abcd Clinical Study Synopsis for Public Disclosure This clinical study synopsis is provided in line with s Policy on Transparency and Publication of Clinical Study Data. The synopsis - which is part of the clinical study report - had been prepared in accordance with best practice and applicable legal and regulatory requirements at the time of study completion. The synopsis may include approved and non-approved uses, doses, formulations, treatment regimens and/or age groups; it has not necessarily been submitted to regulatory authorities. A synopsis is not intended to provide a comprehensive analysis of all data currently available regarding a particular drug. More current information regarding a drug is available in the approved labeling information which may vary from country to country. Additional information on this study and the drug concerned may be provided upon request based on s Policy on Transparency and Publication of Clinical Study Data. The synopsis is supplied for informational purposes only in the interests of scientific disclosure. It must not be used for any commercial purposes and must not be distributed, published, modified, reused, posted in any way, or used for any other purpose without the express written permission of. Additional data are available under http://clinicaltrials.gov/. V1.0/2014
Page 3 BI Trial No.: 248.549 U10-1 of 6 Title of trial: Post Marketing Surveillance of BI-Sifrol () Special drug use result survey in 3 years treatment in patients with Parkinson's disease without concomitant use of L-Dopa Trial sites: 119 Publication (reference): Clinical phase: Objectives: Methodology: No. of subjects: Data of this Post Marketing Surveillance has not been published IV planned: entered: 300 The objective of this Post Marketing Surveillance was conducted to collect safety and efficacy data on the use of BI-Sifrol Tablets in the patients without concomitant use of L-Dopa in routine medical practice, and to obtain information for proper use of this product. Drug use based, non-interventional, prospective, observational, Post Marketing Surveillance actual: enrolled: 416 Treatment BI-Sifrol : entered: 416 treated: 359 analysed (for safety): 346, (for efficacy): 339 Diagnosis and main criteria for inclusion: Test product: dose: mode of admin.: batch no.: Idiopathic Parkinson s disease patients who do not receive L-Dopa BI-Sifrol Tablets 0.125 mg, 0.5 mg oral Not applicable as using market products
Page 4 BI Trial No.: 248.549 U10-2 of 6 Reference therapy: dose: mode of admin.: batch no.: Duration of treatment: Criteria for evaluation: Efficacy / clinical pharmacology: Safety: 3 years At 1 year, 2 years and 3 years of the treatment with pramipexole as well as at the time of withdrawal/dropout, the attending investigators assessed the clinical global impression with the following 5 categories from a comprehensive consideration of modified Hoehn & Yahr rating scale, Unified Parkinson s Disease Rating Scale (UPDRS) Part III total score and other efficacy observations. 1. Very much improved 2. Much improved 3. Minimally improved 4. No effect* 5. Unassessable *: including the meaning of no change and worsened All adverse events occurring during pramipexole treatment in this Post Marketing Surveillance were recorded in detail (e.g. name of symptom, date of onset, seriousness, outcome, causal relationship with this drug) by the investigator. This information of adverse events was usually reported to the sponsor by case report forms from the investigator. In case of serious adverse events, the information was reported to the drug safety department of the sponsor via sales persons by fax within 24 hours when sales persons obtained the information of serious adverse events from the investigator. Haematological examination and blood chemistry examination were performed before and after pramipexole treatment, if possible. The investigator checked the results of examinations, and considered whether abnormal values were adverse event and assessed a causal relationship to pramipexole treatment.
Page 5 BI Trial No.: 248.549 U10-3 of 6 Statistical methods: SUMMARY CONCLUSIONS: Efficacy / clinical pharmacology results: Categorical data was summarized by using the frequency and proportion. Quantitative data was summarized by using the descriptive statistics (number of patients, mean, standard deviation, etc.). The incidences of adverse drug reactions stratified by specific patient factors have been compared. The change from baseline at the final observation for efficacy variables (modified Hoehn & Yahr rating scale and UPDRS Part III total score) and safety variables (laboratory tests and vital sign) have been compared within patients using paired t-test. A significance level was 5% with two-tailed in the statistical tests. Efficacy was evaluated in the data set consisting of 339 (81.5%) out of 416 patients enrolled. The mean value of UPDRS Part III total score was 24.8 (SD=13.2) at baseline, and 19.6 (SD=13.4) at 3 years or at the time of discontinuation within 3 years. The mean change of UPDRS Part III total score from baseline was -5.2 (SD=11.2), and it significantly improved (p<0.0001). Compared with the value at baseline, the mean value of UPDRS Part III total score was significantly decreased at 6 month [16.4 (SD=10.7)] after the initiation of pramipexole treatment and it continued to improve during 3-year observation period [17.3 (SD=12.3) at 3 years]. The mean value of modified Hoehn & Yahr rating scale was 2.2 (SD=0.8) at baseline, and 2.1 (SD=0.9) at the evaluation time. The mean change of modified Hoehn & Yahr rating scale from baseline was -0.1 (SD=0.7), and it also significantly improved (p=0.0025). Compared with the value at baseline, the mean value of modified Hoehn & Yahr rating scale was significantly decreased at 6 month [1.9 (SD=0.8)] after the initiation of pramipexole treatment and it continued to improve during 3-year observation period [2.0 (SD=0.9) at 3 years]. Clinical global impression of improvement as very much improved or much improved at 3 years or at the time of discontinuation within 3 years was found in 46.0% (156 of 339 patients).
Page 6 BI Trial No.: 248.549 U10-4 of 6 Efficacy / clinical pharmacology results: (continued) Safety results: Moreover, there were 205 patients (60.5%) who never received any supplemental L-Dopa during the observational period. The mean duration of pramipexole treatment was 669.0 days (SD=527.8, range: 2-1802 days). In the patients without supplemental L-Dopa therapy, the mean value of UPDRS Part III total score was 23.5 (SD=12.8) at baseline, and 17.7 (SD=13.1) at 3 years or at the time of discontinuation within 3 years. The mean change of UPDRS Part III total score from baseline was -5.8 (SD=10.4), and it also significantly improved (p<0.0001). Clinical global impression of improvement as very much improved or much improved at 3 years or at the time of discontinuation within 3 years was found in 43.9% (90 of 205 patients). A total of 134 (39.5%) out of 339 patients received supplemental L-Dopa during the observational period. The mean duration from initiation of pramipexole treatment to adding L-Dopa first was 419.2 days (SD=302.9). The cumulative ratio curve for patients who have not received supplemental L-Dopa decreased approximately linearly during 3 years. About half of patients of pramipexole treatment did not need to be added L-Dopa during 3 years. Safety was evaluated in a data set consisting of 346 (83.2%) out of 416 patients enrolled. The mean administration period of pramipexole was 821.1 days. Adverse events were reported in 179 patients (with 403 adverse events) out of 346 patients and the proportion of patients with adverse events was 51.7%. The reported adverse event with the highest proportion was somnolence in 59 patients (17.1%), followed by hallucination in 28 (8.1%), constipation in 25 (7.2%), nausea in 20 (5.8%), blood creatine phosphokinase increased in 10 (2.9%), dizziness in 9 (2.6%) and oedema peripheral in 9 (2.6%).
Page 7 BI Trial No.: 248.549 U10-5 of 6 Safety results: (continued) Adverse drug reactions (i.e. adverse events with an investigator or the sponsor suspected causal relationship to the use of pramipexole) were reported in 143 patients (with 258 adverse drug reactions) out of 346 patients and proportion of patients with adverse drug reactions was 41.3%. The reported adverse drug reaction with the highest proportion was somnolence in 57 patients (16.5%), followed by hallucination in 25 (7.2%), nausea in 18 (5.2%), constipation in 15 (4.3%), blood creatine phosphokinase increased in 10 (2.9%), dizziness in 9 (2.6%) and oedema peripheral in 8 (2.3%). A stratified analysis of adverse drug reactions by specific patient factors, such as patient demographics, baseline characteristics, extent of pramipexole treatment and concomitant medications, showed significantly different proportion of adverse drug reactions for the factor of maintenance daily dose only (p=0.0203). In 208 (60.1%) out of 346 patients, they had not needed to add L-Dopa therapy for treatment of Parkinson s disease during the observational period. But the others (138 patients) had needed. Adverse drug reactions were reported in 87 (with 146 adverse drug reactions) out of 208 patients without L-Dopa therapy, and the proportion of patients with adverse drug reactions was 41.8%. On the other hand, adverse drug reactions were reported in 56 (with 108 adverse drug reactions) out of 138 patients with L-Dopa therapy, and the proportion of patients with adverse drug reactions was 40.6%. There were no significant differences between with and without concomitant use of L-Dopa (p=0.9051). There were 46 serious adverse events in 29 out of 346 patients and the proportion of patients with serious adverse events was 8.4%. In 38 (82.6%) out of 46 serious adverse events, no causal relationship to pramipexole treatment was reported. Seven (2.0%) out of 346 patients died during the observational period. However there was no causal relationship to pramipexole treatment. No clinically significant changes in laboratory test values and vital signs, such as blood pressure, were observed.
Page 8 BI Trial No.: 248.549 U10-6 of 6 Conclusions: As the result of this Post Marketing Surveillance, pramipexole was confirmed to be safe and effective for treatment of Japanese Parkinson s disease patients without concomitant use of L-Dopa in routine medical practice.