The purpose of this study is to determine if varenicline is effective in improving gait and balance impairment in patients with 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 United Kingdom (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 monoamine oxidase inhibitors (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.

36 participants were randomized. Six participants terminated participation early with 2 having sufficient data for last observations carried forward. 32 were used in the analysis and demographics are reported here.

Adverse events were collected throughout subject participation (e.g. 9 weeks).

Definition: Any untoward or unfavorable medical occurrence in a participant, including any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the participant's participation in the research, whether or not considered related to the participant's participation in the research. During follow-up visits and phone calls subjects were asked if they had experienced any problems and/or side effects since their last visit.

The sensitivity of the BBS is poor to moderate, with frequent uncertainty in its scoring; The study also faced challenges in recruitment, which was slow and spanned 8 years, potentially biasing the sample; High attrition resulted in a smaller sample size than estimated by power analysis; Although the authors intended to recruit tremor predominant and PIGD patients in equal numbers, the PIGD subtype was overrepresented. Thus, the PIGD subtype was unintentionally favored.