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

NCT ID: NCT01098383

Last Updated: 2016-10-14

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE4
• Total Enrollment: 84 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-03-31
• Study Completion Date: 2017-12-31

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.

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.

Conditions

Autism

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Placebo for AChEI and Choline

Group Type: PLACEBO_COMPARATOR

Indistinguishable placebo tablets, matching both donepezil and choline

Intervention Type: DRUG

Indistinguishable placebo tablets, matching both donepezil and choline, will be given in the same amounts and schedules

AChEI and Choline

Acetyl-choline Esterase Inhibitor and Choline supplements

Group Type: EXPERIMENTAL

Acetyl-Choline Esterase Inhibitors and Choline supplements

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: 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

Intervention Type: DRUG

Eligibility 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

• Minimum Eligible Age: 10 Years
• Maximum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

The Israeli Society of Clinical Pediatrics (HIPAK)

UNKNOWN

Sponsor Role: collaborator

Sheba Medical Center

OTHER_GOV

Sponsor Role: lead

Responsible Party

Dr. Lidia Gabis MD

Dr. Lidia Gabis

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Lidia Gabis, MD

Role: PRINCIPAL_INVESTIGATOR

Sheba Medical Center

Dorit Ben-Shalom, Ph.D

Role: STUDY_DIRECTOR

Ben-Gurion University of the Negev

Shefer Shahar, Dr.

Role: STUDY_DIRECTOR

Sheba Medical Center

Rotem Chayu Ben-Hur, MA

Role: STUDY_DIRECTOR

Sheba Medical Center

Locations

Sheba Medical Center

Tel Litwinsky, Ramat Gan, Israel

Site Status: RECRUITING

Countries

Israel

Facility Contacts

Shahar Shefer, Dr

Role: primary

DRShahar.Shefer@sheba.health.gov.il

+972-(0)54-4381594

References

Iffland M, Livingstone N, Jorgensen M, Hazell P, Gillies D. Pharmacological intervention for irritability, aggression, and self-injury in autism spectrum disorder (ASD). Cochrane Database Syst Rev. 2023 Oct 9;10(10):CD011769. doi: 10.1002/14651858.CD011769.pub2.

Reference Type: DERIVED

PMID: 37811711 (View on PubMed)

Ure A, Cox GR, Haslam R, Williams K. Acetylcholinesterase inhibitors for autistic spectrum disorders. Cochrane Database Syst Rev. 2023 Jun 1;6(6):CD013851. doi: 10.1002/14651858.CD013851.pub2.

Reference Type: DERIVED

PMID: 37267443 (View on PubMed)

Other Identifiers

SHEBA-09-7151-LG-CTIL

Identifier Type: -

Identifier Source: org_study_id