A Comparison of Ropinirole Immediate Release With Ropinirole Prolonged Release in Patients With Advanced Parkinson's

Study Overview
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Brief Summary
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This study was designed to compare the effectiveness and tolerability of a new prolonged release formulation of ropinirole with the currently marketed immediate release formulation which is prescribed in many countries. The new prolonged release formulation allows the drug to be taken once a day rather than three times a day. This study will also evaluate the side effects of the new prolonged release formulation of ropinirole

Official Title
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A Randomised, Double-Blind, Double-Dummy, Parallel Group Comparison of 24 Weeks of Treatment With Ropinirole Immediate Release Tablets (REQUIP IR) or Ropinirole Prolonged Release Tablets (SK&F-101468) in Advanced Stage Parkinson's Disease Subjects Who Are Not Adequately Controlled on L-dopa.

Conditions
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Parkinson Disease

Intervention / Treatment
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* Drug: Ropinirole prolonged release
* Drug: ropinirole immediate release


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Patients with a diagnosis of advanced idiopathic Parkinson's disease (according to modified Hoehn & Yahr criteria Stages II-IV) whose symptoms are not adequately controlled with L-dopa. Exclusion criteria: Patients with late stage advanced Parkinson's disease with incapacitating dyskinesias on a stable dose of L-dopa. Current, or history of, (within the previous 3 months), significant and/or uncontrolled psychiatric, haematological, renal, hepatic, endocrinological, neurological, or cardiovascular disease or active malignancy. Recent history of severe dizziness or fainting on standing. Dementia, neurotic behaviour, crippling degenerative arthritis or limb amputations, or prior or current major psychosis. Recent history or current evidence of drug abuse or alcoholism. Use of a dopamine agonist within 4 weeks of starting the study. Personal or family history of an allergic reaction to ropinirole.

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: Parallel Assignment


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: Ropinirole prolonged release|nan|
|Drug: ropinirole immediate release|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants with at least a 20% maintained reduction in Baseline time spent off at Week 24 last observation carried forward (LOCF) | Diary cards completed by the participants was used to assess the duration of off and on periods. During the treatment period 2, 24 hour diary cards were completed by the participants (except for the Baseline period when four diary cards were completed). The participants completed diary cards on the same 2 days of each relevant week. Each 30 minute period was marked as either off, on or asleep. Troublesome dyskinesias were involuntary twisting, turning movements which caused discomfort were also recorded. The general definition of off included a lack of mobility with or without additional features such as tremor or rigidity. The total number of hours spent both off and on or asleep were summed for the two (four for the Baseline Period) 24 hour diary cards and the amount of awake time spent off per 24 hour period was determined. Percentage of participants with at least a 20% maintained reduction in baseline time spent off at Week 24 were presented. | Baseline (Week 0) and Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean change from Baseline in percentage awake time spent off at Week 24 LOCF | Diary cards completed by the Participants was used to assess the duration of off and on periods. During the Treatment Period 2 24 hour diary cards were completed by the Participants (except for the Baseline Period when four diary cards were completed). The Participants completed diary cards on the same 2 days of each relevant week. Each 30 minute period was marked as either off, on or asleep. Troublesome dyskinesias were involuntary twisting, turning movements which caused discomfort were also recorded. The general definition of off included a lack of mobility with or without additional features such as tremor or rigidity. The total number of hours spent both off and on or asleep were summed for the two (four for the Baseline Period) 24 hour diary cards and the amount of awake time spent off per 24 hour period was determined. Week 0 was the baseline and change from Baseline was calculated by subtracting the baseline values from the on-treatment values. | Baseline (Week 0) and Week 24 | 
| Number of participants with a score of 'much improved' or 'very much improved' on the clinical global impression-global improvement (CGI-I) scale at Week 24 LOCF | The CGI-I global improvement scale allows the investigator to rate the participant's total improvement from beginning the treatment (baseline). The scale was rated as 1-7, from 1: very much improved, 2: much improved, 3: minimally improved, 4: no change, 5: minimally worse, 6: much worse and 7: very much worse. CGI global improvement scale was assessed at Week 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24 (and at early withdrawal, if applicable. Higher score indicates worsening and lower score indicates very much improvement. A participant was considered as a CGI-I responder when he/she had a score of (1) Very Much Improved or (2) Much Improved. | Week 24 | 
| Mean change from baseline in the total motor score (part III) of the Unified Parkinson's Disease Rating Scale (UPDRS), with participants in an on state at Week 24 LOCF | The UPDRS Part III assessed motor examination on 18-31 items. Participants receive a score of 0-4 points per item. The maximum total score is 108 points. A higher score indicates more severe PD symptoms and lower score indicates less severe PD symptoms. On state was where PD symptoms were well controlled by the drug. Week 0 was the Baseline and change from Baseline for an individual participant was calculated by subtracting the Baseline values from the on-treatment values. Mean change from Baseline in the total motor score with participants in an on state was reported. | Baseline (Week 0) and Week 24 | 
| Mean change from baseline in the total motor score (part III) of the UPDRS, with participants in an off state at Week 24 LOCF | The UPDRS Part III assessed motor examination on 18-31 items. Participants receive a score of 0-4 points per item. The maximum total score is 108 points. A higher score indicates more severe PD symptoms and lower score indicates less severe PD symptoms. Week 0 was the baseline and change from Baseline for an individual participant was calculated by subtracting the baseline values from the on-treatment values. Mean change from baseline in the total motor score with participants in an off state was reported. | Baseline (Week 0) and Week 24 | 
| Mean change from baseline in the total Activities of daily living (ADL) score (part II) of the UPDRS, with participants in an on state at Week 24 LOCF | This component included items 5-17 of the UPDRS was evaluated by calculating the total score for the 13 items. Participants receive a score of 0-4 points per item and had a value ranging from 0 to 52. The maximum total score was 52. The total ADL Score of the UPDRS ranged from 0 to 52, where 0=normal/no symptoms and 52=worst possible case. Participants recorded responses in both on and off states at each visit due to the nature of questionnaire which generated ADL score at each visit. A higher score indicates more severe PD symptoms. On state was where PD symptoms were well controlled by the drug. Week 0 was the Baseline and change from Baseline for an individual participant was calculated by subtracting the baseline values from the on-treatment values for each state separately. | Baseline (Week 0) and Week 24 | 
| Mean change from baseline in the total ADL score (part II) of the UPDRS, with participants in an off state at Week 24 LOCF | This component included items 5-17 of the UPDRS was evaluated by calculating the total score for the 13 items. Participants receive a score of 0-4 points per item and had a value ranging from 0 to 52. The maximum total score was 52. The total ADL Score of the UPDRS ranged from 0 to 52, where 0=normal/no symptoms and 52=worst possible case. Participants recorded responses in both on and off states at each visit due to the nature of questionnaire which generated ADL score at each visit. A higher score indicates more severe PD symptoms. Off state was where PD symptoms were not adequately controlled by the drug. Week 0 was the baseline and change from Baseline for an individual participant was calculated by subtracting the baseline values from the on-treatment values for each state separately. | Baseline (Week 0) and Week 24 | 
| Mean change from baseline in the total score (parts I-III) of the UPDRS, with participants in an on state at Week 24 LOCF | 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 scored mentation, behavior and mood and scores ranged from 0-16. The UPDRS Part II was the ADL and score ranged from 0-52. The UPDRS Part III was the Motor Examination (Total Motor Score )and scores ranged from 0-108. The total UPDRS (Part I + II + III) score ranged from 0-176 with the higher score indicating the worse condition. Tests were performed when the participant was in the on state of Parkinson's. Baseline was defined as Week 0 assesment. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. | Baseline (Week 0) and Week 24 | 
| Mean change from baseline in the total score (parts I-III) of the UPDRS, with participants in an off state at Week 24 LOCF | 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 scored mentation, behavior and mood and scores ranged from 0-16. The UPDRS Part II was the ADL and score ranged from 0-52. The UPDRS Part III was the Motor Examination (Total Motor Score)and scores ranged from 0-108. The total UPDRS (Part I + II + III) score ranged from 0-176 with the higher score indicating the worse condition. Tests were performed when the participant was in the off state of Parkinson's. Baseline was defined as Week 0 assessment. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. | Baseline (Week 0) and Week 24 | 
| Mean change from baseline to Week 24 LOCF in the thermometer score of the Euro-Qol 5D (EQ-5D) | The EQ-5D was a standardized, participant-administered instrument which produced a simple descriptive profile (thermometer) and a single index value (utility) of a participant's current health status. Thermometer was a 20-cm Visual Analogue Scale (VAS) anchored at 0: worse imaginable health state and 100: best imaginable health state. Participants were required to indicate how good or bad was their health by marking a line on the scale. The point at which the line crossed the thermometer was taken as the score. Week 0 was the baseline and change from Baseline was calculated by subtracting the baseline values from the on-treatment values. | Baseline (Week 0) and Week 24 | 
| Mean change from baseline to Week 24 LOCF in the utility score of the EQ-5D | The EQ-5D was a standardized, participant-administered instrument which produced a simple descriptive profile (thermometer) and a single index value (utility) of a participant's current health status. Utility score was computed from 5 dimensions of health: (mobility, self-care, usual activities, pain/discomfort, anxiety /depression). Each dimension comprised 3 levels (some, moderate, extreme problems), and generated a total of 243 theoretically possible health states. The Utility score was combined scores from 5 dimensions, which valued between -0.594 (representing the worse possible health) and 1 (representing the perfect health). Week 0 was the baseline and change from Baseline was calculated by subtracting the baseline values from the on-treatment values. | Baseline (Week 0) and Week 24 | 
| Mean change from Baseline in the total score of the Parkinson's Disease Sleep Scale (PDSS) at Week 24 LOCF | The PDSS comprised of a series of 15 VAS addressing commonly reported symptoms associated with sleep disturbance in PD. The participant or caregiver completed the scale based on their experiences in the past week. Scores for each item ranged from 0 (representing the most severe) to 10 (the least severe). The maximum score for the PDSS was 150 (participant was free of all symptoms). Week 0 was the baseline and change from Baseline was calculated by subtracting the baseline values from the on-treatment values. | Baseline (Week 0) and Week 24 | 
| Mean change from Baseline in the total movement severity score of the abnormal involuntary movement scale (AIMS), with participants in an on state at Week 24 LOCF | The AIMS was a 12 item, investigator performed assessment of facial and oral movements, extremity movements, trunk movements, global judgments and dental status according to predefined criteria. Items 1-10 were rated on a 5 point severity scale with 0: none to 4: severe. Items 11 and 12 were yes or no items. The AIMS total movement severity score was obtained by summing together the responses to the first seven items and ranged from 0 to 28, with higher scores representing more severe involuntary movement. The AIMS was assessed at Week 0, 12, 24. Week 0 was the baseline and change from Baseline was calculated by subtracting the baseline values from the on-treatment values. | Baseline (Week 0) and Week 24 | 
| Percentage of participants requiring re-instatement of L-dopa | Participants were defined as having a re-instatement of L-dopa, if at any point during the on-treatment phase (excluding down-titration), their dose of L-dopa was increased, up to, or above their baseline level. Percentage of participants requiring reinstatement of L-dopa was reported at Week 24. | Week 24 | 
| Mean change from baseline in the dose of L-dopa at Week 24 LOCF | The start and stop dates of L-Dopa medication were used to determine the dose being taken on a specific date or at an assessment. The dose recorded on the actual date of assessment was used when reporting the corresponding dose. The total daily dose of L-dopa (mg) was calculated as Unit dose per tablet (mg) * Daily Frequency * No of Tablets per administration. Mean change from baseline in the dose of L-dopa at Week 24 was reported. Week 0 was the baseline and change from Baseline was calculated by subtracting the baseline values from the on-treatment values. | Baseline (Week 0) and Week 24 | 
| Incidence of all adverse events (AE) and serious adverse events (SAE) | Data for number of participants who presented one or more adverse events (serious or non serious) was reported. An AE was defined as any untoward medical occurrence (MO) in a participant temporally associated with the use of a medicinal product (MP), whether or not considered related to the MP and can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with its use. The SAE was any untoward MO that, at any dose, results in death, life threatening, persistent or significant disability/incapacity, results in or prolongs inpatient hospitalization, congenital abnormality or birth defect, that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in this definition. | Up to Week 27 | 
| Number of participants who were unable to titrate weekly during the 4 week forced up titration due to poor tolerability | There was no specific question in the CRF to capture the reason why participants were unable to titrate weekly during this period, the data on the reason for withdrawal in the CRF was thus evaluated in those participants who withdrew during the forced titration period. Data for the number of participants withdrawn (Yes/No) is presented. | Up to Week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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safety, efficacy, L-dopa, ropinirole PR, Parkinson's disease, ropinirole IR, adjunctive therapy, superiority, REQUIP, health outcomes