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)
Condition: Restless Legs Syndrome
MeSH terms: Psychomotor Agitation; Restless Legs Syndrome; Kidney Diseases; Renal Insufficiency, Chronic; Syndrome
Intervention: Ropinirole immediate release (IR); Placebo
Intervention description: 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.; 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.
Intervention MeSH terms: Ropinirole
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 34.0
Sex: All
Minimum age: 18 Years
Maximum age: 79 Years
Healthy volunteers: No
Keywords: ropinirole; haemodialysis; restless legs syndrome

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.
    

Eligibility criteria:

        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.