Clinical Study Synopsis

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1 Clinical Study Synopsis This Clinical Study Synopsis is provided for patients and healthcare professionals to increase the transparency of Bayer's clinical research. This document is not intended to replace the advice of a healthcare professional and should not be considered as a recommendation. Patients should always seek medical advice before making any decisions on their treatment. Healthcare Professionals should always refer to the specific labelling information approved for the patient's country or region. Data in this document or on the related website should not be considered as prescribing advice. The study listed may include approved and non-approved formulations or treatment regimens. Data may differ from published or presented data and are a reflection of the limited information provided here. The results from a single trial need to be considered in the context of the totality of the available clinical research results for a drug. The results from a single study may not reflect the overall results for a drug. The following information is the property of Bayer HealthCare. Reproduction of all or part of this report is strictly prohibited without prior written permission from Bayer HealthCare. Commercial use of the information is only possible with the written permission of the proprietor and is subject to a license fee. Please note that the General Conditions of Use and the Privacy Statement of bayerhealthcare.com apply to the contents of this file.

2 Date: 22 FEB 2017 Study No Page: 1 of Date of report: 22 FEB 2017 Study title: Sponsor s study number: NCT number: Reduced-dosed rivaroxaban and standard-dosed rivaroxaban versus ASA in the long-term prevention of recurrent symptomatic venous thromboembolism in patients with symptomatic deep-vein thrombosis and/or pulmonary embolism. The EINSTEIN CHOICE Study NCT EudraCT number: Sponsor: Clinical phase: Study objectives: Bayer AG III 1. The primary efficacy objective was to evaluate whether rivaroxaban, in doses of 10 mg or 20 mg, is superior to acetylsalicylic acid (ASA) 100 mg in the prevention of the primary efficacy outcome (i.e. fatal or non-fatal symptomatic recurrent venous thromboembolism [VTE]). 2. The secondary efficacy objective was to evaluate whether rivaroxaban, in doses of 10 mg or 20 mg, is superior to ASA 100 mg in the prevention of the secondary efficacy outcome (i.e. fatal or non-fatal symptomatic recurrent VTE, myocardial infarction [MI], ischemic stroke, systemic noncentral nervous system [CNS]-embolism). 3. The principal safety objective was to document the incidence of the principal safety outcome (i.e. major bleeding). 4. The secondary safety objective was to document the incidence of the secondary safety outcome (i.e. clinically relevant non-major bleeding). 5. Additional study objectives were to evaluate a. the composite of non-fatal symptomatic VTE and allcause mortality b. the composite of major bleeding and recurrent VTE c. the composite of major bleeding, recurrent VTE, MI, ischemic stroke and systemic non-cns embolism Test drug: Rivaroxaban (Xarelto, BAY ) Name of active ingredient(s): Rivaroxaban / BAY

3 Date: 22 FEB 2017 Study No Page: 2 of 10 Dose: Route of administration: Oral Duration of treatment: Reference drug: Dose: Route of administration: Oral Duration of treatment: Reference drug: Dose: Route of administration: Oral Duration of treatment: Indication: Diagnosis and main criteria for inclusion: Study design: Methodology 10 mg as immediate-release film coated tablet, once daily 20 mg as immediate-release film coated tablet, once daily Planned: 12 months. Patients randomized last into the study received study medication for 6 months only. Treatment of all patients stopped 6 months after the last patient was randomized and resulted in an individual treatment duration of 12, 9 to less than 12, or 6 months depending on the date of randomization Acetylsalicylic acid (ASA) 100 mg as enteric-coated tablet, once daily Planned: 12 months. Individual treatment duration of 12, 9 to less than 12, or 6 months depending on the date of randomization. Placebo (matching rivaroxaban or ASA) Not applicable. Since the study had a double-dummy design, patients received 2 tablets: 1 tablet of the active study medication and 1 placebo tablet to ensure blinding. Planned: 12 months. Individual treatment duration of 12, 9 to less than 12, or 6 months depending on the date of randomization. Long-term prevention of recurrent symptomatic venous thromboembolism Subjects with confirmed symptomatic deep vein thrombosis (DVT) and/or pulmonary embolism (PE) who completed 6 to 12 months (± 1 months) of anticoagulant therapy for their index acute VTE event and did not interrupt anticoagulation for longer than 1 week Multicenter, randomized, double-blind, double-dummy, activecomparator study. Event-driven, requiring at least 80 confirmed primary efficacy outcomes. Subjects were randomized to receive once daily either: 1. Rivaroxaban 10 mg, 2. Rivaroxaban 20 mg, or 3. ASA 100 mg for a duration of 12 months. Patients randomized last into the study were to be treated for 6 months only. Treatment of all

4 Date: 22 FEB 2017 Study No Page: 3 of 10 patients stopped 6 months after the last patient was randomized and resulted in an individual treatment duration of 12, 9 to less than 12, or 6 months depending on the date of randomization. Randomization was stratified by country and index event (i.e. DVT or PE ± DVT). All index DVTs and/or PEs and suspected recurrent VTEs, myocardial infarctions, ischemic strokes, systemic non-cns embolic events, death and all episodes of bleeding were evaluated by a central, blinded, independent adjudication committee. Adjudication results were the basis for the final analyses. An independent data monitoring committee monitored the patients safety during the study and give recommendations to the steering committee. The study had 7 planned visits. At Visit 4, the interactive web/voice response system (IxRS) was contacted to determine if additional study medication was to be provided. At Visit 6, study medication was stopped. Continuation with anticoagulant or antiplatelet therapy after the study was at the discretion of the treating physician. At all visits/telephone contacts, potential study outcomes and adverse events were elucidated. Visit 7 was the post-study drug observational visit (telephone or clinic visit). If a subject discontinued study treatment prematurely and the post-study drug observational visit was performed, all other study visits needed to take place, unless the subject had refused to further participate in the study. Study center(s): 244 recruiting centers in Australia (10), Austria (4), Belgium (5), Brazil (9), Canada (12), China (31), Czech Republic (9), Denmark (7), France (24), Germany (10), Hungary (7), Israel (10), Italy (9), South Korea (7), Mexico (4), The Netherlands (10), New Zealand (6), Norway (2) Philippines (1), Poland (5), Russia (11), South Africa (7), Spain (5), Sweden (2), Switzerland (6), Taiwan (3), Thailand (2), Turkey (2), United Kingdom (4), United States (17), Vietnam (3) Publications based on the study (references): Weitz JI, Bauersachs R, Beyer-Westendorf J, Bounameaux H, Brighton TA, Cohen AT, Davidson BL, et al. Two doses of rivaroxaban versus aspirin for prevention of recurrent venous thromboembolism. Rationale for and design of the EINSTEIN CHOICE study. Thromb Haemost. 2015;114 (3): Study period: First subject, first visit: 05 MAR 2014 Early termination Last subject, last visit: 04 NOV 2016 No

5 Date: 22 FEB 2017 Study No Page: 4 of 10 Number of subjects: Planned: In this event-driven study, the goal was to reach 80 confirmed recurrent thromboembolic events; number of subjects randomized was based on the observed events. The expected number was 2850 subjects (950 subjects per treatment arm). The number was adjusted to 3300 patients based on the observed overall incidence of the primary efficacy outcome and considering the anticipated number of patients with administrative censoring. Criteria for evaluation Efficacy: Safety: Statistical methods: Analyzed: Full analysis set (FAS): 3365 subjects Per protocol set (PPS): 3178 subjects More details are given in the section on study subjects below. The primary efficacy outcome was the composite of fatal or non-fatal symptomatic recurrent VTE including unexplained death and PE cannot be ruled out. The secondary efficacy outcome was the composite fatal or non-fatal symptomatic recurrent VTE, MI, ischemic stroke, non- CNS systemic embolism. Additional efficacy outcomes were: a) The composite of non-fatal symptomatic VTE or all-cause mortality. b) The composite of major bleeding or the primary efficacy outcome. c) The composite of major bleeding or the secondary efficacy outcome. The principal safety outcome was major bleeding (defined according to the criteria of the International Society on Thrombosis and Hemostasis [ISTH]). The secondary safety outcome was clinically relevant nonmajor (CRNM) bleeding (defined as non-major bleeding associated with a study drug interruption of more than 14 days). Composite efficacy outcomes were analyzed based on time to first event in the intended individual treatment period, using a stratified (strata: index event, i.e., DVT only or PE with or without DVT as indicated at randomization by the investigator) Cox proportional hazard model in the full analysis set (FAS). Adjudication results were the basis for the final analyses. Supportive analyses were done on the per protocol set (PPS). The use of the FAS as primary analysis set instead of an intentto-treat (ITT) approach is justified based on the randomized, controlled, double-blind design of the trial. The FAS includes all

6 Date: 22 FEB 2017 Study No Page: 5 of 10 randomized patients who received at least one dose of study medication. Patients who did not take study medication were excluded from the FAS, because 1. they violated an in/exclusion criterion and this criterion was measured objectively before randomization and/or 2. the decision of whether or not to begin treatment could not be influenced by knowledge of the assigned treatment as recommended by the International Council for Harmonisation (ICH) E9 Guidance on Statistical Principles for Clinical Trials. If one of the two conditions above holds true, then the possibility of introducing bias by excluding patients who did not take study medication is negligible. The PPS excludes patients with insufficient compliance (<80%) to the study medication or with other major protocol deviation(s). The primary analysis used a hierarchical (fixed sequence) testing procedure to control the family-wise error rate for testing superiority of the individual rivaroxaban doses vs. ASA. The rivaroxaban 20 mg vs. ASA 100 mg comparison was tested first and, if significant, then the rivaroxaban 10 mg vs. ASA 100 mg comparison was tested. Each of these tests used a 2-sided alpha level of The rivaroxaban 20 mg to ASA 100 mg and the rivaroxaban 10 mg to ASA 100 mg hazard ratios (HRs) were computed with 95% confidence interval (CI) from the Cox proportional hazard model. Based on the estimates from this model, rivaroxaban 20 mg was considered superior to ASA 100 mg, if the upper limit of the CI for the HR was less than 1. Rivaroxaban 10 mg was considered superior, if rivaroxaban 20 mg was superior to ASA 100 mg and the upper limit of the 95% CI for the rivaroxaban 10 mg vs. ASA 100 mg was less than 1. HR estimate and its 95% CI were to be provided for the comparison of rivaroxaban 20 mg vs. rivaroxaban 10 mg. The primary efficacy analysis was adjusted to control the familywise type I error rate. All other analyses presented were not adjusted for multiplicity. In addition, superiority of either rivaroxaban doses vs. ASA was tested with a stratified log rank test, as supportive analysis. Assuming an HR of 0.40 for rivaroxaban 10 mg/asa 100 mg and an HR of 0.30 for rivaroxaban 20 mg/asa 100 mg, a total of 80 primary efficacy outcomes were expected to give a power of 90% to demonstrate that both dosages of rivaroxaban were superior to ASA. Patients without a primary efficacy outcome were censored using the minimum of last visit date and end date of the individual intended treatment duration. All patients who prematurely stopped study treatment for other reasons than withdrawal of consent had to have follow-up until

7 Date: 22 FEB 2017 Study No Page: 6 of 10 Substantial protocol changes: the end of their individual intended treatment period to enable a complete and comprehensive evaluation of the study and study drug until the end of their individual intended treatment period. For missing data, appropriate imputation strategies were implemented. The study was conducted according to the final study protocol (Version 1.0, dated 26 Nov 2013) and did not include any substantial amendments. Study subjects 3439 patients were screened at 244 sites in 31 countries, of which 43 did not pass screening. Thus, 3396 patients were randomly assigned to treatment, of which 31 patients never received study medication. Thus, 3365 patients were valid for the FAS: 1107 patients were treated with rivaroxaban 20 mg, 1127 patients with rivaroxaban 10 mg, and 1131 patients with ASA 100 mg. Based on the FAS, 187 patients were excluded from the PPS. Thus, 3178 patients were valid for the PPS: 1046 patients in the rivaroxaban 20 mg group, 1063 patients in the rivaroxaban 10 mg group, and 1069 patients in the ASA 100 mg group. Overall, 463 patients (13.8%) in the FAS discontinued treatment prematurely resulting in 2902 patients (86.2%) completing the treatment. More specifically, 138 patients (12.5%) on rivaroxaban 20 mg, 143 patients (12.7%) on rivaroxaban 10 mg, and 182 patients (16.1%) on ASA 100 mg prematurely discontinued treatment (FAS). The vast majority of patients (rivaroxaban 20 mg: 1074 patients [97.0%], rivaroxaban 10 mg: 1091 patients [96.8%], ASA 100 mg: 1095 patients [96.8%]) completed their individual treatment duration of 6, 9 to less than 12, or 12 months (FAS). The post-study drug observational period was completed by 1077 patients (97.3%) in the rivaroxaban 20 mg group, 1107 patients (98.2%) in the rivaroxaban 10 mg group and 1107 patients (97.9%) in the ASA 100 mg group. There were no relevant differences in baseline characteristics and demographics between the treatment groups (FAS). 55.4% of patients were male. The race of patients was white for 69.7%, Asian for 14.2%, and black or African American for 3.7%. For 11.9% of the patients, no information is available as in some participating countries it is not permitted to collect data on race. The age ranged from 18 to 97 years with a mean age of 58.5 years (SD: 14.7 years). 11.7% of patients were above 75 years of age, 27.3% were between 65 and 75 years, 61.0% were younger than 65 years. Mean BMI was kg/m2 (SD: 5.67g/m 2 ) with a range from 15.8 to 69.2 kg/m 2. Efficacy evaluation The primary efficacy outcome was recurrent VTE defined as composite of fatal or non-fatal symptomatic recurrent VTE, including unexplained death for which PE could not be ruled out (as confirmed by the central independent adjudication committee [CIAC]) up to the end of the individual intended duration of treatment.

8 Date: 22 FEB 2017 Study No Page: 7 of 10 The incidence rates of the primary efficacy outcome events were lower with rivaroxaban 20 mg and 10 mg compared with ASA 100 mg, as were the incidence rates of most components of the secondary as well as additional and exploratory outcomes, and across the in the FAS. Similar results were seen in the PPS. This study met its primary objective by showing superiority in the primary efficacy analysis for both rivaroxaban 20 mg and 10 mg compared with ASA 100 mg based on the pre-defined hierarchical testing procedure: the comparison of rivaroxaban 20 mg vs. ASA 100 mg demonstrated a HR of 0.34 (95% CI, 0.20 to 0.59; p=0.0001) and the comparison of rivaroxaban 10 mg vs. ASA 100 mg demonstrated a HR of 0.26 (95% CI, 0.14 to 0.47; p<0.0001). Since the upper limits of the CIs were below the pre-defined superiority criterion (upper limit of the CI less than 1), it was demonstrated that both doses of rivaroxaban were superior to ASA 100 mg. The results were also confirmed when using the stratified log rank test as supportive analysis and using the informative missingness hazard ratio (IMHR) as sensitivity analysis. Comparison of efficacy FAS PPS Primary efficacy outcome up to the end of the individual intended treatment duration Rivaroxaban 20 mg [n/n (%)] 17/1107 (1.5%) 14/1046 (1.3%) Rivaroxaban 10 mg [n/n (%)] 13/1127 (1.2%) 11/1063 (1.0%) ASA 100 mg [n/n (%)] 50/1131 (4.4%) 48/1069 (4.5%) Rivaroxaban 20 mg vs. ASA 100 mg Hazard ratio (95% CI) 0.34 ( ) 0.29 ( ) p-value a < p-value stratified log rank test b < < Rivaroxaban 10 mg vs. ASA 100 mg Hazard ratio (95% CI) 0.26 ( ) 0.23 ( ) p-value a < < p-value stratified log rank test b < < Rivaroxaban 20 mg vs. rivaroxaban 10 mg Hazard ratio (95% CI) 1.34 ( ) 1.30 ( ) p-value a p-value stratified log rank test b Individual actual treatment duration: 6, 9 to less than 12, or 12 months P-value and hazard ratio estimates based on stratified proportional hazards model, with stratification based index event (DVT or PE ± DVT). a) The asymptotic 2-sided p-value from the Cox model was calculated from the Wald test. Wald CIs were calculated for the effect estimate. b) Stratified log rank test (strata by index event, i.e., DVT or PE ± DVT) was performed as supportive analysis. ASA = acetylsalicylic acid, CI = confidence interval, FAS = full analysis set, PPS = per protocol set The results of the primary efficacy analysis were confirmed for the secondary efficacy outcome, where the comparison of rivaroxaban 20 mg vs. ASA 100 mg demonstrated a HR of 0.34 (95% CI, 0.20 to 0.57; p<0.0001) and the comparison of rivaroxaban 10 mg vs. ASA 100 mg demonstrated a HR of 0.32 (95% CI, 0.19 to 0.54; p<0.0001, FAS). The results of the Cox proportional hazard model for the additional outcomes (non-fatal symptomatic VTE or all-cause mortality, major bleeding or the primary efficacy outcome, major bleeding or the secondary efficacy outcome) were also consistent with the results of the primary and secondary efficacy analyses (FAS).

9 Date: 22 FEB 2017 Study No Page: 8 of 10 The results of the FAS were also supported by the PPS as sensitivity analysis, with even more favorable HRs and 95% CIs, confirming the benefit of long-term treatment with rivaroxaban 20 mg or 10 mg. Additionally, the rivaroxaban 20 mg was compared to rivaroxaban 10 mg for all efficacy outcomes. The resulting HRs and 95% CIs indicated no significant differences between the two rivaroxaban doses, even if numerically the incidences of the efficacy outcomes were slightly lower in the rivaroxaban 10 mg group than in the rivaroxaban 20 mg group up to the end of individual intended treatment period. Using the reciprocal testing analysis that was introduced as a post-hoc calculation, the results of the primary efficacy outcome indicated similar efficacy between rivaroxaban 10 mg and 20 mg (HR: 0.77, 95%CI, 0.35 to 1.69). In addition to the composite endpoint of major bleeding or primary efficacy outcome, the net clinical benefit was calculated based on benefit and harm estimates calculated on the absolute risk difference scale for rivaroxaban 20 mg vs. ASA 100 mg, rivaroxaban 10 mg vs. ASA 100 mg, and rivaroxaban 20 mg vs. rivaroxaban 10 mg. Both rivaroxaban groups had a favorable net clinical benefit over the ASA 100 mg group, and the net clinical benefit was similar in the two rivaroxaban groups: rivaroxaban 20 mg vs ASA 100 mg with 2.61% (95% CI: 1.13 to 4.14) and rivaroxaban 10 mg vs ASA 100 mg with 3.09% (95% CI: 1.70 to 4.57). Safety evaluation Of the 3396 randomized patients, 3365 were included in the FAS; a total of 1107 patients were exposed to rivaroxaban 20 mg, 1127 patients to rivaroxaban 10 mg, and 1131 patients to ASA 100 mg. The results indicate a comparable safety profile of rivaroxaban when compared to ASA. This conclusion is based on the following findings: The incidence rates of the principal safety outcome (i.e., first treatment-emergent major bleeding event by ISTH criteria) were low and not significantly different in all 3 treatment groups (rivaroxaban 20 mg: 0.5% [6/1107]; rivaroxaban 10 mg: 0.4% [5/1127]; ASA 100 mg 0.3% [3/1131]). The HRs for the 3 comparisons rivaroxaban 20 mg vs. ASA 100 mg, rivaroxaban 10 mg vs. ASA 100 mg and rivaroxaban 20 mg vs. rivaroxaban 10 mg were 2.01 (0.50 to 8.04); 1.64 (0.39 to 6.84); 1.23 (0.37 to 4.03), respectively. Regarding the first treatment-emergent major bleeding, the following results were obtained: 2 patients had treatment-emergent fatal bleedings. 1 patient (rivaroxaban 20 mg) had a pericardial bleeding due to a dissection of the aorta and 1 patient (ASA 100 mg) had a spontaneous intracranial bleeding. 7 patients had non-fatal critical organ bleedings. Of these, 5 had an intracranial bleeding (rivaroxaban 20 mg: n=3; rivaroxaban 10 mg: n=2; ASA 100 mg: n=1), 1 patient had an intramuscular bleeding (rivaroxaban 10 mg), and 1 patient had a pulmonary bleeding (rivaroxaban 20 mg). 5 patients had non-fatal, non-critical organ bleedings (fall in Hb 2 g/dl and/or transfusions 2 units). Of these, 4 had gastrointestinal bleedings (rivaroxaban 20 mg: n=1; rivaroxaban 10 mg: n=2; ASA 100 mg: n=1), and 1 patient had an intraabdominal bleeding (rivaroxaban 20 mg).

10 Date: 22 FEB 2017 Study No Page: 9 of 10 The incidence rates of the secondary safety outcome (i.e., first treatment-emergent clinically relevant non-major (CRNM) bleeding defined as non-major bleeding associated with a study drug interruption of more than 14 days) were not significantly different in the 3 treatment groups (rivaroxaban 20 mg: 1.5% [17/1107]; rivaroxaban 10 mg: 1.1% [12/1127]; ASA 100 mg 1.1% [12/1131]). The HRs for the 3 comparisons rivaroxaban 20 mg vs. ASA 100 mg, rivaroxaban 10 mg vs. ASA 100 mg and rivaroxaban 20 mg vs. rivaroxaban 10 mg were 1.44 (0.69; 3.02); 0.99 (0.44; 2.20), 1.46 (0.70; 3.06), respectively. Regarding the most frequent location of the first treatment-emergent CRNM bleeding, the following results were obtained: 10 patients had gastrointestinal tract bleedings (rivaroxaban 20 mg: n=6; rivaroxaban 10 mg: n=2; ASA 100 mg: n=2). 7 patients (all females) had genital bleedings (rivaroxaban 20 mg: n=4; rivaroxaban 10 mg: n=3; ASA 100 mg: n=0). 4 patients had skin (other than injection site) bleedings (rivaroxaban 20 mg: n=0; rivaroxaban 10 mg: n=3; ASA 100 mg: n=1). All cases of death were assessed by the CIAC. A total of 20 patients died after randomization (rivaroxaban 20 mg: 0.9% [10/1107]; rivaroxaban 10 mg: 0.3% [3/1127]; ASA 100 mg: 0.6% [7/1131]. 7 of the 20 patients died due to adjudicated outcome events (2 bleeding events, 1 PE, 3 unexplained death and PE cannot be ruled out, and 1 MI) and 13 patients died due to other causes of deaths. Out of the 20 deaths, 3 deaths occurred outside the individual intended treatment period and 17 deaths occurred within the individual intended treatment period. In total, 15 fatal AEs were reported by the investigator (rivaroxaban 20 mg: 0.7% [8/1107]; rivaroxaban 10 mg: 0.3% [3/1127]; ASA 100 mg: 0.4% [4/1131]), among these, 3 were adjudicated by the CIAC as outcome events. The incidence of TEAEs and TESAEs (targeted SAE/AE reporting) was similarly distributed between the 3 treatment groups (rivaroxaban 20 mg: 16.2%; rivaroxaban 10 mg: 15.9%; and ASA 100 mg: 15.5% and rivaroxaban 20 mg group 7.6%, rivaroxaban 10 mg group 8.7%, and ASA 100 mg group 8.4%, respectively). Premature discontinuation of study medication due to TEAEs was also similar across the 3 treatment groups (rivaroxaban 20 mg: 4.4%; rivaroxaban 10 mg: 4.3%, and ASA 100 mg: 4.0%). AEs of special interest were 1) Hb < 10 g/dl / anemia, 2) White blood cells < 3.0 GIGA/L / Neutrophils < 0.5 GIGA/L / Leukopenia-related AEs, 3) Platelets < 50 GIGA/L / thrombocytopenia, and 4) allergic skin/systemic reactions. There was only a low number of AEs of special interest and the number of events across treatment groups was similar. As reported, the increase in the menstrual flow length from 353 women with menstrual cycles ranged from 11.9% to 17.7% (rivaroxaban 20 mg), from 5.6% to 11.9% (rivaroxaban 10 mg), and from 9.2% to 12.3% (ASA 100 mg). The increase in menstrual flow intensity ranged from 19.0% to 24.2% (rivaroxaban 20 mg), from 14.3% to 20.8% (rivaroxaban 10 mg), and from 12.9% to 20.2% (ASA 100 mg).

11 Date: 22 FEB 2017 Study No Page: 10 of 10 Separate analyses of urogenital bleedings in women <60 years of age (61 women in total) resulted in a higher incidence of bleedings in the rivaroxaban groups vs. ASA 100 mg (20 mg: 12.9%, 10 mg: 10.3%; ASA 100 mg: 3.2%). No major urogenital bleedings occurred. The incidence of CRNM bleeding was similarly distributed in the 2 rivaroxaban groups. The vast majority were trivial bleedings with the highest proportion in the rivaroxaban 20 mg group (10.0%) compared to 8.5% (rivaroxaban 10 mg) and 2.8% (ASA 100 mg). A total of 10 out of 819 women 60 years of age had any confirmed urogenital bleeding with a higher incidence in the rivaroxaban 20 mg group (2.7%) compared to rivaroxaban 10 mg (0.4%) and ASA 100 mg (0.7%). A total of 13 pregnancies were reported during the study. Of these, 12 were in randomized patients and 1 was the partner of a male patient. In the rivaroxaban 20 mg group, 6 pregnancies were reported (2 abortions, 1 early miscarriage, 1 pre-term birth, 1 unknown case, 1 exposure via father). In the rivaroxaban 10 mg group, 4 pregnancies were reported (2 elective abortions, 2 unknown cases). In the ASA group, 2 pregnancies were reported (1 elective abortion, 1 full term live birth). An additional pregnancy occurred in a patient who was randomized in error and never received study medication. In addition to the time of the first bleeding event analysis, the pattern of multiple bleedings within patients was analyzed. The time to recurrent event analyses considering multiple bleeding events led to similar results as the time to first event analyses. Overall conclusions In the Einstein CHOICE study, rivaroxaban 20 mg and 10 mg were superior to ASA 100 mg in the long-term prevention of recurrent VTE and demonstrated no significant differences in bleeding rates. No new adverse drug reaction was identified in the study. In addition, patients treated with rivaroxaban 20 mg and 10 mg had comparable efficacy and safety outcome rates. Both rivaroxaban groups had a favorable net clinical benefit over the ASA 100 mg group, and the net clinical benefit was similar in the two rivaroxaban groups. Thus, rivaroxaban 10 mg is an additional treatment option to the approved 20 mg dose for long-term prevention of recurrent VTE. This may allow patients and physicians to adapt the individual rivaroxaban dose based on the individual assessment of the patient s risk profile (including risk of recurrent VTE vs. risk of bleeding).

12 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 BAY 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