Long-term Study Of Ropinirole In Restless Legs Syndrome

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.

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.