Crossover Target Engagement Study of Cholinergic Mechanisms of Gait Dysfunction in Parkinson's Disease (Project #3 - Experiment 3 [UdallP3E3])
Condition: Parkinson's Disease
MeSH terms: Parkinson Disease
Intervention: Varenicline; Placebo
Intervention description: Initial 0.25 mg oral dose of varenicline administered with monitoring over 4 hours, then total daily dose escalated over the next 2 days until final 0.5 mg BID oral varenicline administered for the remaining 3 weeks.; Initial placebo oral dose administered with monitoring over 4 hours, then total daily dose escalated over the next 2 days until final placebo BID dosing administered orally for the remaining 3 weeks.
Intervention MeSH terms: Varenicline
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 34.0
Sex: All
Minimum age: 45 Years
Healthy volunteers: No

Summary:

      With an appropriate oral dose of Varenicline (VCN) identified from experiments 1 & 2 of the
      study (see NCT02933372), the investigators will administer VCN to Parkinson Disease (PD)
      participants to determine if VCN improves walking speed and measures of balance. PD
      participants will receive VCN or a placebo (fake drug) for 3 weeks to assess the effects of
      VCN administration on gait speed and balance. Participants will undergo examinations to
      assess the intensity of their Parkinsonism and asked questions to assess their mood and
      thinking.
    

Eligibility criteria:

        Inclusion Criteria:

          1. PD diagnosis will be based on the United Kingdom Parkinson's Disease Society Brain
             Bank Research Center (UKPDSBRC) clinical diagnostic criteria. The investigators will
             enrich the cohort by recruiting subjects at modified Hoehn and Yahr stages 2 or
             higher, duration of motor disease 5 years or longer, age >65 years, or the Postural
             Instability and Gait Disorder (PIGD) phenotype. Duration of motor disease will be
             defined as the time between onset of motor symptoms and time of entry into the study.
             The PIGD phenotype is defined as described previously. PD subjects with defined
             cholinergic deficits will be recruited as described in Project II. PD subjects will
             have cortical cholinergic deficits based on 5th percentile cutoff of the normal
             controls as defined previously.

          2. Stable dopaminergic replacement therapy for 3 months prior to enrollment and expected
             to maintain stable dopaminergic therapy for duration of study participation.

        Exclusion Criteria:

          1. Other disorders which may resemble PD with or without dementia, such as vascular
             dementia, normal pressure hydrocephalus, progressive supranuclear palsy, multiple
             system atrophy, corticobasal ganglionic degeneration, or toxic causes of parkinsonism.
             Prototypical cases have distinctive clinical profiles, like vertical supranuclear gaze
             palsy, early and severe dysautonomia or appendicular apraxia, which may differentiate
             them from idiopathic PD. The use of the UKPDSBRC clinical diagnostic criteria for PD
             will mitigate the inclusion of subjects with atypical parkinsonism and all
             participants will undergo [11-Carbon]dihydrotetrabenazine PET to confirm striatal
             dopaminergic denervation.

          2. Subjects on neuroleptic, anticholinergic (trihexphenidyl, benztropine), or
             cholinesterase inhibitor drugs.

          3. Current or previous (within last 6 months) use of any product or medication containing
             nicotinic agents,including use of tobacco products such as cigarettes, cigars, pipes,
             chewing tobacco, etc., electronic cigarettes, over-the-counter nicotine patches,
             chewing gum containing nicotine, or varenicline.

          4. Evidence of a stroke or mass lesion on structural brain imaging (MRI).

          5. Participants in whom magnetic resonance imaging (MRI) is contraindicated including,
             but not limited to, those with a pacemaker, presence of metallic fragments near the
             eyes or spinal cord, or cochlear implant.

          6. Severe claustrophobia precluding MR or PET imaging

          7. Subjects limited by participation in research procedures involving ionizing radiation.

          8. Pregnancy (test within 48 hours of each PET session) or breastfeeding.

          9. Significant risk of cardiovascular event.

         10. Active, significant mood disorder.