Parkinson's Disease
Conditions
Brief summary
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.
Interventions
DRUGDonepezil
Sponsors
Michael J. Fox Foundation for Parkinson's Research
Oregon Health and Science University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
30 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 30 years old or older * Diagnosis of idiopathic Parkinson's disease * Stand unassisted (without use of an assistance device) and walk continuously for at least 2 minutes.
Exclusion criteria
* musculoskeletal disorders that affect standing and walking * Uncorrected vision disturbance * Vestibular problems * Major depression * Hallucinations or other psychiatric disturbances * Tachycardia * Bradycardia * Arrhythmias * Peptic ulcer disease * Use of anticholinergics * Use of cholinesterase inhibitors * Use of bladder antispasmodics * Use of tricyclic antidepressants
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Delta Medio-lateral Postural Sway Range (Foam) | Six weeks | 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 \[post-donepezil - pre-donepezil for the donepezil phase, and post-placebo - pre-placebo for the placebo phase\]. |
| Delta of the Variability of Stride Time While Walking | Six weeks | 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 \[post-donepezil - pre-donepezil for the donepezil phase, and post-placebo - pre-placebo for the placebo phase\]. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Short-latency Afferent Inhibition is a Marker of Cortical Cholinergic Activity | Six weeks | 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). |
| Attention Network Test | Six weeks | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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. | 49 |
| Total | 49 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Phase I - First Intervention (6 Weeks) | Withdrawal by Subject | 1 | 1 |
| Phase II - Second Intervention (6 Weeks) | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | All Study Participants | — |
|---|---|---|
| Age, Continuous | 69 years STANDARD_DEVIATION 7 | — |
| Disease Duration | 7 years STANDARD_DEVIATION 5 | — |
| MDS-UPDRS Part III | 43 units on a scale STANDARD_DEVIATION 12 | — |
| MoCA | 26 scores on a scale STANDARD_DEVIATION 3 | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Sex: Female, Male Female | 14 Participants | — |
| Sex: Female, Male Male | 35 Participants | — |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 22 | 0 / 27 | 0 / 21 | 0 / 26 | 0 / 21 | 0 / 26 |
| other Total, other adverse events | 18 / 22 | 18 / 27 | 5 / 21 | 8 / 26 | 4 / 21 | 26 / 26 |
| serious Total, serious adverse events | 0 / 22 | 0 / 27 | 0 / 21 | 1 / 26 | 0 / 21 | 0 / 26 |
Outcome results
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 \[post-donepezil - pre-donepezil for the donepezil phase, and post-placebo - pre-placebo for the placebo phase\].
Time frame: Six weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Donepezil | Delta Medio-lateral Postural Sway Range (Foam) | 0.007 m/s^2 | Standard Deviation 0.045 |
| Placebo | Delta Medio-lateral Postural Sway Range (Foam) | -0.004 m/s^2 | Standard Deviation 0.028 |
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 \[post-donepezil - pre-donepezil for the donepezil phase, and post-placebo - pre-placebo for the placebo phase\].
Time frame: Six weeks
Population: 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)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Donepezil | Delta of the Variability of Stride Time While Walking | -0.32 percentage of gait cycle time | Standard Deviation 4.07 |
| Placebo | Delta of the Variability of Stride Time While Walking | -0.038 percentage of gait cycle time | Standard Deviation 3.98 |
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.
Time frame: Six weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Donepezil | Attention Network Test | -19.5 ms | Standard Deviation 16.3 |
| Placebo | Attention Network Test | -5.1 ms | Standard Deviation 5.9 |
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).
Time frame: Six weeks
Population: The average and standard deviation (SD) of the SAI at the end of each treatment is reported
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Donepezil | Short-latency Afferent Inhibition is a Marker of Cortical Cholinergic Activity | 72.5 percentage of the unconditioned MEP | Standard Deviation 26.9 |
| Placebo | Short-latency Afferent Inhibition is a Marker of Cortical Cholinergic Activity | 74.3 percentage of the unconditioned MEP | Standard Deviation 23.8 |