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 Pharmaceuticals Inc. Reproduction of all or part of this report is strictly prohibited without prior written permission from Bayer HealthCare Pharmaceuticals Inc. 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 Clinical Trial Results Synopsis Study Design Description Study Sponsor: Bayer HealthCare Pharmaceuticals Inc. Study Number: (XA0801) NCT Study Phase: IV (Prospective Non-Interventional) Test Product Official Study Title: XAMOS - Xarelto in the prophylaxis of post-surgical venous thromboembolism after elective major orthopedic surgery of hip or knee Therapeutic Area: CV Risk Management Name of Test Product: Name of Active Ingredient: Dose and Mode of Administration: Rivaroxaban (Xarelto, BAY ) Rivaroxaban Non-interventional study (NIS): dose of drug and mode of administration solely at the discretion of the attending physician (recommended dose according to the summary of product characteristics of Xarelto 10 mg film coated tablet: 10 mg rivaroxaban taken orally once daily) Reference Therapy/Placebo Reference Therapy: Standard of care: any other pharmacological treatment for VTE (venous thromboembolism) prophylaxis (e.g. Fondaparinux, Lowmolecular-weight-heparins [LMWH], vitamin K antagonists [VKA]) Dose and Mode of Administration: Non-interventional study: dose of drug and mode of administration solely at the discretion of the attending physician. Duration of Treatment: Non-interventional study: duration of treatment solely at the discretion of the attending physician Studied period: Date of first subjects first visit: 18 Feb 2009 Date of last subjects last visit: 01 Feb 2013 XAMOS was an international non-interventional study conducted in 39 countries worldwide. The results from the first worldwide analysis (i.e. analysis conducted for European Medicines Agency (EMA)) included 17,701 enrolled patients from 37 countries that were in the database until 18-Aug-2011 (data lock point for EMA analysis). This analysis will be referred to as worldwide analyses in this document. End of enrollment for the EMA analysis was the 3-Feb Three countries (Korea, Philippines and Switzerland) could continue to enroll new patients after this date. In addition, two countries (India and Vietnam) started enrollment after February All patients from those 5 countries which could not be locked on 18-Aug-2011 or which were enrolled after 3-Feb-2011 are referred to as patients post locked. This synopsis summarizes also the analyses for all post locked patients which will be referred to as post EMA in this document. Premature Study Suspension / Termination: Not applicable Page 1 of 6

3 Substantial Study Protocol Amendments: There was one protocol amendment dated 16 Sep 2009 during the course of the study which was generated for the sites in Switzerland. In Switzerland, rivaroxaban was indicated not only for elective hip or knee replacement, but also for any major surgery of the lower limbs. Therefore, the amendment primarily changed the inclusion criteria, allowing the inclusion of patients with any major lower limb surgery to be included into the study. In Switzerland the concept of non-interventional studies according to EU Directive 2001/20/EC does not exist. Therefore, XAMOS-SWISS was conducted as an interventional Phase IV study as agreed with Swissmedic. Study Center(s): For EMA analysis: 260 investigational sites in 37 countries: 252 sites enrolled patients: Australia (5), Austria (5), Belgium (6), Bosnia & Herzegovina (2), Canada (3), Chile (1), China (19), Colombia (5), Cyprus (3), Czech Republic (8), Denmark (4), Finland (5), France (20), Germany (32), Greece (7), Hong Kong (2), Hungary (5), Italy (19), Korea (17), Latvia (2), Lebanon (2), Lithuania (6), Macedonia (3), Mexico (5), Netherlands (15), Norway (3), Philippines (1), Portugal (2), Serbia (3), Singapore (2), Slovakia (5), Spain (15), Sweden (8), Switzerland (2), United Arab Emirate (1) United Kingdom (8) and Venezuela (1). Post EMA: 37 investigational sites treated 1375 patients in 5 countries (India, Korea, Philippines, Switzerland and Vietnam). Methodology: The study was a prospective, international, non-interventional cohort comparison of rivaroxaban vs. any other pharmacological standard treatment for the prophylaxis of VTE after major orthopedic surgery. Indication/ Main Inclusion Criteria: Study Objectives: Patients were followed from the time when VTE prophylaxis treatment was initiated up until 3 months after surgery. Data were recorded in standardized case report forms (CRFs). In some countries, an electronic data capture system (EDC) was used to record the data. The other countries used paper (CRFs). Inclusion criteria: Female and male patients aged 18 years and who were undergoing elective hip or knee arthroplasty (or hip fracture surgery where indicated) and receiving rivaroxaban or other pharmacological standard treatment for VTE prophylaxis. Note: the regulatory approval in Switzerland for rivaroxaban includes fracture related surgery. Exclusion criteria: In conjunction with the local product information. Primary objective of the study was to collect data on serious and nonserious adverse events (AEs), such as: Bleeding events Any symptomatic thromboembolic events (e.g. deep vein thrombosis [DVT], pulmonary embolism [PE]) Uncommon AEs (event rate between 0.1% and 1%) All-cause mortality. The analysis compared The group of patients treated with rivaroxaban with the group treated with any standard VTE prevention therapy (called standard of care group). Page 2 of 6

4 Evaluation Criteria: Statistical Methods: Main: Bleeding events reported as serious or non-serious AEs. Symptomatic thromboembolic events reported as serious or non-serious AEs. The analysis was performed on the full safety analysis set, defined as all patients who: took at least one dose of a VTE prophylactic drug. Patients were assigned to the analysis groups according to the initially used post-surgery VTE prophylactic drug. The EMA analysis was performed on the safety analysis set (17,413 patients). The propensity score method was used to derive an analysis population with balanced baseline covariates (16,516 adjusted full safety sets). For the post EMA analysis the safety analysis set consisted of 1,353 patients All issues concerning patient data consistency checks, permissible data modifications, and coding of medical terms and concomitant medication were described in detail in the Data Management Plan. Particularly, the classification of major and non-major bleeding events was described in the Database Structure. All statistical issues including calculated variables are detailed in the Statistical Analysis Plan (SAP). Safety: All AEs as well as treatment-emergent AEs were evaluated. Treatment-emergent events were defined as events that started on or after the day of the first dose of a VTE prophylactic drug and up to 2 days after the last dose. All patients with AEs were listed with all details from the AE report form and coded according to Medical Dictionary for Regulatory Activities (MedDRA), version 14.0 (EMA analysis) or 15.1 (post EMA), with preferred term (PT) and system organ class (SOC). Patients who died were listed with type and duration of VTE prophylaxis, concomitant medication (including indication) as well as details from all reported AEs. Bleeding events were a subset of AEs and after documentation they were differentiated automatically between major and non-major bleeding events according to two different systems definitions of major bleeding: the adjudication rules as used in the phase III study RECORD 1 (NCT ) The European Medicines Agency (EMA) guideline on clinical investigation of medical products for prophylaxis of high intraand post-operative venous thromboembolic risk. The EMA definition is similar to the phase III study major bleeding definition but with the inclusion of bleeding warranting treatment cessation and surgical-site bleeding events associated with a fall in hemoglobin of 2 g/dl or leading to a transfusion of 2 units of blood or packed cells. Thromboembolic events were a subset of AEs and were reviewed by the Executive Steering Committee in a blinded manner and classified as symptomatic or asymptomatic events. All three types of thromboembolic events were analyzed: Total thromboembolic events (i.e. symptomatic and asymptomatic thromboembolic events) Symptomatic thromboembolic events Page 3 of 6

5 Asymptomatic thromboembolic events Symptomatic thromboembolic events were grouped in arterial or venous events. Number of Subjects: In the worldwide analysis (i.e. EMA analysis), XAMOS enrolled a total 17,701 patients of which the safety analysis set consisted of 17,413 patients. Note: Post-EMA patients were not included in the worldwide analysis. Results Summary Subject Disposition and Baseline Post EMA, a total of 1,375 patients were enrolled in this study. The safety analysis set consisted of 1,353 patients. Study Results For EMA analysis worldwide, a total of 17,413 patients were included in the safety analysis. Of these, 8,778 patients received rivaroxaban and 8,635 standard of care. Standard of care consisted of 81.7% LMWH, 7.9% fondaparinux, 5.5% dabigatran, 1.8% ASA, 1.4% UFH, 0.7% unspecified herbal preparation, 0.5% other prophylactic agents, and 0.5% VKA. The median age was 66.0 years in rivaroxaban and 68.0 years in standard of care patients. The majority of patients were female (62.7% in rivaroxaban, 63.0% in standard of care patients). The median BMI was 27.5 in rivaroxaban and 27.5 in standard of care patients. At inclusion to the study, total hip arthroplasty, total knee arthroplasty and other types of surgery were performed in 53.4% of rivaroxaban and 53.7% of standard of care patients, 44.8% of rivaroxaban and 44.6% of standard of care patients and 1.8% of rivaroxaban and 1.7% of standard of care patients, respectively. Median duration of VTE prophylaxis was 33.0 days in rivaroxaban-treated patients and 32.0 days in standard of care treated patients. Post EMA, a total of 1,353 patients were included in the safety analysis. Of these, 689 patients received rivaroxaban and 664 standard of care. Standard of care consisted of 68.8% LMWH, 17.8% ASA, 10.1% fondaparinux, 1.2% unfractionated heparin (UFH) and 1.1% dabigatran. The median age was 63.0 years in rivaroxaban and 64.0 years in standard of care patients. The majority of patients were female (68.4% in rivaroxaban, 70.3% in standard of care group). The median BMI was 26.7 in rivaroxaban and 26.2 in standard of care patients. At inclusion to the study, total hip arthroplasty, total knee arthroplasty and other types of surgery were performed in 20.0% of rivaroxaban and 24.2% of standard of care patients, 59.5% of rivaroxaban and 57.4% of standard of care patients and 20.5% of rivaroxaban and 18.4% of standard of care patients, respectively. Median duration of VTE prophylaxis was 15.0 days in both rivaroxaban-treated patients and those receiving standard of care. Page 4 of 6

6 Results Summary EMA analyses The incidence of treatment emergent major bleeding (RECORD) was low and similar between the treatment groups with 0.4% in rivaroxaban patients (35/8778) and 0.3% in standard of care patients (29/8635) (OR 1.19, 95%CI [0.73; 1.95]; HR 1.10, 95% CI [0.673; 1.803]) (Abbreviations: OR-odds ratio, HR-Hazard ratio, CI-confidence interval). The analyses in the propensity score adjusted population showed no qualitative and statistical differences in the point estimates of the OR or HR for RECORD major bleeding (OR 1.35, 95% CI [0.94, 1.93]; HR1.33, 95% CI [0.79, 2.25]). In addition, treatment emergent major bleeding according to the EMA definition occurred in 1.7% of rivaroxaban patients (149/8778) and 1.4% of standard of care patients (124/8635) (OR 1.19, 95% CI [0.93; 1.51]; HR 1.16, 95% CI [0.91; 1.47]). In the propensity score adjusted population, the broader definition of EMA major bleeding showed a statistical significance between rivaroxaban patients compared with standard of care patients in the OR, but not in the HR (OR 1.21, 95% CI [1.01, 1.45]; HR 1.19, 95%CI [0.92, 1.53]). The incidence of bleeding leading to treatment cessation only (as a component of EMA major bleeding) was higher in patients receiving rivaroxaban (0.4% vs 0.2%) in the safety population and the propensity score adjusted safety population. Any treatment emergent bleeding occurred more frequently in the rivaroxaban group compared with the standard-of-care group in both safety (rivaroxaban 4.7 % [410/8778]; standard of care 3.2 % [280/8635]; OR 1.46, 95% CI [1.25; 1.71]; HR 1.43, 95% CI [1.23; 1.68]) and propensity score adjusted safety populations (OR 1.50, 95% CI [1.34; 1.68]; HR 1.46, 95% CI [1.24; 1.72]. The number of patients with any symptomatic thromboembolic events was lower in the rivaroxaban group (0.9 %; 78/8778) compared to the standard of care (1.4 %; 117/8635) groups with a statistically significant risk reduction for any symptomatic thromboembolic events (OR 0.65, 95% CI [0.49; 0.87]; HR 0.61, 95% CI [0.44; 0.85]). Overall, the analyses in the propensity score adjusted population were consistent with the findings of the first analyses (OR 0.69, 95% CI [0.54; 0.79]; HR 0.65, 95% CI [0.45; 0.92]). The hip and knee subgroup analyses demonstrated the same pattern. The results of this NIS confirm the efficacy and safety results of rivaroxaban under real-life treatment conditions compared to the current pharmacological standard VTE- prophylaxis. Post EMA analyses RECORD major bleeding occurred at 0.1% (1/689) with rivaroxaban and 0.3% (2/664) with standard of care; and EMA major bleeding at 1.2% (8/689) with rivaroxaban and 0.6% (4/664) with standard of care. Any treatment-emergent bleeding events (composite of non-major and major bleeding) occurred in 2.0% treated with rivaroxaban and 1.4% receiving standard of care. Any symptomatic thromboembolic events occurred in 0.9% of the rivaroxaban group (6/689) and in 0.2% of the standard of care group (1/664). Results Summary Safety Page 5 of 6

7 EMA analyses Rivaroxaban was a well-tolerated and safe VTE prophylaxis in patients undergoing major orthopedic surgery of the hip or knee. The nature and frequency of reported AEs were similar to the standard of care. Treatment-emergent AEs were reported in 2196 (25.0 %) and 2044 (23.7 %) patients receiving rivaroxaban and standard of care treatments, respectively. Treatment-emergent serious AEs (SAEs) were reported in 689 (4.0%) patients (rivaroxaban group: n=351 [4.0%]; standard of care group: n=338 [3.9%]). Study drug related serious adverse events (SAEs) were reported in 156 (0.9 %) patients (rivaroxaban group: 91 [1.0 %] patients; standard of care group: 65 [0.8 %] patients). Twenty-five patients (12 patients [rivaroxaban group], 13 patients [standard of care group]) died during the course of the study. Subgroup analyses consistently demonstrated that overall, there were no relevant differences between the hip and knee subgroups with regards to AEs. No new safety signal was detected. The results of this NIS confirm the safety results of rivaroxaban under real-life treatment conditions compared to the current pharmacological standard VTE- prophylaxis. Post EMA analyses Treatment-emergent AEs were reported in 109 (15.8%) and 112 (16.9%) patients receiving rivaroxaban and standard of care, respectively. Treatment-emergent serious AEs (SAEs) were reported in 42 (3.1%) patients (rivaroxaban group: n=17 [2.5%]; standard of care group: n=25 [3.8%]). No patients treated with rivaroxaban, but 2 (0.3%) patients receiving standard of care, died during the course of the study. Conclusion(s) The results of this NIS confirm the efficacy and safety results of rivaroxaban under real-life treatment conditions compared to the current pharmacological standard VTE- prophylaxis. Rivaroxaban was a well-tolerated VTE prophylaxis in patients undergoing major orthopedic surgery of the hip or knee. The nature and frequency of reported AEs were similar to the standard of care. No new safety signal was detected. The benefit-risk evaluation of rivaroxaban remains unchanged and favorable. In the post EMA group, the low number of patients limits this subanalysis to an exploratory, descriptive nature and no statistical significance of findings can be derived. Within these limitations, the results from XAMOS post EMA analyses were in line with the worldwide results (EMA analyses). Publication(s): Alexander G. G. Turpie, Sylvia Haas, Reinhold Kreutz, Lorenzo G. Mantovani, Cassandra W. Pattanayak, Gerlind Holberg, Waheed Jamal, AndréSchmidt, Martin van Eickels, Michael R. Lassen; A noninterventional comparison of rivaroxaban with standard of care for thromboprophylaxis after major orthopaedic surgery in 17,701 patients with propensity score adjustment; Thromb Haemost 2014; 111 (2): epublished ahead of print: doi: /th Date Created or Date Last Updated: [Mandatory field.] 04 Apr 2014 Date of Clinical Study Report: EMA analysis: 10 Oct 2012 Post EMA: 13 Aug 2013 Page 6 of 6

8 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