Clinical trial NCT02206620
Conditions: Parkinson's Disease
Sponsor: Oregon Health and Science University
Start date: 2014-07-01; Completion date: 2017-07-01
Enrollment: 49 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

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.

Detailed description:

Arms: arm 1: Donepezil 5 mg per day for week 1-3 or 12-14. 10 mg/day for weeks 4-6 or 14-18, if tolerated. arm 2: Placebo 5 mg per day for week 1-3 or 12-14. 10 mg/day for weeks 4-6 or 14-18, if tolerated.
Interventions: intervention 1: Donepezil
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 
IRB Document Approval Date: 1/15/2019 
 
NCT Number: NCT02206620 
 
Title: Effects of Cholinergic Augmentation on Measures of Balance and Gait 
 
Principle Investigator: John Nutt 
 


 
Effects of Cholinergic Augmentation on Measures of Balance and Gait 
 
Abstract. We will compare the effects of placebo and donepezil, a cholinesterase inhibitor that 
will enhance the effects of nicotinic and muscarinic cholinergic neurotransmission, on measures 
of standing postural sway, walking variability, and dual-task cost as indices of fall risk in 
Parkinson’s disease (PD) subjects in a double-blind, placebo controlled, cross-over randomized 
clinical trial.  In addition, short-latency afferent inhibition (SAI), a physiological index of central 
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.  
The attention network test will be administered to determine if changes in gait and balance are 
mediated by changes in attention. 
Hypothesis. Cholinergic systems contribute to mobility in Parkinson’s disease (PD). Measures 
of gait and balance will improve in response to cholinergic augmentation with a cholinesterase 
inhibitor, donepezil. 
 
Aim 1. Examine the effects of a cholinesterase inhibitor, donepezil, on physiological 
markers of mobility associated with falls in PD (postural sway in stance and gait variability).  
Aim 2. Determine the effects of donepezil on dual-tasking during postural sway and gait 
variability and on attention using the Attention Network Test. 
Aim 3. Correlate Short-latency Afferent Inhibition (SAI), a transcranial magnetic 
stimulation-induced marker of cortical cholinergic tone, with mobility deficits at baseline and 
with donepezil treatment.   
The results of this study will be the most direct test of the hypothesized role of cholinergic 
neurotransmission in gait and balance.  The study is exploratory because we do not know 
whether donepezil will affect gait, balance or attention, nor which measures of gait, balance or 
attention will be sensitive to drug manipulation.  Our 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 neurotransmission in balance and gait and eventually to 
Phase II B trials to determine clinical utility of cholinergic manipulation to prevent falls and 
improve mobility. 
Mobility disability and falls are common in PD and lack effective treatment.  Gait and 
balance problems appear within 3 years of diagnosis and progress throughout the course of the 
disease.1  Impaired mobility produces disability and reduces quality of life.  Mobility depends on 
control of gait, balance and attention.  Levodopa does not improve, and may worsen, several 
types of balance control. In general, as the disease progresses, levodopa is less efficacious for 
balance, likely because non-dopaminergic systems are impaired later in the disease course.2  
DBS is generally not effective for improving balance or reducing falls.  
Cholinergic systems degenerate in Parkinson’s disease and correlate with gait and balance 
impairments. The dopaminergic system is preferentially affected in PD, but there are also 
changes in the basal forebrain cholinergic complex that provides cholinergic innervations of the 
cortex. In addition, the pedunculopontine (PPN), part of the midbrain locomotor region (MLR), 
has a prominent cholinergic projection to the thalamus and it degenerates in PD.3  PET imaging 
with[11C]PMP, a substrate for acetylcholinesterase, identifies the integrity of cholinergic 
innervation.  Loss of cortical cholinergic markers in PD representing degeneration of the basal 


forebrain is associated with slower gait4 and impairments in working memory, attention and 
executive function.5  In addition, loss of thalamic [11C]PMP, representing loss of PPN 
cholinergic innervation of the thalamus, is related to falls in PD.6  In contrast, the extent of 
dopaminergic denervation of the striatum evaluated by PET imaging was not correlated with 
falls.6  Finally, neurotoxin lesioning of the cholinergic neurons of the PPN induced gait and 
postural abnormalities in monkeys.7 These observations support the need to examine cholinergic 
treatments in PD subjects with gait and balance difficulties.  
The most direct test of the role of cholinergic systems in postural control to date are two small 
clinical trials.  In a randomized, double-blind, crossover clinical trial of a cholinesterase 
inhibitor, donepezil, our group found that donepezil reduced falls in PD patients.8  An open trial 
with another cholinesterase inhibitor, galantamine, also reported decreases in falls and freezing 
of gait (FoG).  But these small clinical trials are not conclusive. 
Intervention. Cholinesterase inhibitors such as donepezil are standard of care for PD patients 
with cognitive impairment.9  We chose donepezil, an FDA approved drug, because it is possible 
to create a placebo for the donepezil tablet and it requires only once a day dosing.  It is 
recommended to start donepezil at 5 mg per day to reduce adverse effects (FDA approved drug 
insert).  We will increase the dose to 10 mg/day after 3 weeks, if tolerated, because that is the 
schedule used in our pilot study and this titration was well tolerated.8  Donepezil has a half-life 
of 70 hours and it requires approximately 15 days to reach steady state.  The maximum effects on 
cognitive measures occur within 3 weeks and loss of effect requires more than 3 weeks and less 
than 6 weeks (FDA approved drug insert).  In our pilot study there were more falls at 3 weeks 
and 5 mg/day of donepezil than at 6 weeks and 10 mg/day of donepezil and 10 mg was more 
effective than 5 mg on cognitive measures in PD.9  Washout between phases will be 6 weeks to 
minimize carry-over of effects.  
Protocol. Subjects will be identified for 
potential recruitment through electronic medical 
record review; directly through OHSU’s 
neurology clinics and through IRB approved 
advertisements.  Subjects will receive the first 
study phase medications from the research 
pharmacy at the end of the baseline testing.  The 
subject will be called weekly to ask about side 
effects or problems with the protocol.  They will 
also be asked about falls.  These contacts will be 
captured in case report forms.  If there are 
problems, the investigator will call the subject 
or the subject will be brought into clinic to 
evaluate the problem.  At 3 weeks, the subjects 
will have a phone call from one of the 
neurologists for safety; adverse events will be 
captured. At 6 weeks, the subject will return to 
the clinic for repeat testing with the measures captured at baseline and also the subjects will have 
ANT and SAI testing. The subject will be tested “off” their PD medications.  
The subjects will then enter the 6-week washout period.  Although the subjects will be on no 
experimental medications, they will continue to be called weekly to inquire about side-effects, 
Figure 1.  Study design 


problems and falls.  This is partly done to keep the subject involved in the protocol, as well as to 
collect data about falls.  At the conclusion of the 6 weeks, the subjects will return to the clinic for 
repeat testing and to have medications dispensed for the final 6-week phase of the protocol. The 
final 6-week phase will be conducted exactly as was the first six-week phase with repeat testing 
at the end of the 6 weeks.  
Subjects. Subjects will be 30 years or older, of either gender and any racial or ethnic origin.  
Women who are capable of child bearing must employ birth control.  Pregnant women are not 
eligible to participate.  The subjects will have idiopathic Parkinson’s disease as determined from 
history and exam and lack of history or physical findings that would suggest another diagnosis or 
a parkinsonism-plus syndrome.  Subjects may be Hoehn and Yahr stages II to IV.  Subjects must 
be able to stand unassisted for a minute and to walk continuously for 2 minutes without 
assistance or assistive devices.  The subjects must have a Montreal Cognitive Assessment 
(MOCA) of 23 or above and be judged to be able to appreciate the purpose of the research, give 
informed consent to participate, be able to cooperate with the testing and be compliant with 
taking the experimental medications. 
Exclusion criteria include:  significant tremor which would interfere with recording balance and 
walking; other factors affecting gait such as musculoskeletal disorders (particularly symptomatic 
hip, knee and lumbar osteoarthritis), uncorrected vision disturbance, vestibular problems or any 
other health problem judged to interfere with participation. Major depression, hallucinations or 
other psychiatric disturbances will be exclusions. Medical problems that might be worsened by 
donepezil are exclusion criteria and include tachycardia, bradycardia, arrhythmias, and peptic 
ulcer disease.  Finally, use of anticholinergics for parkinsonism, cholinesterase inhibitors for 
cognitive problems, bladder antispasmodics for urinary urgency or tricyclic antidepressants for 
depression are contraindications because of their cholinergic actions. 
Measures and Outcomes. Falls are a difficult endpoint for clinical trials because the data comes 
from patient self-reports and in most patients, falls occur infrequently.  Falls also depend upon 
patient activity and falls may be reduced if patients are less active.  Finally, falls are generally 
multi-factorial so that the environment and context, as well as posture, gait and attention play a 
role in falls.  Because of these problems with falls as an index of disturbed mobility, we plan to 
use two physiological measures associated with falls as surrogate markers for fall risk rather than 
fall counts.  These markers are: 1) increased sway while standing and enhancement of the sway 
by dual tasking, 2) increased gait variability and augmentation with dual-tasking.   
Measurement Device.  Balance and gait kinematic performance will be recorded by small, 
body-worn, inertial sensors, called ‘Opals.’10  The Opals consist of wireless, synchronized, 
triaxial accelerometers and gyroscopes that record body motion at 120 Hz.  The Opals will be 
applied bilaterally to the ankles and wrists as well as to the sternum and pelvis with Velcro belts. 


Postural sway is sensitive to mild PD and progression of 
disease.  Thirteen early, untreated PD subjects with normal gait 
speed and no complaints of imbalance and 13 age-matched control 
subjects were tested with accelerometers on their belt while they 
stood with eyes open for 30 seconds.  Of the 42 different measures 
of postural sway captured with the inertial sensors, mean velocity 
(MV), root mean square of sway frequency (RMS) and jerkiness of 
sway best separated PD from control subjects.11  Postural sway 
measures were abnormal, even when neither the patient nor the 
treating neurologist noted balance problems.  Thus, objective 
measures of postural sway may reflect small changes in neural 
control of balance.  Five of these early PD subjects who did not 
start antiparkinsonian medication and the 13 healthy control 
subjects were followed for 12 months (Fig. 2). Postural sway 
velocity, jerkiness, and mediolateral sway range increased across the year in the untreated PD 
subjects but did not change in age-matched control subjects.12   
Balance Protocol. Standing balance will be studied in six conditions: with subjects standing on 
the floor and on foam, with eyes open and eyes closed, and with or without dual tasking.  
Gait variability is a sensitive measure of postural stability during walking.  Gait variability 
is the fluctuation or variability from step to step 
in the time to step, stride length, stride velocity 
and double support time.13  Variability of stride 
time reflects dynamic postural control during 
gait as lateral foot placement and double support 
time varies from step-to-step to compensate for 
excessive body center of mass (CoM) 
displacement.13  Gait variability is larger in 
elderly fallers than non-fallers and is not related 
to fear and compensatory changes in gait.14  
Gait variability is present in PD and is related to 
severity of PD motor signs and is a surrogate for 
fall risk. 2,15 Variability of step time and double 
support time are independent of gait speed 
unlike variability of stride velocity and stride 
length.16  Some aspects of gait variability are responsive to levodopa15 but others are not, 
suggesting that gait variability may reflect disturbances in non-dopaminergic circuits as well.2  
We examined gait variability during a 2-minute walk in 20 PD subjects and 20 age-matched 
control subjects as part of an ongoing trial.  The coefficient of variation of stride duration and 
cadence were significantly larger in the PD group.  Figure 3 illustrates the variability in stride 
duration for each stride during a 2-minute walk for a representative subject with PD and an age-
matched control subject.  The PD subject’s stride time was longer (1.04 vs 0.98 sec), 
representing slower gait and more variable with a larger coefficient of variation (3.26 vs 1.59) 
than the control subject.   
Gait Protocol.  Gait control measurements will rely upon the ankle gyroscopes for spatial and 
temporal gait measures with stride time variability the primary gait outcome. Subjects will walk 
Figure 2.  Group mean sway 
velocity across 12 months in 
Untreated PD and Control group. 
Figure 3.  Example of coefficient of variation of stride 
duration from a representative PD and control subject. 


at their natural pace down a 20-meter long hallway, turn around at the end and return to the 
starting point and then continue walking back and forth for two minutes.  The 180-degree turns 
during the walking are automatically detected and analyzed separately by Mobility Lab.   
Dual Tasking Unmasks Instability.  There is abundant evidence that gait and balance are under 
cortical control, requiring attention, as demonstrated in studies of gait and balance with 
concurrent mental tasks (dual-tasking).17  Dual tasking increases measures of gait instability in 
patients with PD.18 These observations indicate that cholinergic drug effects could be mediated 
by altering the ability to dual task and thereby influencing the risk of falling.  
Dual Task Paradigm.  The effects of dual tasking on sway and gait variability will be assessed 
with a mental task of counting backwards by 3s from various starting numbers. While 
performing the mental task, subjects will wear a small microphone connected to a small, custom-
made computer with voice recording to record their performance on the mental task. Responses 
will be recorded for accuracy.  Subjects will perform the counting backwards by 3s as a single 
task while sitting and then during standing and walking.  This will allow calculating the dual-task 
costs on balance and walking.18   
Attention.  Deficits in attention are 
related to fall frequency.19  Attention 
may be envisioned as having three 
separable aspects: alerting, orienting 
and executive control.20  These aspects 
of attention can be tested with the 
Attention Network Test.20  Our 
collaborator, Dr. Dimitrova examined 
the ANT in 9 normal and 16 non-
demented (MMSE score >25) PD 
subjects in both the “on” and “off” 
state.  All three attention networks 
were affected in PD (p<0.05).  This 
observation indicates that the ANT is 
a sensitive method to detect attention 
dysfunction in non-demented PD. 
Attention Network Test.  Attention will be tested with the Attention Network test, a 15-minute, 
computerized test that examines the effects of cues and targets within a single reaction time task 
to provide a means of exploring the efficiency of the alerting, orienting, and executive control 
networks involved in attention.20 
Short-latency afferent inhibition (SAI).  SAI will provide an estimate of the extent of 
cholinergic dysfunction in our subjects at baseline as well as the efficacy of our interventions on 
central cholinergic function. Median nerve stimulation 19 to 30 milliseconds prior to 
contralateral motor cortex stimulation with transcranial magnetic stimulation (TMS) attenuates 
the motor evoked potentials in hand muscles.  This inhibition, termed short-latency afferent 
inhibition (SAI), has been related to cholinergic function by neurochemical and pharmacological 
studies. Alzheimer’s disease (AD), Down’s syndrome, dementia with Lewy bodies and 
Parkinson’s disease with REM behavioral disorder, disorders associated with loss of cholinergic 
markers, have reduced SAI, whereas frontotemporal dementia, which is not associated with loss 
 
 Figure 4A. Reaction time.  Both PDmed and PDnomed showed longer mean 
RT than the control subjects (p < 0.001). B. Error rates. PDmed had higher 
error rates than the controls for all three targets. 


of cholinergic markers, does not have alterations in SAI.21 SAI is reduced or abolished by an 
acute dose of the antimuscarinic agent, scopolamine, in normal individuals. In AD subjects who 
had reductions in SAI, the response to a single dose of a cholinesterase inhibitor, 3 mg of 
rivastigmine, predicted the response to long-term anticholinesterase inhibitor treatment; those 
subjects who had an improvement in SAI with the single dose of cholinesterase inhibitor 
improved with long-term therapy.22 These observations suggest that SAI may identify subjects in 
our study who have cholinergic deficits as well as be an indicator of the effects of our 
cholinergic interventions.  
Monitoring Activity at Home.  Monitoring activity at home will be accomplished with the 
small inertial sensors that the subject will be asked to wear on their belt and/or a limb.   
Clinical Measures.  UPDRS, MOCA, , ABC, PDQ-39 total index and mobility domain 
subscores and falls recorded during the study will be collected.   
Data Analysis. A linear mixed model will be used to analyze a crossover with repeated measures 
design that includes treatment effects, random effects of treatment sequence within subjects and 
random effects of subjects within treatments.  The observations on each subject are repeated 
measures (week 0 and 6) under different treatment conditions.  Since in a typical experiment 
using repeated measures, two measurements taken at adjacent times are more highly correlated 
than two measurements taken several time points apart, we will use Bayesian Information 
Criterion (BIC) to explore optimal covariance structure for the model.  The main focus of the 
study is to determine how the two treatments outcomes change over time, I.E. time by treatment 
interaction effect.  Generalized least square (GLS) and restricted maximum likelihood (REML) 
will be used to estimate treatment effects and random effects, respectively.  In crossover designs, 
missing data have much greater influence on the analysis than they would in a parallel groups 
design especially when missing data are not at random such as drop-outs due to the adverse 
effects of treatments.  We will analyze two separate data sets in order to evaluate the impact of 
missing/non-response.  One data set includes all patients who received at least one study drug 
and another data set only includes the patients who complete the complete treatment sequence.   
Interpretation. We are especially interested in determining whether gait and balance are directly 
influenced by cholinergic manipulation or whether changes in attention capacity are primarily 
responsible for changes in balance and gait.  If, for example, we find that ability to balance and 
walk during dual tasking is altered out of proportion to changes during standing and walking 
without dual tasking, it would suggest that cholinergic systems mainly contribute to attentional 
capacity required for balance and gait.  Because of the evidence linking executive dysfunction 
with gait disorders, we expect that the executive attention which has been related to falls and to 
gait may be affected out of proportion to alerting and orienting aspects of attention although 
Posner and colleagues have linked alerting to cholinergic function.   
Privacy, Confidentiality and Data Security. Standard institutional practices will be followed as 
described in the OHSU Information Security and Research Data Resource Guide 
(http://ozone.ohsu.edu/cc/sec/isg/res_sec.pdf) to maintain the confidentiality and security of data 
collected in this study. Study staff is, and will continue to be, trained with regard to these 
procedures. Paper files will be stored in locked filing cabinets in restricted access offices at 
OHSU. Electronic data is stored on restricted drives on the OHSU network and on encrypted 
F


computers. Access to data/specimens is restricted to study personnel and requires OHSU 
ID/password authentication. 
Upon enrollment, subjects will be assigned a code that will be used instead of their name, 
medical record number or other personally identifying information. Electronic files for data 
analysis will contain only the subject code.  
Codes will not contain any part of the 18 HIPAA identifiers (initials, DOB, MRN, etc.)  
The key associating the codes and the subjects personally identifying information will be 
restricted to the PI and study staff. The key will be kept secure on a restricted OHSU network 
drive a in a limited access folder. 
Data will be transferred to/from The Michael J. Fox Foundation in files using encryption. The 
data released to the Michael J. Fox Foundation will include only de-identified (coded) data.  
Data Safety Monitoring Plan (DSMP). There are three safety issues.   
1. Adverse effects of donepezil.  Donepezil is widely used in PD at the doses proposed in this 
trial. We anticipate GI effects (anorexia, nausea, diarrhea and vomiting), muscle cramps, 
insomnia and mild worsening of tremor, which occur commonly but are mild.  Serious but rare 
adverse events include exacerbation of peptic ulcer disease and bradycardia.  Drs. Nutt and 
Chung will personally call each patient to discuss any reported side-effects and work with 
patients on strategies to reduce discomfort. 
2. Fall risk during gait and balance testing.  Subjects are chosen who can ambulate 
independently. Testing is conducted with a research coordinator who is trained to be able to 
assist subjects during testing.  If a subject has precarious balance the research assistant will 
obtain backup assistance and use a safety belt for further safety.   
3.  Short-latency afferent inhibition is performed with transcranial magnetic stimulation.  
Subjects  with a history of recurrent seizures will be excluded.  TMS will occur in the hospital, 
close to emergency care if necessary.  The short-latency afferent inhibition is measured at times 
that exceed the time for a stimulus at the wrist to reach the sensory cortex.  Thus a 
somatosensory evoked potential will be measured at baseline.   
 
Drs. Chung and Nutt will record adverse events and report to the IRB unexpected or serious 
adverse events.  An independent neurologist will review the reported adverse events each six 
months and make recommendations to the trial leadership as well as the IRB about advisability 
of continuation of the trial, changing the protocol or other safety concerns.  Dr. Steve Johnson, 
MD, PhD, a member of the OHSU movement disorder section but with no other connection to 
the clinical trial will serve as the Safety Monitoring Officer.  
 
References 
 
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