A Placebo- and Ropinirole-Controlled Study for SPM 962 in Advanced Parkinson's Disease Patients

Study Overview
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Brief Summary
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To demonstrate the non-inferiority of SPM 962 to ropinirole in terms of efficacy in order to confirm clinical value of SPM 962. To demonstrate the superiority of SPM 962 to placebo in terms of efficacy. To investigate the tolerability and safety of SPM 962 up to 36.0 mg/day.

Official Title
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A Double-Blind, 3-Arm, Parallel Group, Placebo- and Ropinirole-Controlled Study for SPM 962 in Advanced Parkinson's Disease Patients With Concomitant Treatment of L-dopa

Conditions
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Parkinson's Disease

Intervention / Treatment
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* Drug: SPM 962
* Drug: Ropinirole
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject diagnosed as having Parkinson's disease in accordance with Diagnostic Criteria established by the Research Committee of MHLW-specified Intractable Neurodegenerative Diseases (1995). Subject is 30 and more and less than 80 years of age at the time of informed consent. Hoehn & Yahr stage 2-4 (on time). Total UPDRS Part 3 score is over 10 at screening test (on time). Subject is on a stable dose of L-dopa with no change in daily dose or dosing regimen for at least 28 days prior to the initial treatment of SPM 962. Subject has any of the following problematic symptoms; 1) Wearing off phenomenon (including frozen gait at off time and dystonia at off time) 2) On and off phenomenon 3) Delayed-on and/or No-on phenomenon 4) Dyskinesia 5) Not well controlled with L-dopa. Exclusion Criteria: Subject who has previously participated in a clinical trial of SPM962 and taken the investigational product (IP). Subject has psychiatric symptoms, e.g. confusion, hallucination, delusion, excitation, delirium, abnormal behavior at screening test or baseline. Subject whose SBP declines by at least 30 mmHg from supine to standing position based on the orthostatic hypotension assessment, or subject who develops orthostatic hypotension at baseline. Subject has a history of epilepsy, convulsion and other. Subject who has complications or a history of serious cardiac diseases or arrhythmia (eg, congestive heart failure of class 3 or 4 in the NYHA classification, second or third degree atrioventricular block, complete left bundle branch block, sick sinus syndrome, ventricular fibrillation, myocardial infarction within 12 months prior to the screening test, or a complication of angina pectoris). Subjects has QTc-interval >450 msec twice at screening. Subject has a the average QTc-interval from two ECGs >450 msec in males and >470 msec in females at baseline. Subject has congenital long QT syndrome. Subject whose serum potassium level is < 3.5mEq/L at the screening test. Subject has a total bilirubin >= 3.0 mg/dL or AST(GOT) or ALT(GPT) greater than 2.5 times of the upper limit of the reference range (or >= 100 IU/L) at screening test, or suffers complications of active phase of chronic hepatitis or liver cirrhosis. Subject has BUN >= 30 mg/dL or serum creatinine >= 2.0 mg/dl at screening test. Subject has a history of allergic reaction to topical agents such as transdermal patch. Subject has a history of known intolerance/hypersensitivity to ropinirole and/or adverse drug reactions that prevent subject from receiving treatment. Subject is pregnant or nursing or woman who plans pregnancy during the trial. Subject is receiving therapy with prohibited drug specified in the study protocol. Subject has a history of pallidotomy, thalamotomy, deep brain stimulation or fetal tissue transplant. Subject has dementia, including DLB and PDD (MMSE score <= 24 at screening). Subject who has a complication or history of malignant neoplastic disease, or received treatment for the disease within 12 months prior to the screening test. Subject is unable to give consent. Subject who is unable to properly record information in a diary. Subject is participating in another trial of IPs or received other IPs within 12 weeks prior to commencement of study treatment. Investigator judges that subject is inappropriate as a study subject with other reasons.

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 79 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 |
| --- | --- |
| Experimental: SPM 962<br>SPM 962 transdermal patch | Drug: SPM 962<br>* SPM 962 transdermal patch once a daily up to 36.0 mg/day<br>|
| Active Comparator: Ropinirole<br>Ropinirole tablet | Drug: Ropinirole<br>* Ropinirole oral administration TID up to 15.0 mg/day<br>|
| Placebo Comparator: Placebo<br>SPM962 placebo patch and Ropinirole placebo tab | Drug: Placebo<br>* SPM962-placebo patch and Ropinirole-placebo tab<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Unified Parkinson's Disease Rating Score (UPDRS) Part 3 Sum Score | Mean change (LOCF) from baseline in UPDRS Part 3 sum score (on state) at 16 weeks after dosing. UPDRS is a scale for monitoring Parkinson's Disease-related disability and impairment. The UPDRS consists of the following four sub-scales. Part 1: Mentation, Part 2: Activities of Daily Living, Part 3: Motor, Part 4: Complications. Part 3 assesses 14 items. Each item is scored from 0 (normal) to 4 (severe). The sum score serves as the sub-scale score. A higher score indicates a greater severity of symptoms. Thus a decrease in the scores means improvement. | baseline, 16 weeks after dosing | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| UPDRS Part 3 Sum Score | Mean change (LOCF) from baseline in UPDRS Part 3 sum score (on state) at 8 and 10 weeks after dosing. UPDRS Part 3 assesses 14 items. Each item is scored from 0 (normal) to 4 (severe). The sum score serves as the sub-scale score. A higher score indicates a greater severity of symptoms. Thus a decrease in the scores means improvement. | baseline, 8 and 10 weeks after dosing | 
| UPDRS Part 2 Sum Score | Mean change (LOCF) from baseline in UPDRS Part 2 sum score (average scores of on state and off state) at 16 weeks after dosing. UPDRS 2 assesses 13 items. Each item is scored from 0 (normal) to 4 (severe). The sum score serves as the sub-scale score. A higher score indicates a greater severity of symptoms. Thus a decrease in the scores means improvement. | Baseline, 16 weeks after dosing | 
| Off Time | Mean change (LOCF) from baseline in off time at 16 weeks after dosing. Off-time is a state where L-Dopa becomes ineffective. Off-time was measured by patient diary in hours/day. | Baseline, 16 weeks after dosing | 
| Parkinson's Disease Sleep Scale-2 (PDSS-2) | Mean change (LOCF) from baseline in PDSS-2 sum score at 16 weeks after dosing. PDSS-2 is a scale for assessing sleep disorders in Parkinson's disease. PDSS consists of 15 questions about sleep and nocturnal disturbances. The score of each question ranges from 0 (never) to 4 (very frequent). The sum of each question serves as the scale score. Thus a decrease in the scores means improvement. | Baseline, 16 weeks after dosing | 
| On Time | Mean change (LOCF) from baseline in on time at 16 weeks after dosing. On-time is a state where L-Dopa is effective. On-time was measured by patient diary in hours/day. | Baseline, 16 weeks after dosing | 
| On Time Without Dyskinesia Disturbing Daily Activities | Mean change (LOCF) from baseline in on time without dyskinesia disturbing daily activities at 16 weeks after dosing. On-time is a state where L-Dopa is effective. On-time was measured by patient diary in hours/day. | Baseline, 16 weeks after dosing | 
| On Time With Dyskinesia Disturbing Daily Activities | Mean change (LOCF) from baseline in on time with dyskinesia disturbing daily activities at 16 weeks after dosing (rate against on time). | Baseline, 16 weeks after dosing | 
| Effective Rate in UPDRS Part 3 Sum Score | Effective rate (percentage of subjects with 20% or 30% decrease) (LOCF) in UPDRS Part 3 sum score (on state) at 16 weeks after dosing. | Baseline, 16 weeks after dosing | 
| Effective Rate in UPDRS Part 2 Sum Score | Effective rate (percentage of subjects with 20% or 30% decrease) (LOCF) in UPDRS Part 2 sum score (average scores of on state and off state) at 16 weeks after dosing. | Baseline, 16 weeks after dosing | 
| Effective Rate in Off Time | Effective rate (percentage of subjects with 20% or 30% decrease) (LOCF) in off time at 16 weeks after dosing. On-time is a state where L-Dopa is effective. On-time was measured by patient diary in hours/day. | Baseline, 16 weeks after dosing | 
| Clinical Global Impression (CGI) | Change (LOCF) from baseline in CGI score. CGI improvement is a clinician-reported scale for assessing how much the patient's illness has improved or worsened from baseline. The scale scoring criteria are 1: very much improved, 2: much improved, 3: minimally improved, 4: no change, 5: minimally worse, 6: much worse, 7: very much worse. A decrease in the scores means improvement. | Baseline, 16 weeks after dosing | 
| Dystonia (at an Early Hour) | Change (LOCF) from baseline in occurrence of Dystonia (at an early hour). | Baseline, 16 weeks after dosing | 
| Dystonia (in the Daytime) | Change (LOCF) from baseline in occurrence of Dystonia (in the daytime). | Baseline, 16 weeks after dosing |