Parkinson's Disease
Conditions
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).
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.
Interventions
DRUGVarenicline
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 for both Parkinson's disease participants and healthy volunteers were 0.25mg once a day, 0.25mg twice a day, and 0.5mg twice a day. A fourth dosing group of 1 mg varenicline twice a day was studied in Parkinson's disease participants, but not in healthy volunteers.
Sponsors
University of Michigan
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Intervention model description
All participants (Parkinson's disease patients and healthy controls) will receive the study drug varenicline.
Eligibility
Sex/Gender
ALL
Age
45 Years to No maximum
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Varenicline Occupancy of alpha4beta2* Nicotinic Acetylcholine Receptors | 15 days | Varenicline occupancy of alpha4beta2\* nicotinic acetylcholine receptors (nAChR) was assessed with ascending doses of varenicline and the selective alpha4beta2\* nAChR positron emission tomography (PET) ligand \[18F\]Flubatine. Alpha4beta2\* nAChR agonists may induce nAChR expression. Consequently, we imaged participants at the end of their drug exposure periods (Day 10) and again after 5 days (\ 5 half-lives) of washout from drug exposure (Day 15). We used the difference between the two PET scans, (Day 10 - Day 15)/Day 15 x 100%, to determine the receptor occupancy of alpha4beta2\* nicotinic acetylcholine receptors (nAChR) by each dose of varenicline. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Parkinson's Disease Patients 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. | 15 |
| Healthy Controls : 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, and 0.5mg twice a day. | 10 |
| Total | 25 |
Baseline characteristics
| Characteristic | Healthy Controls | Parkinson's Disease Patients | Total |
|---|---|---|---|
| Age, Continuous | 66.4 years STANDARD_DEVIATION 8.95 | 67.3 years STANDARD_DEVIATION 5.2 | 66.9 years STANDARD_DEVIATION 6.78 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 15 Participants | 25 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Geriatric Depression Scale | 1.6 units on a scale STANDARD_DEVIATION 2.01 | 3.2 units on a scale STANDARD_DEVIATION 3.75 | 2.6 units on a scale STANDARD_DEVIATION 3.22 |
| MDS-UPDRS III | 3.5 units on a scale STANDARD_DEVIATION 1.84 | 31.9 units on a scale STANDARD_DEVIATION 12.83 | 20.5 units on a scale STANDARD_DEVIATION 17.27 |
| Montreal Cognitive Assessment | 26.8 units on a scale STANDARD_DEVIATION 2.3 | 25.5 units on a scale STANDARD_DEVIATION 1.73 | 26.0 units on a scale STANDARD_DEVIATION 2.04 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 10 Participants | 14 Participants | 24 Participants |
| Region of Enrollment United States | 10 Participants | 15 Participants | 25 Participants |
| Sex: Female, Male Female | 2 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Male | 8 Participants | 14 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 10 |
| other Total, other adverse events | 6 / 15 | 0 / 10 |
| serious Total, serious adverse events | 0 / 15 | 0 / 10 |
Outcome results
Primary
Varenicline Occupancy of alpha4beta2* Nicotinic Acetylcholine Receptors
Varenicline occupancy of alpha4beta2\* nicotinic acetylcholine receptors (nAChR) was assessed with ascending doses of varenicline and the selective alpha4beta2\* nAChR positron emission tomography (PET) ligand \[18F\]Flubatine. Alpha4beta2\* nAChR agonists may induce nAChR expression. Consequently, we imaged participants at the end of their drug exposure periods (Day 10) and again after 5 days (\ 5 half-lives) of washout from drug exposure (Day 15). We used the difference between the two PET scans, (Day 10 - Day 15)/Day 15 x 100%, to determine the receptor occupancy of alpha4beta2\* nicotinic acetylcholine receptors (nAChR) by each dose of varenicline.
Time frame: 15 days
Population: All consented and treated participants who had adequate PET scans. In Parkinson's Disease cohort, there were technical difficulties with PET scans in 5 participants. In the Healthy Controls cohort, one participant's data was excluded because of suspected covert tobacco abuse and there were technical difficulties with the PET scan for one participant.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Parkinson's Disease Patients | Varenicline Occupancy of alpha4beta2* Nicotinic Acetylcholine Receptors | 0.5 mg twice daily Varenicline | 66.3 percentage of VCN-alpha4beta2* nAChRs | Standard Deviation 5 |
| Parkinson's Disease Patients | Varenicline Occupancy of alpha4beta2* Nicotinic Acetylcholine Receptors | 0.25 mg twice daily Varenicline | 65.7 percentage of VCN-alpha4beta2* nAChRs | Standard Deviation 8 |
| Parkinson's Disease Patients | Varenicline Occupancy of alpha4beta2* Nicotinic Acetylcholine Receptors | 1 mg twice daily Varenicline | 71.5 percentage of VCN-alpha4beta2* nAChRs | Standard Deviation 10.6 |
| Parkinson's Disease Patients | Varenicline Occupancy of alpha4beta2* Nicotinic Acetylcholine Receptors | 0.25 mg once daily Varenicline | 67.0 percentage of VCN-alpha4beta2* nAChRs | Standard Deviation 4.9 |
| Healthy Controls | Varenicline Occupancy of alpha4beta2* Nicotinic Acetylcholine Receptors | 0.25 mg twice daily Varenicline | 70.6 percentage of VCN-alpha4beta2* nAChRs | Standard Deviation 1.9 |
| Healthy Controls | Varenicline Occupancy of alpha4beta2* Nicotinic Acetylcholine Receptors | 0.25 mg once daily Varenicline | 67.9 percentage of VCN-alpha4beta2* nAChRs | Standard Deviation 3.1 |
| Healthy Controls | Varenicline Occupancy of alpha4beta2* Nicotinic Acetylcholine Receptors | 0.5 mg twice daily Varenicline | 69.6 percentage of VCN-alpha4beta2* nAChRs | Standard Deviation 4 |