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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Restless Legs Syndrome

Intervention / Treatment
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* Drug: Pramipexole
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Male or female out-patients aged 18-85 years 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. RLS symptoms present at least 2 to 3 days per week during the last 3 months prior to baseline (Visit 2) IRLS total score >15 at baseline (Visit 2) Exclusion Criteria: 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 Any woman of child-bearing potential not having a negative pregnancy test at screening Breastfeeding women Patients with known hypersensitivity to pramipexole or any other component of the investigational product or placebo tablets Diagnosis of augmentation under previous pharmacological RLS treatment 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);

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pramipexole<br>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<br> <br> |
| Placebo Comparator: Placebo<br>4 weeks of flexible dose-titration as for the investigational product; with the dose subsequently fixed for 22 weeks. | Drug: Placebo<br> <br> |

What is the study measuring?
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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 |