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| Name | Class |
|---|---|
| Michael J. Fox Foundation for Parkinson's Research | OTHER |
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This study will compare the effects of placebo and donepezil, a drug that helps conserve concentrations of the neurotransmitter, acetylcholine, on measures of balance and gait in subjects with Parkinson's disease (PD). This study is a double-blind, placebo controlled, cross-over randomized clinical trial. Short-latency afferent inhibition (SAI), a physiological index of cholinergic function will be measured to determine if the deficits in balance and gait correlate with abnormalities of the SAI and if SAI is altered by donepezil as a measure of drug efficacy. Cognitive tests like the Attention Network Test (ANT) will be administered to determine if changes in gait and balance are mediated by changes in attention.
The results of this study will be the most direct test of the hypothesized role of cholinergic neurons and the neurotransmitter, acetylcholine in terms of gait and balance. The study is exploratory because it is not known whether donepezil will affect gait, balance or attention, nor which measures of gait, balance or attention will be sensitive to drug manipulation. The study's immediate goal is to determine the potential utility of cholinergic manipulation as a strategy for preventing or treating balance and gait dysfunction in PD. The findings of this trial are intended to lead to more sharply focused questions about the role of cholinergic neurons in balance and gait and eventually to Phase II B trials to determine clinical utility of cholinergic manipulation to prevent falls and improve mobility.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Donepezil | Experimental | Donepezil 5 mg per day for week 1-3 or 12-14. 10 mg/day for weeks 4-6 or 14-18, if tolerated. |
|
| Placebo | Placebo Comparator | Placebo 5 mg per day for week 1-3 or 12-14. 10 mg/day for weeks 4-6 or 14-18, if tolerated. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Donepezil | Drug |
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| Measure | Description | Time Frame |
|---|---|---|
| Delta Medio-lateral Postural Sway Range (Foam) | Increased body sway while standing may be markers for increased risk of falling in Parkinson's disease. Sway was measured with an inertial sensor attached to the waist. Participants did this task on a foam pad. We reported the delta in the donepezil and placebo phases [post-donepezil - pre-donepezil for the donepezil phase, and post-placebo - pre-placebo for the placebo phase]. | Six weeks |
| Delta of the Variability of Stride Time While Walking | Variability in stride time time and an increase with dual tasking is another marker for increased fall risk in Parkinson's disease. Stride time variability was measured with inertial sensors attached to both feet. The delta for each phase is reported [post-donepezil - pre-donepezil for the donepezil phase, and post-placebo - pre-placebo for the placebo phase]. | Six weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Short-latency Afferent Inhibition is a Marker of Cortical Cholinergic Activity | Short-latency afferent inhibition (SAI) by a peripheral stimulation is a transcranial magnetic stimulation method to evaluate cortical cholinergic activity. Short-latency afferent Inhibition will be used to determine if our subjects with Parkinson's disease have evidence of reduced cholinergic tone which correlates with their measures of postural and gait instability. We report the SAI at the end of each phase (post-placebo phase and post-donepezil phase). SAI is reported in motor-evoked potential (MEP). |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| John Nutt, M.D. | Oregon Health and Science University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Oregon Health & Science University | Portland | Oregon | 97239-3098 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 26697847 | Derived | Mancini M, Fling BW, Gendreau A, Lapidus J, Horak FB, Chung K, Nutt JG. Effect of augmenting cholinergic function on gait and balance. BMC Neurol. 2015 Dec 23;15:264. doi: 10.1186/s12883-015-0523-x. |
| Label | URL |
|---|---|
| The Michael J. Fox Foundation "Fox Trial Finder" Study Listing | View source |
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| ID | Title | Description |
|---|---|---|
| FG000 | Donepezil, Then Placebo | Donepezil 5 mg per day for weeks 1-3. 10 mg/day for weeks 4-6. Then 6 week washout followed by 6 weeks of placebo. Placebo (identical appearing capsules), two capsules per day for 2 weeks and four capsules per day for the following 2 weeks. |
| FG001 | Placebo, Then Donepezil | Placebo (identical appearing capsules), two capsules per day for weeks 1-3 and four capsules per day for 4-6 weeks followed by washout for 6 weeks and then crossover to donepezil for six weeks. Donepezil 5 mg per day for 2 weeks, then 10 mg/day for the following 2 weeks. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Phase I - First Intervention (6 Weeks) |
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| Washout (6 Weeks) |
| |||||||||||||||||||
| Phase II - Second Intervention (6 Weeks) |
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| ID | Title | Description |
|---|---|---|
| BG000 | All Study Participants | Donepezil was taken for 3 weeks at 5mg/day (1 tablet/day) and then increased to 10mg/day (2 tablets/day) for another 3 weeks. The same was done for the placebo (1 tablet for the first 3 weeks, then 2 tablets for the following 3 weeks). There was a washout period of 6 weeks between the interventions. Participants were randomized to start with donepezil or placebo. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Delta Medio-lateral Postural Sway Range (Foam) | Increased body sway while standing may be markers for increased risk of falling in Parkinson's disease. Sway was measured with an inertial sensor attached to the waist. Participants did this task on a foam pad. We reported the delta in the donepezil and placebo phases [post-donepezil - pre-donepezil for the donepezil phase, and post-placebo - pre-placebo for the placebo phase]. | Posted | Mean | Standard Deviation | m/s^2 | Six weeks |
|
Adverse Events were collected through study completion, an average of 18 weeks.
Adverse Events were systematically collected by phone call every week. Study clinicians recorded adverse events and reported to the IRB unexpected or serious adverse events. An independent neurologist reviewed the reported adverse events each six months and made recommendations to the trial leadership as well as the IRB about advisability of continuation of the trial.
The adverse events are reported below per intervention for each Arm/Group of the study.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Donepezil, Then Placebo (Phase I) | Participants took a donepezil 5mg tablet each day for 3 weeks, then increased the dose to 10mg (2 tablets each day) for 3 weeks. (This was followed by 6 weeks of a washout period and then taking the placebo in the same format -- 3 weeks of one tablet, followed by 3 weeks of 2 tablets to replicate the dosage increase.) |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Pulmonary Embolus | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anorexia | Gastrointestinal disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Martina Mancini | Oregon Health & Science University | 5034182602 | mancinim@ohsu.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jan 15, 2019 | Sep 24, 2019 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D010300 | Parkinson Disease |
| ID | Term |
|---|---|
| D020734 | Parkinsonian Disorders |
| D001480 | Basal Ganglia Diseases |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
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| ID | Term |
|---|---|
| D000077265 | Donepezil |
| ID | Term |
|---|---|
| D007189 | Indans |
| D007192 | Indenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D006841 | Hydrocarbons, Aromatic |
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| Six weeks |
| Attention Network Test | Attention Network Test (ANT) is 15 minute computerized test or reaction times with various cues and targets designed to assess alerting, orienting and executive control of attention. Deficits of attention are related to fall risk and may be affected by donepezil. The delta of the Orienting Network Efficiency is reported for each phase (pre- and post-donepezil phase and pre- and post-placebo phase). Details: In accordance with Fan et al. (2002), the subtraction method was applied to isolate the efficiency of the three attentional networks as follows: for the alerting network efficiency: mean RT NC trials - mean RT DC trials; for the orienting network efficiency: mean RT CC trials - mean RT SC trials; and for the executive network efficiency: mean RT I trials - mean RT C trials. For both the alerting and orienting effects, higher subtraction scores indicate greater efficiency; by contrast, the more efficient the executive network is, the lower the subtraction score. | Six weeks |
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| years |
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| Sex: Female, Male | Count of Participants | Participants |
|
| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
|
| Disease Duration | Mean | Standard Deviation | years |
|
| MoCA | Montreal Cognitive Assessment: overall cognition. Scale from 0 to 30. 30 represents intact cognitive status | Mean | Standard Deviation | scores on a scale |
|
| MDS-UPDRS Part III | Unified Parkinson's Disease Rating Scale (UPDRS), Movement Disorders Society (MDS) revised. Participants are rated on a variety of motor functions in a series of subscales. Subscale scores range from 0 to 4. The sub scales are summed to get the total score. The total score minimum score is 0 and the maximum score is 132. Higher values represent further disease progression. | Mean | Standard Deviation | units on a scale |
|
|
|
| Primary | Delta of the Variability of Stride Time While Walking | Variability in stride time time and an increase with dual tasking is another marker for increased fall risk in Parkinson's disease. Stride time variability was measured with inertial sensors attached to both feet. The delta for each phase is reported [post-donepezil - pre-donepezil for the donepezil phase, and post-placebo - pre-placebo for the placebo phase]. | Variability of stride time was calculated from the stride time time-series as the coefficient of variation (CV, 100 multiplied by the SD of the stride times divided by the mean of each subject's stride times) | Posted | Mean | Standard Deviation | percentage of gait cycle time | Six weeks |
|
|
|
| Secondary | Short-latency Afferent Inhibition is a Marker of Cortical Cholinergic Activity | Short-latency afferent inhibition (SAI) by a peripheral stimulation is a transcranial magnetic stimulation method to evaluate cortical cholinergic activity. Short-latency afferent Inhibition will be used to determine if our subjects with Parkinson's disease have evidence of reduced cholinergic tone which correlates with their measures of postural and gait instability. We report the SAI at the end of each phase (post-placebo phase and post-donepezil phase). SAI is reported in motor-evoked potential (MEP). | The average and standard deviation (SD) of the SAI at the end of each treatment is reported | Posted | Mean | Standard Deviation | percentage of the unconditioned MEP | Six weeks |
|
|
|
| Secondary | Attention Network Test | Attention Network Test (ANT) is 15 minute computerized test or reaction times with various cues and targets designed to assess alerting, orienting and executive control of attention. Deficits of attention are related to fall risk and may be affected by donepezil. The delta of the Orienting Network Efficiency is reported for each phase (pre- and post-donepezil phase and pre- and post-placebo phase). Details: In accordance with Fan et al. (2002), the subtraction method was applied to isolate the efficiency of the three attentional networks as follows: for the alerting network efficiency: mean RT NC trials - mean RT DC trials; for the orienting network efficiency: mean RT CC trials - mean RT SC trials; and for the executive network efficiency: mean RT I trials - mean RT C trials. For both the alerting and orienting effects, higher subtraction scores indicate greater efficiency; by contrast, the more efficient the executive network is, the lower the subtraction score. | Posted | Mean | Standard Deviation | ms | Six weeks |
|
|
|
| 0 |
| 22 |
| 0 |
| 22 |
| 18 |
| 22 |
| EG001 | Placebo, Then Donepezil (Phase I) | Participants took the placebo at one tablet each day for 3 weeks, then increased the dosage to 2 tablets each day for 3 weeks. (This was followed by 6 weeks of a washout period and then taking donepezil in the same format -- donepezil 5mg tablet each day for 3 weeks, followed by 3 weeks of an increased dose of 10mg (2 tablets each day).) | 0 | 27 | 0 | 27 | 18 | 27 |
| EG002 | Donepezil, Then Placebo (Washout) | There were 6 weeks of a washout period after participants had taken donepezil for 6 weeks. | 0 | 21 | 0 | 21 | 5 | 21 |
| EG003 | Placebo, Then Donepezil (Washout) | There were 6 weeks of a washout period after participants had taken the placebo for 6 weeks. | 0 | 26 | 1 | 26 | 8 | 26 |
| EG004 | Donepezil, Then Placebo (Phase II) | After the washout period, participants took the placebo in the same format as the donepezil -- 3 weeks of one tablet, followed by 3 weeks of 2 tablets to replicate the dosage increase. | 0 | 21 | 0 | 21 | 4 | 21 |
| EG005 | Placebo, Then Donepezil (Phase II) | Then participants took donepezil in the same formats the placebo -- the donepezil 5mg tablet each day for 3 weeks, followed by 3 weeks of an increased dose of 10mg (2 tablets each day). | 0 | 26 | 0 | 26 | 26 | 26 |
| Nausea | Gastrointestinal disorders | Systematic Assessment |
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| Diarrhea | Gastrointestinal disorders | Systematic Assessment |
|
| Constipation | Gastrointestinal disorders | Systematic Assessment |
|
| Abdominal Pain | Gastrointestinal disorders | Systematic Assessment |
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| Insomnia | General disorders | Systematic Assessment |
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| Vivid Dreams | General disorders | Systematic Assessment |
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| Fatigue | Musculoskeletal and connective tissue disorders | Systematic Assessment |
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| Muscle Cramps | Musculoskeletal and connective tissue disorders | Systematic Assessment |
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| Light Headedness | General disorders | Systematic Assessment |
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| Headache | General disorders | Systematic Assessment |
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| Hallucinations | General disorders | Systematic Assessment |
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| Memory Disturbances | General disorders | Systematic Assessment |
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| Increased Saliva | General disorders | Systematic Assessment |
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| Decreased Saliva | General disorders | Systematic Assessment |
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| Urinary Frequency | Renal and urinary disorders | Systematic Assessment |
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| Upper Respiratory Tract Infection | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Other | General disorders | Systematic Assessment | other adverse events consisting of Irregular Heartbeat, Pain, Weakness, Anxiety, Excessive Sweating, Trouble Swallowing, Infection, Rash, Food Poisoning, Impulse Control, Increased Freezing of Gait, etc |
|
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| D009422 | Nervous System Diseases |
| D009069 | Movement Disorders |
| D000080874 | Synucleinopathies |
| D019636 | Neurodegenerative Diseases |
| D006844 |
| Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D010880 | Piperidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D011083 | Polycyclic Compounds |