Clinical Evaluation of Ropinirole CR-RLS ( SK&F101468)Tablets in Restless Legs Syndrome

• Drug Related Adverse Events-On-Therapy [ Time Frame: Weeks 1 - 12 Treatment Period ] [ Designated as safety issue: No ]
• Haematology Clinical Lab Values Change From Baseline [ Time Frame: Baseline - Week 13 (Follow-up) ] [ Designated as safety issue: No ]
  Standard units of measure vary. Therefore, Mean Change is represented in Standard Units: Hematocrit = SI unit of GSK; Hemoglobin = G/L; Platelet count, White Blood Cell count = GI/L; Red Blood Cell count = TI/L. n = number of subjects evaluated. EW = Early Withdrawal.
• Blood Chemistry Clinical Lab Values Change From Baseline [ Time Frame: Baseline - Week 13 (Follow-up) ] [ Designated as safety issue: No ]
  Mean Change in Standard Units of Measure: Albumin, Total Protein=G/L; Alkaline Phosphatase, Alanine Amino Transferase, Aspartate Amino Transferase, Lactate Dehydrogenase, Creatine Phosphokinase, Gamma Glutamyl Transferase=IU/L; Total Bilirubin, Creatinine=UMOL/L; Blood Urea Nitrogen, Cholesterol, Chloride, Sodium, Potassium=MMOL/L; Prolactin=MCG/L
• Urinalysis Clinical Lab Values [ Time Frame: Baseline - Week 13 (Follow-up) ] [ Designated as safety issue: No ]
  Dipstick test values: Neg Value, Trace, +1, +2, +3. No subjects tested higher than +3.
• 12-Lead Electrocardiogram (ECG) Findings Transitions From Baseline [ Time Frame: Baseline, Week 4, 8, 12, 13 (Follow-up) ] [ Designated as safety issue: No ]
  Baseline Finding/Time Period Finding. Abbreviations: N = normal; A = abnormal; CS = clinically significant; NCS = not clinically significant. Options include N/N, N/ANCS, N/ACS, ANCS/N, ANCS/ANCS, ANCS/ACS, ACS/N, ACS/ANCS, and ACS/ACS.
• Vital Signs and Body Weight Change From Baseline [ Time Frame: Baseline to Week 12/EW ] [ Designated as safety issue: No ]
  Units of Measure Vary: Weight = kg; Semi-supine and Standing Systolic and Diastolic BP = mmHg; Semi-supine and Standing Pulse Rate = bpm; EW = early withdrawal; Semi-supine = lying down; Orthostatic = lying, sitting, and standing.

• Change From Baseline to Week 12 in International Restless Leg Syndrome (IRLS) Rating Scale Total Score [ Time Frame: Baseline and after Week 12 ] [ Designated as safety issue: No ]
  The IRLS Scale assesses the severity of sensory and motor symptoms, sleep disturbance, daytime somnolence, and impact on activities of daily living and mood. The questionnaire scores various questions and totals them using the following scale: Very severe=31-40 points, Severe=21-30 points, Moderate=11-20 points, Mild=1-10 points, None=0 points.
• Clinical Global Impression Scale - Severity of Illness (CGI-S) [ Time Frame: Baseline - Final assessment point ] [ Designated as safety issue: No ]
  The CGI-S scale measures the overall severity of illness on a 7 point scale. Normal = 1, Borderline = 2, Mildly = 3, Moderately = 4, Markedly = 5, Severely = 6, Extremely Severe = 7(no subjects scored a 7).
• Clinical Global Impression Global Improvement (CGI-GI) [ Time Frame: Baseline - Final assessment point ] [ Designated as safety issue: No ]
  CGI-GI is a 7 point scale assessing Global Improvement. 1 = Very much improved, 2 = Much improved, 3 = Minimally improved, 4 = No change, 5 = Minimally worse, 6 = Much worse, 7 = Very much worse (no patients scored a 5, 6, or 7).
• Change From Baseline at Week 12/Early Withdrawal (EW) in Pittsburgh Sleep Quality Index (PSQI) Total Score [ Time Frame: Baseline - Week 12/EW ] [ Designated as safety issue: No ]
  The PSQI generates seven scores that correspond to different domains. Each component score ranges from 0 (no difficulty) to 3 (severe difficulty). The domain scores are totaled to produce a global score (range of 0-21). A PSQI global score > 5 is considered to be suggestive of significant sleep disturbance.
• Change From Baseline to Week 12/EW in Pittsburgh Sleep Quality Index (PSQI) Total Score by Domains [ Time Frame: Baseline - Week 12/EW ] [ Designated as safety issue: No ]
  The PSQI generates seven scores that correspond to different domains. Each component score ranges from 0 (no difficulty) to 3 (severe difficulty). The domain scores are totaled to produce a global score (range of 0-21). A PSQI global score > 5 is considered to be suggestive of significant sleep disturbance.
• Change From Baseline at Week 12/Early Withdrawal (EW) in Johns Hopkins Restless Leg Syndrome Quality of Life Questionnaire (RLSQOL) on the Overall Life Impact Score [ Time Frame: Baseline and Week 12/EW ] [ Designated as safety issue: No ]
  The RLSQOL scale consists of 18 items, 13 of which are scored on a 5-point scale. Ten of the items can be summed to the overall life impact score, which can be transformed to a 0-100 score. Mild = 84.48, Moderate = 62.93, or Severe = 37.47
• Change From Baseline at Week 12/Early Withdrawal (EW) in Profile of Mood Status (POMS) [ Time Frame: Baseline and Week 12/EW ] [ Designated as safety issue: No ]

  The POMS Standard form contains 65 items (0-232). The respondent rates each item on a 5-point scale, ranging from "Not at all (0)" to "Extremely (4)." The assessment measures six identified mood factors:

  • Tension-Anxiety
  • Depression-Dejection
  • Anger-Hostility
  • Vigor-Activity
  • Fatigue-Inertia
  • Confusion-Bewilderment
• Change From Baseline at Week 12/Early Withdrawal (EW) in Hospital Anxiety and Depression Scale (HADS) [ Time Frame: Baseline - Week 12/EW ] [ Designated as safety issue: No ]
  Self screening questionnaire that requires the first response to questions. Questionnaire consists of 14 questions, seven for anxiety "0-21" and seven for depression "0-21". Questions are answered on a four point scale from 0-3; Items 1, 3, 5, 6, 8, 10, 11, and 13 are reversed for summation.
• Pharmacokinetic Analysis: Plasma Concentrations of SK&F101468, an Unchanged Form of Ropinirole. [ Time Frame: Weeks 1-12 ] [ Designated as safety issue: No ]
  Plasma samples taken at 24 hours after dosing had been administered for 3 days or longer. This was repeated if the dose was escalated. Lower Limits of Quantitation (LLQ) for SK&101468 = 20 pg/mL. The lowest concentration of analyte can be measured with established acceptable accuracy and precision.
• Pharmacokinetic Analysis: Plasma Concentrations of SK&F104557, a Circulating Metabolite of Ropinirole. [ Time Frame: Weeks 1 -12 ] [ Designated as safety issue: No ]
  Plasma samples taken at 24 hours after dosing had been administered for 3 days or longer. This was repeated if the dose was escalated. Lower Limits of Quantitation (LLQ) for SK&104557 = 20 pg/mL. The lowest concentration of analyte can be measured with established acceptable accuracy and precision.
• Pharmacokinetic Analysis: Plasma Concentrations of SK&F89124, a Circulating Metabolite of Ropinirole. [ Time Frame: Weeks 1-12 ] [ Designated as safety issue: No ]
  Plasma samples taken at 24 hours after dosing had been administered for 3 days or longer. This was repeated if the dose was escalated. Lower Limits of Quantitation (LLQ) for SK&89124 = 20 pg/mL. The lowest concentration of analyte can be measured with established acceptable accuracy and precision.

This study was designed to evaluate the safety, pharmacokinetic profile and efficacy in Restless Legs Syndrome patients.

Inclusion Criteria:

• A subject will be considered eligible for inclusion in this study only if all of the following criteria apply:

At Week -1 (at the start of Screening period)

• Patients who are diagnosed with RLS according to the International RLS Study Group's (IRLSSG) Diagnostic Criteria.
• Age: Patients aged at least 18 years and under 80 years.
• Patients who have had RLS symptoms in the evening or nighttime (17:00 to 7:00 next day) for at least 20 days within one month before the start of the screening period. Patients treated for RLS before the start of the Screening period and who do not meet this criterion are considered eligible if the previous therapy can be discontinued from the Screening period.
• Patients who experience RLS symptoms requiring treatment after 17:00 but prior to bedtime.

• Gender: male and female Female of child-bearing potential will be eligible for inclusion in this study. However they must have a negative pregnancy test at the Screening visit. They agree are perform pregnancy test at the time determined and practice one of the following method of contraception from the Screening visit till the end of follow-up examination.

  • Abstinence
  • Oral Contraceptive, either combined or progestogen alone
  • Injectable progestogen
  • Implants of levonorgestrel
  • Estrogenic vaginal ring
  • Percutaneous contraceptive patches
  • 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
• Inpatient or outpatient status: Outpatient status
• Patients who are able to give informed written consent in person. For patients aged under 20 years, their legally acceptable representatives are able to give informed written consent.

At Week 0 (at the start of treatment period)

• Patients who experience RLS symptoms in the evening and nighttime (17:00 to 7:00 next day) for at least 4 days within 7 days before the start of the treatment period.
• Patients who have sleep impairment 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.

Exclusion Criteria:

• Patients requiring treatment for daytime RLS symptoms (7:00 to 17:00).
• Patients with signs of secondary RLS (e.g. chronic renal failure, iron-deficiency anemia, pregnancy, rheumatoid arthritis and Parkinson's disease).
• Patients whose serum ferritin level is <10 μg/L (ng/mL) at the start of Screening period.
• Patients with following sleep disorder not associated with RLS e.g. narcolepsy, sleep terror disorder, sleep walking disorder, breathing related sleep disorder (Patients with obvious apnea in nighttime sleeping when they do not have alcohol drinking or over 15 times/hour is used to a target for apnea hypopnea index,in which case to implement polysomnography), etc.
• Patients with complication of movement disorder (e.g. Parkinson's disease, dyskinesia, dystonia, etc.).
• Patients with severe hepatic/renal/cardiac/pulmonary disorder or hematopoietic disorder.

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 the medical history or complication of cancer or malignant tumour.
• Patients with the medical history or complication of substance abuse (e.g. alcohol or drug) or dependency of substance for the last one year
• Patients whose diastolic blood pressure (BP) is >110 mmHg or <50 mmHg or whose systolic BP is >180 mmHg or <90 mmHg at the start of Screening period and Week0.
• Patients intolerant for ropinirole hydrochloride (HCl) or other dopamine agonists.
• Patients with the medical history of allergy to ropinirole HCl in the past.
• Patients with the medical history of Augmentation to ropinirole HCl or other dopamine agonists in the past and those who have experienced early morning RLS symptoms.

Augmentation is defined as below:

RLS appear 2 hours earlier than the pre-treatment. Symptoms become severer than the pre-treatment. Symptoms which start after less time at rest than they did before treatment. The RLS extend to other sites (e.g. arm and trunk).

• Patients without nighttime 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 screening period.
• Female patients who are pregnant or lactating, who may be pregnant, or who plan for pregnancy during the study .
• Patients with chronic hepatitis typeB and /or typeC which is positive of hepatitis B surface antigen （HBsAg）and/or hepatitis C antibody.
• Patients who have medical conditions which, in the opinion of investigator could affect efficacy and safety assessment. This may include, but are not limited to the following disorders: diabetes, peripheral neuropathy, fibromyalgia syndrome, symptomatic orthostatic hypotension, hepatic or renal failure, pleuro-pulmonary fibrosis.
• Patients who have received treatment of an estrogen drug product and a drug that are known to substantially inhibit CYP1A2 and have changed the dose from baseline visit to Week 0.
• Others whom the investigator (sub investigator) considers ineligible for the study.