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

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

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.

Study Overview

• Status: Completed
• Conditions: Attention-deficit/Hyperactivity Disorder
• Intervention / Treatment: Drug: Extended-release Guanfacine Hydrochloride; Other: Placebo

• Study Type: Interventional
• Enrollment (Actual): 528
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium, 1200
    • Cliniques Universitaires Saint Luc
  • Ham, Belgium, 3945
    • Huisartspraktijk Jaak Mortelmans
  • Namur, Belgium, 5000
    • Centre de référence Neuropédiatrique Multidisciplinaire
  • Uccle, Belgium, 1180
    • Psypluriel
  • Vlezenbeek, Belgium, 1602
    • Ziekenhuis Inkendaal Koninklijke Instelling v.z.w.
  • Antwerpen
    • Hoboken, Antwerpen, Belgium, 2660
      • Ziekenhuis Netwerk Antwerpen
  • Brussels
    • Jette, Brussels, Belgium, 1090
      • Universitair Ziekenhuis Brussel
  • Oost-vlaanderen
    • Ghent, Oost-vlaanderen, Belgium, 9000
      • Universitair Ziekenhuis Gent
• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6H3N1
      • Children's and Women's Health Centre of British Columbia
  • Ontario
    • Ottawa, Ontario, Canada, K2G1W2
      • JPM van Stralen Medicine Professional Corporation
    • Whitby, Ontario, Canada, L1N8M7
      • ADHD Clinic/The Kid's Clinic
  • Saskatchewan
    • Saskatoon, Saskatchewan, Canada, S7N-OW8
      • Royal University Hospital
• France
  • Dijon Cedex, France, 21033
    • Centre Hospitalier Universitaire Bocage-Hôpital d'enfants
  • Paris, France, 75 015
    • Hopital Robert Debre Centre pediatrique des pathologies du sommeil
  • Paris cedex 19, France, 75935
    • Hopital Robert-Debre'
  • Tours, France, 37 000
    • Hopital Gatien de Clocheville CHU de Tours
  • Alsace
    • Rouffach, Alsace, France, 68250
      • CENTRE HOSPITALIER DE ROUFFACH
  • Languedoc-roussillon
    • Montpellier Cedex 5, Languedoc-roussillon, France, 34295
      • Hopital Gui de Chauliac
  • Picardie
    • Amiens Cedex, Picardie, France, 80054
      • Centre Hospitalier Universitaire d'Amiens, Hôpital Nord
  • Provcence Alpes Cote D'Azur
    • Nice, Provcence Alpes Cote D'Azur, France, 06200
      • Hopitaux Pediatriques de Nice - CHI Lenval
• Germany
  • Berlin, Germany, 10629
    • emovis GmbH
  • Freiburg, Germany, 79104
    • Universitätsklinikum Freiburg
  • Baden-wuerttemberg
    • Tübingen, Baden-wuerttemberg, Germany, 72076
      • Center for Pediatric Clinical Studies
    • Ulm, Baden-wuerttemberg, Germany, 89075
      • Universitätsklinik Ulm
  • Bayern
    • München, Bayern, Germany, 81241
      • Praxis Dr. med. Dipl. Psych. Anton Lindermüller
    • Wurzburg, Bayern, Germany, 97070
      • Medizinisches Studienzentrum Würzburg
  • Nordrhein-westfalen
    • Dorsten, Nordrhein-westfalen, Germany, 46282
      • Sozialpsychiatrisches Centrum Dr. med. Ralph Meyers
  • Rheinland-pfalz
    • Mainz, Rheinland-pfalz, Germany, 55131
      • Klinikum der Johannes-Gutenberg-Universität Mainz
  • Thuringen
    • Jena, Thuringen, Germany, 07743
      • Friedrich-Schiller-Universität Jena
• Italy
  • Catania, Italy, 95123
    • Azienda Ospedaliero-Universitaria Policlinico-Vittorio
  • Milano, Italy, 20129
    • Azienda Osp. Fatebenefratelli - Polo Territoriale UONPIA
  • Padova, Italy, 35143
    • Azienda ULSS 16 Padova
  • Roma, Italy, 00168
    • Università Cattolica del Sacro Cuore
  • Roma, Italy, 00168
    • Drottning Silvias barnsjukhus
  • Milan
    • Rho, Milan, Italy, 20017
      • Azienda Ospedaliera "Guido Salvini"
  • Pisa
    • Calambrone, Pisa, Italy, 56018
      • IRCCS Fondazione Stella Maris
• Netherlands
  • Maastricht, Netherlands, 6229
    • Mondriaan Zorggroep Heerlen, Kinder en Jeugdp sychiatrie
  • Flevoland
    • Almere, Flevoland, Netherlands, 1311 RL
      • FlevoResearch
  • Limburg
    • Maastricht, Limburg, Netherlands, 6229 HX
      • Academisch Ziekenhuis Maastricht
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d'Hebron
  • Madrid, Spain, 28031
    • Hospital Infanta Leonor
  • Valencia, Spain, 46010
    • Instituto Valenciano de Neurología Pediatrica
  • Guipuzcoa
    • Donostia-San Sebastián, Guipuzcoa, Spain, 20009
      • Policlínica Guipuzkoa
  • Islas Baleares
    • Palma, Islas Baleares, Spain, 07198
      • Hospital Son Llàtzer, Laboratorio de Neurociencias IUNICS
  • Madrid
    • Alcorcon, Madrid, Spain, 289221
      • Hospital Fundación Alcorcón
  • Navarra
    • Pamplona, Navarra, Spain, 31008
      • Clinica Universitaria de Navarra
• Sweden
  • Mölnlycke, Sweden, 435 30
    • Barn och Ungdomsmedicin klinik Mölnlycke
• United Kingdom
  • Grays, United Kingdom, RM16 2PX
    • Thurrock Community Hospital
  • Liverpool, United Kingdom, L12 2AP
    • Royal Liverpool University Hospital
  • Stevenage, United Kingdom, SG1 4AB
    • Lister Hospital
  • England
    • Norwich, England, United Kingdom, NR4 7PA
      • Norfolk Community Health and Care NHS Trust
    • Sheffield, England, United Kingdom, S10 5DD
      • Ryegate Children's Centre
    • Sheffield, England, United Kingdom, S6 3BR
      • Centenary House Child and Adolescent Mental Health Services
    • Welwyn Garden City, England, United Kingdom, AL7 4HQ
      • Queen Elizabeth II Hospital
• United States
  • Alabama
    • Dothan, Alabama, United States, 36303
      • Harmonex Neuroscience Research
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Clinical Study Centers, LLC
  • California
    • San Diego, California, United States, 92108
      • Psychiatric Centers at San Diego, Feighner Research
    • Spring Valley, California, United States, 91978
      • Encompass Clinical Research - North Coast
    • Wildomar, California, United States, 92595
      • Elite Clinical Trials, Inc.
  • Florida
    • Bradenton, Florida, United States, 34208
      • Florida Clinical Research Center, LLC
    • Gainesville, Florida, United States, 32607
      • Sarkis Clinical Trials
    • Hialeah, Florida, United States, 33013
      • Amedica Research Institute, Inc.
    • Jacksonville, Florida, United States, 32216
      • Clinical Neuroscience Solutions, Inc.
    • Maitland, Florida, United States, 32751
      • Florida Clinical Research Center, LLC
    • Orlando, Florida, United States, 32806
      • Clinical Neuroscience Solutions, Inc.
  • Illinois
    • Naperville, Illinois, United States, 60563
      • AMR-Baber Research Inc.
  • Indiana
    • Indianapolis, Indiana, United States, 46260
      • Goldpoint Clinical Research, LLC
  • Louisiana
    • New Orleans, Louisiana, United States, 70114
      • Louisiana Research Associates, Inc.
  • Maryland
    • Salisbury, Maryland, United States, 21801
      • Delmarva Family Resources
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska Medical Center
  • Nevada
    • Las Vegas, Nevada, United States, 89128
      • Center for Psychiatry and Behavioral Medicine, Inc.
  • New York
    • New York, New York, United States, 10029
      • Mount Sinai School of Medicine
  • North Carolina
    • Durham, North Carolina, United States, 27707
      • Triangle Neuropsychiatry, PLLC
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University, Nisonger Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73103
      • IPS Research Company
  • Oregon
    • Salem, Oregon, United States, 97301
      • Oregon Center for Clinical Investigations, Inc. (OCCI, Inc.)
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19139
      • CRI Worldwide, LLC
  • Texas
    • Austin, Texas, United States, 78756
      • FutureSearch Clinical Trials
    • San Antonio, Texas, United States, 78247
      • ADHD Clinic of San Antonio
  • Virginia
    • Richmond, Virginia, United States, 23230
      • Alliance Research Group, LLC
  • Washington
    • Kirkland, Washington, United States, 98033
      • Eastside Therapeutic Resource

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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 age and weight.
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 age and weight.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
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
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
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
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
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
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
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
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
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
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

Collaborators and Investigators

• Sponsor: Shire

Publications and helpful links

General Publications

• Newcorn JH, Harpin V, Huss M, Lyne A, Sikirica V, Johnson M, Ramos-Quiroga JA, van Stralen J, Dutray B, Sreckovic S, Bloomfield R, Robertson B. Extended-release guanfacine hydrochloride in 6-17-year olds with ADHD: a randomised-withdrawal maintenance of efficacy study. J Child Psychol Psychiatry. 2016 Jun;57(6):717-28. doi: 10.1111/jcpp.12492. Epub 2016 Feb 12.

Study record dates

Study Major Dates

• Study Start (Actual): May 11, 2010
• Primary Completion (Actual): June 3, 2013
• Study Completion (Actual): June 3, 2013

Study Registration Dates

• First Submitted: March 3, 2010
• First Submitted That Met QC Criteria: March 4, 2010
• First Posted (Estimate): March 5, 2010

Study Record Updates

• Last Update Posted (Actual): June 14, 2021
• Last Update Submitted That Met QC Criteria: June 10, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Nervous System Diseases; Neurologic Manifestations; Dyskinesias; Attention Deficit and Disruptive Behavior Disorders; Neurodevelopmental Disorders; Attention Deficit Disorder with Hyperactivity; Hyperkinesis; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic Agonists; Guanfacine
• Other Study ID Numbers: SPD503-315; 2009-018161-12 (EudraCT Number)