Clinical Study Synopsis

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14 Apr 2014 Study no. 15960 Page: 1 of 6 2. Synopsis Date of report: 14 Apr 2014 Study title: Randomized, open-label, parallel-group, active-controlled study of rivaroxaban in patients with acute symptomatic pulmonary embolism, with or without symptomatic deep vein thrombosis Sponsor s study number: 15960 NCT number: EudraCT number: Sponsor: Clinical phase: Study objectives: NCT01516814 Not Applicable Bayer Yakuhin III The objective of this study was to evaluate the efficacy, safety, pharmacokinetics (PK) and pharmacodynamics (PD) of rivaroxaban in the treatment of pulmonary embolism (PE) and the prevention of the occurrence and the recurrence of deep vein thrombosis (DVT) or PE in Japanese patients with acute symptomatic PE with or without symptomatic DVT Test drug: Rivaroxaban (Xarelto; BAY 59-7939) Name of active ingredient(s): Rivaroxaban Dose: 15 mg twice daily (bid) for 21 days, followed by 15 mg once daily (od) Route of administration: Oral (tablet) Duration of treatment: Reference drug: Dose: Route of administration: Duration of treatment: Indication: 3, 6 and 12 months (to be determined by the investigator individually at randomization) Unfractionated heparin (UFH), Warfarin UFH: to be adjusted to maintain the activated partial thromboplastin time (aptt) prolongation (1.5 to 2.5 times the control) Warfarin: to be adjusted on the basis of prothrombin time-international normalized ratio (PT-INR) values target range (1.5 to 2.5) UFH: Intravenous Warfarin: Oral UFH: 5 days or more until PT-INR values reach the target range Warfarin: 3, 6 and 12 months (to be determined by the investigator individually at randomization) Acute symptomatic pulmonary embolism

14 Apr 2014 Study no. 15960 Page: 2 of 6 Diagnosis and main criteria for inclusion: Study design: Methodology Study center(s): Men and women 20 years of age in patients with confirmed acute symptomatic PE with or without symptomatic DVT Written informed consent Thrombectomy, insertion of a caval filter, or use of a fibrinolytic agent to treat the current episode of PE More than 48 hours pre-randomization treatment with therapeutic dosages of anti-coagulant treatment or more than a single dose of warfarin from the onset of the current episode of PE to randomization. Calculated creatinine clearance (CL CR ) < 30 ml/min Subjects with hepatic disease which is associated with coagulopathy leading to a clinically relevant bleeding risk Active bleeding or high risk for bleeding contraindicating treatment with UFH or warfarin Systolic blood pressure > 180 mmhg or diastolic blood pressure > 110 mmhg Multi-center, randomized, open-label, assessor-blind, active-controlled, and parallel-group designed study This was a study to evaluate the efficacy, safety, PK and PD of rivaroxaban in the treatment of patients with acute symptomatic PE with or without symptomatic DVT for the prevention of recurrent venous thromboembolic events. 40 patients were planned to be enrolled in this study. Each patient was allocated to either of 2 groups; the rivaroxaban group or the reference group. Allocation to treatment was done centrally by interactive web response system (IWRS) and was be stratified by intended treatment duration. The decision to treat for 3, 6 or 12 months was based on the risk profile of the patient and was made by the investigator at the time of randomization. After randomization, patients allocated to rivaroxaban received rivaroxaban 15 mg bid for a total of 3 weeks followed by rivaroxaban 15 mg od. Patients allocated to the reference received dose adjusted UFH to maintain aptt prolongation (1.5 to 2.5 times the control) that corresponded to plasma heparin levels of 0.3 to 0.7 IU/mL anti-xa activity for at least 5 days in combination with warfarin (overlap 4 to 5 days) and continued with warfarin alone if the PT-INR had been 1.5 on two consecutive measurements at least 24 hours apart. The dose of warfarin was adjusted to maintain PT-INR within 1.5 to 2.5. This study consisted of Screening, Treatment Period 1 (rivaroxaban 15 mg bid or UFH/warfarin was administered in this period): Day 1 to Day 21 (±2 days), Treatment Period 2 (rivaroxaban 15 mg od or warfarin was administered in this period): Day 22 (±2 days) to Day 85 (±7 days), Day 169 (±7 days) or Day 365 (±7 days), and Follow-up visit: 30 days after the end of treatment (±7 days). At the end-of-treatment visit or at an early study medication discontinuation visit, subjects proceeded to an appropriate therapy. Until a follow-up visit, observation was continued. The study was conducted at 24 centers in Japan

14 Apr 2014 Study no. 15960 Page: 3 of 6 Publication(s) based on the study (references): None at the time of report creation Study period: Study Start Date: 20 FEB 2012 Study Completion Date: 15 NOV 2013 Early termination No Number of subjects: Planned: Total 40 subjects: Rivaroxaban group: 32 subjects Reference (UFH + Warfarin) group: 8 subjects Analyzed: More details are given in the section on study subjects below. Criteria for evaluation Efficacy: Safety: The symptomatic VTE (composite endpoint of symptomatic DVT or symptomatic fatal or non-fatal PE). The combination of treatment-emergent major and non-major clinically relevant bleedings. Statistical methods: Substantial protocol changes: Efficacy analysis The primary efficacy analysis was performed in patients valid for intention-to-treat (ITT) analysis. For the primary efficacy endpoint, the point estimate of the incidence rate and the corresponding 2-sided 95% exact confidence interval (CI) were calculated by treatment group. The incidence of any other efficacy variables are tabulated and stratified by treatment group. The ITT on treatment analysis and the per-protocol (PP) analysis was performed as supportive analysis. Safety analysis The safety analysis was performed in the population of subjects valid for safety analysis. For the main safety endpoint, the point estimate of the incidence rate and the corresponding 2-sided 95% exact CI were calculated for each treatment. The incidences of any other safety variables were tabulated and stratified by treatment group. The study was conducted according to final Study Protocol from 14 Dec 2012, and included no substantial amendments.

14 Apr 2014 Study no. 15960 Page: 4 of 6 Subject Disposition and Baseline Of the 40 subjects who were screened, no subjects were screening failures. Subsequently, 33 subjects were randomized to rivaroxaban treatment and 7 to UFH/Warfarin. There was an investigational site which committed the major GCP violation (falsification of data). The study team decided to remove all patients enrolled in this site from all analysis sets (ITT, ITT on treatment, safety, PP, ITT population for secondary efficacy variables and PP population for secondary efficacy variables) in the preliminary validity review meeting on 02 Oct 2013. Because source document couldn t be reliable. In 3 subjects, CUS and sct at baseline, Week 3 or the end of treatment were not conducted within the time frame (+/- 14 days) the planned date. These subjects were excluded from PP population, ITT population for secondary efficacy variables, and PP population for secondary efficacy variables. In 6 subjects, the thrombotic burden evaluations to be made at week 3 or at the end of treatment were done later than 10 days after the last intake of study medication. These subjects were excluded from PP population for secondary efficacy variables. Of the 33 subjects who received rivaroxaban, 15.2% (5/33) of the subjects had an intended treatment duration of 3 months, 48.5% (16/33) had an intended treatment duration of 6 months, and 36.4% (12/33) had an intended treatment duration of 12 months. Of the 7 subjects who received UFH/Warfarin, 14.3% (1/7) of the subjects had an intended treatment duration of 3 months, 42.9% (3/7) had an intended treatment duration of 6 months, and 42.9% (3/7) had an intended treatment duration of 12 months. Efficacy evaluation For ITT population, no recurrence of symptomatic VTE (composite endpoint of symptomatic DVT or symptomatic fatal or non-fatal PE) during the intended treatment was reported in both groups. The improvement in thrombotic burden was confirmed: - For the ITT population for secondary efficacy sets, the incidence rates of improvement at Week 3 were 96.3% (26/27 subjects) in the rivaroxaban group and 100% (7/7) in the UFH/warfarin group. The percentages of subjects with improvement in thrombotic burden at Week 3 for normalized were 14.8% (4/27) in the rivaroxaban group, and 0.0% (0/7) in the UFH/Warfarin group, respectively. The results in the ITT population were similar to that in the ITT population for secondary efficacy sets. - For the ITT population for secondary efficacy sets, the incidence rates of improvement at end of intended treatment period were 100% (27/27) in the rivaroxaban group and 85.7% (6/7) in the UFH/warfarin group. The percentages of subjects with improvement in thrombotic burden at the end of the treatment for normalized were 55.6% (15/27) in the rivaroxaban group, and 14.3% (1/7) in the UFH/Warfarin group, respectively. The results in the ITT population were similar to that in the ITT population for secondary efficacy sets. - For the ITT population for secondary efficacy sets, the incident rates of the composite of symptomatic VTE or asymptomatic deterioration of thrombus during the intended treatment period were 0.0% (0/27) in the rivaroxaban group and 14.3% (1/7) in the UFH/warfarin group. The results in the ITT population were similar to that in the ITT population for secondary efficacy sets. Two subjects in the rivaroxaban group and none in the UFH/Warfarin group had no recurrent VTE but no end of treatment scan available. Regarding the exploratory analysis, the incidence rates of the secondary efficacy variables (Part 2) were totally small and there was no obvious difference between two groups : - The incidence rates of the secondary efficacy outcome until the intended end of treatment were 6.7% (2/30) in the rivaroxaban group and 0% (0/7) in the UFH/Warfarin group for the ITT population (Difference to UFH/Warfarin: 6.7% [95%CI: -30.7% to 23.2%]). - The incidence rates of net clinical benefit 1 until the intended end of treatment were 3.3% (1/30) in the rivaroxaban group and 0% (0/7) in the UFH/Warfarin group for the ITT population (Difference to UFH/Warfarin: 3.3% [95%CI: -34.6% to 17.2%]).

14 Apr 2014 Study no. 15960 Page: 5 of 6 - The incidence rates of net clinical benefit 2 until the intended end of treatment were 10.0% (3/30) in the rivaroxaban group and 0% (0/7)in the UFH/Warfarin group for the ITT population (Difference to UFH/Warfarin: 10.0% [95%CI: -27.0% to 26.2%]). Generally, the study showed consistency throughout the individual components of the primary efficacy outcome, intended treatment duration, demographics, baseline characteristics, and coagulation status. Since the absolute number of events was small, no general conclusion could be drawn based on the results of this study only. Safety evaluation The safety profile of rivaroxaban 15 mg od/bid was comparable to that of UFH/Warfarin. This conclusion is based on the following findings: The incidence rates of TEAEs were 90.0% (27/30 subjects) in the rivaroxaban group and 100% (7/7) in UFH/Warfarin group The incidence rates of drug-related TEAE were 50.0% (15/30) in the rivaroxaban group and 57.1% (4/7) in the UFH/Warfarin group There were 2 deaths reported in rivaroxaban group ( cardiac failure and shock haemorrhagic ). Causal relationships to study drug were denied. - On Day 2, the study drug was discontinued permanently due to liver enzymes elevation (ALT 55 U/L [baseline] to 305 U/L [Day 2]) and marketed warfarin and UFH started on that day for treatment of PE. On Day 5, gastrointestinal hemorrhage was observed. Marketed warfarin and UFH continued. On Day 10, the subject died due to shock hemorrhage. - On Day 21, the subject was hospitalized to the other hospital due to pneumonia and cardiac failure, and the study drug was discontinued permanently on Day 127, The subject died due to cardiac failure on Day 154. The incidence rates of SAEs were 23.3% (7/30) in the rivaroxaban group and 0.0% (0/7) in UFH/Warfarin group. - There were no drug-related TESAEs reported. The incidence rates of the treatment-emergent principle safety outcome based on the first event occurring were 3.3% (1/30) in the rivaroxaban group and 0.0% (0/7) in the UFH/Warfarin group (Difference to UFH/Warfarin: 3.3% [95%CI: -34.6% to 17.2%]). The incidence rates of major bleeding were 0.0% (0/30) in the rivaroxaban group and 0.0% (0/7) in the UFH/Warfarin group for the safety population (Difference to UFH/Warfarin: 0.0% [95%CI: -25.0% to 6.2%]). The incidence rates of non-major clinically relevant bleeding were 3.3% (1/30) in the rivaroxaban group and 0.0% (0/7) in the UFH/Warfarin group for the safety population (Difference to UFH/Warfarin: 3.3% [95%CI: -34.6% to 17.2%]). One clinically relevant non-major bleeding was observed for the skin (other than injection site) at 3.3% (1/30) in the rivaroxaban group. The incidence rates of all confirmed treatment-emergent bleeding events were 36.7% (11/30) in the rivaroxaban group and 57.1% (4/7) in the UFH/Warfarin group. During the on-treatment period, there was no cardiovascular event reported in both treatment groups. There were 5 subjects who showed ALT elevations >3 x ULN (rivaroxaban group: 13.3% [4/30], UFH/Warfarin group: 14.3% [1/7]). 20.0% (6/30) of the subjects in the rivaroxaban group had hepatic disorder AEs compared with 42.9% (3/7) subjects in the UFH/Warfarin group. No combined concurrent elevations of ALT >3 x ULN/total bilirubin >2 x ULN, AST >3 x ULN/total bilirubin >2 x ULN, ALT >3 x ULN/total bilirubin >2 x ULN/direct/total bilirubin 50%, and AST >3 x ULN and total bilirubin >2 x ULN/direct/total bilirubin 50%, (measurement from central laboratory) occurred in any treatment groups.

14 Apr 2014 Study no. 15960 Page: 6 of 6 Overall conclusions Overall, the results of this study demonstrated that rivaroxaban 15 mg bid/od regimen (rivaroxaban 15 mg bid for a total of 3 weeks followed by rivaroxaban 15 mg od) was well tolerated in the treatment of PE and the prevention of the occurrence and the recurrence of DVT or PE in Japanese patients with acute symptomatic PE with or without symptomatic DVT. The numbers of each efficacy event is small in general. Almost all the subjects in both groups showed the improvement in thrombotic burden.

Appendix to Clinical Study Synopsis Product Identification Information Product Type US Brand/Trade Name(s) Brand/Trade Name(s) ex-us Generic Name Main Product Company Code Drug Xarelto Xarelto rivaroxaban BAY59-7939 Other Company Code(s) Chemical Description Other Product Aliases IUPAC Name: 5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4- morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2- thiophenecarboxamide Date of last Update/Change: 04 Mar 2013