Fragile X SyndromePhase 2NCT01120626
Randomized Controlled Study of Donepezil in Fragile X Syndrome
A Phase 2 study testing donepezil and sugar pill in people with Fragile X Syndrome, run by Stanford University at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 12 to 29 years
- Conditions the study is for
- Fragile X Syndrome
- What is being tested?
- donepezil and sugar pill
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 45 participants
- Where
- 1 siteUnited States
- Study dates
- Sep 2009to Dec 2013
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 12 to 29 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- confirmed genetic diagnosis of fragile X syndrome
- age >=12, <=29
- Verbal IQ >= 50, <=75
- Tanner pubertal stage >= 3
Who cannot join
- 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.)
Trial locations and contacts
1 site in 1 country.
United States1 site
Stanford University School of Medicine
Stanford, California, 94305
About this study
Official title: Augmentation of the Cholinergic System in Fragile X Syndrome: A Double-Blind Placebo-Controlled Randomized Study of Donepezil
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.
Read the 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.
- Conditions
- Fragile X Syndrome
- Being tested
- donepezil, sugar pill
- Medical subject headings
- Fragile X Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
donepezilDrug
Also called Aricept
donepezil (2.5 mg to 10.0 mg per day for 12 weeks)
sugar pillDrug
Also called lactose
sugar pill (2.5 mg to 10.0 mg per day for 12 weeks)
| Study group | Role | What they receive |
|---|---|---|
| donepezil | Active comparator | donepezil (2.5 mg to 10.0 mg per day for 12 weeks) Receives: Drug: donepezil |
| sugar pill | Placebo comparator | sugar pill (2.5 mg to 10.0 mg per day for 12 weeks) Receives: Drug: sugar pill |
What is being measured
The primary outcome is the main question the study is designed to answer.
Contingency Naming Test (CNT) Performance Score
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.
Measured: Week 12
Secondary outcomes (1)
Aberrant Behavior Checklist (ABC)
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.
Measured: Week 12
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 May 2010 (estimated)
- Study startSep 2009
- Primary completionDec 2013
- Study completionDec 2013
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Fragile X SyndromeStudies of the same condition, open and under way.
- More trials run by Stanford UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 45 participants (actual)
Sponsor and investigators
- Lead sponsor
- Stanford University
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute of Mental Health (NIMH), Autism Speaks
- Responsible party
- Principal investigator, Allan Reiss, Stanford University
- Investigators
- Allan L Reiss, Principal investigator, Stanford University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01120626
- Sponsor's protocol ID
- SU-02042010-4923
- Other IDs
- Autism Speaks 5907, R34MH085899-01A1, SPO#42922, SPO#45612, eProtocol 13773 (SQL 96239)
- Status last verified
- Feb 2016
- First submitted
- 7 May 2010
- Last updated
- 17 Mar 2016
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 17 Mar 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Augmentation of the Cholinergic System in Fragile X Syndrome: A Double-Blind Placebo-Controlled Randomized Study of Donepezil
- ClinicalTrials.gov ID
- NCT01120626
- Acronym / sponsor ID
- SU-02042010-4923
- Conditions
- Fragile X Syndrome
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 45 participants (actual)
- Lead sponsor
- Stanford UniversityUniversity, hospital or other
- Collaborators
- National Institute of Mental Health (NIMH), Autism Speaks
- Study start
- Sep 2009
- Primary completion
- Dec 2013 (actual)
- Study completion
- Dec 2013 (actual)
- First posted
- 11 May 2010 (estimated)
- Results
- Posted 17 Mar 2016
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| donepezil | Active comparator | Drug: donepezildonepezil (2.5 mg to 10.0 mg per day for 12 weeks) |
| sugar pill | Placebo comparator | Drug: sugar pillsugar pill (2.5 mg to 10.0 mg per day for 12 weeks) |
Who may qualify
- Ages
- 12 to 29 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (4 listed)
- confirmed genetic diagnosis of fragile X syndrome
- age >=12, <=29
- Verbal IQ >= 50, <=75
- Tanner pubertal stage >= 3
Key exclusion criteria (7 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| donepezilAlso: Ariceptdonepezil (2.5 mg to 10.0 mg per day for 12 weeks) | Drug | donepezil |
| sugar pillAlso: lactosesugar pill (2.5 mg to 10.0 mg per day for 12 weeks) | Drug | sugar pill |
Primary outcome
Contingency Naming Test (CNT) Performance Score
Time frame: 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.
1 secondary outcome
Aberrant Behavior Checklist (ABC)
Time frame: Week 12
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Mar 2016.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Center for Interdisciplinary Brain Sciences Research at StanfordLink provided by the sponsor.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Allan L Reiss principal investigator
Stanford University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing donepezil and sugar pill in people with Fragile X Syndrome, run by Stanford University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 17 Mar 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 17 Mar 2016). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Contingency Naming Test (CNT) Performance Score (time frame: Week 12). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Mar 2016.