Back to resultsCrossover Target Engagement Study of Cholinergic Mechanisms of Gait Dysfunction in Parkinson's Disease (Project #3 - Experiment 3 [UdallP3E3]) (UdallP3E3)
Primary Purpose
Parkinson's Disease
Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Varenicline
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Parkinson's Disease
Eligibility Criteria
Inclusion Criteria:
- 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.
- Stable dopaminergic replacement therapy for 3 months prior to enrollment and expected to maintain stable dopaminergic therapy for duration of study participation.
Exclusion Criteria:
- 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.
- Subjects on neuroleptic, anticholinergic (trihexphenidyl, benztropine), or cholinesterase inhibitor drugs.
- 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.
- Evidence of a stroke or mass lesion on structural brain imaging (MRI).
- 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.
- Severe claustrophobia precluding MR or PET imaging
- Subjects limited by participation in research procedures involving ionizing radiation.
- Pregnancy (test within 48 hours of each PET session) or breastfeeding.
- Significant risk of cardiovascular event.
- Active, significant mood disorder.
Sites / Locations
- University of Michigan
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Varenicline then Placebo
Placebo then Varenicline
Arm Description
Varenicline 0.5 mg BID orally for 3 weeks, followed by a 3-week washout period, then placebo BID orally for 3 weeks
Placebo BID orally for 3 weeks, followed by a 3-week washout period, then Varenicline 0.5 mg BID orally for 3 weeks
Outcomes
Primary Outcome Measures
Gait Speed
Gait speed, how fast a person can walk down a corridor, at normal pace with no distractors (i.e., no dual task).
JERK
JERK is the time based derivative of spontaneous lower trunk accelerations during standing. It was assessed with the Ambulatory Parkinson's Disease Monitoring (APDM) wearable sensor system (APDM Wearable Technologies, Inc.) using the iSWAY protocol, with participants standing on a foam pad with eyes closed. JERK was calculated using the manufacturer's software (Mobility Lab Version 1).
Secondary Outcome Measures
Attention
Attention function will be measured with a standard computer test, the Sustained Attention Test (SAT), without a distractor condition. Results are reported as the vigilance index, a measure that corrects estimates of accurate detection with penalties for false detection and not confounded by errors of omission. (Frey PW, Colliver JA. Sensitivity and responsivity measures for discrimination learning. Learn Motiv 1973; 4:327-342.) The minimum score is -1.00 (indicating that all recorded responses were misses or false alarms) and maximum is +1 (indicating that all recorded responses were hits or correct rejections). Higher values indicate better attentional performance.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT04403399
Brief Title
Crossover Target Engagement Study of Cholinergic Mechanisms of Gait Dysfunction in Parkinson's Disease (Project #3 - Experiment 3 [UdallP3E3])
Acronym
UdallP3E3
Official Title
Cholinergic Mechanisms of Gait Dysfunction in Parkinson's Disease Experiment 3 - Project #3
Study Type
Interventional
2. Study Status
Record Verification Date
January 2021
Overall Recruitment Status
Completed
Study Start Date
June 29, 2017 (Actual)
Primary Completion Date
June 26, 2019 (Actual)
Study Completion Date
June 26, 2019 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Michigan
4. Oversight
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.
Yes
Data Monitoring Committee
Yes
5. Study Description
Brief 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.
Detailed Description
To demonstrate that α4β2* nAChRs are appropriate therapeutic targets in Parkinson's Disease (PD), it is necessary to study key pharmacokinetic-pharmacodynamic features of α4β2* nAChR in the context of the PD brain with loss of nerve cells that produce the neurotransmitter acetylcholine, a pathologic environment in which they may exhibit unique features. This personalized medicine approach focuses our studies on the subgroup of PD subjects with loss of nerve cells that produce the neurotransmitter acetylcholine identified by Project II and the Clinical Resource Core. The investigators will assess α4β2* nAChR features using PET imaging with the α4β2* nAChR ligand [18-Fluorine]flubatine, subacute administration of the α4β2* nAChR partial agonist Varenicline (VCN), and laboratory measures of gait, balance, and attention. The investigators will use [18-Fluorine] flubatine PET to assess VCN occupancy of brain α4β2* nAChRs (experiments 1 & 2). VCN will be administered to both PD participants (experiment 1) and healthy controls (experiment 2) and both populations will undergo a flubatine PET scan to assess VCN occupancy. Using this PET data to select an appropriate VCN dose, the investigators will perform a pharmacodynamic study (experiment 3) with subacute VCN administration to determine if α4β2* nAChR stimulation improves laboratory measures of gait function, postural control, and attentional function in PD subjects with loss of nerve cells that produce the neurotransmitter acetylcholine.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Parkinson's Disease
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
34 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Varenicline then Placebo
Arm Type
Experimental
Arm Description
Varenicline 0.5 mg BID orally for 3 weeks, followed by a 3-week washout period, then placebo BID orally for 3 weeks
Arm Title
Placebo then Varenicline
Arm Type
Experimental
Arm Description
Placebo BID orally for 3 weeks, followed by a 3-week washout period, then Varenicline 0.5 mg BID orally for 3 weeks
Intervention Type
Drug
Intervention Name(s)
Varenicline
Other Intervention Name(s)
Chantix
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.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
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.
Primary Outcome Measure Information:
Title
Gait Speed
Description
Gait speed, how fast a person can walk down a corridor, at normal pace with no distractors (i.e., no dual task).
Time Frame
end of each period: 22 and 64 days
Title
JERK
Description
JERK is the time based derivative of spontaneous lower trunk accelerations during standing. It was assessed with the Ambulatory Parkinson's Disease Monitoring (APDM) wearable sensor system (APDM Wearable Technologies, Inc.) using the iSWAY protocol, with participants standing on a foam pad with eyes closed. JERK was calculated using the manufacturer's software (Mobility Lab Version 1).
Time Frame
end of each period: 22 and 64 days
Secondary Outcome Measure Information:
Title
Attention
Description
Attention function will be measured with a standard computer test, the Sustained Attention Test (SAT), without a distractor condition. Results are reported as the vigilance index, a measure that corrects estimates of accurate detection with penalties for false detection and not confounded by errors of omission. (Frey PW, Colliver JA. Sensitivity and responsivity measures for discrimination learning. Learn Motiv 1973; 4:327-342.) The minimum score is -1.00 (indicating that all recorded responses were misses or false alarms) and maximum is +1 (indicating that all recorded responses were hits or correct rejections). Higher values indicate better attentional performance.
Time Frame
end of period: days 22 and 64
10. Eligibility
Sex
All
Minimum Age & Unit of Time
45 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
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.
Stable dopaminergic replacement therapy for 3 months prior to enrollment and expected to maintain stable dopaminergic therapy for duration of study participation.
Exclusion Criteria:
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.
Subjects on neuroleptic, anticholinergic (trihexphenidyl, benztropine), or cholinesterase inhibitor drugs.
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.
Evidence of a stroke or mass lesion on structural brain imaging (MRI).
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.
Severe claustrophobia precluding MR or PET imaging
Subjects limited by participation in research procedures involving ionizing radiation.
Pregnancy (test within 48 hours of each PET session) or breastfeeding.
Significant risk of cardiovascular event.
Active, significant mood disorder.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Roger L Albin, MD
Organizational Affiliation
University of Michigan
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Michigan
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
22750016
Citation
Mancini M, Carlson-Kuhta P, Zampieri C, Nutt JG, Chiari L, Horak FB. Postural sway as a marker of progression in Parkinson's disease: a pilot longitudinal study. Gait Posture. 2012 Jul;36(3):471-6. doi: 10.1016/j.gaitpost.2012.04.010. Epub 2012 Jun 29.
Results Reference
result
Learn more about this trial
Crossover Target Engagement Study of Cholinergic Mechanisms of Gait Dysfunction in Parkinson's Disease (Project #3 - Experiment 3 [UdallP3E3])
We'll reach out to this number within 24 hrs