Clinical trial NCT01341080: Varenicline for Gait and Balance Impairment in Parkinson Disease
Official title: Varenicline for the Treatment of Postural and Gait Dysfunction in Parkinson Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Parkinson Disease
Keywords: Balance
Postural impairment
Falls
Parkinson Disease
Lead sponsor: Rush University Medical Center
Sponsor class: OTHER
First posted: 2011-04-25
Enrollment: 40
Sex: ALL
Minimum age (years): 40
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine if varenicline is effective in improving gait and balance impairment in patients with Parkinson disease.

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Berg Balance Scale
timeFrame: 9 weeks
Secondary outcomes:
measure: Frontal Assessment Battery
timeFrame: 9 weeks
measure: Mini Mental Status Exam (MMSE)
timeFrame: 9 weeks
Other outcomes:
Locations:
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
Study officials:
affiliation: Rush University Medical Center
name: Deborah A Hall, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bohnen NI, Muller ML, Koeppe RA, Studenski SA, Kilbourn MA, Frey KA, Albin RL. History of falls in Parkinson disease is associated with reduced cholinergic activity. Neurology. 2009 Nov 17;73(20):1670-6. doi: 10.1212/WNL.0b013e3181c1ded6.
citation: Qutubuddin AA, Pegg PO, Cifu DX, Brown R, McNamee S, Carne W. Validating the Berg Balance Scale for patients with Parkinson's disease: a key to rehabilitation evaluation. Arch Phys Med Rehabil. 2005 Apr;86(4):789-92. doi: 10.1016/j.apmr.2004.11.005.
citation: Zesiewicz TA, Sullivan KL. Treatment of ataxia and imbalance with varenicline (chantix): report of 2 patients with spinocerebellar ataxia (types 3 and 14). Clin Neuropharmacol. 2008 Nov-Dec;31(6):363-5. doi: 10.1097/WNF.0b013e31818736a9.
citation: Perez XA, Quik M. Focus on alpha4beta2* and alpha6beta2* nAChRs for Parkinson's Disease Therapeutics. Mol Cell Pharmacol. 2011;3(1):1-6.
citation: Bohnen NI, Albin RL. The cholinergic system and Parkinson disease. Behav Brain Res. 2011 Aug 10;221(2):564-73. doi: 10.1016/j.bbr.2009.12.048. Epub 2010 Jan 7.
citation: Karachi C, Grabli D, Bernard FA, Tande D, Wattiez N, Belaid H, Bardinet E, Prigent A, Nothacker HP, Hunot S, Hartmann A, Lehericy S, Hirsch EC, Francois C. Cholinergic mesencephalic neurons are involved in gait and postural disorders in Parkinson disease. J Clin Invest. 2010 Aug;120(8):2745-54. doi: 10.1172/JCI42642. Epub 2010 Jul 12.