Treatment With Acetyl-Choline Esterase Inhibitors in Children With Autism Spectrum Disorders

Study Overview
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Brief Summary
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We propose a study which will combine multiple modalities in evaluating the treatment response of children with autism spectrum disorders (ASD) to acetyl-choline esterase (AChE) inhibitors and choline supplements. The primary objective of the study is to examine the efficacy of this treatment in improving core autistic symptoms. The Secondary objective of the study is to evaluate the safety and tolerability of the treatment protocol in ASD children. Exploratory objectives include evaluation of the influence of the treatment on linguistic performance, comorbid behaviors, adaptive functioning and executive functions.

Detailed Description
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Autism Spectrum Disorders (ASD) are a group of developmental disorders of brain function resulting in a distinct phenotype, most probably related to many specific causes. Individuals with a disorder in the autism spectrum are a heterogeneous group of patients with early childhood onset of deficits in social interaction, communication and language, and repetitive and stereotypic behaviors. ASD has become increasingly prevalent during the last few decades (Wiznitzer, 2005). The neuro-anatomical substrate of ASD has been the subject of intense investigation, but current findings are inconclusive, limited and sometimes even contradictory. Medical treatment of autism is still a matter of dispute. Medications used are mainly aimed to treat the comorbid symptoms, such as epilepsy, tics, obsessive-compulsive or hyperactive behaviors (Wiznitzer, 2005). Although many efforts were invested in establishing a model of autistic pathophysiology, no such model is currently accepted, and there is no evidence for an efficient treatment of the core autistic symptoms (Wiznitzer, 2005). Previous studies indicate that many brain systems are involved in the expression of autism. Specifically, it has been suggested that autism involves neurotransmitter dysregulations (Lam et al, 2006). A recent investigation of the cholinergic system in autism, detailed below, has provided promising findings. Our study aims to assess the clinical outcomes associated with cholinergic manipulations using pharmacological agents and nutritional supplements. The study approved by the Helsinki committee for clinical research.

Official Title
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Treatment With Acetyl-Choline Esterase Inhibitors in Children With Autism

Conditions
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Autism

Intervention / Treatment
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* Drug: Acetyl-Choline Esterase Inhibitors and Choline supplements
* Drug: Indistinguishable placebo tablets, matching both donepezil and choline


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: A formal diagnosis of Autism or Pervasive Developmental Disorder not otherwise specified (PDD-NOS), given by a child neurologist. Age: 10-18 years. A signed parental consent form. Exclusion criteria: Evidence for one of the following conditions: an underlying infectious disease chromosomal abnormality metabolic disorder specific brain related disorder (such as tuberous sclerosis) history of fetal cytomegalovirus infection birth asphyxia a history of major head injury a chronic use of non-steroidal anti-inflammatory drugs, (NSAID) known brain damage Epilepsy Abnormal Electro-cardiogram (ECG) Epileptiform EEG Use of psychostimulants, anti-depressants, neuroleptics or anti-convulsive agents within the past month. Lack of cooperation in the screening phase

Ages Eligible for Study
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Minimum Age: 10 Years
Maximum Age: 18 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: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo for AChEI and Choline<br> | Drug: Indistinguishable placebo tablets, matching both donepezil and choline<br>* Indistinguishable placebo tablets, matching both donepezil and choline, will be given in the same amounts and schedules<br>|
| Experimental: AChEI and Choline<br>Acetyl-choline Esterase Inhibitor and Choline supplements | Drug: Acetyl-Choline Esterase Inhibitors and Choline supplements<br>* Donepezil will be used at initial dose of 2.5 mg/day (during the first two weeks), and an increased dose of 5 mg/day (from the 3rd week and on), according to the treatment protocol listed below. The tablets will be taken during breakfast. AChE inhibitors are considered as potent agents for clinical use in Alzheimer's and Parkinson's dementias (Wevers & Schroder, 1999) and treatment with these agents was proven to be well-tolerated, safe and effective in these populations. Cholinergic side effects are generally transient, mild and dose-related, and primarily include diarrhea, nausea, and vomiting. Choline tablets will be taken at daily doses of 250 mg (in children with up to 40 kg body weight) and 500 mg (in children with more than 40 kg body weight), based on half of the adult daily dose.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Core autistic symptoms (ATEC) | The parents will fill out this questionnaire about their child once every 4 weeks during the first Phase (12 weeks)- the Treatment phase. | Once every 4 weeks during the first three mounth | 
| Side effects and adverse events questionnaire | A detailed parent questionnaire to assess side effects and adverse events. The parents will fill out these questionnaires about their child once every 4 weeks during the first phase(12 weeks)- which is the treatment phase. | Once every 4 weeks during the first phase(12 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Linguistic performance (CELF-4) | The subject will be diagnosed on his Linguistic performance - using the CELF-4 diagnosis. | After 6 mounth of washout | 
| Adaptive functioning (Vineland-II) | The parents will be interviwed using the Adaptive functioning (Vineland-II) | After 6 mounth of washout | 
| Comorbid behaviors (CSI-4 questionnaire) | The parents will fill out the Comorbid behaviors (CSI-4) questionnaire | After 6 mouth of washout | 
| Executive functions (BRIEF questionnaire) | The parents will fill out the Executive functions (BRIEF) questionnaire. | After 6 mounth of washout | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Autism