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 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 Clinical Trial Results Synopsis Study Sponsor: Study Number: Study Phase: I Bayer HealthCare AG Study Design Description NCT Official Study Title: Single-dose, open-label, randomized, 2-way crossover pivotal bioequivalence study of 2x5 mg tablets Rivaroxaban versus 1x10 mg tablet Rivaroxaban under fasted condition in healthy subjects. Therapeutic Area: Cardiology/Coagulation Test Product Name of Test Product: Name of Active Ingredient: Dose and Mode of Administration: Rivaroxaban (Xarelto, BAY ) Rivaroxaban Two 5 mg tablets (Tablet 5 mg US CS [coated]), administered orally. Reference Therapy/Placebo Reference Therapy: Rivaroxaban (BAY ) Dose and Mode of Administration: 10 mg tablet (Tablet 10 mg US CS [coated]), administered orally. Duration of Treatment: Rivaroxaban tablet(s) were administered as a single dose each of test and reference therapy. [ Studied period: Date of first subjects first visit: 17 AUG 2009 Premature Study Suspension / Termination: Substantial Study Protocol Amendments: Date of last subjects last visit: 30 SEP 2009 No None Study Centre(s): The study was conducted at a single center in Germany. Methodology: Subjects fasted for at least 10 hours before study drug treatment in each period and continued fasting until at least 4 hours after study drug administration. There was a wash-out phase of approximately 7 days between the two treatment periods. Blood sampling for evaluation of pharmacokinetic parameters was done from 0-72 h. The total duration of the study was approximately 2-3 months. Follow-up examination took place approximately 1-2 weeks after the last administration of the test substance. Indication/ Main Inclusion Criteria: Indication: Main Inclusion Criteria: Healthy male subjects, 18 to 45 years of age, with Body Mass Index (BMI) between 18 and 30 kg/m 2. Page 1 of 5

3 Study Objectives: Primary: To establish the bioequivalence of 2x5 mg tablets rivaroxaban vs 1x10 mg tablet rivaroxaban (both immediate-release tablets) when administered as single oral dose under fasting conditions. Secondary: To evaluate safety and tolerability of rivaroxaban. Evaluation Criteria: Efficacy (Primary): Efficacy (Secondary): Statistical Methods: Efficacy (Primary): Safety: Incidence of abnormal findings in measurements for objective tolerability: Physical examination, vital parameters (blood pressure and pulse rate), electrocardiogram (ECG) findings, laboratory findings, and the occurrence of adverse events after drug administration. Pharmacokinetics: Primary parameters: AUC, AUC(0-tn), Cmax Secondary parameters: AUCnorm, Cmax,norm, MRT, tmax, t1/2 Other parameters: AUC(tn- ), points terminal Efficacy (Secondary): Safety: Descriptive statistics were used for quantitative data (hematology, blood chemistry, vital signs, ECG). These summary statistics were presented by treatment for the original data as well as for the difference to baseline. Frequency tables were provided for qualitative data. The incidence of treatment-emergent adverse events and drug-related adverse events, respectively, were summarized by treatment using Medical Dictionary for Regulatory Activities (MedDRA) terms. Pharmacokinetics: Only the data from subjects who completed the study were included in the statistical analysis. The pharmacokinetic characteristics AUC, AUC(0-tn), and Cmax of rivaroxaban were analyzed assuming log-normally distributed data. To compare pharmacokinetics between treatments, the logarithms of these pharmacokinetic characteristics were analyzed using analysis of variance (ANOVA) including sequence, subject (sequence), period, and treatment effects. Based on these analyses point estimates and confirmatory 90% confidence Page 2 of 5

4 Number of Subjects: intervals for the treatment ratios were calculated by retransformation of the logarithmic results given by the ANOVA. Both treatments were considered bioequivalent if the 90% confidence intervals for the ratio of the means fell within 80% to 125% for all pharmacokinetic characteristics under view. Planned: 28 subjects, minimum number of valid subjects with complete study treatments: 25 subjects Enrolled: 28 subjects Valid for pharmacokinetics: 26 subjects Valid for safety: 28 subjects Study Results Results Summary Subject Disposition and Baseline Out of 28 subjects who were enrolled into the study, 2 subjects (one from each treatment group) terminated the study prematurely after withdrawal of their informed consent. Therefore, 26 subjects completed the study. All subjects were White. Their mean age was 31.4 years (range: years) and mean BMI was 24.6 kg/m 2 (range: kg/m 2 ). Results Summary Safety Twenty-eight healthy male subjects received at least one dose of study medication in this 2-way crossover study and were valid for the evaluation of safety. Of these 28 subjects, 2 subjects withdrew their informed consent and terminated the study prematurely after their 1 st study period. One had received the 1x10 mg dose only and the other one had received the 2x5 mg dose only. Accordingly, taken together 27 subjects were exposed to rivaroxaban 1x10 mg and rivaroxaban 2x5 mg. Ten of the 28 subjects of the safety population (36%) experienced at least one adverse event. No adverse event was severe or serious and none of the subjects terminated the study prematurely due to adverse events. The majority of adverse events (76%) were of mild intensity, 4 (24%) were of moderate intensity. Adverse event rates were comparable between treatments with 6 of 27 subjects (22%) reporting at least one adverse event after 1x10 mg and 2x5 mg rivaroxaban, respectively. Four subjects reported 6 drug-related adverse events (injection-site hematoma/elevated lipase and amylase [one subject], elevated glutamate dehydrogenase (GLDH), diarrhea and fatigue). Non drug-related adverse events were single cases of sinus bradycardia, hemoglobinuria (9 days after last study medication), multiple contusions, elevated aspartate transaminase (AST), alanine transaminase (ALT) and GLDH, sore throat, heartburn, constipation, and headache. A limited number of relevant increases in laboratory values were observed: Four subjects presented with elevated GLDH values two were already present prior to the first administration of study drug. A third case occurred in conjunction with elevations of AST and ALT after the subject had multiple contusions after a car accident (18 days after a single dose administration). GLDH of the fourth case was only elevated in the first, but was normal during the second study period. Prothrombin time (PT) and partial thromboplastin time (PTT) prolongation by around 4 sec was observed 4 hours after both rivaroxaban regimens. Changes were shown to have reversed by the next assessment 24 hours after dosing. Vital signs and ECG parameters were not affected by rivaroxaban administration. Page 3 of 5

5 Table 1 provides an overview of treatment-emergent adverse events. Table 1: Incidence of treatment-emergent adverse events, all subjects valid for safety (n=28) Results Summary Pharmacokinetics Rivaroxaban was administered as single doses of 1x10 mg and 2x5 mg to healthy male volunteers in a 2-way crossover pivotal study to assess bioequivalence. Twenty-six subjects completed the study according to protocol and were valid for the evaluation of pharmacokinetics (PK). Results of the PK analysis provided evidence for bioequivalence of the treatment regimens under investigation. The ratios of 2x5 mg (test)/1x10 mg (reference) for the parameters AUC and Cmax were (AUC) and (Cmax). The respective 90% confidence intervals were completely contained within the limits of 0.80 to 1.25, which is the accepted range for the proof of bioequivalence. No differences between treatments were Page 4 of 5

6 observed with regard to tmax and terminal half-life. Furthermore, results were comparable to previous studies with single dose rivaroxaban at a dose of 10 mg. Table 2 provides summary statistics of the pharmacokinetic characteristics of rivaroxaban in the 2 dosing regimens investigated in this study. Table 3 summarizes results of the ANOVA based on the evaluation of key pharmacokinetic parameters. Table 2: Pharmacokinetic parameters of rivaroxaban in plasma following a single oral dose of 10 mg rivaroxaban [geometric mean/%cv (range)], all subjects valid for PK (n=26) Table 3: Treatment comparisons based on ANOVA results, all subjects valid for PK (n=26) Conclusion(s) In this study rivaroxaban was administered orally as a single dose of 1x10 mg immediate-release (IR) tablet and as a single dose of 2x5 mg IR tablets to 28 healthy male subjects, was safe and well tolerated. The rivaroxaban regimens compared (1x10 mg and 2x5 mg IR tablets) were bioequivalent as evidenced by comparisons of the key PK parameters AUC, AUC(0-tn) and Cmax. 90% confidence intervals of the ratios "2x5 mg/1x10 mg" provided for the key parameters were completely contained within the range of 0.80 to Publication(s): Date Created or Date Last Updated: None 14 MAR 2012 Date of Clinical Study Report: 08 JUN 2010 Page 5 of 5

7 Marketing Authorization Holder in Germany Appendix to Clinical Study Synopsis for study Investigational Site List Name Bayer Pharma AG Postal Address D Berlin Deutschland Sponsor in Germany Legal Entity Name Bayer HealthCare AG Postal Address D Leverkusen, Germany List of Investigational Sites No Investigator Name Facility Name Street ZIP Code City Country 1 Fr. Dr. Doris Neuenhofer CRS Clinical- Research-Services Mönchengladbach GmbH Hindenburgstras se Mönchengladbach GERMANY Page 1 of 1

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: 12 Oct 2011