Varenicline for Gait and Balance Impairment in Parkinson Disease

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. More 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 (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. The
unique method of action of varenicline may make it an ideal drug for the treatment of
balance impairment in PD.

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 V 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 (Folstein Mini Mental Status Exam score less than 25).

- Concurrent treatment with trihexyphenidyl (Artane) or benztropine mesylate
(Cogentin).

- Significant degree of dysphagia, by history.

- 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 protection during participation of 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.