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Randomized Controlled Study of Donepezil in Fragile X Syndrome

This study has been completed.
National Institute of Mental Health (NIMH)
Autism Speaks
Information provided by (Responsible Party):
Allan Reiss, Stanford University Identifier:
First received: May 7, 2010
Last updated: February 18, 2016
Last verified: February 2016
Fragile X syndrome (FraX) is the most common known heritable cause of human intellectual disability. Though recent research has revealed much about the genetic and neurobiological bases of FraX, knowledge about specific and effective treatments for affected individuals is lacking. Based on information from both human and animal studies, one cause of intellectual disability in FraX may be related to deficits in a particular brain neurotransmitter system (the "cholinergic" system). Thus, the investigators propose to use a specific medication, donepezil, to augment cholinergic system in adolescents affected by FraX. If found to be effective, the knowledge generated by this research may also be relevant to other developmental disorders that share common disease pathways with FraX.

Condition Intervention Phase
Fragile X Syndrome
Drug: donepezil
Drug: sugar pill
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Augmentation of the Cholinergic System in Fragile X Syndrome: A Double-Blind Placebo-Controlled Randomized Study of Donepezil

Resource links provided by NLM:

Further study details as provided by Stanford University:

Primary Outcome Measures:
  • Contingency Naming Test (CNT) Performance Score [ Time Frame: Week 12 ] [ Designated as safety issue: No ]
    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.

Secondary Outcome Measures:
  • Aberrant Behavior Checklist (ABC) [ Time Frame: Week 12 ] [ Designated as safety issue: No ]
    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.

Enrollment: 45
Study Start Date: September 2009
Study Completion Date: December 2013
Primary Completion Date: December 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: donepezil
donepezil (2.5 mg to 10.0 mg per day for 12 weeks)
Drug: donepezil
donepezil (2.5 mg to 10.0 mg per day for 12 weeks)
Other Name: Aricept
Placebo Comparator: sugar pill
sugar pill (2.5 mg to 10.0 mg per day for 12 weeks)
Drug: sugar pill
sugar pill (2.5 mg to 10.0 mg per day for 12 weeks)
Other Name: lactose

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.


Ages Eligible for Study:   12 Years to 29 Years   (Child, Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. confirmed genetic diagnosis of fragile X syndrome
  2. age >=12, <=29
  3. Verbal IQ >= 50, <=75
  4. Tanner pubertal stage >= 3

Exclusion Criteria:

  1. Current or lifetime DSM-IV diagnosis of bipolar disorder, schizophrenia, schizoaffective disorder, or psychotic disorder, NOS based upon reported history
  2. 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
  3. Concomitant or anticipated use of other medications having prominent effects on the cholinergic system (e.g., bethanechol, benztropine, atropine, succinylcholine)
  4. 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)
  5. Medical illnesses where donepezil could worsen the condition such as asthma, cardiac conduction abnormalities, urinary obstruction or gastrointestinal disease with gastric bleeding
  6. Pregnancy or sexually active females not using a reliable method of contraception
  7. 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.)
  Contacts and Locations
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Please refer to this study by its identifier: NCT01120626

United States, California
Stanford University School of Medicine
Stanford, California, United States, 94305
Sponsors and Collaborators
Stanford University
National Institute of Mental Health (NIMH)
Autism Speaks
Principal Investigator: Allan L Reiss Stanford University
  More Information

Additional Information:
Responsible Party: Allan Reiss, Principle Investigator, Stanford University Identifier: NCT01120626     History of Changes
Other Study ID Numbers: SU-02042010-4923  Autism Speaks 5907  R34MH085899-01A1  SPO#42922  SPO#45612  eProtocol 13773 (SQL 96239) 
Study First Received: May 7, 2010
Results First Received: November 19, 2015
Last Updated: February 18, 2016
Health Authority: United States: Institutional Review Board
Individual Participant Data  
Plan to Share IPD: No

Additional relevant MeSH terms:
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 processed this record on October 25, 2016