A Randomised, Comparing Fixed Doses of Pramipexole to Investigate the Efficacy and Safety in Patients With RLS.

Study Overview
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Brief Summary
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The objective of double blind phase in this trial is to compare the efficacy and safety at the fixed dose of 0.25 mg,0.5 mg and 0.75 mg pramipexole in RLS. The objective of open label phase in this trial is to investigate the long term safety and efficacy of pramipexole in RLS.

Official Title
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A Randomised, Double-blind Study to Evaluate the Efficacy and Safety of Pramipexole at Fixed Doses of 0.25 mg, 0.5 mg, and 0.75 mg in Patients With Idiopathic Restless Legs Syndrome for 6 Weeks, Followed by a 46-week Open-label Long-term Study

Conditions
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Idiopathic Restless Legs Syndrome

Intervention / Treatment
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* Drug: Pramipexole 0.125 mg tablet
* Drug: Pramipexole 0.5 mg tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients between 20 and 80 years Patients with a diagnosis of restless legs syndrome (RLS) according to the following diagnosis criteria of National institute of health (NIH)/International restless legs syndrome study group (IRLSSG): An urge to move the legs, usually accompanied or caused by uncomfortable and unpleasant sensations in the legs. The urge to move or unpleasant sensations begin or worsen during periods of rest or inactivity such as lying or sitting. The urge to move or unpleasant sensations are partially or totally relieved by movement, such as walking or stretching, at least as long as the activity continues. The urge to move or unpleasant sensations are worse in the evening or night than during the day or only occur in the evening or night. Patients with a total score larger than 15 on the IRLS at Visit 2 Exclusion Criteria: Premenopausal women who meet any of the following 1) to 3) 1) Patients who are pregnant or possibly pregnant 2) Patients who are lactating 3) Patients who wish to become pregnant during the study period Patients who cannot take adequate contraceptive measures Patients with a history of akathisia induced by neuroleptics Patients with diabetes mellitus requiring insulin therapy Patients who are judged to have microcytic anaemia by the investigator or sub-investigator Patients with a history or signs of peripheral neuropathy, myelopathy, multiple sclerosis, Parkinson's disease or other neurological diseases that may result in the occurrence of secondary RLS in the physical function tests or neurological tests Patients with other sleep disorders such as abnormal behaviour during Rapid eye movement (REM) sleep, narcolepsy and sleep apnoea syndrome (patients with an apnoea-hypopnoea index (AHI) exceeding 15 determined by polysomnography at the relevant trial site or those with loud snoring at least 5 nights/week and an experience of respiratory arrest during sleep or excessive daytime sleepiness)

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 80 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 0.25 mg once daily<br>Pramipexole 0.25 mg given once daily | Drug: Pramipexole 0.125 mg tablet<br> <br> |
| Experimental: Pramipexole 0.5 mg once daily<br>Pramipexole 0.5 mg given once daily | Drug: Pramipexole 0.5 mg tablet<br> <br> |
| Experimental: Pramipexole 0.75 mg once daily<br>Pramipexole 0.75 mg given once daily | Drug: Pramipexole 0.125 mg tablet<br> <br> Drug: Pramipexole 0.5 mg tablet<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 (IRLS) Total Score at 6 Weeks | The International Restless Legs Syndrome Study Group (IRLSSG) proposes classification of severity based on the total score on the IRLS (0-10, mild; 11-20, moderate; 21-30, severe; 31-40, very severe). A decrease in the score of the IRLS by 10 or more points corresponds to the improvement of severity by one rank and has clinical importance. Therefore, the primary endpoint in the double-blind period was set as a decrease by 10 or more points in the mean change on the total score of the IRLS from the baseline to Visit 5 (last observation day in the double-blind period) at all doses of 0.25 mg, 0.5 mg, and 0.75 mg/day of pramipexole. | Week 6 - change from baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| IRLS Responder | The percentage of patients with 50 % or more reduction of IRLS (The measure means the percentage of high responder on the trial medications) | baseline to week 6 | 
| Change From Baseline in Pittsburgh Sleep Quality Index (PSQI) Total Score at 6 Weeks | PSQI developed to evaluate the quality of sleep is a self-recording questionnaire consisting of 18 questions focused on 7 factors such as sleep quality, sleep period time, sleep latency, sleep efficiency, sleep difficulty, use of hypnotics, and hindrance to activities of daily living due to daytime sleepiness. Each score (0-3 points) in the respective factors was added to calculate the total score (0-21 points). Rating scale scored from 0 (best sleep) to 21 (worst sleep). | Week 6 - change from baseline | 
| Change From Baseline in Japanese Version of the Epworth Sleepiness Scale (JESS) Total Score at 6 Weeks | ESS is a self-recording scale used to evaluate sleepiness experienced in daily activities and it consists of 8 items focused on specific situations such as reading books and watching television. Each score (0-3 points) to 8 questions was added simply to calculate the total ESS score. A Japanese translation of the ESS (a provisional version provided by the Japanese Respiratory Society) used so far had not been prepared through the international scale development and validation process, but the version prepared through this process was published at the 31st meeting of the Japanese Society of Sleep Research. The questions in JESS had been discussed with the original author of the ESS and their measurement concepts had been confirmed. The JESS is the Japanese version of ESS prepared through the international scale development and validation process. Rating scale scored from 0 (no daytime sleep) to 24 (worst daytime sleep) | Week 6 - change from baseline | 
| Clinical Global Impression Global Improvement (CGI-I) Responder | CGI is extensively used for risk-benefit evaluation (efficacy) of drug therapies. The CGI evaluates the severity and improvement in 7 ranks. It also evaluates the therapeutic effect and side effects in 4 ranks, separately. Rating scale from 1 (very much improved) to 7 (very much worse). The percentage of patients who were evaluated as 1(very much improved) or 2(much improved) by the investigator were considered responders. | baseline to week 6 | 
| Patient Global Impression (PGI) Responder | PGI is used to evaluate a global impression by patients themselves in 7 ranks. Rating scale from 1 (very much better) to 7 (very much worse). The percentage of patients where the patient evaluated himself/herself as 1(very much better) or 2(much better)were considered responders. | baseline to week 6 | 
| Clinically Significant Abnormalities in Vital Signs (Blood Pressure and Pulse Rate in Both Supine and Standing Positions), ECG, Laboratory Tests - Double Blind Period. |  | baseline to 6 weeks | 
| Change From Baseline in International Restless Legs Syndrome (IRLS) Total Score at 52 Weeks for Open-Label Period | The International Restless Legs Syndrome Study Group (IRLSSG) proposes classification of severity based on the total score on the IRLS (0-10, mild; 11-20, moderate; 21-30, severe; 31-40, very severe). | Week 52 - change from baseline | 
| IRLS Responder for Open-label Period | The percentage of patients with 50 % or more reduction of IRLS (The measure means the percentage of high responder on the trial medications) | baseline to week 52 | 
| Change From Baseline in Pittsburgh Sleep Quality Index (PSQI) Total Score at 52 Weeks for Open-Label Period | PSQI developed to evaluate the quality of sleep is a self-recording questionnaire consisting of 18 questions focused on 7 factors such as sleep quality, sleep period time, sleep latency, sleep efficiency, sleep difficulty, use of hypnotics, and hindrance to activities of daily living due to daytime sleepiness. Each score (0-3 points) in the respective factors was added to calculate the total score (0-21 points). Rating scale scored from 0 (best sleep) to 21 (worst sleep). | Week 52 - change from baseline | 
| Change From Baseline in Japanese Version of the Epworth Sleepiness Scale (JESS) Total Score at 52 Weeks for Open-Label Period | ESS is a self-recording scale used to evaluate sleepiness experienced in daily activities and it consists of 8 items focused on specific situations such as reading books and watching television. Each score (0-3 points) to 8 questions was added simply to calculate the total ESS score. A Japanese translation of the ESS (a provisional version provided by the Japanese Respiratory Society) used so far had not been prepared through the international scale development and validation process, but the version prepared through this process was published at the 31st meeting of the Japanese Society of Sleep Research. The questions in JESS had been discussed with the original author of the ESS and their measurement concepts had been confirmed. The JESS is the Japanese version of ESS prepared through the international scale development and validation process. Rating scale scored from 0 (no daytime sleep) to 24 (worst daytime sleep) | Week 52 - change from baseline | 
| Clinical Global Impression Global Improvement (CGI-I) Responder at 52 Weeks for Open-label Period | CGI is extensively used for risk-benefit evaluation (efficacy) of drug therapies. The CGI evaluates the severity and improvement in 7 ranks. It also evaluates the therapeutic effect and side effects in 4 ranks, separately. Rating scale from 1 (very much improved) to 7 (very much worse). The percentage of patients who were evaluated as 1(very much improved) or 2(much improved) by the investigator were considered responders. | baseline to week 52 | 
| Patient Global Impression (PGI) Responder at 52 Weeks for Open-Label Period | PGI is used to evaluate a global impression by patients themselves in 7 ranks. Rating scale from 1 (very much better) to 7 (very much worse). The percentage of patients where the patient evaluated himself/herself as 1(very much better) or 2(much better)were considered responders. | baseline to week 52 | 
| Possible Augmentation in RLS Symptoms at 52 Weeks for Open-Label Period | Possible augmentation defined as persistence of a state in which RLS symptoms begin to occur 2 hours earlier than the usual time zone for 5 days or more a week | baseline to week 52 |