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Boehringer Ingelhei International Page: 1 of 7 This is the International and may not - in International 30 MAR 2005 Title of study: A randomised, double-blind, placebo-controlled dose titration trial with 0.125-0.75 mg pramipexole () orally to investigate the safety and efficacy in out-patients with idiopathic Restless Legs Syndrome for 6 weeks followed by 46 weeks open-label or double-blind treatment period Investigator: Study center(s): Publication (reference): Clinical phase: Objectives: Germany Multicentre study involving 37 study centres in 5 European countries (Austria, Germany, Norway, The Netherlands, Sweden) Data from this trial were not yet published. III Period 1: To determine efficacy and safety of pramipexole 0.125 mg to 0.75 mg daily compared to placebo in the treatment of restless legs syndrome (RLS) over 6 weeks. Period 2: Long term safety and effectiveness of pramipexole in treatment of restless legs syndrome over 46 weeks. Methodology: Randomised, double-blind, placebo-controlled for 6 weeks with an open-label or double-blind extension treatment of 46 weeks. No. of subjects: planned: entered: 300 actual: enrolled: 435 Placebo: entered: 115 treated: 115 analysed (for primary endpoint): 114 : entered: 230 treated: 230 analysed (for primary endpoint): 214 Diagnosis and main criteria for inclusion: Test product: Adult patients of 18 to 80 years of age with a diagnosis of idiopathic restless legs syndrome according to the IRLSSG criteria, RLS rating scale for severity total score above 15, symptom presence of at least 2 to 3 days per week within the previous 3 months.
Boehringer Ingelheim International Page: 2 of 7 This is the International and may not - in International dose: mode of admin.: 0.125 mg/day to 0.75 mg/day (tablets, pramipexole salt) oral, once daily batch no.: 202976 Duration of treatment: Reference therapy: dose: mode of admin.: 6 weeks plus 46 weeks Placebo n.a. oral, once daily batch no.: 204055 Criteria for evaluation: Efficacy: Safety: Statistical methods: Period 1: Primary endpoints: RLS rating scale for severity, change from baseline and CGI-Improvement ( much improved and very much improved ) Secondary endpoints: ESS, QoL (SF-36), PGI, VASs. Period 2: Secondary endpoints: Change from baseline in RLS rating scale for severity, CGI, ESS, PGI, QoL (SF-36), VAS of severity of RLS Pulse rate, systolic and diastolic blood pressure, ECG, routine laboratory tests, adverse event reporting, concomitant medication, physical examination. Confirmatory analysis of the RLS severity score (baseline adjusted ANCOVA or Wilcoxon-Mann-Whitney test), and CGI-I (Cochran-Mantel-Haenszel test with pooled centre stratification), exploratory analysis of CGI-severity of illness, therapeutic effect, side effects, ESS, SF-36 including subscales, PGI, and VASs (ANCOVA using baseline as covariate or Wilcoxon-Mann-Whitney test). SUMMARY CONCLUSIONS: Efficacy results: Patient demography and baseline characteristics were similar in both treatment groups. Almost all patients were of Caucasian origin and the proportion of female patients was similar with 68.4% (DB placebo) and 64.3% (DB pramipexole). The overall mean age was 55.5 years. At baseline the mean RLSRS total scores were 24.9 (DB placebo) and 24.7 (DB pramipexole) indicating a patient population with moderate to severe RLS. While period 1 (weeks 0 to 6) was a randomized comparison of placebo and pramipexole, the allocation of patients to the treatment groups in period 2 (weeks 7 to 52)
Boehringer Ingelheim International Page: 3 of 7 This is the International and may not - in International depended on their PGI-responder status at Visit 7 (week 6). PGI-responders continued with double-blind medication (DB placebo or DB pramipexole), nonresponders received open-label pramipexole treatment (OL pramipexole). This procedure introduced the following imbalances: the DB placebo group had a larger proportion of female patients, a larger proportion of pre-treated patients, a longer mean duration of RLS, and comprised a smaller proportion of patients with severe RLS than the DB and the OL pramipexole groups, respectively. PERIOD 1 (weeks 0 to 6) After 6 weeks treatment the adjusted mean changes in RLSRS total score were 5.7 (DB placebo) and 12.3 (DB pramipexole), p<0.0001. The CGI-I responder rates were 32.5% (DB placebo) and 62.9% (DB pramipexole); (p<0.0001). Also for all secondary endpoints like RLSRS responders (28.9% vs. 52.2%, p<0.0001), PGI responders after 1 week (7.0% vs. 30.4%, p<0.0001), persistent PGI response after 1 week (3.5% vs. 19.6%, p=0.0001), CGI-severity of illness (sufficiently improved 22.8% vs. 48.7%, p<0.0001), CGI therapeutic effect ( marked or moderate effect 34.2% vs. 68.3%, p<0.0001) the pramipexole group exhibited superior results. At week 6, the assessment of side effects in the CGI was very similar in both treatment groups, 97.4% (DB placebo) and 93.3% (DB pramipexole) of patients were assessed as experiencing no significant interference by side effects. The adjusted mean ESS score at week 6 in the pramipexole group showed a greater reduction than in the placebo group ( 0.3 vs. 1.0, p=0.0669). Health-related quality of life was assessed by the SF-36. At baseline, the study population showed a substantial impairment in bodily pain compared to a healthy reference population. After 6 weeks for bodily pain a significantly larger improvement was seen in the pramipexole group than in the placebo group (+5.1 vs. +10.5, p=0.0412). Furthermore, for vitality (+4.0 vs. +9.0, p=0.0064) and social functioning ( 0.3 vs. +6.0, p=0.0027) the improvements observed in the pramipexole group were significantly larger than in the placebo group. PERIOD 2 (weeks 7 to 52) Thirty-five patients (30.4%) of the placebo group entered period 2 on doubleblind treatment, while 142 (61.7%) patients of the pramipexole group continued on double-blind treatment in period 2. PGI non-responders from both groups were treated with open-label pramipexole (N=142). Overall, the efficacy improvements achieved after 6 weeks of treatment were sustained until month 12
Boehringer Ingelheim International Page: 4 of 7 This is the International and may not - in International but the effect sizes were slightly reduced at month 12. The mean change in RLSRS total score from baseline to month 12 was 16.0 (DB placebo) and 14.8 (DB pramipexole). In the OL pramipexole group, at week 6 the mean change in RLSRS score was minimal ( 1.9) but had increased to 10.3 at month 12. The RLSRS responder rate had slightly decreased at month 12 compared with week 6. In the DB placebo group the RLSRS responder rate sank from 82.4% to 75.0% and in the DB pramipexole group from 80.0% to 61.2%. In the OL pramipexole group the RLSRS responder rate increased from 3.0% (week 6) to 39.6% (month 12). For the PGI-responders (assessments much better or very much better ), a sizeable reduction in responder rate was observed in the DB placebo group (week 6: 97.1% to month 12: 79.3%) while the reduction in the DB pramipexole group was small (week 6: 96.4% to month 12: 89.7%). In the OL pramipexole group 71.3% of patients were PGI-responders at month 12 compared with no patient at week 6. For the CGI-subscales of global improvement, severity of illness, and therapeutic effect the proportions of patients with improvement were slightly reduced at month 12 compared with week 6 in the double-blind treatment groups. In the OL pramipexole group, the proportion of patients with improvements was substantially increased at month 12. For the CGI-I the following changes from week 6 to month 12 in the frequency of responders (CGI-I of much improved or very much improved ) were observed. In the DB placebo group the CGI-responder rate decreased from 97.1% to 89.7%, in the DB pramipexole group it decreased from 97.9% to 90.3%, and in the OL pramipexole group it increased from 3.8% to 67.7%. The proportion of patients with a moderate or marked treatment effect was reduced in the double-blind treatment groups from a 100.0% at week 6 to 96.6% (DB placebo) and 91.1% (DB pramipexole). In the OL pramipexole group it increased from 6.8% (week 6) to 79.8% (month 12). For the CGI subscale of side effects, almost all patients continued not to be affected by side effects of treatment. At month 12 still 100.0% (DB placebo), 97.6% (DB pramipexole) and 98.0% (OL pramipexole) of patients were assessed as experiencing no significant interference from side effects. Daytime sleepiness was not increased by long-term pramipexole treatment. At month 12, the ESS was reduced by 1.7 (DB placebo), 2.6 (DB pramipexole), and by 0.5 (OL pramipexole) compared with baseline. The assessment of health-related quality of life generally showed considerable improvements at month 12. For bodily pain, general health, and role emotional, substantial improvements were seen in all treatment groups; however in the DB pramipexole group, the 95% CI for the changes from baseline excluded zero at all time points indicating a statistically significant
Boehringer Ingelheim International Page: 5 of 7 This is the International and may not - in International Safety results: PERIOD 1 (weeks 0 to 6) difference at the 0.05 level. For vitality, social functioning, and mental health considerable increases in mean score were observed in all treatment groups, with the exclusion of zero in the 95% CI for the change from baseline in the DB placebo group and the DB pramipexole group. For the mental component summary, also all groups showed improvements, an indication for a statistical significant difference from baseline was only seen in the DB pramipexole group. In period 1, the frequency of adverse events was lower with placebo treatment (47.8%) than with pramipexole treatment (65.2%). The most frequent adverse events were gastrointestinal disorders; they occurred with a substantially lower frequency in the placebo group (8.7%) than in the pramipexole group (26.1%). Within this system organ class, nausea was the most frequent event and it was considerably less frequent with placebo (6.1%) than with pramipexole (12.2%). The second most frequent adverse events were nervous system disorders occurring with similar frequencies in both treatment groups (18.3% vs. 20.9%). Also infections and infestations occurred with similar frequency in both treatment groups (14.8% vs. 15.2%). A difference was seen for general disorders and administration site conditions: they were less frequent with placebo (8.7%) than with pramipexole (13.5%); fatigue was the most frequent adverse event in this system organ class with 6.1% (DB placebo) and 9.1% (DB pramipexole). Musculoskeletal and connective tissue disorders were slightly less frequent in the placebo group (6.1%) than in the pramipexole group (10.0%). Psychiatric disorders (6.1% vs. 7.0%) and skin and subcutaneous tissue disorders (5.2% vs. 4.3%) occurred with similar frequencies in both treatment groups. The majority of adverse events were mild in both treatment groups. The placebo group (7.8%) exhibited a higher frequency of adverse events of severe intensity than the pramipexole group (3.5%). The frequency of drug-related adverse events was substantially lower with placebo treatment (21.7%) than with pramipexole treatment (36.5%). Also, adverse events leading to either dose-reduction or withdrawal were less frequent with in the placebo group (8.7%) than in the pramipexole group (13.9%). In the placebo group, a higher proportion of patients withdrew from the study because of adverse events than in the pramipexole group (4.3% vs. 2.6%). The frequency of other significant adverse events, i.e. adverse events that led to dose reduction or withdrawal, was lower in the placebo group (8.7%) than in the pramipexole group (13.9%). Orthostatic reactions were reported by 1 patient in each treatment group. Overall, 2 patients (1.7%) in the placebo group but no patient in the pramipexole group experienced serious
Boehringer Ingelheim International Page: 6 of 7 This is the International and may not - in International adverse events. During period 1, no patient experienced an episode of sudden onset of sleep. In period 2, the overall frequency of adverse events was slightly lower in the DB placebo group than in the DB pramipexole group (71.4% vs. 78.2%) but higher than in the OL pramipexole group (68.3%). Nervous system disorders ( headache ), gastrointestinal disorders ( nausea ), and psychiatric disorders ( insomnia ) were considerably less frequent in the DB placebo group than in the DB and OL pramipexole groups. Generally, the adverse event pattern observed in the DB pramipexole group and in the OL pramipexole was similar. As in period 1, the majority of adverse events in all treatment groups was of mild intensity. The frequency of adverse events with severe intensity was lower in the DB placebo group (8.6%) than in the DB pramipexole group (14.1%) and the OL pramipexole group (12.0%). For drug-related adverse events, a substantially lower frequency was observed in the DB placebo group (11.4%) than in the DB pramipexole group (28.2%) and the OL pramipexole group (36.6%). In period 2, considerably fewer patients in the DB placebo group discontinued the study because of adverse events (5.7%) than in the DB pramipexole (12.7%) and the OL pramipexole group (12.7%). Serious adverse events occurred with similar frequencies in all treatment groups (DB placebo 5.7%, DB pramipexole 6.3%, OL pramipexole 2.8%) in period 2. Adverse events leading to dose reduction or withdrawal were substantially less frequent in the DB placebo group (8.6%) than in both the DB pramipexole group (18.3%) and the OL pramipexole group (21.1%). Adverse events belonging to the gastrointestinal system ( nausea ), nervous system ( dizziness, worsening of RLS ), and general disorders and administration site conditions ( fatigue ) were the most frequent which led to study discontinuation in the pramipexole groups. In period 2, for no patient the adverse event orthostatic hypotension was reported; however, for 3 patients investigators reported orthostatism, and for 2 patients hypotension. Overall 2 patients reported episodes of sudden onset of sleep; 1 patient in the DB pramipexole group and 1 patient in the OL pramipexole group. Both patients had reported abnormal daytime sleepiness in the period prior to the episode of sudden onset of sleep. Both for period 1 and 2, clinical laboratory parameters and vital signs (blood pressure, pulse rate) were generally not affected by pramipexole treatment.
Boehringer Ingelheim International Page: 7 of 7 This is the International and may not - in International Conclusions: Over the entire dose range tested, pramipexole was efficacious and safe in the treatment of RLS as demonstrated after 6 weeks of randomised, double-blind treatment and, within the methodological limitations of a responder-based extension study, for up to 12 months.