Effects of Cholinergic Augmentation on Measures of Balance and Gait

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.

Study Overview

• Status: Completed
• Conditions: Parkinson's Disease
• Intervention / Treatment: Drug: Donepezil

• Study Type: Interventional
• Enrollment (Actual): 49
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Oregon
    • Portland, Oregon, United States, 97239-3098
      • Oregon Health & Science University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Secondary Outcome Measures

Outcome Measure	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).	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

Collaborators and Investigators

• Sponsor: Oregon Health and Science University
• Collaborators: Michael J. Fox Foundation for Parkinson's Research
• Investigators: Principal Investigator: John Nutt, M.D., Oregon Health and Science University

Publications and helpful links

General Publications

• 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.

Helpful Links

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

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2014
• Primary Completion (Actual): July 1, 2017
• Study Completion (Actual): July 1, 2017

Study Registration Dates

• First Submitted: July 29, 2014
• First Submitted That Met QC Criteria: July 31, 2014
• First Posted (Estimate): August 1, 2014

Study Record Updates

• Last Update Posted (Actual): November 14, 2019
• Last Update Submitted That Met QC Criteria: November 11, 2019
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Parkinson Disease; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Cholinergic Agents; Enzyme Inhibitors; Nootropic Agents; Cholinesterase Inhibitors; Donepezil
• Other Study ID Numbers: 9437

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided