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: Bayer Schering Pharmaceutical AG Study Number: NCT Study Phase: Phase IIb Study Title: Oral Direct Factor Xa Inhibitor BAY in the Prevention of VTE in Patients Undergoing Total Knee Replacement ODIXa-KNEE - a randomized, controlled, double-blind, double-dummy phase IIb dose-ranging trial (Study 10945) Therapeutic Area: Cardiovascular Name of Test Product: BAY Active Ingredient: Factor Xa Inhibitor Dosage: 2.5 mg bid by mouth (PO), 5 mg bid PO, 10 mg bid PO, 20 mg bid PO or 30 mg bid PO. Reference Therapy: Enoxaparin Dosage: 30 mg bid subcutaneously (SC), provided as Lovenox 0.3 ml syringes containing 30 mg enoxaparin sodium (corresponding to 3000 IU anti-xa). Placebo: N/A Route of Administration: By mouth (PO) Treatment Duration: 6 to 10 days Study Period: Date of first subjects first visit: 26 Feb 2004 Date of last subjects last visit 23 Nov 2004 Methodology: Prospective, randomized, multi-center, double-blinded, double-dummy, active comparator-controlled, parallel-group and dose-ranging study. The study was designed as a dose confirmative study in the prevention of VTE in men and postmenopausal women undergoing elective total knee replacement. Study Site: This study was conducted at 43 centers from 2 countries; Canada (26 sites), United States (17 sites). Main Inclusion Criteria: Men 18 years and postmenopausal women scheduled to receive elective unilateral total knee replacement. Women aged 18 years or above with history of hysterectomy could be enrolled. Study Objectives: To assess the efficacy and safety of BAY at the dose range of 2.5 mg twice daily (bid) to 30 mg bid compared to enoxaparin 30 mg bid in the prevention of VTE following elective total knee replacement Primary: To assess the effect of BAY as a composite endpoint of any deep vein thrombosis (DVT) (proximal and/or distal), nonfatal pulmonary embolism and death from all causes, on Day 6 to 10. Secondary: Population pharmacokinetics (PK) and pharmacodynamics (PD) (Factor Xa activity, prothrombin time [PT], activated partial thromboplastin time [aptt], Heptest and International Normalized Ratio [PT INR]) were also to be assessed.

3 Efficacy (Primary): The primary efficacy endpoint was a composite endpoint of: Evaluation Criteria: Any DVT (proximal and/or distal) Non-fatal pulmonary embolism Death from all causes The primary endpoint was evaluated 5 to 9 days after surgery or earlier in case of symptoms indicating VTE. The analysis of the primary efficacy endpoint was solely based on the assessments made by the Adjudication Committee/Venography (AC/V) and the Adjudication Committee/Venous Thromboembolism (AC/VTE). Efficacy (Secondary): The secondary efficacy endpoints were: Incidence of DVTs (total, proximal, distal) Incidence of symptomatic VTEs The composite endpoint that resulted from the primary endpoint by substituting VTE-related death for all deaths Incidence of symptomatic VTEs (total, pulmonary embolism, DVT) within 30 days after stop of treatment with the study drug Health care resource utilization (HRU), assessed up to the follow-up visit. It included: Duration of hospitalization, any re-hospitalization during the entire study period, and rehabilitation stay following discharge Physician and nurse consultations (at home and in the hospital) following discharge from the hospital Frequency of anticoagulation monitoring following discharge from hospital and until the end of study follow-up The analysis of the secondary efficacy endpoint related to VTE was solely based on the assessments made by the AC/V and AC/VTE. The assessments made by the Adjudication Committee/Complete Compression Ultrasound (AC/CCUS) were part of a separate study for validation of complete compression ultrasound (CCUS) (VENUS study). Safety The main safety endpoint was the incidence of major bleeding observed after the first intake of study drug and not later than 2 days after last intake of study drug. Major bleeding observed after this period was considered separately. The analysis of the main safety endpoint was solely based on the classification made by the Safety Committee and Bleeding Committee. Other safety variables were: Incidence of non-major bleeding (clinically significant and minor bleeding) Treatment-emergent adverse events Treatment-emergent serious adverse events Deaths Adverse events starting more than 7 days after the stop of treatment Incidence of (prolonged) hospitalization Transfusion requirements (homologous and autologous transfusions) Total volume (ml) of blood loss (intra-operative blood loss) Post-operative volume in drainage Laboratory parameters

4 Statistical Methods: Efficacy (Primary): The primary efficacy analysis was performed in subjects valid for per-protocol (PP) analysis. The intent-to-treat (ITT) analysis was performed as supportive analysis. The dose-response relationship of BAY was investigated by a trend test. For this purpose, the primary efficacy endpoint was evaluated by a logistic regression model including the total daily dosage of BAY as a covariate and center as a fixed effect. Only subjects treated with BAY were included in this analysis. In order to check for a trend in the dose-response relationship, the hypothesis that the regression parameter of the covariate equals zero was tested in the logistic regression model by the Likelihood Ratio Test. Subsequent to the trend test, each of the individual BAY treatment groups was compared with enoxaparin. The incidences for the secondary efficacy parameters related to VTE were tabulated stratified by treatment group. Efficacy (Secondary): The secondary efficacy parameters related to HRU was stratified by treatment group with appropriate statistical methods. Safety The safety analysis was performed in the population of subjects valid for safety analysis. The incidence of major bleeding was tabulated and further analyzed by the logistic regression model already specified for the primary efficacy analysis. However, no center effect was considered in the logistic regression analysis due to the small number of major bleeding events that was to be expected. Furthermore, the individual comparisons of each BAY treatment group with enoxaparin were performed based on Fisher s exact test. All other safety endpoints were analyzed by appropriate descriptive methods (ie, sample statistics or frequency tables) stratified by treatment group. Pharmacokinetics (PK)/pharmacodynamics (PD):The following statistics were to be calculated for each of the sampling points for both PK and PD: Arithmetic mean, standard deviation (SD) and coefficient of variation (CV), geometric mean, geometric SD (re-transformed SD of the logarithms) and CV, minimum, median, maximum value and the number of measurements Means at any time were only to be calculated if at least 2/3 of the individual data were measured and were above the limit of quantification (LOQ). For the calculation of the mean value a data point below LOQ was to be substituted by one half of this limit. In tables showing mean values, where values below LOQ are included in the calculation of mean values, these means were to be marked. Individual and mean concentration versus time profiles were to be plotted by dose using both linear and semilogarithmic scale. Pharmacokinetic (PK) characteristics (t max excluded) were to be summarized by the statistics mentioned above. t max was to be described utilizing minimum, maximum as well as frequency counts. The PK characteristics AUC(0-12)norm and Cmax,norm were to be analyzed assuming log-normally distributed data. To compare PK and PD between both profile days, the logarithms of these PK and PD characteristics were to be analyzed using paired t-tests. Based on these analyses, point estimates and exploratory 90% confidence intervals (CIs) for the ratios were to be calculated by re-transformation of the logarithmic results given by the t-tests. Number of Subjects: Seven hundred nine subjects were enrolled at 37 centers. Six hundred twenty-one subjects were randomized. Out of the 621 subjects randomized, 613 subjects were treated with either BAY or enoxaparin bid. All treated subjects were included in the population valid for safety analysis. Five hundred seventy of the randomized subjects (91.8%) completed the entire treatment period. Results Summary Subject Disposition Seven hundred nine subjects were enrolled at 37 centers, 22 in Canada and 15 in the United States. Six hundred twenty-one subjects were randomized. Of the 621 subjects randomized, 613 subjects were treated with either BAY or enoxaparin bid. All treated subjects were included in the population valid for safety analysis.

5 Results Summary Efficacy: All dose groups exhibited a comparable level of efficacy in relation to enoxaparin; the 10 mg bid and 30 mg bid dose groups were statistically superior to the enoxaparin group. The VTE incidence in the 30 mg bid dose group was 25.4% and that of the 10 mg bid group 23.3%, in comparison to 44.3% in the enoxaparin group. The reduction of VTE incidence (primary composite endpoint) by BAY was not found to be dose-dependent. All doses of BAY had comparable incidence of major VTE versus enoxaparin (4.3%). Major VTE occurred in 2 to 4 subjects (3.2% to 6.7%) in each treatment group, except for the BAY mg bid group in which no cases occurred. In subjects valid for analysis of ITT, prior to the post-treatment follow-up, there were no incidences of VTE-related death and 2 cases of pulmonary embolism; the number of proximal DVTs was low. As expected, dose-dependent decreases in Factor Xa activity and increases in PT, PT INR, aptt, and Heptest were observed with increasing doses of BAY A 6- to 10-day treatment with BAY using a wide, 12-fold dose range (2.5 mg bid to 30 mg bid) prevented VTE in adult subjects undergoing elective knee replacement to the same extent as enoxaparin, thus supporting the efficacy of BAY in this indication. Venous thromboembolism (VTE) incidences observed with twice daily administration of BAY were lower than that observed with enoxaparin. The results indicate a broad therapeutic range of BAY Results Summary Pharmacodynamics and Pharmacokinetics: Selected centers took blood samples and urine samples for PK and PD measurements from 13 subjects willing to participate in the full profile PK/PD part of this study. For the investigation of PK, the concentrations of BAY in plasma and urine were determined. For the investigation of PD, factor Xa activity, PT, PT INR, HepTest and aptt were determined. Due to the low number of subjects with full profile data, no statistical evaluations have been performed. Results Summary Safety: Bleeding events increased with increasing doses of BAY The incidences of post-operative major bleeding events increased with increasing doses of BAY The percentages of major bleeding events were similar for BAY at doses of 2.5 mg bid, 5 mg bid, and 10 mg bid and enoxaparin. Differences in post-operative major bleeding events between each of the BAY dose groups and enoxaparin were not statistically significant. It is important to note that no fatal bleeds or bleeds into critical organs occurred during the study. In addition, most bleeding events were related to the surgical site. About 78% of first post-operative bleeding events occurred on the day of surgery or within 3 days after surgery and all events occurred by the sixth day after surgery. No treatment arm was stopped because of bleeding events or other safety concerns. There were small differences between treatment groups in overall incidence of treatment-emergent adverse events: 84 of 100 (84.0%) in the 2.5 mg bid group, 87 of 102 (85.3%) in the 5 mg bid group, 92 of 103 (89.3%) in the 10 mg bid group, 87 of 98 (88.8%) in the 20 mg bid group, 88 of 106 (83.0%) in the 30 mg bid group, and 85 of 104 (81.7%) in the enoxaparin group. In addition, the incidences of treatment-emergent serious adverse events were similar among the 2.5 mg bid, 10 mg bid, 20 mg bid, 30 mg groups and enoxaparin. The group with the lowest incidence of treatment-emergent serious adverse events was the 5 mg bid group. The most frequent treatment-emergent adverse events were as expected for subject s undergoing this surgical procedure with these anesthesiological interventions. BAY had similar incidence of treatment-emergent laboratory abnormalities as the enoxaparin group. Incidences of combined serum glutamic pyruvic transaminase (SGPT)/alanine aminotransferase (ALT) or serum glutamic oxaloacetic transaminase (SGOT)/aspartate aminotransferase (AST) and bilirubin increases appeared early in the post-surgical course. All subjects with elevated SGPT/ALT, SGOT/AST, and bilirubin had improvements in their laboratory values by study end. BAY did not have any untoward effect on electrocardiogram (ECG) parameters. In particular, there was no indication for any treatment-emergent QTc-prolonging effects. BAY was generally well tolerated with a similar safety/tolerability profile as enoxaparin. Conclusion(s) An 8 2-day treatment with BAY using a wide, 12-fold dose-range shows comparable efficacy to enoxaparin, thus supporting the efficacy of BAY in preventing VTE in adult subjects undergoing elective total knee replacement. Venous thromboembolism (VTE) incidence observed with twice daily administration of all study doses of BAY , 2.5 mg (31.7%), 5 mg (40.4%), 10 mg (23.3%), 20 mg (35.1%) and 30 mg (25.4%), were lower than that observed with enoxaparin 30 mg (44.3%). The results indicate a broad therapeutic range of BAY Major VTE incidence ranged from 0% to 6.7% for the BAY treatment groups. The lowest incidences occurred in the 2.5 mg bid (3.2%), 20 mg bid (3.5%), and 30 mg bid (0.0%) groups and were lower than enoxaparin (4.3%). The incidence in the 5 mg (5.3%) and 10 mg (6.7%) groups were higher than enoxaparin. However, the total actual numbers of major VTE events were too small in all groups to draw any meaningful conclusions. The incidence of major VTE in this study is similar to that seen in the total hip replacement Study where incidence ranged from

6 Conclusion(s) 0.9% to 3.4% with an enoxaparin incidence of 4.7% and thus confirm the low incidence of major VTE incidence seen in Study for BAY arms. The incidences of treatment-emergent adverse events were comparable across all treatment groups and were as expected for subject s undergoing this surgical procedure. Bleeding events increased with increasing doses of BAY Differences in post-operative major bleeding events between each of the BAY dose groups and enoxaparin were not statistically significant. For subjects taking BAY , no relevant laboratory abnormalities were observed at any dose level. It should be noted that more subjects treated with 20 mg bid of BAY developed elevated amylase levels > 3 upper limit of normal (ULN) (6.2%) than those treated with any other dose. However, the majority of these elevations occurred on Day 1 or Day 2 following surgery, most likely indicating an effect of the surgical procedure than the study drug. The frequencies of hepatic and pancreatic laboratory test abnormalities (post-surgery Visit 2 values) were similar for the BAY and enoxaparin groups; however, more enoxaparintreated subjects developed gamma glutamyl transferase (GGT) values > 3 ULN than did BAY treated subjects. BAY had lower incidence of treatment-emergent laboratory abnormalities for SGOT/AST and SGPT/ALT than were seen in the enoxaparin group. The study did not show a linear dose response for BAY in the dose-response relationship for the primary efficacy endpoint. This can be explained by the higher than expected observed incidence and the lower than expected relative range of rates for the primary endpoint. The smaller than planned effective sample sizes and higher than expected incidence for the primary efficacy variable across all treatment groups indicates that the study was not adequately powered to show a dose response. In summary, this study demonstrated the efficacy of BAY in preventing VTE in subjects undergoing knee replacement. BAY appears to be safe and well-tolerated in the dose of 2.5 mg bid to 10 mg bid. Overall, doses of 2.5 mg bid, 5 mg bid, and 10 mg bid (a 4-fold dose range) of BAY are appropriate for subjects undergoing knee replacement surgery. No dose adjustment is required regardless of body weight. Publication(s) Turpie AGG, Fisher WD, Bauer KA, et al. Bay : an oral, direct factor Xa inhibitor for the prevention of venous thromboembolism in patients after total knee replacement. A phase II dose-ranging study. J Thromb Haemost. 2005;3(11): Updated: Oct 2008