Placebo-controlled Study in Patients With Parkinson's Disease to Evaluate the Effect of Rotigotine on Non-motor Symptoms

Study Overview
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Brief Summary
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The primary objective of this study was to demonstrate that Rotigotine improves non-motor symptoms compared to Placebo in subjects with Parkinson's Disease.

Official Title
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Multicenter, Double-blind, Placebo-controlled, Parallel-group, Phase IV Study to Assess the Effect of Rotigotine on Non-motor Symptoms in Patients With Idiopathic Parkinson's Disease

Conditions
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Idiopathic Parkinson's Disease

Intervention / Treatment
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* Other: Placebo
* Drug: Rotigotine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is male or female, ≥18 years of age Subject has idiopathic Parkinson's disease with at least 2 of the following cardinal signs being present: bradykinesia, resting tremor, rigidity or postural instability, and without any other known or suspected cause of Parkinsonism Subject has a Hoehn and Yahr stage score ≤4 Subject has a total Non-Motor Symptoms Scale (NMSS) score ≥40 If the subject is taking levodopa (L-DOPA), he/she must be on a stable dose of L-DOPA (in combination with benserazide or carbidopa) for at least 28 days prior to the Baseline Visit If the subject is receiving anticholinergics, monoamine oxidase (MAO) B inhibitors, or amantadine, he/she must have been on a stable dose for at least 28 days prior to the Baseline Visit and must be maintained on that dose for the duration of the study Exclusion Criteria: Subject discontinued from previous therapy with a dopamine agonist after an adequate length of treatment, at an adequate dose, due to lack of efficacy as assessed by the investigator Subject is receiving therapy with 1 of the following drugs, either concurrently or within 28 days prior to the Baseline Visit: alpha-methyl dopa, metoclopramide, reserpine, neuroleptics (except specific atypical neuroleptics: olanzapine, ziprasidone, aripiprazole, clozapine, and quetiapine), monoamine oxidase-A (MAO-A) inhibitors, methylphenidate, amphetamine, or other dopamine agonists (DAs) Subject is receiving central nervous system (CNS) therapy (eg, sedatives, hypnotics, selective serotonin reuptake inhibitors [SSRIs], anxiolytics, or other sleep-modifying medication) unless dose has been stable daily for at least 28 days prior to the Baseline Visit and is likely to remain stable for the duration of the study Subject has evidence of an impulse control disorder according to the modified Minnesota Impulsive Disorders Interview at the Screening Visit (Visit 1), confirmed by a positive structured clinical interview

Ages Eligible for Study
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Minimum Age: 18 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br> | Other: Placebo<br>* Placebo patches of 2, 4, 6 & 8 mg / 24 hours Daily application of Placebo patches starting at 2 mg / 24 hours (early Parkinson's Disease (PD) patients) or 4 mg / 24 hours (advanced PD patients). Dose was up-titrated in weekly increments of 2 mg / 24 hours until optimal or maximal dose was reached. Maximal dose was 8 mg / 24 hours for early PD patients and 16 mg / 24 hours for advanced PD patients. Optimal or maximal dose was maintained for 12 weeks followed by a de-escalation by 2 mg / 24 hours every other day.<br>|
| Experimental: Rotigotine<br> | Drug: Rotigotine<br>* Rotigotine patches of 2, 4, 6, and 8 mg / 24 hours Once daily application of Rotigotine patches starting at 2 mg / 24 hours (early Parkinson's Disease (PD) patients) or 4 mg / 24 hours (advanced PD patients). Dose was up-titrated in weekly increments of 2 mg / 24 hours until optimal or maximal dose was reached. Maximal dose is 8 mg / 24 hours for early PD patients and 16 mg / 24 hours for advanced PD patients. Optimal or maximal dose was maintained for 12 weeks followed by a de-escalation by 2 mg / 24 hours every other day.<br>* Other names: Neupro®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to the End of Maintenance in Total Nonmotor Symptoms Scale (NMSS) Score | The Nonmotor Symptoms Scale (NMSS) is a validated tool for rating frequency and severity of nonmotor symptoms in Parkinson's Disease (PD). The severity and frequency of the subject's nonmotor symptoms is assessed by the investigator in the following 9 domain categories: cardiovascular, including falls; sleep/fatigue; mood/cognition; perceptual problems/hallucinations; attention/memory; gastrointestinal tract; urinary; sexual function; miscellaneous. Severity and frequency are rated using a 4-point scale ranging from 0 (none) to 3 (severe; major source of distress or disturbance to subject) for severity and from 1 (rarely) to 4 (very frequent [daily or all the time]) for frequency. The total NMSS score ranges from 0 to 350. A negative change from Baseline to end of Maintenance indicates an improvement in NMSS. | From Baseline (Day 1) to end of 12-week Maintenance (Day 84) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to the End of Maintenance in Total Unified Parkinson's Disease Rating Scale (UPDRS) Part III Score | The Unified Parkinson's Disease Rating Scale (UPDRS) Part III is a scale for the assessment of function in Parkinson's Disease. UPDRS Part III measures Motor Function. It consists of 14 items with 27 questions, each ranging from 0 to 4. The sum score for the UPDRS Part III ranges from 0 to 108. A higher score indicates greater disability. A negative change from Baseline to end of Maintenance score indicates improvement. | From Baseline (Day 1) to end of 12-week Maintenance (Day 84) | 
| Change From Baseline to the End of Maintenance in Health-related Quality of Life (HRQL) Measured by a 39-item Parkinson's Disease Questionnaire (PDQ-39) | Parkinson's Disease Questionnaire - 39 (PDQ-39) is a self-administered questionnaire. It comprises of 39 questions, relating to eight key areas of health and daily activities, including both Motor and Non-motor symptoms. It is scored on a scale of zero to 100, with lower scores indicating better health and high scores more severe symptoms in change from Baseline to end of Maintenance. | From Baseline (Day 1) to end of 12-week Maintenance (Day 84) | 
| Change From Baseline to the End of Maintenance in the Nonmotor Symptoms Scale Score: Subdomain Cardiovascular | The Nonmotor Symptoms Scale (NMSS) is a validated tool for rating frequency and severity of nonmotor symptoms in Parkinson's Disease (PD). The severity and frequency of the subject's nonmotor symptoms is assessed by the investigator in 9 different domains. Severity (ranges: 0 = None, 1 = Mild, 2 = Moderate, 3 = Severe) and frequency (ranges: 1 = Rarely (<1/wk), 2 = Often (1/wk), 3 = Frequent (several times per week), 4 = Very Frequent (daily or all the time) are rated using a 4-point scale. The final score is derived from multiplying the severity score and the frequency score. A negative change from Baseline to end of Maintenance indicates an improvement in NMSS. The possible min/max final scores per subdomain are calculated as follows: Range of final score per subdomain: 0 - 12 per question multiplied by the number of questions per subdomain: Subdomain Cardiovascular (2 questions): range 0 - 24 | From Baseline (Day 1) to end of 12-week Maintenance (Day 84) | 
| Change From Baseline to the End of Maintenance in the Nonmotor Symptoms Scale Score: Subdomain Sleep/Fatigue | The Nonmotor Symptoms Scale (NMSS) is a validated tool for rating frequency and severity of nonmotor symptoms in Parkinson's Disease (PD). The severity and frequency of the subject's nonmotor symptoms is assessed by the investigator in 9 different domains. Severity (ranges: 0 = None, 1 = Mild, 2 = Moderate, 3 = Severe) and frequency (ranges: 1 = Rarely (<1/wk), 2 = Often (1/wk), 3 = Frequent (several times per week), 4 = Very Frequent (daily or all the time) are rated using a 4-point scale. The final score is derived from multiplying the severity score and the frequency score. A negative change from Baseline to end of Maintenance indicates an improvement in NMSS. The possible min/max final scores per subdomain are calculated as follows: Range of final score per subdomain: 0 - 12 per question multiplied by the number of questions per subdomain: Subdomain Sleep/Fatigue (4 questions): range 0-48 | From Baseline (Day 1) to end of 12-week Maintenance (Day 84) | 
| Change From Baseline to the End of Maintenance in the Nonmotor Symptoms Scale Score: Subdomain Mood/Cognition | The Nonmotor Symptoms Scale (NMSS) is a validated tool for rating frequency and severity of nonmotor symptoms in Parkinson's Disease (PD). The severity and frequency of the subject's nonmotor symptoms is assessed by the investigator in 9 different domains. Severity (ranges: 0 = None, 1 = Mild, 2 = Moderate, 3 = Severe) and frequency (ranges: 1 = Rarely (<1/wk), 2 = Often (1/wk), 3 = Frequent (several times per week), 4 = Very Frequent (daily or all the time) are rated using a 4-point scale. The final score is derived from multiplying the severity score and the frequency score. A negative change from Baseline to end of Maintenance indicates an improvement in NMSS. The possible min/max final scores per subdomain are calculated as follows: Range of final score per subdomain: 0 - 12 per question multiplied by the number of questions per subdomain: Subdomain Mood/Cognition (6 questions): range 0 - 72 | From Baseline (Day 1) to end of 12-week Maintenance (Day 84) | 
| Change From Baseline to the End of Maintenance in the Nonmotor Symptoms Scale Score: Subdomain Perception/Hallucinations | The Nonmotor Symptoms Scale (NMSS) is a validated tool for rating frequency and severity of nonmotor symptoms in Parkinson's Disease (PD). The severity and frequency of the subject's nonmotor symptoms is assessed by the investigator in 9 different domains. Severity (ranges: 0 = None, 1 = Mild, 2 = Moderate, 3 = Severe) and frequency (ranges: 1 = Rarely (<1/wk), 2 = Often (1/wk), 3 = Frequent (several times per week), 4 = Very Frequent (daily or all the time) are rated using a 4-point scale. The final score is derived from multiplying the severity score and the frequency score. A negative change from Baseline to end of Maintenance indicates an improvement in NMSS. The possible min/max final scores per subdomain are calculated as follows: Range of final score per subdomain: 0 - 12 per question multiplied by the number of questions per subdomain: Subdomain Perception/Hallucinations (3 questions): range 0 - 36 | From Baseline (Day 1) to end of 12-week Maintenance (Day 84) | 
| Change From Baseline to the End of Maintenance in the Nonmotor Symptoms Scale Score: Subdomain Attention/Memory, | The Nonmotor Symptoms Scale (NMSS) is a validated tool for rating frequency and severity of nonmotor symptoms in Parkinson's Disease (PD). The severity and frequency of the subject's nonmotor symptoms is assessed by the investigator in 9 different domains. Severity (ranges: 0 = None, 1 = Mild, 2 = Moderate, 3 = Severe) and frequency (ranges: 1 = Rarely (<1/wk), 2 = Often (1/wk), 3 = Frequent (several times per week), 4 = Very Frequent (daily or all the time) are rated using a 4-point scale. The final score is derived from multiplying the severity score and the frequency score. A negative change from Baseline to end of Maintenance indicates an improvement in NMSS. The possible min/max final scores per subdomain are calculated as follows: Range of final score per subdomain: 0 - 12 per question multiplied by the number of questions per subdomain: Subdomain Attention/Memory (3 questions): range 0 - 36 | From Baseline (Day 1) to end of 12-week Maintenance (Day 84) | 
| Change From Baseline to the End of Maintenance in the Nonmotor Symptoms Scale Score: Subdomain Gastrointestinal Tract | The Nonmotor Symptoms Scale (NMSS) is a validated tool for rating frequency and severity of nonmotor symptoms in Parkinson's Disease (PD). The severity and frequency of the subject's nonmotor symptoms is assessed by the investigator in 9 different domains. Severity (ranges: 0 = None, 1 = Mild, 2 = Moderate, 3 = Severe) and frequency (ranges: 1 = Rarely (<1/wk), 2 = Often (1/wk), 3 = Frequent (several times per week), 4 = Very Frequent (daily or all the time) are rated using a 4-point scale. The final score is derived from multiplying the severity score and the frequency score. A negative change from Baseline to end of Maintenance indicates an improvement in NMSS. The possible min/max final scores per subdomain are calculated as follows: Range of final score per subdomain: 0 - 12 per question multiplied by the number of questions per subdomain: Subdomain Gastrointestinal tract (3 questions): range 0 - 36 | From Baseline (Day 1) to end of 12-week Maintenance (Day 84) | 
| Change From Baseline to the End of Maintenance in the Nonmotor Symptoms Scale Score: Subdomain Urinary | The Nonmotor Symptoms Scale (NMSS) is a validated tool for rating frequency and severity of nonmotor symptoms in Parkinson's Disease (PD). The severity and frequency of the subject's nonmotor symptoms is assessed by the investigator in 9 different domains. Severity (ranges: 0 = None, 1 = Mild, 2 = Moderate, 3 = Severe) and frequency (ranges: 1 = Rarely (<1/wk), 2 = Often (1/wk), 3 = Frequent (several times per week), 4 = Very Frequent (daily or all the time) are rated using a 4-point scale. The final score is derived from multiplying the severity score and the frequency score. A negative change from Baseline to end of Maintenance indicates an improvement in NMSS. The possible min/max final scores per subdomain are calculated as follows: Range of final score per subdomain: 0 - 12 per question multiplied by the number of questions per subdomain: Subdomain Urinary (3 questions): range 0 - 36 | From Baseline (Day 1) to end of 12-week Maintenance (Day 84) | 
| Change From Baseline to the End of Maintenance in the Nonmotor Symptoms Scale Score: Subdomain Sexual Function | The Nonmotor Symptoms Scale (NMSS) is a validated tool for rating frequency and severity of nonmotor symptoms in Parkinson's Disease (PD). The severity and frequency of the subject's nonmotor symptoms is assessed by the investigator in 9 different domains. Severity (ranges: 0 = None, 1 = Mild, 2 = Moderate, 3 = Severe) and frequency (ranges: 1 = Rarely (<1/wk), 2 = Often (1/wk), 3 = Frequent (several times per week), 4 = Very Frequent (daily or all the time) are rated using a 4-point scale. The final score is derived from multiplying the severity score and the frequency score. A negative change from Baseline to end of Maintenance indicates an improvement in NMSS. The possible min/max final scores per subdomain are calculated as follows: Range of final score per subdomain: 0 - 12 per question multiplied by the number of questions per subdomain: Subdomain Sexual function (2 questions): range 0 - 24 | From Baseline (Day 1) to end of 12-week Maintenance (Day 84) | 
| Change From Baseline to the End of Maintenance in the Nonmotor Symptoms Scale Score: Subdomain Miscellaneous | The Nonmotor Symptoms Scale (NMSS) is a validated tool for rating frequency and severity of nonmotor symptoms in Parkinson's Disease (PD). The severity and frequency of the subject's nonmotor symptoms is assessed by the investigator in 9 different domains. Severity (ranges: 0 = None, 1 = Mild, 2 = Moderate, 3 = Severe) and frequency (ranges: 1 = Rarely (<1/wk), 2 = Often (1/wk), 3 = Frequent (several times per week), 4 = Very Frequent (daily or all the time) are rated using a 4-point scale. The final score is derived from multiplying the severity score and the frequency score. A negative change from Baseline to end of Maintenance indicates an improvement in NMSS. The possible min/max final scores per subdomain are calculated as follows: Range of final score per subdomain: 0 - 12 per question multiplied by the number of questions per subdomain: Subdomain Miscellaneous (4 questions): range 0 - 48 | From Baseline (Day 1) to end of 12-week Maintenance (Day 84) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rotigotine, Neupro®, Non-motor symptoms