A Feasibility Study of N-acetylcysteine for Self-injurious Behavior in Children With Autism Spectrum Disorder

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to demonstrate the feasibility of a 9-week, randomized trial of N-acetylcysteine (NAC) compared to placebo in 14 children (age 5 to 12 years) with Autism Spectrum Disorder (ASD) and a moderate level of repetitive self-injurious behavior (SIB). Additional aims are to evaluate the positive predictive value of a screening method to classify children with automatically maintained self-injurious behavior; to evaluate the preliminary efficacy of NAC for reducing repetitive SIB in children with ASD; and to evaluate biomarkers and possible mechanisms of action of NAC in children with ASD.

Detailed Description
-----------------
Self-injurious behavior (SIB) in children with autism spectrum disorder (ASD) can cause physical harm to the child and interfere with the child's ability to make use of educational programs and helpful treatments such as speech therapy. The turmoil caused by self-injurious behaviors in children with ASD invariably interferes with daily routines because family life often stops during these episodes and family members worry about setting off SIB between episodes. This project will use the detailed assessment methods developed in the field of behavior therapy to evaluate the potential for N-acetylcysteine (NAC) to treat children with ASD and moderate repetitive SIB. NAC is an over-the-counter dietary supplement that may have beneficial effects on the brain through its well-documented antioxidant effects and/or reduced glutamate signaling. In the proposed study, 14 children with ASD and repetitive SIB between the ages of 5 and 12 will be randomly assigned to gradually increasing doses of NAC or placebo for 9 weeks. The research team, parents and children will be blind to the treatment with NAC or placebo. Participants will come to the research site periodically to complete measures and behavioral assessments. After the 9 weeks of treatment, children randomized to NAC who showed improvement will be encouraged to continue taking the supplement outside the study. Children who were randomly assigned to the placebo and showed no improvement will be offered open-label treatment with NAC. Children who did not improve while taking NAC or those who improved while on the placebo will be advised on next steps by the study team. The goal of this feasibility study is establish the acceptability viability of study procedures in this vulnerable population, to learn about the potential benefits and adverse effects of NAC. Demonstrating these feasibility aims and the preliminary efficacy and safety of NAC is a prerequisite for planning a larger, more definitive, study.

Official Title
-----------------
A Feasibility Study of N-acetylcysteine for Self-injurious Behavior in Children With Autism Spectrum Disorder

Conditions
-----------------
Autism Spectrum Disorder

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Confirmed diagnosis of Autism Spectrum Disorder (ASD) Confirmed presence of moderate Self Injurious Behavior (SIB) Score > 16 on the parent-rated Aberrant Behavior Checklist Irritability subscale (moderate level of disruptive behavior) Classified as having automatically maintained SIB (determined during screening by a detailed functional analysis) Exclusion Criteria: On a stable medication dose for less than 4 weeks Planned change in medication during the 9-week trial Had one or more seizures in the last 6 months

Ages Eligible for Study
-----------------
Minimum Age: 5 Years
Maximum Age: 12 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Participants taking NAC<br>Participants randomized to the active treatment study arm will receive gradually increasing doses of N-acetylcysteine (NAC) given as a dissolving tablet in juice or water. NAC is an over-the-counter oral dietary supplement that will be used a higher than usual doses in this study. | Drug: N-acetylcysteine<br>* Participants will start with taking 900mg of NAC once per day for one week (study days 1-7). At Day 7, parents (or primary caregiver) and subjects will return to the study site to review adverse events. In the absence of dose limiting adverse events attributable to the study drug, the dose will be gradually increased to 900 mg twice per day for study days 8-28. If this dose is well-tolerated, the dose will be increased to 900 three times per day for study days 29-63.<br>* Other names: NAC;|
| Placebo Comparator: Participants taking Placebo<br>Participants randomized to placebo will receive dissolving tablets identical in size and appearance to the active treatment. Placebo capsules contain inactive ingredients. | Drug: Placebo<br>* Participants will start with taking 900mg of the placebo once per day for one week (study days 1-7). At Day 7, parents (or primary caregiver) and subjects will return to the study site to review adverse events. The dosing for the placebo will increase in the same fashion as the active treatment. In the absence of dose limiting adverse events attributable to the study drug, the dose will be gradually increased to 900 mg twice per day for study days 8-28. If this dose is well-tolerated, the dose will be increased to 900 three times per day for study days 29-63.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Randomized | Goal: randomize 1.75 participants per month | 12 months (throughout the duration of the study) | 
| Attrition Rate | Attrition rate is defined as the percent of subjects who did not complete the study. Goal:less than 15% (to indicate that study was acceptable to participants and parents). | 12 months (throughout the duration of the study) | 
| Study Medication Compliance | Goal: at least 70% treatment compliance (tablet counts and drug dairies). | 12 months (throughout the duration of the study) | 
| Successful Collection of Outcome Measures | Goal: at least 80% collection of essential outcome data to demonstrate the feasibility of data collection procedures. | 12 months (throughout the duration of the study) | 
| Parent Satisfaction Rating | Goal: at least 80% of parents will agree or strongly agree when asked in an anonymous survey that they would recommend the study and the study treatment to other parents of children with ASD and SIB. | Week 9 (at the end of the study intervention) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Positive Predictive Value of Screening Method of Classifying Self-injurious Behavior (SIB) by Type. | Goal: at least 75% positive predictive value of our screening method to classify children with automatically maintained self-injurious behavior using a semi-structured interview at screening compared to the findings of five- to six-hour functional analysis at baseline. Only children who appear to have automatically maintained SIB will be referred for the baseline evaluation. Demonstrating a high positive predictive value for the screening method is a necessary prerequisite for launching a larger study. Using the formula: Positive Predictive Value (PPV) = screen positive and true cases ÷ all positive screens, a value of 75% or greater would indicate success of the screening method used. | 12 months (duration of the study) | 
| Aberrant Behavior Checklist Irritability Subscale Score at Baseline and 9 Weeks Post-intervention | The Aberrant Behavior Checklist (ABC) is a commonly used 58-item parent-rated measure of overall behavioral problems. The Irritability subscale is comprised of 15 items reflecting tantrums, aggression and self injury. Range is 0 to 45, higher scores indicate higher severity. As a preliminary efficacy outcome, it was calculated the average score at baseline and Week 9 post-intervention. | Baseline, Week 9 | 
| Number of Self-Injurious Behavior Events | Direct observation of the frequency of SIB was collected at baseline in a separate observational session after completing the functional analysis and again at Week 9. Investigators set a benchmark of an average decline in the frequency of SIB of 50% within the NAC group. | Baseline, Week 9 | 
| Change in Clinical Global Impression (CGI-I) Scale at 9 Weeks Post-intervention | The Clinical Global Impression (CGI-I) scale is a 7-item scale from 1 (Very Much Improved) through 4 (No Change) to 7 (Very Much Worse). By convention, scores of 2 (Much Improved) or 1 (Very Much Improved) are used to define positive response. | Week 9 | 
| Change in Biomarkers and Possible Mechanisms of Action of NAC in Children With ASD. | Changes amino acid levels before and after NAC treatment: cysteine/cystine and glutathione/glutathione disulfide (GSH/GSSG) ratios (antioxidant effects), glutamate and glutamate/glutamine ratio (glutamate signaling) and GABA levels. | Baseline, Week 9 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Repetitive Self-Injurious Behavior, N-acetylcysteine (NAC)