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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT00329602
Registration number
NCT00329602
Ethics application status
Date submitted
23/05/2006
Date registered
25/05/2006
Date last updated
23/03/2017
Titles & IDs
Public title
Long-term Study Of Ropinirole In Restless Legs Syndrome
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Scientific 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.
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Secondary ID [1]
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ROR104836
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Restless Legs Syndrome
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Condition category
Condition code
Mental Health
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Anxiety
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Mental Health
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Other mental health disorders
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Neurological
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Other neurological disorders
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Other
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Research that is not of generic health relevance and not applicable to specific health categories listed above
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - Placebo
Treatment: Drugs - Ropinirole
Placebo Comparator: Double-blind for 12 to 26 Weeks - Double-blind (Ropinirole:Placebo) for 12 to 26 weeks
Other: Open-label ropinirole for 40-Weeks - Open label ropinirole for 40 weeks
Treatment: Drugs: Placebo
Matching Placebo
Treatment: Drugs: Ropinirole
Ropinirole IR 0.25mg/day to 4mg/day for RLS
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Mean Change From Baseline in the International Restless Legs Syndrome (IRLS) Rating Scale Total Score at Week 12 and Week 26
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Assessment method [1]
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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.
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Timepoint [1]
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Baseline and Weeks 12 and 26
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Primary outcome [2]
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Number of Participants With Clinically Meaningful Augmentation and Early Morning Rebound (EMR) Cases
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Assessment method [2]
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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.
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Timepoint [2]
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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
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Secondary outcome [1]
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Mean Change From Baseline in the International RLS (IRLS) Rating Scale Total Score at Weeks 1, 4, 8, 16, and 20
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Assessment method [1]
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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.
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Timepoint [1]
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Baseline and Weeks 1, 4, 8, 16, and 20
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Secondary outcome [2]
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Change From Baseline in the Domains of the 12-item Medical Outcomes Study (MOS-12) Sleep Scale at Weeks 12 and 26
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Assessment method [2]
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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.
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Timepoint [2]
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Baseline and Weeks 12 and 26
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Secondary outcome [3]
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Change From Baseline in Sleep Quantity, a Domain of the 12-item Medical Outcomes Study (MOS-12) Sleep Scale, at Weeks 12 and 26
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Assessment method [3]
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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.
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Timepoint [3]
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Baseline and Weeks 12 and 26
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Secondary outcome [4]
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Change From Baseline in the Johns Hopkins RLS Quality of Life (RLS QoL) Questionnaire Overall Life Impact Score at Weeks 12 and 26
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Assessment method [4]
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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.
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Timepoint [4]
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Baseline and Weeks 12 and 26
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Secondary outcome [5]
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Change From Baseline in the Domains of the MOS 36-item Short Form Health Survey (SF-36) at Weeks 12 and 26
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Assessment method [5]
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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.
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Timepoint [5]
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Baseline and Weeks 12 and 26
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Secondary outcome [6]
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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
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Assessment method [6]
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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.
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Timepoint [6]
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Weeks 1, 12 and 26
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Secondary outcome [7]
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Number of Participants Withdrawing Due to Lack of Efficacy During the First 26 Weeks of the Study
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Assessment method [7]
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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.
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Timepoint [7]
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Baseline to Week 26
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Secondary outcome [8]
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Number of Participants Rated as Normal or Borderline Ill on the CGI Severity of Illness (CGI-S) Scale at Week 26
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Assessment method [8]
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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).
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Timepoint [8]
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Week 26
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Secondary outcome [9]
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Median Time to First CGI-I Response of Much/Very Much Improved During the Double-blind Phase
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Assessment method [9]
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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.
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Timepoint [9]
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Baseline to Week 26
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Secondary outcome [10]
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Number of Participants With a Score of Much/Very Much Improved on the CGI-I Scale at Week 67
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Assessment method [10]
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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.
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Timepoint [10]
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Week 67
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Secondary outcome [11]
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Mean Change From Baseline in the IRLS Rating Scale Total Score at Week 67
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Assessment method [11]
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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.
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Timepoint [11]
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Baseline and Week 67
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Eligibility
Key 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.
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Minimum age
18
Years
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Maximum age
79
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
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.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Blinded (masking used)
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Who is / are masked / blinded?
The people receiving the treatment/s
The people analysing the results/data
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 4
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
1/03/2006
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
1/09/2008
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Sample size
Target
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Accrual to date
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Final
404
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Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,VIC
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Recruitment hospital [1]
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GSK Investigational Site - Camperdown
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Recruitment hospital [2]
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GSK Investigational Site - Kippa Ring
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Recruitment hospital [3]
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GSK Investigational Site - Woodville
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Recruitment hospital [4]
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GSK Investigational Site - Clayton
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Recruitment hospital [5]
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GSK Investigational Site - East Melbourne
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Recruitment postcode(s) [1]
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2050 - Camperdown
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Recruitment postcode(s) [2]
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4021 - Kippa Ring
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Recruitment postcode(s) [3]
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5011 - Woodville
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Recruitment postcode(s) [4]
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3168 - Clayton
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Recruitment postcode(s) [5]
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3002 - East Melbourne
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Recruitment outside Australia
Country [1]
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Czech Republic
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State/province [1]
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Olomouc
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Country [2]
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Czech Republic
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State/province [2]
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Ostrava
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Czech Republic
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State/province [3]
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Pardubice
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Country [4]
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Czech Republic
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State/province [4]
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Praha 2
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Country [5]
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Denmark
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State/province [5]
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Aalborg
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Country [6]
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Denmark
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State/province [6]
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Odense C
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Country [7]
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Denmark
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State/province [7]
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Vejle
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Country [8]
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Germany
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State/province [8]
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Bayern
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Country [9]
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Germany
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State/province [9]
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Hessen
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Country [10]
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Germany
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State/province [10]
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Mecklenburg-Vorpommern
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Country [11]
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Germany
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State/province [11]
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Niedersachsen
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Country [12]
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Germany
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State/province [12]
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Berlin
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Italy
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State/province [13]
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Emilia-Romagna
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Italy
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State/province [14]
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Lazio
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Italy
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State/province [15]
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Lombardia
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Country [16]
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Norway
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Hamar
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Portugal
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Coimbra
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Portugal
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State/province [18]
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Lisboa
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Slovakia
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State/province [19]
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Bratislava
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Slovakia
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Dubnica nad Vahom
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Slovakia
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State/province [21]
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Levoca
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0
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Slovakia
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State/province [22]
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Zilina
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Spain
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State/province [23]
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Barcelona
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Spain
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State/province [24]
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Madrid
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Spain
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State/province [25]
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San Sebastián
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Sweden
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State/province [26]
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Avesta
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Sweden
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State/province [27]
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Göteborg
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Sweden
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Örebro
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Switzerland
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Bern
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Country [30]
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Switzerland
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State/province [30]
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Zürich
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
GlaxoSmithKline
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Address
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Country
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Ethics approval
Ethics application status
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Summary
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.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT00329602
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Trial related presentations / publications
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.
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Public notes
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Contacts
Principal investigator
Name
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GSK Clinical Trials
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Address
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GlaxoSmithKline
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Country
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Phone
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Fax
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Email
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Contact person for public queries
Name
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Address
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Country
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Phone
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Fax
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Email
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT00329602
Download to PDF