Parkinson's Disease
Conditions
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.
Interventions
DRUGVarenicline
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.
DRUGPlacebo
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.
Sponsors
University of Michigan
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
45 Years to No maximum
Healthy volunteers
No
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 |
|---|---|---|
| Gait Speed | end of each period: 22 and 64 days | Gait speed, how fast a person can walk down a corridor, at normal pace with no distractors (i.e., no dual task). |
| JERK | end of each period: 22 and 64 days | 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
| Measure | Time frame | Description |
|---|---|---|
| Attention | end of period: days 22 and 64 | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Varenicline Then Placebo Patients will take varenicline initially for 3 weeks, then after a 3 week washout period, they will switch to placebo for 3 weeks. | 18 |
| Placebo Then Varenicline Patients will take placebo initially for 3 weeks, then after a 3 week washout period, they will switch to varenicline for 3 weeks. | 16 |
| Total | 34 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 2 | Physician Decision | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo Then Varenicline | Total | Varenicline Then Placebo |
|---|---|---|---|
| Age at Diagnosis of Parkinson's Disease | 57.7 years STANDARD_DEVIATION 7.22 | 59.6 years STANDARD_DEVIATION 7.06 | 61.3 years STANDARD_DEVIATION 6.66 |
| Age, Continuous | 64.2 years STANDARD_DEVIATION 5.3 | 66.3 years STANDARD_DEVIATION 5.78 | 68.1 years STANDARD_DEVIATION 5.7 |
| Geriatric Depression Scale | 4.3 units on a scale STANDARD_DEVIATION 4.19 | 3.3 units on a scale STANDARD_DEVIATION 3.34 | 2.4 units on a scale STANDARD_DEVIATION 2.06 |
| MDS-UPDRS III | 30.7 units on a scale STANDARD_DEVIATION 12.4 | 32.0 units on a scale STANDARD_DEVIATION 13.07 | 33.2 units on a scale STANDARD_DEVIATION 13.92 |
| Montreal Cognitive Assessment | 26.8 units on a scale STANDARD_DEVIATION 1.97 | 27.0 units on a scale STANDARD_DEVIATION 2.17 | 27.2 units on a scale STANDARD_DEVIATION 2.37 |
| 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 | 16 Participants | 33 Participants | 17 Participants |
| Region of Enrollment United States | 16 Participants | 34 Participants | 18 Participants |
| Sex: Female, Male Female | 3 Participants | 6 Participants | 3 Participants |
| Sex: Female, Male Male | 13 Participants | 28 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 34 | 0 / 34 |
| other Total, other adverse events | 17 / 34 | 8 / 34 |
| serious Total, serious adverse events | 1 / 34 | 1 / 34 |
Outcome results
Primary
Gait Speed
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
Population: All randomized participants were included in the mixed effects model. One participant randomized to the placebo then varenicline group was withdrawn by the physician early in period 2; 1 participant randomized to the varenicline then placebo group did not complete the gait assessment in period 2.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Varenicline | Gait Speed | 121.27 cm/s | Standard Error 1.36 |
| Placebo | Gait Speed | 124.89 cm/s | Standard Error 1.36 |
p-value: 0.003Mixed Models Analysis
Primary
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).
Time frame: end of each period: 22 and 64 days
Population: All randomized participants were included in the mixed effects model. One participant randomized to the placebo then varenicline group was withdrawn by the physician early in period 2; two participants randomized to the varenicline then placebo group did not complete the iSWAY protocol in period 2.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Varenicline | JERK | 0.97 m^2/sec^5 | Standard Error 0.2 |
| Placebo | JERK | 1.04 m^2/sec^5 | Standard Error 0.2 |
p-value: 0.73Mixed Models Analysis
Secondary
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.
Time frame: end of period: days 22 and 64
Population: All randomized participants with at least one post-treatment value were included in the mixed effects model. Six participants (1 in the placebo then varenicline, 6 in the varenicline then placebo) were unable to pass practice trials due to delayed response time (task not completed at all visits). Technical errors resulted in missing data for 2 placebo and 1 varenicline participants; 3 varenicline participants requested skipping task due to physical ailments.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Varenicline | Attention | 0.73 units on a scale | Standard Error 0.06 |
| Placebo | Attention | 0.66 units on a scale | Standard Error 0.06 |
p-value: 0.03Mixed Models Analysis