Clinical trial NCT00329602: Long-term Study Of Ropinirole In Restless Legs Syndrome
Official title: 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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Restless Legs Syndrome
Keywords: Moderate
Restless Legs Syndrome
Severe
ropinirole
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2006-05-25
Enrollment: 404
Sex: ALL
Minimum age (years): 18
Maximum age (years): 79
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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:

1. Non-childbearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is post-menopausal); or,
2. 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.

Primary outcomes:
measure: Mean Change From Baseline in the International Restless Legs Syndrome (IRLS) Rating Scale Total Score at Week 12 and Week 26
timeFrame: Baseline and Weeks 12 and 26
measure: Number of Participants With Clinically Meaningful Augmentation and Early Morning Rebound (EMR) Cases
timeFrame: 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 outcomes:
measure: Mean Change From Baseline in the International RLS (IRLS) Rating Scale Total Score at Weeks 1, 4, 8, 16, and 20
timeFrame: Baseline and Weeks 1, 4, 8, 16, and 20
measure: Change From Baseline in the Domains of the 12-item Medical Outcomes Study (MOS-12) Sleep Scale at Weeks 12 and 26
timeFrame: Baseline and Weeks 12 and 26
measure: Change From Baseline in Sleep Quantity, a Domain of the 12-item Medical Outcomes Study (MOS-12) Sleep Scale, at Weeks 12 and 26
timeFrame: Baseline and Weeks 12 and 26
measure: Change From Baseline in the Johns Hopkins RLS Quality of Life (RLS QoL) Questionnaire Overall Life Impact Score at Weeks 12 and 26
timeFrame: Baseline and Weeks 12 and 26
measure: Change From Baseline in the Domains of the MOS 36-item Short Form Health Survey (SF-36) at Weeks 12 and 26
timeFrame: Baseline and Weeks 12 and 26
measure: 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
timeFrame: Weeks 1, 12 and 26
measure: Number of Participants Withdrawing Due to Lack of Efficacy During the First 26 Weeks of the Study
timeFrame: Baseline to Week 26
measure: Number of Participants Rated as Normal or Borderline Ill on the CGI Severity of Illness (CGI-S) Scale at Week 26
timeFrame: Week 26
measure: Median Time to First CGI-I Response of Much/Very Much Improved During the Double-blind Phase
timeFrame: Baseline to Week 26
measure: Number of Participants With a Score of Much/Very Much Improved on the CGI-I Scale at Week 67
timeFrame: Week 67
measure: Mean Change From Baseline in the IRLS Rating Scale Total Score at Week 67
timeFrame: Baseline and Week 67
Other outcomes:
Locations:
city: Camperdown
country: Australia
facility: GSK Investigational Site
state: New South Wales
city: Kippa Ring
country: Australia
facility: GSK Investigational Site
state: Queensland
city: Woodville
country: Australia
facility: GSK Investigational Site
state: South Australia
city: Clayton
country: Australia
facility: GSK Investigational Site
state: Victoria
city: East Melbourne
country: Australia
facility: GSK Investigational Site
state: Victoria
city: Olomouc
country: Czech Republic
facility: GSK Investigational Site
city: Ostrava
country: Czech Republic
facility: GSK Investigational Site
city: Pardubice
country: Czech Republic
facility: GSK Investigational Site
city: Praha 2
country: Czech Republic
facility: GSK Investigational Site
city: Aalborg
country: Denmark
facility: GSK Investigational Site
city: Odense C
country: Denmark
facility: GSK Investigational Site
city: Vejle
country: Denmark
facility: GSK Investigational Site
city: Bamberg
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Muenchen
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Regensburg
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Marburg
country: Germany
facility: GSK Investigational Site
state: Hessen
city: Schwerin
country: Germany
facility: GSK Investigational Site
state: Mecklenburg-Vorpommern
city: Westerstede
country: Germany
facility: GSK Investigational Site
state: Niedersachsen
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Bologna
country: Italy
facility: GSK Investigational Site
state: Emilia-Romagna
city: Roma
country: Italy
facility: GSK Investigational Site
state: Lazio
city: Pavia
country: Italy
facility: GSK Investigational Site
state: Lombardia
city: Hamar
country: Norway
facility: GSK Investigational Site
city: Coimbra
country: Portugal
facility: GSK Investigational Site
city: Lisboa
country: Portugal
facility: GSK Investigational Site
city: Bratislava
country: Slovakia
facility: GSK Investigational Site
city: Bratislava
country: Slovakia
facility: GSK Investigational Site
city: Dubnica nad Vahom
country: Slovakia
facility: GSK Investigational Site
city: Levoca
country: Slovakia
facility: GSK Investigational Site
city: Zilina
country: Slovakia
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: San Sebastián
country: Spain
facility: GSK Investigational Site
city: Avesta
country: Sweden
facility: GSK Investigational Site
city: Göteborg
country: Sweden
facility: GSK Investigational Site
city: Örebro
country: Sweden
facility: GSK Investigational Site
city: Bern
country: Switzerland
facility: GSK Investigational Site
city: Zürich
country: Switzerland
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Garcia-Borreguero D, Hogl B, Ferini-Strambi L, Winkelman J, Hill-Zabala C, Asgharian A, Allen R. Systematic evaluation of augmentation during treatment with ropinirole in restless legs syndrome (Willis-Ekbom disease): results from a prospective, multicenter study over 66 weeks. Mov Disord. 2012 Feb;27(2):277-83. doi: 10.1002/mds.24889. Epub 2012 Jan 4.
citation: Giorgi L, Asgharian A, Hunter B. Ropinirole in patients with restless legs syndrome and baseline IRLS total scores >/= 24: efficacy and tolerability in a 26-week, double-blind, parallel-group, placebo-controlled study followed by a 40-week open-label extension. Clin Ther. 2013 Sep;35(9):1321-36. doi: 10.1016/j.clinthera.2013.06.016. Epub 2013 Aug 9.