment. Outcome measure is at 10 weeks for ages 6-12 years and at 13 weeks for ages 13-17 years.

7. Change From Baseline in the WFIRS-P Academic Performance Domain Score at Week 10/13 - LOCF [Up to 10 weeks for children aged 6-12 years and up to 13 weeks for adolescents aged 13-17 years]

   The WFIRS-P Academic Performance Domain is the mean of 4 items, ranging from 0 (never/not at all) to 3 (very often/very much). Higher scores indicate greater functional impairment. Outcome measure is at 10 weeks for ages 6-12 years and at 13 weeks for ages 13-17 years.

8. Change From Baseline in the WFIRS-P Behavior in School Domain Score at Week 10/13 - LOCF [Up to 10 weeks for children aged 6-12 years and up to 13 weeks for adolescents aged 13-17 years]

   The WFIRS-P Behavior in School Domain is the mean of 6 items, ranging from 0 (never/not at all) to 3 (very often/very much). Higher scores indicate greater functional impairment. Outcome measure is at 10 weeks for ages 6-12 years and at 13 weeks for ages 13-17 years.

9. Change From Baseline in the WFIRS-P Life Skills Domain Score at Week 10/13 - LOCF [Up to 10 weeks for children aged 6-12 years and up to 13 weeks for adolescents aged 13-17 years]

   The WFIRS-P Life Skills Domain is the mean of 10 items, ranging from 0 (never/not at all) to 3 (very often/very much). Higher scores indicate greater functional impairment. Outcome measure is at 10 weeks for ages 6-12 years and at 13 weeks for ages 13-17 years.

10. Change From Baseline in the WFIRS-P Child Self-Concept Domain Score at Week 10/13 - LOCF [Up to 10 weeks for children aged 6-12 years and up to 13 weeks for adolescents aged 13-17 years]

    The WFIRS-P Child Self-Concept Domain is the mean of 3 items, ranging from 0 (never/not at all) to 3 (very often/very much). Higher scores indicate greater functional impairment. Outcome measure is at 10 weeks for ages 6-12 years and at 13 weeks for ages 13-17 years.

11. Change From Baseline in the WFIRS-P Social Domain Score at Week 10/13 - LOCF [Up to 10 weeks for children aged 6-12 years and up to 13 weeks for adolescents aged 13-17 years]

    The WFIRS-P Social Domain is the mean of 7 items, ranging from 0 (never/not at all) to 3 (very often/very much). Higher scores indicate greater functional impairment. Outcome measure is at 10 weeks for ages 6-12 years and at 13 weeks for ages 13-17 years.

12. Change From Baseline in the WFIRS-P Risk Domain Score at Week 10/13 - LOCF [Up to 10 weeks for children aged 6-12 years and up to 13 weeks for adolescents aged 13-17 years]

    The WFIRS-P Risk Domain is the mean of 10 items, ranging from 0 (never/not at all) to 3 (very often/very much). Higher scores indicate greater functional impairment. Outcome measure is at 10 weeks for ages 6-12 years and at 13 weeks for ages 13-17 years.

13. Change From Baseline in Brief Psychiatric Rating Scale for Children (BPRS-C) Total Score at Weeks 10/13 - LOCF [Baseline and up to 10 weeks for children aged 6-12 years and up to 13 weeks for adolescents aged 13-17 years]

    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. Outcome measure is at 10 weeks for ages 6-12 years and at 13 weeks for ages 13-17 years.

14. Structure Side-Effect Questionnaire [Up to 12 weeks for children aged 6-12 years and up to 15 weeks for adolescents aged 13-17 years]

    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' on the checklist for each of the events listed. Outcome measure is at 12 weeks for ages 6-12 years and at 15 weeks for ages 13-17 years.

15. Columbia-Suicide Severity Rating Scale (C-SSRS) [Up to 12 weeks for children aged 6-12 years and up to 15 weeks for adolescents aged 13-17 years]

    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. Outcome measure is at 12 weeks for ages 6-12 years and at 15 weeks for ages 13-17 years.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Male or female, aged 6 17 years at the time of consent/assent at Screening (Visit 1).

2. Subject's parent or legally authorised representative (LAR) must provide signature of informed consent, and there must be documentation of assent (if applicable) 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, and applicable regulations before completing any study related procedures at Screening (Visit 1).

3. Subject meets Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) criteria for a primary diagnosis of ADHD, combined sub-type, hyperactive/impulsive sub-type, or inattentive sub-type based on a detailed psychiatric evaluation using the Kiddie Schedule for Affective Disorders and Schizophrenia - Present and Lifetime version (K-SADS-PL).

4. Subject has a minimum ADHD-RS-IV total score of 32 at Baseline (Visit 2).

5. Subject has a minimum CGI-S score of 4 at Baseline (Visit 2).

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

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

8. Subject is able to swallow intact tablets and capsules.

9. Subject who is a female of child-bearing potential (FOCP), defined as greater than or equal to 9 years of age or <9 years of age and is menarchal, must have a negative serum beta Human Chorionic Gonadotropin (hCG) pregnancy test at Screening (Visit 1) and a negative urine pregnancy test at Baseline (Visit 2) and agree to comply with any applicable contraceptive requirements of the protocol.

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

Exclusion Criteria:

1. Subject has a current, controlled (requiring a prohibited medication or behavioural modification program) or uncontrolled, co-morbid psychiatric diagnosis [except oppositional defiant disorder (ODD)], including any severe co-morbid Axis II disorders or severe Axis I disorders such as post traumatic stress disorder (PTSD), bipolar illness, psychosis, pervasive developmental disorder, obsessive-compulsive disorder (OCD), substance abuse disorder, or other symptomatic manifestations or lifetime history of bipolar illness, psychosis or conduct disorder that, in the opinion of the Investigator, contraindicate treatment with SPD503 or STRATTERA or confound efficacy or safety assessments.

2. Subject is well-controlled on their current medication, with acceptable tolerability, and the parent/caregiver does not object to the current medication.

3. Subject has any condition or illness including a clinically significant abnormal Screening (Visit 1) 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. Mild stable asthma treated without the use of beta-2 agonist is not exclusionary.

4. Subject has a known history or presence of structural cardiac abnormalities, cardiovascular or cerebrovascular disease, serious heart rhythm abnormalities, syncope, tachycardia, cardiac conduction problems (eg, clinically significant heart block or QT interval prolongation), exercise-related cardiac events including syncope and pre syncope, or clinically significant bradycardia.

5. Subject has a known family history of sudden cardiac death, ventricular arrhythmia, or QT prolongation.

6. Subjects with orthostatic hypotension or a known history of hypertension.

7. Subject has glaucoma.

8. Subject has clinically significant ECG findings as judged by the Investigator with consideration of the central ECG laboratory's interpretation.

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

10. Current use of any prohibited medication or other medications, including monoamine oxidase inhibitors, herbal supplements, that affect BP or heart rate potent CYP2D6 inhibitors, medications known to prolong the QT/QTc interval, medications that lower seizure threshold, pressor agents, beta-2 agonists, medications that affect noradrenaline, medications that 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 [ie, antihistamines]) in violation of the protocol specified washout criteria at Baseline (Visit 2).

11. Subject has a history of alcohol or other substance abuse or dependence, as defined by DSM-IV (with the exception of nicotine) within the last 6 months.

12. Subject has taken another investigational product within 30 days prior to Baseline (Visit 2).

13. Subject is significantly overweight based on Center for Disease Control and Prevention Body Mass Index (BMI)-for-age gender specific charts at the Screening (Visit 1). Significantly overweight is defined as a BMI >95th percentile.

14. Children aged 6 12 years with a body weight of less than 25kg or adolescents aged 13 17 years with a body weight of less than 34kg or greater than 91kg at Screening (Visit 1).

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

16. Clinically important abnormality on drug and alcohol screen (excluding the subject's current ADHD stimulant if applicable) at Screening (Visit 1)

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

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

19. Subject is currently considered a suicide risk in the opinion of the Investigator, has previously made a suicide attempt, or has a prior history of, or is currently demonstrating active suicide ideation. Subjects with intermittent passive suicidal ideation are not necessarily excluded based on the assessment of the Investigator.

20. History of failure to respond to an adequate trial of an α2-agonist or atomoxetine hydrochloride for the treatment of ADHD (consisting of an appropriate dose and adequate duration of therapy in the opinion of the investigator).

21. Subjects with renal or hepatic insufficiency.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Psychiatric Centers at San Diego, Feighner Research	San Diego	California	United States	92108
2	Florida Clinical Research Center, LLC	Maitland	Florida	United States	32751
3	Atlanta Center for Medical Research	Atlanta	Georgia	United States	30308
4	Psychiatric Associates	Overland Park	Kansas	United States	66211
5	Rochester Center for Behavioral Medicine	Rochester Hills	Michigan	United States	48307
6	University of Nebraska Medical Center, Dept. of Psychiatry	Omaha	Nebraska	United States	68198-5581
7	Innovis Health	Fargo	North Dakota	United States	58103
8	Clinical Neuroscience Solutions, Inc.	Memphis	Tennessee	United States	38119
9	Claghorn-Lesem Research Clinic	Houston	Texas	United States	77008
10	R/D Clincial Research, Inc.	Lake Jackson	Texas	United States	77566
11	NeuroScience Inc.	Herndon	Virginia	United States	20170
12	Medizinische Universitat Graz-Universitaklinik fur Kinder-und Jugendheilkunde	Graz		Austria	8036
13	Institut für Psychosomatik	Wien		Austria	1010
14	Dr Grazyna B. Jackiewicz, MD	Niagara Falls	Ontario	Canada	L2E 6A4
15	JPM Van Stralen Medicine Professional Corp.	Ottawa	Ontario	Canada	K2G 1W2
16	Centre HospitalierUniversitaire d'Amiens, Hoptial Nord	Amiens Cedex	Picardie	France	80054
17	Centre Hospitalier Charles Perens - Service de Psychiatrie de l'Enfant et de l'Adolescent	Bordeaux		France	33076
18	Centre Hospitalier des Pyrenees	Chartres		France	28018
19	Praxis Dr. Wolff	Hagen	Nordrhein-Westfalen	Germany	58093
20	Praxis Dr. Andreas Mahler	Achim		Germany	28832
21	Emovis GmbH	Berlin		Germany	10629
22	Universitaetsklinikum Carl Gustav Carus an der Technischen Universitaet Dresden	Dresden		Germany	01307
23	Praxisgemeinschaft Drs. Willem Geraets/Gabriele Lucassen	Dusseldorf		Germany	40215
24	Praxis Dr. Walter Robert Otto	Fulda		Germany	36037
25	Praxis Dr. Friedrich Kaiser un Ingrid Marinesse	Hamburg		Germany	22415
26	Institut fur Ganzheitiche Medzin und Wissenschaft GmbH	Huttenberg		Germany	35625
27	Klinikum der Johannes-Guttenberg-Universitat Mainz	Mainz		Germany	55131
28	Zentralinstitut fur Seelische Geseundheit Mannheim Klinik for Psuchiatrie und Psychotherapie des Kindes	Mannheim		Germany	68159
29	Somni Bene GmbH - Institut für Medizinische Forschung und Schlafmedizin	Schwerin		Germany
30	Department of Child and Adolescent Psychiatry	Dublin		Ireland	12
31	IRCCS Stella Maris - U.O. Psichiatria e Psicofarmacologia Eta' Evolutiva	Pisa		Italy	56018
32	Università Cattolica del Sacro Cuore	Rome		Italy	00168
33	Ospedale Policlinico G.B.Rossi - Azienda Ospedaliera Universitaria Integrata Verona	Verona		Italy	37134
34	Centrum Neuropsychiatrii Neuromed	Wroclaw	Dolnoslaskie	Poland	54-235
35	Indywidualna Specjalistyczna Praktyka Lekarska Borys Gniot	Torun	Kujawsko-pomorskie	Poland	87-100
36	Samodzielny Publiczny Dzieciecy Szpital Kliniczny	Warszawa	Mazowieckie	Poland	00-576
37	Centrum Badan Klinicznych PI-House Sp. z o.o.	Gdansk	Pomorskie	Poland	80-546
38	NZOZ Gdan Skie Centrum Zdrowia	Gdansk		Poland	80-542
39	Gabinet Psychiatrii Doroslych, Dzieci i Mlodziezy, Miroslaw Dabkowski	Torun		Poland	87-100
40	Spitalul Clinic de Urgenta Pentru Copii Cluj	Cluj Napoca	Cluj	Romania	400660
41	Spitalul Clinic de Urgenta pentru Copii "Louis Turcanu"	Timisoara	Timis	Romania	300239
42	Spitalul Clinic de Psihiatrie "Prof. Dr. Alexandru Obregia"	Bucuresti		Romania
43	Spitalul Clinic de Psihiatrie Socola	Iasi		Romania
44	Mutua de Terrassa	Terrassa	Barcelona	Spain	08221
45	Hospital Universitari Vall d'Hebron	Barcelona		Spain	08035
46	Policlínica Guipuzkoa	Donostia-San Sebastián		Spain	20009
47	Hospital Marítimo, (USMI-J)	Malaga		Spain	29620
48	Hospital de Dia Infantil y Juvenil Dr Diego Guigou y Costa	Santa Cruz de Tenerife		Spain	38003
49	Hospital Universitario Marques de Valdecilla	Santander		Spain	39011
50	Instituto Valenciano de Neurología Pediatrica	Valencia		Spain	46010
51	Drottning Silvias Barnsjukhus	Goteborg		Sweden	411 18
52	Barn och Ungdomsmedicin klinik Mölnlycke	Mölnlycke		Sweden	43530
53	BUP mottagningen Varberg	Varberg		Sweden	432 43
54	Institute of Neurology, Psychiatry and Narcology of the AMS of Ukraine	Kharkov	Kharkiv	Ukraine	61068
55	Regional Clinical Psychiatric Hospital	Donetsk		Ukraine	83037
56	Municipal Institution "Institute of healthcare for children and adolescences NAMNU	Kharkiv		Ukraine	61153
57	Kherson Regional Psychiatric Hospital	Kherson		Ukraine	73488
58	Lviv Regional Clinical Psychiatric Hospital	Lviv		Ukraine	79021
59	Odesa Regional Psychoneurological Dispensary, Outpatient Dept	Odesa		Ukraine	65084
60	O.F. Maltsev Poltava Regional Psychiatric Hospital	Poltava		Ukraine	36000
61	Vinnytsia National Medical University - Vinnytsia Regional Psycho-Neurological Hospital	Vinnytsia		Ukraine	21005
62	Victoria Hospital	Kirkcaldy	Fife	United Kingdom	KY2 5AH
63	James Paget University Hospital NHS Trust	Great Yarmouth	Norfolk	United Kingdom	NR31 6SQ
64	Ashurt Child and Family Centre	Ashurst	Southampton	United Kingdom	SO40 7AR
65	Horsham Child and Adolescent Mental Health Services	Horsham		United Kingdom
66	5 Boroughs Partnership NHS Trust	Wigan		United Kingdom	WN2 2JA

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: NCT01244490
• Other Study ID Numbers: SPD503-316; 2010-018579-12
• First Posted: Nov 19, 2010
• Last Update Posted: Jul 2, 2021
• Last Verified: Jun 1, 2021

• Keywords provided by Shire: ADHD
• Additional relevant MeSH terms: Hyperkinesis; Attention Deficit Disorder with Hyperactivity; Guanfacine; Atomoxetine Hydrochloride

Study Results

Participant Flow

Arm/Group Title	Placebo	Guanfacine Hydrochloride	Atomoxetine Hydrochloride
Arm/Group Description	Once daily	Tablet, once daily, optimised dose (1mg to 7mg based on age and weight)	Capsule, once daily, optimised dose (10mg to 100mg based on weight)
Period Title: Overall Study
STARTED	111	115	112
COMPLETED	92	91	89
NOT COMPLETED	19	24	23

Baseline Characteristics

Arm/Group Title	Placebo	Guanfacine Hydrochloride	Atomoxetine Hydrochloride	Total
Arm/Group Description	Once daily	Tablet, once daily, optimised dose (1mg to 7mg based on age and weight)	Capsule, once daily, optimised dose (10mg to 100mg based on weight)	Total of all reporting groups
Overall Participants	111	114	112	337
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	11.0 (2.76)	10.9 (2.77)	10.5 (2.81)	10.8 (2.78)
Age, Customized (Count of Participants)
6-12 years	79 71.2%	81 71.1%	82 73.2%	242 71.8%
13-17 years	32 28.8%	33 28.9%	30 26.8%	95 28.2%
Sex: Female, Male (Count of Participants)
Female	25 22.5%	38 33.3%	25 22.3%	88 26.1%
Male	86 77.5%	76 66.7%	87 77.7%	249 73.9%
Region of Enrollment (Count of Participants)
AUSTRIA	2 1.8%	4 3.5%	5 4.5%	11 3.3%
CANADA	6 5.4%	7 6.1%	6 5.4%	19 5.6%
FRANCE	2 1.8%	2 1.8%	2 1.8%	6 1.8%
GERMANY	23 20.7%	23 20.2%	22 19.6%	68 20.2%
IRELAND	0 0%	1 0.9%	1 0.9%	2 0.6%
ITALY	5 4.5%	4 3.5%	4 3.6%	13 3.9%
POLAND	11 9.9%	14 12.3%	12 10.7%	37 11%
ROMANIA	5 4.5%	3 2.6%	6 5.4%	14 4.2%
SPAIN	16 14.4%	18 15.8%	17 15.2%	51 15.1%
SWEDEN	1 0.9%	1 0.9%	2 1.8%	4 1.2%
UKRAINE	21 18.9%	18 15.8%	15 13.4%	54 16%
UNITED KINGDOM	1 0.9%	0 0%	1 0.9%	2 0.6%
UNITED STATES	18 16.2%	19 16.7%	19 17%	56 16.6%

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 10/13 - 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. Outcome measure is at 10 weeks for ages 6-12 years and at 13 weeks for ages 13-17 years.
Time Frame	Baseline and Up to 10 weeks for children aged 6-12 years and up to 13 weeks for adolescents aged 13-17 years

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) defined as all randomized subjects who took at least 1 dose of investigational product. If more than 20% of the items used for summing a score were missing, the score was set to missing.

Arm/Group Title	Placebo	Guanfacine Hydrochloride	Atomoxetine Hydrochloride
Arm/Group Description	Once daily	Tablet, once daily, optimised dose (1mg to 7mg based on age and weight)	Capsule, once daily, optimised dose (10mg to 100mg based on weight)
Measure Participants	111	112	112
Least Squares Mean (Standard Error) [units on a scale]	-15.0 (1.1612)	-23.9 (1.1531)	-18.8 (1.1549)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Guanfacine Hydrochloride
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in Least Squares Mean
	Estimated Value	-8.9
	Confidence Interval	(2-Sided) 95%; -11.9 to -5.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Atomoxetine Hydrochloride
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.017
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in Least Squares Mean
	Estimated Value	-3.8
	Confidence Interval	(2-Sided) 95%; -6.8 to -0.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Percentage of Participants With Improvement on Clinical Global Impression-Improvement (CGI-I) Scores
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. Outcome measure is at 10 weeks for ages 6-12 years and at 13 weeks for ages 13-17 years.
Time Frame	Up to 10 weeks for children aged 6-12 years and up to 13 weeks for adolescents aged 13-17 years

Outcome Measure Data

Analysis Population Description

Full Analysis Set. Not all subjects in the FAS population had data for this outcome.

Arm/Group Title	Placebo	Guanfacine Hydrochloride	Atomoxetine Hydrochloride
Arm/Group Description	Once daily	Tablet, once daily, optimised dose (1mg to 7mg based on age and weight)	Capsule, once daily, optimised dose (10mg to 100mg based on weight)
Measure Participants	111	112	112
Number [percentage of participants]	44.1 39.7%	67.9 59.6%	56.3 50.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Guanfacine Hydrochloride
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Difference in Percentage Improvement
	Estimated Value	23.7
	Confidence Interval	(2-Sided) 95%; 11.1 to 36.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Atomoxetine Hydrochloride
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.024
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Difference in Percentage Improvement
	Estimated Value	12.1
	Confidence Interval	(2-Sided) 95%; -0.9 to 25.1
	Parameter Dispersion	Type: Value:
	Estimation 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 10/13 - LOCF
Description	The WFIRS-P Learning in School Domain is the mean of 10 items, ranging from 0 (never/not at all) to 3 (very often/very much). Higher scores indicate greater functional impairment. Outcome measure is at 10 weeks for ages 6-12 years and at 13 weeks for ages 13-17 years.
Time Frame	Baseline and Up to 10 weeks for children aged 6-12 years and up to 13 weeks for adolescents aged 13-17 years

Outcome Measure Data

Analysis Population Description

Full Analysis Set. If more than 30% of items used to derive the score were missing, the corresponding score was considered as missing.

Arm/Group Title	Placebo	Guanfacine Hydrochloride	Atomoxetine Hydrochloride
Arm/Group Description	Once daily	Tablet, once daily, optimised dose (1mg to 7mg based on age and weight)	Capsule, once daily, optimised dose (10mg to 100mg based on weight)
Measure Participants	100	103	100
Least Squares Mean (Standard Error) [units on a scale]	-0.419 (0.0537)	-0.636 (0.0527)	-0.581 (0.0534)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Guanfacine Hydrochloride
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in Least Squares Mean
	Estimated Value	-0.217
	Confidence Interval	(2-Sided) 95%; -0.358 to -0.076
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Atomoxetine Hydrochloride
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.026
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in Least Squares Mean
	Estimated Value	-0.162
	Confidence Interval	(2-Sided) 95%; -0.305 to -0.019
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline in the WFIRS-P Family Domain Score at Week 10/13 - LOCF
Description	The WFIRS-P Family Domain is the mean of 10 items, ranging from 0 (never/not at all) to 3 (very often/very much). Higher scores indicate greater functional impairment. Outcome measure is at 10 weeks for ages 6-12 years and at 13 weeks for ages 13-17 years.
Time Frame	Baseline and Up to 10 weeks for children aged 6-12 years and up to 13 weeks for adolescents aged 13-17 years

Outcome Measure Data

Analysis Population Description

Full Analysis Set. If more than 30% of items used to derive the score were missing, the corresponding score was considered as missing.

Arm/Group Title	Placebo	Guanfacine Hydrochloride	Atomoxetine Hydrochloride
Arm/Group Description	Once daily	Tablet, once daily, optimised dose (1mg to 7mg based on age and weight)	Capsule, once daily, optimised dose (10mg to 100mg based on weight)
Measure Participants	106	109	105
Least Squares Mean (Standard Error) [units on a scale]	-0.409 (0.0568)	-0.617 (0.0558)	-0.499 (0.0566)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Guanfacine Hydrochloride
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.006
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in Least Squares Mean
	Estimated Value	-0.209
	Confidence Interval	(2-Sided) 95%; -0.358 to -0.059
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Atomoxetine Hydrochloride
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.242
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in Least Squares Mean
	Estimated Value	-0.090
	Confidence Interval	(2-Sided) 95%; -0.241 to 0.061
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Clinical Global Impression-Severity of Illness (CGI-S) - 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). Outcome measure is at 10 weeks for ages 6-12 years and at 13 weeks for ages 13-17 years.
Time Frame	Up to 10 weeks for children aged 6-12 years and up to 13 weeks for adolescents aged 13-17 years

Outcome Measure Data

Analysis Population Description

Full Analysis Set. Not all subjects in the FAS population had data for this outcome.

Arm/Group Title	Placebo	Guanfacine Hydrochloride	Atomoxetine Hydrochloride
Arm/Group Description	Once daily	Tablet, once daily, optimised dose (1mg to 7mg based on age and weight)	Capsule, once daily, optimised dose (10mg to 100mg based on weight)
Measure Participants	111	112	112
1 (Normal, not at all ill)	9.9 8.9%	14.3 12.5%	6.3 5.6%
2 (Borderline mentally ill)	15.3 13.8%	23.2 20.4%	19.6 17.5%
3 (Mildly ill)	20.7 18.6%	31.3 27.5%	32.1 28.7%
4 (Moderately ill)	20.7 18.6%	22.3 19.6%	19.6 17.5%
5 (Markedly ill)	25.2 22.7%	5.4 4.7%	13.4 12%
6 (Severely ill)	6.3 5.7%	3.6 3.2%	7.1 6.3%
7 (Amongst the most extremely ill)	1.8 1.6%	0 0%	1.8 1.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Guanfacine Hydrochloride
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Nominal p-value uncorrected for multiplicity.
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Atomoxetine Hydrochloride
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.196
	Comments	Nominal p-value uncorrected for multiplicity.
	Method	Cochran-Mantel-Haenszel
	Comments

6. Secondary Outcome

Title	Health Utilities Index-2/3 (HUI 2/3) Scores - LOCF
Description	HUI is used to describe health status and to obtain utility scores by collecting data using one or more questionnaires in formats selected to match the specific study design criteria. Scoring ranges from 0.00 (dead) to 1.00 (perfect health). Higher scores represent better health status. Outcome measure is at 10 weeks for ages 6-12 years and at 13 weeks for ages 13-17 years.
Time Frame	Up to 10 weeks for children aged 6-12 years and up to 13 weeks for adolescents aged 13-17 years

Outcome Measure Data

Analysis Population Description

Full Analysis Set. Not all subjects in the FAS population had data for this outcome.

Arm/Group Title	Placebo	Guanfacine Hydrochloride	Atomoxetine Hydrochloride
Arm/Group Description	Once daily	Tablet, once daily, optimised dose (1mg to 7mg based on age and weight)	Capsule, once daily, optimised dose (10mg to 100mg based on weight)
Measure Participants	106	110	106
Mean (Standard Deviation) [units on a scale]	0.927 (0.0950)	0.922 (0.0908)	0.913 (0.1052)

7. Secondary Outcome

Title	Change From Baseline in the WFIRS-P Global Score at Week 10/13 - LOCF
Description	The WFIRS-P Global Score is the mean of 50 items, ranging from 0 (never/not at all) to 3 (very often/very much). Higher scores indicate greater functional impairment. Outcome measure is at 10 weeks for ages 6-12 years and at 13 weeks for ages 13-17 years.
Time Frame	Baseline and Up to 10 weeks for children aged 6-12 years and up to 13 weeks for adolescents aged 13-17 years

Outcome Measure Data

Analysis Population Description

Full Analysis Set. If more than 30% of items used to derive the score were missing, the corresponding score was considered as missing.

Arm/Group Title	Placebo	Guanfacine Hydrochloride	Atomoxetine Hydrochloride
Arm/Group Description	Once daily	Tablet, once daily, optimised dose (1mg to 7mg based on age and weight)	Capsule, once daily, optimised dose (10mg to 100mg based on weight)
Measure Participants	104	110	104
Least Squares Mean (Standard Error) [units on a scale]	-0.321 (0.0387)	-0.487 (0.0374)	-0.425 (0.0384)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Guanfacine Hydrochloride
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	Nominal p-value uncorrected for multiplicity.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.165
	Confidence Interval	(2-Sided) 95%; -0.266 to -0.064
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Atomoxetine Hydrochloride
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.048
	Comments	Nominal p-value uncorrected for multiplicity.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.104
	Confidence Interval	(2-Sided) 95%; -0.207 to -0.001
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Change From Baseline in the WFIRS-P Academic Performance Domain Score at Week 10/13 - LOCF
Description	The WFIRS-P Academic Performance Domain is the mean of 4 items, ranging from 0 (never/not at all) to 3 (very often/very much). Higher scores indicate greater functional impairment. Outcome measure is at 10 weeks for ages 6-12 years and at 13 weeks for ages 13-17 years.
Time Frame	Up to 10 weeks for children aged 6-12 years and up to 13 weeks for adolescents aged 13-17 years

Outcome Measure Data

Analysis Population Description

Full Analysis Set. If more than 30% of items used to derive the score were missing, the corresponding score was considered as missing.

Arm/Group Title	Placebo	Guanfacine Hydrochloride	Atomoxetine Hydrochloride
Arm/Group Description	Once daily	Tablet, once daily, optimised dose (1mg to 7mg based on age and weight)	Capsule, once daily, optimised dose (10mg to 100mg based on weight)
Measure Participants	96	103	101
Least Squares Mean (Standard Error) [units on a scale]	-0.555 (0.0784)	-0.766 (0.0757)	-0.681 (0.0759)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Guanfacine Hydrochloride
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.043
	Comments	Nominal p-value uncorrected for multiplicity.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in Least Squares Mean
	Estimated Value	-0.211
	Confidence Interval	(2-Sided) 95%; -0.416 to -0.007
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Atomoxetine Hydrochloride
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.231
	Comments	Nominal p-value uncorrected for multiplicity.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in Least Squares Mean
	Estimated Value	-0.125
	Confidence Interval	(2-Sided) 95%; -0.331 to 0.080
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Change From Baseline in the WFIRS-P Behavior in School Domain Score at Week 10/13 - LOCF
Description	The WFIRS-P Behavior in School Domain is the mean of 6 items, ranging from 0 (never/not at all) to 3 (very often/very much). Higher scores indicate greater functional impairment. Outcome measure is at 10 weeks for ages 6-12 years and at 13 weeks for ages 13-17 years.
Time Frame	Up to 10 weeks for children aged 6-12 years and up to 13 weeks for adolescents aged 13-17 years

Outcome Measure Data

Analysis Population Description

Full Analysis Set. If more than 30% of items used to derive the score were missing, the corresponding score was considered as missing.

Arm/Group Title	Placebo	Guanfacine Hydrochloride	Atomoxetine Hydrochloride
Arm/Group Description	Once daily	Tablet, once daily, optimised dose (1mg to 7mg based on age and weight)	Capsule, once daily, optimised dose (10mg to 100mg based on weight)
Measure Participants	100	103	100
Least Squares Mean (Standard Error) [units on a scale]	-0.363 (0.0512)	-0.592 (0.0502)	-0.544 (0.0509)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Guanfacine Hydrochloride
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Nominal p-value uncorrected for multiplicity.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Diiference in Least Squares Mean
	Estimated Value	-0.229
	Confidence Interval	(2-Sided) 95%; -0.364 to -0.094
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Atomoxetine Hydrochloride
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.009
	Comments	Nominal p-value uncorrected for multiplicity.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in Least Squares Mean
	Estimated Value	-0.181
	Confidence Interval	(2-Sided) 95%; -0.317 to -0.045
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Change From Baseline in the WFIRS-P Life Skills Domain Score at Week 10/13 - LOCF
Description	The WFIRS-P Life Skills Domain is the mean of 10 items, ranging from 0 (never/not at all) to 3 (very often/very much). Higher scores indicate greater functional impairment. Outcome measure is at 10 weeks for ages 6-12 years and at 13 weeks for ages 13-17 years.
Time Frame	Up to 10 weeks for children aged 6-12 years and up to 13 weeks for adolescents aged 13-17 years

Outcome Measure Data

Analysis Population Description

Full Analysis Set. If more than 30% of items used to derive the score were missing, the corresponding score was considered as missing.

Arm/Group Title	Placebo	Guanfacine Hydrochloride	Atomoxetine Hydrochloride
Arm/Group Description	Once daily	Tablet, once daily, optimised dose (1mg to 7mg based on age and weight)	Capsule, once daily, optimised dose (10mg to 100mg based on weight)
Measure Participants	105	110	104
Least Squares Mean (Standard Error) [units on a scale]	-0.383 (0.0422)	-0.477 (0.0411)	-0.450 (0.0422)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Guanfacine Hydrochloride
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.096
	Comments	Nominal p-value uncorrected for multiplicity.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in Least Squares Mean
	Estimated Value	-0.094
	Confidence Interval	(2-Sided) 95%; -0.204 to 0.017
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Atomoxetine Hydrochloride
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.242
	Comments	Nominal p-value uncorrected for multiplicity.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in Least Squares Mean
	Estimated Value	-0.067
	Confidence Interval	(2-Sided) 95%; -0.180 to 0.046
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Change From Baseline in the WFIRS-P Child Self-Concept Domain Score at Week 10/13 - LOCF
Description	The WFIRS-P Child Self-Concept Domain is the mean of 3 items, ranging from 0 (never/not at all) to 3 (very often/very much). Higher scores indicate greater functional impairment. Outcome measure is at 10 weeks for ages 6-12 years and at 13 weeks for ages 13-17 years.
Time Frame	Up to 10 weeks for children aged 6-12 years and up to 13 weeks for adolescents aged 13-17 years

Outcome Measure Data

Analysis Population Description

Full Analysis Set. If more than 30% of items used to derive the score were missing, the corresponding score was considered as missing.

Arm/Group Title	Placebo	Guanfacine Hydrochloride	Atomoxetine Hydrochloride
Arm/Group Description	Once daily	Tablet, once daily, optimised dose (1mg to 7mg based on age and weight)	Capsule, once daily, optimised dose (10mg to 100mg based on weight)
Measure Participants	101	108	103
Least Squares Mean (Standard Error) [units on a scale]	-0.312 (0.0544)	-0.361 (0.0528)	-0.390 (0.0536)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Guanfacine Hydrochloride
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.500
	Comments	Nominal p-value uncorrected for multiplicity.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in Least Squares Mean
	Estimated Value	-0.049
	Confidence Interval	(2-Sided) 95%; -0.191 to 0.094
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Atomoxetine Hydrochloride
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.288
	Comments	Nominal p-value uncorrected for multiplicity.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in Least Squares Mean
	Estimated Value	-0.078
	Confidence Interval	(2-Sided) 95%; -0.222 to 0.066
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Secondary Outcome

Title	Change From Baseline in the WFIRS-P Social Domain Score at Week 10/13 - LOCF
Description	The WFIRS-P Social Domain is the mean of 7 items, ranging from 0 (never/not at all) to 3 (very often/very much). Higher scores indicate greater functional impairment. Outcome measure is at 10 weeks for ages 6-12 years and at 13 weeks for ages 13-17 years.
Time Frame	Up to 10 weeks for children aged 6-12 years and up to 13 weeks for adolescents aged 13-17 years

Outcome Measure Data

Analysis Population Description

Full Analysis Set. If more than 30% of items used to derive the score were missing, the corresponding score was considered as missing.

Arm/Group Title	Placebo	Guanfacine Hydrochloride	Atomoxetine Hydrochloride
Arm/Group Description	Once daily	Tablet, once daily, optimised dose (1mg to 7mg based on age and weight)	Capsule, once daily, optimised dose (10mg to 100mg based on weight)
Measure Participants	104	110	104
Least Squares Mean (Standard Error) [units on a scale]	-0.322 (0.0537)	-0.555 (0.0519)	-0.434 (0.0532)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Guanfacine Hydrochloride
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	Nominal p-value uncorrected for multiplicity.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in Least Squares Mean
	Estimated Value	-0.233
	Confidence Interval	(2-Sided) 95%; -0.374 to -0.092
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Atomoxetine Hydrochloride
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.124
	Comments	Nominal p-value uncorrected for multiplicity.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in Least Squares Mean
	Estimated Value	-0.111
	Confidence Interval	(2-Sided) 95%; -0.253 to 0.031
	Parameter Dispersion	Type: Value:
	Estimation Comments

13. Secondary Outcome

Title	Change From Baseline in the WFIRS-P Risk Domain Score at Week 10/13 - LOCF
Description	The WFIRS-P Risk Domain is the mean of 10 items, ranging from 0 (never/not at all) to 3 (very often/very much). Higher scores indicate greater functional impairment. Outcome measure is at 10 weeks for ages 6-12 years and at 13 weeks for ages 13-17 years.
Time Frame	Up to 10 weeks for children aged 6-12 years and up to 13 weeks for adolescents aged 13-17 years

Outcome Measure Data

Analysis Population Description

Full Analysis Set. If more than 30% of items used to derive the score were missing, the corresponding score was considered as missing.

Arm/Group Title	Placebo	Guanfacine Hydrochloride	Atomoxetine Hydrochloride
Arm/Group Description	Once daily	Tablet, once daily, optimised dose (1mg to 7mg based on age and weight)	Capsule, once daily, optimised dose (10mg to 100mg based on weight)
Measure Participants	99	105	97
Least Squares Mean (Standard Error) [units on a scale]	-0.134 (0.0284)	-0.190 (0.0275)	-0.173 (0.0285)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Guanfacine Hydrochloride
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.139
	Comments	Nominal p-value uncorrected for multiplicity.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in Least Squares Mean
	Estimated Value	-0.056
	Confidence Interval	(2-Sided) 95%; -0.131 to 0.018
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Atomoxetine Hydrochloride
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.315
	Comments	Nominal p-value uncorrected for multiplicity.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in Least Squares Mean
	Estimated Value	-0.039
	Confidence Interval	(2-Sided) 95%; -0.115 to 0.037
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. Secondary Outcome

Title	Change From Baseline in Brief Psychiatric Rating Scale for Children (BPRS-C) Total Score at Weeks 10/13 - LOCF
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. Outcome measure is at 10 weeks for ages 6-12 years and at 13 weeks for ages 13-17 years.
Time Frame	Baseline and up to 10 weeks for children aged 6-12 years and up to 13 weeks for adolescents aged 13-17 years

Outcome Measure Data

Analysis Population Description

Safety Population defined as of randomized subjects who took at least 1 dose of investigational product.

Arm/Group Title	Placebo	Guanfacine Hydrochloride	Atomoxetine Hydrochloride
Arm/Group Description	Once daily	Tablet, once daily, optimised dose (1mg to 7mg based on age and weight)	Capsule, once daily, optimised dose (10mg to 100mg based on weight)
Measure Participants	102	101	99
Mean (Standard Deviation) [units on a scale]	-5.6 (8.82)	-8.3 (8.40)	-6.5 (9.23)

15. Secondary Outcome

Title	Structure Side-Effect Questionnaire
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' on the checklist for each of the events listed. Outcome measure is at 12 weeks for ages 6-12 years and at 15 weeks for ages 13-17 years.
Time Frame	Up to 12 weeks for children aged 6-12 years and up to 15 weeks for adolescents aged 13-17 years

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	Placebo	Guanfacine Hydrochloride	Atomoxetine Hydrochloride
Arm/Group Description	Once daily	Tablet, once daily, optimised dose (1mg to 7mg based on age and weight)	Capsule, once daily, optimised dose (10mg to 100mg based on weight)
Measure Participants	111	112	112
Nausea	19 17.1%	30 26.3%	39 34.8%
Vomiting	11 9.9%	7 6.1%	25 22.3%
Diarrhea	15 13.5%	18 15.8%	8 7.1%
Abdominal Pain	26 23.4%	45 39.5%	42 37.5%
Decreased Appetite	25 22.5%	31 27.2%	48 42.9%
Increased Appetite	30 27%	40 35.1%	25 22.3%
Headache	35 31.5%	52 45.6%	34 30.4%
Dizziness	16 14.4%	28 24.6%	23 20.5%
Fatigue	30 27%	55 48.2%	35 31.3%
Nervousnes/Anxiety	25 22.5%	37 32.5%	34 30.4%
Insomnia	19 17.1%	32 28.1%	24 21.4%
Somnolence	26 23.4%	57 50%	38 33.9%
Depression	7 6.3%	7 6.1%	9 8%
Itching	7 6.3%	13 11.4%	10 8.9%
Rash	4 3.6%	9 7.9%	8 7.1%
Missed Menses	0 0%	1 0.9%	0 0%

16. 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. Outcome measure is at 12 weeks for ages 6-12 years and at 15 weeks for ages 13-17 years.
Time Frame	Up to 12 weeks for children aged 6-12 years and up to 15 weeks for adolescents aged 13-17 years

Outcome Measure Data

Analysis Population Description

SP

Arm/Group Title	Placebo	Guanfacine Hydrochloride	Atomoxetine Hydrochloride
Arm/Group Description	Once daily	Tablet, once daily, optimised dose (1mg to 7mg based on age and weight)	Capsule, once daily, optimised dose (10mg to 100mg based on weight)
Measure Participants	111	112	112
Suicidal Ideation	2 1.8%	3 2.6%	5 4.5%
Suicidal Behaviour	0 0%	0 0%	0 0%

Adverse Events

Arm/Group Title	Placebo		Guanfacine Hydrochloride		Atomoxetine Hydrochloride
Arm/Group Description	Once daily		Tablet, once daily, optimised dose (1mg to 7mg based on age and weight)		Capsule, once daily, optimised dose (10mg to 100mg based on weight)
All Cause Mortality
	Placebo		Guanfacine Hydrochloride		Atomoxetine Hydrochloride
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Guanfacine Hydrochloride		Atomoxetine Hydrochloride
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/111 (0.9%)		1/114 (0.9%)		0/112 (0%)
Nervous system disorders
Syncope	1/111 (0.9%)	1	1/114 (0.9%)	1	0/112 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo		Guanfacine Hydrochloride		Atomoxetine Hydrochloride
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	62/111 (55.9%)		79/114 (69.3%)		67/112 (59.8%)
Gastrointestinal disorders
Abdominal pain	20/111 (18%)	32	19/114 (16.7%)	29	19/112 (17%)	31
Abdominal pain upper	6/111 (5.4%)	6	7/114 (6.1%)	7	2/112 (1.8%)	3
Diarrhoea	15/111 (13.5%)	18	10/114 (8.8%)	16	2/112 (1.8%)	3
Nausea	11/111 (9.9%)	13	18/114 (15.8%)	19	30/112 (26.8%)	54
Vomiting	8/111 (7.2%)	9	6/114 (5.3%)	8	18/112 (16.1%)	29
General disorders
Fatigue	20/111 (18%)	22	29/114 (25.4%)	45	24/112 (21.4%)	32
Pyrexia	4/111 (3.6%)	4	7/114 (6.1%)	9	3/112 (2.7%)	4
Infections and infestations
Nasopharyngitis	6/111 (5.4%)	7	6/114 (5.3%)	7	3/112 (2.7%)	3
Metabolism and nutrition disorders
Decreased appetite	12/111 (10.8%)	23	15/114 (13.2%)	20	31/112 (27.7%)	44
Increased appetite	9/111 (8.1%)	11	12/114 (10.5%)	15	4/112 (3.6%)	4
Nervous system disorders
Dizziness	9/111 (8.1%)	9	14/114 (12.3%)	18	17/112 (15.2%)	24
Headache	27/111 (24.3%)	46	30/114 (26.3%)	51	22/112 (19.6%)	36
Somnolence	16/111 (14.4%)	18	50/114 (43.9%)	94	20/112 (17.9%)	32
Psychiatric disorders
Anxiety	8/111 (7.2%)	15	9/114 (7.9%)	16	7/112 (6.3%)	18
Insomnia	7/111 (6.3%)	7	13/114 (11.4%)	21	8/112 (7.1%)	10
Nervousness	6/111 (5.4%)	7	6/114 (5.3%)	7	6/112 (5.4%)	6

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.