REQUIP (Ropinirole Hydrochloride) IR Long-Term Phase 4 Study

Study Overview
=================
Brief Summary
-----------------
Ropinirole Hydrochloride (ROP) was granted approval for the treatment of Parkinson's Disease (PD) on 20 October 2006. ROP is expected to be used for a long term in clinical practice. However, no long-term clinical data with ROP administered three times daily are currently available from Japanese patients, and the clinical experience with ROP at >10mg/day is limited. For this reason, this study was designed as a multicenter open-label uncontrolled study. This study will evaluate the long-term efficacy (Japanese Unified Parkinson's Disease Rating Scale (UPDRS), Awake time spent Off/On, Modified Hoehn & Yahr stage, Schwab-England scale, Proportion of subjects remaining in this study and Clinical Global Impression (CGI)) and the long-term safety of ROP administered three times daily for in PD patients.

Official Title
-----------------
Post-Marketing Clinical Study of REQUIP (Ropinirole Hydrochloride) Tablets in Patients With Parkinson's Disease- Evaluation of Long-Term Efficacy and Safety -

Conditions
-----------------
Parkinson Disease, Parkinson's Disease

Intervention / Treatment
-----------------
* Drug: ROP
* Drug: ROP+L-Dopa


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: Subjects eligible for enrollment in the study must meet all of the following criteria. Note that both inpatients and outpatients are eligible. Patients with a diagnosis of PD (including juvenile parkinsonism) with Modified Hoehn & Yahr Stages I to IV. Patients who have been receiving another dopamine agonist for at least 4 weeks prior to the start of the screening phase and are expected to benefit from conversion to ROP. Age: 20 years (at the time of written informed consent). Informed consent: Patients who are able to give written informed consent in person (i.e., patients who are capable of giving written informed consent on their own). Gender: Male or female Females of childbearing potential are eligible for enrollment in the study, only if the subject has a negative pregnancy test at the start of the screening phase and agrees to conduct pregnancy testing at the protocol-specified visits during the study and use one of the following acceptable methods of contraceptions properly and accurately: Abstinence Oral contraceptive, either combined or progestogen alone Injectable progestogen Implants of levonorgestrel Estrogenic vaginal ring (Caution: This should be used cautiously, because the blood concentration of the study drug may be increased.) Percutaneous contraceptive patches Intrauterine device (IUD) or intrauterine system (IUS) Male partner sterilization (vasectomy with documentation of azoospermia) prior to the female subject's entry into the study, and this male is the sole partner for that subject) Double barrier method: condom or occlusive cap (diaphragm or cervical / vault caps) plus spermicidal agent (foam/gel/film/cream/suppository) Exclusion criteria: Subjects meeting any of the following criteria must not be enrolled in the study: Patients who present with any serious medical condition other than PD (e.g., cardiac, hepatic or renal disorder or hematopoietic disorder). Serious is defined as Grade 3 as a rule according to the Classification of the Severity of Adverse Experiences. Patients with postural hypotension with any subjective symptoms (e.g., dizziness and syncope). Patients who have had any serious psychiatric symptoms (e.g., confusion, hallucination, delusion, abnormal behavior) (including symptoms caused by anti-PD drugs) within 6 months (26 weeks) prior to written informed consent. Patients who have initiated any of the following drugs within 4 weeks of the start of the screening phase and have the dosing regimen of the drug changed within 4 weeks of the start of the screening phase. L-dopa (+DCI) (NOTE: This does not apply to the monotherapy group.) Anticholinergic agents: trihexyphenidyl hydrochloride, piroheptine hydrochloride, mazaticol hydrochloride, metixene hydrochloride, biperiden, profenamine amantadine hydrochloride droxidopa citicoline selegiline hydrochloride entacapone zonisamide Patients with severe dementia with a Japanese UPDRS Part I (mentation, behavior, and mood) score of 3 or 4. Female patients who are pregnant or lactating, who may be pregnant, or who plan for pregnancy during the study period or within 30 days after the last dose of the study drug. Patients with a history of drug allergy to any ingredients of ROP tablets. 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 product within 12 weeks prior to the start of the screening phase. Patients who, in the judgement of the investigator (or sub-investigator), have evidence of alcohol or drug abuse. Others whom the investigator (or 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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ropinirole Hydrochloride<br> | Drug: ROP<br>* Ropinirole Hydrochloride monotherapy group (ROP): Patients will receive ROP tablets 3 times daily. In the 4-week Fixed Titration Phase (from Week 0 as Baseline), the dose will start at 0.75 mg/day and will be increased weekly by 0.75 mg/day up to 3.0 mg/day. In the 48-week Flexible Titration and Maintenance Phase, the dose will be increased by 1.5 mg/day at intervals of at least 1 week up to a maximum of 15.0 mg/day. The dose will be maintained at a level without further symptomatic improvement is expected. Concomitant use of L-dopa is prohibited during the study.<br>Drug: ROP+L-Dopa<br>* Ropinirole Hydrochloride with L-Dopa adjunct therapy group (ROP+L-Dopa): Patients will receive ropinirole hydrochloride (ROP) tablets 3 times daily. In the 4-week Fixed Titration Phase (from Week 0 as Baseline), the dose will start at 0.75 milligrams (mg)/day and will be increased weekly by 0.75 mg/day up to 3.0 mg/day. In the 48-week Flexible Titration and Maintenance Phase, the dose will be increased by 1.5 mg/day at intervals of at least 1 week up to a maximum of 15.0 mg/day. The dose will be maintained at a level without further symptomatic improvement is expected. The dosing regimen of L-dopa remain unchanged from 4 weeks prior to the start of the Screening Phase throughout the study.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in the Japanese Unified Parkinson's Disease Rating Scale (UPDRS) Part III Total Score (in On State for the ROP+L-Dopa Group) at Week 52 and Final Assessment Point (FAP) | The Japanese UPDRS assesses the status of Parkinson's Disease (PD) patients objectively. Part III assesses motor examination on 27 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. On state is where PD symptoms are well controlled by the drug. Participants with off state at baseline or without post-baseline data were not included in the ROP+L-dopa group at FAP. These participants as well as one with off state at Week 52 and those prematurely withdrawn were not included at Week 52. | Baseline, Week 52, and FAP (up to Week 52) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in the Japanese UPDRS Part I Total Score at Week 52 and FAP | The Japanese UPDRS assesses the status of PD patients objectively. Part I assesses mentation, behavior, and mood on 4 items. Participants receive a score of 0-4 points per item. The maximum total score is 16 points. A higher score indicates more severe mental symptoms. | Baseline, Week 52, and FAP (up to Week 52) | 
| Mean Change From Baseline in the Japanese UPDRS Part II Total Score at Week 52 and FAP by On/Off State in the ROP+L-Dopa Group | The Japanese UPDRS assesses the status of PD patients objectively. Part II assesses activities of daily living on 13 items. Participants receive a score of 0-4 points per item. The maximum total score is 52 points. A higher score indicates more severe PD symptoms. On state is where PD symptoms are well controlled by the drug. Off state is where PD symptoms are not adequately controlled by the drug. | Baseline, Week 52, and FAP (up to Week 52) | 
| Mean Change From Baseline in the Japanese UPDRS Part II Total Score at Week 52 and FAP in the ROP Group | The Japanese UPDRS assesses the status of PD patients objectively. Part II assesses activities of daily living on 13 items. Participants receive a score of 0-4 points per item. The maximum total score is 52 points. A higher score indicates more severe PD symptoms. | Baseline, Week 52, and FAP (up to Week 52) | 
| Mean Change From Baseline in the Japanese UPDRS Part IV Total Score at Week 52 and FAP | The Japanese UPDRS assesses the status of PD patients objectively. Part IV assesses complications of therapy on 11 items. Participants receive a score of 0-4 or 0-1 points per item depending on the item. The maximum total score is 23 points. A higher score indicates more severe symptoms of complications. | Baseline, Week 52, and FAP (up to Week 52) | 
| Japanese UPDRS Part I Mean Total Score at Baseline, Week 52, and FAP | The Japanese UPDRS assesses the status of PD patients objectively. Part I assesses mentation, behavior, and mood on 4 items. Participants receive a score of 0-4 points per item. The maximum total score is 16 points. A higher score indicates more severe mental symptoms. | Baseline, Week 52, and FAP (up to Week 52) | 
| Mean Percent Change From Baseline in the Japanese UPDRS Part I Total Score at Week 52 and FAP | The Japanese UPDRS assesses the status of PD patients objectively. Part I assesses mentation, behavior, and mood on 4 items. Participants receive a score of 0-4 points per item. The maximum total score is 16 points. A higher score indicates more severe mental symptoms. Percent change from baseline was calculated as (change from baseline score/baseline score) * 100; change from baseline was calculated as thescore at the observation day minus the baseline score. | Baseline, Week 52, and FAP (up to Week 52) | 
| Japanese UPDRS Part II Mean Total Score at Baseline, Week 52, and FAP by On/Off State in the ROP+L-Dopa Group | The Japanese UPDRS assesses the status of PD patients objectively. Part II assesses activities of daily living on 13 items. Participants receive a score of 0-4 points per item. The maximum total score is 52 points. A higher score indicates more severe PD symptoms. On state is where PD symptoms are well controlled by the drug. Off state is where PD symptoms are not adequately controlled by the drug. LOCF was used for the FAP data. Some participants were not included at FAP as having no post-baseline data in on state or having no data in off state at Week 52/withdrawal. | Baseline, Week 52, and FAP (up to Week 52) | 
| Japanese UPDRS Part II Mean Total Score at Baseline, Week 52, and FAP in ROP Group | The Japanese UPDRS assesses the status of PD patients objectively. Part II assesses activities of daily living on 13 items. Participants receive a score of 0-4 points per item. The maximum total score is 52 points. A higher score indicates more severe PD symptoms. | Baseline, Week 52, and FAP (up to Week 52) | 
| Mean Percent Change From Baseline in the Japanese UPDRS Part II Total Score at Week 52 and FAP by On/Off State in the ROP+L-Dopa Group | The Japanese UPDRS assesses the status of PD patients objectively. Part II assesses activities of daily living on 13 items. Participants receive a score of 0-4 points per item. The maximum total score is 52 points. A higher score indicates more severe PD symptoms. On state is where PD symptoms are well controlled by the drug. Off state is where PD symptoms are not adequately controlled by the drug. Percent change from baseline was calculated as (change from baseline score/baseline score) * 100; change from baseline was calculated as thescore at the observation day minus the baseline score. | Baseline, Week 52, and FAP (up to Week 52) | 
| Mean Percent Change From Baseline in the Japanese UPDRS Part II Total Score at Week 52 and FAP in the ROP Group | The Japanese UPDRS assesses the status of PD patients objectively. Part II assesses activities of daily living on 13 items. Participants receive a score of 0-4 points per item. The maximum total score is 52 points. A higher score indicates more severe PD symptoms. Percent change from baseline was calculated as (change from baseline score/baseline score) * 100; change from baseline was calculated as thescore at the observation day minus the baseline score. | Baseline, Week 52, and FAP (up to Week 52) | 
| Japanese UPDRS Part III Mean Total Score (in On State for the ROP+L-Dopa Group) at Baseline, Week 52, and FAP | The Japanese UPDRS assesses the status of PD patients objectively. Part III assesses motor examination on 27 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. On state is where PD symptoms are well controlled by the drug. LOCF was used for the FAP data to impute post-baseline missing values. One participant was not included in the ROP+L-dopa group at FAP as having no post-baseline data. | Baseline, Week 52, and FAP (up to Week 52) | 
| Mean Percent Change From Baseline in the Japanese UPDRS Part III Total Score (in On State for the ROP+L-Dopa Group) at Week 52 and FAP | The Japanese UPDRS assesses the status of PD patients objectively. Part III assesses motor examination on 27 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. On state is where PD symptoms are well controlled by the drug. Percent change from baseline was calculated as (change from baseline score/baseline score) * 100; change from baseline was calculated as thescore at the observation day minus the baseline score. | Baseline, Week 52, and FAP (up to Week 52) | 
| Japanese UPDRS Part IV Mean Total Score at Baseline, Week 52, and FAP | The Japanese UPDRS assesses the status of PD patients objectively. Part IV assesses complications of therapy on 11 items. Participants receive a score of 0-4 or 0-1 points per item depending on the item. The maximum total score is 23 points. A higher score indicates more severe symptoms of complications. | Baseline, Week 52, and FAP (up to Week 52) | 
| Mean Percent Change From Baseline in the Japanese UPDRS Part IV Total Score at Week 52 and FAP | The Japanese UPDRS assesses the status of PD patients objectively. Part IV assesses complications of therapy on 11 items. Participants receive a score of 0-4 or 0-1 points per item depending on the item. The maximum total score is 23 points. A higher score indicates more severe symptoms of complications. Percent change from baseline was calculated as (change from baseline score/baseline score) * 100; change from baseline was calculated as thescore at the observation day minus the baseline score. | Baseline, Week 52, and FAP (up to Week 52) | 
| Number of Participants at Each Stage of the Modified Hoehn & Yahr Scale at Baseline, Week 52, and FAP by On/Off State in the ROP+L-Dopa Group | The Modified Hoehn & Yahr criteria are measured on the following 8-point scale for staging: 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; 4, Severe disability; and 5, Wheelchair bound or bedridden unless aided. LOCF was used for the FAP data to impute post-baseline missing values. Some participants in each state were not included at FAP as having no post-baseline data in the corresponding state or having no data in the corresponding state at Week 52/withdrawal. | Baseline, Week 52, and FAP (up to Week 52) | 
| Number of Participants at Each Stage of the Modified Hoehn & Yahr Scale at Baseline, Week 52, and FAP in the ROP Group | The Modified Hoehn & Yahr criteria are measured on the following 8-point scale for staging: 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; 4, Severe disability; and 5, Wheelchair bound or bedridden unless aided. | Number of Participants at Each Stage of the Modified Hoehn & Yahr Scale at Baseline, Week 52, and FAP in the ROP Group | 
| Mean Change From Baseline in the Schwab and England Activities of Daily Living Scale Score by Clinician at Week 52 and FAP by On/Off State in the ROP+L-Dopa Group | The Schwab and England Activities of Daily Living Scale Score is measured as percentage, from 100% (Completely independent. Able to do all chores without slowness, difficulty or impairment. Essentially normal. Unaware of any difficulty) to 0% (Vegetative functions such as swallowing, bladder and bowel functions are not functioning. Bedridden). | Baseline, Week 52, and FAP (up to Week 52) | 
| Mean Change From Baseline in the Schwab and England Activities of Daily Living Scale Score by Clinician at Week 52 and FAP in ROP Group | The Schwab and England Activities of Daily Living Scale Score is measured as percentage, from 100% (Completely independent. Able to do all chores without slowness, difficulty or impairment. Essentially normal. Unaware of any difficulty) to 0% (Vegetative functions such as swallowing, bladder and bowel functions are not functioning. Bedridden). | Baseline, Week 52, and FAP (up to Week 52) | 
| Percentage of Participants Remaining in the Study on the Indicated Days in the ROP+L-Dopa Group | The percentage of participants remaining in the study was presented by Kaplan-Meier method, where premature discontinuation (i.e., withdrawal before Week 52) was the event, and participants who had completed the study were censored. | Days 0-422 | 
| Percentage of Participants Remaining in the Study on the Indicated Days in the ROP Group | The percentage of participants remaining in the study was presented by Kaplan-Meier method, where premature discontinuation (i.e., withdrawal before Week 52) was the event, and participants who had completed the study were censored. | Days 0-419 | 
| Number of Participants Scored as Responders on the Clinician's Global Impression (CGI) Scale at Week 52 and FAP | CGI is measured on the following 7-point scale: 1, Very much improved; 2, Much Improved; 3, Minimally improved; 4, No change; 5, Minimally worse; 6, Much worse; and 7, Very much worse. Responders are defined as those participants scored as very much improved or much improved. | Week 52 and FAP (up to Week 52) | 
| Mean Change From Baseline in Awake Time Off (Hours) and Awake Time On (Hours) at Week 52 and FAP in the ROP+L-Dopa Group Excluding Participants With 0 Off (Hour) at Baseline | Off state is where PD symptoms are not adequately controlled by the drug. On state is where PD symptoms are well controlled by the drug. The off's duration (awake time spent off) and the on's duration (awake time spent on) on each day were calculated. | Baseline, Week 52, and FAP (up to Week 52) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Ropinirole hydrochloride, L-dopa, Parkinson's Disease, Dopamine agonist