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.
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 recerving an adequate haemodialysis prescription (i. e. single-pool
Kt/V >1. 0) *.
- 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 overread, 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.
- Shinzato calculating formula [Shinzato, 1994] using in Japanese Society for
Dialysis Therapy will be used.
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)** < 2xULN; and bilirubin ≤ 1. 5xULN (isolated bilirubin >
1. 5ULN is acceptable if bilirubin is fractionated and direct bilirubin < 35%) at week
- 1(at the screening visit).
- A female subject has a negative pregnancy test at week -1(at the screening visit).
- ULN of ALT(GTP) and AST(GOT) is 20 IU/L [Kurokawa, 2002].
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
- atients 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 in situ carcinoma of the 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.
