A Fixed Dose, Dose Response Study for Ropinirole Prolonged Release in Patients With Early Stage Parkinson's Disease

Study Overview
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Brief Summary
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This study is a fixed dose, dose response study to characterize the dose response for ropinirole PR in early stage PD patients (Hoehn & Yahr stages I-III). After screening and baseline assessments, subjects will be randomized to one of six final target treatment groups (placebo, 2, 4, 8, 12 or 24mg/day ropinirole PR). The study will consist of a screening period, an up-titration period, a maintenance period, a down titration period and a follow up period. This study utilizes change from baseline in the UPDRS motor score as the primary endpoint, in line with that used in the ropinirole PR monotherapy pivotal study (SK&F101468/168). Clinical review of the primary and secondary endpoints will be performed in order to establish the lowest maximally effective therapeutic dose.

Official Title
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A Fixed Dose, Dose Response Study for Ropinirole Prolonged Release (PR) in Patients With Early Stage Parkinson's Disease

Conditions
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Parkinson Disease

Intervention / Treatment
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* Drug: ropinirole monotherapy
* Drug: placebo monotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of idiopathic Parkinson's disease (according to modified Hoehn & Yahr criteria Stages I-III.) Subjects aged 30 years or greater at screening. Women of child-bearing potential must be practicing a clinically accepted method of contraception during the study and for at least one month prior to randomization and one month following completion of the study. Acceptable contraceptive methods include abstinence, oral contraception, injectable progestogen, implants of levonorgestrel, estrogenic vaginal ring, percutaneous contraceptive patches, surgical sterilisation, male partner sterilization, intrauterine device [IUD], or double barrier method: condom or occlusive cap (diaphragm or cervical/vault caps) plus spermicidal agent (foam/gel/film/cream/suppository. A baseline UPDRS motor score of at least 10. Limited prior exposure to low or moderate doses of L-DOPA (up to 3 months in total) or dopamine agonists including ropinirole (up to 6 months in total) is allowed provided treatment is discontinued for a minimum of 4 weeks prior to screening. Provide written informed consent for this study. Be willing and able to comply with study procedures. Exclusion Criteria: Subjects with Parkinson's disease in whom dopaminergic therapy is not warranted at the time of screening. Subjects with severe, clinically significant condition(s) other than Parkinson's disease which, in the opinion of the investigator, render the subject unsuitable for the study (e.g., psychiatric, haematological, renal, hepatic, endocrinology, neurological [other than Parkinson's disease], cardiovascular, or active malignancy [other than basal cell carcinoma]). Subjects with crippling degenerative arthritis or other physical or mental conditions precluding accurate assessment of efficacy or safety. Subjects with prior or current major psychosis (e.g., schizophrenia or psychotic depression) e.g. scoring 3 or 4 on UPDRS item 2 [thought disorder] or item 3 [depression]. Subjects with severe clinical dementia e.g. scoring 3 or 4 on UPDRS item 1 [mentation]. Subjects with severe dizziness or fainting due to postural hypotension on standing. Subjects with a personal history of melanoma. Subjects with clinically significant abnormalities in laboratory or ECG tests at Screening. If findings are outside the normal range and the subject is included, it must be documented by the investigator that the findings are not of clinical significance. Subjects diagnosed with an impulse control disorder. The modified MIDI will be conducted at screening. Subjects who score positive for this screen must be referred to a specialist for diagnostic evaluation prior to enrolling (screening) in the study. Subjects with an active suicidal plan/intent or have had active suicidal thoughts in the past 6 months. Subjects with a history of suicide attempt in the last 2 years or more than 1 lifetime suicide attempt. Current alcohol or drug dependence. Definite or suspected personal or family history of clinically significant adverse reactions or hypersensitivity to ropinirole (or to drugs with a similar chemical structure) that would preclude long-term dosing with ropinirole. Withdrawal, introduction, or change in dose of hormone replacement therapy and/or any drug known to substantially inhibit CYP1A2 (e.g. ciprofloxacine, fluvoxamine, cimetidine, ethinyloestradiol) or induce CYP1A2 (e.g. tobacco, omeprazole) within 7 days prior to baseline (randomization). Subjects on chronic therapy with any of these agents may be enrolled but doses must have remained stable from 7 days prior to baseline (randomization) through the end of the treatment period. Smokers should maintain normal smoking habit. Women who are pregnant or breast-feeding. Use of an investigational drug from 30 days or 5 half-lives (which ever is longer) prior to baseline (randomization) to the end of the treatment period.

Ages Eligible for Study
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Minimum Age: 30 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: Single Group Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ropinirole<br>ropinirole 2, 4, 8, 12, or 24 mg/day | Drug: ropinirole monotherapy<br>* ropinirole as monotherapy in Parkinson's disease<br>|
| Placebo Comparator: placebo<br>placebo comparator 2, 4, 8, 12, or 24 mg/day | Drug: ropinirole monotherapy<br>* ropinirole as monotherapy in Parkinson's disease<br>Drug: placebo monotherapy<br>* placebo as monotherapy in Parkinson's disease<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline (BL) in Unified Parkinson Disease (PD) Rating Scale (UPDRS) Motor Score | The UPDRS is a clinician based rating scale used to measure motor impairments and disability. The UPDRS assesses six features of PD impairment. These are evaluated using a combination of data collected by interview and examination of the participant. One of the six features include the Part III - Motor Examination where scores can range 0-108 where the maximum score indicates the worse condition. BL is defined as the last non-missing assessment measured on or before the first dose date. The change from BL was calculated by subtracting the BL values from the individual post-randomization values. The least squares(LS) means were estimated using the mixed model repeated measures(MMRM) adjusting for BL UPDRS motor score and race(white versus other) or by using the non-parametric rank analysis of covariance(ANCOVA). | Baseline and Week 4 of the Maintenance Period (Study Week 17) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With a >=5 Points Reduction From Baseline in UPDRS Motor Score | The UPDRS motor scores can range from 0-108 where the maximum score indicates the worse condition. Baseline is defined as the last non-missing assessment measured on or before the first dose date. The change from Baseline will be calculated by subtracting the Baseline values from the individual post-randomization values. | Baseline and Week 4 of the Maintenance Period (Study Week 17) | 
| Number of Participants With a >=10 Points Reduction From Baseline in UPDRS Motor Score | The UPDRS motor scores can range from 0-108 where the maximum score indicates the worse condition. Baseline is defined as the last non-missing assessment measured on or before the first dose date. The change from Baseline will be calculated by subtracting the Baseline values from the individual post-randomization values. | Baseline and Week 4 of the Maintenance Period (Study Week 17) | 
| Number of Participants With a >=10 Points Reduction From Baseline in UPDRS Parts II and III Combined | The UPDRS Part II is the Activities of Daily Living (ADL) score and can range from 0-52 as determined by the physician. The UPDRS Part III is the Motor Examination (Total Motor Score [TMS]) and is defined as the total score, ranging from 0-108 as determined by the physician, of the tests given in the motor examination section. The combined scores of Parts II and III can range from 0-160 with the higher score indicating the worse condition. Tests were performed when the participant is in the on state of Parkinson's. Baseline is defined as the last non-missing assessment measured on or before the first dose date. | Baseline and Week 4 of the Maintenance Period (Study Week 17) | 
| Responder Rate Defined as Participants With a >=30% Reduction in Baseline UPDRS Motor Score | The responder rate is defined as the percentage of participants with a greater than or equal to (>=)30% reduction in their individual Baseline UPDRS motor score at Week 4 of the Maintenance Period (Study Week 17). Baseline is defined as the last non-missing assessment measured on or before the first dose date. The change from Baseline will be calculated by subtracting the Baseline values from the individual post-randomization values. | Baseline and Week 4 of the Maintenance Period (Study Week 17) | 
| Change From Baseline in UPDRS Parts II and III Combined | The UPDRS Part II is the Activities of Daily Living (ADL) score and can range from 0-52 as determined by the physician. The UPDRS Part III is the Motor Examination (Total Motor Score [TMS]) and is defined as the total score, ranging from 0-108 as determined by the physician, of the tests given in the motor examination section. The combined scores of Parts II and III can range from 0-160 with the higher score indicating the worse condition. Tests were performed when the participant is in the on state of Parkinson's. Baseline is defined as the last non-missing assessment measured on or before the first dose date. The change from Baseline will be calculated by subtracting the Baseline values from the individual post-randomization values. | Baseline and Week 4 of the Maintenance Period (Study Week 17) | 
| Change From Baseline in UPDRS Activities of Daily Living | The UPDRS Part II is the Activities of Daily Living (ADL) score and can range from 0-52 as determined by the physician. The higher score indicates the worse condition. Tests were performed when the participant is in the on state of Parkinson's. Baseline is defined as the last non-missing assessment measured on or before the first dose date. The change from Baseline will be calculated by subtracting the Baseline values from the individual post-randomization values. | Baseline and Week 4 of the Maintenance Period (Study Week 17) | 
| Change From Baseline in the Total UPDRS Score (Parts I-III) | The total UPDRS score was calculated by the sum of the values for each component (Part I + Part II + Part III) as determined by the physician. The UPDRS Part I scores mentation, behavior and mood and scores can range from 0-16. The UPDRS Part II is the Activities of Daily Living (ADL) score and can range from 0-52. The UPDRS Part III is the Motor Examination (Total Motor Score [TMS]) and scores range from 0-108. The total UPDRS (Part I + II + III) scores can range from 0-176 with the higher score indicating the worse condition. Tests were performed when the participant is in the on state of Parkinson's. Baseline is defined as the last non-missing assessment measured on or before the first dose date. The change from Baseline will be calculated by subtracting the Baseline values from the individual post-randomization values. | Baseline and Week 4 of the Maintenance Period (Study Week 17) | 
| Change From Baseline in the UPDRS Part I (Mentation) | The UPDRS Part I scores mentation, behavior and mood as determined by a physician and participants were tested during the on phase of Parkinson's. This component of the UPDRS is the total score for 4 items (the items 1- 4 include intellectual impairment, thought disorder, motivation/initiative, and depression) and may have a value ranging from 0 to 16 as determined by a physician where 16 indicates the maximum score and the worse condition. All 4 items have to be present for a total score to be calculated. If one or more items are missing, the total score for the component will also be missing. Baseline is defined as the last non-missing assessment measured on or before the first dose date. The change from Baseline will be calculated by subtracting the Baseline values from the individual post-randomization values. | Baseline and Week 4 of the Maintenance Period (Study Week 17) | 
| Responder Rate According to the Clinical Global Impression - Global Improvement (CGI-I) Scale | The CGI-I scale allows the investigator to rate the participant's total improvement since the beginning of treatment (Baseline). Baseline is defined as the last non-missing assessment measured on or before the first dose date. The scale is rated from 1-7 where 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse. The responder rate is defined as the percentage of participants with a score of 1 or 2. | Week 4 of the Maintenance Period (Study Week 17) | 
| Percentage of Participants Withdrawn From the Study Due to Lack of Efficacy | The percentage of participants who withdrew from the study due to lack of efficacy as defined by either the participant or the investigator is presented here. | Up to Week 4 of the Maintenance Period (Study Week 17) |