AutismPhase 4NCT01098383
Treatment With Acetyl-Choline Esterase Inhibitors in Children With Autism Spectrum Disorders
A Phase 4 study testing Acetyl-Choline Esterase Inhibitors and Choline supplements in people with Autism, run by Sheba Medical Center at 1 site in Israel.
Trial 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. Read more about this study
- Who is it for?
- Ages 10 to 18 years
- Conditions the study is for
- Autism
- What is being tested?
- Acetyl-Choline Esterase Inhibitors and Choline supplements
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 84 participants
- Where
- 1 siteIsrael
- Study dates
- Mar 2010to Dec 2017
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 10 to 18 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- 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.
Who cannot join
- 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
Show all 15Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
Israel1 site, 1 recruiting
- Recruiting
Sheba Medical Center
Tel HaShomer, Ramat Gan, 52621
Shahar Shefer, Dr, +972-(0)54-4381594, DRShahar.Shefer@sheba.health.gov.il
Maaian Millikovsky, BA
About this study
Official title: 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.
Read the 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
- Being tested
- Acetyl-Choline Esterase Inhibitors and Choline supplements, Indistinguishable placebo tablets, matching both donepezil and choline
- Keywords
- Autism
- Medical subject headings
- Autistic Disorder
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Acetyl-Choline Esterase Inhibitors and Choline supplementsDrug
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.
Indistinguishable placebo tablets, matching both donepezil and cholineDrug
Indistinguishable placebo tablets, matching both donepezil and choline, will be given in the same amounts and schedules
| Study group | Role | What they receive |
|---|---|---|
| Placebo for AChEI and Choline | Placebo comparator | Not described Receives: Drug: Indistinguishable placebo tablets, matching both donepezil and choline |
| AChEI and Choline | Experimental | Acetyl-choline Esterase Inhibitor and Choline supplements Receives: Drug: Acetyl-Choline Esterase Inhibitors and Choline supplements |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: Once every 4 weeks during the first phase(12 weeks)
Secondary outcomes (4)
Linguistic performance (CELF-4)
The subject will be diagnosed on his Linguistic performance - using the CELF-4 diagnosis.
Measured: After 6 mounth of washout
Adaptive functioning (Vineland-II)
The parents will be interviwed using the Adaptive functioning (Vineland-II)
Measured: After 6 mounth of washout
Comorbid behaviors (CSI-4 questionnaire)
The parents will fill out the Comorbid behaviors (CSI-4) questionnaire
Measured: After 6 mouth of washout
Executive functions (BRIEF questionnaire)
The parents will fill out the Executive functions (BRIEF) questionnaire.
Measured: After 6 mounth of washout
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Apr 2010 (estimated)
- Study startMar 2010
- Primary completionDec 2017 (estimated)
- Study completionDec 2017 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for AutismStudies of the same condition, open and under way.
- More trials run by Sheba Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 84 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Sheba Medical Center
- Sponsor type
- Other government
- Collaborators
- The Israeli Society of Clinical Pediatrics (HIPAK)
- Responsible party
- Principal investigator, Dr. Lidia Gabis MD, Sheba Medical Center
- Investigators
- Lidia Gabis, MD, Principal investigator, Sheba Medical CenterDorit Ben-Shalom, Ph.D, Study director, Ben-Gurion University of the NegevShefer Shahar, Dr., Study director, Sheba Medical CenterRotem Chayu Ben-Hur, MA, Study director, Sheba Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01098383
- Sponsor's protocol ID
- SHEBA-09-7151-LG-CTIL
- Status last verified
- Oct 2016
- First submitted
- 11 Mar 2010
- Last updated
- 14 Oct 2016
- Results posted
- No
- Data monitoring committee
- No
Publications
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.
PubMed 37811711Ure 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.
PubMed 37267443
Study at a glance
From the registry record, last updated by the sponsor on 14 Oct 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Treatment With Acetyl-Choline Esterase Inhibitors in Children With Autism
- ClinicalTrials.gov ID
- NCT01098383
- Acronym / sponsor ID
- SHEBA-09-7151-LG-CTIL
- Conditions
- Autism
- Keywords
- Autism
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 84 participants (estimated)
- Lead sponsor
- Sheba Medical CenterOther government
- Collaborators
- The Israeli Society of Clinical Pediatrics (HIPAK)
- Study start
- Mar 2010
- Primary completion
- Dec 2017 (estimated)
- Study completion
- Dec 2017 (estimated)
- First posted
- 2 Apr 2010 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Placebo for AChEI and Choline | Placebo comparator | Drug: Indistinguishable placebo tablets, matching both donepezil and choline |
| AChEI and Choline | Experimental | Drug: Acetyl-Choline Esterase Inhibitors and Choline supplementsAcetyl-choline Esterase Inhibitor and Choline supplements |
Who may qualify
- Ages
- 10 to 18 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (3 listed)
- 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.
Key exclusion criteria (15 listed)
- Evidence for one of the following conditions:
- Epilepsy
- Abnormal Electro-cardiogram (ECG)
- Epileptiform EEG
- Use of psychostimulants, anti-depressants, neuroleptics or anti-convulsive agents within the past month.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Acetyl-Choline Esterase Inhibitors and Choline supplementsDonepezil 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. | Drug | AChEI and Choline |
| Indistinguishable placebo tablets, matching both donepezil and cholineIndistinguishable placebo tablets, matching both donepezil and choline, will be given in the same amounts and schedules | Drug | Placebo for AChEI and Choline |
Primary outcome
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.
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.
4 secondary outcomes
Linguistic performance (CELF-4)
Time frame: After 6 mounth of washout
Adaptive functioning (Vineland-II)
Time frame: After 6 mounth of washout
Comorbid behaviors (CSI-4 questionnaire)
Time frame: After 6 mouth of washout
Executive functions (BRIEF questionnaire)
Time frame: After 6 mounth of washout
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Oct 2016.
- Derived from this study: PubMed 37811711Iffland 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.
- Derived from this study: PubMed 37267443Ure 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Lidia Gabis, MD principal investigator
Sheba Medical Center
Dorit Ben-Shalom, Ph.D study director
Ben-Gurion University of the Negev
Shefer Shahar, Dr. study director
Sheba Medical Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Acetyl-Choline Esterase Inhibitors and Choline supplements in people with Autism, run by Sheba Medical Center at 1 site in Israel.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 14 Oct 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Israel. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Each site lists its own contact: choose the nearest one under Trial locations. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Core autistic symptoms (ATEC) (time frame: Once every 4 weeks during the first three mounth). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01098383, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Oct 2016.