TOP-DYSK: Topiramate as an Adjunct to Amantadine in the Treatment of Dyskinesia in Parkinson's Disease

• Sponsor: Rush University Medical Center (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01789047
• Collaborator: Michael J. Fox Foundation for Parkinson's Research (Other)
• Enrollment: 42
• Locations: 5
• Arms: 2
• Duration (Months): 40
• Patients Per Site: 8.4
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The study will involve an eighteen-week, double-blind, placebo-controlled parallel designed comparison between add-on topiramate and add-on placebo to stable treatment with amatadine in the treatment of Parkinson's disease (PD) patients who continue to have dyskinesia on amantadine.

Condition or Disease	Intervention/Treatment	Phase
Idiopathic Parkinson's Disease; Drug Induced Dyskinesia	Drug: Topiramate; Drug: Placebo; Drug: Amantadine	Phase 2

Detailed Description

We conducted a randomized placebo controlled trial of topiramate in PD dyskinetic subjects already on amantadine but with continuing dyskinesia. Topiramate or placebo was introduced in blinded fashion with a gradual titration (topiramate 25-150 mg/d) over 6 weeks and then a maintenance period of 8 weeks. The primary outcome of interest was change from baseline to end of study in total Unified Dyskinesia Rating Scale (UDysRS) score using Intention to Treat analysis.

Study Design

• Study Type: Interventional
• Actual Enrollment: 42 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Topiramate as an Adjunct to Amantadine in the Treatment of Dyskinesia in Parkinson's Disease
• Study Start Date: Mar 1, 2013
• Actual Primary Completion Date: Jul 1, 2016
• Actual Study Completion Date: Jul 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Topiramate Topiramate as adjunct to amantadine.	Drug: Topiramate; Topiramate as adjunct to amantadine; Other Names: Topamax ; Drug: Amantadine; Existing treatment for all participants; Other Names: Symmetrel
Placebo Comparator: Placebo (sugar pill) Placebo	Drug: Placebo; Placebo control; Other Names: sugar pill ; Drug: Amantadine; Existing treatment for all participants; Other Names: Symmetrel

Outcome Measures

Primary Outcome Measures

1. The Unified Dyskinesia Rating Scale (UDysRS) [Change from baseline to week 14 (end of study) on the Unified Dyskinesia Rating Scale]

   The Unified Dyskinesia Rating Scale (UDysRS) will be the primary outcome measure for this study. This choice is based on the outcome of the Validation of Dyskinesia Rating Scales study. In this study, the UDysRS was identified as the most sensitive scale to detect change in dyskinesia in an 8-week, double-blind, placebo-controlled trial of amatadine. The UDysRS utilizes rater information, patient self-report and objective measures of dyskinesia to provide assessments of impairment and disability due to dyskinesia. Score ranges are 0-108 with higher scores representing more severe impairment.

Other Outcome Measures

1. Clinical Global Impression - Change Score [Assessed at Week 10 and 14 by blinded treating physician and subject]

   The Clinical Global Impression - Change score is an ordinal measure of change with a range of 0 (not assessed) to 7 (very much worse). A score of 4 is associated with "no change".

2. Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) [Assessed at baseline, week 6, week 10 and week 14]

   This is a 4-part scale that rates both non-motor and motor (including dyskinesia) aspects of Parkinson's disease. Parts of the scales will be completed by the blinded treating physician while assessing the subject and other parts will be self-completed by the subject

3. Hoehn & Yahr Staging [Assessment completed at baseline, week 6, week 10 and week 14]

   Hoehn & Yahr staging of Parkinson's disease is completed by the blinded treating physician assessing the subject

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 (UK) Brain Bank criteria

2. Current age between 30-90

3. Clinically pertinent dyskinesias defined by Clinical Global Impression - Severity (CGI-s) score (see attachment) > 3 (mild) established by clinician's total assessment of patient including objective observation during the screening process. *

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

5. Stable treatment with at least 200 mg amantadine for at least 4 weeks.

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

7. 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.

8. Subjects must be free of dementia, depression and psychosis as determined by clinical examination.

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

Exclusion criteria:

1. Any subjects with clinical evidence suggestive of an atypical or secondary form of Parkinson's Disease

2. Any subject who, in the opinion of the Principal Investigator, has a concomitant medical illness which would preclude them from being treated with amantadine,

3. Any subject who, in the opinion of the Principal Investigator, will be unable to maintain current stable dosing of their anti-parkinsonian medications for the duration of the trial,

4. Any subject with evidence for dementia, depression, or psychosis, as determined by clinical examination.

5. Any subject who has not signed informed consent, or unable or unwilling to participate in all of the study related activities.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama	Birmingham	Alabama	United States	35233
2	University of South Florida	Tampa	Florida	United States	33612
3	Rush University Medical Center	Chicago	Illinois	United States	60612
4	Duke University	Durham	North Carolina	United States	27705
5	Oregon Health Sciences University	Portland	Oregon	United States	97201

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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Christopher G. Goetz, MD, MD, Rush University Medical Center
• ClinicalTrials.gov Identifier: NCT01789047
• Other Study ID Numbers: TOP-DYSK
• First Posted: Feb 11, 2013
• Last Update Posted: Apr 16, 2019
• Last Verified: Mar 1, 2019

• Keywords provided by Christopher G. Goetz, MD, MD, Rush University Medical Center: Parkinson's disease; dyskinesia; Indonesia; amantadine
• Additional relevant MeSH terms: Parkinson Disease; Dyskinesias; Dyskinesia, Drug-Induced; Topiramate; Amantadine

Study Results

Participant Flow

Arm/Group Title	Topiramate	Placebo (Sugar Pill)
Arm/Group Description	Topiramate as adjunct to amantadine. Topiramate: Topiramate as adjunct to amantadine	Placebo Placebo: Placebo control
Period Title: Overall Study
STARTED	21	21
COMPLETED	17	17
NOT COMPLETED	4	4

Baseline Characteristics

Arm/Group Title	Topiramate	Placebo (Sugar Pill)	Total
Arm/Group Description	Topiramate as adjunct to amantadine. Topiramate: Topiramate as adjunct to amantadine	Placebo Placebo: Placebo control	Total of all reporting groups
Overall Participants	21	21	42
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.5 (6.9)	63.1 (8.9)	62.7 (7.4)
Sex: Female, Male (Count of Participants)
Female	6 28.6%	9 42.9%	15 35.7%
Male	15 71.4%	12 57.1%	27 64.3%
Region of Enrollment (Count of Participants)
United States	21 100%	21 100%	42 100%

Outcome Measures

1. Primary Outcome

Title	The Unified Dyskinesia Rating Scale (UDysRS)
Description	The Unified Dyskinesia Rating Scale (UDysRS) will be the primary outcome measure for this study. This choice is based on the outcome of the Validation of Dyskinesia Rating Scales study. In this study, the UDysRS was identified as the most sensitive scale to detect change in dyskinesia in an 8-week, double-blind, placebo-controlled trial of amatadine. The UDysRS utilizes rater information, patient self-report and objective measures of dyskinesia to provide assessments of impairment and disability due to dyskinesia. Score ranges are 0-108 with higher scores representing more severe impairment.
Time Frame	Change from baseline to week 14 (end of study) on the Unified Dyskinesia Rating Scale

Outcome Measure Data

Analysis Population Description

Last Observation Carried Forward imputation

Arm/Group Title	Topiramate	Placebo (Sugar Pill)
Arm/Group Description	Topiramate as adjunct to amantadine. Topiramate: Topiramate as adjunct to amantadine	Placebo Placebo: Placebo control
Measure Participants	21	21
Mean (Standard Deviation) [units on a scale]	4.00 (11.34)	1.67 (10.27)

2. Other Pre-specified Outcome

Title	Clinical Global Impression - Change Score
Description	The Clinical Global Impression - Change score is an ordinal measure of change with a range of 0 (not assessed) to 7 (very much worse). A score of 4 is associated with "no change".
Time Frame	Assessed at Week 10 and 14 by blinded treating physician and subject

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Other Pre-specified Outcome

Title	Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS)
Description	This is a 4-part scale that rates both non-motor and motor (including dyskinesia) aspects of Parkinson's disease. Parts of the scales will be completed by the blinded treating physician while assessing the subject and other parts will be self-completed by the subject
Time Frame	Assessed at baseline, week 6, week 10 and week 14

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Other Pre-specified Outcome

Title	Hoehn & Yahr Staging
Description	Hoehn & Yahr staging of Parkinson's disease is completed by the blinded treating physician assessing the subject
Time Frame	Assessment completed at baseline, week 6, week 10 and week 14

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Arm/Group Title	Topiramate		Placebo (Sugar Pill)
Arm/Group Description	Topiramate as adjunct to amantadine. Topiramate: Topiramate as adjunct to amantadine		Placebo Placebo: Placebo control
All Cause Mortality
	Topiramate		Placebo (Sugar Pill)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/21 (0%)		0/21 (0%)
Serious Adverse Events
	Topiramate		Placebo (Sugar Pill)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/21 (9.5%)		0/21 (0%)
Injury, poisoning and procedural complications
Fall leading to hospitalization	1/21 (4.8%)	1	0/21 (0%)	0
Nervous system disorders
Transit Ischemic Attack-like symptoms	1/21 (4.8%)	1	0/21 (0%)	0
Other (Not Including Serious) Adverse Events
	Topiramate		Placebo (Sugar Pill)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/21 (76.2%)		12/21 (57.1%)
Eye disorders
Blurred vision	3/21 (14.3%)	3	1/21 (4.8%)	1
Gastrointestinal disorders
Decreased appetite	2/21 (9.5%)	2	0/21 (0%)	0
Worsening constipation	0/21 (0%)	0	1/21 (4.8%)	1
General disorders
Biting lower lip	1/21 (4.8%)	1	0/21 (0%)	0
Dry mouth	1/21 (4.8%)	1	2/21 (9.5%)	2
Falls	2/21 (9.5%)	2	1/21 (4.8%)	1
Fatigue	1/21 (4.8%)	1	1/21 (4.8%)	1
Headache	1/21 (4.8%)	1	0/21 (0%)	0
Tingling fingers and toes	1/21 (4.8%)	1	0/21 (0%)	0
Infections and infestations
Common cold	1/21 (4.8%)	1	0/21 (0%)	0
Ottis media	1/21 (4.8%)	1	0/21 (0%)	0
Sinus infection	1/21 (4.8%)	1	2/21 (9.5%)	2
Metabolism and nutrition disorders
Weight gain	0/21 (0%)	0	1/21 (4.8%)	1
Weight loss	3/21 (14.3%)	3	0/21 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Pre cancerous lesion	1/21 (4.8%)	1	0/21 (0%)	0
Nervous system disorders
Balance instability	1/21 (4.8%)	1	1/21 (4.8%)	1
cognitive decline	0/21 (0%)	0	1/21 (4.8%)	1
Confusion	0/21 (0%)	0	1/21 (4.8%)	1
Dizziness	2/21 (9.5%)	2	1/21 (4.8%)	1
Increased OFF time	2/21 (9.5%)	2	3/21 (14.3%)	3
Increased dreaming	0/21 (0%)	0	1/21 (4.8%)	1
Increased freezing of gait	0/21 (0%)	0	1/21 (4.8%)	1
Speech abnormalities	1/21 (4.8%)	1	1/21 (4.8%)	1
Psychiatric disorders
Hallucinations	2/21 (9.5%)	2	2/21 (9.5%)	2
Respiratory, thoracic and mediastinal disorders
Cough	2/21 (9.5%)	2	0/21 (0%)	0
Intermittent SOB	1/21 (4.8%)	1	0/21 (0%)	0

Limitations/Caveats

[Not Specified]

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.