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

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

Official Title
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Clinical Evaluation of Ropinirole CR-RLS Tablets in Restless Legs Syndrome-Open-Label, Uncontrolled Study. Classification: Clinical Pharmacology, Exploratory

Conditions
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Restless Legs Syndrome

Intervention / Treatment
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* Drug: ropinirole controlled release (CR)-RLS


Participation Criteria
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Eligibility Criteria
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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.

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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ropinirole CR-RLS<br>Subjects will orally take ropinirole CR-RLS tablet(s) once daily 1-2 hours before the onset of RLS symptoms at about the same time of the day. The time of taking ropinirole must be after 16:00.Adjustment of the Ropinirole CR-RLS tablets should be completed after the Week 1 visit up to the Week 10 visit. The dose will be increased at intervals of at least one week until sufficient efficacy is obtained (use much improved as a guide) without safety problem. Dose escalation will start at the initial dose 0.5 mg/day to 1 mg/day; after 1 mg/day, the dose will be increased by 1 mg/day to the maximum 6 mg/day. | Drug: ropinirole controlled release (CR)-RLS<br>* White film-coated round-shaped tablet<br>* Other names: Ropinirole CR-RLS (SK&F101468);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Drug Related Adverse Events-On-Therapy |  | Weeks 1 - 12 Treatment Period | 
| Haematology Clinical Lab Values Change From Baseline | 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. | Baseline - Week 13 (Follow-up) | 
| Blood Chemistry Clinical Lab Values Change From Baseline | 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 | Baseline - Week 13 (Follow-up) | 
| Urinalysis Clinical Lab Values | Dipstick test values: Neg Value, Trace, +1, +2, +3. No subjects tested higher than +3. | Baseline - Week 13 (Follow-up) | 
| 12-Lead Electrocardiogram (ECG) Findings Transitions From Baseline | 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. | Baseline, Week 4, 8, 12, 13 (Follow-up) | 
| Vital Signs and Body Weight Change From Baseline | 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. | Baseline to Week 12/EW | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 12 in International Restless Leg Syndrome (IRLS) Rating Scale Total Score | 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. | Baseline and after Week 12 | 
| Clinical Global Impression Scale - Severity of Illness (CGI-S) | 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). | Baseline - Final assessment point | 
| Clinical Global Impression Global Improvement (CGI-GI) | 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). | Baseline - Final assessment point | 
| Change From Baseline at Week 12/Early Withdrawal (EW) in Pittsburgh Sleep Quality Index (PSQI) Total Score | 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. | Baseline - Week 12/EW | 
| Change From Baseline to Week 12/EW in Pittsburgh Sleep Quality Index (PSQI) Total Score by Domains | 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. | Baseline - Week 12/EW | 
| 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 | 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 | Baseline and Week 12/EW | 
| Change From Baseline at Week 12/Early Withdrawal (EW) in Profile of Mood Status (POMS) | 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 | Baseline and Week 12/EW | 
| Change From Baseline at Week 12/Early Withdrawal (EW) in Hospital Anxiety and Depression Scale (HADS) | 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. | Baseline - Week 12/EW | 
| Pharmacokinetic Analysis: Plasma Concentrations of SK&F101468, an Unchanged Form of Ropinirole. | 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. | Weeks 1-12 | 
| Pharmacokinetic Analysis: Plasma Concentrations of SK&F104557, a Circulating Metabolite of Ropinirole. | 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. | Weeks 1 -12 | 
| Pharmacokinetic Analysis: Plasma Concentrations of SK&F89124, a Circulating Metabolite of Ropinirole. | 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. | Weeks 1-12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Restless Legs Syndrome