Effects of Cholinergic Augmentation on Measures of Balance and Gait

• Sponsor: Oregon Health and Science University (Other)
• Overall Status: Completed
• CT.gov ID: NCT02206620
• Collaborator: Michael J. Fox Foundation for Parkinson's Research (Other)
• Enrollment: 49
• Location: 1
• Arms: 2
• Actual Duration (Months): 36
• Patients Per Site Per Month: 1.4

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Parkinson's Disease	Drug: Donepezil	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 49 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Effects of Cholinergic Augmentation on Measures of Balance and Gait
• Actual Study Start Date: Jul 1, 2014
• Actual Primary Completion Date: Jul 1, 2017
• Actual Study Completion Date: Jul 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Donepezil Donepezil 5 mg per day for week 1-3 or 12-14. 10 mg/day for weeks 4-6 or 14-18, if tolerated.	Drug: Donepezil; Other Names: Aricept
Placebo Comparator: Placebo Placebo 5 mg per day for week 1-3 or 12-14. 10 mg/day for weeks 4-6 or 14-18, if tolerated.	Drug: Donepezil; Other Names: Aricept

Outcome Measures

Primary Outcome Measures

1. 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].

2. 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 Outcome Measures

1. 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).

2. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 30 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Oregon Health & Science University	Portland	Oregon	United States	97239-3098

Sponsors and Collaborators

• Oregon Health and Science University
• Michael J. Fox Foundation for Parkinson's Research

Investigators

• Principal Investigator: John Nutt, M.D., Oregon Health and Science University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jan 15, 2019

More Information

Additional Information:

• The Michael J. Fox Foundation "Fox Trial Finder" Study Listing

Publications

None provided.

• Responsible Party: John G. Nutt, M.D., Oregon Health and Science University
• ClinicalTrials.gov Identifier: NCT02206620
• Other Study ID Numbers: 9437
• First Posted: Aug 1, 2014
• Last Update Posted: Nov 14, 2019
• Last Verified: Nov 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Additional relevant MeSH terms: Parkinson Disease; Donepezil

Study Results

Participant Flow

Arm/Group Title	Donepezil, Then Placebo	Placebo, Then Donepezil
Arm/Group Description	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.	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.
Period Title: Phase I - First Intervention (6 Weeks)
STARTED	22	27
COMPLETED	21	26
NOT COMPLETED	1	1
Period Title: Phase I - First Intervention (6 Weeks)
STARTED	21	26
COMPLETED	21	26
NOT COMPLETED	0	0
Period Title: Phase I - First Intervention (6 Weeks)
STARTED	21	26
COMPLETED	21	24
NOT COMPLETED	0	2

Baseline Characteristics

Arm/Group Title	All Study Participants
Arm/Group Description	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.
Overall Participants	49
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	69 (7)
Sex: Female, Male (Count of Participants)
Female	14 28.6%
Male	35 71.4%
Race and Ethnicity Not Collected (Count of Participants)
Disease Duration (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	7 (5)
MoCA (scores on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [scores on a scale]	26 (3)
MDS-UPDRS Part III (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	43 (12)

Outcome Measures

1. Primary Outcome

Title	Delta Medio-lateral Postural Sway Range (Foam)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Donepezil	Placebo
Arm/Group Description	Donepezil 5 mg per day for week 1-3 or 12-14. 10 mg/day for weeks 4-6 or 14-18, if tolerated. Donepezil	Placebo 5 mg per day for week 1-3 or 12-14. 10 mg/day for weeks 4-6 or 14-18, if tolerated. Donepezil
Measure Participants	49	49
Mean (Standard Deviation) [m/s^2]	0.007 (0.045)	-0.004 (0.028)

2. Primary Outcome

Title	Delta of the Variability of Stride Time While Walking
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Donepezil	Placebo
Arm/Group Description	Donepezil 5 mg per day for week 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 week 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.
Measure Participants	49	49
Mean (Standard Deviation) [percentage of gait cycle time]	-0.32 (4.07)	-0.038 (3.98)

3. Secondary Outcome

Title	Short-latency Afferent Inhibition is a Marker of Cortical Cholinergic Activity
Description	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

Outcome Measure Data

Analysis Population Description

The average and standard deviation (SD) of the SAI at the end of each treatment is reported

Arm/Group Title	Donepezil	Placebo
Arm/Group Description	Donepezil 5 mg per day for week 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 week 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.
Measure Participants	49	49
Mean (Standard Deviation) [percentage of the unconditioned MEP]	72.5 (26.9)	74.3 (23.8)

4. Secondary Outcome

Title	Attention Network Test
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Donepezil	Placebo
Arm/Group Description	Donepezil 5 mg per day for week 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 week 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.
Measure Participants	49	49
Mean (Standard Deviation) [ms]	-19.5 (16.3)	-5.1 (5.9)

Adverse Events

Time Frame	Adverse Events were collected through study completion, an average of 18 weeks.
Adverse Event Reporting Description	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.
Arm/Group Title	Donepezil, Then Placebo (Phase I)		Placebo, Then Donepezil (Phase I)		Donepezil, Then Placebo (Washout)		Placebo, Then Donepezil (Washout)		Donepezil, Then Placebo (Phase II)		Placebo, Then Donepezil (Phase II)
Arm/Group Description	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.)		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).)		There were 6 weeks of a washout period after participants had taken donepezil for 6 weeks.		There were 6 weeks of a washout period after participants had taken the placebo for 6 weeks.		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.		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).
All Cause Mortality
	Donepezil, Then Placebo (Phase I)		Placebo, Then Donepezil (Phase I)		Donepezil, Then Placebo (Washout)		Placebo, Then Donepezil (Washout)		Donepezil, Then Placebo (Phase II)		Placebo, Then Donepezil (Phase II)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/22 (0%)		0/27 (0%)		0/21 (0%)		0/26 (0%)		0/21 (0%)		0/26 (0%)
Serious Adverse Events
	Donepezil, Then Placebo (Phase I)		Placebo, Then Donepezil (Phase I)		Donepezil, Then Placebo (Washout)		Placebo, Then Donepezil (Washout)		Donepezil, Then Placebo (Phase II)		Placebo, Then Donepezil (Phase II)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/22 (0%)		0/27 (0%)		0/21 (0%)		1/26 (3.8%)		0/21 (0%)		0/26 (0%)
Respiratory, thoracic and mediastinal disorders
Pulmonary Embolus	0/22 (0%)	0	0/27 (0%)	0	0/21 (0%)	0	1/26 (3.8%)	1	0/21 (0%)	0	0/26 (0%)	0
Other (Not Including Serious) Adverse Events
	Donepezil, Then Placebo (Phase I)		Placebo, Then Donepezil (Phase I)		Donepezil, Then Placebo (Washout)		Placebo, Then Donepezil (Washout)		Donepezil, Then Placebo (Phase II)		Placebo, Then Donepezil (Phase II)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	18/22 (81.8%)		18/27 (66.7%)		5/21 (23.8%)		8/26 (30.8%)		4/21 (19%)		26/26 (100%)
Gastrointestinal disorders
Anorexia	0/22 (0%)		1/27 (3.7%)		0/21 (0%)		0/26 (0%)		0/21 (0%)		2/26 (7.7%)
Nausea	6/22 (27.3%)		2/27 (7.4%)		0/21 (0%)		1/26 (3.8%)		2/21 (9.5%)		8/26 (30.8%)
Diarrhea	2/22 (9.1%)		1/27 (3.7%)		0/21 (0%)		0/26 (0%)		0/21 (0%)		3/26 (11.5%)
Constipation	1/22 (4.5%)		2/27 (7.4%)		0/21 (0%)		0/26 (0%)		0/21 (0%)		2/26 (7.7%)
Abdominal Pain	1/22 (4.5%)		1/27 (3.7%)		0/21 (0%)		0/26 (0%)		0/21 (0%)		1/26 (3.8%)
General disorders
Insomnia	3/22 (13.6%)		5/27 (18.5%)		1/21 (4.8%)		1/26 (3.8%)		1/21 (4.8%)		6/26 (23.1%)
Vivid Dreams	2/22 (9.1%)		2/27 (7.4%)		0/21 (0%)		0/26 (0%)		0/21 (0%)		2/26 (7.7%)
Light Headedness	3/22 (13.6%)		4/27 (14.8%)		0/21 (0%)		2/26 (7.7%)		1/21 (4.8%)		3/26 (11.5%)
Headache	2/22 (9.1%)		0/27 (0%)		0/21 (0%)		0/26 (0%)		0/21 (0%)		0/26 (0%)
Hallucinations	2/22 (9.1%)		0/27 (0%)		1/21 (4.8%)		1/26 (3.8%)		1/21 (4.8%)		1/26 (3.8%)
Memory Disturbances	1/22 (4.5%)		2/27 (7.4%)		0/21 (0%)		1/26 (3.8%)		0/21 (0%)		0/26 (0%)
Increased Saliva	1/22 (4.5%)		1/27 (3.7%)		0/21 (0%)		0/26 (0%)		0/21 (0%)		0/26 (0%)
Decreased Saliva	0/22 (0%)		2/27 (7.4%)		0/21 (0%)		0/26 (0%)		0/21 (0%)		0/26 (0%)
Other	4/22 (18.2%)		5/27 (18.5%)		2/21 (9.5%)		2/26 (7.7%)		1/21 (4.8%)		7/26 (26.9%)
Musculoskeletal and connective tissue disorders
Fatigue	4/22 (18.2%)		1/27 (3.7%)		0/21 (0%)		0/26 (0%)		2/21 (9.5%)		3/26 (11.5%)
Muscle Cramps	3/22 (13.6%)		3/27 (11.1%)		2/21 (9.5%)		0/26 (0%)		1/21 (4.8%)		5/26 (19.2%)
Renal and urinary disorders
Urinary Frequency	2/22 (9.1%)		4/27 (14.8%)		0/21 (0%)		0/26 (0%)		0/21 (0%)		4/26 (15.4%)
Respiratory, thoracic and mediastinal disorders
Upper Respiratory Tract Infection	4/22 (18.2%)		3/27 (11.1%)		0/21 (0%)		1/26 (3.8%)		0/21 (0%)		0/26 (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.