Long-term Study Of Ropinirole In Restless Legs Syndrome

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00329602
• Collaborator: (none)
• Enrollment: 404
• Locations: 39
• Arms: 2
• Duration (Months): 30.1
• Patients Per Site: 10.4
• Patients Per Site Per Month: 0.3

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Restless Legs Syndrome	Drug: Placebo; Drug: Ropinirole	Phase 4

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 404 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• 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 Start Date: Mar 1, 2006
• Actual Primary Completion Date: Sep 1, 2008
• Actual Study Completion Date: Sep 1, 2008

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Mean Change From Baseline in the International Restless Legs Syndrome (IRLS) Rating Scale Total Score at Week 12 and Week 26 [Baseline and Weeks 12 and 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.

2. Number of Participants With Clinically Meaningful Augmentation and Early Morning Rebound (EMR) Cases [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]

   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.

Secondary Outcome Measures

1. Mean Change From Baseline in the International RLS (IRLS) Rating Scale Total Score at Weeks 1, 4, 8, 16, and 20 [Baseline and 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.

2. Change From Baseline in the Domains of the 12-item Medical Outcomes Study (MOS-12) Sleep Scale at Weeks 12 and 26 [Baseline and 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.

3. Change From Baseline in Sleep Quantity, a Domain of the 12-item Medical Outcomes Study (MOS-12) Sleep Scale, at Weeks 12 and 26 [Baseline and 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.

4. Change From Baseline in the Johns Hopkins RLS Quality of Life (RLS QoL) Questionnaire Overall Life Impact Score at Weeks 12 and 26 [Baseline and 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.

5. Change From Baseline in the Domains of the MOS 36-item Short Form Health Survey (SF-36) at Weeks 12 and 26 [Baseline and 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.

6. 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 [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.

7. Number of Participants Withdrawing Due to Lack of Efficacy During the First 26 Weeks of the Study [Baseline to Week 26]

   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.

8. Number of Participants Rated as Normal or Borderline Ill on the CGI Severity of Illness (CGI-S) Scale at Week 26 [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).

9. Median Time to First CGI-I Response of Much/Very Much Improved During the Double-blind Phase [Baseline to Week 26]

   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.

10. Number of Participants With a Score of Much/Very Much Improved on the CGI-I Scale at Week 67 [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.

11. Mean Change From Baseline in the IRLS Rating Scale Total Score at Week 67 [Baseline and 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 79 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Camperdown	New South Wales	Australia	2050
2	GSK Investigational Site	Kippa Ring	Queensland	Australia	4021
3	GSK Investigational Site	Woodville	South Australia	Australia	5011
4	GSK Investigational Site	Clayton	Victoria	Australia	3168
5	GSK Investigational Site	East Melbourne	Victoria	Australia	3002
6	GSK Investigational Site	Olomouc		Czech Republic	775 20
7	GSK Investigational Site	Ostrava		Czech Republic	702 00
8	GSK Investigational Site	Pardubice		Czech Republic	535 03
9	GSK Investigational Site	Praha 2		Czech Republic	120 00
10	GSK Investigational Site	Aalborg		Denmark	9000
11	GSK Investigational Site	Odense C		Denmark	5000
12	GSK Investigational Site	Vejle		Denmark	7100
13	GSK Investigational Site	Bamberg	Bayern	Germany	96047
14	GSK Investigational Site	Muenchen	Bayern	Germany	80331
15	GSK Investigational Site	Regensburg	Bayern	Germany	93053
16	GSK Investigational Site	Marburg	Hessen	Germany	35039
17	GSK Investigational Site	Schwerin	Mecklenburg-Vorpommern	Germany	19053
18	GSK Investigational Site	Westerstede	Niedersachsen	Germany	26655
19	GSK Investigational Site	Berlin		Germany	10787
20	GSK Investigational Site	Berlin		Germany	10969
21	GSK Investigational Site	Bologna	Emilia-Romagna	Italy	40123
22	GSK Investigational Site	Roma	Lazio	Italy	00163
23	GSK Investigational Site	Pavia	Lombardia	Italy	27100
24	GSK Investigational Site	Hamar		Norway	2317
25	GSK Investigational Site	Coimbra		Portugal	3000-075
26	GSK Investigational Site	Lisboa		Portugal	1649-035
27	GSK Investigational Site	Bratislava		Slovakia	831 03
28	GSK Investigational Site	Bratislava		Slovakia	833 05
29	GSK Investigational Site	Dubnica nad Vahom		Slovakia	018 41
30	GSK Investigational Site	Levoca		Slovakia	054 01
31	GSK Investigational Site	Zilina		Slovakia	010 01
32	GSK Investigational Site	Barcelona		Spain	08017
33	GSK Investigational Site	Madrid		Spain	28036
34	GSK Investigational Site	San Sebastián		Spain	20014
35	GSK Investigational Site	Avesta		Sweden	SE-774 82
36	GSK Investigational Site	Göteborg		Sweden	SE-412 55
37	GSK Investigational Site	Örebro		Sweden	701 85
38	GSK Investigational Site	Bern		Switzerland	3010
39	GSK Investigational Site	Zürich		Switzerland	8091

Sponsors and Collaborators

• GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

Publications

• García-Borreguero D, Högl 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.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT00329602
• Other Study ID Numbers: ROR104836
• First Posted: May 25, 2006
• Last Update Posted: Mar 23, 2017
• Last Verified: Mar 1, 2017

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by GlaxoSmithKline: Moderate; Restless Legs Syndrome; Severe; ropinirole
• Additional relevant MeSH terms: Psychomotor Agitation; Restless Legs Syndrome; Syndrome; Ropinirole

Study Results

Participant Flow

Recruitment Details	Participants (par.) could enter the Open-Label (OL) phase at the end of the Double-Blind (DB) phase. If a par. did not complete the DB phase due to lack of efficacy, he/she could also be considered for entry into the OL phase if the investigator considered it appropriate and the par. met the protocol-defined criteria in describing lack of efficacy.

Arm/Group Title	Double-blind Placebo	Double-blind Ropinirole IR	Open-label Ropinirole IR
Arm/Group Description	Matching placebo tablets	Ropinirole IR (immediate release) tablets containing ropinirole hydrochloride equivalent to 0.25 mg, 0.5 mg, 1.0 mg, or 2.0 mg of the active drug substance, taken once a day	Ropinirole IR (immediate release) tablets containing ropinirole hydrochloride equivalent to 0.5 mg, 1.0 mg, or 2.0 mg of the active drug substance, taken once a day
Period Title: 26-Week Double-Blind Treatment Phase
STARTED	207	197	0
COMPLETED	88	98	0
NOT COMPLETED	119	99	0
Period Title: 26-Week Double-Blind Treatment Phase
STARTED	0	0	269
COMPLETED	0	0	233
NOT COMPLETED	0	0	36

Baseline Characteristics

Arm/Group Title	Double-Blind Placebo	Double-Blind Ropinirole IR	Total
Arm/Group Description	Matching placebo tablets	Ropinirole IR (immediate release) tablets containing ropinirole hydrochloride equivalent to 0.25 mg, 0.5 mg, 1.0 mg, or 2.0 mg of the active drug substance, taken once a day	Total of all reporting groups
Overall Participants	207	197	404
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55.9 (11.53)	56.5 (11.97)	56.2 (11.73)
Sex: Female, Male (Count of Participants)
Female	132 63.8%	124 62.9%	256 63.4%
Male	75 36.2%	73 37.1%	148 36.6%
Race/Ethnicity, Customized (participants) [Number]
White	204 98.6%	197 100%	401 99.3%
Asian	2 1%	0 0%	2 0.5%
Hawaiian or other Pacific Islander	1 0.5%	0 0%	1 0.2%

Outcome Measures

1. Primary Outcome

Title	Mean Change From Baseline in the International Restless Legs Syndrome (IRLS) Rating Scale Total Score at Week 12 and Week 26
Description	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.
Time Frame	Baseline and Weeks 12 and 26

Outcome Measure Data

Analysis Population Description

Intention-to-Treat (ITT) Population: all randomised participants who received at least one dose of study medication, and for whom at least one valid post-baseline efficacy assessment was available. Analysis is based on the observed cases for each visit.

Arm/Group Title	Double-blind Placebo	Double-blind Ropinirole IR
Arm/Group Description	Matching placebo tablets	Ropinirole IR (immediate release) tablets containing ropinirole hydrochloride equivalent to 0.25 mg, 0.5 mg, 1.0 mg, or 2.0 mg of the active drug substance, taken once a day
Measure Participants	205	196
Week 12, n=165, 164	-12.1 (0.70)	-14.2 (0.71)
Week 26, n=119, 123	-13.4 (0.77)	-15.9 (0.76)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Double-blind Placebo, Double-blind Ropinirole IR
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.039
	Comments	P-value is for Week 12.
	Method	Repeated Measures Mixed Model
	Comments	Adjusted for baseline IRLS Rating Scale total score, treatment group, visit, visit by treatment group interaction, and center group.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Double-blind Placebo, Double-blind Ropinirole IR
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.023
	Comments	P-value is for Week 26.
	Method	Repeated Measures Mixed Model
	Comments	Adjusted for baseline IRLS Rating Scale total score, treatment group, visit, visit by treatment group interaction, and center group.

2. Secondary Outcome

Title	Mean Change From Baseline in the International RLS (IRLS) Rating Scale Total Score at Weeks 1, 4, 8, 16, and 20
Description	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.
Time Frame	Baseline and Weeks 1, 4, 8, 16, and 20

Outcome Measure Data

Analysis Population Description

Intention-to-Treat (ITT) Population: all randomised participants who received at least one dose of study medication, and for whom at least one valid post-baseline efficacy assessment was available. Analysis is based on the observed cases for each visit.

Arm/Group Title	Double-blind Placebo	Double-blind Ropinirole IR
Arm/Group Description	Matching placebo tablets	Ropinirole IR (immediate release) tablets containing ropinirole hydrochloride equivalent to 0.25 mg, 0.5 mg, 1.0 mg, or 2.0 mg of the active drug substance, taken once a day
Measure Participants	205	196
Week 1, n=198, 194	-5.5 (0.52)	-7.8 (0.52)
Week 4, n=183, 180	-10.5 (0.60)	-13.6 (0.60)
Week 8, n=168, 170	-13.0 (0.66)	-15.3 (0.66)
Week 16, n=137, 144	-12.6 (0.75)	-15.0 (0.74)
Week 20, n=125, 132	-12.3 (0.78)	-15.7 (0.77)

3. Secondary Outcome

Title	Change From Baseline in the Domains of the 12-item Medical Outcomes Study (MOS-12) Sleep Scale at Weeks 12 and 26
Description	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.
Time Frame	Baseline and Weeks 12 and 26

Outcome Measure Data

Analysis Population Description

Intention-to-Treat (ITT) Population: all randomised participants who received at least one dose of study medication, and for whom at least one valid post-baseline efficacy assessment was available. Analysis is based on the observed cases for each visit.

Arm/Group Title	Double-blind Placebo	Double-blind Ropinirole IR
Arm/Group Description	Matching placebo tablets	Ropinirole IR (immediate release) tablets containing ropinirole hydrochloride equivalent to 0.25 mg, 0.5 mg, 1.0 mg, or 2.0 mg of the active drug substance, taken once a day
Measure Participants	205	196
Sleep disturbance, Week 12, n=153, 143	-15.0 (1.62)	-24.0 (1.67)
Sleep disturbance, Week 26, n=105, 97	-16.4 (1.80)	-24.6 (1.87)
Sleep adequacy, Week 12, n=153, 143	15.0 (1.91)	22.8 (1.98)
Sleep adequacy, Week 26, n=105, 97	14.9 (2.16)	26.0 (2.25)
Daytime somnolence, Week 12, n=153, 143	-7.5 (1.28)	-11.4 (1.33)
Daytime somnolence, Week 26, n=105, 97	-9.1 (1.59)	-11.4 (1.65)

4. Secondary Outcome

Title	Change From Baseline in Sleep Quantity, a Domain of the 12-item Medical Outcomes Study (MOS-12) Sleep Scale, at Weeks 12 and 26
Description	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.
Time Frame	Baseline and Weeks 12 and 26

Outcome Measure Data

Analysis Population Description

Intention-to-Treat (ITT) Population: all randomised participants who received at least one dose of study medication, and for whom at least one valid post-baseline efficacy assessment was available. Analysis is based on the observed cases for each visit.

Arm/Group Title	Double-blind Placebo	Double-blind Ropinirole IR
Arm/Group Description	Matching placebo tablets	Ropinirole IR (immediate release) tablets containing ropinirole hydrochloride equivalent to 0.25 mg, 0.5 mg, 1.0 mg, or 2.0 mg of the active drug substance, taken once a day
Measure Participants	205	196
Week 12, n=153, 143	0.5 (0.10)	0.7 (0.11)
Week 26, n=105, 97	0.5 (0.11)	0.7 (0.11)

5. Secondary Outcome

Title	Change From Baseline in the Johns Hopkins RLS Quality of Life (RLS QoL) Questionnaire Overall Life Impact Score at Weeks 12 and 26
Description	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.
Time Frame	Baseline and Weeks 12 and 26

Outcome Measure Data

Analysis Population Description

Intention-to-Treat (ITT) Population: all randomised participants who received at least one dose of study medication, and for whom at least one valid post-baseline efficacy assessment was available. Analysis is based on the observed cases for each visit.

Arm/Group Title	Double-blind Placebo	Double-blind Ropinirole IR
Arm/Group Description	Matching placebo tablets	Ropinirole IR (immediate release) tablets containing ropinirole hydrochloride equivalent to 0.25 mg, 0.5 mg, 1.0 mg, or 2.0 mg of the active drug substance, taken once a day
Measure Participants	205	196
Week 12, n=149, 141	14.0 (1.29)	18.0 (1.33)
Week 26, n=103, 94	16.5 (1.35)	18.5 (1.41)

6. Secondary Outcome

Title	Change From Baseline in the Domains of the MOS 36-item Short Form Health Survey (SF-36) at Weeks 12 and 26
Description	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.
Time Frame	Baseline and Weeks 12 and 26

Outcome Measure Data

Analysis Population Description

Intention-to-Treat (ITT) Population: all randomised participants who received at least one dose of study medication, and for whom at least one valid post-baseline efficacy assessment was available. Analysis is based on the observed cases for each visit.

Arm/Group Title	Double-blind Placebo	Double-blind Ropinirole IR
Arm/Group Description	Matching placebo tablets	Ropinirole IR (immediate release) tablets containing ropinirole hydrochloride equivalent to 0.25 mg, 0.5 mg, 1.0 mg, or 2.0 mg of the active drug substance, taken once a day
Measure Participants	205	196
Bodily pain, Week 12, n=149, 142	12.3 (1.72)	14.4 (1.76)
Bodily pain, Week 26, n=104, 94	13.3 (2.01)	14.0 (2.11)
General health, Week 12, n=149, 142	3.0 (1.08)	4.5 (1.11)
General health, Week 26, n=104, 94	2.6 (1.31)	4.1 (1.37)
Mental health, Week 12, n=149, 142	5.0 (1.22)	7.6 (1.26)
Mental health, Week 26, n=104, 94	4.6 (1.25)	6.2 (1.31)
Physical functioning, Week 12, n=149, 142	2.4 (1.22)	5.5 (1.25)
Physical functioning, Week 26, n=104, 94	3.5 (1.48)	2.6 (1.54)
Role emotional, Week 12, n=149, 142	5.1 (1.62)	7.0 (1.67)
Role emotional, Week 26, n=104, 94	5.9 (1.66)	6.6 (1.74)
Role physical, Week 12, n=149, 142	5.2 (1.66)	7.7 (1.71)
Role physical, Week 26, n=104, 94	7.5 (1.85)	6.7 (1.94)
Social functioning, Week 12, n=149, 142	6.3 (1.58)	9.8 (1.62)
Social functioning, Week 26, n=104, 94	7.1 (1.56)	8.8 (1.63)
Vitality, Week 12, n=149, 142	8.0 (1.37)	9.3 (1.41)
Vitality, Week 26, n=104, 94	6.0 (1.54)	9.2 (1.61)

7. Secondary Outcome

Title	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
Description	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.
Time Frame	Weeks 1, 12 and 26

Outcome Measure Data

Analysis Population Description

Intention-to-Treat (ITT) Population. Analysis is based on the observed cases for each visit.

Arm/Group Title	Double-blind Placebo	Double-blind Ropinirole IR
Arm/Group Description	Matching placebo tablets	Ropinirole IR (immediate release) tablets containing ropinirole hydrochloride equivalent to 0.25 mg, 0.5 mg, 1.0 mg, or 2.0 mg of the active drug substance, taken once a day
Measure Participants	192	192
Week 1, n=192, 192	39 18.8%	50 25.4%
Week 12, n=165, 160	86 41.5%	109 55.3%
Week 26, n=112, 108	72 34.8%	91 46.2%

8. Secondary Outcome

Title	Number of Participants Withdrawing Due to Lack of Efficacy During the First 26 Weeks of the Study
Description	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.
Time Frame	Baseline to Week 26

Outcome Measure Data

Analysis Population Description

Intention-to-Treat (ITT) Population: all randomised participants who received at least one dose of study medication, and for whom at least one valid post-baseline efficacy assessment was available

Arm/Group Title	Double-blind Placebo	Double-blind Ropinirole IR
Arm/Group Description	Matching placebo tablets	Ropinirole IR (immediate release) tablets containing ropinirole hydrochloride equivalent to 0.25 mg, 0.5 mg, 1.0 mg, or 2.0 mg of the active drug substance, taken once a day
Measure Participants	205	196
Number [participants]	2 1%	3 1.5%

9. Secondary Outcome

Title	Number of Participants Rated as Normal or Borderline Ill on the CGI Severity of Illness (CGI-S) Scale at Week 26
Description	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).
Time Frame	Week 26

Outcome Measure Data

Analysis Population Description

Intention-to-Treat (ITT) Population: all randomised participants who received at least one dose of study medication, and for whom at least one valid post-baseline efficacy assessment was available. Data are presented for the participants still in the study and assessed at Week 26, which is less than those randomised at baseline.

Arm/Group Title	Double-blind Placebo	Double-blind Ropinirole IR
Arm/Group Description	Matching placebo tablets	Ropinirole IR (immediate release) tablets containing ropinirole hydrochloride equivalent to 0.25 mg, 0.5 mg, 1.0 mg, or 2.0 mg of the active drug substance, taken once a day
Measure Participants	112	108
Number [participants]	50 24.2%	50 25.4%

10. Secondary Outcome

Title	Median Time to First CGI-I Response of Much/Very Much Improved During the Double-blind Phase
Description	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.
Time Frame	Baseline to Week 26

Outcome Measure Data

Analysis Population Description

Intention-to-Treat (ITT) Population: all randomised participants who received at least one dose of study medication, and for whom at least one valid post-baseline efficacy assessment was available

Arm/Group Title	Double-blind Placebo	Double-blind Ropinirole IR
Arm/Group Description	Matching placebo tablets	Ropinirole IR (immediate release) tablets containing ropinirole hydrochloride equivalent to 0.25 mg, 0.5 mg, 1.0 mg, or 2.0 mg of the active drug substance, taken once a day
Measure Participants	205	196
Median (95% Confidence Interval) [days]	28	21

11. Secondary Outcome

Title	Number of Participants With a Score of Much/Very Much Improved on the CGI-I Scale at Week 67
Description	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.
Time Frame	Week 67

Outcome Measure Data

Analysis Population Description

Open-Label (OL) ITT Population: all participants who were enrolled into the OL Phase of the study, received at least one dose of OL study medication, and had a baseline IRLS total score and on-treatment IRLS assessment. Data are presented for participants still in the study and assessed at Week 26, which is less than those randomized at baseline.

Arm/Group Title	Open-label Ropinirole IR
Arm/Group Description	Ropinirole IR (immediate release) tablets containing ropinirole hydrochloride equivalent to 0.5 mg, 1.0 mg, or 2.0 mg of the active drug substance, taken once a day
Measure Participants	200
Number [participants]	184 88.9%

12. Primary Outcome

Title	Number of Participants With Clinically Meaningful Augmentation and Early Morning Rebound (EMR) Cases
Description	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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

Safety Population: all participants who received at least one dose of study medication

Arm/Group Title	Overall Study	Double-blind Placebo	Double-blind Ropinirole IR	Open-label Ropinirole IR
Arm/Group Description	Matching placebo tablets	Ropinirole IR (immediate release) tablets containing ropinirole hydrochloride equivalent to 0.25 mg, 0.5 mg, 1.0 mg, or 2.0 mg of the active drug substance, taken once a day	Ropinirole IR (immediate release) tablets containing ropinirole hydrochloride equivalent to 0.5 mg, 1.0 mg, or 2.0 mg of the active drug substance, taken once a day
Measure Participants	404	207	197	269
Confirmed augmentation	15 7.2%	1 0.5%	7 1.7%	8 NaN
Clinically meaningful augmentation	11 5.3%	1 0.5%	5 1.2%	5 NaN
Confirmed EMR	7 3.4%	1 0.5%	4 1%	2 NaN

13. Secondary Outcome

Title	Mean Change From Baseline in the IRLS Rating Scale Total Score at Week 67
Description	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.
Time Frame	Baseline and Week 67

Outcome Measure Data

Analysis Population Description

Open-Label ITT Population: all participants who were enrolled into the Open-Label Phase of the study, received at least one dose of Open-Label study medication, and had a baseline IRLS total score and on-treatment IRLS assessment. Analysis is based on the observed cases for each visit.

Arm/Group Title	Open-label Ropinirole IR
Arm/Group Description	Ropinirole IR (immediate release) tablets containing ropinirole hydrochloride equivalent to 0.5 mg, 1.0 mg, or 2.0 mg of the active drug substance, taken once a day
Measure Participants	268
Mean (Standard Deviation) [points on a scale]	-20.4 (8.36)

14. Post-Hoc Outcome

Title	Post-hoc Analysis of Mean Change From Baseline in the International Restless Legs Syndrome (IRLS) Rating Scale Total Score at Week 12 and Week 26, Exploring the Impact of Center Group on Treatment Effect
Description	A post-hoc analysis of the primary outcome measure, exploring the variation in treatment effects across center groups by excluding those with the most extreme treatment effects, was conducted. Centers were grouped into five center groups.
Time Frame	Baseline and Weeks 12 and 26

Outcome Measure Data

Analysis Population Description

ITT Population excluding the two center groups with the most extreme treatment effects. Analysis is based on the observed cases for each visit.

Arm/Group Title	Double-blind Placebo	Double-blind Ropinirole IR
Arm/Group Description	Double-Blind Placebo participants (receiving matching placebo tablets) who were not in the center groups with the highest or lowest treatment effects	Double-Blind Ropinirole participants (receiving Ropinirole IR [immediate release] tablets containing ropinirole hydrochloride equivalent to 0.25 mg, 0.5 mg, 1.0 mg, or 2.0 mg of the active drug substance, taken once a day) who were not in the center groups with the highest or lowest treatment effects
Measure Participants	136	134
Week 12, n=136, 134	-12.2 (0.78)	-13.8 (0.79)
Week 26, n=103, 105	-14.0 (0.84)	-15.7 (0.83)

15. Post-Hoc Outcome

Title	Post-hoc Analysis of Percentage of Participants With a Score of Much/Very Much Improved on the Clinical Global Impression-Global Improvement (CGI-I) Scale at Weeks 12 and 26, Exploring the Impact of Center Group on Treatment Effect
Description	A post-hoc analysis of CGI-I, exploring the variation in treatment effects across center groups by excluding the same two center groups as in the IRLS post-hoc analysis, was conducted. Centers were grouped into five center groups.
Time Frame	Weeks 12 and 26

Outcome Measure Data

Analysis Population Description

ITT Population excluding the same two center groups as in the IRLS post-hoc analysis. Analysis is based on the observed cases for each visit.

Arm/Group Title	Double-blind Placebo	Double-blind Ropinirole IR
Arm/Group Description	Double-Blind Placebo participants (receiving matching placebo tablets) who were not excluded from the IRLS post-hoc analysis	Double-Blind Ropinirole participants (receiving Ropinirole IR [immediate release] tablets containing ropinirole hydrochloride equivalent to 0.25 mg, 0.5 mg, 1.0 mg, or 2.0 mg of the active drug substance, taken once a day) who were not excluded from the IRLS post-hoc analysis
Measure Participants	136	134
Week 12, n=136, 134	75	93
Week 26, n=99, 96	63	82

Adverse Events

Arm/Group Title	Double-blind Placebo		Double-blind Ropinirole IR		Open-Label Ropinirole IR
Arm/Group Description	Matching placebo tablets		Ropinirole IR (immediate release) tablets containing ropinirole hydrochloride equivalent to 0.25 mg, 0.5 mg, 1.0 mg, or 2.0 mg of the active drug substance, taken once a day		Ropinirole IR (immediate release) tablets containing ropinirole hydrochloride equivalent to 0.5 mg, 1.0 mg, or 2.0 mg of the active drug substance, taken once a day
All Cause Mortality
	Double-blind Placebo		Double-blind Ropinirole IR		Open-Label Ropinirole IR
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Double-blind Placebo		Double-blind Ropinirole IR		Open-Label Ropinirole IR
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/207 (2.9%)		6/197 (3%)		11/269 (4.1%)
Ear and labyrinth disorders
Vertigo	0/207 (0%)		0/197 (0%)		1/269 (0.4%)
Gastrointestinal disorders
Abdominal pain	1/207 (0.5%)		0/197 (0%)		0/269 (0%)
Abdominal pain upper	0/207 (0%)		1/197 (0.5%)		0/269 (0%)
Peptic ulcer	0/207 (0%)		1/197 (0.5%)		0/269 (0%)
General disorders
Chest pain	0/207 (0%)		0/197 (0%)		1/269 (0.4%)
Hepatobiliary disorders
Gallbladder disorder	1/207 (0.5%)		0/197 (0%)		0/269 (0%)
Cholelithiasis	0/207 (0%)		0/197 (0%)		1/269 (0.4%)
Infections and infestations
Appendicitis	1/207 (0.5%)		0/197 (0%)		0/269 (0%)
Post procedural infection	0/207 (0%)		1/197 (0.5%)		0/269 (0%)
Pyelonephritis	1/207 (0.5%)		0/197 (0%)		0/269 (0%)
Injury, poisoning and procedural complications
Joint dislocation	1/207 (0.5%)		0/197 (0%)		0/269 (0%)
Femoral neck fracture	0/207 (0%)		0/197 (0%)		1/269 (0.4%)
Head injury	0/207 (0%)		0/197 (0%)		1/269 (0.4%)
Musculoskeletal and connective tissue disorders
Myalgia	0/207 (0%)		1/197 (0.5%)		0/269 (0%)
Bursa calcification	0/207 (0%)		0/197 (0%)		1/269 (0.4%)
Osteoarthritis	0/207 (0%)		0/197 (0%)		1/269 (0.4%)
Osteonecrosis	0/207 (0%)		0/197 (0%)		1/269 (0.4%)
Rotator cuff syndrome	0/207 (0%)		0/197 (0%)		1/269 (0.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
B-cell lymphoma	0/207 (0%)		1/197 (0.5%)		0/269 (0%)
Uterine cancer	0/207 (0%)		1/197 (0.5%)		0/269 (0%)
Nervous system disorders
Cerebral infarction	1/207 (0.5%)		0/197 (0%)		0/269 (0%)
Brain stem ischaemia	0/207 (0%)		0/197 (0%)		1/269 (0.4%)
Syncope	0/207 (0%)		0/197 (0%)		1/269 (0.4%)
Reproductive system and breast disorders
Fallopian tube cyst	0/207 (0%)		1/197 (0.5%)		0/269 (0%)
Ovarian cyst	0/207 (0%)		1/197 (0.5%)		0/269 (0%)
Ovarian cyst torsion	1/207 (0.5%)		0/197 (0%)		0/269 (0%)
Postmenopausal haemorrhage	0/207 (0%)		0/197 (0%)		1/269 (0.4%)
Vascular disorders
Hypertension	1/207 (0.5%)		0/197 (0%)		0/269 (0%)
Other (Not Including Serious) Adverse Events
	Double-blind Placebo		Double-blind Ropinirole IR		Open-Label Ropinirole IR
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	71/207 (34.3%)		123/197 (62.4%)		122/269 (45.4%)
Gastrointestinal disorders
Nausea	16/207 (7.7%)		83/197 (42.1%)		67/269 (24.9%)
Vomiting	0/207 (0%)		22/197 (11.2%)		13/269 (4.8%)
Diarrhea	5/207 (2.4%)		10/197 (5.1%)		3/269 (1.1%)
General disorders
Fatigue	14/207 (6.8%)		28/197 (14.2%)		29/269 (10.8%)
Infections and infestations
Nasopharyngitis	14/207 (6.8%)		21/197 (10.7%)		33/269 (12.3%)
Musculoskeletal and connective tissue disorders
Back pain	11/207 (5.3%)		7/197 (3.6%)		9/269 (3.3%)
Nervous system disorders
Headache	23/207 (11.1%)		29/197 (14.7%)		20/269 (7.4%)
Dizziness	6/207 (2.9%)		20/197 (10.2%)		16/269 (5.9%)
Somnolence	4/207 (1.9%)		9/197 (4.6%)		14/269 (5.2%)
Psychiatric disorders
Insomnia	5/207 (2.4%)		12/197 (6.1%)		1/269 (0.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.