Clinical Study Synopsis

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1 Clinical Study Synopsis This file is posted on the Bayer HealthCare Clinical Trials Registry and Results website or on the website hosted by the Pharmaceutical Research and Manufacturers of America (PhRMA). It 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 labeling 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 AG. Reproduction of all or part of this report is strictly prohibited without prior written permission from Bayer HealthCare AG. 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 Webposting Clinical Trial Results Synopsis Study Sponsor: BSP AG Germany/Bayer Healthcare Pharmaceuticals Study Number: NCT Study Phase: IIb Study Title: Controlled, double-blind, randomized, dose-ranging study on the prevention of VTE in patients undergoing elective total hip replacement ODIXa-HIP2 Study Therapeutic Area: Prevention of venous thromboembolism Name of Test Product: / Rivaroxaban Active Ingredient: Rivaroxaban Dosage: Rivaroxaban: 2.5 mg bid, 5 mg bid, 10 mg bid, 20 mg bid and 30 mg bid Reference Therapy: Enoxaparin Dosage: Enoxaparin: 40 mg od Placebo: In accordance with the double-blind design of the study rivaroxaban and enoxaparin placebo were administered to the respective treatment groups to maintain blindness Route of Administration: Rivaroxaban: oral administration, Enoxaparin: subcutaneous administration Treatment Duration: 9 2 days. Study Period: Date of first subjects first visit: 12 Jan 2004 Date of last subjects last visit 16 Sep 2004 Methodology: Prospective, randomized, double-blind, double-dummy, active comparator controlled, multi-center and multi-national trial designed as a dose finding study in patients undergoing elective primary total hip replacement. The French health authorities raised concerns about the use of the 30 mg bid treatment arm. Consequently, this dose was discontinued and accounts for the small sample size of this treatment arm. Study Site: 47 centers: Germany (7), Poland (6), Italy (5), Spain (4), Israel (4), Sweden (4), Denmark (3), Austria (3), France (3), Norway (3), the Netherlands (3), Belgium (1), and the UK (1). Main Inclusion Criteria: Men 18 years of age and postmenopausal women undergoing elective primary total hip replacement. Study Objectives: Overall: Assessment of safety, tolerability, and efficacy of at oral doses of 2.5, 5, 10, 20, and 30 mg bid compared with subcutaneously administered enoxaparin 40 mg od in the prevention of venous thromboembolism in men and postmenopausal women undergoing elective primary total hip replacement. Primary: Not applicable Secondary: Not applicable

3 Evaluation Criteria: Statistical Methods: Efficacy (Primary): The primary efficacy endpoint was a composite endpoint of Any deep vein thrombosis (DVT) (proximal and/or distal). Non-fatal pulmonary embolism (PE). Death from all causes. The primary endpoint was evaluated 5-9 days after surgery. The analysis of the primary efficacy endpoint was solely based on the assessments made by the Venography and VTE Adjudication Committees. Efficacy (Secondary): Secondary efficacy endpoints were: Incidence of DVT (total, proximal, distal); incidence of symptomatic venous thromboembolism (VTE); the composite endpoint that results from the primary endpoint by substituting VTE-related deaths for all deaths; incidence of symptomatic VTE (total, PE, DVT) within 30 days after stop of treatment with the study drug; incidence of major VTE (proximal DVT, PE, VTE-related death). The analyses of the secondary efficacy endpoints related to VTE were solely based on the assessments made by the Venography and VTE Adjudication Committees. Safety The main safety endpoint was the incidence of post-operative major bleeding events, ie, major bleeding events starting more than 6 h after surgery (or after first post-operative study drug intake, whatever comes first) and not later than 2 days after last intake of study drug. Major bleeding observed after this period was assessed separately. The analysis of the primary safety endpoint was solely based on the classification made by the Bleeding Committee. Pharmacokinetics Not applicable Efficacy (Primary): The primary efficacy analysis was performed in patients valid for per-protocol (PP) analysis. The intent-totreat (ITT) analysis was performed as a supportive analysis. The dose-response relationship of was investigated by a trend test. Subsequent to the trend test, each of the individual treatment groups was compared with enoxaparin. Efficacy (Secondary): Secondary efficacy endpoints related to health care resource utilization (HCRU) were analyzed stratified by treatment groups with appropriate statistical methods: categorical variables by frequency tables and continuous variables by sample statistics. Safety The safety analysis was performed in the population of patients valid for safety analysis. Incidence rates of postoper-ative major bleeding were analyzed by a logistic regression model. Fisher s exact test was used for individual comparisons of each treatment group with enoxaparin. Pharmacokinetics: Not applicable Number of Subjects: 726 subjects enrolled, 722 randomized, 706 treated, 704 of them valid for safety. Results Summary Subject Disposition and Baseline 704 subjects were analyzed as safety population. 560 and 548 subjects were valid-for-itt analysis and PP analysis, respectively. Results Summary Efficacy A 9 2-day treatment with using a wide, 12-fold dose range (2.5 to 30 mg bid) prevents VTE in adult subjects undergoing elective hip replacement compared with enoxaparin, thus supporting evidence for the efficacy of in this indication. All tested doses were comparable to enoxaparin with most of the observed incidence rates below the rate seen with enoxaparin. However, caution must be exercised not to over interpret the data in any specific direction because of widely overlapping confidence intervals.

4 The reduction of VTE incidence rates (primary composite endpoint) by was dose-dependent in the range from 2.5 to 10 mg bid with incidence rates declining from 15.4% to 11.9% compared with 17.0% in the enoxaparin group (Table 1). The incidence rate in the 30 mg bid dose group was 6.9% and that of the 20 mg bid group 18.2%. Numerically, subjects receiving at doses of 2.5, 5, 10, and 30 mg bid had lower VTE incidence rates than those receiving enoxaparin. However, a flat dose response was observed for BAY with respect to the primary efficacy endpoint and thus no trend was detected in the confirmative trend test (P=0.9319) derived from the logistic regression model. This is primarily caused by the good efficacy observed in the lower dose groups, in which incidence rates were substantially lower than anticipated for sample size determination. The higher incidence rate of total VTE with the 20 mg bid dose, which was only slightly higher compared with enoxaparin, cannot be explained at this time and may be a chance finding. The 17.0% VTE incidence rate as well as the 4.7% incidence rate of proximal DVT for enoxaparin were well in line with published data. All doses of had lower incidence rates of major VTE than enoxaparin ( % vs 4.7%). Major VTE incidence rates were lowest at doses of 2.5, 5, and 10 mg bid. 2 cases of death, 2 cases of PE, and 3 cases of symptomatic DVT occurred during the follow-up period. The events were equally distributed between the treatment groups with 2 events in the enoxaparin group (1 case of DVT and 1 case of PE) and 1 event in each of the dose groups. Dose-dependent decreases in factor Xa activity and prolongation of PT and PT INR were observed with increasing doses of. Table 1: Incidence rate of primary efficacy endpoint and its individual components (PP population) Endpoint 2.5 mg bid (N = 104) 5 mg bid (N = 109) 10 mg bid (N = 101) Primary efficacy endpoint 16 (15.4%) 15 (13.8%) 12 (11.9%) Death (any cause) 0 ( 0.0%) 0 ( 0.0%) 0 ( 0.0%) Pulmonary embolism 0 ( 0.0%) 0 ( 0.0%) 0 ( 0.0%) Deep vein thrombosis 16 (15.4%) 15 (13.8%) 12 (11.9%) VTE subsets VTE-related death 0 ( 0.0%) 0 ( 0.0%) 0 ( 0.0%) Deep vein thrombosis, proximal 3 ( 2.9%) 1 ( 0.9%) 1 ( 1.0%) Deep vein thrombosis, distal 14 (13.5%) 14 (12.8%) 12 (11.9%) Symptomatic deep vein thrombosis 0 ( 0.0%) 0 ( 0.0%) 0 ( 0.0%) Endpoint 20 mg bid (N = 99) 30 mg bid (N = 29) Enoxaparin 40 mg od (N = 106) Primary efficacy endpoint 18 (18.2%) 2 ( 6.9%) 18 (17.0%) Death (any cause) 0 ( 0.0%) 0 ( 0.0%) 0 ( 0.0%) Pulmonary embolism 0 ( 0.0%) 0 ( 0.0%) 0 ( 0.0%) Deep vein thrombosis 18 (18.2%) 2 ( 6.9%) 18 (17.0%) VTE subsets VTE-related death 0 ( 0.0%) 0 ( 0.0%) 0 ( 0.0%) Deep vein thrombosis, proximal 3 ( 3.0%) 1 ( 3.4%) 5 ( 4.7%) Deep vein thrombosis, distal 17 (17.2%) 2 ( 6.9%) 17 (16.0%) Symptomatic deep vein thrombosis 0 ( 0.0%) 0 ( 0.0%) 0 ( 0.0%) Results Summary Pharmacokinetics: Not applicable (subject of a separate report). Results Summary Safety There were 2 deaths: 1 subject in the 5 mg bid dose group because of total exhaustion due to different SAEs and 1 subject receiving 10 mg bid due to a bronchopneumonia. None of the deaths was considered related to study drug. The number of postoperative bleeding events increased with increasing doses indicating a clear dose-response, when ignoring the small-sized 30 mg bid treatment arm (Table 2). The percentages of major bleeding events increased with increasing doses indicating a clear dose-response. Percentages of post-operative major bleeds were similar for at doses of 2.5, 5, and 10 mg bid and enoxaparin. It is important to note that there were neither fatal bleeds or bleeds in critical organs, nor clinically significant bleeds that could not be treated. Most bleeds adjudicated as major were related to the surgical site and no wound healing complications were reported in these subjects. Differences between enoxaparin and any of the dose groups with regard to the number of post-operative major bleeding events were not statistically significant.

5 About 69% of first post-operative bleeding events occurred on the day of surgery or within 3 days after surgery and 12% of first postoperative bleeding events occurred 6 or more days after surgery. No cases of post-procedural hemorrhage were reported as treatment-emergent adverse events in any of the 6 treatment groups. Table 2: Incidence rates of post-operative bleeding events (safety population) a Bleeding event 2.5 mg bid (N=132) 5 mg bid (N=136) 10 mg bid (N=133) Any event 7 ( 5.3%) 15 (11.0%) 16 (12.0%) Major bleeding 1 ( 0.8%) 3 ( 2.2%) 3 ( 2.3%) Clinically overt bleeding associated with fall in Hbb 0 ( 0.0%) 1 ( 0.7%) 1 ( 0.8%) Clinically overt bleeding leading to blood transfusionc 1 ( 0.8%) 1 ( 0.7%) 1 ( 0.8%) Bleeding leading to re-operation 0 ( 0.0%) 2 ( 1.5%) 2 ( 1.5%) Clinically overt bleeding warranting treatment cessation 0 ( 0.0%) 0 ( 0.0%) 0 ( 0.0%) Bleeding event 20 mg bid (N=134) 30 mg bid (N=37) Enoxaparin 40 mg od (N=132) Any event 25 (18.7%) 4 (10.8%) 8 ( 6.1%) Major bleeding 6 ( 4.5%) 2 ( 5.4%) 2 ( 1.5%) Clinically overt bleeding associated with fall in Hbb 3 ( 2.2%) 1 ( 2.7%) 2 ( 1.5%) Clinically overt bleeding leading to blood transfusionc 4 ( 3.0%) 2 ( 5.4%) 2 ( 1.5%) Bleeding leading to re-operation 0 ( 0.0%) 0 ( 0.0%) 0 ( 0.0%) Clinically overt bleeding warranting treatment cessation 1 ( 0.7%) 1 ( 2.7%) 1 ( 0.8%) a Bleeding events starting more than 2 days after last study medication intake were not considered. b Associated with a fall in Hb of 2g/dL within 24 h from first post-operative day. c Leading to transfusion of 2 units of blood. The net clinical benefit of the individual treatments was assessed based on a composite endpoint given by major VTE (proximal DVT, PE, VTE-related death) and post-operative major bleeding events. Low incidences of the composite endpoint indicate a high net clinical benefit. The lowest incidence rates and thus the highest net clinical benefit were seen in the dose groups of 2.5, 5, and 10 mg bid (3.6% 3.8%) compared with 6.4% in the enoxaparin group. Incidence rates of 8.7% and 6.7% were observed in the 20 mg bid and 30 mg bid dose group, respectively. did not have untoward effects on ECG parameters. In particular, there was no indication for any treatment-emergent QTcprolonging effects of the drug in a total of 496 subjects with normal QTc at baseline receiving. did not reveal any substance-specific effects on laboratory parameters, including liver enzymes, for the treatment duration used in this study when compared with enoxaparin. In considering any laboratory changes, interventions related to surgery and anesthesiology must be taken into account. No signal of liver toxicity was detected. Conclusion(s) This study supports evidence for the efficacy of in preventing DVT, PE, and death (primary composite endpoint) in subjects undergoing elective hip replacement. The net clinical benefit (major bleeding events plus major VTE) of doses ranging from 2.5 to 10 mg bid was comparable to enoxaparin. If also clinically relevant bleeding events are taking into consideration, the dose of 2.5 mg bid seems to be the recommendable dose. Publication(s) Eriksson BI, Borris L, Dahl OE, Haas S, Huisman MV, Kakkar AK, et al. Oral, direct Factor Xa inhibition with for the prevention of venous thromboembolism after total hip replacement. J Thromb Haemost 2006;4(1): Updated: 14 Oct 2008