Long-term Efficacy, Safety and Tolerability of Pramipexole in Patients With Idiopathic Moderate to Severe Restless Legs Syndrome (RLS)

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00472199
• Collaborator: (none)
• Enrollment: 331
• Locations: 42
• Arms: 2
• Patients Per Site: 7.9

Study Details

Study Description

Brief Summary

The primary objective of the current study will be the evaluation of long-term efficacy of a 26-weeks treatment with pramipexole in patients with idiopathic moderate to severe Restless Legs Syndrome (RLS) in comparison to placebo.

The key secondary objectives are to assess the effects on clinical global impressions - global improvement (CGI-I) (based on CGI-I responder rate) and on RLS (based on IRLS responder rate) for 26 weeks under pramipexole in comparison to placebo. Further secondary objectives are to investigate the incidence and severity of augmentation and rebound and to assess the effects on patient global impression (PGI) (based on PGI responder rate), on RLS symptoms (based on the RLS-6 scales), on associated mood disturbance (based on item 10 of the IRLS), on pain in limbs (based on a visual analogue scale (VAS)), on quality of life in RLS (based on Johns Hopkins RLS-QoL), on general quality of life Short Form 36 (SF-36) and on safety (based on adverse events (AE) profile) of pramipexole in comparison to placebo.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 331 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase IV Randomised, Double-blind, Placebo-controlled, Dose Titration Trial With Pramipexole (Sifrol, Mirapexin) 0.125-0.75 mg/Day Per os to Investigate the Long-term Efficacy, Safety and Tolerability in Patients With Idiopathic Moderate to Severe Restless Legs Syndrome for 26 Weeks Followed by a 26 Week Open-label Extension Treatment Period
• Study Start Date: May 1, 2007
• Actual Primary Completion Date: Jul 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pramipexole 4 weeks of flexible dose-titration (to optimise efficacy and tolerability), starting at 0.125 mg once daily with the potential to increase or decrease the dose in steps to 0.25 mg, 0.5 mg and 0.75 mg, with the final dose level subsequently fixed for 22 weeks.	Drug: Pramipexole
Placebo Comparator: Placebo 4 weeks of flexible dose-titration as for the investigational product; with the dose subsequently fixed for 22 weeks.	Drug: Placebo

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in International Restless Legs Syndrome Study Group Rating Scale (IRLS) Total Score After 26 Weeks [Baseline and 26 weeks]

   IRLS total score ranging from 0 (no RLS symptoms) to 40 (very severe RLS symptoms)

Secondary Outcome Measures

1. Clinical Global Impression - Global Improvement (CGI-I) Responder Rate [after 26 weeks of treatment]

   CGI-I scores ranging from '1' (very much improved) to '7' (very much worse), CGI-I responder have scoring 1 or 2 (at least much improved)

2. International Restless Legs Syndrome (IRLS) Study Group Rating Scale Responder Rate [after 26 weeks of treatment]

   IRLS response was defined as at least 50% reduction in IRLS total score from baseline. IRLS total score ranging from 0 (no RLS symptoms) to 40 (very severe symptoms)

3. Patient Global Impression (PGI) Responder Rate [after 26 weeks of treatment]

   PGI scores ranging from '1' (very much better) to '7' (very much worse), PGI responder have scoring 1 or 2 (at least much better)

4. Change From Baseline in Restless Legs Syndrome-6 (RLS-6) Score "Satisfaction With Sleep" After 26 Weeks [baseline and 26 weeks of treatment]

   The score is an 11-point Likert scale, ranging from "none/not at all" (0) to "very severe" (10), to reflect the patient's condition during the previous week

5. Change From Baseline in RLS-6 Score "Severity Falling Asleep" After 26 Weeks [Baseline and 26 weeks of treatment]

   The score is an 11-point Likert scale, ranging from "none/not at all" (0) to "very severe" (10), to reflect the patient's condition during the previous week

6. Change From Baseline in RLS-6 Score "Severity During the Night" After 26 Weeks [baseline and 26 weeks of treatment]

   The question was rated on an 11-point Likert scale, ranging from "none/not at all" (0) to "very severe" (10), to reflect the patient's condition during the previous week

7. Change From Baseline in RLS-6 Score "Severity During the Day When at Rest" After 26 Weeks [Baseline and 26 weeks of treatment]

   The score is an 11-point Likert scale, ranging from "none/not at all" (0) to "very severe" (10), to reflect the patient's condition during the previous week

8. Change From Baseline RLS-6 Score "Severity During the Day Engaged in Activities" After 26 Weeks [Baseline and 26 weeks of treatment]

   The score is an 11-point Likert scale, ranging from "none/not at all" (0) to "very severe" (10), to reflect the patient's condition during the previous week

9. Change From Baseline in RLS-6 Score "Tired or Sleepy During the Day" After 26 Weeks [Baseline and 26 weeks of treatment]

   The score is an 11-point Likert scale, ranging from "none/not at all" (0) to "very severe" (10), to reflect the patient's condition during the previous week

10. Change From Baseline in IRLS Mood Disturbance Score (Item 10) After 26 Weeks [Baseline and 26 weeks of treatment]

    Mood disturbance associated with RLS symptoms ranging from 0 (none) to 4 (very severe)

11. Change From Baseline in Visual Analogue Scale (VAS) Score for Pain in Limbs After 26 Weeks [Baseline and 26 weeks of treatment]

    The scale measures pain on a continuous 100 mm axis ranging from no pain (0 mm) to unbearable pain (100 mm)

12. Change From Baseline in Quality of Life in RLS (RLS QoL) Score After 26 Weeks [Baseline and 26 weeks of treatment]

    RLS QoL total score ranging from 0 to 100 with higher values indicating better quality of life

13. Change From Baseline in Short Form-36 (SF-36) Dimension Bodily Pain After 26 Weeks [Baseline and 26 weeks]

    Score ranging from 0 to 100 with higher scores indicating less bodily pain

14. Change From Baseline in SF-36 Dimension General Health After 26 Weeks [Baseline and 26 weeks]

    Score ranging from 0 to 100 with higher scores indicating better health status

15. Change From Baseline in SF-36 Dimension Mental Health After 26 Weeks [Baseline and 26 weeks]

    Score ranging from 0 to 100 with higher scores indicating better mental health

16. Change From Baseline in SF-36 Dimension Physical Functioning After 26 Weeks [Baseline and 26 weeks]

    Score ranging from 0 to 100 with higher scores indicating better physical functioning

17. Change From Baseline in SF-36 Dimension Role Limitations Due to Emotional Problems After 26 Weeks [Baseline and 26 weeks]

    Score ranging from 0 to 100 with higher scores indicating less limitations due to emotional problems

18. Change From Baseline in SF-36 Dimension Role Limitations Due to Physical Problems After 26 Weeks [Baseline and 26 weeks]

    Score ranging from 0 to 100 with higher scores indicating less limitations due to physical problems

19. Change From Baseline in SF-36 Dimension Social Functioning After 26 Weeks [Baseline and 26 weeks]

    Score ranging from 0 to 100 with higher scores indicating better social functioning

20. Change From Baseline in SF-36 Dimension Vitality After 26 Weeks [Baseline and 26 weeks]

    Score ranging from 0 to 100 with higher scores indicating better vitality

21. Change From Baseline in SF-36 Dimension Mental Component Summary After 26 Weeks [Baseline and 26 weeks]

    Score ranging from 0 to 100 with higher scores indicating better health

22. Change From Baseline in SF-36 Dimension Physical Component Summary After 26 Weeks [Baseline and 26 weeks]

    Score ranging from 0 to 100 with higher scores indicating better health

23. Diagnosis of Classified Augmentation According to Independent Expert Panel [after at least 4 weeks of treatment]

    Augmentation is a worsening of RLS symptoms and may manifest as increased severity and the involvement of other extremities or as a shift of RLS symptoms to a time period that is 2 or more hours earlier than was typical of the time of symptom onset during the initial course of beneficial stable treatment or the state before recently starting treatment.

24. Worsening of RLS Symptoms (by at Least 4 Points in the IRLS Total Score Compared to Baseline) After Treatment Discontinuation [after at least 1 week of treatment discontinuation]

    Worsening of RLS symptoms, in comparison to baseline, following abrupt treatment discontinuation (for patients with no added RLS therapy after study drug discontinuation). Assessment of worsening of RLS was based on the IRLS total score assessed 7 ± 1 days after treatment discontinuation (the end of the study or premature discontinuation) compared with that at baseline. Analysis considered the number of patients experiencing a clinically relevant deterioration of ≥4 points in total IRLS score 7 ± 1 days after discontinuation of trial medication compared with baseline.

25. Baseline, Week 26 Mean Supine Systolic Blood Pressure [Baseline, Week 26]

26. Baseline, Week 26 Mean Standing Systolic Blood Pressure [Baseline, Week 26]

27. Baseline, Week 26 Mean Supine Diastolic Blood Pressure [Baseline, Week 26]

28. Baseline, Week 26 Mean Standing Diastolic Blood Pressure [Baseline, Week 26]

29. Baseline, Week 26 Mean Supine Pulse Rate [Baseline, Week 26]

30. Baseline, Week 26 Mean Standing Pulse Rate [Baseline, Week 26]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Written informed consent consistent with International Conference on Harmonization - Good Clinical Practice (ICH-GCP) and local Institutional Review Board/Independent Ethics Committee (IRB/IEC) requirements obtained prior to any study procedures being performed and the ability and willingness to comply with study treatment regimen and to attend study assessments

2. Male or female out-patients aged 18-85 years

3. Diagnosis of idiopathic RLS according to the clinical RLS criteria of the International Restless Legs Syndrome Study Group (IRLSSG) [P03-03355]. All four criteria must be present to fulfil the diagnosis of RLS.

4. RLS symptoms present at least 2 to 3 days per week during the last 3 months prior to baseline (Visit 2)

5. IRLS total score >15 at baseline (Visit 2)

Exclusion Criteria:

1. Women of child-bearing potential (i.e. premenopausal women, or postmenopausal women less than 6 months after last menses) who do not use during the clinical trial an adequate method of contraception such as: double barrier protection (e.g. diaphragm or condom and spermicide), intrauterine device, hormonal therapy (oral, injectable, or subcutaneous), or partner's surgical sterilization

2. Any woman of child-bearing potential not having a negative pregnancy test at screening

3. Breastfeeding women

4. Patients with known hypersensitivity to pramipexole or any other component of the investigational product or placebo tablets

5. Diagnosis of augmentation under previous pharmacological RLS treatment

6. Concomitant or previous pharmacologic therapy as follows: Any intake of dopamine agonists within 14 days prior to baseline (Visit 2); Any intake of levodopa within 14 days prior to baseline (Visit 2); Unsuccessful prior treatment with non-ergot dopamine agonists (e.g. pramipexole, ropinirole);

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	248.629.4302 Boehringer Ingelheim Investigational Site	Innsbruck		Austria
2	248.629.4304 Boehringer Ingelheim Investigational Site	Linz		Austria
3	248.629.3201 Boehringer Ingelheim Investigational Site	Edegem		Belgium
4	248.629.35801 Boehringer Ingelheim Investigational Site	Espoo		Finland
5	248.629.35805 Boehringer Ingelheim Investigational Site	Helsinki		Finland
6	248.629.35804 Boehringer Ingelheim Investigational Site	Joensuu		Finland
7	248.629.35802 Boehringer Ingelheim Investigational Site	Oulu		Finland
8	248.629.35806 Boehringer Ingelheim Investigational Site	Tampere		Finland
9	248.629.4904 Boehringer Ingelheim Investigational Site	Berlin (Hellersdorf)		Germany
10	248.629.4903 Boehringer Ingelheim Investigational Site	Berlin-Steglitz		Germany
11	248.629.4902 Boehringer Ingelheim Investigational Site	Berlin		Germany
12	248.629.4908 Boehringer Ingelheim Investigational Site	Bochum		Germany
13	248.629.4901 Boehringer Ingelheim Investigational Site	Ellwangen		Germany
14	248.629.4906 Boehringer Ingelheim Investigational Site	Herborn		Germany
15	248.629.4905 Boehringer Ingelheim Investigational Site	Leipzig		Germany
16	248.629.4909 Boehringer Ingelheim Investigational Site	Schwerin		Germany
17	248.629.4907 Boehringer Ingelheim Investigational Site	Würzburg		Germany
18	248.629.35301 Boehringer Ingelheim Investigational Site	Carrigtwohill		Ireland
19	248.629.35302 Boehringer Ingelheim Investigational Site	Co. Kildare		Ireland
20	248.629.35303 Boehringer Ingelheim Investigational Site	Co. Tipperary		Ireland
21	248.629.31001 Boehringer Ingelheim Investigational Site	Bennebroek		Netherlands
22	248.629.31005 Boehringer Ingelheim Investigational Site	Hoogwoud		Netherlands
23	248.629.31006 Boehringer Ingelheim Investigational Site	Musselkanaal		Netherlands
24	248.629.31002 Boehringer Ingelheim Investigational Site	Oude Pekela		Netherlands
25	248.629.31003 Boehringer Ingelheim Investigational Site	Oude Pekela		Netherlands
26	248.629.31004 Boehringer Ingelheim Investigational Site	Rijswijk		Netherlands
27	248.629.4204 Boehringer Ingelheim Investigational Site	Bratislava		Slovakia
28	248.629.4205 Boehringer Ingelheim Investigational Site	Bratislava		Slovakia
29	248.629.4202 Boehringer Ingelheim Investigational Site	Brezno		Slovakia
30	248.629.4201 Boehringer Ingelheim Investigational Site	Kosice		Slovakia
31	248.629.4203 Boehringer Ingelheim Investigational Site	Martin		Slovakia
32	248.629.3402 Boehringer Ingelheim Investigational Site	Barcelona		Spain
33	248.629.3405 Boehringer Ingelheim Investigational Site	Granada		Spain
34	248.629.3401 Boehringer Ingelheim Investigational Site	Madrid		Spain
35	248.629.3403 Boehringer Ingelheim Investigational Site	San Sebastián		Spain
36	248.629.3406 Hospital Arnau de Vilanova	Valencia		Spain
37	248.629.44003 Boehringer Ingelheim Investigational Site	Chorley		United Kingdom
38	248.629.44006 Boehringer Ingelheim Investigational Site	Edgbaston, Birmingham		United Kingdom
39	248.629.44004 Boehringer Ingelheim Investigational Site	Glasgow		United Kingdom
40	248.629.44001 Boehringer Ingelheim Investigational Site	Manchester		United Kingdom
41	248.629.44002 Boehringer Ingelheim Investigational Site	Reading		United Kingdom
42	248.629.44005 Boehringer Ingelheim Investigational Site	Waterloo, Liverpool		United Kingdom

Sponsors and Collaborators

• Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info
• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT00472199
• Other Study ID Numbers: 248.629; EUDRACT2006-006431-42
• First Posted: May 11, 2007
• Last Update Posted: Jun 27, 2014
• Last Verified: May 1, 2012

• Additional relevant MeSH terms: Psychomotor Agitation; Restless Legs Syndrome; Syndrome; Pramipexole

Study Results

Participant Flow

Pre-assignment Detail	Of 331 patients enrolled, 329 were treated with study drug. Two patients were randomized, but before their first intake of trial medication they decided to not participate in the study.

Arm/Group Title	Pramipexole	Placebo
Arm/Group Description	4 weeks of flexible dose-titration (to optimise efficacy and tolerability), starting at 0.125 mg once daily with the potential to increase the dose to 0.25mg and to further increase or decrease the dose in steps to 0.5 mg and 0.75 mg, with the final dose level subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets	4 weeks of flexible dose-titration as for the investigational product; with the dose subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets
Period Title: Overall Study
STARTED	166	163
COMPLETED	131	103
NOT COMPLETED	35	60

Baseline Characteristics

Arm/Group Title	Pramipexole	Placebo	Total
Arm/Group Description	4 weeks of flexible dose-titration (to optimise efficacy and tolerability), starting at 0.125 mg once daily with the potential to increase the dose to 0.25mg and to further increase or decrease the dose in steps to 0.5 mg and 0.75 mg, with the final dose level subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets	4 weeks of flexible dose-titration as for the investigational product; with the dose subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets	Total of all reporting groups
Overall Participants	166	163	329
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.9 (12.7)	55.8 (11.4)	56.8 (12.1)
Sex: Female, Male (Count of Participants)
Female	102 61.4%	94 57.7%	196 59.6%
Male	64 38.6%	69 42.3%	133 40.4%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in International Restless Legs Syndrome Study Group Rating Scale (IRLS) Total Score After 26 Weeks
Description	IRLS total score ranging from 0 (no RLS symptoms) to 40 (very severe RLS symptoms)
Time Frame	Baseline and 26 weeks

Outcome Measure Data

Analysis Population Description

Intent to treat analysis. Number of randomized patients with a baseline and at least one non-missing post-baseline measure. Imputation by last observation carried forward (LOCF) for post-baseline values

Arm/Group Title	Pramipexole	Placebo
Arm/Group Description	4 weeks of flexible dose-titration (to optimise efficacy and tolerability), starting at 0.125 mg once daily with the potential to increase the dose to 0.25mg and to further increase or decrease the dose in steps to 0.5 mg and 0.75 mg, with the final dose level subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets	4 weeks of flexible dose-titration as for the investigational product; with the dose subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets
Measure Participants	162	159
Least Squares Mean (Standard Error) [Scores on a scale]	-13.7 (0.8)	-11.1 (0.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pramipexole, Placebo
	Comments	Analysis of covariance for changes from baseline with factors treatment and country and using baseline as covariate
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0077
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-2.6
	Confidence Interval	() 95%; -4.6 to -0.7
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1
	Estimation Comments

2. Secondary Outcome

Title	Clinical Global Impression - Global Improvement (CGI-I) Responder Rate
Description	CGI-I scores ranging from '1' (very much improved) to '7' (very much worse), CGI-I responder have scoring 1 or 2 (at least much improved)
Time Frame	after 26 weeks of treatment

Outcome Measure Data

Analysis Population Description

Intent to treat analysis. Number of randomized patients with a baseline and at least one non-missing post-baseline measure. Imputation by last observation carried forward (LOCF) for post-baseline values.

Arm/Group Title	Pramipexole	Placebo
Arm/Group Description	4 weeks of flexible dose-titration (to optimise efficacy and tolerability), starting at 0.125 mg once daily with the potential to increase the dose to 0.25mg and to further increase or decrease the dose in steps to 0.5 mg and 0.75 mg, with the final dose level subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets	4 weeks of flexible dose-titration as for the investigational product; with the dose subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets
Measure Participants	162	159
CGI-I responder (at least much improved)	111 66.9%	80 49.1%
CGI-I non-responder	51 30.7%	79 48.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pramipexole, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0010
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

3. Secondary Outcome

Title	International Restless Legs Syndrome (IRLS) Study Group Rating Scale Responder Rate
Description	IRLS response was defined as at least 50% reduction in IRLS total score from baseline. IRLS total score ranging from 0 (no RLS symptoms) to 40 (very severe symptoms)
Time Frame	after 26 weeks of treatment

Outcome Measure Data

Analysis Population Description

Intent to treat analysis. Number of randomized patients with a baseline and at least one non-missing post-baseline measure. Imputation by last observation carried forward (LOCF) for post-baseline values

Arm/Group Title	Pramipexole	Placebo
Arm/Group Description	4 weeks of flexible dose-titration (to optimise efficacy and tolerability), starting at 0.125 mg once daily with the potential to increase the dose to 0.25mg and to further increase or decrease the dose in steps to 0.5 mg and 0.75 mg, with the final dose level subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets	4 weeks of flexible dose-titration as for the investigational product; with the dose subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets
Measure Participants	162	159
IRLS responder	95 57.2%	68 41.7%
IRLS non-responder	67 40.4%	91 55.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pramipexole, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0044
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

4. Secondary Outcome

Title	Patient Global Impression (PGI) Responder Rate
Description	PGI scores ranging from '1' (very much better) to '7' (very much worse), PGI responder have scoring 1 or 2 (at least much better)
Time Frame	after 26 weeks of treatment

Outcome Measure Data

Analysis Population Description

Intent to treat analysis. Number of randomized patients with a baseline and at least one non-missing post-baseline measure. Imputation by last observation carried forward (LOCF) for post-baseline values

Arm/Group Title	Pramipexole	Placebo
Arm/Group Description	4 weeks of flexible dose-titration (to optimise efficacy and tolerability), starting at 0.125 mg once daily with the potential to increase the dose to 0.25mg and to further increase or decrease the dose in steps to 0.5 mg and 0.75 mg, with the final dose level subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets	4 weeks of flexible dose-titration as for the investigational product; with the dose subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets
Measure Participants	162	159
PGI responder (much better or very much better)	101 60.8%	70 42.9%
PGI non-responder	61 36.7%	89 54.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pramipexole, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0011
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

5. Secondary Outcome

Title	Change From Baseline in Restless Legs Syndrome-6 (RLS-6) Score "Satisfaction With Sleep" After 26 Weeks
Description	The score is an 11-point Likert scale, ranging from "none/not at all" (0) to "very severe" (10), to reflect the patient's condition during the previous week
Time Frame	baseline and 26 weeks of treatment

Outcome Measure Data

Analysis Population Description

Intent to treat analysis. Number of randomized patients with a baseline and at least one non-missing post-baseline measure. Imputation by last observation carried forward (LOCF) for post-baseline values

Arm/Group Title	Pramipexole	Placebo
Arm/Group Description	4 weeks of flexible dose-titration (to optimise efficacy and tolerability), starting at 0.125 mg once daily with the potential to increase the dose to 0.25mg and to further increase or decrease the dose in steps to 0.5 mg and 0.75 mg, with the final dose level subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets	4 weeks of flexible dose-titration as for the investigational product; with the dose subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets
Measure Participants	162	159
Median (Inter-Quartile Range) [Scores on a scale]	-2.5	-2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pramipexole, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0489
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-1.0
	Confidence Interval	() 95%; -1.1 to -0.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Change From Baseline in RLS-6 Score "Severity Falling Asleep" After 26 Weeks
Description	The score is an 11-point Likert scale, ranging from "none/not at all" (0) to "very severe" (10), to reflect the patient's condition during the previous week
Time Frame	Baseline and 26 weeks of treatment

Outcome Measure Data

Analysis Population Description

Intent to treat analysis. Number of randomized patients with a baseline and at least one non-missing post-baseline measure. Imputation by last observation carried forward (LOCF) for post-baseline values

Arm/Group Title	Pramipexole	Placebo
Arm/Group Description	4 weeks of flexible dose-titration (to optimise efficacy and tolerability), starting at 0.125 mg once daily with the potential to increase the dose to 0.25mg and to further increase or decrease the dose in steps to 0.5 mg and 0.75 mg, with the final dose level subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets	4 weeks of flexible dose-titration as for the investigational product; with the dose subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets
Measure Participants	162	159
Median (Inter-Quartile Range) [Scores on a scale]	-3	-1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pramipexole, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0315
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -0.0 to 0.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Change From Baseline in RLS-6 Score "Severity During the Night" After 26 Weeks
Description	The question was rated on an 11-point Likert scale, ranging from "none/not at all" (0) to "very severe" (10), to reflect the patient's condition during the previous week
Time Frame	baseline and 26 weeks of treatment

Outcome Measure Data

Analysis Population Description

Intent to treat analysis. Number of randomized patients with a baseline and at least one non-missing post-baseline measure. Imputation by last observation carried forward (LOCF) for post-baseline values

Arm/Group Title	Pramipexole	Placebo
Arm/Group Description	4 weeks of flexible dose-titration (to optimise efficacy and tolerability), starting at 0.125 mg once daily with the potential to increase the dose to 0.25mg and to further increase or decrease the dose in steps to 0.5 mg and 0.75 mg, with the final dose level subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets	4 weeks of flexible dose-titration as for the investigational product; with the dose subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets
Measure Participants	162	159
Median (Inter-Quartile Range) [Scores on a scale]	-3	-2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pramipexole, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0735
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -0.0 to 0.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Change From Baseline in RLS-6 Score "Severity During the Day When at Rest" After 26 Weeks
Description	The score is an 11-point Likert scale, ranging from "none/not at all" (0) to "very severe" (10), to reflect the patient's condition during the previous week
Time Frame	Baseline and 26 weeks of treatment

Outcome Measure Data

Analysis Population Description

Intent to treat analysis. Number of randomized patients with a baseline and at least one non-missing post-baseline measure. Imputation by last observation carried forward (LOCF) for post-baseline values

Arm/Group Title	Pramipexole	Placebo
Arm/Group Description	4 weeks of flexible dose-titration (to optimise efficacy and tolerability), starting at 0.125 mg once daily with the potential to increase the dose to 0.25mg and to further increase or decrease the dose in steps to 0.5 mg and 0.75 mg, with the final dose level subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets	4 weeks of flexible dose-titration as for the investigational product; with the dose subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets
Measure Participants	162	159
Median (Inter-Quartile Range) [Scores on a scale]	-3	-1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pramipexole, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8410
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -0.0 to 0.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Change From Baseline RLS-6 Score "Severity During the Day Engaged in Activities" After 26 Weeks
Description	The score is an 11-point Likert scale, ranging from "none/not at all" (0) to "very severe" (10), to reflect the patient's condition during the previous week
Time Frame	Baseline and 26 weeks of treatment

Outcome Measure Data

Analysis Population Description

Intent to treat analysis. Number of randomized patients with a baseline and at least one non-missing post-baseline measure. Imputation by last observation carried forward (LOCF) for post-baseline values

Arm/Group Title	Pramipexole	Placebo
Arm/Group Description	4 weeks of flexible dose-titration (to optimise efficacy and tolerability), starting at 0.125 mg once daily with the potential to increase the dose to 0.25mg and to further increase or decrease the dose in steps to 0.5 mg and 0.75 mg, with the final dose level subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets	4 weeks of flexible dose-titration as for the investigational product; with the dose subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets
Measure Participants	162	159
Median (Inter-Quartile Range) [Scores on a scale]	0	0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pramipexole, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9241
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -0.0 to 0.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Change From Baseline in RLS-6 Score "Tired or Sleepy During the Day" After 26 Weeks
Description	The score is an 11-point Likert scale, ranging from "none/not at all" (0) to "very severe" (10), to reflect the patient's condition during the previous week
Time Frame	Baseline and 26 weeks of treatment

Outcome Measure Data

Analysis Population Description

Intent to treat analysis. Number of randomized patients with a baseline and at least one non-missing post-baseline measure. Imputation by last observation carried forward (LOCF) for post-baseline values

Arm/Group Title	Pramipexole	Placebo
Arm/Group Description	4 weeks of flexible dose-titration (to optimise efficacy and tolerability), starting at 0.125 mg once daily with the potential to increase the dose to 0.25mg and to further increase or decrease the dose in steps to 0.5 mg and 0.75 mg, with the final dose level subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets	4 weeks of flexible dose-titration as for the investigational product; with the dose subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets
Measure Participants	162	159
Median (Inter-Quartile Range) [Scores on a scale]	-1	-1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pramipexole, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8093
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -0.0 to 0.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Change From Baseline in IRLS Mood Disturbance Score (Item 10) After 26 Weeks
Description	Mood disturbance associated with RLS symptoms ranging from 0 (none) to 4 (very severe)
Time Frame	Baseline and 26 weeks of treatment

Outcome Measure Data

Analysis Population Description

Intent to treat analysis. Number of randomized patients with a baseline and at least one non-missing post-baseline measure. Imputation by last observation carried forward (LOCF) for post-baseline values

Arm/Group Title	Pramipexole	Placebo
Arm/Group Description	4 weeks of flexible dose-titration (to optimise efficacy and tolerability), starting at 0.125 mg once daily with the potential to increase the dose to 0.25mg and to further increase or decrease the dose in steps to 0.5 mg and 0.75 mg, with the final dose level subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets	4 weeks of flexible dose-titration as for the investigational product; with the dose subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets
Measure Participants	162	159
Median (Inter-Quartile Range) [scores on a scale]	-1	-1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pramipexole, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0583
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -0.0 to 0.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Secondary Outcome

Title	Change From Baseline in Visual Analogue Scale (VAS) Score for Pain in Limbs After 26 Weeks
Description	The scale measures pain on a continuous 100 mm axis ranging from no pain (0 mm) to unbearable pain (100 mm)
Time Frame	Baseline and 26 weeks of treatment

Outcome Measure Data

Analysis Population Description

Intent to treat analysis. Number of randomized patients with a baseline and at least one non-missing post-baseline measure. Imputation by last observation carried forward (LOCF) for post-baseline values

Arm/Group Title	Pramipexole	Placebo
Arm/Group Description	4 weeks of flexible dose-titration (to optimise efficacy and tolerability), starting at 0.125 mg once daily with the potential to increase the dose to 0.25mg and to further increase or decrease the dose in steps to 0.5 mg and 0.75 mg, with the final dose level subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets	4 weeks of flexible dose-titration as for the investigational product; with the dose subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets
Measure Participants	162	158
Median (Inter-Quartile Range) [Scores on a scale]	-26	-15

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pramipexole, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0916
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-5.0
	Confidence Interval	(2-Sided) 95%; -5.5 to -4.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

13. Secondary Outcome

Title	Change From Baseline in Quality of Life in RLS (RLS QoL) Score After 26 Weeks
Description	RLS QoL total score ranging from 0 to 100 with higher values indicating better quality of life
Time Frame	Baseline and 26 weeks of treatment

Outcome Measure Data

Analysis Population Description

Intent to treat analysis. Number of randomized patients with a baseline and at least one non-missing post-baseline measure. Imputation by last observation carried forward (LOCF) for post-baseline values

Arm/Group Title	Pramipexole	Placebo
Arm/Group Description	4 weeks of flexible dose-titration (to optimise efficacy and tolerability), starting at 0.125 mg once daily with the potential to increase the dose to 0.25mg and to further increase or decrease the dose in steps to 0.5 mg and 0.75 mg, with the final dose level subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets	4 weeks of flexible dose-titration as for the investigational product; with the dose subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets
Measure Participants	157	153
Median (Inter-Quartile Range) [Scores on a scale]	15	12.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pramipexole, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5905
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	2.5
	Confidence Interval	(2-Sided) 95%; 2.2 to 2.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. Secondary Outcome

Title	Change From Baseline in Short Form-36 (SF-36) Dimension Bodily Pain After 26 Weeks
Description	Score ranging from 0 to 100 with higher scores indicating less bodily pain
Time Frame	Baseline and 26 weeks

Outcome Measure Data

Analysis Population Description

Intent to treat analysis. Number of randomized patients with a baseline and at least one non-missing post-baseline measure. Imputation by last observation carried forward (LOCF) for post-baseline values

Arm/Group Title	Pramipexole	Placebo
Arm/Group Description	4 weeks of flexible dose-titration (to optimise efficacy and tolerability), starting at 0.125 mg once daily with the potential to increase the dose to 0.25mg and to further increase or decrease the dose in steps to 0.5 mg and 0.75 mg, with the final dose level subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets	4 weeks of flexible dose-titration as for the investigational product; with the dose subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets
Measure Participants	157	152
Median (Inter-Quartile Range) [Scores on a scale]	12	9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pramipexole, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0179
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	2.0
	Confidence Interval	(2-Sided) 95%; 1.6 to 2.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

15. Secondary Outcome

Title	Change From Baseline in SF-36 Dimension General Health After 26 Weeks
Description	Score ranging from 0 to 100 with higher scores indicating better health status
Time Frame	Baseline and 26 weeks

Outcome Measure Data

Analysis Population Description

Intent to treat analysis. Number of randomized patients with a baseline and at least one non-missing post-baseline measure. Imputation by last observation carried forward (LOCF) for post-baseline values

Arm/Group Title	Pramipexole	Placebo
Arm/Group Description	4 weeks of flexible dose-titration (to optimise efficacy and tolerability), starting at 0.125 mg once daily with the potential to increase the dose to 0.25mg and to further increase or decrease the dose in steps to 0.5 mg and 0.75 mg, with the final dose level subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets	4 weeks of flexible dose-titration as for the investigational product; with the dose subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets
Measure Participants	155	152
Median (Inter-Quartile Range) [Scores on a scale]	0	0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pramipexole, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5450
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	2.0
	Confidence Interval	(2-Sided) 95%; 1.7 to 2.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

16. Secondary Outcome

Title	Change From Baseline in SF-36 Dimension Mental Health After 26 Weeks
Description	Score ranging from 0 to 100 with higher scores indicating better mental health
Time Frame	Baseline and 26 weeks

Outcome Measure Data

Analysis Population Description

Intent to treat analysis. Number of randomized patients with a baseline and at least one non-missing post-baseline measure. Imputation by last observation carried forward (LOCF) for post-baseline values

Arm/Group Title	Pramipexole	Placebo
Arm/Group Description	4 weeks of flexible dose-titration (to optimise efficacy and tolerability), starting at 0.125 mg once daily with the potential to increase the dose to 0.25mg and to further increase or decrease the dose in steps to 0.5 mg and 0.75 mg, with the final dose level subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets	4 weeks of flexible dose-titration as for the investigational product; with the dose subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets
Measure Participants	155	152
Median (Inter-Quartile Range) [Scores on a scale]	5	5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pramipexole, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1456
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -0.3 to 0.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

17. Secondary Outcome

Title	Change From Baseline in SF-36 Dimension Physical Functioning After 26 Weeks
Description	Score ranging from 0 to 100 with higher scores indicating better physical functioning
Time Frame	Baseline and 26 weeks

Outcome Measure Data

Analysis Population Description

Intent to treat analysis. Number of randomized patients with a baseline and at least one non-missing post-baseline measure. Imputation by last observation carried forward (LOCF) for post-baseline values

Arm/Group Title	Pramipexole	Placebo
Arm/Group Description	4 weeks of flexible dose-titration (to optimise efficacy and tolerability), starting at 0.125 mg once daily with the potential to increase the dose to 0.25mg and to further increase or decrease the dose in steps to 0.5 mg and 0.75 mg, with the final dose level subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets	4 weeks of flexible dose-titration as for the investigational product; with the dose subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets
Measure Participants	156	152
Median (Inter-Quartile Range) [Scores on a scale]	0	0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pramipexole, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2915
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -0.4 to 0.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

18. Secondary Outcome

Title	Change From Baseline in SF-36 Dimension Role Limitations Due to Emotional Problems After 26 Weeks
Description	Score ranging from 0 to 100 with higher scores indicating less limitations due to emotional problems
Time Frame	Baseline and 26 weeks

Outcome Measure Data

Analysis Population Description

Intent to treat analysis. Number of randomized patients with a baseline and at least one non-missing post-baseline measure. Imputation by last observation carried forward (LOCF) for post-baseline values

Arm/Group Title	Pramipexole	Placebo
Arm/Group Description	4 weeks of flexible dose-titration (to optimise efficacy and tolerability), starting at 0.125 mg once daily with the potential to increase the dose to 0.25mg and to further increase or decrease the dose in steps to 0.5 mg and 0.75 mg, with the final dose level subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets	4 weeks of flexible dose-titration as for the investigational product; with the dose subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets
Measure Participants	156	152
Median (Inter-Quartile Range) [Scores on a scale]	0	0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pramipexole, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3131
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -0.4 to 0.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

19. Secondary Outcome

Title	Change From Baseline in SF-36 Dimension Role Limitations Due to Physical Problems After 26 Weeks
Description	Score ranging from 0 to 100 with higher scores indicating less limitations due to physical problems
Time Frame	Baseline and 26 weeks

Outcome Measure Data

Analysis Population Description

Intent to treat analysis. Number of randomized patients with a baseline and at least one non-missing post-baseline measure. Imputation by last observation carried forward (LOCF) for post-baseline values

Arm/Group Title	Pramipexole	Placebo
Arm/Group Description	4 weeks of flexible dose-titration (to optimise efficacy and tolerability), starting at 0.125 mg once daily with the potential to increase the dose to 0.25mg and to further increase or decrease the dose in steps to 0.5 mg and 0.75 mg, with the final dose level subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets	4 weeks of flexible dose-titration as for the investigational product; with the dose subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets
Measure Participants	156	152
Median (Inter-Quartile Range) [Scores on a scale]	6.3	6.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pramipexole, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5713
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -0.4 to 0.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

20. Secondary Outcome

Title	Change From Baseline in SF-36 Dimension Social Functioning After 26 Weeks
Description	Score ranging from 0 to 100 with higher scores indicating better social functioning
Time Frame	Baseline and 26 weeks

Outcome Measure Data

Analysis Population Description

Intent to treat analysis. Number of randomized patients with a baseline and at least one non-missing post-baseline measure. Imputation by last observation carried forward (LOCF) for post-baseline values

Arm/Group Title	Pramipexole	Placebo
Arm/Group Description	4 weeks of flexible dose-titration (to optimise efficacy and tolerability), starting at 0.125 mg once daily with the potential to increase the dose to 0.25mg and to further increase or decrease the dose in steps to 0.5 mg and 0.75 mg, with the final dose level subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets	4 weeks of flexible dose-titration as for the investigational product; with the dose subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets
Measure Participants	157	152
Median (Inter-Quartile Range) [Scores on a scale]	0	0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pramipexole, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8432
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -0.4 to 0.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

21. Secondary Outcome

Title	Change From Baseline in SF-36 Dimension Vitality After 26 Weeks
Description	Score ranging from 0 to 100 with higher scores indicating better vitality
Time Frame	Baseline and 26 weeks

Outcome Measure Data

Analysis Population Description

Intent to treat analysis. Number of randomized patients with a baseline and at least one non-missing post-baseline measure. Imputation by last observation carried forward (LOCF) for post-baseline values

Arm/Group Title	Pramipexole	Placebo
Arm/Group Description	4 weeks of flexible dose-titration (to optimise efficacy and tolerability), starting at 0.125 mg once daily with the potential to increase the dose to 0.25mg and to further increase or decrease the dose in steps to 0.5 mg and 0.75 mg, with the final dose level subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets	4 weeks of flexible dose-titration as for the investigational product; with the dose subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets
Measure Participants	155	152
Median (Inter-Quartile Range) [Scores on a scale]	6.3	3.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pramipexole, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0206
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	6.3
	Confidence Interval	(2-Sided) 95%; 5.9 to 6.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

22. Secondary Outcome

Title	Change From Baseline in SF-36 Dimension Mental Component Summary After 26 Weeks
Description	Score ranging from 0 to 100 with higher scores indicating better health
Time Frame	Baseline and 26 weeks

Outcome Measure Data

Analysis Population Description

Intent to treat analysis. Number of randomized patients with a baseline and at least one non-missing post-baseline measure. Imputation by last observation carried forward (LOCF) for post-baseline values

Arm/Group Title	Pramipexole	Placebo
Arm/Group Description	4 weeks of flexible dose-titration (to optimise efficacy and tolerability), starting at 0.125 mg once daily with the potential to increase the dose to 0.25mg and to further increase or decrease the dose in steps to 0.5 mg and 0.75 mg, with the final dose level subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets	4 weeks of flexible dose-titration as for the investigational product; with the dose subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets
Measure Participants	155	152
Median (Inter-Quartile Range) [Scores on a scale]	1.7	1.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pramipexole, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5602
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	0.6
	Confidence Interval	(2-Sided) 95%; 0.4 to 0.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

23. Secondary Outcome

Title	Change From Baseline in SF-36 Dimension Physical Component Summary After 26 Weeks
Description	Score ranging from 0 to 100 with higher scores indicating better health
Time Frame	Baseline and 26 weeks

Outcome Measure Data

Analysis Population Description

Intent to treat analysis. Number of randomized patients with a baseline and at least one non-missing post-baseline measure. Imputation by last observation carried forward (LOCF) for post-baseline values

Arm/Group Title	Pramipexole	Placebo
Arm/Group Description	4 weeks of flexible dose-titration (to optimise efficacy and tolerability), starting at 0.125 mg once daily with the potential to increase the dose to 0.25mg and to further increase or decrease the dose in steps to 0.5 mg and 0.75 mg, with the final dose level subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets	4 weeks of flexible dose-titration as for the investigational product; with the dose subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets
Measure Participants	155	152
Median (Inter-Quartile Range) [Scores on a scale]	2.1	2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pramipexole, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1360
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	1.0
	Confidence Interval	(2-Sided) 95%; 0.8 to 1.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

24. Secondary Outcome

Title	Diagnosis of Classified Augmentation According to Independent Expert Panel
Description	Augmentation is a worsening of RLS symptoms and may manifest as increased severity and the involvement of other extremities or as a shift of RLS symptoms to a time period that is 2 or more hours earlier than was typical of the time of symptom onset during the initial course of beneficial stable treatment or the state before recently starting treatment.
Time Frame	after at least 4 weeks of treatment

Outcome Measure Data

Analysis Population Description

Treated Set and where patients received study medication for at least 4 weeks (Treated Set includes all patients who were documented to have taken at least one dose of of treatment)

Arm/Group Title	Pramipexole	Placebo
Arm/Group Description	4 weeks of flexible dose-titration (to optimise efficacy and tolerability), starting at 0.125 mg once daily with the potential to increase the dose to 0.25mg and to further increase or decrease the dose in steps to 0.5 mg and 0.75 mg, with the final dose level subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets	4 weeks of flexible dose-titration as for the investigational product; with the dose subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets
Measure Participants	152	149
Number [participants]	18 10.8%	14 8.6%

25. Secondary Outcome

Title	Worsening of RLS Symptoms (by at Least 4 Points in the IRLS Total Score Compared to Baseline) After Treatment Discontinuation
Description	Worsening of RLS symptoms, in comparison to baseline, following abrupt treatment discontinuation (for patients with no added RLS therapy after study drug discontinuation). Assessment of worsening of RLS was based on the IRLS total score assessed 7 ± 1 days after treatment discontinuation (the end of the study or premature discontinuation) compared with that at baseline. Analysis considered the number of patients experiencing a clinically relevant deterioration of ≥4 points in total IRLS score 7 ± 1 days after discontinuation of trial medication compared with baseline.
Time Frame	after at least 1 week of treatment discontinuation

Outcome Measure Data

Analysis Population Description

Treated Set, all patients who were documented to have taken at least one dose of study medication

Arm/Group Title	Pramipexole	Placebo
Arm/Group Description	4 weeks of flexible dose-titration (to optimise efficacy and tolerability), starting at 0.125 mg once daily with the potential to increase the dose to 0.25mg and to further increase or decrease the dose in steps to 0.5 mg and 0.75 mg, with the final dose level subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets	4 weeks of flexible dose-titration as for the investigational product; with the dose subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets
Measure Participants	135	133
Number [participants]	14 8.4%	2 1.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pramipexole, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0022
	Comments
	Method	Mantel Haenszel
	Comments

26. Secondary Outcome

Title	Baseline, Week 26 Mean Supine Systolic Blood Pressure
Time Frame	Baseline, Week 26

Outcome Measure Data

Analysis Population Description

Treated Set, all patients who were documented to have taken at least one dose of study medication

Arm/Group Title	Pramipexole	Placebo
Arm/Group Description	4 weeks of flexible dose-titration (to optimise efficacy and tolerability), starting at 0.125 mg once daily with the potential to increase the dose to 0.25mg and to further increase or decrease the dose in steps to 0.5 mg and 0.75 mg, with the final dose level subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets	4 weeks of flexible dose-titration as for the investigational product; with the dose subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets
Measure Participants	166	163
Baseline	133.4 (16.9)	132.7 (18.4)
Week 26	132.3 (16.4)	132.2 (16.5)

27. Secondary Outcome

Title	Baseline, Week 26 Mean Standing Systolic Blood Pressure
Time Frame	Baseline, Week 26

Outcome Measure Data

Analysis Population Description

Treated Set, all patients who were documented to have taken at least one dose of study medication

Arm/Group Title	Pramipexole	Placebo
Arm/Group Description	4 weeks of flexible dose-titration (to optimise efficacy and tolerability), starting at 0.125 mg once daily with the potential to increase the dose to 0.25mg and to further increase or decrease the dose in steps to 0.5 mg and 0.75 mg, with the final dose level subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets	4 weeks of flexible dose-titration as for the investigational product; with the dose subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets
Measure Participants	166	163
Baseline	132.6 (17.3)	130.6 (18.2)
Week 26	132.4 (18.2)	130.1 (17.1)

28. Secondary Outcome

Title	Baseline, Week 26 Mean Supine Diastolic Blood Pressure
Time Frame	Baseline, Week 26

Outcome Measure Data

Analysis Population Description

Treated Set, all patients who were documented to have taken at least one dose of study medication

Arm/Group Title	Pramipexole	Placebo
Arm/Group Description	4 weeks of flexible dose-titration (to optimise efficacy and tolerability), starting at 0.125 mg once daily with the potential to increase the dose to 0.25mg and to further increase or decrease the dose in steps to 0.5 mg and 0.75 mg, with the final dose level subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets	4 weeks of flexible dose-titration as for the investigational product; with the dose subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets
Measure Participants	166	163
Baseline	79.2 (9.7)	79.6 (9.7)
Week 26	78.3 (9.7)	79.5 (9.4)

29. Secondary Outcome

Title	Baseline, Week 26 Mean Standing Diastolic Blood Pressure
Time Frame	Baseline, Week 26

Outcome Measure Data

Analysis Population Description

Treated Set, all patients who were documented to have taken at least one dose of study medication

Arm/Group Title	Pramipexole	Placebo
Arm/Group Description	4 weeks of flexible dose-titration (to optimise efficacy and tolerability), starting at 0.125 mg once daily with the potential to increase the dose to 0.25mg and to further increase or decrease the dose in steps to 0.5 mg and 0.75 mg, with the final dose level subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets	4 weeks of flexible dose-titration as for the investigational product; with the dose subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets
Measure Participants	166	163
Baseline	82.7 (10.5)	81.7 (10.7)
Week 26	80.5 (10.6)	80.8 (10.0)

30. Secondary Outcome

Title	Baseline, Week 26 Mean Supine Pulse Rate
Time Frame	Baseline, Week 26

Outcome Measure Data

Analysis Population Description

Treated Set, all patients who were documented to have taken at least one dose of study medication

Arm/Group Title	Pramipexole	Placebo
Arm/Group Description	4 weeks of flexible dose-titration (to optimise efficacy and tolerability), starting at 0.125 mg once daily with the potential to increase the dose to 0.25mg and to further increase or decrease the dose in steps to 0.5 mg and 0.75 mg, with the final dose level subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets	4 weeks of flexible dose-titration as for the investigational product; with the dose subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets
Measure Participants	166	163
Baseline	68.5 (9.6)	68.7 (10.6)
Week 26	69.1 (8.9)	68.3 (10.6)

31. Secondary Outcome

Title	Baseline, Week 26 Mean Standing Pulse Rate
Time Frame	Baseline, Week 26

Outcome Measure Data

Analysis Population Description

Treated Set, all patients who were documented to have taken at least one dose of study medication

Arm/Group Title	Pramipexole	Placebo
Arm/Group Description	4 weeks of flexible dose-titration (to optimise efficacy and tolerability), starting at 0.125 mg once daily with the potential to increase the dose to 0.25mg and to further increase or decrease the dose in steps to 0.5 mg and 0.75 mg, with the final dose level subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets	4 weeks of flexible dose-titration as for the investigational product; with the dose subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets
Measure Participants	166	163
Baseline	74.6 (10.2)	74.0 (10.7)
Week 26	74.1 (8.9)	75.0 (10.6)

Adverse Events

Time Frame	26 weeks
Arm/Group Title	Pramipexole		Placebo
Arm/Group Description	4 weeks of flexible dose-titration (to optimise efficacy and tolerability), starting at 0.125 mg once daily with the potential to increase the dose to 0.25mg and to further increase or decrease the dose in steps to 0.5 mg and 0.75 mg, with the final dose level subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets		4 weeks of flexible dose-titration as for the investigational product; with the dose subsequently fixed for 22 weeks. mode of administration: Oral, once daily in the evening (2 to 3 hours before bedtime) form: tablets
All Cause Mortality
	Pramipexole		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Pramipexole		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/166 (4.8%)		3/163 (1.8%)
Cardiac disorders
Myocardial infarction	1/166 (0.6%)		0/163 (0%)
Gastrointestinal disorders
Crohn's disease	0/166 (0%)		1/163 (0.6%)
Haemorrhoidal haemorrhage	1/166 (0.6%)		0/163 (0%)
Vomiting	0/166 (0%)		1/163 (0.6%)
Infections and infestations
Appendicitis	0/166 (0%)		1/163 (0.6%)
Urinary tract infection	1/166 (0.6%)		0/163 (0%)
Viral infection	0/166 (0%)		1/163 (0.6%)
Injury, poisoning and procedural complications
Extradural haematoma	1/166 (0.6%)		0/163 (0%)
Humerus fracture	1/166 (0.6%)		0/163 (0%)
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion	1/166 (0.6%)		0/163 (0%)
Neck pain	1/166 (0.6%)		0/163 (0%)
Reproductive system and breast disorders
Uterine prolapse	1/166 (0.6%)		0/163 (0%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/166 (0.6%)		0/163 (0%)
Vascular disorders
Orthostatic hypotension	0/166 (0%)		1/163 (0.6%)
Other (Not Including Serious) Adverse Events
	Pramipexole		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	70/166 (42.2%)		58/163 (35.6%)
Gastrointestinal disorders
Nausea	24/166 (14.5%)		6/163 (3.7%)
General disorders
Fatigue	18/166 (10.8%)		15/163 (9.2%)
Infections and infestations
Nasopharyngitis	7/166 (4.2%)		10/163 (6.1%)
Musculoskeletal and connective tissue disorders
Muscle spasms	10/166 (6%)		4/163 (2.5%)
Arthralgia	9/166 (5.4%)		2/163 (1.2%)
Nervous system disorders
Headache	13/166 (7.8%)		17/163 (10.4%)
Restless legs syndrome	11/166 (6.6%)		11/163 (6.7%)
Somnolence	11/166 (6.6%)		8/163 (4.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Any publication of the result of this trial must be consistent with the Boehringer Ingelheim publication policy. The rights of the investigator and of the sponsor with regard to publication of the results of this trial are described in the investigator contract.