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

Treatment With Acetyl-Choline Esterase Inhibitors in Children With Autism

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.

Study Overview

• Status: Unknown
• Conditions: Autism
• Intervention / Treatment: Drug: Indistinguishable placebo tablets, matching both donepezil and choline; Drug: Acetyl-Choline Esterase Inhibitors and Choline supplements

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 84
• Phase: Phase 4

Contacts and Locations

Study Locations

• Israel
  • Ramat Gan
    • Tel Hashomer, Ramat Gan, Israel, 52621
      • Recruiting
      • Sheba Medical Center
      • Contact: Shahar Shefer, Dr; Phone Number: +972-(0)54-4381594; Email: DRShahar.Shefer@sheba.health.gov.il
      • Sub-Investigator: Maaian Millikovsky, BA

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 years to 16 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo for AChEI and Choline	Drug: Indistinguishable placebo tablets, matching both donepezil and choline; Indistinguishable placebo tablets, matching both donepezil and choline, will be given in the same amounts and schedules
Experimental: AChEI and Choline; Acetyl-choline Esterase Inhibitor and Choline supplements	Drug: Acetyl-Choline Esterase Inhibitors and Choline supplements; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Sheba Medical Center
• Collaborators: The Israeli Society of Clinical Pediatrics (HIPAK)
• Investigators: Study Director: Dorit Ben-Shalom, Ph.D, Ben-Gurion University of the Negev; Study Director: Shefer Shahar, Dr., Sheba Medical Center; Study Director: Rotem Chayu Ben-Hur, MA, Sheba Medical Center

Study record dates

Study Major Dates

• Study Start: March 1, 2010
• Primary Completion (Anticipated): December 1, 2017
• Study Completion (Anticipated): December 1, 2017

Study Registration Dates

• First Submitted: March 11, 2010
• First Submitted That Met QC Criteria: April 1, 2010
• First Posted (Estimate): April 2, 2010

Study Record Updates

• Last Update Posted (Estimate): October 14, 2016
• Last Update Submitted That Met QC Criteria: October 13, 2016
• Last Verified: October 1, 2016

More Information

Terms related to this study

• Keywords: Autism
• Additional Relevant MeSH Terms: Mental Disorders; Neurodevelopmental Disorders; Child Development Disorders, Pervasive; Autism Spectrum Disorder; Autistic Disorder; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Cholinergic Agents; Enzyme Inhibitors; Antimetabolites; Gastrointestinal Agents; Hypolipidemic Agents; Lipid Regulating Agents; Cholinergic Agonists; Nootropic Agents; Lipotropic Agents; Cholinesterase Inhibitors; Choline; Donepezil; Acetylcholine
• Other Study ID Numbers: SHEBA-09-7151-LG-CTIL