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Cholinergic Mechanisms of Gait Dysfunction in Parkinson's Disease Experiments 1 & 2 - Proj #3 (UdallP3)

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ClinicalTrials.gov Identifier: NCT02933372
Recruitment Status : Completed
First Posted : October 14, 2016
Last Update Posted : May 29, 2020
Sponsor:
Information provided by (Responsible Party):
Roger L. Albin, University of Michigan

Brief Summary:
Varying oral doses of Varenicline (VCN), starting with very low doses, will be administered to participants with Parkinson's Disease (PD) or healthy controls without PD for several days. Positron emission tomography (PET) scans after administration of VCN will be used to determine the lowest oral dose of VCN producing an adequate brain level of VCN. These experiments (1 & 2) will be used to determine an appropriate oral dose of VCN to administer to PD participants for experiment 3 of the study (see NCT04403399).

Condition or disease Intervention/treatment Phase
Parkinson's Disease Drug: Varenicline Radiation: [18-Fluorine] Flubatine PET Scan Other: Evaluation by Investigator Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 25 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: All participants (Parkinson's disease patients and healthy controls) will receive the study drug varenicline.
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Cholinergic Mechanisms of Gait Dysfunction in Parkinson's Disease Experiments 1 & 2 - Projects #3
Actual Study Start Date : October 5, 2015
Actual Primary Completion Date : June 26, 2019
Actual Study Completion Date : June 26, 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Parkinson's Disease Patients
Participants take varenicline for several days and have two Positron Emission Tomography (PET) scans. PET scans are used to estimate how much varenicline is actually in the brain. Safety monitoring with clinical assessments of severity of Parkinson disease (PD) and cognition are performed.
Drug: Varenicline
Participants take varenicline for 10 days. Each participant will be on one dosage throughout the 10 days, but not all participants receive the same dosage. The dosages that were utilized were 0.25mg once a day, 0.25mg twice a day, 0.5mg twice a day and 1mg twice a day.
Other Name: Chantix

Radiation: [18-Fluorine] Flubatine PET Scan
Participants will undergo 2 different PET scanning sessions. Radiotracers will be injected into the participant's vein through an IV (intravenous catheter or plastic "tube" inserted in an arm vein). A tracer refers to a small amount of a radioactive substance that does not alter body function.

Other: Evaluation by Investigator
Participants will undergo cognitive testing, a physical exam, and gait and posture assessments

Experimental: Healthy Controls
Participants take varenicline for several days and have two Positron Emission Tomography (PET) scans. The PET scans are used to estimate how much varenicline is actually in the brain. Safety monitoring with clinical assessments for presence of Parkinson disease (PD) and cognition are performed.
Drug: Varenicline
Participants take varenicline for 10 days. Each participant will be on one dosage throughout the 10 days, but not all participants receive the same dosage. The dosages that were utilized were 0.25mg once a day, 0.25mg twice a day, 0.5mg twice a day and 1mg twice a day.
Other Name: Chantix

Radiation: [18-Fluorine] Flubatine PET Scan
Participants will undergo 2 different PET scanning sessions. Radiotracers will be injected into the participant's vein through an IV (intravenous catheter or plastic "tube" inserted in an arm vein). A tracer refers to a small amount of a radioactive substance that does not alter body function.

Other: Evaluation by Investigator
Participants will undergo cognitive testing, a physical exam, and gait and posture assessments




Primary Outcome Measures :
  1. Brain Varenicline Measurements with PET Scans [ Time Frame: 10 days ]
    Brain varenicline levels will be measured with PET scans to assess the dose of varenicline appropriate for experiment 3 of this study (see separate record).



Information from the National Library of Medicine

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Ages Eligible for Study:   45 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02933372


Sponsors and Collaborators
University of Michigan
Investigators
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Principal Investigator: Roger L Albin, MD University of Michigan
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Responsible Party: Roger L. Albin, Professor of Neurology, University of Michigan
ClinicalTrials.gov Identifier: NCT02933372    
Other Study ID Numbers: HUM00093188
First Posted: October 14, 2016    Key Record Dates
Last Update Posted: May 29, 2020
Last Verified: May 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Additional relevant MeSH terms:
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Parkinson Disease
Parkinsonian Disorders
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Movement Disorders
Neurodegenerative Diseases
Varenicline
Nicotinic Agonists
Cholinergic Agonists
Cholinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs