A Study of the Effectiveness and Safety of Two Doses of Risperidone in the Treatment of Children and Adolescents With Autistic Disorder

• ClinicalTrials.gov Identifier: NCT00576732
• Recruitment Status: Completed
• First Posted: December 19, 2007
• Results First Posted: September 28, 2010
• Last Update Posted: May 9, 2014
• Sponsor: Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
• Information provided by (Responsible Party): Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

Study Description

Brief Summary:

The purpose of this study is to evaluate the effectiveness (change in level of irritability and related behaviors) and safety and tolerability of the administration of 2 different fixed dose levels of risperidone (an atypical antipsychotic drug) compared with placebo in children or adolescents who have autism, and to evaluate the safety and tolerability of the drug for additional 26 weeks after the initial 6-week study period.

Condition or disease	Intervention/treatment	Phase
Autistic Disorder; Autism	Drug: Placebo; Drug: Risperidone high dose; Drug: Risperidone low dose	Phase 4

Detailed Description:

Autistic Disorder is a condition that develops early in childhood and persists throughout life. Seventy-five percent of children and adolescents with autistic disorder have irritability symptoms such as aggression towards others, deliberate self-injurious behavior, temper tantrums, and quickly changing moods. These symptoms affect their daily functioning such as school performance, interactions with family members and compliance to treatment. Risperidone is an atypical antipsychotic agent that has been recently approved for the treatment of irritability associated with Autistic Disorder in children and adolescents aged 5 to 16 years. The approved dose range is 0.5-3 mg per day. The aim of this study is to evaluate the effectiveness (change in level of irritability and related behaviors) of a lower dose (0.125 mg or 0.175 mg risperidone per day depending on body weight). The study will include three treatment groups. A placebo group, a low dose risperidone group and a higher dose risperidone group (1.25 mg or 1.75mg per day depending on body weight). This phase of the study will be 6 weeks. During the study, neither investigators nor the patients will be told which treatment the patient received. This is called "double blind". The placebo treatment is not expected to be effective. The higher dose group is expected to be effective. At the end of the study, data from the lower dose group will be compared to the placebo group to see if it is effective. Another aim of this study is to evaluate the safety and tolerability of risperidone. At the end of the 6-week double-blind period, patients may enter a 6-month open-label period during which all patients will receive risperidone. During this phase of the study, the doses can be adjusted to a maximum of 1.25 mg or 1.75mg per day depending on body weight. Both investigator and the patient will know what dose the patient is taking. About 93 patients will be randomized. The study will be conducted by investigators from about 15 clinics. Assessments of effectiveness include the Aberrant Behavior Checklist (ABC) subscales including the irritability subscale (ABC-I), the Clinical Global Impression of Change (CGI C); the Clinical Global Impression of Severity (CGI-S); the response rate, and the Compulsions Subscale of the Children's Yale-Brown Obsessive Compulsive Scale (CY BOCS). Safety evaluations include monitoring of adverse events, physical examinations, clinical laboratory tests, nighttime sleep quality and daytime drowsiness, and extrapyramidal symptoms (EPS) as assessed using the Abnormal Involuntary Movement Scale (AIMS), the Barnes Akathisia Rating Scale (BARS) and the Simpson-Angus Scale (SAS). Venous blood samples will be collected for the determination of plasma concentrations of risperidone and 9-hydroxyrisperidone. The study hypotheses are that the higher dose level of risperidone is significantly superior to placebo as measured by change from baseline on the ABC-I Subscale score at end point (Week 6 or early withdrawal) and that the lower dose level of risperidone is significantly superior to placebo as measured by change from baseline on the ABC-I Subscale score at end point (Week 6 or early withdrawal). Double-blind phase: Risperidone oral solutions taken once daily. Depending on body weight patients take 1.25 mL or 1.75 mL of either a 0.1 mg/mL or a 1.0 mg/mL risperidone solution or matching placebo, for 6 weeks. Open-label phase: Medication can be taken once or twice a day. Starting from 0.125mg or 0.175mg per day, drug levels are titrated over 2 weeks to a maximum dose level of 1.25 mg risperidone/day or 1.75 mg /day depending on body weight, for 26 weeks.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 96 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Risperidone in the Treatment of Children and Adolescents With Autistic Disorder: A Double-Blind, Placebo-Controlled Study of Efficacy and Safety, Followed by an Open-Label Extension Study of Safety
• Study Start Date: December 2007
• Actual Primary Completion Date: September 2009
• Actual Study Completion Date: March 2010

Arms and Interventions

Arm	Intervention/treatment
Experimental: 001; Risperidone low dose Risperidone oral solution 0.125 mg (if <45 kg) or 0.175 mg (if >=45 kg) qd or bid for 6 weeks	Drug: Risperidone low dose; Risperidone oral solution 0.125 mg (if <45 kg) or 0.175 mg (if >=45 kg) qd or bid for 6 weeks
Experimental: 002; Risperidone high dose Risperidone oral solution 1.25 mg (if <45 kg) or 1.75 mg (if >=45 kg) qd or bid for 6 weeks	Drug: Risperidone high dose; Risperidone oral solution 1.25 mg (if <45 kg) or 1.75 mg (if >=45 kg) qd or bid for 6 weeks
Placebo Comparator: 003; Placebo Oral solution qd or bid for 6 weeks	Drug: Placebo; Oral solution qd or bid for 6 weeks

Outcome Measures

Primary Outcome Measures :

1. Change in Aberrant Behavior Checklist Irritability (ABC-I) Subscale [ Time Frame: Baseline and 6 weeks ]
   Measure of irritability symptoms of autism. Score range 0 to 45 (lower score = lesser severity).

Secondary Outcome Measures :

1. Number of Participants Who Had at Least 25% Improvement in ABC-I [ Time Frame: 6 weeks ]
   ABC-I is a measure of irritability symptoms of autism with score range 0 to 45 (lower score = lesser severity).
2. Change in Clinical Global Impression Severity (CGI-S) [ Time Frame: Baseline and 6 weeks ]
   Investigator evaluation of severity of illness and functional impairment on a 7-point scale (1="not ill", 2="very mild", 3="mild", 4="moderate", 5="marked", 6="severe", 7="extremely severe").
3. Number of Participants Who Had Clinical Global Impression Change Ratings of Much or Very Much Improved. [ Time Frame: 6 weeks ]
   Investigator impression of change over time from double-blind baseline on a 7-point scale (1="very much improved", 2="much improved", 3="minimally improved", 4="no change", 5="minimally worse", 6="much worse", 7="very much worse").
4. Change in Fasting Glucose (mg/dL) at 6 Weeks [ Time Frame: Baseline and 6 weeks ]
5. Change in Insulin Resistance (IR) at 6 Weeks [ Time Frame: Baseline and 6 weeks ]
   Insulin resistance calculated using the homeostatic model assessment 1 (HOMA1)formula: fasting glucose (mmol/L) times fasting insulin (uU/L) divided by 22.5. HOMA-IR is a widely used clinical tool for estimating insulin resistance based upon the balance between glucose output and insulin secretion. Normal values should be close to 1, while an increase indicates a decrease in insulin sensitivity (or increase in insulin resistance), a potential predictor for the development of Type 2 Diabetes Mellitus.
6. Change in Fasting Glucose (mg/dL) at 6 Months [ Time Frame: Baseline and 6 months ]
7. Change in Insulin Resistance (IR) at 6 Months [ Time Frame: Baseline and 6 months ]
   Insulin resistance calculated using the homeostatic model assessment 1 (HOMA1) formula: fasting glucose (mmol/L) times fasting insulin (uU/L) divided by 22.5. HOMA-IR is a widely used clinical tool for estimating insulin resistance based upon the balance between glucose output and insulin secretion. Normal values should be close to 1, while an increase indicates a decrease in insulin sensitivity (or increase in insulin resistance), a potential predictor for the development of Type 2 Diabetes Mellitus.

Eligibility Criteria

• Ages Eligible for Study: 5 Years to 17 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• DSM-IV diagnosis of Autistic Disorder (299.00)
• ABC-I Subscale score of greater than or equal to 18
• CGI-S of greater than or equal to 4
• mental age >18 months, body weight of at least 20 kg, seizure-free for at least 6 consecutive months and if on anticonvulsants must be on a dosage that has been stable for at least 4 weeks
• Medication free for 1 week before the start of the study for all psychotropic drugs, except 4 weeks for fluoxetine and at least 8 weeks for injectable medications
• Female patients must be premenarchal or sexually abstinent or, if heterosexually active, must practice an effective method of birth control.

Exclusion Criteria:

• History of prior or current DSM-IV psychotic disorder (e.g., schizophrenia, bipolar disorder, other psychosis), Pervasive Developmental Disorder not otherwise specified (PDD NOS), Asperger's, or Rett's
• Any history of hypersensitivity to risperidone, or its excipients in formulation, or other known drug allergy
• Patients who received risperidone within 3 months before screening (except p.r.n. use)
• Patients who did not demonstrate sufficient clinical response to an adequate trial of risperidone treatment in the past (an adequate trial is defined as a period of at least 4 weeks at an adequate dose)
• Neurologic disorder (e.g., Neuroleptic Malignant Syndrome, seizure disorders that are unstable, seizure activity within the past 6 months)
• History of alcohol or substance dependence within 3 months of screening
• Female subject who is pregnant (positive beta-HCG) or breast feeding
• Patients with existing moderate or severe EPS or history of tardive dyskinesia
• Patients who have received an experimental drug or used an experimental medical device within 3 months before the planned start of treatment.

Contacts and Locations

Locations

United States, Alabama

Dothan, Alabama, United States

United States, Arizona

Phoenix, Arizona, United States

United States, California

Sacramento, California, United States

Santa Ana, California, United States

United States, Florida

Boca Raton, Florida, United States

Miami, Florida, United States

United States, Georgia

Smyrna, Georgia, United States

United States, Illinois

Hoffman Estates, Illinois, United States

Naperville, Illinois, United States

United States, Louisiana

Lake Charles, Louisiana, United States

United States, New York

Bronx, New York, United States

Manhasset, New York, United States

New York, New York, United States

Staten Island, New York, United States

United States, Ohio

Columbus, Ohio, United States

United States, Oklahoma

Oklahoma City, Oklahoma, United States

United States, Pennsylvania

Philadelphia, Pennsylvania, United States

United States, Texas

Houston, Texas, United States

United States, Virginia

Fairfax, Virginia, United States

Portsmouth, Virginia, United States

Sponsors and Collaborators

Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

Investigators

• Study Director: Johnson & Johnson Pharmaceutical Research & Development, L.L. C. Clinical Trial; Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

More Information

Additional Information:

A Study of the Effectiveness and Safety of Two Doses of Risperidone in the Treatment of Children and Adolescents With Autistic Disorder 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Kent JM, Hough D, Singh J, Karcher K, Pandina G. An open-label extension study of the safety and efficacy of risperidone in children and adolescents with autistic disorder. J Child Adolesc Psychopharmacol. 2013 Dec;23(10):676-86. doi: 10.1089/cap.2012.0058.

Kent JM, Kushner S, Ning X, Karcher K, Ness S, Aman M, Singh J, Hough D. Risperidone dosing in children and adolescents with autistic disorder: a double-blind, placebo-controlled study. J Autism Dev Disord. 2013 Aug;43(8):1773-83. doi: 10.1007/s10803-012-1723-5.

• Responsible Party: Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
• ClinicalTrials.gov Identifier: NCT00576732
• Other Study ID Numbers: CR014740; RISAUT4002
• First Posted: December 19, 2007
• Results First Posted: September 28, 2010
• Last Update Posted: May 9, 2014
• Last Verified: April 2014

Keywords provided by Johnson & Johnson Pharmaceutical Research & Development, L.L.C.:

Irritability; Risperidone; Antipsychotic agent; Autism; Adolescents; Children

Additional relevant MeSH terms:

Autistic Disorder; Autism Spectrum Disorder; Child Development Disorders, Pervasive; Neurodevelopmental Disorders; Mental Disorders; Risperidone; Serotonin Antagonists; Serotonin Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Physiological Effects of Drugs; Antipsychotic Agents; Tranquilizing Agents; Central Nervous System Depressants; Psychotropic Drugs; Dopamine Antagonists; Dopamine Agents