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)

Phase 2

Terminated

Conditions: Restless Legs Syndrome

Interventions: Drug: Ropinirole immediate release (IR)
Drug: Placebo

Registration Number: NCT00996944

Lead Sponsor: GlaxoSmithKline

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 34

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Ropinirole IR	Ropinirole immediate release (IR)	-
Placebo	Placebo	-

Primary Outcome Measures

Name	Time	Method
International Restless Legs Syndrome (IRLS) Rating Scale Total Score at Week 0 and Week 12	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.
IRLS Rating Scale Total Score for Participants Who Withdrew From the Double-Blind Treatment Period (DBT WD)	DBT WD (up to 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, and 2 participants had missing DBT WD data.

Secondary Outcome Measures

Name	Time	Method
Johns Hopkins Restless Legs Syndrome Quality of Life (RLSQOL) Questionnaire Overall Life Impact Score at Week 0 and Week 12	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.
Johns Hopkins RLSQOL Questionnaire Overall Life Impact Score for Participants Who Withdrew From the Double-Blind Treatment Period (DBT WD)	DBT WD (up to 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.
The PSQI Total Score for Participants Who Withdrew From the Double-Blind Treatment Period (DBT WD)	DBT WD (up to 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.
Number of Participants With the Indicated Responses to the Patient Satisfaction Question at Week 0 and Week 12	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.
IRLS Rating Scale Total Score for Participants Who Withdrew in the Long-term Treatment Period (LONG WD)	LONG WD (up to Week 64)	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.
Number of Participants With the Indicated Clinical Global Impression-Improvement (CGI-I) Scores at Week 12	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.
Number of Participants With the Indicated CGI-I Scores for Participants Who Withdrew From the Double-Blind Treatment Period (DBT WD)	DBT WD (up to 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.
Johns Hopkins RLSQOL Questionnaire Overall Life Impact Score for Participants Who Withdrew in the Long-term Treatment Period (LONG WD)	LONG WD (up to Week 64)	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.
Number of Participants With the Indicated CGI-I Scores for Participants Who Withdrew fn the Long-term Treatment Period (LONG WD)	LONG WD (up to Week 64)	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.
Number of Participants With the Indicated Responses to the Patient Satisfaction Question for Participants Who Withdrew From the Double-Blind Treatment Period (DBT WD)	DBT WD (up to 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.
Drug Clearance Rate On-Dialysis and Off-Dialysis During the Maintenance Dose Treatment Phase (in the Long-term Treatment Period)	Week 12 through Week 64	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.
Number of Participants With the Indicated Responses to the Patient Satisfaction Question for Participants Who Withdrew fn the Long-term Treatment Period (LONG WD)	LONG WD (up to Week 64)	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.
The Pittsburgh Sleep Quality Index (PSQI) Total Score at Week 0 and Week 12	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.
The PSQI Total Score for Participants Who Withdrew fn the Long-term Treatment Period (LONG WD)	LONG WD (up to Week 64)	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.
Mean Daily Number of Hours of RLS Symptoms by Timeframe at Week 0 and Week 12	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.
Mean Daily Number of Hours of RLS Symptoms by Timeframe for Participants Who Withdrew From the Double-Blind Treatment Period (DBT WD)	DBT WD (up to 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.
Mean Daily Number of Hours of RLS Symptoms by Timeframe for Participants Who Withdrew fn the Long-term Treatment Period (LONG WD)	LONG WD (up to Week 64)	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.