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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Autistic Disorder, Autism

Intervention / Treatment
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* Drug: Placebo
* Drug: Risperidone high dose
* Drug: Risperidone low dose


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 001<br>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<br>* Risperidone oral solution 0.125 mg (if <45 kg) or 0.175 mg (if >=45 kg) qd or bid for 6 weeks<br>|
| Experimental: 002<br>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<br>* Risperidone oral solution 1.25 mg (if <45 kg) or 1.75 mg (if >=45 kg) qd or bid for 6 weeks<br>|
| Placebo Comparator: 003<br>Placebo Oral solution qd or bid for 6 weeks | Drug: Placebo<br>* Oral solution qd or bid for 6 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Had at Least 25% Improvement in ABC-I | ABC-I is a measure of irritability symptoms of autism with score range 0 to 45 (lower score = lesser severity). | 6 weeks | 
| Change in Clinical Global Impression Severity (CGI-S) | 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). | Baseline and 6 weeks | 
| Number of Participants Who Had Clinical Global Impression Change Ratings of Much or Very Much Improved. | 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). | 6 weeks | 
| Change in Fasting Glucose (mg/dL) at 6 Weeks |  | Baseline and 6 weeks | 
| Change in Insulin Resistance (IR) at 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. | Baseline and 6 weeks | 
| Change in Fasting Glucose (mg/dL) at 6 Months |  | Baseline and 6 months | 
| Change in Insulin Resistance (IR) at 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. | Baseline and 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Irritability, Risperidone, Antipsychotic agent, Autism, Adolescents, Children