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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim
ClinicalTrials.gov Identifier:
NCT00472199
First received: May 10, 2007
Last updated: June 17, 2014
Last verified: May 2012
  Purpose

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 Intervention Phase
Restless Legs Syndrome
Drug: Pramipexole
Drug: Placebo
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, 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

Resource links provided by NLM:


Further study details as provided by Boehringer Ingelheim:

Primary Outcome Measures:
  • Change From Baseline in International Restless Legs Syndrome Study Group Rating Scale (IRLS) Total Score After 26 Weeks [ Time Frame: Baseline and 26 weeks ] [ Designated as safety issue: No ]
    IRLS total score ranging from 0 (no RLS symptoms) to 40 (very severe RLS symptoms)


Secondary Outcome Measures:
  • Clinical Global Impression - Global Improvement (CGI-I) Responder Rate [ Time Frame: after 26 weeks of treatment ] [ Designated as safety issue: No ]
    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)

  • International Restless Legs Syndrome (IRLS) Study Group Rating Scale Responder Rate [ Time Frame: after 26 weeks of treatment ] [ Designated as safety issue: No ]
    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)

  • Patient Global Impression (PGI) Responder Rate [ Time Frame: after 26 weeks of treatment ] [ Designated as safety issue: No ]
    PGI scores ranging from '1' (very much better) to '7' (very much worse), PGI responder have scoring 1 or 2 (at least much better)

  • Change From Baseline in Restless Legs Syndrome-6 (RLS-6) Score "Satisfaction With Sleep" After 26 Weeks [ Time Frame: baseline and 26 weeks of treatment ] [ Designated as safety issue: No ]
    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

  • Change From Baseline in RLS-6 Score "Severity Falling Asleep" After 26 Weeks [ Time Frame: Baseline and 26 weeks of treatment ] [ Designated as safety issue: No ]
    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

  • Change From Baseline in RLS-6 Score "Severity During the Night" After 26 Weeks [ Time Frame: baseline and 26 weeks of treatment ] [ Designated as safety issue: No ]
    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

  • Change From Baseline in RLS-6 Score "Severity During the Day When at Rest" After 26 Weeks [ Time Frame: Baseline and 26 weeks of treatment ] [ Designated as safety issue: No ]
    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

  • Change From Baseline RLS-6 Score "Severity During the Day Engaged in Activities" After 26 Weeks [ Time Frame: Baseline and 26 weeks of treatment ] [ Designated as safety issue: No ]
    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

  • Change From Baseline in RLS-6 Score "Tired or Sleepy During the Day" After 26 Weeks [ Time Frame: Baseline and 26 weeks of treatment ] [ Designated as safety issue: No ]
    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

  • Change From Baseline in IRLS Mood Disturbance Score (Item 10) After 26 Weeks [ Time Frame: Baseline and 26 weeks of treatment ] [ Designated as safety issue: No ]
    Mood disturbance associated with RLS symptoms ranging from 0 (none) to 4 (very severe)

  • Change From Baseline in Visual Analogue Scale (VAS) Score for Pain in Limbs After 26 Weeks [ Time Frame: Baseline and 26 weeks of treatment ] [ Designated as safety issue: No ]
    The scale measures pain on a continuous 100 mm axis ranging from no pain (0 mm) to unbearable pain (100 mm)

  • Change From Baseline in Quality of Life in RLS (RLS QoL) Score After 26 Weeks [ Time Frame: Baseline and 26 weeks of treatment ] [ Designated as safety issue: No ]
    RLS QoL total score ranging from 0 to 100 with higher values indicating better quality of life

  • Change From Baseline in Short Form-36 (SF-36) Dimension Bodily Pain After 26 Weeks [ Time Frame: Baseline and 26 weeks ] [ Designated as safety issue: No ]
    Score ranging from 0 to 100 with higher scores indicating less bodily pain

  • Change From Baseline in SF-36 Dimension General Health After 26 Weeks [ Time Frame: Baseline and 26 weeks ] [ Designated as safety issue: No ]
    Score ranging from 0 to 100 with higher scores indicating better health status

  • Change From Baseline in SF-36 Dimension Mental Health After 26 Weeks [ Time Frame: Baseline and 26 weeks ] [ Designated as safety issue: No ]
    Score ranging from 0 to 100 with higher scores indicating better mental health

  • Change From Baseline in SF-36 Dimension Physical Functioning After 26 Weeks [ Time Frame: Baseline and 26 weeks ] [ Designated as safety issue: No ]
    Score ranging from 0 to 100 with higher scores indicating better physical functioning

  • Change From Baseline in SF-36 Dimension Role Limitations Due to Emotional Problems After 26 Weeks [ Time Frame: Baseline and 26 weeks ] [ Designated as safety issue: No ]
    Score ranging from 0 to 100 with higher scores indicating less limitations due to emotional problems

  • Change From Baseline in SF-36 Dimension Role Limitations Due to Physical Problems After 26 Weeks [ Time Frame: Baseline and 26 weeks ] [ Designated as safety issue: No ]
    Score ranging from 0 to 100 with higher scores indicating less limitations due to physical problems

  • Change From Baseline in SF-36 Dimension Social Functioning After 26 Weeks [ Time Frame: Baseline and 26 weeks ] [ Designated as safety issue: No ]
    Score ranging from 0 to 100 with higher scores indicating better social functioning

  • Change From Baseline in SF-36 Dimension Vitality After 26 Weeks [ Time Frame: Baseline and 26 weeks ] [ Designated as safety issue: No ]
    Score ranging from 0 to 100 with higher scores indicating better vitality

  • Change From Baseline in SF-36 Dimension Mental Component Summary After 26 Weeks [ Time Frame: Baseline and 26 weeks ] [ Designated as safety issue: No ]
    Score ranging from 0 to 100 with higher scores indicating better health

  • Change From Baseline in SF-36 Dimension Physical Component Summary After 26 Weeks [ Time Frame: Baseline and 26 weeks ] [ Designated as safety issue: No ]
    Score ranging from 0 to 100 with higher scores indicating better health

  • Diagnosis of Classified Augmentation According to Independent Expert Panel [ Time Frame: after at least 4 weeks of treatment ] [ Designated as safety issue: No ]
    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.

  • Worsening of RLS Symptoms (by at Least 4 Points in the IRLS Total Score Compared to Baseline) After Treatment Discontinuation [ Time Frame: after at least 1 week of treatment discontinuation ] [ Designated as safety issue: No ]

    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.


  • Baseline, Week 26 Mean Supine Systolic Blood Pressure [ Time Frame: Baseline, Week 26 ] [ Designated as safety issue: No ]
  • Baseline, Week 26 Mean Standing Systolic Blood Pressure [ Time Frame: Baseline, Week 26 ] [ Designated as safety issue: No ]
  • Baseline, Week 26 Mean Supine Diastolic Blood Pressure [ Time Frame: Baseline, Week 26 ] [ Designated as safety issue: No ]
  • Baseline, Week 26 Mean Standing Diastolic Blood Pressure [ Time Frame: Baseline, Week 26 ] [ Designated as safety issue: No ]
  • Baseline, Week 26 Mean Supine Pulse Rate [ Time Frame: Baseline, Week 26 ] [ Designated as safety issue: No ]
  • Baseline, Week 26 Mean Standing Pulse Rate [ Time Frame: Baseline, Week 26 ] [ Designated as safety issue: No ]

Enrollment: 331
Study Start Date: May 2007
Primary Completion Date: July 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

  Eligibility

Ages Eligible for Study:   18 Years to 85 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00472199

  Show 42 Study Locations
Sponsors and Collaborators
Boehringer Ingelheim
Investigators
Study Chair: Boehringer Ingelheim Boehringer Ingelheim
  More Information

Additional Information:
No publications provided

Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT00472199     History of Changes
Other Study ID Numbers: 248.629, EUDRACT2006-006431-42
Study First Received: May 10, 2007
Results First Received: July 2, 2009
Last Updated: June 17, 2014
Health Authority: Austria: Federal Office for Safety in Health Care
Belgium: Federal Agency for Medicines and Health Products, FAMHP
Finland: Finnish Medicines Agency
Germany: Federal Institute for Drugs and Medical Devices
Great Britain: MHRA
Ireland: Irish Medicines Board
Netherlands: Central Committee on Research involving Human Subjects (CCMO)
Slovakia: State Institute for Drug Control
Spain: Spanish Agency for Medicines and Health Products

Additional relevant MeSH terms:
Psychomotor Agitation
Restless Legs Syndrome
Syndrome
Dyskinesias
Neurologic Manifestations
Nervous System Diseases
Psychomotor Disorders
Neurobehavioral Manifestations
Signs and Symptoms
Sleep Disorders, Intrinsic
Dyssomnias
Sleep Disorders
Parasomnias
Mental Disorders
Disease
Pathologic Processes
Pramipexole
Antioxidants
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Protective Agents
Physiological Effects of Drugs
Antiparkinson Agents
Anti-Dyskinesia Agents
Central Nervous System Agents
Therapeutic Uses
Dopamine Agonists
Dopamine Agents
Neurotransmitter Agents

ClinicalTrials.gov processed this record on September 16, 2014