The objective of this trial is to investigate efficacy and safety of pramipexole (BI•Sifrol®) (0.125-0.75 mg) orally once daily as compared with placebo for 6 weeks in patients with primary Restless Legs Syndrome.

Condition	Intervention	Phase
Restless Legs Syndrome	Drug: Pramipexole 0.125 mg tablets	Phase II

Further Study Details: 

Primary Outcomes: For primary comparison change from baseline in periodic limb movements during time in bed index (PLMI) in the PSG will be expressed.
Secondary Outcomes: -Total score of RLS severity scale-J by IRLSSG; -Periodic Limb Movements during Sleep Index (PLMSI) in the PSG; -Periodic Limb Movements during Wakefulness Index (PLMWI) in the PSG; -Periodic Limb Movements in Sleep with Arousal Index (PLMAI) in the PSG )
Expected Total Enrollment:  42

The study is a double-blind, placebo-controlled, multi centre, parallel group comparison, forced dose titration trial with maximum 0.75 mg pramipexole (BI•Sifrol®) for 6 weeks in primary RLS. Patients are randomized to either placebo or pramipexole. Pramipexole (BI•Sifrol®) 0.125mg tablet or the matching placebo tablets will be started with 1 tablet orally once daily 2-3 hours before sleep and escalated the dose by 1 week intervals up to a maximum dose of 6 tablets. There are four dose levels (1, 2, 4 and 6 tablets of pramipexole (BI•Sifrol®) 0.125mg tablet or the matching placebo tablet; 0.125, 0.25, 0.5 and 0.75 mg for pramipexole (BI•Sifrol®) group). The dose for all patients should be escalated to 6 tablets of pramipexole (BI•Sifrol®) 0.125mg tablet or the matching placebo tablet (0.75 mg for pramipexole group) unless any adverse event occurs, even if investigator finds any efficacy with lower doses

The hypothesis is that pramipexole (BI•Sifrol®) is significantly different from that of placebo in the change from baseline in periodic limb movements during time in bed index (PLMI) in the PSG.

For primary comparison change from baseline in periodic limb movements during time in bed index (PLMI) in the PSG will be expressed.

Ages Eligible for Study:  20 Years   -   80 Years,  Genders Eligible for Study:  Both

Criteria

Inclusion Criteria:

According to the essential diagnostic criteria for RLS of NIH and IRLSSG, the following four all criterias must be presented:

1. An urge to move the legs, usually accompanied or caused by uncomfortable and unpleasant sensations in legs
2. The urge to move or unpleasant sensations begin or worsen during periods of rest or inactivity such as lying or sitting
3. The urge to move or unpleasant sensations are partially or totally relieved by movement, such as walking or stretching, at least as long as the activity continues

4. The urge to move or unpleasant sensations are worse in the evening or night than during the day or only occur in the evening or night

   • PLM (during time in bed) index of at least 5 per hour (in the worst affected leg) at Visit 3
   • Total score of RLS severity scale-Japanese version by IRLSSG > 15 at Visit 3
   • At least 1 time per week of RLS symptoms interfering with sleep within the last one month at Visit 1.

   Exclusion Criteria:

   1)Pre-menopausal women who meet any one of the following (1) – (3):

   1. Pregnant or possibly pregnant
   2. In lactation
   3. Desire to be pregnant during study period Even when a patient was confirmed not to fall under the criteria above at initiation of study, if the patient is of childbearing potential, pregnancy tests should be performed when possible. If pregnancy test is positive, the investigational product should be discontinued.

   2)Males not using an adequate form of contraception. 3)Patients who took the neuroleptics within 4 weeks before the screening Visit 1, or neuroleptic-induced akathisia.

   4)Patients who can not stop the treatment with medication or dietary supplements, which could significantly influence RLS symptoms to wash-out at least 14 days before drug administration (refer to Appendix 3 for prohibited medication), e.g. dopaminergic drugs (levodopa or dopamine agonists) or antidopaminergic drugs (neuroleptics or metoclopramide etc.), MAO inhibitors, sympathomimetics, antidepressants, hypnotics, any benzodiazepines, antiepileptics, opioids, clonidine, magnesium, ferrous salts, folic acid, vitamin B12, antihistaminics, lithium, melatonin.

   5) Patients with diabetes mellitus requiring insulin therapy. 6) Patients with microcytic anemia at investigators discretion. 7) History or clinical signs of peripheral neuropathy (PNP) of any origin in physical, neurological examination, myelopathy or multiple sclerosis or any other neurological disease, with potential to secondarily cause RLS symptoms.

   8) Other sleep disorder, such as, REM sleep behaviour disorder, narcolepsy or sleep apnea syndrome (with AHI >15 at Visit 3, or a history of loud snoring occurring at least 5 nights a week combined with a history of breathing pauses during sleep and excessive daytime sleepiness).

   9) Clinically significant renal disease or creatinine higher than upper limit of normal (ULN) at screening.

   10) Clinically significant hepatic disease or SGPT > 2 times the upper limit of normal range at screening.

   11) Patients with any clinically significant abnormalities in laboratory parameters at screening at the investigator’s discretion.

   12) Other clinically significant metabolic-endocrine, haematological, gastro-intestinal disease or pulmonary disease. Poorly controlled cardiovascular disease (including hypotension and severe coronary artery disease).

   13) History of schizophrenia or any psychotic disorder, history of mental disorders due to a general medical condition or any present axis I psychiatric disorder according DSM IV requiring any medical therapy.

   14) Patients with alcohol abuse or drug addiction before screening. Current nicotine addiction requiring night time smoking. 15) History of or clinical signs for any form of epilepsy or seizures apart from fever related seizures in early childhood.

   16) History of or clinical signs of malignant neoplasm. 17) Known hypersensitivity to pramipexole. 18) Patients who are unable to follow a regular sleep-wake cycle (a shift-work-schedule etc.), or unable to use study medication at times indicated.

   19) Participation in a drug study within two months prior to the start of this study.

   20) Patients who are not suitable for entering into this study in the opinion of the investigator or the sub-investigator.

Please refer to this study by ClinicalTrials.gov identifier  NCT00152997

Kouji Sha      +81 (72) 790-2447    SHA@kaw.boehringer-ingelheim.com

Japan
      Yoyogi Somnological, Clinic, Somnological centre, Shibuya, Tokyo,  151-0053,  Japan; Recruiting
      Osaka Medical College Hospital, Takatsuki, Osaka,  569-0801,  Japan; Recruiting
      Hannan Hospital, Sakai, Osaka,  599-8263,  Japan; Recruiting
      Kurume University Hospital, Kurume, Fukuoka,  830-0011,  Japan; Recruiting
      Kochi Kagamingawa Hospital, Somnological center, Kochi, Kochi,  780-8037,  Japan; Recruiting
      Akita University Hospital, Akita, Akita,  010-0000,  Japan; Recruiting
      Wellness Bouyoudai Clinic, Otaru, Hokkaido,  047-0155,  Japan; Recruiting

Study chairs or principal investigators

Kouji Sha,  Study Chair,  Nippon Boehringer/Kawanishi   

Study ID Numbers:  248.557
Last Updated:  September 9, 2005
Record first received:  September 9, 2005
ClinicalTrials.gov Identifier:  NCT00152997
Health Authority: Japan: Ministry of Health, Labor and Welfare
ClinicalTrials.gov processed this record on 2005-09-13