Dyskinesia, Drug-Induced, Parkinson Disease
Conditions
Brief summary
In this study, the investigators will examine the association of statin use and dyskinesia in a convenience sample Parkinson's disease patients in the Veterans Administration Health Care System.
Detailed description
Long term treatment with levodopa, the gold standard treatment of Parkinson's disease (PD), can lead to the development of abnormal involuntary movements called levodopa induced dyskinesia (LID). The severity of LID can range from mild to severely debilitating. A majority of PD patients will develop LID in their treatment life-time. In a recent study of the MPTP monkey model of PD, statin use was found to reduce LID (45%) without a worsening of Parkinsonism symptoms1. Another study showed rats treated with lovastatin prior to and with initiation of levodopa after substantia nigra lesioning showed dramatically less LID evolution compared to animals without lovastatin exposure2. In this study, the investigators will examine the association of statin use and dyskinesia in a convenience sample Parkinson's disease patients in the Veterans Administration Health Care System. This study is a retrospective three cohort design and will compare statin exposure BEFORE beginning LD, versus statin exposure AFTER LD is begun, versus NO statin exposure in PD subjects controlling for disease characteristics (severity), gender, and total LD exposure The primary endpoint is the severity of LID between the groups after years of opportunity to develop LID. Levodopa-Induced dyskinesia is a major cause of reduced quality of life for Veterans with PD and, in some cases, leads to costly surgical interventions. This project examines the impact of statin use on the presence of LID, and could lead to a future intervention trial. The reduction, delayed onset, or elimination of LID could improve the quality of life of many Veterans nationwide.
Interventions
DRUGIntravenous Infusion
Intravenous levodopa given 1.0 to 1.5 mg/kg/hr from 0930 - 1130 on a single visit day.
Sponsors
Oregon Health and Science University
VA Office of Research and Development
Study design
Observational model
CASE_CONTROL
Time perspective
RETROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Parkinson's Disease * Age diagnosed with Parkinson's Disease greater than or equal to 50 years * Treatment with levodopa greater than or equal to 5 years
Exclusion criteria
* Deep Brain stimulation * Unable to stand for 1 minute intervals, or sensory deficits in the feet * Significant cognitive impairment as measured by the Montreal Cognitive Assessment score of \< 18 * Subjects with unstable medical or psychiatric conditions (including hallucinations). * History of unstable medical conditions (i.e. active cardiac disease, recent unwellness, surgery etc.) * Current use of drugs that may affect parkinsonism or dyskinesia: * dopamine receptor blocking medications * depakote * lithium * amiodarone * tetrabenazine * metoclopramide * dronabinol * and illicit drugs such as marijuana (THC) * cocaine * methamphetamine * Statins other than simvastatin or lovastatin, atorvastatin ie. fluvastatin (rationale is that while all other statins are thought to not cross the blood brain barrier well, the central nervous system penetrating nature of others is not perfectly clear and could confound results)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Peak Unified Dyskinesia Rating Score (UDysRS) | 11:00 am | The Unified Dyskinesia Rating Scale (UDysRS) combines patient, caregiver, and treating physician perspectives on both historical (Parts 1 & 2) and objective (Part 3 & 4) assessments of dyskinesia and dystonia. The historical portion and the objective ratings are added together to form total score ranging from 0 to 104 with higher scores indicating more severe dyskinesia. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Peak Unified Dyskinesia Rating Scale - Objective Measures | 11:00 am | The Unified Dyskinesia Rating Scale (UDysRS) objective (Part 3 & 4) assessments of dyskinesia and dystonia. The objective ratings are added together to form total score ranging from 0 to 44 with higher scores indicating more severe dyskinesia. |
| Presence/Absence of Levodopa-induced Dyskinesia (LID). | Every half hour from 0900 to 1500 | Any score greater than or equal to 1 on the Clinical Dyskinesia Rating Scale (CDRS) during the intravenous levodopa cycle from 0900 - 1500. The CDRS is a commonly utilized scale that is completed by an observer who judges the severity of LID (0-4) in 7 body parts (face, neck, trunk, both legs, and both arms) during as the subject performs the cognitive distraction task while standing on the force plate for 60 seconds. CDRS ratings are made every half hour during the LD dose cycle by the principal investigator (KC) or co-investigator. |
| Clinical Dyskinesia Rating Scale (Peak) | 11:00 am | The Clinical Dyskinesia Rating Scale (CDRS) is a commonly utilized scale that is completed by an observer who judges the severity of Levodopa induced dyskinesia (LID) in 7 body parts (face, neck, trunk, both legs, and both arms) during the force plate stance with a cognitive distraction task for 60 seconds. All body parts are rated separately on this 0 (none) to 4 (severe - markedly impairs activities) scale. Thus, the total score can range from 0 - 28 with 28 indicating the most severe LID. Peak CDRS ratings are the 11:00 am ratings. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited based on physician referral at 2 academic medical centers and 1 Veterans administration hospital between July 2019 and March 2024. The first participant was enrolled on August 2019 and the last participant was enrolled in February 2024.
Pre-assignment details
Of the 93 consented participants, 5 did not meet inclusion criteria. Of the 88 enrolled participants, 8 did not complete the intravenous levodopa day visit - 1 was cancelled and did not want to reschedule due to COVID-19 restrictions, 2 past away in the time between the screen and the day visit, 1 no-showed for the day visit, 2 were lost to follow-up, and 2 indicated that they were too busy to attend a full day visit. 80 participants attended the day visit.
Participants by arm
| Arm | Count |
|---|---|
| Statin Before Levodopa Historical use of a statin BEFORE beginning levodopa
Intravenous Infusion: Intravenous levodopa given 1.0 to 1.5 mg/kg/hr from 0930 - 1130 on a single visit day. | 28 |
| Statin After Levodopa Historical use of a statin AFTER beginning levodopa
Intravenous Infusion: Intravenous levodopa given 1.0 to 1.5 mg/kg/hr from 0930 - 1130 on a single visit day. | 16 |
| No Statin No historical use of a statin
Intravenous Infusion: Intravenous levodopa given 1.0 to 1.5 mg/kg/hr from 0930 - 1130 on a single visit day. | 35 |
| Total | 79 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Statin Before Levodopa | Total | No Statin | Statin After Levodopa |
|---|---|---|---|---|
| Age at Parkinson's Diagnosis | 66.2 years STANDARD_DEVIATION 5.7 | 62.3 years STANDARD_DEVIATION 6.9 | 60.7 years STANDARD_DEVIATION 6.4 | 59.4 years STANDARD_DEVIATION 7.2 |
| Age, Continuous | 75.1 years STANDARD_DEVIATION 4.3 | 72.5 years STANDARD_DEVIATION 6.1 | 70.6 years STANDARD_DEVIATION 6.4 | 72.0 years STANDARD_DEVIATION 7 |
| Duration of Parkinson's Disease | 8.9 years STANDARD_DEVIATION 3 | 10.1 years STANDARD_DEVIATION 4 | 9.9 years STANDARD_DEVIATION 3.7 | 12.7 years STANDARD_DEVIATION 5 |
| Education | 16.6 years STANDARD_DEVIATION 2.6 | 16.5 years STANDARD_DEVIATION 2.8 | 16.4 years STANDARD_DEVIATION 3 | 16.9 years STANDARD_DEVIATION 3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 27 Participants | 77 Participants | 34 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Hoehn & Yahr Rating | 2.8 units on a scale STANDARD_DEVIATION 0.8 | 2.6 units on a scale STANDARD_DEVIATION 0.7 | 2.5 units on a scale STANDARD_DEVIATION 0.7 | 2.6 units on a scale STANDARD_DEVIATION 0.7 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 28 Participants | 78 Participants | 34 Participants | 16 Participants |
| Region of Enrollment United States | 28 Participants | 79 Participants | 35 Participants | 16 Participants |
| Sex: Female, Male Female | 7 Participants | 18 Participants | 9 Participants | 2 Participants |
| Sex: Female, Male Male | 21 Participants | 61 Participants | 26 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 32 | 1 / 17 | 0 / 39 |
| other Total, other adverse events | 0 / 29 | 1 / 16 | 1 / 35 |
| serious Total, serious adverse events | 1 / 29 | 1 / 16 | 3 / 35 |
Outcome results
Primary
Peak Unified Dyskinesia Rating Score (UDysRS)
The Unified Dyskinesia Rating Scale (UDysRS) combines patient, caregiver, and treating physician perspectives on both historical (Parts 1 & 2) and objective (Part 3 & 4) assessments of dyskinesia and dystonia. The historical portion and the objective ratings are added together to form total score ranging from 0 to 104 with higher scores indicating more severe dyskinesia.
Time frame: 11:00 am
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Statin Before Levodopa | Peak Unified Dyskinesia Rating Score (UDysRS) | 10.9 score on a scale | Standard Deviation 10.5 |
| Statin After Levodopa | Peak Unified Dyskinesia Rating Score (UDysRS) | 10.8 score on a scale | Standard Deviation 11.1 |
| No Statin | Peak Unified Dyskinesia Rating Score (UDysRS) | 13.2 score on a scale | Standard Deviation 10.9 |
p-value: 0.63ANOVA
Secondary
Clinical Dyskinesia Rating Scale (Peak)
The Clinical Dyskinesia Rating Scale (CDRS) is a commonly utilized scale that is completed by an observer who judges the severity of Levodopa induced dyskinesia (LID) in 7 body parts (face, neck, trunk, both legs, and both arms) during the force plate stance with a cognitive distraction task for 60 seconds. All body parts are rated separately on this 0 (none) to 4 (severe - markedly impairs activities) scale. Thus, the total score can range from 0 - 28 with 28 indicating the most severe LID. Peak CDRS ratings are the 11:00 am ratings.
Time frame: 11:00 am
Population: Historical use of a statin BEFORE beginning levodopa: excluded 2 participants that could not stand for 1 minute; No historical use of a statin: excluded 1 participant that had a pre-syncopal episode and was given time to recover before resuming ratings.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Statin Before Levodopa | Clinical Dyskinesia Rating Scale (Peak) | 1.9 score on a scale | Standard Deviation 2.6 |
| Statin After Levodopa | Clinical Dyskinesia Rating Scale (Peak) | 1.6 score on a scale | Standard Deviation 2.8 |
| No Statin | Clinical Dyskinesia Rating Scale (Peak) | 3.6 score on a scale | Standard Deviation 3.1 |
p-value: 0.033ANOVA
Secondary
Peak Unified Dyskinesia Rating Scale - Objective Measures
The Unified Dyskinesia Rating Scale (UDysRS) objective (Part 3 & 4) assessments of dyskinesia and dystonia. The objective ratings are added together to form total score ranging from 0 to 44 with higher scores indicating more severe dyskinesia.
Time frame: 11:00 am
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Statin Before Levodopa | Peak Unified Dyskinesia Rating Scale - Objective Measures | 5.5 score on a scale | Standard Deviation 5.1 |
| Statin After Levodopa | Peak Unified Dyskinesia Rating Scale - Objective Measures | 3.8 score on a scale | Standard Deviation 4.2 |
| No Statin | Peak Unified Dyskinesia Rating Scale - Objective Measures | 6.8 score on a scale | Standard Deviation 4.3 |
p-value: 0.09ANOVA
Secondary
Presence/Absence of Levodopa-induced Dyskinesia (LID).
Any score greater than or equal to 1 on the Clinical Dyskinesia Rating Scale (CDRS) during the intravenous levodopa cycle from 0900 - 1500. The CDRS is a commonly utilized scale that is completed by an observer who judges the severity of LID (0-4) in 7 body parts (face, neck, trunk, both legs, and both arms) during as the subject performs the cognitive distraction task while standing on the force plate for 60 seconds. CDRS ratings are made every half hour during the LD dose cycle by the principal investigator (KC) or co-investigator.
Time frame: Every half hour from 0900 to 1500
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Statin Before Levodopa | Presence/Absence of Levodopa-induced Dyskinesia (LID). | 16 Participants |
| Statin After Levodopa | Presence/Absence of Levodopa-induced Dyskinesia (LID). | 8 Participants |
| No Statin | Presence/Absence of Levodopa-induced Dyskinesia (LID). | 30 Participants |
p-value: 0.011Chi-squared