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

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

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.

Study Overview

• Status: Completed
• Conditions: Restless Legs Syndrome
• Intervention / Treatment: Drug: Placebo; Drug: Pramipexole

• Study Type: Interventional
• Enrollment (Actual): 331
• Phase: Phase 4

Contacts and Locations

Study Locations

• Austria
  • Innsbruck, Austria
    • 248.629.4302 Boehringer Ingelheim Investigational Site
  • Linz, Austria
    • 248.629.4304 Boehringer Ingelheim Investigational Site
• Belgium
  • Edegem, Belgium
    • 248.629.3201 Boehringer Ingelheim Investigational Site
• Finland
  • Espoo, Finland
    • 248.629.35801 Boehringer Ingelheim Investigational Site
  • Helsinki, Finland
    • 248.629.35805 Boehringer Ingelheim Investigational Site
  • Joensuu, Finland
    • 248.629.35804 Boehringer Ingelheim Investigational Site
  • Oulu, Finland
    • 248.629.35802 Boehringer Ingelheim Investigational Site
  • Tampere, Finland
    • 248.629.35806 Boehringer Ingelheim Investigational Site
• Germany
  • Berlin, Germany
    • 248.629.4902 Boehringer Ingelheim Investigational Site
  • Berlin (Hellersdorf), Germany
    • 248.629.4904 Boehringer Ingelheim Investigational Site
  • Berlin-Steglitz, Germany
    • 248.629.4903 Boehringer Ingelheim Investigational Site
  • Bochum, Germany
    • 248.629.4908 Boehringer Ingelheim Investigational Site
  • Ellwangen, Germany
    • 248.629.4901 Boehringer Ingelheim Investigational Site
  • Herborn, Germany
    • 248.629.4906 Boehringer Ingelheim Investigational Site
  • Leipzig, Germany
    • 248.629.4905 Boehringer Ingelheim Investigational Site
  • Schwerin, Germany
    • 248.629.4909 Boehringer Ingelheim Investigational Site
  • Würzburg, Germany
    • 248.629.4907 Boehringer Ingelheim Investigational Site
• Ireland
  • Carrigtwohill, Ireland
    • 248.629.35301 Boehringer Ingelheim Investigational Site
  • Co. Kildare, Ireland
    • 248.629.35302 Boehringer Ingelheim Investigational Site
  • Co. Tipperary, Ireland
    • 248.629.35303 Boehringer Ingelheim Investigational Site
• Netherlands
  • Bennebroek, Netherlands
    • 248.629.31001 Boehringer Ingelheim Investigational Site
  • Hoogwoud, Netherlands
    • 248.629.31005 Boehringer Ingelheim Investigational Site
  • Musselkanaal, Netherlands
    • 248.629.31006 Boehringer Ingelheim Investigational Site
  • Oude Pekela, Netherlands
    • 248.629.31002 Boehringer Ingelheim Investigational Site
  • Oude Pekela, Netherlands
    • 248.629.31003 Boehringer Ingelheim Investigational Site
  • Rijswijk, Netherlands
    • 248.629.31004 Boehringer Ingelheim Investigational Site
• Slovakia
  • Bratislava, Slovakia
    • 248.629.4204 Boehringer Ingelheim Investigational Site
  • Bratislava, Slovakia
    • 248.629.4205 Boehringer Ingelheim Investigational Site
  • Brezno, Slovakia
    • 248.629.4202 Boehringer Ingelheim Investigational Site
  • Kosice, Slovakia
    • 248.629.4201 Boehringer Ingelheim Investigational Site
  • Martin, Slovakia
    • 248.629.4203 Boehringer Ingelheim Investigational Site
• Spain
  • Barcelona, Spain
    • 248.629.3402 Boehringer Ingelheim Investigational Site
  • Granada, Spain
    • 248.629.3405 Boehringer Ingelheim Investigational Site
  • Madrid, Spain
    • 248.629.3401 Boehringer Ingelheim Investigational Site
  • San Sebastián, Spain
    • 248.629.3403 Boehringer Ingelheim Investigational Site
  • Valencia, Spain
    • 248.629.3406 Hospital Arnau de Vilanova
• United Kingdom
  • Chorley, United Kingdom
    • 248.629.44003 Boehringer Ingelheim Investigational Site
  • Edgbaston, Birmingham, United Kingdom
    • 248.629.44006 Boehringer Ingelheim Investigational Site
  • Glasgow, United Kingdom
    • 248.629.44004 Boehringer Ingelheim Investigational Site
  • Manchester, United Kingdom
    • 248.629.44001 Boehringer Ingelheim Investigational Site
  • Reading, United Kingdom
    • 248.629.44002 Boehringer Ingelheim Investigational Site
  • Waterloo, Liverpool, United Kingdom
    • 248.629.44005 Boehringer Ingelheim Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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);

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Global Impression - Global Improvement (CGI-I) Responder Rate	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)	after 26 weeks of treatment
International Restless Legs Syndrome (IRLS) Study Group Rating Scale Responder Rate	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)	after 26 weeks of treatment
Patient Global Impression (PGI) Responder Rate	PGI scores ranging from '1' (very much better) to '7' (very much worse), PGI responder have scoring 1 or 2 (at least much better)	after 26 weeks of treatment
Change From Baseline in Restless Legs Syndrome-6 (RLS-6) Score "Satisfaction With Sleep" After 26 Weeks	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	baseline and 26 weeks of treatment
Change From Baseline in RLS-6 Score "Severity Falling Asleep" After 26 Weeks	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	Baseline and 26 weeks of treatment
Change From Baseline in RLS-6 Score "Severity During the Night" After 26 Weeks	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	baseline and 26 weeks of treatment
Change From Baseline in RLS-6 Score "Severity During the Day When at Rest" After 26 Weeks	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	Baseline and 26 weeks of treatment
Change From Baseline RLS-6 Score "Severity During the Day Engaged in Activities" After 26 Weeks	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	Baseline and 26 weeks of treatment
Change From Baseline in RLS-6 Score "Tired or Sleepy During the Day" After 26 Weeks	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	Baseline and 26 weeks of treatment
Change From Baseline in IRLS Mood Disturbance Score (Item 10) After 26 Weeks	Mood disturbance associated with RLS symptoms ranging from 0 (none) to 4 (very severe)	Baseline and 26 weeks of treatment
Change From Baseline in Visual Analogue Scale (VAS) Score for Pain in Limbs After 26 Weeks	The scale measures pain on a continuous 100 mm axis ranging from no pain (0 mm) to unbearable pain (100 mm)	Baseline and 26 weeks of treatment
Change From Baseline in Quality of Life in RLS (RLS QoL) Score After 26 Weeks	RLS QoL total score ranging from 0 to 100 with higher values indicating better quality of life	Baseline and 26 weeks of treatment
Change From Baseline in Short Form-36 (SF-36) Dimension Bodily Pain After 26 Weeks	Score ranging from 0 to 100 with higher scores indicating less bodily pain	Baseline and 26 weeks
Change From Baseline in SF-36 Dimension General Health After 26 Weeks	Score ranging from 0 to 100 with higher scores indicating better health status	Baseline and 26 weeks
Change From Baseline in SF-36 Dimension Mental Health After 26 Weeks	Score ranging from 0 to 100 with higher scores indicating better mental health	Baseline and 26 weeks
Change From Baseline in SF-36 Dimension Physical Functioning After 26 Weeks	Score ranging from 0 to 100 with higher scores indicating better physical functioning	Baseline and 26 weeks
Change From Baseline in SF-36 Dimension Role Limitations Due to Emotional Problems After 26 Weeks	Score ranging from 0 to 100 with higher scores indicating less limitations due to emotional problems	Baseline and 26 weeks
Change From Baseline in SF-36 Dimension Role Limitations Due to Physical Problems After 26 Weeks	Score ranging from 0 to 100 with higher scores indicating less limitations due to physical problems	Baseline and 26 weeks
Change From Baseline in SF-36 Dimension Social Functioning After 26 Weeks	Score ranging from 0 to 100 with higher scores indicating better social functioning	Baseline and 26 weeks
Change From Baseline in SF-36 Dimension Vitality After 26 Weeks	Score ranging from 0 to 100 with higher scores indicating better vitality	Baseline and 26 weeks
Change From Baseline in SF-36 Dimension Mental Component Summary After 26 Weeks	Score ranging from 0 to 100 with higher scores indicating better health	Baseline and 26 weeks
Change From Baseline in SF-36 Dimension Physical Component Summary After 26 Weeks	Score ranging from 0 to 100 with higher scores indicating better health	Baseline and 26 weeks
Diagnosis of Classified Augmentation According to Independent Expert Panel	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.	after at least 4 weeks of treatment
Worsening of RLS Symptoms (by at Least 4 Points in the IRLS Total Score Compared to Baseline) After 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.	after at least 1 week of treatment discontinuation
Baseline, Week 26 Mean Supine Systolic Blood Pressure		Baseline, Week 26
Baseline, Week 26 Mean Standing Systolic Blood Pressure		Baseline, Week 26
Baseline, Week 26 Mean Supine Diastolic Blood Pressure		Baseline, Week 26
Baseline, Week 26 Mean Standing Diastolic Blood Pressure		Baseline, Week 26
Baseline, Week 26 Mean Supine Pulse Rate		Baseline, Week 26
Baseline, Week 26 Mean Standing Pulse Rate		Baseline, Week 26

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

Helpful Links

• Related Info
• Related Info

Study record dates

Study Major Dates

• Study Start: May 1, 2007
• Primary Completion (Actual): July 1, 2008

Study Registration Dates

• First Submitted: May 10, 2007
• First Submitted That Met QC Criteria: May 10, 2007
• First Posted (Estimate): May 11, 2007

Study Record Updates

• Last Update Posted (Estimate): June 27, 2014
• Last Update Submitted That Met QC Criteria: June 17, 2014
• Last Verified: May 1, 2012

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Nervous System Diseases; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Neurologic Manifestations; Neurobehavioral Manifestations; Disease; Dyskinesias; Psychomotor Disorders; Parasomnias; Syndrome; Psychomotor Agitation; Restless Legs Syndrome; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Protective Agents; Dopamine Agonists; Dopamine Agents; Antioxidants; Antiparkinson Agents; Anti-Dyskinesia Agents; Pramipexole
• Other Study ID Numbers: 248.629; EUDRACT2006-006431-42