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An Open-Label Trial of Donepezil in Fragile X Syndrome

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00220584
Recruitment Status : Completed
First Posted : September 22, 2005
Last Update Posted : December 13, 2012
Information provided by (Responsible Party):
Stanford University

Brief Summary:
Fragile X syndrome is the most common known inherited cause of neurodevelopmental disability. Functional magnetic resonance imaging (fMRI) studies from our laboratory indicate that specific brain regions using the neurochemical, acetylcholine, show significantly reduced activation during learning. Since donepezil is a medication that enhances acetylcholine function in the brain, the purpose of this study is to determine if donepezil has any beneficial effect on behavior or cognition in subjects with fragile X syndrome.

Condition or disease Intervention/treatment Phase
Fragile X Syndrome Drug: donepezil Phase 1

Detailed Description:

Fragile X syndrome is the most common genetically inherited cause of neurodevelopmental disability in humans, affecting approximately 1:2000 to 4000 live births. Affected individuals have significant, long-term problems with learning, and often with behavior as well. The disorder is caused by the presence of a greatly expanded CGG repeat within the FMR1 gene on the long arm of the X chromosome. Abnormal methylation of this repeat, and adjacent areas within the FMR1 gene impedes transcription, ultimately resulting in reduced production of the FMR1 protein (FMRP). This protein is expressed in neurons, with particularly high levels of gene transcription occurring in the nucleus basalis (basal forebrain) and hippocampus. A recent functional imaging study from our group showed girls with fragile X to have greatly reduced levels of brain activation in the basal forebrain and hippocampal activation during a memory task. The nucleus basalis, is a cholinergic nucleus with widespread connections to the neocortex. It is critical to visuospatial attention in rodents and primates and is presumed to play a similar role in humans. The finding of decreased basal forebrain activation in girls with fragile X, considered in light of histological evidence showing high transcription levels of FMR1 in healthy nucleus basalis, suggests the possibility of a functional cholinergic deficit in fragile X syndrome.

Donepezil is an acetylcholinesterase inhibitor which slows the degradation of synaptic acetylcholine thereby increasing its availability. It is approved for the treatment of mild-moderate Alzheimer's disease. It has been studied in several other neurologic disorders--including vascular dementia, Lewy Body dementia, and Down's syndrome (with and without dementia)--where it has shown varying degrees of efficacy but consistently high degrees of safety and tolerability. The goal of the proposed study is to determine if enhancing cholinergic activity with donepezil has beneficial effects on behavior or cognition in subjects with fragile X syndrome.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 10 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-Label Trial of Donepezil in Fragile X Syndrome
Study Start Date : July 2005
Actual Primary Completion Date : July 2009
Actual Study Completion Date : July 2009

Arm Intervention/treatment
Experimental: Open donepezil
open donepezil
Drug: donepezil
donepezil 5 mg daily for 3 weeks (days 1-21); 10 mg daily for 3 weeks (days 22-42)
Other Names:
  • Aricept
  • donepezil hydrochloride

Primary Outcome Measures :
  1. Scores on learning tests at baseline [ Time Frame: baseline, day 21, day 42 ]
  2. score on test of attention [ Time Frame: baseline, day 21, day 42 ]
  3. score on measures of behavior [ Time Frame: baseline, day 21, day 42 ]
  4. scores on learning tests [ Time Frame: baseline, day 21, day 42 ]
  5. scores on working memory tests [ Time Frame: baseline, day 21, day 42 ]

Information from the National Library of Medicine

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Ages Eligible for Study:   14 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:1. Confirmed genetic diagnosis of fragile X syndrome

2. Age e 14

3. Verbal IQ e 60 Exclusion Criteria:1. Currently taking any anticholinergic medications, tricyclic antidepressant medications, or diphenhydramine.

2. Presence of cardiac disease or bradycardia (< 60 beats/minute) at initial evaluation.

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 identifier (NCT number): NCT00220584

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United States, California
Stanford University School of Medicine
Stanford, California, United States, 94305
Sponsors and Collaborators
Stanford University
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Principal Investigator: Allan L Reiss Stanford University

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Responsible Party: Stanford University Identifier: NCT00220584    
Other Study ID Numbers: 96239
First Posted: September 22, 2005    Key Record Dates
Last Update Posted: December 13, 2012
Last Verified: December 2012
Additional relevant MeSH terms:
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Fragile X Syndrome
Pathologic Processes
Mental Retardation, X-Linked
Intellectual Disability
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Sex Chromosome Disorders
Chromosome Disorders
Congenital Abnormalities
Genetic Diseases, Inborn
Genetic Diseases, X-Linked
Heredodegenerative Disorders, Nervous System
Cholinesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Cholinergic Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Nootropic Agents