Randomized Controlled Study of Donepezil in Fragile X Syndrome
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Purpose
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 hydrochloride 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 |
- scores on behavior assessments [ Time Frame: baseline, week 6, week 12 ] [ Designated as safety issue: No ]
- scores on working memory tests [ Time Frame: baseline, week 12 ] [ Designated as safety issue: No ]
| Estimated Enrollment: | 50 |
| Study Start Date: | September 2009 |
| Estimated Study Completion Date: | June 2013 |
| Estimated Primary Completion Date: | June 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 hydrochloride
donepezil (2.5 mg to 10.0 mg per day for 12 weeks)
Other Names:
|
|
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.
Eligibility| Ages Eligible for Study: | 12 Years to 29 Years |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
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.)
Contacts and Locations| Contact: Mai K Manchanda, AB | 650-704-9763 | maik@stanford.edu |
| United States, California | |
| Stanford University School of Medicine | Recruiting |
| Stanford, California, United States, 94305 | |
| Contact: Mai K Manchanda, AB 650-704-9763 maik@stanford.edu | |
| Principal Investigator: Allan L Reiss | |
| Sub-Investigator: Lynne C. Huffman | |
| Sub-Investigator: Antonio Hardan | |
| Sub-Investigator: Booil Jo | |
| Sub-Investigator: Mr Xu Cui | |
| Principal Investigator: | Allan L Reiss | Stanford University |
More Information
Additional Information:
No publications provided
| Responsible Party: | Stanford University |
| ClinicalTrials.gov 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 |
| Last Updated: | December 11, 2012 |
| Health Authority: | United States: Institutional Review Board |
Additional relevant MeSH terms:
|
Fragile X Syndrome Mental Retardation, X-Linked Mental Retardation 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 |
Donepezil Cholinesterase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Pharmacologic Actions Cholinergic Agents Neurotransmitter Agents Physiological Effects of Drugs Nootropic Agents Central Nervous System Agents Therapeutic Uses |
ClinicalTrials.gov processed this record on May 22, 2013