Randomized Controlled Study of Donepezil in Fragile X Syndrome

• Sponsor: Stanford University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01120626
• Collaborator: National Institute of Mental Health (NIMH) (NIH), Autism Speaks (Other)
• Enrollment: 45
• Location: 1
• Arms: 2
• Duration (Months): 51
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

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 or Disease	Intervention/Treatment	Phase
Fragile X Syndrome	Drug: donepezil; Drug: sugar pill	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 45 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, 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
• Study Start Date: Sep 1, 2009
• Actual Primary Completion Date: Dec 1, 2013
• Actual Study Completion Date: Dec 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
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 Names: 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 Names: lactose

Outcome Measures

Primary Outcome Measures

1. Contingency Naming Test (CNT) Performance Score [Week 12]

   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

1. Aberrant Behavior Checklist (ABC) [Week 12]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years to 29 Years
• Sexes Eligible for Study: All
• 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

Locations

	Site	City	State	Country	Postal Code
1	Stanford University School of Medicine	Stanford	California	United States	94305

Sponsors and Collaborators

• Stanford University
• National Institute of Mental Health (NIMH)
• Autism Speaks

Investigators

• Principal Investigator: Allan L Reiss, Stanford University

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Center for Interdisciplinary Brain Sciences Research at Stanford

Publications

None provided.

• Responsible Party: Allan Reiss, Principle Investigator, Stanford University
• ClinicalTrials.gov Identifier: NCT01120626
• Other Study ID Numbers: SU-02042010-4923; Autism Speaks 5907; R34MH085899-01A1; SPO#42922; SPO#45612; eProtocol 13773 (SQL 96239)
• First Posted: May 11, 2010
• Last Update Posted: Mar 17, 2016
• Last Verified: Feb 1, 2016

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Fragile X Syndrome; Syndrome; Donepezil

Study Results

Participant Flow

Pre-assignment Detail	45 participants consented/enrolled in study. Of these, 3 failed to meet inclusion criteria at the baseline visit and thus were not randomized to receive study drug.

Arm/Group Title	Donepezil	Sugar Pill
Arm/Group Description	donepezil (2.5 mg to 10.0 mg per day for 12 weeks) donepezil: donepezil (2.5 mg to 10.0 mg per day for 12 weeks)	sugar pill (2.5 mg to 10.0 mg per day for 12 weeks) sugar pill: sugar pill (2.5 mg to 10.0 mg per day for 12 weeks)
Period Title: Overall Study
STARTED	20	22
COMPLETED	19	22
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	Donepezil	Sugar Pill	Total
Arm/Group Description	donepezil (2.5 mg to 10.0 mg per day for 12 weeks) donepezil: donepezil (2.5 mg to 10.0 mg per day for 12 weeks)	sugar pill (2.5 mg to 10.0 mg per day for 12 weeks) sugar pill: sugar pill (2.5 mg to 10.0 mg per day for 12 weeks)	Total of all reporting groups
Overall Participants	20	22	42
Age (Count of Participants)
<=18 years	10 50%	9 40.9%	19 45.2%
Between 18 and 65 years	10 50%	13 59.1%	23 54.8%
>=65 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	7 35%	8 36.4%	15 35.7%
Male	13 65%	14 63.6%	27 64.3%
Region of Enrollment (participants) [Number]
United States	20 100%	22 100%	42 100%
Contingency Naming Test (CNT) Performance Score (correct responses per minute) [Mean (Standard Deviation) ]
CNT Performance Rule 2	52.63 (18.54)	38.77 (26.49)	45.37 (23.83)
CNT Performance Rule 3	23.08 (12.56)	13.77 (13.44)	18.21 (13.71)
Aberrant Behavior Checklist (ABC) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	19.70 (15.34)	30.77 (25.54)	21.26 (19.50)

Outcome Measures

1. Primary Outcome

Title	Contingency Naming Test (CNT) Performance Score
Description	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.
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

41 of 42 randomized participants completed the 12-week randomized controlled trial. 37 of 42 randomized participants completed CNT Rule 2 at week 12. 34 of 42 randomized participants completed CNT Rule 3 at week 12.

Arm/Group Title	Donepezil	Sugar Pill
Arm/Group Description	donepezil (2.5 mg to 10.0 mg per day for 12 weeks) donepezil: donepezil (2.5 mg to 10.0 mg per day for 12 weeks)	sugar pill (2.5 mg to 10.0 mg per day for 12 weeks) sugar pill: sugar pill (2.5 mg to 10.0 mg per day for 12 weeks)
Measure Participants	19	18
CNT Performance Score Rule 2	37.05 (14.60)	40.50 (31.11)
CNT Performance Score Rule 3	66.94 (46.92)	61.56 (23.06)

2. Secondary Outcome

Title	Aberrant Behavior Checklist (ABC)
Description	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.
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

41 of 42 randomized participants completed the 12-week randomized controlled trial. 39 of 42 participants were administered the ABC at week 12.

Arm/Group Title	Donepezil	Sugar Pill
Arm/Group Description	donepezil (2.5 mg to 10.0 mg per day for 12 weeks) donepezil: donepezil (2.5 mg to 10.0 mg per day for 12 weeks)	sugar pill (2.5 mg to 10.0 mg per day for 12 weeks) sugar pill: sugar pill (2.5 mg to 10.0 mg per day for 12 weeks)
Measure Participants	18	21
Mean (Standard Deviation) [units on a scale]	17.56 (13.65)	24.43 (23.27)

Adverse Events

Arm/Group Title	Donepezil		Sugar Pill
Arm/Group Description	donepezil (2.5 mg to 10.0 mg per day for 12 weeks) donepezil: donepezil (2.5 mg to 10.0 mg per day for 12 weeks)		sugar pill (2.5 mg to 10.0 mg per day for 12 weeks) sugar pill: sugar pill (2.5 mg to 10.0 mg per day for 12 weeks)
All Cause Mortality
	Donepezil		Sugar Pill
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Donepezil		Sugar Pill
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/22 (0%)
Other (Not Including Serious) Adverse Events
	Donepezil		Sugar Pill
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/22 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.