Maintenance of Efficacy of Extended-Release Guanfacine HCl in Children and Adolescents With Attention-deficit/Hyperactivity Disorder (ADHD)

Attention-deficit/Hyperactivity Disorder Clinical Trial

Official title:

A Phase 3, Double-blind, Placebo-controlled, Multicentre, Randomised Withdrawal, Long-term Maintenance of Efficacy and Safety Study of Extended-release Guanfacine Hydrochloride in Children and Adolescents Aged 6-17 With Attention Deficit/Hyperactivity Disorder

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01081145
• Other study ID #: SPD503-315
• Secondary ID: 2009-018161-12
• Status: Completed
• Phase: Phase 3
• Start date: May 11, 2010
• Est. completion date: June 3, 2013

Study information

• Verified date: June 2021
• Source: Takeda
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The primary objective of this study is to evaluate the long-term maintenance of efficacy of Extended-Release Guanfacine HCl in children and adolescents (6-17 years) with attention-deficit/hyperactivity disorder (ADHD) who respond to an initial open-label, short term treatment with SPD503.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 528
• Est. completion date: June 3, 2013
• Est. primary completion date: June 3, 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Years to 17 Years

Eligibility

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) Guideline E6 (1996) and applicable regulations before completing any study-related procedures at Screening/Visit 1.

3. Subject meets DSM-IV-TR criteria for a primary diagnosis of ADHD, combined subtype, hyperactive/impulsive subtype, 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 Enrolment/Visit 2.

5. Subject has a minimum CGI-S score of 4 at Enrolment/Visit 2.

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

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

8. Subject is able to swallow intact tablets.

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

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

Exclusion Criteria:

1. Subject has a current, controlled (requiring a prohibited medication or behavioural modification program) or uncontrolled, comorbid psychiatric diagnosis, except oppositional defiant disorder (ODD), including 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 or lifetime history of bipolar illness, psychosis, or conduct disorder 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/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.

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

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

6. Current use of any prohibited medication or other medications, including herbal supplements, that affect BP or heart rate or that have 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]) in violation of the protocol specified washout criteria at Enrolment/Visit 2.

7. Subject has used an investigational product within 30 days prior to Enrolment/Visit 2.

8. Subject is significantly overweight based on Centre for Disease Control and Prevention Body Mass Index (BMI)-for-age gender specific charts. Significantly overweight is defined as a BMI >95th percentile.

9. Children aged 6-12 years with a body weight of <25kg or adolescents aged 13-17 years with a body weight of <34kg or >91kg at Screening/Visit 1.

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

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

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

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

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

15. 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 suicidal ideation. Subjects with intermittent passive suicidal ideation are not necessarily excluded based on the assessment of the Investigator (see protocol Section 7.2.4.2 for additional guidance).

16. History of failure to respond to an adequate trial of an alpha 2-agonist for the treatment of ADHD (consisting of an appropriate dose and adequate duration of therapy in the opinion of the Investigator).

17. 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).

18. Subject has another member of the same household currently participating in this study.

Related Conditions & MeSH terms

• Attention Deficit Disorder with Hyperactivity
• Attention-deficit/Hyperactivity Disorder
• Hyperkinesis

Intervention

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 age and weight.

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 age and weight.

Locations

Country	Name	City	State
Belgium	Cliniques Universitaires Saint Luc	Brussels
Belgium	Universitair Ziekenhuis Gent	Ghent	Oost-vlaanderen
Belgium	Huisartspraktijk Jaak Mortelmans	Ham
Belgium	Ziekenhuis Netwerk Antwerpen	Hoboken	Antwerpen
Belgium	Universitair Ziekenhuis Brussel	Jette	Brussels
Belgium	Centre de référence Neuropédiatrique Multidisciplinaire	Namur
Belgium	Psypluriel	Uccle
Belgium	Ziekenhuis Inkendaal Koninklijke Instelling v.z.w.	Vlezenbeek
Canada	JPM van Stralen Medicine Professional Corporation	Ottawa	Ontario
Canada	Royal University Hospital	Saskatoon	Saskatchewan
Canada	Children's and Women's Health Centre of British Columbia	Vancouver	British Columbia
Canada	ADHD Clinic/The Kid's Clinic	Whitby	Ontario
France	Centre Hospitalier Universitaire d'Amiens, Hôpital Nord	Amiens Cedex	Picardie
France	Centre Hospitalier Universitaire Bocage-Hôpital d'enfants	Dijon Cedex
France	Hôpital Gui de Chauliac	Montpellier Cedex 5	Languedoc-roussillon
France	Hopitaux Pediatriques de Nice - CHI Lenval	Nice	Provcence Alpes Cote D'Azur
France	Hopital Robert Debre Centre pediatrique des pathologies du sommeil	Paris
France	Hopital Robert-Debre'	Paris cedex 19
France	Centre Hospitalier de Rouffach	Rouffach	Alsace
France	Hopital Gatien de Clocheville CHU de Tours	Tours
Germany	Emovis GmbH	Berlin
Germany	Sozialpsychiatrisches Centrum Dr. med. Ralph Meyers	Dorsten	Nordrhein-westfalen
Germany	Universitatsklinikum Freiburg	Freiburg
Germany	Friedrich-Schiller-Universitat Jena	Jena	Thuringen
Germany	Klinikum der Johannes-Gutenberg-Universität Mainz	Mainz	Rheinland-pfalz
Germany	Praxis Dr. med. Dipl. Psych. Anton Lindermüller	München	Bayern
Germany	Center for Pediatric Clinical Studies	Tübingen	Baden-wuerttemberg
Germany	Universitätsklinik Ulm	Ulm	Baden-wuerttemberg
Germany	Medizinisches Studienzentrum Wurzburg	Wurzburg	Bayern
Italy	IRCCS Fondazione Stella Maris	Calambrone	Pisa
Italy	Azienda Ospedaliero-Universitaria Policlinico-Vittorio	Catania
Italy	Azienda Osp. Fatebenefratelli - Polo Territoriale UONPIA	Milano
Italy	Azienda ULSS 16 Padova	Padova
Italy	Azienda Ospedaliera "Guido Salvini"	Rho	Milan
Italy	Drottning Silvias Barnsjukhus	Roma
Italy	Università Cattolica del Sacro Cuore	Roma
Netherlands	FlevoResearch	Almere	Flevoland
Netherlands	Academisch Ziekenhuis Maastricht	Maastricht	Limburg
Netherlands	Mondriaan Zorggroep Heerlen, Kinder en Jeugdp sychiatrie	Maastricht
Spain	Hospital Fundacion Alcorcon	Alcorcon	Madrid
Spain	Hospital Universitari Vall d'Hebron	Barcelona
Spain	Policlínica Guipuzkoa	Donostia-San Sebastián	Guipuzcoa
Spain	Hospital Infanta Leonor	Madrid
Spain	Hospital Son Llàtzer, Laboratorio de Neurociencias IUNICS	Palma	Islas Baleares
Spain	Clínica Universitaria de Navarra	Pamplona	Navarra
Spain	Instituto Valenciano de Neurología Pediatrica	Valencia
Sweden	Barn och Ungdomsmedicin klinik Mölnlycke	Mölnlycke
United Kingdom	Thurrock Community Hospital	Grays
United Kingdom	Royal Liverpool University Hospital	Liverpool
United Kingdom	Norfolk Community Health and Care NHS Trust	Norwich	England
United Kingdom	Centenary House Child and Adolescent Mental Health Services	Sheffield	England
United Kingdom	Ryegate Children's Centre	Sheffield	England
United Kingdom	Lister Hospital	Stevenage
United Kingdom	Queen Elizabeth II Hospital	Welwyn Garden City	England
United States	FutureSearch Clinical Trials	Austin	Texas
United States	Florida Clinical Research Center, LLC	Bradenton	Florida
United States	Ohio State University, Nisonger Center	Columbus	Ohio
United States	Harmonex Neuroscience Research	Dothan	Alabama
United States	Triangle Neuropsychiatry, PLLC	Durham	North Carolina
United States	Sarkis Clinical Trials	Gainesville	Florida
United States	Amedica Research Institute, Inc.	Hialeah	Florida
United States	Goldpoint Clinical Research, LLC	Indianapolis	Indiana
United States	Clinical Neuroscience Solutions, Inc.	Jacksonville	Florida
United States	Eastside Therapeutic Resource	Kirkland	Washington
United States	Center for Psychiatry and Behavioral Medicine, Inc.	Las Vegas	Nevada
United States	Clinical Study Centers, LLC	Little Rock	Arkansas
United States	Florida Clinical Research Center, LLC	Maitland	Florida
United States	AMR-Baber Research Inc.	Naperville	Illinois
United States	Louisiana Research Associates, Inc.	New Orleans	Louisiana
United States	Mount Sinai School of Medicine	New York	New York
United States	IPS Research Company	Oklahoma City	Oklahoma
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Clinical Neuroscience Solutions, Inc.	Orlando	Florida
United States	CRI Worldwide, LLC	Philadelphia	Pennsylvania
United States	Alliance Research Group, LLC	Richmond	Virginia
United States	Oregon Center for Clinical Investigations, Inc. (OCCI, Inc.)	Salem	Oregon
United States	Delmarva Family Resources	Salisbury	Maryland
United States	ADHD Clinic of San Antonio	San Antonio	Texas
United States	Psychiatric Centers at San Diego, Feighner Research	San Diego	California
United States	Encompass Clinical Research - North Coast	Spring Valley	California
United States	Elite Clinical Trials, Inc.	Wildomar	California

Sponsors (1)

Lead Sponsor	Collaborator
Shire

Countries where clinical trial is conducted

United States,  Belgium,  Canada,  France,  Germany,  Italy,  Netherlands,  Spain,  Sweden,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With Treatment Failures During the Double-Blind Randomized-Withdrawal Phase	Treatment failure was defined as >= 50% increase (worsening) in ADHD-RS-IV total score and a >= 2 point increase (worsening) in CGI-S score compared with the respective scores at the Double-blind Randomized-withdrawal Baseline Visit at 2 consecutive Double-blind Randomized-withdrawal Phase visits. Subjects meeting these criteria were regarded as treatment failures regardless of whether or not they were withdrawn. All subjects who discontinued the study for any reason were regarded as treatment failures for the primary analysis.	26 weeks
Secondary	Time to Treatment Failure During the Double-Blind Randomized-Withdrawal Phase	Treatment failure was defined as >= 50% increase (worsening) in ADHD-RS-IV total score and a >= 2 point increase (worsening) in CGI-S score compared with the respective scores at the Double-blind Randomized-withdrawal Baseline Visit at 2 consecutive Double-blind Randomized-withdrawal Phase visits. Subjects meeting these criteria were regarded as treatment failures regardless of whether or not they were withdrawn. All subjects who discontinued the study for any reason were regarded as treatment failures for the primary analysis.	26 weeks
Secondary	Change From Double-Blind Randomized-Withdrawal Baseline in Attention Deficit Hyperactivity Disorder Rating Scale-fourth Edition (ADHD-RS-IV) Total Score at Week 26 of the Double-Blind Randomized-Withdrawal Phase - Last Observation Carried Forward (LOCF)	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.	Baseline and week 26
Secondary	Percent of Subjects With an Assessment of Normal/Borderline Mentally Ill on Clinical Global Impression-Severity of Illness (CGI-S) Scale During the Double-Blind Randomized-Withdrawal Phase - LOCF	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)	26 weeks
Secondary	Change From Double-Blind Randomized-Withdrawal Baseline in the Weiss Functional Impairment Rating Scale - Parent Report (WFIRS-P) Global Score at Week 26 of the Double-Blind Randomized-Withdrawal Phase - LOCF	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.	Baseline and week 26
Secondary	Health Utilities Index-2/3 (HUI 2/3) Scores During the Double-Blind Randomized-Withdrawal Phase - LOCF	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.	26 weeks
Secondary	Columbia-Suicide Severity Rating Scale During Double-Blind Randomized-Withdrawal Phase	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.	26 weeks
Secondary	Change From Open-Label Baseline in ADHD-RS-IV Total Score at Week 13 of the Open-Label Phase - LOCF	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.	Baseline and 13 weeks
Secondary	Percentage of Responders in the Open-Label Phase - LOCF	Response is defined as a percentage decrease (improvement) from Baseline in the ADHD-RS-IV total score of >=30% and a CGI-S score of 1 or 2.	13 weeks
Secondary	Percent of Subjects With Improvement on Clinical Global Impression-Improvement (CGI-I) Scores During Open-Label Phase - LOCF	Clinical Global Impression-Improvement (CGI-I) consists of a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). Improvement is defined as a score of 1 (very much improved) or 2 (much improved) on the scale.	13 weeks
Secondary	Percent of Subjects With an Assessment of Normal/Borderline Mentally Ill on CGI-S Scale During the Open-Label Phase - LOCF	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)	13 weeks
Secondary	Change From Open-Label Baseline in WFIRS-P Global Score at Week 13 of the Open-Label Phase - LOCF	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.	Baseline and week 13
Secondary	HUI 2/3 Scores During the Open-Label Phase - LOCF	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.	13 weeks
Secondary	Columbia-Suicide Severity Rating Scale During Open-Label Phase	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.	13 weeks