Parkinson Disease
Conditions
Keywords
Balance, Postural impairment, Falls, Parkinson Disease
Brief summary
The purpose of this study is to determine if varenicline is effective in improving gait and balance impairment in patients with Parkinson disease.
Detailed description
Parkinson disease (PD) is a clinical entity characterized by bradykinesia, rigidity, tremor, and postural instability. Current treatments primarily focus on replacement of dopamine to compensate for the degeneration of the substantia nigra pars compacta dopaminergic neuronal population. Though dopamine treats many of the motor symptoms of PD, postural instability (which often leads to falls) typically is least responsive to therapy. More recently, the degeneration of the cholinergic system arising from the pedunculopontine nucleus (PPN) in the brainstem has been implicated in gait dysfunction in PD. Striatal cholinergic inputs are supplied from the PPN both via the intralaminar complex of the thalamus and through direct inputs. The primary subtypes of cholinergic receptors present in the striatum are nicotinic and include α4β2, α6β2, and α7 receptors. Varenicline (Chantix) is a novel partial α4β2 agonist and full α7 agonist developed as an aid for smoking cessation and has been shown in initial studies to improve imbalance in patients with inherited spinocerebellar ataxia. The unique method of action of varenicline may make it an ideal drug for the treatment of balance impairment in PD.
Interventions
DRUGVarenicline
Varenicline 1mg twice daily for eight weeks after a one week dose escalation period.
DRUGSugar pill
1mg twice daily for eight weeks after a one week dose escalation phase.
Sponsors
Rush University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
* Subjects will be diagnosed with Parkinson Disease (PD) by the United Kingdom (UK) Brain Bank criteria. * Subjects will have to be at least stage 2 on the Hoehn and Yahr staging system of PD and have a history of at least 1 fall or near fall in the last 6 months * Subjects must have a stable medication regimen. * All subjects will be over the age of 40 in an attempt to exclude inherited forms of parkinsonism. * Serum creatine kinase, complete metabolic panel, complete blood count, liver function tests, renal function tests, platelets and EKG are within normal limits (results obtained from primary care physician and dated within the past 6 months or obtained at screening visit).
Exclusion criteria
* Hoehn and Yahr stage V subjects. * Subjects with a history of major psychiatric disorder, deep brain stimulation surgery, recent cerebral trauma, cardiac arrhythmia, or renal insufficiency. * A cardiovascular procedure in the last 5 years (eg, percutaneous transluminal coronary angioplasty) or have cardiovascular instability (including myocardial infarction or unstable angina). Other cardiovascular exclusions include uncontrolled hypertension, significant neurological sequelae of cerebrovascular disease, peripheral vascular disease with prior amputation, or severe congestive heart failure (New York Heart Association class III or IV). * Concurrent treatment with any monoamine oxidase inhibitors (MAOIs), bupropion (Wellbutrin), or nicotine patches. * Dementia or other psychiatric illness that prevents the patient from giving informed consent (Folstein Mini Mental Status Exam score less than 25). * Concurrent treatment with trihexyphenidyl (Artane) or benztropine mesylate (Cogentin). * Significant degree of dysphagia, by history. * Legal incapacity or limited legal capacity. * Presence of severe renal disease (BUN 50% greater than normal or creatinine clearance \<60 mL/min) or hepatic disease. * Abnormal creatine kinase and/or platelet count in the past 6 months (as determined by lab reports obtained from primary care physicians or conducted at baseline). * Use of varenicline within the previous 30 days. * Women of childbearing potential who are pregnant at the time of screening or who will not use adequate protection during participation of the study. * Allergy/sensitivity to the drug or its formulations. * Concurrent participation in another clinical study. * Active substance or tobacco use or dependence. * Moderate or severe chronic obstructive pulmonary disease. * Serious illness (requiring systemic treatment/or hospitalization) until the subject either completes therapy or is clinically stable on therapy, in the opinion of the site investigator, for at least 60 days prior to study entry. * Inability or unwillingness of the subject or legal guardian/representative to give written informed consent.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Berg Balance Scale | 9 weeks | Efficacy was measured as a change on the Berg Balance Scale (BBS) from baseline to the end of the study after 8 weeks on drug. The BBS is a 14-item measure consisting of basic balance tasks, with a final score indicative of overall balance ability. The maximum score is 56 and minimum is 0. Higher scores reflect better balance. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Frontal Assessment Battery | 9 weeks | The change in cognitive functioning was measured with the Frontal Assessment Battery (FAB, score range 0-18) and the Mini-Mental State Exam (MMSE, score range 0-30) from baseline to 8 weeks on drug. High scores on both scales indicate better performance. The FAB measures executive functioning and consists of the following 6 sections: conceptualization, mental flexibility, motor programming, sensitivity to interference, inhibitory control, and environmental autonomy. |
| Mini Mental Status Exam (MMSE) | 9 weeks | The change in cognitive functioning was measured with the Mini-Mental State Exam (MMSE) from baseline to 8 weeks on drug. The maximum score on the MMSE is 30 and lowest score 0, with higher score indicating better cognitive function. |
Countries
United States
Participant flow
Recruitment details
Subjects were recruitment from the Parkinson's Disease and Movement Disorder clinic at Rush University Medical Center over the course of the study (2011-2018).
Pre-assignment details
40 participants signed an informed consent form and 36 were randomized. Six participants terminated participation early, with 2 having sufficient data for last observations carried forward intention-to-treat analyses. The remaining 32 were used in the analysis.
Participants by arm
| Arm | Count |
|---|---|
| Varenicline Varenicline: Varenicline 1mg twice daily for eight weeks after a one week dose escalation period. | 18 |
| Sugar Pill Sugar pill: 1mg twice daily for eight weeks after a one week dose escalation phase. | 18 |
| Total | 36 |
Baseline characteristics
| Characteristic | Sugar Pill | Varenicline | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 14 Participants | 12 Participants | 26 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 3 Participants | 6 Participants |
| Age, Continuous | 70.24 years STANDARD_DEVIATION 7.9 | 71.93 years STANDARD_DEVIATION 8.5 | 71.03 years STANDARD_DEVIATION 8.134 |
| Race/Ethnicity, Customized White | 17 Participants | 15 Participants | 32 Participants |
| Region of Enrollment United States | 17 participants | 15 participants | 32 participants |
| Sex: Female, Male Female | 3 Participants | 3 Participants | 6 Participants |
| Sex: Female, Male Male | 14 Participants | 12 Participants | 26 Participants |
| Unified Parkinson's Disease Rating Scale | 35.7 units on a scale STANDARD_DEVIATION 12.7 | 33.1 units on a scale STANDARD_DEVIATION 9.7 | 34.74 units on a scale STANDARD_DEVIATION 11.558 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 18 | 0 / 18 |
| other Total, other adverse events | 0 / 18 | 0 / 18 |
| serious Total, serious adverse events | 0 / 18 | 0 / 18 |
Outcome results
Primary
Berg Balance Scale
Efficacy was measured as a change on the Berg Balance Scale (BBS) from baseline to the end of the study after 8 weeks on drug. The BBS is a 14-item measure consisting of basic balance tasks, with a final score indicative of overall balance ability. The maximum score is 56 and minimum is 0. Higher scores reflect better balance.
Time frame: 9 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Varenicline | Berg Balance Scale | Baseline | 43.93 score on a scale | Standard Deviation 1.97 |
| Varenicline | Berg Balance Scale | End Point | 43.25 score on a scale | Standard Deviation 1.84 |
| Sugar Pill | Berg Balance Scale | Baseline | 41.14 score on a scale | Standard Deviation 2.55 |
| Sugar Pill | Berg Balance Scale | End Point | 45.13 score on a scale | Standard Deviation 2.34 |
Comparison: Efficacy was measured as a change on the Berg Balance Scale (BBS) from baseline to the end of study after 8 weeks on drug. The BBS has a scale range of 0-56, with 56 indicating normal balance. To evaluate efficacy, repeated measures analysis of variance was run on BBS scores. The scale score was the dependent measure, time point (baseline or end of study) was the repeat measure, and treatment group (varenicline or sugar pill) was the independent measure. Significance was defined as alpha \<0.05.p-value: 0.0595% CI: [-4.01, 4.61]Repeated measures analysis or variance
Secondary
Frontal Assessment Battery
The change in cognitive functioning was measured with the Frontal Assessment Battery (FAB, score range 0-18) and the Mini-Mental State Exam (MMSE, score range 0-30) from baseline to 8 weeks on drug. High scores on both scales indicate better performance. The FAB measures executive functioning and consists of the following 6 sections: conceptualization, mental flexibility, motor programming, sensitivity to interference, inhibitory control, and environmental autonomy.
Time frame: 9 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Varenicline | Frontal Assessment Battery | Baseline | 17.40 score on a scale | Standard Deviation 0.97 |
| Varenicline | Frontal Assessment Battery | End point | 17.70 score on a scale | Standard Deviation 2.16 |
| Sugar Pill | Frontal Assessment Battery | Baseline | 15.25 score on a scale | Standard Deviation 2.77 |
| Sugar Pill | Frontal Assessment Battery | End point | 15.19 score on a scale | Standard Deviation 2.74 |
Comparison: Change in cognitive functioning was measured in part with the Frontal Assessment Battery (FAB) from Baseline to 8 weeks on drug. Repeated analysis of variance was run on the FAB scores. Scale cores was the dependent measure, time point (Baseline or end of study) was the repeated measure, and treatment group (varenicline or sugar pill) was the independent measure. Significant was defined as \<0.05.p-value: 0.0595% CI: [-1.39, 1.53]Repeated measures analysis or variance
Secondary
Mini Mental Status Exam (MMSE)
The change in cognitive functioning was measured with the Mini-Mental State Exam (MMSE) from baseline to 8 weeks on drug. The maximum score on the MMSE is 30 and lowest score 0, with higher score indicating better cognitive function.
Time frame: 9 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Varenicline | Mini Mental Status Exam (MMSE) | End point | 28.00 score on a scale | Standard Deviation 2 |
| Varenicline | Mini Mental Status Exam (MMSE) | Baseline | 29.08 score on a scale | Standard Deviation 1.17 |
| Sugar Pill | Mini Mental Status Exam (MMSE) | Baseline | 28.19 score on a scale | Standard Deviation 1.72 |
| Sugar Pill | Mini Mental Status Exam (MMSE) | End point | 28.13 score on a scale | Standard Deviation 1.7 |
Comparison: Change in cognitive functioning was measured in part with the Mini Mental State Exam (MMSE) from Baseline to 8 weeks on drug. Repeated analysis of variance was run on the MMSE scores. Scale score was the dependent measure, time point (Baseline or end of study) was the repeated measure, and treatment group (varenicline or sugar pill) was the independent measure. Significant was defined as \<0.05.p-value: 0.0595% CI: [-0.4, 1.4]Repeated measures analysis or variance