A Study of Oral N-Acetylcysteine in Children With Autism Spectrum Disorders

Study Overview
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Brief Summary
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The purpose of this study is to determine whether treatment with oral N-acetylcysteine (NAC) will improve behavior problems often associated with autism spectrum disorders.

Detailed Description
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Autism is increasingly being recognized as a common disorder with enormous public health significance. The core symptoms of autism include severe deficits in social relatedness and communication, and interfering repetitive behavior. No medications have been shown to consistently improve any of these symptoms. The central hypothesis of this study is that NAC will improve behavioral manifestations of autism which may include core or associated symptoms. We plan to test our hypothesis and complete the objectives of this project by pursuing the following specific aims: Evaluate the efficacy of oral NAC in a 12-week, double-blind, placebo-controlled study involving 32 children and adolescents with autism spectrum disorders. Evaluate the safety and tolerability of oral NAC in 32 children and adolescents with autism spectrum disorders.

Official Title
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A Pilot Study of Oral N-Acetylcysteine in Children With Autism Spectrum Disorders

Conditions
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Autistic Disorder, Asperger Syndrome, Child Development Disorders, Pervasive

Intervention / Treatment
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* Drug: N-acetylcysteine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 4 to 12 years. Diagnosis of autistic disorder, Asperger's disorder, or PDD NOS. If taking concomitant psychotropic medications, the medication must be at a constant dose for 60 days with no dose changes planned for the duration of the trial. Able to swallow capsules. Exclusion Criteria: Presence of any medical condition that significantly increases risk or hampers assessment (e.g., unstable hypertension or cardiac disease, unstable asthma, kidney disease, unstable seizure disorder, pregnancy or any other medical condition as determined by the investigator). Weight < 15 kg. Subjects taking concomitant medications or supplements known for their glutamatergic effects (e.g., dextromethorphan, D-cycloserine, amantadine, memantine, lamotrigine, riluzole) or antioxidant properties (high dose vitamin supplements, DMG, TMG, many alternative treatments) within 30 days of the baseline visit with the exception of short term use of dextromethorphan as needed as a cough suppressant. The use of this medicine must be stopped at least 7 days prior to the baseline visit. Regular multivitamins will be allowed. Subjects taking daily acetaminophen or nonsteroidal anti-inflammatory drugs within 30 days of the baseline visit. Profound mental retardation as evidenced by a mental age below 18 months. Subjects taking concomitant medications with the potential for pharmacokinetic or pharmacodynamic drug-drug interactions (e.g., carbamazepine) within 30 days of the baseline visit. Subjects who are likely to experience significant changes in their ongoing psychosocial or medical treatments for autism over the course of the trial (e.g., initiation of new behavioral therapy, initiation of new medication or alternative treatment [e.g., chelation]). Minor changes in ongoing treatment (e.g., missed therapy sessions due to holiday/vacation; planned break in therapy due to school holidays) will not be considered significant. History of prior treatment with NAC. Evidence of hypersensitivity/allergy to NAC. Presence of certain neurodevelopmental disorders such as Fragile X Syndrome, Tuberous Sclerosis, or other neurological disorders known to be associated with autism or autistic features. Diagnosis of Rett's disorder, childhood disintegrative disorder, schizophrenia, bipolar disorder, another psychotic disorder, or substance abuse disorder.

Ages Eligible for Study
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Minimum Age: 4 Years
Maximum Age: 12 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: 1<br>Target dose for n-acetylcysteine is 60 mg/kg/day. Capsules available in 300 mg and 600 mg strengths. | Drug: N-acetylcysteine<br>* Capsules available in 300 mg or 600mg strength. Target dose of n-acetylcysteine will be 60mg/kg/day TID. Dosage will be increased to this target dose from week 1 to week 3 barring side effects. Dose reduction will be allowed at any time for adverse side effects. Maximum dose of n-acetylcysteine will be 4200mg/day.<br>|
| Placebo Comparator: 2<br>Subjects randomized to placebo arm will receive capsules identical in size and appearance to those subjects receiving study drug. Placebo capsules contain inactive ingredients. | Drug: Placebo<br>* Subjects randomized to placebo arm will receive placebo pill for duration of study.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Global Impression - Severity | The Clinical Global Impression - Severity scale (CGI-S) is a 7-point scale that requires the clinician to rate the severity of the patient's illness at the time of assessment, relative to the clinician's past experience with patients who have the same diagnosis. Considering total clinical experience, a patient is assessed on severity of mental illness at the time of rating 1, normal, not at all ill; 2, borderline ill; 3, mildly ill; 4, moderately ill; 5, markedly ill; 6, severely ill; or 7, extremely ill. | Week 12 | 
| Clinical Global Impression - Improvement | Clinical Global Impression - 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 (1=very much improved; 2=much improved, 3=minimally Improved, 4=no change, 5=minimally worse, 6= much worse and 7=very much worse). Participants with a CGI-I score of 1 or 2 were classified as improved. Participants with a CGI score of 3, 4 or 5 were classified as no response. No participants scored 6 or 7. | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Aberrant Behavior Checklist | The Aberrant Behavior Checklist (ABC) is a 58-item measure of maladaptive behaviors and is used as a measure of drug effects. Each of the 58 items are rated from 0 (not at all) to 3 (severe).The ABC has 5 subscales: Irritability (15 items) ranging from 0 (not at all) to 45 (severe), Lethargy (16 items) ranging from 0 (not at all) to 48 (severe), Stereotypy (7 items) ranging from 0 (not at all) to 21 (severe), Hyperactivity (16 items) ranging from 0 (not at all) to 48 (severe), and Inappropriate Speech (4 items) ranging from 0 (not at all) to 12 (severe). Higher scores indicate a higher level of maladaptive behavior. | Week 12 | 
| Social Responsiveness Scale | The Social Responsiveness Scale (SRS) is a 65-item scale that assesses social impairment in the aspects of social awareness, social cognition, social communication, social motivation and autistic mannerisms. Each item is scored from 0 (not true) to 3 (almost always true). The total SRS raw score may range from 0-195, where higher scores indicate greater severity. | Week 12 | 
| Pervasive Developmental Disorder Behavior Index | The PDD Behavior Inventory (PDDBI) is a rating scale filled out by caregivers or teachers that was designed to assess children having a Pervasive Developmental Disorder (PDD; autism, Asperger disorder, PDD-NOS, or childhood disintegrative disorder). Both adaptive and maladaptive behaviors are assessed in the scale, making it useful for treatment studies in which decreases in maladaptive behaviors and improvements in adaptive social and language skills relevant to PDD are expected. | Week 12 | 
| Vineland Adaptive Behavior Scales-II (VABS-II) | The VABS-II is a semi-structured interview designed to assess adaptive functioning in the domains of communication, daily living skills and socialization. Items in each domain are rated as either 0 (does not), 1(sometimes) or 2(independently) performs a given behavior or skill. The communication domain has 99 items with scores ranging from 0-198. The daily living skills domain has 109 items with scores ranging from 0-218. The socialization domain has 99 items with scores ranging from 0-198. The domains scores are combined to form the adaptive composite score (ranging from 20-160). The raw scores from the communication, daily living skills and socialization domains along with the composite score were selected for use in this study. Higher scores indicate a higher level of adaptive functioning. | Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Autistic Disorder, Asperger's, PDD NOS, Pervasive Developmental Disorder, Autism, N-acetylcysteine, acetylcysteine, NAC, antioxidant, treatment, core symptoms, Autism Spectrum Disorders, Asperger's Disorder, Pervasive Developmental Disorder Not Otherwise Specified, Pervasive Developmental Disorders