Reducing Falls With Varenicline in Hypocholinergic Parkinson Disease (CRANE)

This trial aims to test whether one year of Varenicline, when compared to placebo, can reduce fall risk and show improvement in the ability to multitask while walking.

Participants that are eligible after screening for the study will be randomized to receive Varenicline or placebo. Along with the study medication participants will have visits (over the phone and in person), various tests and imaging, questionnaires, and laboratory collections.

Study Overview

• Status: Recruiting
• Conditions: Parkinson Disease
• Intervention / Treatment: Drug: Placebo; Drug: Varenicline

Detailed Description

The hypothesis of the trial are:

• The primary hypothesis is that varenicline will result in less progress in dual-task cost gait performance after 12 months of treatment compared to placebo in hypocholinergic Parkinson disease (PD) Mild Cognitive Impairment (MCI) patients.
• The primary secondary hypothesis assesses whether the magnitude of effect of varenicline relative to placebo is consistent with the minimal clinically important difference (MCID) for the relative risk of falls in the 12-month double-blind treatment period.

• Study Type: Interventional
• Enrollment (Estimated): 102
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Dawn Keys; Phone Number: 734-615-4334; Email: dmkeys@med.umich.edu

Study Locations

• United States
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Recruiting
      • University of Michigan
      • Contact: Dawn Keys; Phone Number: 734-615-4334; Email: dmkeys@med.umich.edu
      • Principal Investigator: Vikas Kotagal, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Participants with a PD diagnosis based on the Movement Disorders Society Clinical Diagnostic Criteria for Parkinson's Disease at the time of baseline screening/enrollment visit
• Participants with occipital association cortex cholinergic denervation in the lowest tertile of the normal range on F-fluoroethoxybenzovesamicol (FEOBV) Positron Emission Tomography (PET)
• Participants with legally authorized representatives (LARs) able to co-sign documented informed consent or participants that have capacity to provide informed consent upon study enrollment as ascertained by the study-specific University of California, San Diego Brief Assessment of Capacity to Consent (UBACC)
• Mild Cognitive Impairment consistent with Parkinson disease Mild Cognitive Impairment (PD-MCI)

Exclusion Criteria:

• Atypical Parkinsonian conditions other than Parkinson disease (PD)
• Participants initially on certain dopamine blocking drugs (per protocol), specific anticholinergic drugs (trihexyphenidyl, benztropine), or specific cholinesterase inhibitor drugs (per protocol) at the in-person screening visit
• Modified Hoehn and Yahr score of 4.0 or greater at the in-person screening visit
• Current or previous (within last 6 months of in-person screening visit) use of any product or medication containing nicotinic agents, including use of tobacco products such as cigarettes, cigars, pipes, chewing tobacco, etc., e-cigarettes, over the counter (OTC) nicotine patches, chewing gum containing nicotine, or varenicline
• Evidence of a stroke with both cortical and subcortical involvement or occipital lobe mass lesion on structural magnetic brain imaging (MRI) obtained at the in-person screening visit that would preclude co-registration and analysis of FEOBV PET data
• Participants where 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
• Severe claustrophobia precluding MRI or PET imaging
• Participants limited by participation in research procedures involving ionizing radiation
• Pregnancy (test within 48 hours of the PET imaging session in women of childbearing potential) or breastfeeding at the time of in-person screening visit
• Participants with stage 4 or 5 chronic kidney disease at the time of in-person screening visit (estimated Creatinine Clearance < 30 milliliters per minute)
• Current, significant mood disorder at the time of in-person screening/enrollment visit defined as follows: persistent (lasting longer than 2 weeks) symptoms of depression or anxiety in the 30 days preceding informed consent, as determined by self-report
• Evidence of active suicidal ideation as defined by an affirmative answer to either question 1 or 2 on the Columbia Suicide Severity Rating Scale (C-SSRS)
• History of a myocardial infarction or unstable angina in the 90 days preceding enrollment visit
• A current or previous history of epilepsy or any epileptic seizures in the 12 months preceding enrollment
• Heavy alcohol use as defined by a score of 8 or greater on the Alcohol Use Disorders Identification Test (AUDIT-self-report version) at the time of screening/enrollment visit
• Participants that are unable to swallow pills
• Participants with a history of allergic reaction to varenicline
• Participants that are actively taking part in another ongoing interventional (i.e., not observational) clinical trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; Participants will take one pill (.5 milligrams) a day for days 1-3 and then one pill (.5 milligrams) in the morning and one pill in the evening days 4-30 and months 2-12. In month 13 participants will take one pill in the morning days 1-3. Participants will be off study drug month 13 days 4-30.
Experimental: Varenicline	Drug: Varenicline; Participants will take one pill (.5 milligrams) a day for days 1-3 and then one pill (.5 milligrams) in the morning and one pill in the evening days 4-30 and months 2-12. In month 13 participants will take one pill in the morning days 1-3. Participants will be off study drug month 13 days 4-30.; Other Names: Chantix

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in normal pace-dual task cost (npDTC) from baseline to 12 months.	Normal pace-dual task cost is defined as the within-subject difference between normal pace walking speed without dual tasking to normal pace walking speed with dual tasking divided by normal pace walking speed without dual tasking, multiplied by 100.	Baseline, 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of falls from the first dose of study drug to the 12-month visit	Participants will complete a fall diary to collect this data.	First dose (day 0) to 12 month visit

Collaborators and Investigators

• Sponsor: Vikas Kotagal
• Collaborators: National Institute of Neurological Disorders and Stroke (NINDS)
• Investigators: Principal Investigator: Vikas Kotagal, MD, University of Michigan

Study record dates

Study Major Dates

• Study Start (Actual): April 9, 2025
• Primary Completion (Estimated): January 1, 2029
• Study Completion (Estimated): January 1, 2029

Study Registration Dates

• First Submitted: November 5, 2024
• First Submitted That Met QC Criteria: November 5, 2024
• First Posted (Actual): November 7, 2024

Study Record Updates

• Last Update Posted (Actual): March 31, 2026
• Last Update Submitted That Met QC Criteria: March 25, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Mild Cognitive impairment; Multitasking; Reduce falls; Hypocholinergic
• Additional Relevant MeSH Terms: Synucleinopathies; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Neurocognitive Disorders; Cognition Disorders; Neurodegenerative Diseases; Movement Disorders; Parkinsonian Disorders; Basal Ganglia Diseases; Cognitive Dysfunction; Parkinson Disease; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Benzazepines; Quinoxalines; Varenicline
• Other Study ID Numbers: HUM00254213; 1UG3NS133515-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

The study team will ensure the dataset is shared by the occurrence of the earlier of the following two milestones: either the date of primary publication or within 9 months of lifting of the data lock.

De-identified subject data will be uploaded in a timely manner to a data repository using an established data transfer mechanism and the NINDS supported Common Data Elements (CDEs) as appropriate. Pending appropriate permissions, biospecimens (DNA) will be banked in the NINDS biorepository. Uploaded datasets will be coded and stripped of identifiers in order to prevent the possibility of identifying participants in this study from the publicly available dataset.

• IPD Sharing Time Frame: Access to the dataset that is uploaded to the data repository is available to any individual that applies to them for data access. This process does not place any limitations on the use of the data for commercial purposes.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No