A dose-ranging study of pramipexole for the symptomatic treatment of restless legs syndrome: polysomnographic evaluation of periodic leg movements and sleep disturbance.

OBJECTIVE: To evaluate, both polysomnographically and by subjective scales, the efficacy and safety profile of pramipexole for restless legs syndrome (RLS) via a 3-week, double-blind, placebo-controlled, parallel-group, dose-ranging study. METHODS: At baseline and after 3 weeks, periodic limb movements (PLM) and sleep parameters were assessed by polysomnography, and patients self-assessed their sleep disturbance and overall RLS severity using the international RLS study group rating scale (IRLS). Four pramipexole doses were evaluated: 0.125, 0.25, 0.50, and 0.75mg/d. Data from 107 patients were included in the intent-to-treat (ITT) analysis. RESULTS: For pramipexole recipients, the primary outcome measure, PLM per hour in bed asleep or awake (the PLM index, or PLMI), decreased by a median of -26.55 to -52.70 depending on dosage group, vs. -3.00 for placebo (p<0.01 or 0.001 for each group vs. placebo; Wilcoxon-Mann-Whitney test). Improvements in the secondary endpoints of PLM while asleep and while awake were also significantly superior for pramipexole. At 3 weeks, all pramipexole doses reduced the median for PLM while asleep to levels considered normal (<5PLM/h). Except for delta-sleep time and awakenings/arousals, sleep parameters remained unchanged or favored pramipexole. Median sleep latency was reduced by -5.00 to -11.75min in the pramipexole groups, vs. -2.00 for placebo (p<0.05 for all groups except 0.25mg/d). Median total sleep time increased by 25.75-66.75min, vs. 25.50 (p<0.05 for 0.50mg/d), and median time in stages 2-4/rapid eye movement (REM) sleep increased by 37.00-68.00min, vs. 26.75 (p<0.05 for 0.50mg/d). By subjective IRLS ratings, all pramipexole doses were significantly superior to placebo. Safety analysis demonstrated no dose-dependent increase in adverse events, and no drug-related increase in daytime somnolence was observed. CONCLUSIONS: Pramipexole is effective and well tolerated in RLS, most notably among objective measures, for reducing PLM and decreasing sleep latency. Although other sleep parameters showed lesser, usually insignificant change, patients' subjective ratings of RLS severity and sleep disturbance were significantly improved (p0.0023).

Open-label study of the long-term efficacy and safety of pramipexole in patients with Restless Legs Syndrome (extension of the PRELUDE study).

BACKGROUND AND OBJECTIVE: To demonstrate the long-term efficacy and safety of pramipexole for Restless Legs Syndrome (RLS) using physician and patient RLS ratings, along with subjective assays of sleep parameters, in a 26-week, open-label trial. PATIENTS AND METHODS: Among 107 Finnish adults with moderate to severe RLS, pramipexole initiated at 0.125 mg/day was titrated to a maximum 0.75 mg/day. Efficacy evaluations included the International RLS Study Group Rating Scale (IRLS), Patient Global Impression (PGI) scale, Clinical Global Impressions-Improvement (CGI-I) scale, Epworth Sleepiness Scale (ESS), and Short Form-36 (SF-36) Health Survey. Subjective Sleep Quality was assessed by patient ratings of sleep and morning tiredness. Safety was documented by Adverse Events reported in >5% of patients. RESULTS: The mean reduction in IRLS score was 73.5% (P<0.05). The IRLS responder rate, defined by score reduction of >or= 50%, was 81.3%. On the PGI scale, 89.7% of patients rated themselves as "very much" or "much" better. By CGI-I assessment, 94.8% of patients were considered either "very much" or "much" improved. Mean ESS score showed a modest but statistically significant reduction (P<0.05) within the normal range, indicating that long-term pramipexole did not increase daytime sleepiness. On the SF-36 all 8 domains showed improvement, 5 of them statistically significant (P<0.05) and 4 of these 5 (role-physical, bodily pain, vitality, and role-emotional) by >10 points on a 100-point scale. Subjective Sleep Quality also improved. The most frequent Adverse Events were influenza (17.8%), headache (15.0%), and fatigue (10.3%). CONCLUSION: Pramipexole is well tolerated and effective for long-term treatment of RLS.

Efficacy of pramipexole in restless legs syndrome: a six-week, multicenter, randomized, double-blind study (effect-RLS study).

We evaluated the efficacy of pramipexole versus placebo in restless legs syndrome (RLS) for 6 weeks. Overall, 345 patients were randomly assigned in a 1:2 ratio to receive either placebo (n = 115) or pramipexole (n = 230) with a starting dose of 0.125 mg/day. The dose was individually optimized according to the Patient Global Impression (PGI) assessment, up to a maximum of 0.75 mg/day. The primary endpoint consisted of two assessments: the change from baseline in the International RLS Study Group Rating Scale (IRLS) and the proportion of patients with Clinical Global Impressions-Improvement (CGI-I) assessments of "much/very much improved" (CGI-I responders) at week 6. Secondary endpoints included PGI and IRLS responder rates. Patient demographics and baseline characteristics were comparable between treatment groups. At baseline, mean IRLS scores were 24.9 (placebo) and 24.7 (pramipexole), representing severely affected patients. After 6 weeks, adjusted mean reductions (+/-SE) in IRLS score were 5.7 (+/-0.9) for placebo (median dose 0.47 mg/day) and 12.3 (+/-0.6) for pramipexole (median dose 0.35 mg/day; P < 0.0001). CGI-I responder rates were 32.5% (placebo) and 62.9% (pramipexole) (P < 0.0001). For all secondary endpoints, pramipexole showed superior results. Pramipexole was well tolerated throughout the study.

Efficacy and safety of pramipexole in idiopathic restless legs syndrome: a polysomnographic dose-finding study--the PRELUDE study.

BACKGROUND AND PURPOSE: To evaluate the effects of pramipexole (0.125-0.75 mg/d) on polysomnographic (PSG) measures and patient and clinician ratings of restless legs syndrome (RLS). PATIENTS AND METHODS: Patients (n=109) with moderate to severe RLS were randomized to placebo or fixed doses of pramipexole during a 3-week, double-blind, placebo-controlled, dose-finding study. RESULTS: In each pramipexole dose group, the periodic limb movements during time in bed index (PLMI) decreased significantly, compared with placebo (adjusted mean difference in log-transformed data: 0.125 mg, -1.54; 0.25 mg, -1.93; 0.50 mg, -1.89; and 0.75 mg, -1.52; P<0.0001). At all doses, International RLS Study Group Rating Scale (IRLS) scores were also significantly reduced, with the greatest adjusted mean reduction in the 0.50mg group (-17.01). At all but the lowest pramipexole dose, the percentage of responders (> or =50% reduction of IRLS score) was substantially higher than for placebo (61.9-77.3, vs 33.3%). In the pramipexole groups, 50.0-77.3% of patients rated their condition as 'much better' or 'very much better', compared with 38.1% of patients in the placebo group (P=0.0139 for the 0.50 mg dose). Clinical global impressions (CGI) scale ratings of 'much improved' or 'very much improved' were given to 61.9-86.4% of patients in the pramipexole groups, compared with 42.9% in the placebo group (P<0.05 for the 0.25, 0.50, and 0.75 mg groups). Pramipexole was well tolerated and did not produce somnolence at any dose. CONCLUSION: Pramipexole is effective and safe in the treatment of both objective and subjective facets of RLS.

Controlled withdrawal of pramipexole after 6 months of open-label treatment in patients with restless legs syndrome.

Although dopamine agonists are becoming first-line therapy for restless legs syndrome (RLS), few reports describe treatment periods exceeding 12 weeks. Here, 150 RLS patients who had responded to pramipexole during a 6-month run-in period (mean dose, 0.50 mg) were randomly assigned to receive placebo or continue receiving pramipexole at an individually optimized dose of 0.125 to 0.75 mg/day for a further 3 months. Patients switched to placebo reached the primary endpoint (a predefined worsening on both the Clinical Global Impressions-Global Improvement scale and the International RLS Study Group Rating Scale) significantly more often than patients who continued to receive pramipexole (85.5% vs. 20.5%; P < 0.0001). They also reached the primary endpoint faster, in 5 versus 42 days to a Kaplan-Meier survival estimate of 0.85 and 7 versus > 84 days to an estimate of 0.5. Over the total 9 months, clinician and patient ratings of symptoms, sleep, and quality of life identified no decline in pramipexole's benefit or tolerability. The great majority of adverse events (AEs) were mild or moderate, and of expected types. Augmentation was considered an AE, but in this population of responders it did not occur.

An item response analysis of the international restless legs syndrome study group rating scale for restless legs syndrome.

BACKGROUND AND PURPOSE: Restless legs syndrome (RLS) is a common central nervous system disorder; however, there is currently a lack of well-validated and easily-administered measures of RLS severity available. The International Restless Legs Syndrome Study Group has recently developed a 10-item scale to meet this need. The International Restless Legs Severity Scale (IRLS) has been shown to have a high degree of reliability, validity, and internal consistency. In order to further demonstrate the validity of the IRLS, the present study examined the relationship between scores on individual IRLS items and overall RLS severity. PATIENTS AND METHODS: The 10-item IRLS was administered to 196 RLS patients. Option characteristic curves (the probability of scoring different options for a given item as a function of overall IRLS score) were generated in order to illustrate the scoring patterns for each item across the range of total RLS severity. Item characteristic curves (the expected score on an item as a function of overall IRLS score) were also generated to illustrate the relationship between scores on the individual items and total RLS severity. RESULTS: The IRLS items demonstrated excellent item response properties, with option and item characteristic curves closely approximating those of an ideal item. Item 3 (relief of arm or leg discomfort from moving around) was the most problematic item in that a 'floor' effect was evident; however, the item response characteristics for this item were still acceptable. CONCLUSIONS: Each IRLS item showed a good relationship between responses on that item and overall RLS severity, providing further evidence for the validity of the IRLS as a measure of RLS severity in RLS patients.