Long-term Study Of Ropinirole In Restless Legs Syndrome

Study Overview
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Brief Summary
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This is an initial placebo-controlled study followed by open treatment evaluating the effectiveness and tolerability of ropinirole long-term in patients with moderate to severe Restless Legs Syndrome.

Detailed Description
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A randomised, double-blind, placebo-controlled, parallel group study to evaluate the efficacy and safety of ropinirole for 26 weeks and to further evaluate the incidence of augmentation and rebound for a further 40 weeks open-label extension treatment period in subjects suffering from moderate to severe Restless Legs Syndrome.

Official Title
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A Parallel Group Study to Evaluate the Efficacy and Safety of Ropinirole for 26 Weeks and to Further Evaluate the Incidence of Augmentation and Rebound for a Further 40 Weeks Open-label Extension Treatment Period in Subjects Suffering From Moderate to Severe Restless Legs Syndrome.

Conditions
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Restless Legs Syndrome

Intervention / Treatment
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* Drug: Placebo
* Drug: Ropinirole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female subjects, between the ages of 18 and 79, inclusive A female is eligible to enter and participate in the study if she is of: Non-childbearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is post-menopausal); or, Childbearing potential, has a negative result on all required pregnancy tests prior to randomisation, and agrees to an acceptable contraceptive method. Subjects with a diagnosis of idiopathic RLS using the RLS Diagnostic Clinical Interview and the International RLS Study Group (IRLSSG) Diagnostic Criteria during the Screening Visit. Subjects have had RLS symptoms with a history of a minimum of 15 RLS episodes during the previous month. If this is not possible due to the subject being on previous medication to treat RLS the investigator should ensure that the subject should have experienced 4-5 episodes of RLS symptoms during the last 7 days of the wash-out phase (see below). The subject must discontinue and wash-out any previous medication for the treatment of RLS or sleep prior to the Baseline Visit (Day 0). The minimum discontinuation period for wash-out is generally 5 half-lives of the medication or 7 consecutive evenings/nights medication-free prior to baseline, whichever is the longer period. During the Wash-out and Screening Phase, RLS symptoms must be present for at least 4 of the last 7 nights immediately prior to the Baseline Visit (e.g., any combination of evenings and /or nights for = 4 days). Subjects with a total score = 24 on the IRLS Rating Scale at baseline (Day 0). Subjects with RLS symptoms that cause significant sleep impairment based on clinical judgment and guided by subject response to Question 4 of the IRLS Rating Scale (e.g., ordinarily this will include a response of (3) severe or (4) very severe sleep disturbance) at the Baseline Visit OR RLS symptoms that cause severe/very severe discomfort in the limbs based on clinical judgment and guided by subject response to Question 1 of the IRLS Rating Scale (e.g., this will include a response of (3) severe or (4) very severe discomfort in limbs) at the Baseline Visit (Day 0). Subjects must be experiencing RLS symptoms requiring treatment at night-time. Subjects must have given written informed consent prior to any specific study procedures. Exclusion criteria: Subjects suffering from augmentation and/ or 'end of treatment' rebound RLS symptoms at baseline (Day 0). Augmentation is defined as RLS symptoms that occurred while on treatment and occur earlier in the afternoon/evening 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, or symptoms which involve other parts of the body, such as the arms or trunk. 'End of treatment' rebound describes worsening of symptoms from baseline that occur after pharmacological treatment is stopped. Subjects with a previous history of augmentation. Subjects who have exhibited intolerance to ropinirole or any other dopamine agonist. Subjects requiring treatment of daytime RLS symptoms (daytime defined as 10:00 hours until 17:00 hours). Signs of secondary RLS (e.g., end stage renal disease, iron deficient anaemia or pregnancy at Baseline Visit). Subjects with a serum ferritin level of < 10 mcg/L (ng/mL) at Screening Visit. Subjects who suffer from a primary sleep disorder other than RLS that may significantly affect the symptoms of RLS (e.g. narcolepsy, sleep terror disorder, sleepwalking disorder, breathing related sleep disorder). Subjects diagnosed with movement disorders (e.g., Parkinson's Disease, dyskinesias, and dystonias). Subjects who have medical conditions which could affect efficacy assessments or clinically significant or unstable medical conditions that present a safety concern. These may include, but are not limited to, the following disorders: diabetes, peripheral neuropathy, rheumatoid arthritis, fibromyalgia syndrome, symptomatic orthostatic hypotension, severe cardiovascular disease, hepatic or renal failure, pleuro-pulmonary fibrosis, major psychotic illness. Subjects having a clinically significant abnormal laboratory value, ECG, or physical examination findings not resolved by the time of the baseline examinations (Day 0). Abnormal 12-lead ECG findings include, but are not limited to, the following: myocardial ischemia, clinically significant conduction abnormalities, or clinically significant arrhythmias. Subjects with a diastolic blood pressure = 110mmHg or = 50mmHg or systolic blood pressure = 180mmHg or = 90mmHg at the Screening or Baseline Visit. Subjects with a history of alcohol or substance abuse within the past year. Subjects taking any medication known to induce drowsiness, affect RLS or sleep and which have not been discontinued prior to the Baseline Visit. These medications include the following: Atypical and typical antipsychotics, anticonvulsants, opioids (including propoxyphene and oxycodone), anxiolytics, all sedatives/hypnotics (including benzodiazepines), lithium, oral neuroleptics, stimulants (including methylphenidate), dopamine agonists (including ropinirole), dopamine antagonists (e.g., typical neuroleptics, metoclopramide), levodopa/carbidopa, clonidine, and sedating antihistamines (e.g., chlorpheniramine, diphenhydramine, hydroxyzine) or any preparations containing these antihistamines. The minimum discontinuation period is generally 5 half lives or 7 consecutive evenings/nights medication free, prior to baseline, whichever is the longer period. Exceptions to this general rule are: fluoxetine, monoamine oxidase inhibitors: 4 weeks. For subjects entering the 40-week, open-label treatment phase, the GSK Medical Monitor can be contacted to discuss individual cases where adherence to the above may not have occurred. Withdrawal, introduction, or change in dose of hormone replacement therapy (HRT) and/or any drug known to substantially inhibit CYP1A2 (e.g., ciprofloxacin, cimetidine, fluvoxamine, HRT) or induce CYP1A2 (e.g., tobacco, omeprazole) within 7 days prior to enrolment. Subjects already on these agents may be enrolled, but must remain on stable doses of the agents from 7 days prior to enrolment through to the follow-up visit at the end of the study. Night workers or any others whose sleeping habits are incompatible with the study design, or who would be required to make significant changes to their bedtime during the course of the study. Participation in any clinical drug or device trial in the one month prior to the Baseline Visit. Subjects who, in the opinion of the investigator, would be non-compliant with the visit schedules or other study procedures. Women who have a positive pregnancy test or who are lactating.

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: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Double-blind for 12 to 26 Weeks<br>Double-blind (Ropinirole:Placebo) for 12 to 26 weeks | Drug: Placebo<br>* Matching Placebo<br>Drug: Ropinirole<br>* Ropinirole IR 0.25mg/day to 4mg/day for RLS<br>|
| Other: Open-label ropinirole for 40-Weeks<br>Open label ropinirole for 40 weeks | Drug: Ropinirole<br>* Ropinirole IR 0.25mg/day to 4mg/day for RLS<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in the International Restless Legs Syndrome (IRLS) Rating Scale Total Score at Week 12 and Week 26 | A 10-item, participant-reported scale covering different symptoms of the condition. Each item is scored from 0 to 4; 0 represents the absence of a problem and 4 reflects a very severe problem. The best and worst possible scores are 0 and 40, respectively; higher scores represent a greater severity of symptoms. A negative change from baseline indicates improvement, and a negative treatment difference indicates a benefit of Ropinirole IR over placebo. The primary assessment was made by calculating the difference in the average score obtained at Baseline with scores at Week 12 and then Week 26. | Baseline and Weeks 12 and 26 | 
| Number of Participants With Clinically Meaningful Augmentation and Early Morning Rebound (EMR) Cases | Clinically meaningful augmentation and early morning rebound (EMR) were assessed and confirmed by an independent Adjudication Board. EMR describes the development of RLS symptoms during the early morning, following therapeutic intervention. EMR is differentiated from augmentation, in which the earlier onset of symptoms occurs in the evening. | During 15-month study duration at scheduled (Weeks 16, 20, 26, or early withdrawal for DB phase; Weeks 39, 47, 55, 63, 67, or early withdrawal for the OL phase) and unscheduled (26-week DB phase and 40-week OL phase) visits | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in the International RLS (IRLS) Rating Scale Total Score at Weeks 1, 4, 8, 16, and 20 | A 10-item, participant-reported scale covering different RLS symptoms. Each item is scored from 0 to 4; 0 represents the absence of a problem and 4 reflects a very severe problem. The best and worst possible scores are 0 and 40, respectively; higher scores represent a greater severity of symptoms. The primary assessment from this study was made by calculating the difference in the average score obtained at Baseline with scores at Weeks 1, 4, 8, 16, and 20. Scores were adjusted for baseline IRLS total score, treatment group, visit, visit by treatment group interaction, and center group. | Baseline and Weeks 1, 4, 8, 16, and 20 | 
| Change From Baseline in the Domains of the 12-item Medical Outcomes Study (MOS-12) Sleep Scale at Weeks 12 and 26 | The MOS-12 Sleep Scale is a comprehensive battery, which measures specific aspects of sleep in participants that may have varying co-morbidities, and, as a result, is appropriate for a medically diverse participant population. Domain values are presented on a 0-100 scale, where a higher score means a greater degree of the attribute implied by the scale name. Scores were adjusted for baseline MOS sleep scale domain value, treatment group, visit, visit by treatment interaction, and center group. | Baseline and Weeks 12 and 26 | 
| Change From Baseline in Sleep Quantity, a Domain of the 12-item Medical Outcomes Study (MOS-12) Sleep Scale, at Weeks 12 and 26 | The MOS-12 Sleep Scale is a comprehensive battery, which measures specific aspects of sleep in participants that may have varying co-morbidities, and, as a result, is appropriate for a medically diverse participant population.Scores were adjusted for baseline MOS sleep scale domain value, treatment group, visit, visit by treatment interaction, and center group. | Baseline and Weeks 12 and 26 | 
| Change From Baseline in the Johns Hopkins RLS Quality of Life (RLS QoL) Questionnaire Overall Life Impact Score at Weeks 12 and 26 | The Johns Hopkins RLS QoL Questionnaire is a disease-specific instrument that assesses the impact of RLS on the daily life, emotional well-being, social life, and work life of participants. The overall life impact score for the John Hopkins RLS QoL scale ranges from a lowest possible score of 0 to a highest possible score of 100. Higher scores represent better quality of life. Scores were adjusted for baseline RLS Quality of Life score, treatment group, visit, visit by treatment interaction, and center group. | Baseline and Weeks 12 and 26 | 
| Change From Baseline in the Domains of the MOS 36-item Short Form Health Survey (SF-36) at Weeks 12 and 26 | The MOS SF-36 is a generic QoL instrument measuring functional status and well-being. Positive change from baseline for all domains indicates improvement. For all MOS SF-36 domains, the minimum and maximum scores are 0 and 100, respectively, for the transformed scale. Scores were adjusted for baseline domain score, treatment group, visit, visit by treatment interaction, and center group. | Baseline and Weeks 12 and 26 | 
| Percentage of Participants With a Score of Much/Very Much Improved on the Clinical Global Impression-Global Improvement (CGI-I) Scale at Weeks 1, 12 and 26 | The CGI-I is a psychometric instrument that is used to measure general clinical status in a variety of disease states. The CGI-I allows the investigator to rate the participant's global improvement or worsening compared with the condition at Baseline (Day 0). The scale is rated from 1-7 (1 = very much improved; 7 = very much worse). Typically, a participant with a score of 1 or 2 (much improved) is considered a responder. | Weeks 1, 12 and 26 | 
| Number of Participants Withdrawing Due to Lack of Efficacy During the First 26 Weeks of the Study | Lack of efficacy is defined as up to a 10% improvement in the IRLS Rating Scale total score from the participant's Baseline value and at least 12 weeks of treatment during the double-blind phase. | Baseline to Week 26 | 
| Number of Participants Rated as Normal or Borderline Ill on the CGI Severity of Illness (CGI-S) Scale at Week 26 | The CGI-S scale is a psychometric instrument that is used to measure general clinical status in a variety of disease states. The CGI-S allows the investigator to rate the severity of the participant's illness considering their total clinical experience with the subject population being studied and on all information available at the time of rating. The scale is rated from 1-7 (1 = normal, not at all ill; 2 = borderline ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severly ill; 7 = among the most extremely ill participants). | Week 26 | 
| Median Time to First CGI-I Response of Much/Very Much Improved During the Double-blind Phase | The median time to first CGI-I response of much/very much improved was calculated. The CGI-I is a psychometric instrument that is used to measure general clinical status in a variety of disease states. The CGI-I allows the investigator to rate the participant's global improvement or worsening compared with the condition at Baseline (Day 0). The scale is rated from 1-7 (1 = very much improved; 7 = very much worse). Typically, a participant with a score of 1 or 2 (much improved) is considered a responder. | Baseline to Week 26 | 
| Number of Participants With a Score of Much/Very Much Improved on the CGI-I Scale at Week 67 | The CGI-I is a psychometric instrument that is used to measure general clinical status in a variety of disease states. The CGI-I allows the investigator to rate the participant's global improvement or worsening compared with the condition at Baseline (Day 0). The scale is rated from 1-7 (1 = very much improved; 7 = very much worse). Typically, a participant with a score of 1 or 2 (much improved) is considered a responder. | Week 67 | 
| Mean Change From Baseline in the IRLS Rating Scale Total Score at Week 67 | A 10-item, participant-reported scale covering different symptoms of the condition. Each item is scored from 0 to 4, with 0 representing the absence of a problem and 4 reflecting a very severe problem. The best and worst possible scores are 0 and 40, respectively. The primary assessment was made by calculating the difference in the average score obtained at Baseline with score at Week 67. | Baseline and Week 67 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Moderate, Restless Legs Syndrome, Severe, ropinirole