Evaluating the Effectiveness of Aripiprazole and D-Cycloserine to Treat Symptoms Associated With Autism

Study Overview
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Brief Summary
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This study will determine the effectiveness of aripiprazole and D-Cycloserine in treating symptoms associated with autism in children.

Detailed Description
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Autism is a developmental disorder that affects every child differently. A wide range of symptoms accompany autism, including self-injurious behavior, aggression, and severe tantrums. Despite an improved ability to reduce these symptoms, existing drug treatments continue to be associated with adverse side effects. Also, there is no existing drug treatment that reliably improves social behavior, a core deficit in autism. Studies on drug treatment combinations that are designed to reduce self-injurious behavior, aggression, and severe tantrums and improve social behavior in children with autism have yet to be conducted. This study will address the above-mentioned limitations by evaluating aripiprazole in reducing self-injurious behavior, aggression, and severe tantrums and by evaluating the addition of D-Cycloserine in improving social behavior among children with autism. This study will include three phases and an add-on component for some children. Participants will be randomly assigned to receive either aripiprazole or a placebo treatment for 8 weeks. Assessments measuring irritability, behavior, and social skills will be conducted at the end of this first phase. Those patients who respond well to aripiprazole will continue to receive aripiprazole treatment for another 16 weeks. This second phase will determine whether aripiprazole is associated with long-term maintenance of symptomatic improvement in patients who respond well to short-term treatment. Assessments will again be conducted at the end of this 16-week period. Those patients whose symptoms have stabilized and continue to improve while on aripiprazole will be asked to participate in the final phase of this study. During the this pilot phase, D-Cycloserine will be added to ongoing treatment with aripiprazole. Patients will take both aripiprazole and D-Cycloserine for an additional 8 weeks to determine if this combination of drug treatments results in improved social behavior once patients' aggression and self-injurious behavior have been stabilized with aripiprazole. At the end of this 8-week period, participants will be assessed for any changes in behavior, irritability, or social skills. Results from this study may aid in developing safer and more effective drug treatments for children and adolescents with autism.

Official Title
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Novel Pharmacological Strategies in Autism

Conditions
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Autistic Disorder

Intervention / Treatment
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* Drug: Aripiprazole
* Drug: Placebo
* Drug: D-cycloserine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Weight of at least 15 kg (33.75 lbs) Meets DSM-IV criteria for autistic disorder Outpatient Medication-free for at least 2 weeks prior to baseline for all psychotropic medications. More information about this criterion, including exceptions, can be found in the protocol. Clinical Global Impression Scale Severity score (CGI-S) of at least 4 Irritability subscale of the Aberrant Behavior Checklist (ABC) score of at least 18 An IQ of at least 35 or a mental age of at least 18 months In good physical health Exclusion Criteria: Meets DSM-IV criteria for Asperger's disorder, Rett's disorder, childhood disintegrative disorder, any other pervasive developmental disorder (PDD), schizophrenia, psychotic disorder, or bipolar disorder Current or past history of alcohol or other substance abuse within 6 months of study entry Comorbid neurodevelopmental disorder with possible association to autism (e.g., fragile-X syndrome, tuberous sclerosis) A significant medical condition such as heart, liver, kidney, or lung disease, or a seizure disorder Pregnant Prior adequate use of aripiprazole. More information about this criterion can be found in the protocol. Evidence of hypersensitivity to aripiprazole History of neuroleptic malignant syndrome

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: 1 Placebo<br>Participants will take placebo | Drug: Placebo<br>* Participants assigned to placebo will take a placebo pill for the initial 8 weeks of treatment.<br>|
| Active Comparator: 2 Aripiprazole<br>Participants will take aripiprazole | Drug: Aripiprazole<br>* Participants will receive 8 weeks of initial treatment with aripiprazole. If responsive to treatment, participants may be assigned to an additional 16 weeks of aripiprazole and then an additional 8 more weeks of aripiprazole with D-cycloserine. Dosing schedule for participants less than 50 kg maximum dose will be 10 mg per day. Dosing schedule for participants greater than 50 kg maximum dose will be 15 mg.<br>* Other names: Abilify;|
| Active Comparator: 3 Aripiprazole + D-cycloserine<br>Participants first will take aripiprazole then will also take D-cycloserine | Drug: Aripiprazole<br>* Participants will receive 8 weeks of initial treatment with aripiprazole. If responsive to treatment, participants may be assigned to an additional 16 weeks of aripiprazole and then an additional 8 more weeks of aripiprazole with D-cycloserine. Dosing schedule for participants less than 50 kg maximum dose will be 10 mg per day. Dosing schedule for participants greater than 50 kg maximum dose will be 15 mg.<br>* Other names: Abilify;Drug: D-cycloserine<br>* D-cycloserine will be dosed in the range of 25 to 200 mg daily for the final 8 weeks of treatment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Post-baseline Aberrant Behavior Checklist Irritability Score, Parent Report, Double-blind Phase | The Aberrant Behavior Checklist (ABC) is a symptom checklist for assessing problem behaviors in individuals ages 6 to 54 with mental retardation. The full ABC is a 58-item parent rating with five factors: Irritability, Social Withdrawal, Stereotypy, Hyperactivity and Inappropriate Speech. It has been used as a primary outcome measure in several trials of children with developmental disabilities. The interpretation of the tool and its subscales is that higher scores, indicate greater severity. Fifteen item scores with values ranging from 0 (not a problem) to 3 (problem is severe) are summed to arrive at the total irritability scale store ranging from 0 to 45. Means were estimated using a repeated measures linear regression model with treatment group, baseline score, study week (in categories), and sex x Tanner stage stratum as covariates. A linear contrast estimated the average across study timepoints. Confidence intervals reflect a Bonferroni multiple testing correction accounting | Weeks 1, 2, 3, 4, 6, and 8 | 
| Odds of Improvement as Measured by the Clinical Global Impression-Global Improvement Scale (Improvement Defined as CGI-I=1 or CGI-I=2) | Clinical Global Impressions (Guy, 1976) global improvement (CGI-I) is designed to take into account all factors to arrive at an assessment of response to treatment. The CGI-I scale ranges from 1 to 7, with lower scores indicating greater improvement (1=very much improved and 2=much improved). Participants with a CGI-I score of 1 or 2 were classified as improved. Odds were estimated using a repeated measures logistic regression model with treatment group, study week (in categories), and sex x Tanner stage stratum as covariates. A linear contrast estimated the average log odds across study timepoints. Confidence intervals reflect a Bonferroni multiple testing correction accounting for the selection of two primary outcomes. | Weeks 1, 2, 3, 4, 6 and 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Post-baseline Aberrant Behavior Checklist Hyperactivity Score, Parent Report, Double-blind Phase | The Aberrant Behavior Checklist (ABC) is a symptom checklist for assessing problem behaviors in individuals ages 6 to 54 with mental retardation. The full ABC is a 58-item Parent rating with five factors: Irritability, Social Withdrawal, Stereotypy, Hyperactivity and Inappropriate Speech. The 16-item Hyperactivity subscale covers overactivity, impulsiveness, inattention and noncompliance. It has been used as a primary outcome measure in several trials of children with developmental disabilities. The interpretation of the tool and its subscale is that higher scores, indicate greater severity. Sixteen item scores with values ranging from 0 (not a problem) to 3 (problem is severe) are summed to arrive at the total score ranging from 0 to 48. Means were estimated using a repeated measures linear regression model with treatment group, baseline score, study week (in categories), and sex x Tanner stage stratum as covariates. A linear contrast estimated the average across study timepoints. | Weeks 1, 2, 3, 4, 6 and 8 | 
| Mean Post-baseline Aberrant Behavior Checklist Inappropriate Speech Score, Parent Report, Double-blind Phase | The Aberrant Behavior Checklist (ABC) is a symptom checklist for assessing problem behaviors in individuals ages 6 to 54 with mental retardation. The full ABC is a 58-item Parent rating with five factors: Irritability, Social Withdrawal, Stereotypy, Hyperactivity and Inappropriate Speech. It has been used as a primary outcome measure in several trials of children with developmental disabilities. The interpretation of the tool and its subscales is that higher scores, indicate greater severity. Four item scores with values ranging from 0 (not a problem) to 3 (problem is severe) are summed to arrive at the total inappropriate speech scale score ranging from 0 to 12. Means were estimated using a repeated measures linear regression model with treatment group, baseline score, study week (in categories), and sex x Tanner stage stratum as covariates. A linear contrast estimated the average across study timepoints. | Weeks 1, 2, 3, 4, 6, and 8 | 
| Mean Post-baseline Aberrant Behavior Checklist Social Withdrawal Score, Parent Report, Double-blind Phase | The Aberrant Behavior Checklist (ABC) is a symptom checklist for assessing problem behaviors in individuals ages 6 to 54 with mental retardation. The full ABC is a 58-item Parent rating with five factors: Irritability, Social Withdrawal, Stereotypy, Hyperactivity and Inappropriate Speech. It has been used as a primary outcome measure in several trials of children with developmental disabilities. The interpretation of the tool and its subscales is that higher scores, indicates greater severity. Sixteen item scores with values ranging from 0 (not a problem) to 3 (problem is severe) are summed to arrive at the total social withdrawal scale score ranging from 0 to 48. Means were estimated using a repeated measures linear regression model with treatment group, baseline score, study week (in categories), and sex x Tanner stage stratum as covariates. A linear contrast estimated the average across study timepoints. | Weeks 1, 2, 3, 4, 6, and 8 | 
| Mean Post-baseline Aberrant Behavior Checklist Stereotypy Score, Parent Report, Double-blind Phase | The Aberrant Behavior Checklist (ABC) is a symptom checklist for assessing problem behaviors in individuals ages 6 to 54 with mental retardation. The full ABC is a 58-item Parent rating with five factors: Irritability, Social Withdrawal, Stereotypy, Hyperactivity and Inappropriate Speech. It has been used as a primary outcome measure in several trials of children with developmental disabilities. The interpretation of the tool and its subscales is that higher scores, indicates greater severity. Seven item scores with values ranging from 0 (not a problem) to 3 (problem is severe) are summed to arrive at the total stereotypy scale score ranging from 0 to 21. Means were estimated using a repeated measures linear regression model with treatment group, baseline score, study week (in categories), and sex x Tanner stage stratum as covariates. A linear contrast estimated the average across study timepoints. | Weeks 1, 2, 3, 4, 6, and 8 | 
| Mean Post-baseline Score on a Modified Version of the Compulsion Subscale of the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS) | The CYBOCS- PDD is a semi-structured clinician-rated scale designed to rate the current severity of repetitive behavior in children with idiopathic autism spectrum disorders. Once the current repetitive behaviors are identified, they are rated on: Time Spent, Interference, Distress, Resistance, and Control. Each of these items is scored from 0 (least symptomatic) to 4 (most symptomatic), yielding a Total score from 0 to 20. Higher scores indicate higher severity. Means were estimated using a repeated measures linear regression model with treatment group, baseline score, study week (in categories), and sex x Tanner stage stratum as covariates. A linear contrast estimated the average across study timepoints. | Weeks 2, 4, 6 and 8 | 
| Mean Vineland Maladaptive Behavior Subscales Total Score, Week 8 | The Vineland Adaptive Behavior Scales, (Survey Interview Form) is a measure of adaptive behavior in children, adolescents and adults. It yields an overall standard score (Adaptive Behavior Composite, ABC) and age standard scores in four domains. ABC scores have a mean of 100 and a standard deviation of 15 (range = 20 to 160). Higher scores suggest a higher level of adaptive functioning. An increase in standard scores from Baseline to the Final Visit indicates improvement. Means were estimated using a repeated measures linear regression model with treatment group, study week (in categories, baseline or 8 weeks), and sex x Tanner stage stratum as covariates. | Week 8 | 
| Mean Autism Diagnostic Observation Schedule (ADOS) Social Affect and Restricted and Repetitive Behaviors Total Score, Week 8 | Autism Diagnostic Observation Scale (ADOS) (Lord), Modules 1-3 yields scores in 2 scales: Social Affect and Restricted and Repetitive Behavior. The ADOS has been repeatedly evaluated as a diagnostic measure, it has also been used as an outcome measure of autism severity (Aldred et al., 2004; Gutstein, 2007; Owly et al, 2001, Green et al, 2010). For modules 1-3, scores ranging from 0-2 on 14 items are summed to arrive at the Social Affect and Restricted and Repetitive Behavior Total Score, which ranges from 0 to 28. Higher scores indicate greater autism severity. Means were estimated using a repeated measures linear regression model with treatment group, study week (in categories, baseline or 8 weeks), and sex x Tanner stage stratum as covariates | Week 8 | 
| Mean Social Reciprocity Scale (SRS) Total Score, Week 8 | The 65-item SRS is a standardized measure of the core symptoms of autism. Each item is scored on a 4-point Likert scale. The score of each individual item is summed to create a total raw score. A total score results are as follows: 0-62: Within normal limits 63-79: Mild range of impairment 80-108: Moderate range of impairment 109-149: Severe range of impairment. Means were estimated using a repeated measures linear regression model with treatment group, study week (in categories, baseline or 8 weeks), and sex x Tanner stage stratum as covariates. | Week 8 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Children, Adolescents, Aripiprazole, Cycloserine, Aggression, Irritability, Self-Injurious Behavior, Social Interaction, Antipsychotics, Pharmacology, Glutamatergic Agents