Clinical Evaluation of Ropinirole PR/XR Tablets in Monotherapy for Parkinson's Disease (PD)

Study Overview
=================
Brief Summary
-----------------
This study was designed to evaluate the pharmacokinetic profile, safety and efficacy in Parkinson's Disease patients.

Official Title
-----------------
Clinical Evaluation of Ropinirole PR/XR Tablets in Monotherapy for Parkinson's Disease - an Open-Label, Uncontrolled Study -

Conditions
-----------------
Parkinson Disease

Intervention / Treatment
-----------------
* Drug: Ropinirole prolonged release/extended release(PR/XR)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients who are diagnosed with PD with severity of the Modified Hoehn & Yahr staging at Stage I to III. Age: 20 years or older (at the time of giving informed consent) Gender: male and female Both inpatient and outpatient status Informed consent: Patients who are able to give informed written consent in person (i.e. patients who are capable of giving informed written consent on one's own) Limited prior exposure to low or moderate doses of L-dopa (up to 3 months in total) or dopamine agonists (up to 6 months in total) provided treatment is discontinued for a minimum of 4 weeks prior to screening. Exclusion Criteria: Patients who present serious physical signs and symptoms other than those of the PD (e.g. cardiac/hepatic/renal disorder and haematopoietic disorder). The seriousness refers to Grade 3 according to the Classification of the Severity of Adverse Experiences (Pharmaceutical affairs bureau/Safety division (PAB/SD) Notification No. 80, dated 29 June 1992). Patients with symptomatic postural hypotension. (e.g. dizziness and syncope). Patients who have had serious psychiatric symptoms (e.g. confusion, hallucination, delusion, abnormal behaviour, alcohol or drug dependence) during the past six months (26 weeks) (including symptoms caused by anti-Parkinson drugs). Patients who have been treated with the following drugs at Week -4, and whose treatment regimen of the drug has been changed from Week -4 to Week 0. Anticholinergic agents: trihexyphenidyl hydrochloride (e.g. Artane®), piroheptine hydrochloride (Trimol®), mazaticol hydrochloride (Pentona®), metixene hydrochloride (Cholinfall®), biperiden hydrochloride (Akineton®), profenamine (Parkin®) amantadine hydrochloride (e.g. Symmetrel®) droxidopa (Dops®) citicoline (e.g. Nicholin®) selegiline hydrochloride (FP®) zonisamide estrogen: estriol (e.g.Estriel®) CYP1A2 inhibitors: Ciprofloxacin HCl (e.g. Ciproxan®, enoxacin and fluvoxamine) Patients with severe dementia such as score 3 or 4 of the UPDRS Part I (Mentation, behaviour, and mood) Female patients who are pregnant or lactating, who may be pregnant, or who plan for pregnancy during the study or within 30 days after the last dose of the study drug. Patients with current history or complication of carcinoma or malignant tumour. Patients who have history of drug allergy to ropinirole hydrochloride (HCl). Patients who have received surgical treatment for PD in the past (e.g. pallidectomy, deep brain stimulation). Patients who have been treated with any other investigational drug within 12weeks prior to the treatment phase. Others whom the investigator (sub investigator) considers ineligible for the study.

Ages Eligible for Study
-----------------
Minimum Age: 20 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ropinirole PR/XR<br> | Drug: Ropinirole prolonged release/extended release(PR/XR)<br>* Subjects will take the investigational drug once daily at the same time each day, it is recommended that this is in the morning for optimal benefit. Investigational drug is taken for 52 weeks, starting on the next day of the Week 0 visit. One tablet of ropinirole PR/XR 2 mg tablets will be orally dosed as the initial dose. The dose will be titrated weekly by 2 mg/day, and increased to 8 mg/day in Week 4. From Week 5 up to 16, the dose will be increased at minimum intervals of one week between titration steps until sufficient efficacy is obtained, according to individual clinical response and tolerability (the dose may be titrated up to 16 mg/day). In Week 16 and further, treatment dose at Week 16 will be continuously administered up to Week 52. If insufficient efficacy is judged in a subject during treatment, or unable to maintain the dose due to adverse event, the treatment dose may be changed. The dose is down tapered according to the maintenance dose at Week 52 (or withdrawal).<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Food Effects on Cmax and Cmin of SKF101468 (Ropinirole) and Its Metabolites | The dose of SKF101468 and its metabolites was normalized to 1 mg. Blood sampling at steady state up to 24 hours post dose after receiving the maintenance dose was conducted. In order to investigate the effect of a meal on pharmacokinetics, blood was sampled twice (after a standard morning meal and at fasted state) from identical participants. Cmax: maximum concentration, Cmin: trough plasma concentration. | Weeks 5-16 | 
| Food Effects on AUC0-24 of SKF101468 (Ropinirole) and Its Metabolites | The dose of SKF101468 and its metabolites was normalized to 1 mg. Blood sampling at steady state up to 24 hours (hr) post dose after receiving the maintenance dose was conducted. In order to investigate the effect of a meal on pharmacokinetics, blood was sampled twice (after a standard morning meal and at fasted state) from identical participants. AUC0-24: area under the drug concentration 24 hr curve. | Weeks 5-16 | 
| Food Effects on Tmax of SKF101468 (Ropinirole) and Its Metabolites | The dose of SKF101468 and its metabolites was normalized to 1 mg. Blood sampling at steady state up to 24 hours post dose after receiving the maintenance dose was conducted. In order to investigate the effect of a meal on pharmacokinetics, blood was sampled twice (after a standard morning meal and at fasted state) from identical participants. Tmax: time of maximum concentration. Data are presented as the median difference between fed and fasted states for ropinirole and each metabolite. | Weeks 5-16 | 
| Plasma Trough Concentrations of SKF101468 (Ropinirole) and Its Metabolites | Blood sampling in the fixed titration phase will be performed at 24 hour post dose of the last dose of 2, 4, and 8 mg (immediately before the morning dose). Blood sampling in the maintenance dose phase will be performed at 24 hour post dose of 10 mg or more for one week or longer (immediately before the morning dose), as sampling needs to be conducted at steady state. | Weeks 1-16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Score in the Japanese UPDRS Part III | The Unified Parkinson's Disease Rating Scale (UPDRS) assesses the status of Parkinson's Disease (PD) patients objectively. The Japanese UPDRS Part III assesses motor examination on 27 items. Participants receive a score of 0-4 points per each item. The maximum total score is 108 points. A higher score indicates more severe PD symptoms. | Weeks 0-52 | 
| Change From Baseline in the Japanese UPDRS Part III | The UPDRS assesses the status of PD patients objectively. The Japanese UPDRS Part III assesses motor examination on 27 items. Participants receive a score of 0-4 points per each item. The maximum total score is 108 points. A higher score indicates more severe PD symptoms. | Baseline (Week 0) and Weeks 1-52 | 
| Percent Change From Baseline in the Japanese UPDRS Part III | The UPDRS assesses the status of PD patients objectively. The Japanese UPDRS Part III assesses motor examination on 27 items. Participants receive a score of 0-4 points per each item. A maximum total score is 108 points.The higher score indicates more severe PD symptoms. | Baseline (Week 0) and Weeks 1-52 | 
| Percentage of Responders of the Total Score in the Japanese UPDRS Total Score in Part III | A responder is defined as a participant with a 30% or more reduction at baseline. The UPDRS assesses the status of PD patients objectively. The Japanese UPDRS Part III assesses motor examination on 27 items. Participants receive a score of 0-4 points per each item. The maximum total score is 108 points. A higher score indicates more severe PD symptoms. | Baseline (Week 0) and Weeks 1-52 | 
| Total Score in the Japanese UPDRS Part I | The UPDRS assesses the status of PD patients objectively. The Japanese UPDRS Part I assesses mentation, behavior, and mood on 4 items. Participants receive a score of 0-4 points per each item. The maximum total score is 16 points. A higher score indicates more severe mental symptoms. | Weeks 0-52 | 
| Change From Baseline in the Japanese UPDRS Part I | The UPDRS (Unified Parkinson's Disease Rating Scale) assesses the status of PD patients objectively. The Japanese UPDRS Part I assesses mentation, behavior, and mood on 4 items. Participants receive a score of 0-4 points per each item. The maximum total score is 16 points. A higher score indicates more severe mental symptoms. | Baseline (Week 0) and Weeks 1-52 | 
| Percent Change From Baseline in the Japanese UPDRS Part I | The UPDRS (Unified Parkinson's Disease Rating Scale) assesses the status of PD patients objectively. The Japanese UPDRS Part I assesses mentation, behavior, and mood on 4 items. Participants receive a score of 0-4 points per each item. The maximum total score is 16 points. A higher score indicates more severe mental symptoms. | Baseline (Week 0) and Weeks 1-52 | 
| Total Score in the Japanese UPDRS Part II | The UPDRS assesses the status of PD patients objectively. The Japanese UPDRS Part II assesses activities of daily living on 13 items. Participants receive a score of 0-4 points per each item. The maximum total score is 52 points. A higher score indicates more severe PD symptoms. | Weeks 0-52 | 
| Change From Baseline in the Japanese UPDRS Part II | The UPDRS assesses the status of PD patients objectively. The Japanese UPDRS Part II assesses activities of daily living on 13 items. Participants receive a score of 0-4 points per each item. The maximum total score is 52 points. A higher score indicates more severe PD symptoms. | Baseline (Week 0) and Weeks 1-52 | 
| Percent Change From Baseline in the Japanese UPDRS Part II | The UPDRS assesses the status of PD patients objectively. The Japanese UPDRS Part II assesses activities of daily living on 13 items. Participants receive a score of 0-4 points per each item. The maximum total score is 52 points. A higher score indicates more severe PD symptoms. | Baseline (Week 0) and Weeks 1-52 | 
| Total Score in the Japanese UPDRS Part IV | The UPDRS assesses the status of PD patients objectively. The Japanese UPDRS Part IV assesses complications of therapy on 11 items. Participants receive a score of 0-4 or 0-1 points per each item depending on the item. The maximum total score is 23 points. A higher score indicates more severe symptoms of complications. | Baseline (Week 0) and Weeks 0-52 | 
| Change From Baseline in the Japanese UPDRS Part IV | The UPDRS assesses the status of PD patients objectively. The Japanese UPDRS Part IV assesses complications of therapy on 11 items. Participants receive a score of 0-4 or 0-1 points per each item depending on the item. The maximum total score is 23 points. A higher score indicates more severe symptoms of complications. | Baseline (Week 0) and Weeks 1-52 | 
| Percent Change From Baseline in the Japanese UPDRS Part IV | The UPDRS assesses the status of PD patients objectively. The Japanese UPDRS Part IV assesses complications of therapy on 11 items. Participants receive a score of 0-4 or 0-1 points per each item depending on the item. The maximum total score is 23 points. A higher score indicates more severe symptoms of complications. | Baseline (Week 0) and Weeks 1-52 | 
| Summary of the Modified Hoehn & Yahr Criteria Stages | Hoehn & Yahr criteria were measured on an 8-point scale. 0: No signs of disease, 1: Unilateral disease, 1.5: Unilateral plus axial involvement, 2: Bilateral disease, 2.5: Mild bilateral disease, 3: Mild to moderate bilateral disease. No subjects evaluated had a score of 4 (severe disability) or 5 (wheelchair bound or bedridden unless aided). | Screening-Week 52 | 
| Number of Participants Scored as Responders on the Clinician's Global Impression (CGI) Scale | CGI is measured on a 7-point scale. 1: Very much improved, 2: Much Improved, 3: Minimally improved, 4: No change, 5: Minimally worse, 6: Much worse, 7: Very much worse. Responders are defined as those participants scored as very much improved or much improved. | Weeks 1-52 | 
| Percentage of Participants Who Remained in the Study on the Indicated Days | The percentage of participants remaining in the study was examined using the Kaplan-Meier method, in which a premature discontinuation will be considered as an event. | Days 0-364 | 
| Change From Baseline in Albumin, Total Protein, and Hemoglobin at Weeks 16 and 52 | Change from baseline was calculated as the Week 16 and 52 values minus the baseline values. | Baseline (Screening) and Weeks 16 and 52 | 
| Change From Baseline in Alkaline Phosphatase, Alanine Amino Transferase, Aspartate Amino Transferase, Creatine Kinase, Gamma Glutamyl Transferase, and Lactate Dehydrogenase at Weeks 16 and 52 | Change from baseline was calculated as the Week 16 and 52 values minus the baseline values. | Baseline (Screening) and Weeks 16 and 52 | 
| Change From Baseline in Total Bilirubin, Blood Urea Nitrogen, and Creatinine at Weeks 16 and 52 | Change from baseline was calculated as the Week 16 and 52 values minus the baseline values. | Baseline (Screening) and Weeks 16 and 52 | 
| Change From Baseline in Blood Urea Nitrogen, Cholesterol, Chloride, Potassium, and Sodium at Weeks 16 and 52 | Change from baseline was calculated as the Week 16 and 52 values minus the baseline values. | Baseline (Screening) and Weeks 16 and 52 | 
| Change From Baseline in Prolactin at Weeks 16 and 52 | Change from baseline was calculated as the Week 16 and 52 values minus the baseline values. | Baseline (Screening) and Weeks 16 and 52 | 
| Change From Baseline in Hematocrit at Weeks 16 and 52 | Change from baseline was calculated as the Week 16 and 52 values minus the baseline values. | Baseline (Screening) and Weeks 16 and 52 | 
| Change From Baseline in Platelet Count and White Blood Cell Count at Weeks 16 and 52 | Change from baseline was calculated as the Week 16 and 52 values minus the baseline values. | Baseline (Screening) and Weeks 16 and 52 | 
| Change From Baseline in Red Blood Cell Count at Weeks 16 and 52 | Change from baseline was calculated as the Week 16 and 52 values minus the baseline values. | Baseline (Screening) and Weeks 16 and 52 | 
| Urinalysis Data | The number of participants with the indicated dipstick test values were measured. Dipstick test values: Neg Value, Trace, +1, +2, +3, +4. No participants had a score of +5. | Screening, Week 16, and Week 52 | 
| Number of Participants With the Indicated Shift From Baseline in 12-Lead Electrocardiogram (ECG) Findings at Weeks 16 and 52 | Baseline Finding/Time Period Finding. Abbreviations: N = normal; A = abnormal; CS = clinically significant; NCS = not clinically significant. Options include N/N, N/ANCS, N/ACS, ANCS/N, ANCS/ANCS, ANCS/ACS, ACS/N, ACS/ANCS, and ACS/ACS. | Baseline (Screening) and Weeks 16 and 52 | 
| Change From Baseline in Supine and Standing Systolic and Diastolic Blood Pressure at Weeks 16 and 52 | Change from baseline was calculated as Week 16 and Week 52 values minus baseline values. | Baseline (Screening) and Weeks 16 and 52 | 
| Change From Baseline in Supine and Standing Pulse Rate at Weeks 16 and 52 | Change from baseline was calculated as Week 16 and Week 52 values minus baseline values. | Baseline (Screening) and Weeks 16 and 52 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Parkinson's Disease, PD