- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01120626
Randomized Controlled Study of Donepezil in Fragile X Syndrome
Augmentation of the Cholinergic System in Fragile X Syndrome: A Double-Blind Placebo-Controlled Randomized Study of Donepezil
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Fragile X syndrome (FraX), a neurodevelopmental disorder caused by mutations of the FMR1 gene, is the most common known heritable cause of cognitive and behavioral disability in humans. Though research progress pertaining to FraX has been extraordinary in many areas, many critical gaps in knowledge remain. In particular, there is a dearth of information on treatments designed to address the often-serious cognitive and behavioral symptoms of FraX. Like many other developmental disorders, descriptions of treatments for FraX that do exist in the literature are primarily derived from uncontrolled case studies or series, with both pharmacological and behavioral interventions targeted to symptoms associated with phenomenologically defined "co-morbid" diagnoses such as AD/HD, autism spectrum disorders (ASD) or anxiety disorders. These circumstances are suboptimal as such symptom-based treatments represent a low level of specificity with respect to the underlying pathogenesis of cognitive and behavioral problems. Accordingly, new research to develop more effective, disease-specific treatments for persons with FraX is greatly needed.
Converging evidence from our research group and others strongly support a hypothesis of functional cholinergic deficits contributing to cognitive-behavioral dysfunction in FraX. This evidence includes: (1) abnormalities of cholinergic pathway function and neurochemistry observed with functional MRI and 1H-MRS, respectively, in FraX, (2) an analysis of FMR1 expression during human fetal development indicating particularly high expression in cholinergic brain regions, (3) cholinergic system abnormalities detected in the mouse and fly models of FraX, (4) an analysis of the specific profile of cognitive and behavioral deficits in FraX in relation to current knowledge of cholinergic system functions, and, (5) significant improvements in cognition and behavior observed in 12 individuals with FraX during an open-label trial of donepezil, a cholinesterase inhibitor. Accordingly, the proposed project will consist of a double blind, placebo controlled trial of donepezil in 50 individuals with FraX, ages 12 to 29 years. The primary hypothesis is that subjects receiving donepezil will show greater improvements in specific measures of behavior and cognition, relative to the placebo group. In addition to direct benefit to persons affected by FraX, findings from the proposed research are likely to be highly relevant to subgroups of (currently) idiopathic developmental disorders, such as autism, that might share common pathophysiological mechanisms of disease with FraX. Such shared mechanisms could occur through intersecting pathways involving FMR1 protein function or as a result of similarities in the contribution of cholinergic dysfunction to cognitive and behavioral disability.
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
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California
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Stanford, California, United States, 94305
- Stanford University School of Medicine
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- confirmed genetic diagnosis of fragile X syndrome
- age >=12, <=29
- Verbal IQ >= 50, <=75
- Tanner pubertal stage >= 3
Exclusion Criteria:
- Current or lifetime DSM-IV diagnosis of bipolar disorder, schizophrenia, schizoaffective disorder, or psychotic disorder, NOS based upon reported history
- Poorly controlled seizure disorder or taking more than one anticonvulsant (subjects cannot be prescribed carbamazepine, phenytoin, or phenobarbital due to potential interaction effects with donepezil). The investigators will permit one anticonvulsant as monotherapy for seizures if the seizure disorder is well controlled with no evidence of break through seizures within the past year
- Concomitant or anticipated use of other medications having prominent effects on the cholinergic system (e.g., bethanechol, benztropine, atropine, succinylcholine)
- Medications or nutritional supplements that have the potential to significantly alter donepezil levels, clinical effects or adverse reactions (antifungal agents, corticosteroids, erythromycin, beta-blockers, calcium channel blockers, NSAIDs, gingko biloba, St. John's wort)
- Medical illnesses where donepezil could worsen the condition such as asthma, cardiac conduction abnormalities, urinary obstruction or gastrointestinal disease with gastric bleeding
- Pregnancy or sexually active females not using a reliable method of contraception
- If considering participation in brain MRI part of the study, then any contraindications for MRI (e.g., orthodontia, metal in or on the body, etc.)
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Active Comparator: donepezil
donepezil (2.5 mg to 10.0 mg per day for 12 weeks)
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donepezil (2.5 mg to 10.0 mg per day for 12 weeks)
Other Names:
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Placebo Comparator: sugar pill
sugar pill (2.5 mg to 10.0 mg per day for 12 weeks)
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sugar pill (2.5 mg to 10.0 mg per day for 12 weeks)
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Contingency Naming Test (CNT) Performance Score
Time Frame: Week 12
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Week 12 Contingency Naming Test (CNT) performance score on Rule 2 (naming shapes) and on Rule 3 (If the inside shape matches the outside shape, name the color, otherwise, name the outside shape).
Performance score is the number of correct responses per minute, calculated by dividing the number of correct responses by the time taken to complete the 27 items, and multiplying by 60.
Higher scores indicate faster and more accurate responding.
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Week 12
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Aberrant Behavior Checklist (ABC)
Time Frame: Week 12
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The Aberrant Behavior Checklist is a 58-item symptom checklist for assessing problem behaviors.
The ABC was rated by each participant's parent.
Each item is rated on a four-point Likert scale ranging from 0 (not at all a problem) to 3 (the problem is severe in degree).
The ABC Total score (range 0-174) is the sum of all individual item scores.
Higher score indicates more maladaptive behaviors/worse outcome.
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Week 12
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Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Allan L Reiss, Stanford University
Publications and helpful links
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Pathologic Processes
- Nervous System Diseases
- Neurologic Manifestations
- Neurobehavioral Manifestations
- Disease
- Congenital Abnormalities
- Genetic Diseases, Inborn
- Genetic Diseases, X-Linked
- Mental Retardation, X-Linked
- Intellectual Disability
- Heredodegenerative Disorders, Nervous System
- Chromosome Disorders
- Sex Chromosome Disorders
- Syndrome
- Fragile X Syndrome
- Physiological Effects of Drugs
- Neurotransmitter Agents
- Molecular Mechanisms of Pharmacological Action
- Cholinergic Agents
- Enzyme Inhibitors
- Nootropic Agents
- Cholinesterase Inhibitors
- Donepezil
Other Study ID Numbers
- SU-02042010-4923
- Autism Speaks 5907 (Other Grant/Funding Number: Autism Speaks 5907)
- R34MH085899-01A1 (U.S. NIH Grant/Contract)
- SPO#42922 (Other Identifier: Stanford University Research Management Group)
- SPO#45612 (Other Identifier: Stanford University Research Management Group)
- eProtocol 13773 (SQL 96239) (Other Identifier: Stanford University IRB)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Fragile X Syndrome
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University of California, DavisNational Institute of Mental Health (NIMH)CompletedFragile X PremutationUnited States
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University of California, DavisNational Institute on Aging (NIA); Forest LaboratoriesCompletedFragile X-Associated Tremor/Ataxia Syndrome | Fragile X Premutation CarriersUnited States
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Ovid Therapeutics Inc.CompletedFragile X Syndrome (FXS)United States
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Guido A. Davidzon, MD, SMWithdrawn
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Marinus PharmaceuticalsUniversity of California, Davis; U.S. Army Medical Research and Development...Completed
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RTI InternationalEunice Kennedy Shriver National Institute of Child Health and Human Development...CompletedFragile X Syndrome (FXS)United States
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Novartis PharmaceuticalsTerminated
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Sheba Medical CenterElMindA LtdRecruitingFragile X Associated Tremor-ataxia Syndrome | FXTASIsrael
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University of California, DavisUniversity of Alberta; St. Justine's HospitalRecruitingNeurobehavioral Manifestations | Genetic Diseases, X-Linked | Intellectual Disability | Fragile X Syndrome | Sex Chromosome Disorders | Fragile X Mental Retardation Syndrome | Trinucleotide Repeat Expansion | Fra(X) Syndrome | FXS | Mental Retardation, X LinkedUnited States, Canada
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University of AlbertaSt. Justine's HospitalRecruitingNeurobehavioral Manifestations | Genetic Diseases, X-Linked | Mental Retardation, X-Linked | Intellectual Disability | Fragile X Syndrome | Sex Chromosome Disorders | Fragile X Mental Retardation Syndrome | Trinucleotide Repeat Expansion | Fra(X) Syndrome | FXSCanada
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