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

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by Sheba Medical Center
Sponsor:
Collaborator:
The Israeli Society of Clinical Pediatrics (HIPAK)
Information provided by (Responsible Party):
Dr. Lidia Gabis MD, Sheba Medical Center
ClinicalTrials.gov Identifier:
NCT01098383
First received: March 11, 2010
Last updated: July 17, 2014
Last verified: July 2014
  Purpose

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

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Treatment With Acetyl-Choline Esterase Inhibitors in Children With Autism

Resource links provided by NLM:


Further study details as provided by Sheba Medical Center:

Primary Outcome Measures:
  • Core autistic symptoms (ATEC) [ Time Frame: Once every 4 weeks during the first three mounth ] [ Designated as safety issue: No ]
    The parents will fill out this questionnaire about their child once every 4 weeks during the first Phase (12 weeks)- the Treatment phase.

  • Side effects and adverse events questionnaire [ Time Frame: Once every 4 weeks during the first phase(12 weeks) ] [ Designated as safety issue: Yes ]
    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:
  • Linguistic performance (CELF-4) [ Time Frame: After 6 mounth of washout ] [ Designated as safety issue: No ]
    The subject will be diagnosed on his Linguistic performance - using the CELF-4 diagnosis.

  • Adaptive functioning (Vineland-II) [ Time Frame: After 6 mounth of washout ] [ Designated as safety issue: No ]
    The parents will be interviwed using the Adaptive functioning (Vineland-II)

  • Comorbid behaviors (CSI-4 questionnaire) [ Time Frame: After 6 mouth of washout ] [ Designated as safety issue: No ]
    The parents will fill out the Comorbid behaviors (CSI-4) questionnaire

  • Executive functions (BRIEF questionnaire) [ Time Frame: After 6 mounth of washout ] [ Designated as safety issue: No ]
    The parents will fill out the Executive functions (BRIEF) questionnaire.


Estimated Enrollment: 84
Study Start Date: March 2010
Estimated Study Completion Date: December 2016
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.


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.

  Eligibility

Ages Eligible for Study:   10 Years to 18 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01098383

Locations
Israel
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)
Investigators
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

No publications provided

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
Study First Received: March 11, 2010
Last Updated: July 17, 2014
Health Authority: Israel: Israeli Health Ministry Pharmaceutical Administration

Keywords provided by Sheba Medical Center:
Autism

Additional relevant MeSH terms:
Autistic Disorder
Child Development Disorders, Pervasive
Mental Disorders Diagnosed in Childhood
Mental Disorders
Acetylcholine
Donepezil
Choline
Vasodilator Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
Cholinergic Agonists
Cholinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Lipotropic Agents
Hypolipidemic Agents
Antimetabolites
Gastrointestinal Agents
Lipid Regulating Agents
Nootropic Agents
Central Nervous System Agents
Cholinesterase Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on September 30, 2014