Study of Aripiprazole in the Treatment of Serious Behavioral Problems in Children and Adolescents With Autistic Disorder (AD)

Autistic Disorder Clinical Trial

Official title:

A 52-Week, Open-Label, Multicenter Study of the Safety and Tolerability of Aripiprazole Flexibly Dosed in the Treatment of Children and Adolescents With Autistic Disorder

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00365859
• Other study ID #: CN138-180
• Status: Completed
• Phase: Phase 3
• First received: August 15, 2006
• Last updated: November 7, 2013
• Start date: September 2006
• Est. completion date: June 2009

Study information

• Verified date: June 2010
• Source: Otsuka Pharmaceutical Development & Commercialization, Inc.
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

This study will provide long-term safety data for patients who are taking aripiprazole for up to 1 year. Most patients enrolled in this study will have participated in a short-term study with aripiprazole (CN138-178 [NCT00332241] or CN138-179 [NCT00337571]).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 330
• Est. completion date: June 2009
• Est. primary completion date: June 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 6 Years to 17 Years

Eligibility

Inclusion Criteria - Rollover:

• Completed 8 weeks of treatment in one of the following double-blind clinical trials:

CN138-178 [NCT00332241] or CN138-179 [NCT00337571]

• No significant protocol violations and sufficient medical justification to continue on open-label treatment with aripiprazole

Inclusion Criteria - De Novo:

• Meets current Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV TR) diagnostic criteria for AD and demonstrates serious behavioral problems - diagnosis confirmed by Autism Diagnostic Interview-Revised (ADI-R) or the patient meets the current Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV TR) diagnostic criteria for AD and has a history of behavioral problems that are currently being treated with psychotropic medication

• Mental age of at least 18 months

• Male or female 6 to 17 years of age, inclusive, at the time of enrollment

Exclusion Criteria:

• Patients considered treatment resistant to neuroleptic medication based on lack of therapeutic response to 2 different neuroleptics after treatment of at least 3 weeks each

• Patients previously treated and not responding to aripiprazole treatment

• The patient is currently diagnosed with another disorder on the autism spectrum, including pervasive developmental disorder-not otherwise specified (PDD-NOS), Asperger's Disorder, Rett's Disorder, Fragile-X Syndrome or Childhood Disintegrative Disorder

• Current diagnosis of bipolar disorder, psychosis, schizophrenia, or major depression

• A seizure in the past year

• History of severe head trauma or stroke

• Non-pharmacologic therapy (e.g. psychotherapy, behavior modification) should be stable prior to screening and consistent throughout the study

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Autistic Disorder
• Behavioral Symptoms

Intervention

Drug:
• Aripiprazole
Tablets, Oral, 2, 5, 10, or 15 mg, once daily, 52 weeks

Locations

Country	Name	City	State
United States	Mission Hospitals - Mission Children's Clinics	Asheville	North Carolina
United States	Child Neurology Associates, PC	Atlanta	Georgia
United States	The Children's Hospital	Aurora	Colorado
United States	North Shore - Long Island Jewish Health System	Bethpage	New York
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Neurobehavioral Medicine Group	Bloomfield Hills	Michigan
United States	Offices of Gregory Marsella, MD, PA	Boca Raton	Florida
United States	Pacific Institute of Medical Sciences	Bothell	Washington
United States	Cambridge Health Alliance	Cambridge	Massachusetts
United States	Massachusetts General Hospital	Cambridge	Massachusetts
United States	University of NC	Chapel Hill	North Carolina
United States	University of Illinois at Chicago	Chicago	Illinois
United States	University of Cincinnati	Cincinnati	Ohio
United States	University Hospitals of Cleveland	Cleveland	Ohio
United States	The Nisonger Center	Columbus	Ohio
United States	Clinical Innovations, Inc	Costa Mesa	California
United States	Dallas Pediatric Neurology Associates	Dallas	Texas
United States	Children's Hospital Of Michigan	Detroit	Michigan
United States	Harmonex Neuroscience	Dothan	Alabama
United States	Duke Child and Family Study Center	Durham	North Carolina
United States	Children's National Medical Center	Fairfax	Virginia
United States	Sarkis Clinical Trials	Gainesville	Florida
United States	University of Florida	Gainesville	Florida
United States	Neuroscience, Inc	Herndon	Virginia
United States	Bayou City Research, Ltd.	Houston	Texas
United States	Red Oak Psychiatry Associates, PA	Houston	Texas
United States	Children's Mercy Hospital and Clinics	Kansas City	Missouri
United States	Kansas University Medical Center	Kansas City	Kansas
United States	Center for Psychiatry and Behavioral Medicine	Las Vegas	Nevada
United States	University of Louisville	Louisville	Kentucky
United States	UT Medical Group, Department Of Psychiatry	Memphis	Tennessee
United States	Miami Children's Hospital	Miami	Florida
United States	Children's Hospital of Wisconsin	Milwaukee	Wisconsin
United States	Seaver and New York Autism Center of Excellence	New York	New York
United States	Monarch Research Associates	Norfolk	Virginia
United States	Cutting Edge Research	Oklahoma City	Oklahoma
United States	Munroe-Meyer Institute Diagnostic Center	Omaha	Nebraska
United States	Southwest Autism Research and Resource Center	Phoenix	Arizona
United States	Western Psychiatric Institute and Clinic	Pittsburgh	Pennsylvania
United States	Virginia Treatment Center For Children	Richmond	Virginia
United States	Peninsula Research Assoc	Rolling Hills Estate	California
United States	University Of California-Davis Health Science Center	Sacramento	California
United States	North San Antonio Healthcare Associates	San Antonio	Texas
United States	Sharp Mesa Vista Hospital	San Diego	California
United States	Autism Spectrum Treatment and Research Center	Seattle	Washington
United States	Institute For Behavioral Medicine	Smyrna	Georgia
United States	Regions Hospital	St. Paul	Minnesota
United States	Stanford University School Of Medicine	Stanford	California
United States	Richmond Behavioral Associates	Staten Island	New York
United States	SUNY at Stony Brook - School of Medicine	Stony Brook	New York
United States	University of South Florida	Tampa	Florida
United States	Children's Specialized Hospital	Toms River	New Jersey
United States	Univ of Arizona	Tuscon	Arizona
United States	Ladders Clinic	Wellsley	Massachusetts
United States	Children's Developmental Center	Winter Park	Florida

Sponsors (2)

Lead Sponsor	Collaborator
Otsuka Pharmaceutical Development & Commercialization, Inc.	Otsuka America Pharmaceutical

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Serious Adverse Events (SAEs), Treatment-Emergent Adverse Events (AEs), Deaths, AEs Leading to Discontinuation, Extra Pyramidal Syndrome (EPS)-Related AEs	Participants with Adverse Events (AEs), Deaths, Serious AEs (SAEs), and AEs leading to study discontinuation. AE is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition. SAE is any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a cancer, is a congenital anomaly/birth defect, results in the development of drug dependency or drug abuse, is an important medical event.	From Screening (up to 42 days prior to treatment start) through Week 52 (end of study) for SAEs; from Week 0 (Baseline) through Week 52 (End of Study) for AEs	Yes
Primary	Mean Change From Baseline in Total Simpson-Angus Scale (SAS) At Week 8, Week 26, and Week 52	The SAS is a 10-item instrument used to evaluate the presence and severity of parkinsonian symptomatology. It is the most commonly used rating scale for Parkinsonism in clinical trials over the past 25 years. The ten items focus on rigidity rather than bradykinesia, and do not assess subjective rigidity or slowness. Items are rated for severity on a 0-4 scale, with definitions given for each anchor point. The total SAS Score has a possible range from 10 to 50. Negative change scores indicate improvement.	Baseline, Week 8, Week 26, Week 52	Yes
Primary	Mean Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) At Week 8, Week 26, and Week 52	The AIMS is an assessment of movement dysfunctions. It is a 12-item instrument assessing abnormal involuntary movements associated with antipsychotic drugs and 'spontaneous' motor disturbance related to the illness itself. Scoring the AIMS consists of rating the severity of movement in 3 main anatomic areas (facial/oral, extremities, and trunk), based on a five-point scale (0=none, 4=severe). The AIMS Total Score has a possible range from 0 to 28. Negative change scores indicate improvement in movement dysfunction.	Baseline, Week 8, Week 26, Week 52	Yes
Primary	Mean Change From Baseline in Barnes Akathisia Global Clinical Assessment at Week 8, Week 26, Week 52, and Endpoint	The Barnes Akathisia Rating Scale is a 4-item scale to assess presence and severity of drug-induced akathisia, including both objective items and subjective items, together with a global clinical assessment of akathisia. Global assessment is made on a scale of 0 to 5 with comprehensive definitions provided for each anchor point on scale: 0=absent; 1=questionable; 2=mild akathisia; 3=moderate akathisia; 4=marked akathisia; 5=severe akathisia. Score has a possible range from 0 (absent) to 5 (severe akathisia). Negative change scores indicate improvement in akathisia.	Baseline, Week 8, Week 26, Week 52	Yes
Primary	Number of Participants With Potentially Clinically Relevant Laboratory Metabolic Abnormalities	Abnormal metabolic criterion values include the following: fasting serum glucose =115 mg/dL; non-fasting serum glucose = 200 mg/dL; total cholesterol =240 mg/dL; LDL cholesterol =160 mg/dL; HDL cholesterol =30 mg/dL; triglycerides =120 mg/dL (females), =160 mg/dL (males)	At screening (up to 42 days prior to treatment start), Week 8, Week 26, Week 52	Yes
Primary	Number of Participants With Potentially Clinically Relevant Laboratory Hematology Abnormalities	Abnormal hematology criterion values include the following: hematocrit (ages 6-17, males & females) =33%; hemoglobin (ages 6-17, males & females) <11.3 g/dL; leukocytes =2800 c/mm3 or =16000 c/mm3; eosinophils (ages 6-17, males & females) >17%; neutrophils <15%; platelet count =75,000 c/mm3 or =700,000 c/mm3	At screening (up to 42 days prior to treatment start), Week 8, Week 26, Week 52	Yes
Primary	Number of Participants With Potentially Clinically Relevant Laboratory Chemistry Abnormalities	Abnormal chemistry criterion values include the following: aspartate aminotransferase =3x upper limit of normal (ULN); alanine aminotransferase =3x ULN; alkaline phosphatase =3x ULN; lactate dehydrogenase =3x ULN; creatinine =2.0 mg/dL; uric acid, =10.5 mg/dL (male), =8.5 mg/dL (female); bilirubin (Total) =2.0 mg/dL; serum prolactin >ULN; creatine kinase =3x ULN; blood urea nitrogen =30 mg/dL; sodium =126 mEq/L or =156 mEq/L; potassium =2.5 mEq/L or = 6.5 mEq/L; chloride =90 mEq/L or =118 mEq/L; calcium =8.2 mg/dL or =12 mg/dL	At screening (up to 42 days prior to treatment start), Week 8, Week 26, Week 52	Yes
Primary	Number of Participants With Potentially Clinically Relevant Eletrocardiograph (ECG) Abnormalities	These abbreviations are used in the table of ECG measurements: supraventricular (SV), baseline (BL), 1 degree (1°), atrioventricular (A-V), intraventricular (IVT), symmetrical (SYM), corrected QT interval (QTc). QRS complex is a recording of a single heartbeat on ECG corresponding to the depolarization of the right and left ventricles. PR interval is measured from beginning of P wave to beginning of QRS complex. QT interval is a measure of time between start of Q wave and end of T wave in the heart's electrical cycle. ? = increase from baseline, ? = decrease from baseline, ? = "to"	At screening (up to 42 days prior to treatment start), Week 8, Week 26, Week 52	Yes
Primary	Number of Potentially Clinically Relevant Vital Sign Abnormalities	Clinically significantly abnormal vital signs met age-appropriate (heart rate cohorts: ages 5-14 & ages 15+; blood pressure cohorts: ages 6-12 & ages 13-17) criterion AND represented change from pretreatment value of at least the following magnitudes: systolic blood pressure (=130 mmHg & =144 mmHg w/ increase of =20 mmHg) or (=117 mmHg & =120 mmHg w/ decrease of =20 mmHg); diastolic blood pressure (=86 mmHg & =92 mmHg w/ increase of =15 mmHg) or (=75 mm Hg & =80 mmHg w/ decrease of =15 mmHg); heart rate (140 bpm and 120 bpm w/ increase of =15 bpm) or (50 bpm and 50 bpm w/ decrease of =15 bpm).	At screening (up to 42 days prior to treatment start), Week 0 (Baseline), Week 1, Week 2, Week 4, Week 8, Week 14, Week 20, Week 26, Week 34, Week 42, Week 52 (Endpoint)	Yes
Primary	Mean Change From Baseline in Patient Weight		At screening (up to 42 days prior to treatment start), Week 0 (Baseline), Week 1, Week 2, Week 4, Week 8, Week 14, Week 20, Week 26, Week 34, Week 42, Week 52 (Endpoint)	Yes
Primary	Mean Change From Baseline by Time Period in Body Weight Z-Score	The Z-Score indicates how many standard deviations a person is from the population norm values. The body weight z-scores are designed to take into account the amount of weight gain that would be expected due to normal growth in children and adolescents. The body weight z-scores are by age and gender standardized values (corresponding to a normal distribution with mean 0 and a standard deviation of 1) of the actual weight measurements, based on the Growth Charts provided by the Centers for Disease Control (CDC; see Links section of this record).	At screening (up to 42 days prior to treatment start), Week 0 (Baseline), Week 1, Week 2, Week 4, Week 8, Week 14, Week 20, Week 26, Week 34, Week 42, Week 52 (Endpoint)	Yes
Primary	Mean Change From Baseline in Patient Body Mass Index (BMI)	The body mass index (BMI) is a statistical measurement which compares a person's weight and height. Though it does not actually measure the percentage of body fat, it is used to estimate a healthy body weight based on subject height.	At screening (up to 42 days prior to treatment start), Week 0 (Baseline), Week 1, Week 2, Week 4, Week 8, Week 14, Week 20, Week 26, Week 34, Week 42, Week 52 (Endpoint)	Yes
Primary	Mean Change From Baseline By Time Period in BMI Z-Score	The Z-Score indicates how many standard deviations a person is from the population norm values. The BMI z-scores are designed to take into account the BMI that would be expected due to normal growth in children and adolescents. The BMI z-scores are by age and gender standardized values (corresponding to a normal distribution with mean 0 and a standard deviation of 1) of the actual BMI measurements, based on the Growth Charts provided by the Centers for Disease Control (CDC; see Links section of this record).	At screening (up to 42 days prior to treatment start), Week 0 (Baseline), Week 1, Week 2, Week 4, Week 8, Week 14, Week 20, Week 26, Week 34, Week 42, Week 52 (Endpoint)	Yes
Secondary	Mean Change From Baseline in Clinical Global Impression (CGI)-Severity Score at Week 52 (Endpoint, LOCF)	CGI scale is a global evaluation of improvement over time. CGI-Severity (CGI-S) is a clinician-rated assessment that evaluates the severity of a patient's condition on a 7-point scale ranging from 1 (no symptoms) to 7 (very severe symptoms). CGI-Severity score is from 1 to 7. A negative change score signifies improvement.	Week 0 (Baseline), Week 52 (Endpoint, LOCF)	No
Secondary	CGI-Improvement Score at Week 52 (Endpoint, LOCF)	CGI scale is a global evaluation of improvement over time. CGI-Improvement (CGI-I) is a clinician rated assessment that evaluates improvement relative to symptoms at baseline on a a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). CGI-I Score is from 1 to 7. A lower score signifies larger improvement.	Week 52 (Endpoint, LOCF)	No
Secondary	Mean Change From Baseline in Aberrant Behavior Checklist (ABC) Irritability Score at Week 52 (Endpoint, LOCF)	The ABC is an informant-based symptom checklist for assessing and classifying problem behaviors of children and adolescents with mental retardation. The 58 items are rated on a 4-point scale (0 = not at all a problem to 3 = the problem is severe in degree), and resolve into 5 subscales: (1) irritability and agitation; (2) lethargy and social withdrawal; (3) stereotypic behavior; (4) hyperactivity and noncompliance, and (5) inappropriate speech. ABC Irritability Subscale Score is from 0 to 45. A negative change signifies improvement	Week 0 (Baseline), Week 52 (Endpoint, LOCF)	No
Secondary	Mean Change From Baseline in ABC Hyperactivity Subscale Score at Week 52 (Endpoint, LOCF)	The ABC is an informant-based symptom checklist for assessing and classifying problem behaviors of children and adolescents with mental retardation. The 58 items are rated on a 4-point scale (0 = not at all a problem to 3 = the problem is severe in degree), and resolve into 5 subscales: (1) irritability and agitation; (2) lethargy and social withdrawal; (3) stereotypic behavior; (4) hyperactivity and noncompliance, and (5) inappropriate speech. ABC Hyperactivity Subscale Score is from 0 to 48. A negative change score signifies improvement.	Week 0 (Baseline), Week 52 (Endpoint, LOCF)	No
Secondary	Change From Baseline in ABC Stereotypy Subscale Score at Week 52 (Endpoint, LOCF)	The ABC is an informant-based symptom checklist for assessing and classifying problem behaviors of children and adolescents with mental retardation. The 58 items are rated on a 4-point scale (0 = not at all a problem to 3 = the problem is severe in degree), and resolve into 5 subscales: (1) irritability and agitation; (2) lethargy and social withdrawal; (3) stereotypic behavior; (4) hyperactivity and noncompliance, and (5) inappropriate speech. ABC Stereotypy Subscale Score is from 0 to 21. A negative change score signifies improvement.	Week 0 (Baseline), Week 52 (Endpoint, LOCF)	No
Secondary	Mean Change From Baseline in ABC Social Withdrawal Scale At Week 52 (Endpoint, LOCF)	The ABC is an informant-based symptom checklist for assessing and classifying problem behaviors of children and adolescents with mental retardation. The 58 items are rated on a 4-point scale (0 = not at all a problem to 3 = the problem is severe in degree), and resolve into 5 subscales: (1) irritability and agitation; (2) lethargy and social withdrawal; (3) stereotypic behavior; (4) hyperactivity and noncompliance, and (5) inappropriate speech. ABC Social Withdrawal Subscale Score is from 0 to 48. A negative change score signifies improvement.	Week 0 (Baseline), Week 52 (Endpoint, LOCF)	No
Secondary	Mean Change From Baseline in ABC Inappropriate Speech Subscale Score at Week 52 (Endpoint, LOCF)	The ABC is an informant-based symptom checklist for assessing and classifying problem behaviors of children and adolescents with mental retardation. The 58 items are rated on a 4-point scale (0 = not at all a problem to 3 = the problem is severe in degree), and resolve into 5 subscales: (1) irritability and agitation; (2) lethargy and social withdrawal; (3) stereotypic behavior; (4) hyperactivity and noncompliance, and (5) inappropriate speech. ABC Inappropriate Speech Subscale score is from 1 to 12. A negative change score signifies improvement.	Week 0 (Baseline), Week 52 (Endpoint, LOCF)	No
Secondary	Change From Baseline in Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS) Score at Week 52 (Endpoint, LOCF)	CY-BOCS is a 10-item, clinician-rated scale designed to measure the severity of obsessive-compulsive symptoms in patients below the age of 18. The scale contains 5 items pertaining to obsessions (which were not used in this trial) and 5 items pertaining to compulsions, which rated each symptom domain in terms of time spent, interference with functioning, distress, resistance, and control. Each item was rated on a 5-point scale, from 0 (no symptoms or minimum severity) to 4 (extreme symptoms or maximum severity). CY-BOCS Score is from 0 to 20. A negative change score signifies improvement.	Week 0 (Baseline), Week 52 (Endpoint, LOCF)	No

External Links

•   BMS Clinical Trials Disclosure
•   Centers for Disease Control and Prevention (CDC) algorithm for BMI and body weight z-scores
•   For FDA Safety Alerts and Recalls refer to the following link: http://www.fda.gov/MEDWATCH/safety.htm
•   Investigator Inquiry form