Validation of Dyskinesia Rating Scales

• Sponsor: Rush University Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT01071395
• Collaborator: Michael J. Fox Foundation for Parkinson's Research (Other)
• Enrollment: 68
• Locations: 8
• Arms: 2
• Duration (Months): 41
• Patients Per Site: 8.5
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Parkinson's Disease	Drug: Amantadine; Drug: Placebo	Phase 4

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 68 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Official Title: Validation of Dyskinesia Rating Scales
• Study Start Date: Jan 1, 2010
• Actual Primary Completion Date: Apr 1, 2012
• Actual Study Completion Date: Jun 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Amantadine Amantadine 100mg tab BID or TID for duration of study	Drug: Amantadine; Amantadine hydrochloride 300mg daily in three divided doses; Other Names: Symmetrel
Placebo Comparator: Placebo Placebo one tab BID or TID for duration of study	Drug: Placebo; Sugar pill given 3 times daily; Other Names: sugar pill

Outcome Measures

Primary Outcome Measures

1. 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). [18 months]

   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.

Secondary Outcome Measures

1. Differences in Slope From Baseline (BL) to End of Study (Data Will Include the 4 Week Scores) Between Placebo and Amantadine to Determine Which Scales Demonstrate Sensitivity Across Time. [18 months]

2. Change Score Differences Between Week 4 and 8 to Measure Stability of Scales Over Two Visits on Stable Doses of Amantadine or Placebo [18 months]

3. If Sufficient Number Are Maintained on 200 mg/Day, Differences in Change Scores Between 200 mg/Day and 300 mg/Day Amantadine. (This Analysis Will be BL vs End of Study) [18 months]

4. Correlations Among the Scales [18 months]

5. Correlations Between Scale Values and Clinical Global Impressions-Severity (CGI-s) and Correlations Between Scale Changes and Clinical Global Impression of Change (CGI-c) [18 months]

6. Safety Monitoring Will be Operative Throughout the Study [18 months]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 30 Years to 90 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Parkinson's disease patient, defined by United Kingdom Brain Bank criteria

2. Current age between 30-90

3. 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. *

4. Documentation of creatinine level at screening evaluation that is within the normal range for the local university laboratory.

5. Stable doses of all antiparkinsonian medications for at least 4 weeks

6. No treatment with amantadine for at least 3 months.

7. Presence of a caregiver willing to participate in the study

8. 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).

9. Subjects must be able to provide written informed consent.

10. If the subject received amantadine in the past, the drug was stopped for reason other than adverse events.

11. 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.

12. The subject must be willing to participate in all study related activities and visits.

Exclusion Criteria:

1. Subjects who have had prior brain surgery.

2. Subjects with other major illnesses that could be complicated by amantadine exposure, including glaucoma, current hallucinations, urinary retention.

3. Subjects with dementia, depression and psychosis as determined by clinical examination.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama-Birmingham (UAB)	Birmingham	Alabama	United States	35043
2	University of South Florida	Tampa	Florida	United States	33606
3	Rush University Medical Center	Chicago	Illinois	United States	60612
4	Duke University	Durham	North Carolina	United States	27705
5	Oregon Health & Science University (OHSU)	Portland	Oregon	United States	97239-9059
6	Universitatsklinik fur Neurologie	Innsbruck		Austria	6020
7	Toronto Western Hospital (Movement Disorder Center)	Toronto	Ontario	Canada	M5T2S8
8	Centre d'investigation Clinique, CHU de Toulouse	Toulouse Cedex 9		France	31059

Sponsors and Collaborators

• Rush University Medical Center
• Michael J. Fox Foundation for Parkinson's Research

Investigators

• Principal Investigator: Christopher G Goetz, MD, Rush University Medical Center
• Principal Investigator: Glenn T Stebbins, PhD, Rush University Medical Center

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Parkinson's Disease Foundation

Publications

None provided.

• Responsible Party: Christopher G. Goetz, MD, MD, Rush University Medical Center
• ClinicalTrials.gov Identifier: NCT01071395
• Other Study ID Numbers: Valid Dyskin Rating Scales
• First Posted: Feb 19, 2010
• Last Update Posted: May 28, 2015
• Last Verified: May 1, 2015

• Keywords provided by Christopher G. Goetz, MD, MD, Rush University Medical Center: Parkinson's disease; Dyskinesia; Dyskinesia Rating Scales; Amantadine; Placebo
• Additional relevant MeSH terms: Parkinson Disease; Dyskinesias; Amantadine

Study Results

Participant Flow

Recruitment Details	Location: Medical clinics

Arm/Group Title	Amantadine	Placebo
Arm/Group Description	Amantadine: Amantadine hydrochloride 300mg daily in three divided doses	Placebo: Sugar pill given 3 times daily
Period Title: Overall Study
STARTED	36	32
COMPLETED	31	30
NOT COMPLETED	5	2

Baseline Characteristics

Arm/Group Title	Amantadine	Placebo	Total
Arm/Group Description	Amantadine: Amantadine hydrochloride 300mg daily in three divided doses	Placebo: Sugar pill given 3 times daily	Total of all reporting groups
Overall Participants	36	32	68
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	65.4 (8.2)	68.5 (6.9)	66.8 (7.7)
Sex: Female, Male (Count of Participants)
Female	10 27.8%	11 34.4%	21 30.9%
Male	26 72.2%	21 65.6%	47 69.1%
Region of Enrollment (participants) [Number]
France	2 5.6%	4 12.5%	6 8.8%
United States	25 69.4%	23 71.9%	48 70.6%
Canada	4 11.1%	1 3.1%	5 7.4%
Austria	5 13.9%	4 12.5%	9 13.2%
Movement Disorder Society revision of the Unified Parkinson's Disease Rating Scale MDS-UPDRS Part I (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	9.8 (5.2)	10.2 (5.2)	10.0 (5.2)
MDS-UPDRS Part II (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	13.8 (5.8)	14.3 (6.5)	14.0 (6.1)
MDS-UPDRS Part III (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	24.3 (10.7)	20.3 (13.6)	22.5 (12.2)
MDS-UPDRS Part IV (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	8.5 (3.1)	9.9 (3.6)	9.2 (3.4)
Hoehn & Yahr Stage (units on a scale) [Median (Full Range) ]
Median (Full Range) [units on a scale]	2	2	2

Outcome Measures

1. Primary Outcome

Title	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).
Description	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.
Time Frame	18 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Amantadine	Placebo
Arm/Group Description	Amantadine: Amantadine hydrochloride 300mg daily in three divided doses	Placebo: Sugar pill given daily in three divided doses
Measure Participants	31	30
Number [unitless]	0.061	0.061

2. Secondary Outcome

Title	Differences in Slope From Baseline (BL) to End of Study (Data Will Include the 4 Week Scores) Between Placebo and Amantadine to Determine Which Scales Demonstrate Sensitivity Across Time.
Time Frame	18 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Secondary Outcome

Title	Change Score Differences Between Week 4 and 8 to Measure Stability of Scales Over Two Visits on Stable Doses of Amantadine or Placebo
Time Frame	18 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	If Sufficient Number Are Maintained on 200 mg/Day, Differences in Change Scores Between 200 mg/Day and 300 mg/Day Amantadine. (This Analysis Will be BL vs End of Study)
Time Frame	18 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Correlations Among the Scales
Time Frame	18 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Secondary Outcome

Title	Correlations Between Scale Values and Clinical Global Impressions-Severity (CGI-s) and Correlations Between Scale Changes and Clinical Global Impression of Change (CGI-c)
Time Frame	18 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Secondary Outcome

Title	Safety Monitoring Will be Operative Throughout the Study
Time Frame	18 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	Adverse event recording occurred throughout the study duration.
Arm/Group Title	Amantadine		Placebo
Arm/Group Description	Amantadine: Amantadine hydrochloride 300mg daily in three divided doses		Placebo: Sugar pill given 3 times daily
All Cause Mortality
	Amantadine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Amantadine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/36 (0%)		0/32 (0%)
Other (Not Including Serious) Adverse Events
	Amantadine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/36 (11.1%)		3/32 (9.4%)
Gastrointestinal disorders
Dry mouth	4/36 (11.1%)	4	3/32 (9.4%)	3

Limitations/Caveats

Study limitations include the patient population universally derived from university centers and the short duration of the program.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.