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

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ClinicalTrials.gov Identifier: NCT01098383
Recruitment Status : Recruiting
First Posted : April 2, 2010
Last Update Posted : October 14, 2016
Information provided by (Responsible Party):

Study Description
Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Autism Drug: Acetyl-Choline Esterase Inhibitors and Choline supplements Drug: Indistinguishable placebo tablets, matching both donepezil and choline Phase 4

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 Design

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 84 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Treatment With Acetyl-Choline Esterase Inhibitors in Children With Autism
Study Start Date : March 2010
Estimated Primary Completion Date : December 2017
Estimated Study Completion Date : December 2017

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures :
  1. Core autistic symptoms (ATEC) [ Time Frame: Once every 4 weeks during the first three mounth ]
    The parents will fill out this questionnaire about their child once every 4 weeks during the first Phase (12 weeks)- the Treatment phase.

  2. Side effects and adverse events questionnaire [ Time Frame: Once every 4 weeks during the first phase(12 weeks) ]
    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.

Secondary Outcome Measures :
  1. Linguistic performance (CELF-4) [ Time Frame: After 6 mounth of washout ]
    The subject will be diagnosed on his Linguistic performance - using the CELF-4 diagnosis.

  2. Adaptive functioning (Vineland-II) [ Time Frame: After 6 mounth of washout ]
    The parents will be interviwed using the Adaptive functioning (Vineland-II)

  3. Comorbid behaviors (CSI-4 questionnaire) [ Time Frame: After 6 mouth of washout ]
    The parents will fill out the Comorbid behaviors (CSI-4) questionnaire

  4. Executive functions (BRIEF questionnaire) [ Time Frame: After 6 mounth of washout ]
    The parents will fill out the Executive functions (BRIEF) questionnaire.

Eligibility Criteria

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Ages Eligible for Study:   10 Years to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01098383

Sheba Medical Center Recruiting
Tel Hashomer, Ramat Gan, Israel, 52621
Contact: Shahar Shefer, Dr    +972-(0)54-4381594    DRShahar.Shefer@sheba.health.gov.il   
Sub-Investigator: Maaian Millikovsky, BA         
Sponsors and Collaborators
Sheba Medical Center
The Israeli Society of Clinical Pediatrics (HIPAK)
Principal Investigator: Lidia Gabis, MD Sheba Medical Center
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
More Information

Responsible Party: Dr. Lidia Gabis MD, Dr. Lidia Gabis, Sheba Medical Center
ClinicalTrials.gov Identifier: NCT01098383     History of Changes
Other Study ID Numbers: SHEBA-09-7151-LG-CTIL
First Posted: April 2, 2010    Key Record Dates
Last Update Posted: October 14, 2016
Last Verified: October 2016

Keywords provided by Dr. Lidia Gabis MD, Sheba Medical Center:

Additional relevant MeSH terms:
Autistic Disorder
Autism Spectrum Disorder
Child Development Disorders, Pervasive
Neurodevelopmental Disorders
Mental Disorders
Cholinesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Cholinergic Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Nootropic Agents
Lipotropic Agents
Hypolipidemic Agents
Gastrointestinal Agents
Lipid Regulating Agents
Vasodilator Agents
Cholinergic Agonists