Varenicline for the Treatment of Postural and Gait Dysfunction in Parkinson Disease
Phase: PHASE2
Conditions: Parkinson Disease
Sponsor: Rush University Medical Center

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Revision date: 7-26-2011
PROTOCOL
Study Title
Varenicline for the treatment of postural and gait dysfunction in Parkinson Disease (PD).
Objectives
To determine if varenicline is effective for abnormalities in balance and posture in PD.
Design and Outcomes
The design is a randomized, double-blinded, placebo-controlled study conducted at one 
center.  The primary outcome is the change in the Berg Balance Scale.  Secondary 
outcomes include the Activities-specific Balance Confidence Scale, Parts I-III of the 
MDS-UPDRS, the Timed up and go test, the Folstein Mini Mental Status Exam (MMSE), 
the Beck Depression Inventory, the Beck Scale for Suicidal Ideation, the Frontal 
Assessment Battery (FAB), and total number of falls.
Interventions and Duration
Subjects will be randomized to placebo or varenicline with an escalation phase of one 
week (0.5 mg daily for three days, 0.5 mg twice daily for four days, then 1 mg twice a 
day to begin at week two).  The rating scales will be performed before initiation of the 
drug, and then the subject will remain on drug for eight weeks after which outcomes will 
be reassessed.
Sample Size and Population
Sample size is estimated to be 38 patients; however 42 will be recruited to allow for 
attrition.  All patients will have been diagnosed with PD using the UK Brain Bank 
Criteria.  There will be no stratification of randomization.
STUDY OBJECTIVES
Primary Objective
The hypothesis tested is that varenicline will result in improvement of balance and 
postural instability after eight weeks of treatment compared to placebo.  The null 
hypothesis is that there will be no difference in tests of balance between subjects on 
placebo compared to those on varenicline using the Berg Balance Scale as the primary 
outcome.  The primary and secondary outcomes will be performed by the site investigator 
who will be blinded to treatment.
Secondary Objectives
There are two secondary hypotheses.  First, we hypothesize that subjects with the 
postural-instability-gait disturbance (PIGD) subtype of PD will be more responsive to 
treatment compared to the tremor-predominant subtype.  Patients will be categorized with 
tremor-predominant PD if the ratio of the mean tremor score to the mean PIGD score is 
ORA: 10072203-IRB01   Date IRB Approved: 5/4/2011   Amendment Date: 8/23/2011
1.5 or higher and as PIGD predominant if the ratio is 1 or lower.  The mean PIGD score 

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will be defined as the sum of an individual
's baseline falling, freezing, walking, gait and 
postural stability UPDRS scores divided by five.  
The second hypothesis is that varenicline will improve cognitive functioning in 
PD subjects.  This hypothesis will be tested by comparing the results from the MMSE 
and the FAB at the beginning of the study, at four weeks, and at eight weeks.  
BACKGROUND
Rationale
Parkinson disease (PD) is a clinical entity characterized by bradykinesia, rigidity, tremor, 
and postural instability.  Current treatments primarily focus on replacement of dopamine 
to compensate for the degeneration of the substantia nigra pars compacta dopaminergic 
neuronal population.   Though dopamine treats many of the motor symptoms of PD, 
postural instability (which often leads to falls) typically is least responsive to therapy.  
PD affects 2,000,000 people in the United States.  It affects 49.7 per 100,000 person-
years for those over age 50.
6  The incidence of falls is estimated to be as high as 69% in 
PD patients.
7 Clearly falls in this population can lead to significant sequelae of fractures, 
prolonged hospitalization, and associated medical complications.
Varenicline (Chantix) is a novel partial α4β2 agonist and full α7 agonist developed as an 
aid for smoking cessation and has been shown in initial studies to improve imbalance in 
patients with inherited spinocerebellar ataxia.   Recently, the degeneration of the 
cholinergic system arising from the pedunculopontine nucleus (PPN) in the brainstem has 
been implicated in gait dysfunction in PD.  Striatal cholinergic inputs are supplied from 
the PPN both via the intralaminar complex of the thalamus and through direct inputs.  
The primary subtypes of cholinergic receptors present in the striatum are nicotinic and 
include α4β2, α6β2, and α7 receptors.  Varenicline has been reported in case reports to be 
effective in ataxia for patients with Spinocerebellar Ataxia types 3 and 14, the Fragile-X 
Associated Tremor/Ataxia syndrome (FXTAS), as well as improving subjective 
proprioception in Friedreich’s Ataxia.  Varenicline was given at 1mg twice a day and 
showed improvement on the Scale for the Assessment and Rating of Ataxia (SARA) 
scale.  Other medications used for balance and prevention of falls in PD have not been 
shown to be helpful and thus the mainstay of treatment involves physical therapy.
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The dosage escalation medication regimen in this protocol is similar to those studies 
conducted for smoking cessation and for ataxia.  The active medication will be dosed 
twice daily (1 mg BID) due to convention, though the half-life of the drug is listed as 24 
hours.  A week of dose escalation will allow for maximal tolerability.  The worsening of 
neuropsychiatric symptoms reported in some patients with other disorders on varenicline 
appears to be isolated in patients with prior psychiatric conditions, but this has not always 
been the case.  In order to monitor for this potential side effect and to screen for potential 
sub-clinical depression, the Beck Depression Inventory will be given to all subjects and 
followed during the course of the study.  Suicidal ideation and attempt has also been 
reported in patients taking varenicline, so the Beck Scale for Suicidal Ideation will also 
be administered to participants during the course of the study.  There are no aspects of the 
ORA: 10072203-IRB01   Date IRB Approved: 5/4/2011   Amendment Date: 8/23/2011
proposed dosing schedule that are not FDA-approved for other indications.  This study is 

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of high priority due to the absence of any proven medications to treat imbalance in this 
disorder.
STUDY DESIGN
This is a randomized, double blind, placebo controlled parallel-designed study.  
Varenicline was chosen because of its novel mechanism of action and its preliminary 
success in treating some forms of hereditary ataxia.  This will be the first clinical trial 
testing varenicline in patients with Parkinson Disease.  The specific nicotinic cholinergic 
receptors varenicline targets are located in the human striatum with afferent cholinergic 
input arising from the brainstem where the locomotor center of the brain is thought to 
originate.  The direct and indirect effects on these receptors may provide a mechanism to 
improve postural instability and imbalance in this patient population.
SELECTION AND ENROLLMENT OF SUBJECTS
Inclusion criteria:
Subjects will be diagnosed with Parkinson Disease (PD) by the UK Brain Bank 
criteria.
Subjects will have to be at least stage 2 on the Hoehn and Yahr staging system of 
PD and have a history of at least 1 fall or near fall in the last 6 months.
Subjects must have a stable medication regimen.
All subjects will be over the age of 40 in an attempt to exclude inherited forms of 
parkinsonism.
Serum creatine kinase, complete metabolic panel, complete blood count, liver 
function tests, renal function tests, platelets and EKG are within normal limits 
(results obtained from primary care physician and dated within the past 6 months 
or obtained at screening visit).
Exclusion criteria:
Hoehn and Yahr stage 5 subjects.
Subjects with a history of major psychiatric disorder, deep brain stimulation 
surgery, recent cerebral trauma, cardiac arrhythmia, or renal insufficiency.
a cardiovascular procedure in the last 5 years (eg, percutaneous transluminal 
coronary angioplasty) or have cardiovascular instability (including myocardial 
infarction or unstable angina). Other cardiovascular exclusions include 
uncontrolled hypertension, significant neurological sequelae of cerebrovascular 
disease, peripheral vascular disease with prior amputation, or severe congestive 
heart failure (New York Heart Association class III or IV).Concurrent treatment 
with any MAOIs, bupropion (Wellbutrin), or nicotine patches. 
Dementia or other psychiatric illness that prevents the patient from giving 
informed consent (MMSE score less than 25). 
Concurrent treatment with trihexyphenidyl (Artane) or benztropine mesylate 
(Cogentin).

ORA: 10072203-IRB01   Date IRB Approved: 5/4/2011   Amendment Date: 8/23/2011
Significant degree of dysphagia, by history.

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Legal incapacity or limited legal capacity. 
Presence of severe renal disease (BUN 50% greater than normal or creatinine 
clearance <60 mL/min) or hepatic disease. 
Abnormal creatine kinase and/or platelet count in the past 6 months (as 
determined by lab reports obtained from primary care physicians or conducted at 
baseline). 
Use of varenicline within the previous 30 days. 
Women of childbearing potential who are pregnant at the time of screening or 
who will not use adequate contraception during participation in the study.
Allergy/sensitivity to the drug or its formulations.
Concurrent participation in another clinical study.
Active substance or tobacco use or dependence.
moderate or severe chronic obstructive pulmonary disease
Serious illness (requiring systemic treatment/or hospitalization)  
until the subject 
either completes therapy or is clinically stable on therapy, in the opinion of the 
site investigator, for at least 60 days prior to study entry.
Inability or unwillingness of the subject or legal guardian/representative to give 
written informed consent.
Study Enrollment Procedures
Patients with Parkinson Disease (PD) will be recruited through the Movement Disorders 
clinic located at the Neuroscience Institute at Rush University Medical Center.  There are 
eight movement disorders attending physicians and three fellows who see approximately 
4800 new and follow-up PD patients per year.  Recruitment goals are expected to be 
predominantly achieved through the cohort of individuals seen at Rush, but advertising 
may also be conducted through monthly PD support group meetings or newsletters to 
enhance enrollment.  Potential subjects may be identified by their treating physician in 
the Movement Disorders Clinic at Rush or referred to Rush from elsewhere.  If a patient 
is interested in enrolling in this study, he/she will be invited to an initial study visit, at 
which time he/she will provide informed consent after a full explanation of the study.
Documentation of inclusion and exclusion criteria will occur if the patient is 
interested in enrollment.  Eligible subjects who refuse participation will be given the 
option of later enrollment if desired.
Much of recruitment will occur from physicians who have a treatment 
relationship with the patient.  Prior to the consent process, the Mini Mental State 
Examination will be performed to determine the patient’s level of comprehension.  If the 
potential subject scores less than 25, the patient will be excluded from the study.  Consent 
will be obtained by the primary investigator and the potential subject.  All investigators 
are trained in the conduct of human research.  A copy of the consent form will be 
provided to all subjects.
The independent medical monitor will be responsible for obtaining group 
ORA: 10072203-IRB01   Date IRB Approved: 5/4/2011   Amendment Date: 8/23/2011
assignments.  The assignment will be masked to the PI, the treating physician, the 

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subject, and all other staff conducting the study.  The medical monitor will be responsible 
for correct drug dispensing for each subject based on randomization.
STUDY INTERVENTIONS
Interventions, Administration, and Duration
42 subjects will be randomized to receive 1 mg twice daily of oral varenicline or matched 
placebo.  The therapeutic dose will be escalated over the first week as 0.5 mg daily for 
three days, and then increased to 0.5 mg twice daily for the next four days.  Thereafter, 
subjects will continue on 1 mg twice daily for the remaining eight weeks.  The outcome 
measures will be assessed at the end of week 5 and then repeated at the conclusion of the 
study.  Side effects will be monitored at each of the encounters with the subject, either in 
person or by telephone.  The most common expected side effects include nausea, 
insomnia, abnormal dreams, or headache.  Subjects will be evaluated in the outpatient 
Movement Disorders Clinic at Rush University at the initiation and conclusion of the 
study.  All patients may remain on other medications for neurologic signs (with the 
exception of those mentioned in the exclusion criteria), but the dose of these medications 
must remain stable during the duration of the study. 
The Handling of Study Interventions
The drug and placebo will be manufactured by Pfizer.  Placebo has similar taste and color 
to the active drug.  The drug and placebo will then be shipped to Rush University, and 
dispensed to the study team who will distribute them to the subjects as described above.  
The medication will be stored at room temperature in a climate-controlled room which 
will be secured by lock.  The pills will be dispensed to the subjects in pill bottles.  For the 
escalation phase, subjects will receive one pill of 0.5 mg daily for three days, then two 
pills daily for the next four days, then two pills of 1 mg for the remaining 56 days.  
Subjects will be asked to return any unused medication after nine weeks to Rush 
University.  Study intervention accountability records will be completed according to the 
Manual of Operations.  The subject, investigators, and study staff will be blinded to the 
treatment arm of each subject.  The study team dispensing the drug and the independent 
medical monitor will disclose the randomization to the investigators after the database 
has been locked at approximately three months.
Concomitant Interventions
Medications for neurological signs of Parkinson Disease must remain stable during the 
nine weeks of this study.  The only contraindicated intervention is deep brain stimulation 
surgery.
Required Interventions: oral varenicline 1 mg twice daily or placebo twice daily.
Prohibited Interventions: concomitant use of trihexyphenidyl (Artane) or 
benztropine mesylate (Cogentin).
Modifications to the study intervention can only occur during the open label 
escalation phase.
ORA: 10072203-IRB01   Date IRB Approved: 5/4/2011   Amendment Date: 8/23/2011
Adherence Assessment

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Adherence will be assessed by pill counts and adherence questionnaires that will be 
completed at each of the study visits.  Because the study is using an intent-to-treat 
analysis, adherence will be reported using descriptive statistics.
CLINICAL AND LABORATORY EVALUATIONS
Timing of Evaluations
Subjects will be consented and have initial laboratory studies and rating scales at the 
entry visit.  Once on the study medication, they will be contacted by phone at three weeks 
for questions regarding side effects, clinical issues, and to answer any questions.  The 
subject will be reassessed after five weeks for depression or suicidal ideation, and they 
will continue with the intervention or placebo.  Again, they will be contacted by phone at 
week seven to assess for safety and tolerability.  They will be seen at nine weeks and 
outcome measures will be performed.
Table 1. Timing of Evaluations
Evaluation
Screening
Entry
Week 3
Week 5
Week 7
Week 9
Informed Consent
X
Documentation of PD
X
Medical/Treatment Hx
X
Inclusion/Exclusion
X
Clinical Assessment
X
Neurological Exam
X
Adherence Assessments
X
X
X
X
Questionnaires
MDS-UPDRS and other 
rating scales
X
X
Beck Depression/suicide 
scales
X
X
X
Mental Status exam
X
X
FAB
X
X
EKG
X
Pre-Randomization Evaluations
These evaluations occur prior to the subject receiving any study interventions.
Screening
At the screening visit, the diagnosis of Parkinson disease will be confirmed and medical 
history will be reviewed.  Inclusion and exclusion criteria will be completed.
Pre-Entry
Screening and pre-entry may occur concurrently.  Consent will be obtained.  EKG and 
blood tests will be completed at the visit and randomization will occur.
ORA: 10072203-IRB01   Date IRB Approved: 5/4/2011   Amendment Date: 8/23/2011
On-Study Evaluations

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Blood chemistries, liver function tests, and hematology laboratory tests will be performed 
at two times during the study.  Rating scales for movement disorders and cognitive 
disturbances will be performed twice during the study.  The allowable time window is 
Schedule of Evaluations ± 7 days.
Entry
The entry visit will occur at least two weeks after the screening visit to allow for adequate 
drug supply.  Study drug will be dispensed at the entry visit.
Intervention Discontinuation Evaluations
Evaluations done at the time of discontinuation include blood chemistry, hematology, and 
the rating scales.  In addition, an adherence assessment will also be done.
Post-Intervention Evaluations
Neurological examinations will be performed according to the standard of care by the 
treating neurologist/investigator.
Final Evaluations
The final visit will consist of blood chemistry and hematology, neurological examination, 
rating scales (BBS, MDS-UPDRS, TUG, ABC, MMSE, FAB, BDI, and BSSI), and 
adherence assessment.
Special Instruction and Definitions of Evaluations
The source document will include all of the following listed below:
Informed Consent:  The patient will have an opportunity to review the consent form 
and ask any questions prior to signing the form.  If the patient has dementia, he/she 
will be excluded from the study.  A copy of the signed consent form will be given to 
the subject, and copies will be maintained in the study chart and the hospital record.
Documentation of PD: Diagnosis of PD will be documented in the patient’s chart 
prior to study entry.
Medical History: The subject’s history regarding PD will be obtained or a record of 
this history will be secured for the study chart.  A complete social history, family 
history, and review of systems will also be performed.
Treatment History: Allergies will be reviewed.  Prior and current medications and 
other treatments will be reviewed and documented.
Clinical Assessments: Clinical assessment procedures will be reviewed at the entry 
visit and the neurological examination will be performed.  Clinical assessments to 
review safety, tolerability, and effectiveness will be conducted at each face-to-face 
visit or over the phone.  Neurological examination will occur at the face-to-face visits 
only.  Change in neurological signs or symptoms, adverse events, or tolerability 
issues should be recorded on the CRFs.
Laboratory Evaluations: Blood chemistry and hematology will be performed and the 
resulting laboratory result forms will be placed in the study record.
Questionnaires and Rating Scales: Scoring for each item on the Berg Balance Scale 
ORA: 10072203-IRB01   Date IRB Approved: 5/4/2011   Amendment Date: 8/23/2011
will be recorded in the scoring grid.  Scoring for the MDS-UPDRS, TUG, ABC, 

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MMSE, Beck Depression Inventory, Beck scale for suicidal ideation, and FAB will 
be recorded in the CRF.
Adherence Assessments: Pill counts and questionnaires will be filled out at every 
phone or in-person visit.
Off-Intervention Requirements
Recording of adverse events for subjects after the study will occur in the setting of 
regular care with the treating neurologist.
The Berg Balance Scale
The BBS was designed to measure changes in functional standing balance over time.  
This is a 14-item scale that rates each function from 0 (worst) to 4 (best).  This scale 
measures balance abilities seen during tasks involving sitting, standing, and positional 
changes. Total scores are indicative of overall balance abilities, with scores interpreted in 
the following manner: 0 to 20, wheel-chair bound; 21 to 40, walking with assistance; and 
41 to 56, independent.  The BBS is relatively safe and simple to administer.  It uses a 
quantitative scale format that has strong internal consistency and good inter- and intra-
rater reliability with different patient populations, including brain injury, stroke, and 
geriatric patients.  It has specifically been clinically validated for evaluating postural 
instability in PD patients.
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For this study, improvement will be defined as an 8 point improvement of the scale which 
has been found in one study to be required to reveal a genuine change in function among 
older people who are dependent in activities of daily living and living in residential care 
facilities.
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MANAGEMENT OF ADVERSE EXPERIENCES
The four most common adverse events with varenicline in adult studies are nausea, 
insomnia, abnormal dreams, and headache.  Other side-effects include: constipation, dry 
mouth, flatulence, and dizziness.  Psychiatric side effects have been reported and will be 
strictly monitored.  The four most common placebo side-effects also include: nausea, 
insomnia, abnormal dreams, and headache.  Adverse events will be documented on the 
adverse event form and sent to the independent medical monitor.
CRITERIA FOR INTERVENTION DISCONTINUATION
Criteria and rules for stopping subject treatment include: new toxicological findings or 
serious adverse events, patient withdrawal of consent without need for justification, 
inability of the patient to participate for medical reasons (such as  
surgery), violation of 
eligibility criteria, development of significant neuropsychiatric symptoms such as suicidal 
ideation or psychosis, subject failure to comply with the protocol, development of 
cardiovascular symptoms, new cardiovascular diagnosis, or a cardiovascular event.  
Subjects who stop treatment will still be asked to complete a final visit with rating scales 
and blood work.
STATISTICAL CONSIDERATIONS
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General Design Issues
The primary and secondary outcomes will be analyzed using SPSS.  The independent 
medical monitor will review adverse event data and the final analysis.  There will be no 
interim analysis performed.  The independent medical monitor will not be blinded to 
treatment arm.  There will be no stratification.
Outcomes and Data Analysis
Primary outcome (Aim 1):  The primary hypothesis will be tested using a paired t-test 
using means of the total Berg Balance Scale score before and after treatment.  Linear 
regression will be used to determine if there is an association among outcome, 
gender, age, race, or ethnicity.  This outcome will be determined by the rating of 
patients from a blinded movement disorders neurologist.
Secondary outcomes (Aim 2): Secondary hypotheses will be tested using paired t-
tests on the full MDS-UPDRS, the TUG, and the ABC scale.  For side effect analysis, 
logistic regression will be performed with the treatment arm as the dichotomous 
outcome and the MMSE and FAB as covariates.  In addition, gender and age will also 
be included as covariates.
Side effects (Aim 3): Adverse events will be recorded and classified as to seriousness 
of the side effect and likelihood that the side effect is related to the drug.  Adverse 
events in the treated group versus the untreated group will be compared and any 
events that are significantly more frequent in the treated group will be identified.
Sample Size and Accrual:  Sample size was estimated using published means and 
standard deviations of the BBS in PD subjects
6.  The mean of the rating scale is 40.22 
with a standard deviation of 8.48.  Based on a published effect size of a change of 8 
points, and using a power of 0.80 and a significance of 0.05 with a two sided test, a 
sample size of 19 subjects for each group would be needed for a parallel design.  To 
allow for attrition, 42 subjects will be recruited.  Intent to treat analysis will be 
performed.  The number of subjects lost to follow-up is likely to be low due to the 
relative lack of efficacy of other forms of treatment for this particular symptom of 
PD.  Power for calculating secondary outcomes is lower than 0.8.
Data Monitoring
An independent medical monitor will be established to monitor this study.  An interim 
safety analysis will not be performed.  Guidelines for stopping the study would include 
new toxicological findings of varenicline or serious adverse events reported from the 
subjects on active medication.  The independent medical monitor will meet with the PI as 
needed during the protocol.
DATA COLLECTION, SITE MONITORING, AND ADVERSE EXPERIENCE 
REPORTING
Records to Be Kept
All study forms will be kept at Rush University.  The records will be stored in a locked 
ORA: 10072203-IRB01   Date IRB Approved: 5/4/2011   Amendment Date: 8/23/2011
office of the site investigator.  At the main site, data on the CRF will be entered into a 

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password-protected database.  Access to the database will be restricted to the host site 
CRA, PI, and biostatistician.
Quality Assurance
The PI will meet with the study coordinator once monthly to review records, consent 
forms, protocol compliance, and data quality.  All of the investigators will meet once 
every four months to review issues related to quality.
Adverse Experience Reporting
Adverse events will be recorded on the adverse event CRF and reported within three 
days.  Serious adverse events will be reported within 24 hours.  Detailed definitions of 
adverse experiences, a table for grading their severity, and details of how clinical sites are 
to report them, appear in the Manual of Operations.
HUMAN SUBJECTS
Institutional Review Board (IRB) Review and Informed Consent
This protocol and the informed consent documentation and any subsequent modifications 
will be reviewed and approved by the IRB responsible for oversight of the study.  A 
signed consent form will be obtained from the subject.  Subjects who cannot consent for 
themselves cannot be included in the study.  The consent form will describe the purpose 
of the study, the procedures to be followed, and the risks and benefits of participation.  A 
copy of the consent form will be given to the subject, or legal guardian and this fact will 
be documented in the subject’s record.
Subject Confidentiality
All laboratory specimens, evaluation forms, reports, video recordings, and other records 
that leave the site will be identified only by the Study Identification Number (SID) to 
maintain subject confidentiality.  All records will be kept in a locked file cabinet.  All 
computer entry and networking programs will be done using the SIDs only.  Clinical 
information will not be released without written permission of the subject, except as 
necessary for monitoring by IRB, the FDA, the NINDS, the OHRP, the sponsor, or the 
sponsor’s designee.
Study Modification/Discontinuation
The study may be modified or discontinued at any time by the IRB, the NINDS, the 
sponsor (Pfizer), the OHRP, the FDA, or other government agencies as part of their 
duties to ensure that research subjects are protected.
PUBLICATION OF RESEARCH FINDINGS
Publication of the results of this trial will be governed by the policies and procedures 
developed by the Principal Investigator.
ORA: 10072203-IRB01   Date IRB Approved: 5/4/2011   Amendment Date: 8/23/2011
References

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Parkinson
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3. Gunnell et al. Varenicline and suicidal behaviour: a cohort study based on data 
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6. www.mdvu.org/library/disease/pd/par_epi.asp
7. Tromp AM et al. Predictors for falls and fractures in the Longitudinal Aging 
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8. Morris, Meg E. Movement Disorders in People with Parkinson Disease: A Model 
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9. Qutubiddin AA, et al. Validating the Berg Balance Scale for Patients with 
Parkinson’s Disease. Archive of Physical Medicine and Rehabilitation, Vol 86, 
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10.Conradsson et al. Berg Balance Scale: Intrarater Test-Retest Reliability Among 
Older People Dependent in Activities of Daily Living and Living in Residential 
Care Facilities. 
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PHYS THER; Vol. 87, No. 9, September 2007, pp. 1155-1163.