Clinical Evaluation of Ropinirole IR (Immediate Release) Tablets in Patients Who Are Diagnosed With Symptomatic Restless Legs Syndrome (RLS) Associated With Chronic Kidney Disease (CKD) Managed With Haemodialysis (Including Haemofiltration and Haemodiafiltration)

Study Overview
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Brief Summary
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This is a multicenter, placebo controlled, parallel group, double-blind, randomized comparison study to evaluate the efficacy and safety of ropinirole IR tablets orally administered for 12 weeks in patients with symptomatic restless legs syndrome associated with Chronic kidney disease (CKD) managed with haemodialysis (including haemofiltration and haemodiafiltration) (hereinafter referred to as uRLS), to evaluate the efficacy and safety of long-term administration of ropinirole IR tablets, and assess the effect on the steady state pharmacokinetics in the long-term administration period of ropinirole IR tablets.

Official Title
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Clinical Evaluation of Ropinirole IR (Immediate Release) Tablets in Patients Who Are Diagnosed With Symptomatic Restless Legs Syndrome (RLS) Associated With Chronic Kidney Disease (CKD) Managed With Haemodialysis (Including Haemofiltration and Haemodiafiltration)

Conditions
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Restless Legs Syndrome

Intervention / Treatment
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* Drug: Ropinirole immediate release (IR)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: at Week -1 (at the screening visit) Patients who are diagnosed with symptomatic restless legs syndrome associated with Chronic kidney disease (CKD) managed with haemodialysis (including haemofiltration and haemodiafiltration). RLS are diagnosed based on the International RLS Study Group's (IRLSSG) Diagnostic Criteria. Patients with chronic kidney disease (CKD) on haemodialysis (including haemofiltration and haemodiafiltration) for at least 3 months prior to the screening period with and receiving an adequate haemodialysis prescription (i.e. single-pool Kt/V >1.0. Shinzato calculating formula [Shinzato, 1994] using in Japanese Society for Dialysis Therapy will be used.) Patients aged ≥18 years and <80 years. Patients who have had RLS symptoms for 20 days or more on or after 28 days before the start of the screening period. However, patients who have been receiving drug therapy for RLS before the start of the screening period do not apply to this criterion when meeting the conditions below: The patient's drug therapy (excluding Anxiolytics and Hypnotics and sedatives medication) for RLS can be discontinued at the time of starting the screening period. For RLS symptoms in the subject was considered to have continued for 20 days or more on or after 28 days before the start of the drug treatment for RLS. QTc criteria (QTc [b or f], mechanical or manual reread, male or female): Patients with QTc <450 msec or <480 msec for patients with bundle branch block (BBB) -values based on either single electrocardiogram (ECG) values or triplicate ECG averaged QTc values obtained over a brief recording period. Male or female patients. A female subject is eligible to enter and participate in the study if she: Is of non-childbearing potential or Is of child-bearing potential, is not lactating and agrees to use one of GlaxoSmithKline (GSK)-specified highly effective methods for avoiding pregnancy: abstinence, oral contraceptives, either combined or progestogen alone (see Permitted medications), injectable progestogen, implants of levonorgestrel, estrogenic vaginal ring (see Permitted medications), percutaneous contraceptive patches (see Permitted medications), intrauterine device (IUD) or intrauterine system (IUS) that meets the SOP effectiveness criteria as stated in the product label, 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]). Outpatients Patients who are able to give informed written consent in person. Legal representative also should give informed written consent, if patients are under twenty years old. at Week 0 (at the start of the treatment period) Patients who experience RLS symptoms for at least 4 days within 7 days before the start of the treatment period. Patients who have sleep disturbance associated with RLS. Patients who answered as 3 (severe) or 4 (very severe) to Question 4 (Sleep disturbance) in the IRLS Rating Scale. Patients whose IRLS Rating Scale total scores are 15 points or more. Liver function tests: Patients with aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2 * ULN (upper limit of normal); and bilirubin ≤ 1.5 * ULN (isolated bilirubin > 1.5 ULN is acceptable if bilirubin is fractionated and direct bilirubin < 35%) at week -1(at the screening visit). ULN of ALT(GTP) and AST(GOT) is 20 IU/L [Kurokawa, 2002]. A female subject has a negative pregnancy test at week -1(at the screening visit). Exclusion Criteria: at Week -1 (at the screening visit) Patients with signs of primary RLS (Patients who have developed RLS symptoms since kidney function was normal) Patients with following sleep disorder not associated with RLS e.g. narcolepsy, sleep terror disorder, sleepwalking disorder, breathing related sleep disorder Patients with complication of movement disorder (e.g. Parkinson's disease, dyskinesia, dystonia, etc) Patients with severe hepatic/cardiac/pulmonary disorder or haematopoietic disorder other than those on haemodialysis (including haemofiltration and haemodiafiltration). The severity 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 a history of malignancies within the past 5 years, with the exception of basal cell carcinoma of the skin or carcinoma in situ of cervix. Patients with a medical history or complication of substance abuse (e.g. alcohol or drug) or dependency of substance for the last one year. Patients with supine systolic blood pressure (SBP) of <100 mmHg or >190 mmHg or supine diastolic blood pressure (DBP) of ≥120 mmHg before the dialysis which will be conducted after the longest interval,at the screening visit. Patients intolerant to ropinirole hydrochloride (HCl) or other dopamine agonists. Patients for whom ropinirole HCl or other dopamine agonists are considered to be of safety concern by the investigator/subinvestigator Patients with a history of augmentation or End-of-dose-rebound in the early morning after medications of dopamine agonists (including ropinirole HCl) and/or L-Dopa. Augmentation is defined as follows: RLS symptoms that occurred while on treatment and occur ≧ 2 hours earlier than they did before. Symptoms which are more severe than when not treated. Symptoms which start after less time at rest than they did before treatment. Symptoms which involve other parts of the body, such as the arms or trunk. Patients without night time sleeping habit (e.g. night-shift worker, etc) and those who must drastically change the habitual bedtime during the study duration. Patients who have participated in another clinical study of an investigational product or medical device within the last 12 weeks prior to the start of the screening period. Female patients who are pregnant or lactating, who may be pregnant, or who plan for pregnancy during the study. (Instructions should be given to women of childbearing potential to practice adequate contraception even if they have no plan for pregnancy). Current or chronic history of liver disease, known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones) Presence of hepatitis B surface antigen (HBsAg), positive Hepatitis C test result within 3 months of screening. Patients who have medical conditions which, in the opinion of investigator/subinvestigator could affect efficacy and safety assessment. This may include the following disorders: fibromyalgia syndrome, rheumatoid arthritis, symptomatic orthostatic hypotension, hepatic failure, pulmonary fibrosis. Subject is unable to discontinue prohibited medications during the Screening period. Subjects who know they will imminently receive a transplant Patients who have changed the dose or administration method of Anxiolytics or Hypnotics and sedatives within the last 4 weeks prior to the start of the screening period and or Patients who used more than two drugs. Others whom the investigator/subinvestigator considers ineligible for the study. at Week 0 (start of the treatment period) Patients with supine SBP of <100 mmHg or >190 mmHg or supine DBP of ≥120 mmHg before the dialysis which will be conducted after the longest interval, at Week 0 (start of the treatment period). Patients who have started treatment with medications including an estrogen drug product, a drug that is known to substantially induce or inhibit CYP1A2, an antihistamine (for ocular instillation or dermal application, or a preparation containing fexofenadine HCl or loratadine), Anxiolytics, Hypnotics and sedatives or who have changed the dose or administration method of such medications between Week -1 (start of the screening period) and Week 0 (start of the treatment period). Patients whose serum ferritin level is <10 μg/L (ng/mL) at the screening visit.

Ages Eligible for Study
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Minimum Age: 18 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ropinirole IR<br> | Drug: Ropinirole immediate release (IR)<br>* Subjects completing the screening period will be randomized (1:1) to receive the IR or placebo for 12 weeks. The treatment will be started at the initial dose of 0.25 mg/day within 1 to 3 hours before bedtime. The maximum available dose is 3 mg/day. For all subjects completing short-term period and entering the long-term treatment period, the open-label treatment will be started from IR 0.25 mg/ day regardless of dose levels during short-term period. The dose will be upward titrated from 0.25 mg/day to 0.5 mg/day and after that in increments of 0.5 mg/day until sufficient efficacy is obtained (targeting much improved or very much improved in the CGI-I) without safety/tolerability problem.<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Subjects completing the screening period will be randomized (1:1) to receive the IR or placebo for 12 weeks. The treatment will be started at the initial dose of 0.25 mg/day within 1 to 3 hours before bedtime.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| International Restless Legs Syndrome (IRLS) Rating Scale Total Score at Week 0 and Week 12 | The IRLS rating scale is an investigator-rated scale consisting of 10 questions with a choice of 5 responses each. These responses are numerically scored from 0 (the least severe response) to 4 (the most severe response). The IRLS rating scale total score is calculated by summing the individual response scores. The highest possible score is 40, which represents the most severe RLS; the lowest possible score is 0, which represents an absence of RLS. A total of 17 participants were prematurely withdrawn from the study before Week 12. | Week 0 and Week 12 | 
| IRLS Rating Scale Total Score for Participants Who Withdrew From the Double-Blind Treatment Period (DBT WD) | The IRLS rating scale is an investigator-rated scale consisting of 10 questions with a choice of 5 responses each. These responses are numerically scored from 0 (the least severe response) to 4 (the most severe response). The IRLS rating scale total score is calculated by summing the individual response scores. The highest possible score is 40, which represents the most severe RLS; the lowest possible score is 0, which represents an absence of RLS. A total of 17 participants were prematurely withdrawn from the study before Week 12, and 2 participants had missing DBT WD data. | DBT WD (up to Week 12) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| IRLS Rating Scale Total Score for Participants Who Withdrew in the Long-term Treatment Period (LONG WD) | The IRLS rating scale is an investigator-rated scale consisting of 10 questions with a choice of 5 responses each. These responses are numerically scored from 0 (the least severe response) to 4 (the most severe response). The IRLS rating scale total score is calculated by summing the individual response scores. The highest possible score is 40, which represents the most severe RLS; the lowest possible score is 0, which represents an absence of RLS. | LONG WD (up to Week 64) | 
| Number of Participants With the Indicated Clinical Global Impression-Improvement (CGI-I) Scores at Week 12 | The CGI-I assesses the participant's improvement or worsening of RLS from baseline with the following eight grades: 0 = Not Assessed, 1 = Very Much Improved, 2 = Much Improved, 3 = Minimally Improved, 4 = No Change, 5 = Minimally Worse, 6 = Much Worse, and 7 = Very Much Worse. | Week 12 | 
| Number of Participants With the Indicated CGI-I Scores for Participants Who Withdrew From the Double-Blind Treatment Period (DBT WD) | The CGI-I assesses the participant's improvement or worsening of RLS from baseline with the following eight grades: 0 = Not Assessed, 1 = Very Much Improved, 2 = Much Improved, 3 = Minimally Improved, 4 = No Change, 5 = Minimally Worse, 6 = Much Worse, and 7 = Very Much Worse. | DBT WD (up to Week 12) | 
| Number of Participants With the Indicated CGI-I Scores for Participants Who Withdrew fn the Long-term Treatment Period (LONG WD) | The CGI-I assesses the participant's improvement or worsening of RLS from baseline with the following eight grades: 0 = Not Assessed, 1 = Very Much Improved, 2 = Much Improved, 3 = Minimally Improved, 4 = No Change, 5 = Minimally Worse, 6 = Much Worse, and 7 = Very Much Worse. | LONG WD (up to Week 64) | 
| Johns Hopkins Restless Legs Syndrome Quality of Life (RLSQOL) Questionnaire Overall Life Impact Score at Week 0 and Week 12 | The RLSQOL questionnaire is a participant-rated questionnaire designed to assess the impact of RLS on the lives of participants. It consists of 18 items, 10 of which contribute to a single summary score (overall life impact). The response for each item is coded from 1 to 5, with 1 representing the best quality of life and 5 representing the worst quality of life. The lowest possible overall life impact score is 0, and the highest possible overall life impact score is 100. The score of 100 represents the best possible quality of life. | Week 0 and Week 12 | 
| Johns Hopkins RLSQOL Questionnaire Overall Life Impact Score for Participants Who Withdrew From the Double-Blind Treatment Period (DBT WD) | The RLSQOL questionnaire is a participant-rated questionnaire designed to assess the impact of RLS on the lives of participants. It consists of 18 items, 10 of which contribute to a single summary score (overall life impact). The response for each item is coded from 1 to 5, with 1 representing the best quality of life and 5 representing the worst quality of life. The lowest possible overall life impact score is 0, and the highest possible overall life impact score is 100. The score of 100 represents the best possible quality of life. | DBT WD (up to Week 12) | 
| Johns Hopkins RLSQOL Questionnaire Overall Life Impact Score for Participants Who Withdrew in the Long-term Treatment Period (LONG WD) | The RLSQOL questionnaire is a participant-rated questionnaire designed to assess the impact of RLS on the lives of participants. It consists of 18 items, 10 of which contribute to a single summary score (overall life impact). The response for each item is coded from 1 to 5, with 1 representing the best quality of life and 5 representing the worst quality of life. The lowest possible overall life impact score is 0, and the highest possible overall life impact score is 100. The score of 100 represents the best possible quality of life. | LONG WD (up to Week 64) | 
| The Pittsburgh Sleep Quality Index (PSQI) Total Score at Week 0 and Week 12 | The PSQI consists of the following 7 domains: sleep quality, duration getting to sleep, sleep duration, sleep adequacy, sleep disturbance, use of sleeping pill, and somnolence. These domains are numerically scored from 0 to 3, with 0 representing the least severe response and 3 representing the most severe response. The PSQI total score is calculated by summing the individual domain scores. The highest possible score is 21, which represents the most disturbances in sleep quality; the lowest possible score is 0, which represents an absence of disturbances in sleep quality. | Week 0 and Week 12 | 
| The PSQI Total Score for Participants Who Withdrew From the Double-Blind Treatment Period (DBT WD) | The PSQI consists of the following 7 domains: sleep quality, duration getting to sleep, sleep duration, sleep adequacy, sleep disturbance, use of sleeping pill, and somnolence. These domains are numerically scored from 0 to 3, with 0 representing the least severe response and 3 representing the most severe response. The PSQI total score is calculated by summing the individual domain scores. The highest possible score is 21, which represents the most disturbances in sleep quality; the lowest possible score is 0, which represents an absence of disturbances in sleep quality. | DBT WD (up to Week 12) | 
| The PSQI Total Score for Participants Who Withdrew fn the Long-term Treatment Period (LONG WD) | The PSQI consists of the following 7 domains: sleep quality, duration getting to sleep, sleep duration, sleep adequacy, sleep disturbance, use of sleeping pill, and somnolence. These domains are numerically scored from 0 to 3, with 0 representing the least severe response and 3 representing the most severe response. The PSQI total score is calculated by summing the individual domain scores. The highest possible score is 21, which represents the most disturbances in sleep quality; the lowest possible score is 0, which represents an absence of disturbances in sleep quality. | LONG WD (up to Week 64) | 
| Number of Participants With the Indicated Responses to the Patient Satisfaction Question at Week 0 and Week 12 | Participants responded to a question about their satisfaction with the IP on the following 1 to 7 scale: 1 = very much satisfied; 2 = satisfied; 3 = somewhat satisfied; 4 = neither satisfied nor dissatisfied; 5 = somewhat dissatisfied; 6 = dissatisfied; and 7 = very dissatisfied. At Week 0, participants responded to a question about their satisfaction with their prior medications. | Week 0 and Week 12 | 
| Number of Participants With the Indicated Responses to the Patient Satisfaction Question for Participants Who Withdrew fn the Long-term Treatment Period (LONG WD) | Participants responded to a question about their satisfaction with the IP on the following 1 to 7 scale: 1 = very much satisfied; 2 = satisfied; 3 = somewhat satisfied; 4 = neither satisfied nor dissatisfied; 5 = somewhat dissatisfied; 6 = dissatisfied; and 7 = very dissatisfied. At Week 0, participants responded to a question about their satisfaction with their prior medications. | LONG WD (up to Week 64) | 
| Number of Participants With the Indicated Responses to the Patient Satisfaction Question for Participants Who Withdrew From the Double-Blind Treatment Period (DBT WD) | Participants responded to a question about their satisfaction with the IP on the following 1 to 7 scale: 1 = very much satisfied; 2 = satisfied; 3 = somewhat satisfied; 4 = neither satisfied nor dissatisfied; 5 = somewhat dissatisfied; 6 = dissatisfied; and 7 = very dissatisfied. At Week 0, participants responded to a question about their satisfaction with their prior medications. | DBT WD (up to Week 12) | 
| Mean Daily Number of Hours of RLS Symptoms by Timeframe at Week 0 and Week 12 | Participants recorded the onset time and total duration of RLS symptoms on their diary cards for 7 days from one week before each visit. Timeframes were defined as follows: daytime, 7:00AM to 4:59PM; evening, 5:00PM to 7:59PM; and nighttime, 8:00PM to 6:59AM. | Week 0 and Week 12 | 
| Mean Daily Number of Hours of RLS Symptoms by Timeframe for Participants Who Withdrew From the Double-Blind Treatment Period (DBT WD) | Participants recorded the onset time and total duration of RLS symptoms on their diary cards for 7 days from one week before each visit. Timeframes were defined as follows: daytime, 7:00AM to 4:59PM; evening, 5:00PM to 7:59PM; and nighttime, 8:00PM to 6:59AM. | DBT WD (up to Week 12) | 
| Mean Daily Number of Hours of RLS Symptoms by Timeframe for Participants Who Withdrew fn the Long-term Treatment Period (LONG WD) | Participants recorded the onset time and total duration of RLS symptoms on their diary cards for 7 days from one week before each visit. Timeframes were defined as follows: daytime, 7:00AM to 4:59PM; evening, 5:00PM to 7:59PM; and nighttime, 8:00PM to 6:59AM. | LONG WD (up to Week 64) | 
| Drug Clearance Rate On-Dialysis and Off-Dialysis During the Maintenance Dose Treatment Phase (in the Long-term Treatment Period) | For on-dialysis analysis, measurements were to have been taken 1 hour before dialysis, in the artery/vein at the beginning, during, and end of dialysis, and 1 hour after dialysis. For off-dialysis analysis, measurements were to have been taken 1 hour before dialysis, at the beginning, during, and end of dialysis, and 1 hour after dialysis. | Week 12 through Week 64 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ropinirole, haemodialysis, restless legs syndrome