Trial Outcomes & Findings for A Randomised, Comparing Fixed Doses of Pramipexole to Investigate the Efficacy and Safety in Patients With RLS. (NCT NCT00390689)

NCT ID: NCT00390689

Last Updated: 2014-07-02

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 154 participants
• Primary outcome timeframe: Week 6 - change from baseline
• Results posted on: 2014-07-02

Participant Flow

Participant milestones

Measure	Pramipexole 0.25mg Group Double-blind period: 0.25 mg randomised group Administration as follows: Week 1: 1 tablet of 0.125mg Pramipexole once daily Week 2: 2 tablets of 0.125mg Pramipexole once daily Week 3: 2 tablets of 0.125mg Pramipexole + 2 tablets of the matching placebo once daily Week 4-6: 2 tablets of 0.125mg Pramipexole + 4 tablets of the matching placebo once daily Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.5mg Group Double-blind period: 0.5 mg randomised group Administration as follows: Week 1: 1 tablet of 0.125mg Pramipexole once daily Week 2: 2 tablets of 0.125mg Pramipexole once daily Week 3: 4 tablets of 0.125mg Pramipexole once daily Week 4-6: 4 tablets of 0.125mg Pramipexole + 2 tablets of the matching placebo once daily Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.75mg Group Double-blind period: 0.75 mg randomised group Administration as follows: Week 1: 1 tablet of 0.125mg Pramipexole once daily Week 2: 2 tablets of 0.125mg Pramipexole once daily Week 3: 4 tablets of 0.125mg Pramipexole once daily Week 4-6: 6 tablets of 0.125mg Pramipexole once daily Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. mode of administration.: Oral, once daily, 2-3 hours before bedtime
Overall Study STARTED	48	53	53
Overall Study COMPLETED	43	48	50
Overall Study NOT COMPLETED	5	5	3

Reasons for withdrawal

Measure	Pramipexole 0.25mg Group Double-blind period: 0.25 mg randomised group Administration as follows: Week 1: 1 tablet of 0.125mg Pramipexole once daily Week 2: 2 tablets of 0.125mg Pramipexole once daily Week 3: 2 tablets of 0.125mg Pramipexole + 2 tablets of the matching placebo once daily Week 4-6: 2 tablets of 0.125mg Pramipexole + 4 tablets of the matching placebo once daily Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.5mg Group Double-blind period: 0.5 mg randomised group Administration as follows: Week 1: 1 tablet of 0.125mg Pramipexole once daily Week 2: 2 tablets of 0.125mg Pramipexole once daily Week 3: 4 tablets of 0.125mg Pramipexole once daily Week 4-6: 4 tablets of 0.125mg Pramipexole + 2 tablets of the matching placebo once daily Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.75mg Group Double-blind period: 0.75 mg randomised group Administration as follows: Week 1: 1 tablet of 0.125mg Pramipexole once daily Week 2: 2 tablets of 0.125mg Pramipexole once daily Week 3: 4 tablets of 0.125mg Pramipexole once daily Week 4-6: 6 tablets of 0.125mg Pramipexole once daily Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. mode of administration.: Oral, once daily, 2-3 hours before bedtime
Overall Study Adverse Event	2	5	2
Overall Study Lack of Efficacy	0	0	1
Overall Study Protocol Violation	1	0	0
Overall Study Investigator's judgement	2	0	0

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	Pramipexole 0.25mg Group n=48 Participants Double-blind period: 0.25 mg randomised group Administration as follows: Week 1: 1 tablet of 0.125mg Pramipexole once daily Week 2: 2 tablets of 0.125mg Pramipexole once daily Week 3: 2 tablets of 0.125mg Pramipexole + 2 tablets of the matching placebo once daily Week 4-6: 2 tablets of 0.125mg Pramipexole + 4 tablets of the matching placebo once daily Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.5mg Group n=53 Participants Double-blind period: 0.5 mg randomised group Administration as follows: Week 1: 1 tablet of 0.125mg Pramipexole once daily Week 2: 2 tablets of 0.125mg Pramipexole once daily Week 3: 4 tablets of 0.125mg Pramipexole once daily Week 4-6: 4 tablets of 0.125mg Pramipexole + 2 tablets of the matching placebo once daily Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.75mg Group n=53 Participants Double-blind period: 0.75 mg randomised group Administration as follows: Week 1: 1 tablet of 0.125mg Pramipexole once daily Week 2: 2 tablets of 0.125mg Pramipexole once daily Week 3: 4 tablets of 0.125mg Pramipexole once daily Week 4-6: 6 tablets of 0.125mg Pramipexole once daily Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Total n=154 Participants Total of all reporting groups
Age, Continuous	52.5 years STANDARD_DEVIATION 13.9 • n=5 Participants	52.4 years STANDARD_DEVIATION 12.9 • n=7 Participants	54.3 years STANDARD_DEVIATION 14.4 • n=5 Participants	53.1 years STANDARD_DEVIATION 13.7 • n=4 Participants
Sex: Female, Male Female	30 Participants n=5 Participants	27 Participants n=7 Participants	32 Participants n=5 Participants	89 Participants n=4 Participants
Sex: Female, Male Male	18 Participants n=5 Participants	26 Participants n=7 Participants	21 Participants n=5 Participants	65 Participants n=4 Participants

PRIMARY outcome

Timeframe: Week 6 - change from baseline

Population: Full Analysis Set (FAS).

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.

Outcome measures

Measure	Pramipexole 0.25mg Group n=53 Participants Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. The end-of-trial dosage was 0.25 mg. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.50mg Group n=53 Participants Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. The end-of-trial dosage was 0.5 mg. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.75mg Group Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. The end-of-trial dosage was 0.75 mg. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.25mg Group n=48 Participants Double-blind period: 0.25 mg randomised group Administration as follows: Week 1: 1 tablet of 0.125mg Pramipexole once daily Week 2: 2 tablets of 0.125mg Pramipexole once daily Week 3: 2 tablets of 0.125mg Pramipexole + 2 tablets of the matching placebo once daily Week 4-6: 2 tablets of 0.125mg Pramipexole + 4 tablets of the matching placebo once daily Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. mode of administration.: Oral, once daily, 2-3 hours before bedtime
Change From Baseline in International Restless Legs Syndrome (IRLS) Total Score at 6 Weeks	-12.5 Points on a scale Standard Error 1.1	-11.8 Points on a scale Standard Error 1.1	—	-12.3 Points on a scale Standard Error 1.1

SECONDARY outcome

Timeframe: baseline to week 6

Population: Full Analysis Set (FAS).

The percentage of patients with 50 % or more reduction of IRLS (The measure means the percentage of high responder on the trial medications)

Outcome measures

Measure	Pramipexole 0.25mg Group n=53 Participants Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. The end-of-trial dosage was 0.25 mg. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.50mg Group n=53 Participants Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. The end-of-trial dosage was 0.5 mg. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.75mg Group Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. The end-of-trial dosage was 0.75 mg. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.25mg Group n=48 Participants Double-blind period: 0.25 mg randomised group Administration as follows: Week 1: 1 tablet of 0.125mg Pramipexole once daily Week 2: 2 tablets of 0.125mg Pramipexole once daily Week 3: 2 tablets of 0.125mg Pramipexole + 2 tablets of the matching placebo once daily Week 4-6: 2 tablets of 0.125mg Pramipexole + 4 tablets of the matching placebo once daily Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. mode of administration.: Oral, once daily, 2-3 hours before bedtime
IRLS Responder	58.5 Percentage of patients	49.1 Percentage of patients	—	60.4 Percentage of patients

SECONDARY outcome

Timeframe: Week 6 - change from baseline

Population: Full Analysis Set (FAS).

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).

Outcome measures

Measure	Pramipexole 0.25mg Group n=50 Participants Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. The end-of-trial dosage was 0.25 mg. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.50mg Group n=48 Participants Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. The end-of-trial dosage was 0.5 mg. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.75mg Group Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. The end-of-trial dosage was 0.75 mg. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.25mg Group n=46 Participants Double-blind period: 0.25 mg randomised group Administration as follows: Week 1: 1 tablet of 0.125mg Pramipexole once daily Week 2: 2 tablets of 0.125mg Pramipexole once daily Week 3: 2 tablets of 0.125mg Pramipexole + 2 tablets of the matching placebo once daily Week 4-6: 2 tablets of 0.125mg Pramipexole + 4 tablets of the matching placebo once daily Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. mode of administration.: Oral, once daily, 2-3 hours before bedtime
Change From Baseline in Pittsburgh Sleep Quality Index (PSQI) Total Score at 6 Weeks	-3.2 Points on a scale Standard Error 0.4	-2.5 Points on a scale Standard Error 0.4	—	-3.2 Points on a scale Standard Error 0.4

SECONDARY outcome

Timeframe: Week 6 - change from baseline

Population: Full Analysis Set (FAS).

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)

Outcome measures

Measure	Pramipexole 0.25mg Group n=53 Participants Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. The end-of-trial dosage was 0.25 mg. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.50mg Group n=53 Participants Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. The end-of-trial dosage was 0.5 mg. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.75mg Group Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. The end-of-trial dosage was 0.75 mg. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.25mg Group n=48 Participants Double-blind period: 0.25 mg randomised group Administration as follows: Week 1: 1 tablet of 0.125mg Pramipexole once daily Week 2: 2 tablets of 0.125mg Pramipexole once daily Week 3: 2 tablets of 0.125mg Pramipexole + 2 tablets of the matching placebo once daily Week 4-6: 2 tablets of 0.125mg Pramipexole + 4 tablets of the matching placebo once daily Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. mode of administration.: Oral, once daily, 2-3 hours before bedtime
Change From Baseline in Japanese Version of the Epworth Sleepiness Scale (JESS) Total Score at 6 Weeks	-3.0 Points on a scale Standard Error 0.5	-2.3 Points on a scale Standard Error 0.6	—	-2.6 Points on a scale Standard Error 0.6

SECONDARY outcome

Timeframe: baseline to week 6

Population: Full Analysis Set (FAS).

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.

Outcome measures

Measure	Pramipexole 0.25mg Group n=53 Participants Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. The end-of-trial dosage was 0.25 mg. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.50mg Group n=53 Participants Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. The end-of-trial dosage was 0.5 mg. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.75mg Group Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. The end-of-trial dosage was 0.75 mg. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.25mg Group n=48 Participants Double-blind period: 0.25 mg randomised group Administration as follows: Week 1: 1 tablet of 0.125mg Pramipexole once daily Week 2: 2 tablets of 0.125mg Pramipexole once daily Week 3: 2 tablets of 0.125mg Pramipexole + 2 tablets of the matching placebo once daily Week 4-6: 2 tablets of 0.125mg Pramipexole + 4 tablets of the matching placebo once daily Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. mode of administration.: Oral, once daily, 2-3 hours before bedtime
Clinical Global Impression Global Improvement (CGI-I) Responder	75.5 Percentage of patients	69.8 Percentage of patients	—	77.1 Percentage of patients

SECONDARY outcome

Timeframe: baseline to week 6

Population: Full Analysis Set (FAS).

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.

Outcome measures

Measure	Pramipexole 0.25mg Group n=53 Participants Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. The end-of-trial dosage was 0.25 mg. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.50mg Group n=53 Participants Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. The end-of-trial dosage was 0.5 mg. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.75mg Group Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. The end-of-trial dosage was 0.75 mg. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.25mg Group n=48 Participants Double-blind period: 0.25 mg randomised group Administration as follows: Week 1: 1 tablet of 0.125mg Pramipexole once daily Week 2: 2 tablets of 0.125mg Pramipexole once daily Week 3: 2 tablets of 0.125mg Pramipexole + 2 tablets of the matching placebo once daily Week 4-6: 2 tablets of 0.125mg Pramipexole + 4 tablets of the matching placebo once daily Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. mode of administration.: Oral, once daily, 2-3 hours before bedtime
Patient Global Impression (PGI) Responder	79.2 Percentage of patients	67.9 Percentage of patients	—	72.9 Percentage of patients

SECONDARY outcome

Timeframe: baseline to 6 weeks

Outcome measures

Measure	Pramipexole 0.25mg Group n=53 Participants Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. The end-of-trial dosage was 0.25 mg. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.50mg Group n=53 Participants Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. The end-of-trial dosage was 0.5 mg. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.75mg Group Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. The end-of-trial dosage was 0.75 mg. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.25mg Group n=48 Participants Double-blind period: 0.25 mg randomised group Administration as follows: Week 1: 1 tablet of 0.125mg Pramipexole once daily Week 2: 2 tablets of 0.125mg Pramipexole once daily Week 3: 2 tablets of 0.125mg Pramipexole + 2 tablets of the matching placebo once daily Week 4-6: 2 tablets of 0.125mg Pramipexole + 4 tablets of the matching placebo once daily Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. mode of administration.: Oral, once daily, 2-3 hours before bedtime
Clinically Significant Abnormalities in Vital Signs (Blood Pressure and Pulse Rate in Both Supine and Standing Positions), ECG, Laboratory Tests - Double Blind Period. Blood pressure increased	1 participants	0 participants	—	0 participants
Clinically Significant Abnormalities in Vital Signs (Blood Pressure and Pulse Rate in Both Supine and Standing Positions), ECG, Laboratory Tests - Double Blind Period. Cardiovascular disorder	0 participants	1 participants	—	0 participants

SECONDARY outcome

Timeframe: Week 52 - change from baseline

Population: Full Analysis Set (FAS).

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).

Outcome measures

Measure	Pramipexole 0.25mg Group n=40 Participants Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. The end-of-trial dosage was 0.25 mg. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.50mg Group n=50 Participants Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. The end-of-trial dosage was 0.5 mg. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.75mg Group n=25 Participants Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. The end-of-trial dosage was 0.75 mg. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.25mg Group n=4 Participants Double-blind period: 0.25 mg randomised group Administration as follows: Week 1: 1 tablet of 0.125mg Pramipexole once daily Week 2: 2 tablets of 0.125mg Pramipexole once daily Week 3: 2 tablets of 0.125mg Pramipexole + 2 tablets of the matching placebo once daily Week 4-6: 2 tablets of 0.125mg Pramipexole + 4 tablets of the matching placebo once daily Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. mode of administration.: Oral, once daily, 2-3 hours before bedtime
Change From Baseline in International Restless Legs Syndrome (IRLS) Total Score at 52 Weeks for Open-Label Period	-17.3 Points on a scale Standard Deviation 5.8	-18.3 Points on a scale Standard Deviation 6.1	-14.8 Points on a scale Standard Deviation 8.9	-18.5 Points on a scale Standard Deviation 5.8

SECONDARY outcome

Timeframe: baseline to week 52

Population: Full Analysis Set (FAS).

The percentage of patients with 50 % or more reduction of IRLS (The measure means the percentage of high responder on the trial medications)

Outcome measures

Measure	Pramipexole 0.25mg Group n=40 Participants Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. The end-of-trial dosage was 0.25 mg. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.50mg Group n=50 Participants Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. The end-of-trial dosage was 0.5 mg. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.75mg Group n=25 Participants Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. The end-of-trial dosage was 0.75 mg. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.25mg Group n=4 Participants Double-blind period: 0.25 mg randomised group Administration as follows: Week 1: 1 tablet of 0.125mg Pramipexole once daily Week 2: 2 tablets of 0.125mg Pramipexole once daily Week 3: 2 tablets of 0.125mg Pramipexole + 2 tablets of the matching placebo once daily Week 4-6: 2 tablets of 0.125mg Pramipexole + 4 tablets of the matching placebo once daily Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. mode of administration.: Oral, once daily, 2-3 hours before bedtime
IRLS Responder for Open-label Period	90.0 Percentage of patients	92.0 Percentage of patients	68.0 Percentage of patients	100.0 Percentage of patients

SECONDARY outcome

Timeframe: Week 52 - change from baseline

Population: Full Analysis Set (FAS).

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).

Outcome measures

Measure	Pramipexole 0.25mg Group n=39 Participants Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. The end-of-trial dosage was 0.25 mg. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.50mg Group n=49 Participants Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. The end-of-trial dosage was 0.5 mg. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.75mg Group n=25 Participants Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. The end-of-trial dosage was 0.75 mg. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.25mg Group n=4 Participants Double-blind period: 0.25 mg randomised group Administration as follows: Week 1: 1 tablet of 0.125mg Pramipexole once daily Week 2: 2 tablets of 0.125mg Pramipexole once daily Week 3: 2 tablets of 0.125mg Pramipexole + 2 tablets of the matching placebo once daily Week 4-6: 2 tablets of 0.125mg Pramipexole + 4 tablets of the matching placebo once daily Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. mode of administration.: Oral, once daily, 2-3 hours before bedtime
Change From Baseline in Pittsburgh Sleep Quality Index (PSQI) Total Score at 52 Weeks for Open-Label Period	-3.3 Points on a scale Standard Deviation 3.3	-3.3 Points on a scale Standard Deviation 3.3	-2.4 Points on a scale Standard Deviation 3.8	-4.0 Points on a scale Standard Deviation 2.4

SECONDARY outcome

Timeframe: Week 52 - change from baseline

Population: Full Analysis Set (FAS).

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)

Outcome measures

Measure	Pramipexole 0.25mg Group n=40 Participants Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. The end-of-trial dosage was 0.25 mg. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.50mg Group n=50 Participants Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. The end-of-trial dosage was 0.5 mg. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.75mg Group n=25 Participants Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. The end-of-trial dosage was 0.75 mg. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.25mg Group n=4 Participants Double-blind period: 0.25 mg randomised group Administration as follows: Week 1: 1 tablet of 0.125mg Pramipexole once daily Week 2: 2 tablets of 0.125mg Pramipexole once daily Week 3: 2 tablets of 0.125mg Pramipexole + 2 tablets of the matching placebo once daily Week 4-6: 2 tablets of 0.125mg Pramipexole + 4 tablets of the matching placebo once daily Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. mode of administration.: Oral, once daily, 2-3 hours before bedtime
Change From Baseline in Japanese Version of the Epworth Sleepiness Scale (JESS) Total Score at 52 Weeks for Open-Label Period	-3.8 Points on a scale Standard Deviation 4.3	-4.4 Points on a scale Standard Deviation 4.7	-2.6 Points on a scale Standard Deviation 5.7	-9.5 Points on a scale Standard Deviation 2.9

SECONDARY outcome

Timeframe: baseline to week 52

Population: Full Analysis Set (FAS).

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.

Outcome measures

Measure	Pramipexole 0.25mg Group n=40 Participants Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. The end-of-trial dosage was 0.25 mg. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.50mg Group n=50 Participants Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. The end-of-trial dosage was 0.5 mg. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.75mg Group n=25 Participants Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. The end-of-trial dosage was 0.75 mg. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.25mg Group n=4 Participants Double-blind period: 0.25 mg randomised group Administration as follows: Week 1: 1 tablet of 0.125mg Pramipexole once daily Week 2: 2 tablets of 0.125mg Pramipexole once daily Week 3: 2 tablets of 0.125mg Pramipexole + 2 tablets of the matching placebo once daily Week 4-6: 2 tablets of 0.125mg Pramipexole + 4 tablets of the matching placebo once daily Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. mode of administration.: Oral, once daily, 2-3 hours before bedtime
Clinical Global Impression Global Improvement (CGI-I) Responder at 52 Weeks for Open-label Period	95.0 Percentage of patients	98.0 Percentage of patients	84.0 Percentage of patients	100.0 Percentage of patients

SECONDARY outcome

Timeframe: baseline to week 52

Population: Full Analysis Set (FAS).

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.

Outcome measures

Measure	Pramipexole 0.25mg Group n=40 Participants Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. The end-of-trial dosage was 0.25 mg. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.50mg Group n=50 Participants Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. The end-of-trial dosage was 0.5 mg. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.75mg Group n=25 Participants Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. The end-of-trial dosage was 0.75 mg. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.25mg Group n=4 Participants Double-blind period: 0.25 mg randomised group Administration as follows: Week 1: 1 tablet of 0.125mg Pramipexole once daily Week 2: 2 tablets of 0.125mg Pramipexole once daily Week 3: 2 tablets of 0.125mg Pramipexole + 2 tablets of the matching placebo once daily Week 4-6: 2 tablets of 0.125mg Pramipexole + 4 tablets of the matching placebo once daily Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. mode of administration.: Oral, once daily, 2-3 hours before bedtime
Patient Global Impression (PGI) Responder at 52 Weeks for Open-Label Period	97.5 Percentage of patients	94.0 Percentage of patients	80.0 Percentage of patients	100.0 Percentage of patients

SECONDARY outcome

Timeframe: baseline to week 52

Population: Full Analysis Set (FAS).

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

Outcome measures

Measure	Pramipexole 0.25mg Group n=40 Participants Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. The end-of-trial dosage was 0.25 mg. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.50mg Group n=50 Participants Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. The end-of-trial dosage was 0.5 mg. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.75mg Group n=25 Participants Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. The end-of-trial dosage was 0.75 mg. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.25mg Group n=4 Participants Double-blind period: 0.25 mg randomised group Administration as follows: Week 1: 1 tablet of 0.125mg Pramipexole once daily Week 2: 2 tablets of 0.125mg Pramipexole once daily Week 3: 2 tablets of 0.125mg Pramipexole + 2 tablets of the matching placebo once daily Week 4-6: 2 tablets of 0.125mg Pramipexole + 4 tablets of the matching placebo once daily Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. mode of administration.: Oral, once daily, 2-3 hours before bedtime
Possible Augmentation in RLS Symptoms at 52 Weeks for Open-Label Period	0.0 Percentage of patients	0.0 Percentage of patients	0.0 Percentage of patients	0.0 Percentage of patients

Adverse Events

Pramipexole 0.25mg (Double-blind)

Serious events: 0 serious events

Other events: 32 other events

Deaths: 0 deaths

Pramipexole 0.50mg (Double-blind)

Serious events: 2 serious events

Other events: 42 other events

Deaths: 0 deaths

Pramipexole 0.75mg (Double-blind)

Serious events: 0 serious events

Other events: 42 other events

Deaths: 0 deaths

Pramipexole 0.125mg (Open Label)

Serious events: 1 serious events

Other events: 5 other events

Deaths: 0 deaths

Pramipexole 0.25mg (Open Label)

Serious events: 5 serious events

Other events: 58 other events

Deaths: 0 deaths

Pramipexole 0.50mg (Open Label)

Serious events: 0 serious events

Other events: 50 other events

Deaths: 0 deaths

Pramipexole 0.75mg (Open Label)

Serious events: 0 serious events

Other events: 29 other events

Deaths: 0 deaths

Serious adverse events

Measure	Pramipexole 0.25mg (Double-blind) n=48 participants at risk Double-blind period: 0.25 mg randomised group. Administration as follows: Week 1: 1 tablet of 0.125mg Pramipexole once daily Week 2: 2 tablets of 0.125mg Pramipexole once daily Week 3: 2 tablets of 0.125mg Pramipexole + 2 tablets of the matching placebo once daily Week 4-6: 2 tablets of 0.125mg Pramipexole + 4 tablets of the matching placebo once daily	Pramipexole 0.50mg (Double-blind) n=53 participants at risk Double-blind period: 0.5 mg randomised group Administration as follows: Week 1: 1 tablet of 0.125mg Pramipexole once daily Week 2: 2 tablets of 0.125mg Pramipexole once daily Week 3: 4 tablets of 0.125mg Pramipexole once daily Week 4-6: 4 tablets of 0.125mg Pramipexole + 2 tablets of the matching placebo once daily	Pramipexole 0.75mg (Double-blind) n=53 participants at risk Double-blind period: 0.75 mg randomised group Administration as follows: Week 1: 1 tablet of 0.125mg Pramipexole once daily Week 2: 2 tablets of 0.125mg Pramipexole once daily Week 3: 4 tablets of 0.125mg Pramipexole once daily Week 4-6: 6 tablets of 0.125mg Pramipexole once daily	Pramipexole 0.125mg (Open Label) n=8 participants at risk Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. The end-of-trial dosage was 0.125 mg. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.25mg (Open Label) n=140 participants at risk Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. The end-of-trial dosage was 0.25 mg. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.50mg (Open Label) n=97 participants at risk Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. The end-of-trial dosage was 0.5 mg. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.75mg (Open Label) n=41 participants at risk Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. The end-of-trial dosage was 0.75 mg. mode of administration.: Oral, once daily, 2-3 hours before bedtime
Infections and infestations Gastroenteritis bacterial	0.00% 0/48 • From the first dose of trial medication onwards through the observational phase (52 weeks).	1.9% 1/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/8 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/140 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/97 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/41 • From the first dose of trial medication onwards through the observational phase (52 weeks).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Colon cancer	0.00% 0/48 • From the first dose of trial medication onwards through the observational phase (52 weeks).	1.9% 1/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/8 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/140 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/97 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/41 • From the first dose of trial medication onwards through the observational phase (52 weeks).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer	0.00% 0/48 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/8 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.71% 1/140 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/97 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/41 • From the first dose of trial medication onwards through the observational phase (52 weeks).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Hepatic neoplasm malignant	0.00% 0/48 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/8 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.71% 1/140 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/97 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/41 • From the first dose of trial medication onwards through the observational phase (52 weeks).
Eye disorders Maculopathy	0.00% 0/48 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/8 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.71% 1/140 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/97 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/41 • From the first dose of trial medication onwards through the observational phase (52 weeks).
Respiratory, thoracic and mediastinal disorders Asthma	0.00% 0/48 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	12.5% 1/8 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/140 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/97 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/41 • From the first dose of trial medication onwards through the observational phase (52 weeks).
Gastrointestinal disorders Pancreatitis acute	0.00% 0/48 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/8 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.71% 1/140 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/97 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/41 • From the first dose of trial medication onwards through the observational phase (52 weeks).
Injury, poisoning and procedural complications Fall	0.00% 0/48 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/8 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.71% 1/140 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/97 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/41 • From the first dose of trial medication onwards through the observational phase (52 weeks).
Injury, poisoning and procedural complications Spinal compression fracture	0.00% 0/48 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/8 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.71% 1/140 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/97 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/41 • From the first dose of trial medication onwards through the observational phase (52 weeks).

Other adverse events

Measure	Pramipexole 0.25mg (Double-blind) n=48 participants at risk Double-blind period: 0.25 mg randomised group. Administration as follows: Week 1: 1 tablet of 0.125mg Pramipexole once daily Week 2: 2 tablets of 0.125mg Pramipexole once daily Week 3: 2 tablets of 0.125mg Pramipexole + 2 tablets of the matching placebo once daily Week 4-6: 2 tablets of 0.125mg Pramipexole + 4 tablets of the matching placebo once daily	Pramipexole 0.50mg (Double-blind) n=53 participants at risk Double-blind period: 0.5 mg randomised group Administration as follows: Week 1: 1 tablet of 0.125mg Pramipexole once daily Week 2: 2 tablets of 0.125mg Pramipexole once daily Week 3: 4 tablets of 0.125mg Pramipexole once daily Week 4-6: 4 tablets of 0.125mg Pramipexole + 2 tablets of the matching placebo once daily	Pramipexole 0.75mg (Double-blind) n=53 participants at risk Double-blind period: 0.75 mg randomised group Administration as follows: Week 1: 1 tablet of 0.125mg Pramipexole once daily Week 2: 2 tablets of 0.125mg Pramipexole once daily Week 3: 4 tablets of 0.125mg Pramipexole once daily Week 4-6: 6 tablets of 0.125mg Pramipexole once daily	Pramipexole 0.125mg (Open Label) n=8 participants at risk Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. The end-of-trial dosage was 0.125 mg. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.25mg (Open Label) n=140 participants at risk Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. The end-of-trial dosage was 0.25 mg. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.50mg (Open Label) n=97 participants at risk Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. The end-of-trial dosage was 0.5 mg. mode of administration.: Oral, once daily, 2-3 hours before bedtime	Pramipexole 0.75mg (Open Label) n=41 participants at risk Open-label period: Administration of pramipexole was started at 0.25 mg/day at Week 6 (Visit 5, the last observation day in the double-blind period). Subsequently, the Patient Global Impression (PGI) and tolerability was assessed from Visit 6 and if required, the investigator or subinvestigator determined whether to increase the daily dose to 0.5 mg and then to 0.75 mg/day every two weeks. After checking the PGI and tolerability at each visit, the investigator or sub-investigator determined dose increase, maintenance or reduction. The end-of-trial dosage was 0.75 mg. mode of administration.: Oral, once daily, 2-3 hours before bedtime
Eye disorders Conjunctivitis	0.00% 0/48 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	12.5% 1/8 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.71% 1/140 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/97 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/41 • From the first dose of trial medication onwards through the observational phase (52 weeks).
Ear and labyrinth disorders Eustachian tube stenosis	0.00% 0/48 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	12.5% 1/8 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/140 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/97 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/41 • From the first dose of trial medication onwards through the observational phase (52 weeks).
Cardiac disorders Palpitations	6.2% 3/48 • From the first dose of trial medication onwards through the observational phase (52 weeks).	5.7% 3/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	1.9% 1/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/8 • From the first dose of trial medication onwards through the observational phase (52 weeks).	1.4% 2/140 • From the first dose of trial medication onwards through the observational phase (52 weeks).	2.1% 2/97 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/41 • From the first dose of trial medication onwards through the observational phase (52 weeks).
Gastrointestinal disorders Constipation	14.6% 7/48 • From the first dose of trial medication onwards through the observational phase (52 weeks).	5.7% 3/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	5.7% 3/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/8 • From the first dose of trial medication onwards through the observational phase (52 weeks).	2.9% 4/140 • From the first dose of trial medication onwards through the observational phase (52 weeks).	1.0% 1/97 • From the first dose of trial medication onwards through the observational phase (52 weeks).	4.9% 2/41 • From the first dose of trial medication onwards through the observational phase (52 weeks).
Gastrointestinal disorders Dyspepsia	4.2% 2/48 • From the first dose of trial medication onwards through the observational phase (52 weeks).	5.7% 3/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	1.9% 1/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/8 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/140 • From the first dose of trial medication onwards through the observational phase (52 weeks).	2.1% 2/97 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/41 • From the first dose of trial medication onwards through the observational phase (52 weeks).
Gastrointestinal disorders Nausea	12.5% 6/48 • From the first dose of trial medication onwards through the observational phase (52 weeks).	41.5% 22/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	47.2% 25/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	12.5% 1/8 • From the first dose of trial medication onwards through the observational phase (52 weeks).	7.9% 11/140 • From the first dose of trial medication onwards through the observational phase (52 weeks).	15.5% 15/97 • From the first dose of trial medication onwards through the observational phase (52 weeks).	26.8% 11/41 • From the first dose of trial medication onwards through the observational phase (52 weeks).
Gastrointestinal disorders Stomach discomfort	4.2% 2/48 • From the first dose of trial medication onwards through the observational phase (52 weeks).	7.5% 4/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	7.5% 4/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/8 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.71% 1/140 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/97 • From the first dose of trial medication onwards through the observational phase (52 weeks).	2.4% 1/41 • From the first dose of trial medication onwards through the observational phase (52 weeks).
Gastrointestinal disorders Vomiting	0.00% 0/48 • From the first dose of trial medication onwards through the observational phase (52 weeks).	7.5% 4/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	9.4% 5/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	12.5% 1/8 • From the first dose of trial medication onwards through the observational phase (52 weeks).	2.1% 3/140 • From the first dose of trial medication onwards through the observational phase (52 weeks).	5.2% 5/97 • From the first dose of trial medication onwards through the observational phase (52 weeks).	9.8% 4/41 • From the first dose of trial medication onwards through the observational phase (52 weeks).
Gastrointestinal disorders Abdomial pain upper	2.1% 1/48 • From the first dose of trial medication onwards through the observational phase (52 weeks).	3.8% 2/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	1.9% 1/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	12.5% 1/8 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.71% 1/140 • From the first dose of trial medication onwards through the observational phase (52 weeks).	4.1% 4/97 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/41 • From the first dose of trial medication onwards through the observational phase (52 weeks).
Gastrointestinal disorders Diarrhoea	2.1% 1/48 • From the first dose of trial medication onwards through the observational phase (52 weeks).	1.9% 1/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	1.9% 1/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	12.5% 1/8 • From the first dose of trial medication onwards through the observational phase (52 weeks).	2.1% 3/140 • From the first dose of trial medication onwards through the observational phase (52 weeks).	2.1% 2/97 • From the first dose of trial medication onwards through the observational phase (52 weeks).	4.9% 2/41 • From the first dose of trial medication onwards through the observational phase (52 weeks).
Gastrointestinal disorders Hyperchlorhydria	0.00% 0/48 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	12.5% 1/8 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/140 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/97 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/41 • From the first dose of trial medication onwards through the observational phase (52 weeks).
Musculoskeletal and connective tissue disorders Arthralgia	2.1% 1/48 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	1.9% 1/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	12.5% 1/8 • From the first dose of trial medication onwards through the observational phase (52 weeks).	1.4% 2/140 • From the first dose of trial medication onwards through the observational phase (52 weeks).	3.1% 3/97 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/41 • From the first dose of trial medication onwards through the observational phase (52 weeks).
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/48 • From the first dose of trial medication onwards through the observational phase (52 weeks).	1.9% 1/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	1.9% 1/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	12.5% 1/8 • From the first dose of trial medication onwards through the observational phase (52 weeks).	1.4% 2/140 • From the first dose of trial medication onwards through the observational phase (52 weeks).	2.1% 2/97 • From the first dose of trial medication onwards through the observational phase (52 weeks).	4.9% 2/41 • From the first dose of trial medication onwards through the observational phase (52 weeks).
General disorders Thirst	0.00% 0/48 • From the first dose of trial medication onwards through the observational phase (52 weeks).	3.8% 2/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	7.5% 4/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/8 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/140 • From the first dose of trial medication onwards through the observational phase (52 weeks).	1.0% 1/97 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/41 • From the first dose of trial medication onwards through the observational phase (52 weeks).
General disorders Pyrexia	4.2% 2/48 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	12.5% 1/8 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.71% 1/140 • From the first dose of trial medication onwards through the observational phase (52 weeks).	2.1% 2/97 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/41 • From the first dose of trial medication onwards through the observational phase (52 weeks).
Infections and infestations Nasopharyngitis	12.5% 6/48 • From the first dose of trial medication onwards through the observational phase (52 weeks).	24.5% 13/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	11.3% 6/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	50.0% 4/8 • From the first dose of trial medication onwards through the observational phase (52 weeks).	22.9% 32/140 • From the first dose of trial medication onwards through the observational phase (52 weeks).	29.9% 29/97 • From the first dose of trial medication onwards through the observational phase (52 weeks).	34.1% 14/41 • From the first dose of trial medication onwards through the observational phase (52 weeks).
Infections and infestations Gastroenteritis	2.1% 1/48 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	1.9% 1/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	12.5% 1/8 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/140 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/97 • From the first dose of trial medication onwards through the observational phase (52 weeks).	2.4% 1/41 • From the first dose of trial medication onwards through the observational phase (52 weeks).
Infections and infestations Sinusitis	0.00% 0/48 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	12.5% 1/8 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.71% 1/140 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/97 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/41 • From the first dose of trial medication onwards through the observational phase (52 weeks).
Metabolism and nutrition disorders Hyperkalaemia	0.00% 0/48 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	12.5% 1/8 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/140 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/97 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/41 • From the first dose of trial medication onwards through the observational phase (52 weeks).
Psychiatric disorders Nightmare	0.00% 0/48 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	7.5% 4/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/8 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.71% 1/140 • From the first dose of trial medication onwards through the observational phase (52 weeks).	1.0% 1/97 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/41 • From the first dose of trial medication onwards through the observational phase (52 weeks).
Nervous system disorders Dizziness	4.2% 2/48 • From the first dose of trial medication onwards through the observational phase (52 weeks).	5.7% 3/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	7.5% 4/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	12.5% 1/8 • From the first dose of trial medication onwards through the observational phase (52 weeks).	1.4% 2/140 • From the first dose of trial medication onwards through the observational phase (52 weeks).	5.2% 5/97 • From the first dose of trial medication onwards through the observational phase (52 weeks).	2.4% 1/41 • From the first dose of trial medication onwards through the observational phase (52 weeks).
Nervous system disorders Headache	10.4% 5/48 • From the first dose of trial medication onwards through the observational phase (52 weeks).	18.9% 10/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	3.8% 2/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/8 • From the first dose of trial medication onwards through the observational phase (52 weeks).	7.9% 11/140 • From the first dose of trial medication onwards through the observational phase (52 weeks).	4.1% 4/97 • From the first dose of trial medication onwards through the observational phase (52 weeks).	7.3% 3/41 • From the first dose of trial medication onwards through the observational phase (52 weeks).
Nervous system disorders Somnolence	20.8% 10/48 • From the first dose of trial medication onwards through the observational phase (52 weeks).	28.3% 15/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	17.0% 9/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/8 • From the first dose of trial medication onwards through the observational phase (52 weeks).	6.4% 9/140 • From the first dose of trial medication onwards through the observational phase (52 weeks).	11.3% 11/97 • From the first dose of trial medication onwards through the observational phase (52 weeks).	7.3% 3/41 • From the first dose of trial medication onwards through the observational phase (52 weeks).
Nervous system disorders Dysgeusia	0.00% 0/48 • From the first dose of trial medication onwards through the observational phase (52 weeks).	1.9% 1/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/53 • From the first dose of trial medication onwards through the observational phase (52 weeks).	12.5% 1/8 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/140 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/97 • From the first dose of trial medication onwards through the observational phase (52 weeks).	0.00% 0/41 • From the first dose of trial medication onwards through the observational phase (52 weeks).

Additional Information

Boehringer Ingelheim Pharmaceuticals

Boehringer Ingelheim Pharmaceuticals

Phone: 1-800-243-0127

Email: clintriage.rdg@boehringer-ingelheim.com

Results disclosure agreements

• Principal investigator is a sponsor employee 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.
• Publication restrictions are in place

Restriction type: OTHER