Validation of Dyskinesia Rating Scales

Study Overview
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Brief Summary
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This study will evaluate the responsiveness of a variety of available dyskinesia rating scales to treatment with amantadine or placebo in Parkinson's disease patients with dyskinesia. The study will be a parallel, double-blind, randomized trial of 68 patients treated with amantadine or placebo for 8 weeks. Pre-treatment evaluations will be performed and compared to end of study evaluations on the best treatment dose (200 or 300 mg amantadine or matching placebo) daily. Safety evaluations will be conducted. The responsiveness of the different scales will be evaluated statistically with a mixed model in which changes in the outcome measures over time will include a fixed effect of treatment group assignment. The model will additionally account for random effects of intercepts (the scale scores at baseline) that will include both random variation (person-specific) and specific variation associated with rate of change in outcome. The investigators may include adjustments for possible confounding covariates, including baseline demographics and center. The goal of the program is to provide researchers with the best scale(s) to distinguish dyskinesia change in Parkinson's disease (PD) associated with amantadine in comparison to placebo and to establish the magnitude of effect achievable with amantadine as a comparator gold standard that must be met or surpassed by future anti-dyskinetic agents. Additionally, with the use of paper and pencil questionnaires, the study will investigate the impact of patient optimism and patient and rater expectation of positive effects on the dyskinesia rating outcomes.

Detailed Description
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Objective/Rationale: Dyskinesias, or involuntary jerking movements, are troublesome problems for many Parkinson's disease patients. Chemical studies have led to the development of several new treatment strategies. However, because dyskinesias are cause various degrees of difficulty for patients and are often perceived by patients and caregivers differently than by doctors, the rating of dyskinesias remains a scientific challenge. This program will examine a wide gamut of available rating scales to determine which one(s) detect change during dyskinesia treatment. Establishing excellent measurement tools of dyskinesias will allow future treatments to be evaluated in a uniform and maximally effective manner. Project Description: An team of experts will test several dyskinesia scales in a group of Parkinson's disease patients with dyskinesia. Patients will be treated with either amantadine or placebo (an inactive product). The study will be blinded so that the raters and the patients do not know if a given patient is receiving amantadine or placebo. Amantadine is selected for this trial, because it is the only drug that has received the designation of Efficacious for dyskinesia by the Movement Disorder Society. This conclusion was based however, on small studies and no large clinical trial of this drug has been conducted in dyskinetic patients. The scales will assess dyskinesia before and after several weeks of treatment. Relevance to Diagnosis/Treatment of Parkinson's Disease: This study will establish a gold standard for rating dyskinesia in future trials of treatments in Parkinson's disease patients. It will allow physicians to know the level of change that occurs with a standard and available treatment (amantadine) and to compare that level with changes that occur with newer treatments. Patients will benefit from this new international standard, because they can compare the likelihood and magnitude of anticipated improvement from different dyskinesia treatments, whether medical or surgical. Anticipated Outcome: The anticipated outcomes of this study are: The impact of amantadine treatment on dyskinesia will be clearly defined. The effect that participation in a clinical program, even if no amantadine is given (placebo improvements) will be delineated. A hierarchy of numerous scales will be determined based on their absolute and relative capability to detect change during treatment. The best scale(s) to evaluate dyskinesia in clinical practice and research efforts will be identified.

Official Title
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Validation of Dyskinesia Rating Scales

Conditions
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Parkinson's Disease

Intervention / Treatment
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* Drug: Amantadine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Parkinson's disease patient, defined by United Kingdom Brain Bank criteria Current age between 30-90 Clinically pertinent dyskinesias defined by Clinical Gl;obal Impression-severity score (see attachment) > 3 (mild) established by clinician's total assessment of patient including objective observation during the screening process. * Documentation of creatinine level at screening evaluation that is within the normal range for the local university laboratory. Stable doses of all antiparkinsonian medications for at least 4 weeks No treatment with amantadine for at least 3 months. Presence of a caregiver willing to participate in the study Subjects/caregivers must demonstrate the capacity to complete an accurate home diary based on training and evaluation during the screening period (see attached training rules). Subjects must be able to provide written informed consent. If the subject received amantadine in the past, the drug was stopped for reason other than adverse events. In the opinion of the enrolling investigator, the subject will be able to maintain current dosing schedule of antiparkinsonian drugs for the duration of the trial. The subject must be willing to participate in all study related activities and visits. Exclusion Criteria: Subjects who have had prior brain surgery. Subjects with other major illnesses that could be complicated by amantadine exposure, including glaucoma, current hallucinations, urinary retention. Subjects with dementia, depression and psychosis as determined by clinical examination.

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Amantadine<br>Amantadine 100mg tab BID or TID for duration of study | Drug: Amantadine<br>* Amantadine hydrochloride 300mg daily in three divided doses<br>* Other names: Symmetrel;|
| Placebo Comparator: Placebo<br>Placebo one tab BID or TID for duration of study | Drug: Placebo<br>* Sugar pill given 3 times daily<br>* Other names: sugar pill;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Investigators Will Assess Effect Size With Each Scale for Detecting Change From Baseline and Change Between Amantadine and Placebo; Allowing Assessment of Sensitivity and Specificity for Each Scale Based on Receiver Operator Characteristics (ROC). | Analyses of primary outcome measures tested sensitivity to change in dyskinesia (time effect) as well as sensitivity to differences in treatment effect (time-by-treatment interaction). These analyses were conducted using repeated-measures ANOVA (RM-ANOVA) or nonparametric analyses (Friedman's ANOVA with follow-up Wilcoxon tests). The RM-ANOVAs tested for changes in scale scores over baseline, week 4, and week 8 visits across the entire sample (time effect), as well as differences in these changes over time between treatment groups (time-by-treatment interaction). Effect size of time to change was compared using a partial eta-square estimate of effect size. An eta-squared less than or equal to 0.01 is considered small; 0.06 is considered medium; and, 0.14 is considered large. | 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Parkinson's disease, Dyskinesia, Dyskinesia Rating Scales, Amantadine, Placebo