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2.0 SYNOPSIS STUDY INFORMATION: Sponsor: Takeda Pharmaceutical Company Limited Long Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Phase 2/3 Study to Evaluate the Efficacy and Safety of TVP-1012 at 0.5 mg or 1 mg in Levodopa Treated Parkinson s Disease Patients with Wearing Off Short Title: A Phase 2/3 Study of TVP-1012 at 0.5 mg or 1 mg in Levodopa Treated Parkinson s Disease Patients Name of Active Ingredient: Rasagiline mesilate (JAN) Name of Finished Product: TVP-1012 Tablets Investigator: A total of 71 principle investigators participated in the study, including 4 principle investigators that replaced other principle investigators. Study Sites: The study was conducted in 68 Japanese study sites. Publications Based on the Study (Citations): None Study Dates: Date first subject signed informed consent form: 27 January 2015 Date of last subject s last visit/contact: 15 September 2016 Phase: Phase 2/3 Objectives: Primary Objective: To evaluate the efficacy of TVP-1012 (0.5 mg or 1 mg/day) administered for 26 weeks as an add-on to levodopa to Japanese patients with Parkinson s disease with wearing off phenomenon Secondary Objectives: To evaluate the safety of TVP-1012 (0.5 mg or 1 mg/day) administered for 26 weeks as an add-on to levodopa to Japanese patients with Parkinson s disease with wearing off phenomenon Methodology: This study was a multicenter, randomized, double-blind, placebo-controlled, parallel group, phase 2/3 study to evaluate the efficacy and safety of TVP-1012 as an add-on to levodopa in Japanese patients with Parkinson s disease with wearing off phenomenon. The study period consisted of a 2-week run-in period and a subsequent 26-week treatment period. Patients fulfilled the inclusion criteria and did not meet any of the exclusion criteria at the start of the run-in period (Week -2; VISIT 1) and at the end of the run-in period (Week 0;
VISIT 2) were enrolled into the treatment period. The patients were randomized in a 1:1:1 ratio to TVP-1012 0.5 mg, TVP-1012 1 mg, or placebo group. In each group, patients received TVP-1012 0.5 mg, TVP-1012 1 mg, or placebo once daily for 26 weeks in a double-blinded manner. Patients made a total of 8 visits in this study, i.e., at the start of the run-in period, at the end of the run-in period, and at Weeks 3, 6, 10, 14, 20, and 26 of the treatment period, and underwent designated tests, observations, and assessments. Number of Subjects: Planned: Randomized: Approximately 400 subjects in total (133 per group), Evaluable for the primary endpoint: 375 subjects in total (125 per group). Signed the informed consent form: 463 subjects Randomized: 404 subjects Statistical analysis: Full analysis set (FAS): 403 subjects, safety analysis set: 403 subjects Diagnosis and Main Criteria for Inclusion: Subjects who met the following criteria were enrolled in the study: The Japanese subject of either sex with Parkinson s disease aged 30 and < 80 years at the time of consent. The subject who has Modified Hoehn & Yahr stage 2 to 4 (in the Off state) at the start of the run-in period. The subject who has wearing off phenomenon and has been continuously receiving a levodopa combination drug for 6 months prior to the start of the run-in period. Duration of Treatment: 26 weeks of treatment period Study Drug, Dose and Mode of Administration, and Lot Number: Product Dose Strength and Form Study Drug Study Dosage Mode of Administration Manufacturer TVP-1012 A white to yellowish-white - Orally Teva 0.5 mg round shape tablet which does administered, Pharmaceutical placebo not contain rasagiline, once daily, either Industries Ltd. tablet engraved with GIL 0.5 on before or after TVP-1012 1 mg placebo tablet one surface. A white to yellowish-white round shape tablet which does not contain rasagiline, engraved with GIL 1 on one breakfast - Orally administered, once daily, either before or after Teva Pharmaceutical Industries Ltd. Drug Product Lot Number Z125101 Z125201
TVP-1012 0.5 mg tablet TVP-1012 1 mg tablet surface. A white to yellowish-white round shape tablet containing 0.5 mg of rasagiline, engraved with GIL 0.5 on one surface. A white to yellowish-white round shape tablet containing 1 mg of rasagiline, engraved with GIL 1 on one surface. TVP-1012 0.5 mg TVP-1012 1 mg breakfast Orally administered, once daily, either before or after breakfast Orally administered, once daily, either before or after breakfast Teva Pharmaceutical Industries Ltd. Teva Pharmaceutical Industries Ltd. Z125301 Z125401 Endpoints and Criteria for Evaluation: Efficacy: Primary endpoint Change in the mean daily OFF-time from the end of the run-in period to the treatment period (i.e., Mean for a total of 21 days [three separate 7-day periods preceding the visits at Weeks 6, 14, and 26 of the treatment period] Mean for the 7 days preceding the visit at the end of the run-in period) Secondary endpoints Mean daily OFF-time (mean for the 7 days preceding each study visit) Movement Disorder Society-Unified Parkinson s Disease Rating Scale (MDS-UPDRS) Part II total score MDS-UPDRS Part III total score Parkinson s Disease Questionnaire-39 (PDQ-39) Summary Index score and scores for individual domains Safety: Adverse events, clinical laboratory test values, vital signs, electrocardiogram (ECG), weight, and Mean daily ON-time with troublesome dyskinesia Statistical Methods: Efficacy: (1) Primary endpoint [Primary analysis] The following analyses were performed for the FAS. The change in mean daily OFF-time during the treatment period from the end of the run-in period was analyzed using an ANCOVA model with group and mean daily OFF-time at the end
of the run-in period as factors. Based on this model, the closed testing procedure was performed to compare each of the two TVP-1012 groups in descending order of dose and placebo group. More specifically, a contrast test was performed for a pairwise comparison between TVP-1012 1 mg group and placebo group. If the result was statistically significant, then a pairwise comparison was performed for TVP-1012 0.5 mg group and placebo group. The contrast coefficients used for the contrast test were (-1, 0, 1) and (-1, 1, 0) for placebo group, TVP-1012 0.5 mg group, and TVP-1012 1 mg group, respectively. For reference, irrespective of the result of the contrast test for a pairwise comparison between TVP-1012 1 mg group and placebo group, the result of the contrast test for a pairwise comparison between TVP-1012 0.5 mg group and placebo group was presented. LS means and the two-sided 95% confidence intervals were provided for each group. The difference in the LS means between TVP-1012 dose group and placebo group (TVP-1012 0.5 mg group - placebo group, TVP-1012 1 mg group - placebo group) and the two-sided 95% confidence interval were also provided. In addition, LS means and the two-sided 95% confidence intervals were plotted by group. For the change in mean daily OFF-time during the treatment period from the end of the run-in period, descriptive statistics (number of subjects, mean, standard deviation, maximum, minimum, and quartiles) were provided by group. Safety: The following analyses were based on the safety analysis set. A treatment emergent adverse event (TEAE) was defined as an adverse event whose date of onset occurs on or after the start of treatment period. TEAEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 19.0. The frequency distribution was provided using the system organ class (SOC) and the preferred term (PT) for each group as follows: All TEAEs Drug-related TEAEs Intensity of TEAEs Intensity of drug-related TEAEs TEAEs leading to study drug discontinuation Serious TEAEs TEAEs over time Clinical laboratory tests, vital signs, ECG, weight: For continuous variables, the observed values and the changes from baseline were summarized by group for each visit using descriptive statistics based on the safety analysis set. Case plots
were also presented for the observed values. For categorical variables, shift tables showing the number of subjects in each category at baseline and each post-baseline visit were provided for each group. SUMMARY OF RESULTS: Disposition of Subjects: Of 463 subjects who provided consent, 404 were randomized. Of the 404, 141 subjects were assigned to placebo group, 134 were assigned to TVP-1012 0.5 mg group, and 129 were assigned to TVP-1012 1 mg group. Except for one subject in TVP-1012 0.5 mg group who experienced a major protocol deviation, 403 subjects received the study drug. A total of 326 subjects (119 subjects in placebo group, 104 in TVP-1012 0.5 mg group, and 103 in TVP-1012 1 mg group) completed the study. A total of 77 subjects (22 in placebo group, 29 in TVP-1012 0.5 mg group, and 26 in TVP-1012 1 mg group) discontinued the study drug. Demographics and Other Baseline Characteristics: The mean (standard deviation, the same hereinafter) age was 66.3 (7.62) years old in placebo group, 66.1 (8.74) years old in TVP-1012 0.5 mg group, and 65.8 (8.48) years old in TVP-1012 1 mg group. The ratio of male and female was 37.6% and 62.4% in placebo group, 43.3% and 56.7% in TVP-1012 0.5 mg group, and 35.7% and 64.3% in TVP-1012 1 mg group. The mean duration of Parkinson s disease was 8.90 (4.465) years in placebo group, 8.53 (4.774) years in TVP-1012 0.5 mg group, and 9.49 years (4.992) in TVP-1012 1 mg group. The mean daily dose of levodopa was 399.3 (141.03) mg in placebo group, 407.8 (134.15) mg in TVP-1012 0.5 mg group, and 420.7 (166.42) mg in TVP-1012 1 mg group. The mean value of Modified Hoehn & Yahr stage (in the On state) was 2.44 (0.608) in placebo group, 2.45 (0.542) in TVP-1012 0.5 mg group, and 2.51 (0.566) in TVP-1012 1 mg group. The mean daily OFF-time at the end of the run-in period was 6.05 (2.278) hours in placebo group, 6.33 (2.562) hours in TVP-1012 0.5 mg group, and 6.12 (2.430) hours in TVP-1012 1 mg group. The mean MDS-UPDRS Part II total score was 13.0 (7.29) in placebo group, 13.7 (6.65) in TVP-1012 0.5 mg group, and 14.1 (7.23) in TVP-1012 1 mg group. The mean MDS-UPDRS Part III total score at the end of the run-in period was 26.8 (13.99) in placebo group, 28.7 (13.28) in TVP-1012 0.5 mg group, and 27.5 (13.09) in TVP-1012 1 mg group. The mean PDQ-39 Summary Index at the end of the run-in period was 19.97 (13.177) in placebo group, 20.94 (12.393) in TVP-1012 0.5 mg group, and 22.39 (13.115) in TVP-1012 1 mg group. There were no significant differences among the groups in demographics and other baseline characteristics.
Efficacy Results: (1) Primary endpoint The LS mean change in the mean daily OFF-time from the end of the run-in period to the treatment period was -0.51 (two-sided 95% CI: -0.837, -0.182) hours in placebo group, -1.11 (two-sided 95% CI: -1.448, -0.763) hours in TVP-1012 0.5 mg group, and -1.35 (two-sided 95% CI: -1.700, -1.004) hours in TVP-1012 1 mg group. The difference in the LS mean change between the groups in the mean daily OFF-time from the end of the run-in period to the treatment period was -0.84 (two-sided 95% CI: -1.320, -0.364) between TVP-1012 1 mg group and placebo group and -0.60 (two-sided 95% CI: -1.070, -0.122) between TVP-1012 0.5 mg group and placebo group. TVP-1012 1 mg group showed a statistically significant decrease when compared with placebo group (p = 0.0006). In addition, TVP-1012 0.5 mg group showed a statistically significant decrease when compared with placebo group (p = 0.0140). (2) Secondary endpoints The LS mean change in the MDS-UPDRS Part III total score from the end of the run-in period to Week 26 of the treatment period (LOCF) was -3.50 (two-sided 95% CI: -4.692, -2.314) in placebo group, -5.24 (two-sided 95% CI: -6.467, -4.018) in TVP-1012 0.5 mg group, and -5.65 (two-sided 95% CI: -6.899, -4.396) in TVP-1012 1 mg group. The difference in the LS mean change between the groups in the MDS-UPDRS Part III total score from the end of the run-in period to Week 26 of the treatment period (LOCF) was -1.74 (two-sided 95% CI: -3.449, -0.031) between TVP-1012 0.5 mg group and placebo group and -2.14 (two-sided 95% CI: -3.871, -0.419) between TVP-1012 1 mg group and placebo group. TVP-1012 0.5 mg and TVP-1012 1 mg groups showed a statistically significant decrease when compared with placebo group (p = 0.0460 and p = 0.0150, respectively). The LS mean change in the MDS-UPDRS Part II total score from the end of the run-in period to Week 26 of the treatment period (LOCF) was 0.97 (two-sided 95% CI: 0.168, 1.771) in placebo group, -0.30 (two-sided 95% CI: -1.123, 0.532) in TVP-1012 0.5 mg group, and -0.30 (two-sided 95% CI: -1.147, 0.548) in TVP-1012 1 mg group. The difference in the LS mean change between the groups in the MDS-UPDRS Part II total score from the end of the run-in period to Week 26 of the treatment period (LOCF) was -1.27 (two-sided 95% CI: -2.418, -0.113) between TVP-1012 0.5 mg group and placebo group and -1.27 (two-sided 95% CI: -2.437, -0.102) between TVP-1012 1 mg group and placebo group. TVP-1012 0.5 mg and TVP-1012 1 mg groups showed a statistically significant decrease when compared with placebo group (p = 0.0315 and p = 0.0332, respectively).
The LS mean change in the PDQ-39 Summary Index from the end of the run-in period to Week 26 of the treatment period (LOCF) was 2.84 (two-sided 95% CI: 1.252, 4.433) in placebo group, 0.33 (two-sided 95% CI: -1.297, 1.964) in TVP-1012 0.5 mg group, and -1.00 (two-sided 95% CI: -2.681, 0.690) in TVP-1012 1 mg group. The difference in the LS mean change between the groups in the PDQ-39 Summary Index from the end of the run-in period to Week 26 of the treatment period (LOCF) was -2.51 (two-sided 95% CI: -4.787, -0.232) between TVP-1012 0.5 mg group and placebo group and -3.84 (two-sided 95% CI: -6.158, -1.518) between TVP-1012 1 mg group and placebo group. TVP-1012 0.5 mg and TVP-1012 1 mg groups showed a statistically significant decrease when compared with placebo group (p = 0.0309, p = 0.0012, respectively). Safety Results: The incidence of TEAEs was 50.4% (71 of 141 subjects) in placebo group, 69.9% (93 of 133) in TVP-1012 0.5 mg group, and 73.6% (95 of 129) in TVP-1012 1 mg group. The incidence of TEAEs was higher in TVP-1012 0.5 mg and TVP-1012 1 mg groups when compared with placebo group. TEAEs, reported in at least 5% in any of the groups, were nasopharyngitis for 9.2% (13 of 141 subjects) in placebo group, 18.0% (24 of 133) in TVP-1012 0.5 mg group, and 14.7% (19 of 129) in TVP-1012 1 mg group; dyskinesia for 7.1% (10 of 141 subjects) in placebo group, 8.3% (11 of 133) in TVP-1012 0.5 mg group, and 16.3% (21 of 129) in TVP-1012 1 mg group; fall for 5.7% (8 of 141 subjects) in placebo group, 9.8% (13 of 133) in TVP-1012 0.5 mg group, and 13.2% (17 of 129) in TVP-1012 1 mg group; and contusion for 1.4% (2 of 141 subjects) in placebo group, 6.0% (8 of 133) in TVP-1012 0.5 mg group, and 5.4% (7 of 129) in TVP-1012 1 mg group. Of the incidence of TEAEs reported in at least 5% in any of TVP-1012 groups, the incidence of nasopharyngitis was higher in TVP-1012 0.5 mg and TVP-1012 1 mg groups when compared with placebo group. The incidence of fall and dyskinesia was higher in TVP-1012 1 mg group when compared with placebo group. The incidence of other TEAEs was similar between TVP-1012 0.5 mg and TVP-1012 1 mg groups. The incidence of drug-related TEAEs was 32.6% (46 of 141 subjects) in placebo group, 44.4% (59 of 133) in TVP-1012 0.5 mg group, and 51.2% (66 of 129) in TVP-1012 1 mg group. The incidence of drug-related TEAEs was higher in TVP-1012 0.5 mg and TVP-1012 1 mg groups when compared with placebo group. Drug-related TEAEs, reported in at least 3% in any of the groups, were dyskinesia for 7.1% (10
of 141 subjects) in placebo group, 8.3% (11 of 133) in TVP-1012 0.5 mg group, and 16.3% (21 of 129) in TVP-1012 1 mg group; hallucination for 0.7% (1 of 141 subjects) in placebo group, 3.8% (5 of 133) in TVP-1012 0.5 mg group, and 3.1% (4 of 129) in TVP-1012 1 mg group; nasopharyngitis for 1.4% (2 of 141 subjects) in placebo group, 3.0% (4 of 133) in TVP-1012 0.5 mg group and 3.9% (5 of 129) in TVP-1012 1 mg group; nausea for 0.7% (1 of 141 subjects) in placebo group, 3.0% (4 of 133) in TVP-1012 0.5 mg group, and 2.3% (3 of 129) in TVP-1012 1 mg group; fall for 3.0% (4 of 133 subjects) in TVP-1012 0.5 mg group, and 2.3% (3 of 129) in TVP-1012 1 mg group; dizziness was for 0.7% (1 of 141 subjects) in placebo group, 3.0% (4 of 133) in TVP-1012 0.5 mg group, and 2.3% (3 of 129) in TVP-1012 1 mg group; headache for 1.5% (2 of 133 subjects) in TVP-1012 0.5 mg group and 3.1% (4 of 129) in TVP-1012 1 mg group; somnolence for 0.7% (1 of 141 subjects) in placebo group, 0.8% (1 of 133) in TVP-1012 0.5 mg group, and 3.1% (4 of 129) in TVP-1012 1 mg group. Of the incidence of drug-related TEAEs reported in at least 3% in any of TVP-1012 groups, the incidence of dyskinesia was higher in TVP-1012 1 mg group when compared with placebo group. The incidence of other TEAEs was similar between TVP-1012 0.5 mg and TVP-1012 1 mg groups when compared with placebo group. Most of the TEAEs were mild or moderate in intensity. Severe TEAEs was 2.8% (4 of 141 subjects) in placebo group, 1.5% (2 of 133) in TVP-1012 0.5 mg group, and 2.3% (3 of 129) in TVP-1012 1 mg group. The incidence of moderate TEAEs was higher in TVP-1012 0.5 mg and TVP-1012 1 mg groups, the incidence of mild and severe TEAEs was similar between TVP-1012 0.5 mg and TVP-1012 1 mg groups when compared with placebo group. For adverse events associated with fatal outcomes, haemorrhage intracranial was 0.7% (1 of 141 subjects) in placebo group and hypoxic-ischaemic encephalopathy was 0.8% (1 of 129) in TVP-1012 1 mg group. The incidence of serious TEAEs was 2.8% (4 of 141 subjects) in placebo group, 7.5% (10 of 133) in TVP-1012 0.5 mg group, and 7.8% (10 of 129) in TVP-1012 1 mg group. The incidence of serious TEAEs was higher in TVP-1012 1 mg group when compared with placebo group. The incidence of serious drug-related TEAEs was 2.1% (3 of 141 subjects) in placebo group, 3.0% (4 of 133) in TVP-1012 0.5 mg group, and 3.9% (5 of 129) in TVP-1012 1 mg group. The incidence of serious drug-related TEAEs was similar between TVP-1012 0.5 mg and TVP-1012 1 mg groups when compared with placebo group.
The incidence of TEAEs leading to study drug discontinuation was 6.4% (9 of 141 subjects) in placebo group, 13.5% (18 of 133) in TVP-1012 0.5 mg group, and 15.5% (20 of 129) in TVP-1012 1 mg group. The incidence of TEAEs leading to study drug discontinuation was higher in TVP-1012 0.5 mg and TVP-1012 1 mg groups when compared with placebo group. The mean change in the vital sign systolic blood pressure was lower in TVP-1012 0.5 mg and TVP-1012 1 mg groups at all assessment points when compared with placebo group. The mean change in diastolic blood pressure was not significantly different between TVP-1012 0.5 mg and placebo groups, while it was lower in TVP-1012 1 mg group. The mean change in other vital signs was small at baseline and post-baseline, and clinically meaningful changes were not observed. The mean change in clinical laboratory tests, ECG parameters, and weight was low at baseline and post-baseline, and the percentage of abnormal changes was also low. CONCLUSIONS: For the efficacy of TVP-1012 (0.5 mg or 1 mg daily) administered for 26 weeks as an add-on to levodopa to Japanese patients with Parkinson s disease with wearing off phenomenon, the LS mean change in the mean daily OFF-time from the end of the run-in period to the treatment period, the primary endpoint, showed a statistically significant decrease in TVP-1012 0.5 mg and TVP-1012 1 mg groups when compared with placebo group. An analysis of motor symptoms and their associated aspects which may be encountered in the daily life showed a statistically significant decrease in TVP-1012 0.5 mg and TVP-1012 1 mg groups when compared with placebo group, using the changes in the MDS-UPDRS Part III total score and MDS-UPDRS Part II total score from the end of the run-in period to Week 26 of the treatment period (LOCF), the secondary endpoints, as an indicator. Moreover, an analysis of the PDQ-39 Summary Index, an indicator of QOL, showed a statistically significant decrease in TVP-1012 0.5 mg and TVP-1012 1 mg groups when compared with placebo group. For the safety, the incidence of TEAEs was higher in TVP-1012 0.5 mg and TVP-1012 1 mg groups when compared with placebo group. For TEAEs reported in 5% in any of TVP-1012 groups, the incidence of nasopharyngitis was higher in TVP-1012 0.5 mg and TVP-1012 1 mg groups when compared with placebo group. The incidence of fall and dyskinesia was higher in TVP-1012 1 mg group when compared with placebo group. On the other hand, the incidence of other TEAEs was similar between TVP-1012 0.5 mg and TVP-1012 1 mg groups. The incidence of serious TEAEs was higher in TVP-1012 1 mg group when compared with placebo group.
The incidence of TEAEs leading to study drug discontinuation was higher in TVP-1012 0.5 mg and TVP-1012 1 mg groups when compared with placebo group. However, the incidence of serious drug-related TEAEs was similar between TVP-1012 0.5 mg and TVP-1012 1 mg groups when compared with placebo group. Most of the TEAEs were mild or moderate in intensity. Based on these results, the efficacy of TVP-1012 as an add-on to levodopa was shown in Japanese patients with Parkinson s disease with wearing off phenomenon. In addition, there were no significant concerns about the safety in TVP-1012. Therefore, TVP-1012 was considered to be clinically meaningful as one of the treatment options for these patients. REPORT DATE: 2 March 2017