Protocol. This trial protocol has been provided by the authors to give readers additional information about their work.

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1 Protocol This trial protocol has been provided by the authors to give readers additional information about their work. Protocol for: The EINSTEIN PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366: DOI: /NEJMoa

2 BAYER INTEGRATED PROTOCOL Protocol Title Oral direct factor Xa inhibitor rivaroxaban in patients with acute symptomatic deep-vein thrombosis or pulmonary embolism. Test Drug BAY , rivaroxaban Study Number Original protocol version/ Version 1.1, 30 Nov 2006 date This protocol version/date Version 3.0, 13 Jul 2010 The following Amendments have been incorporated into this Integrated Protocol. AMENDMENT NUMBER VERSION NUMBER DATE Jul Oct May Jul 2010 Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 1 of 88

3 TABLE OF CONTENTS STUDY SYNOPSIS INTRODUCTION AND RATIONALE STUDY OBJECTIVES STUDY DESIGN DESCRIPTION OF THE STUDY STUDY POPULATION PLANNED NUMBER OF PATIENTS INCLUSION CRITERIA EXCLUSION CRITERIA PRIOR AND CONCOMITANT MEDICATION Medication prior to randomization Concomitant medication STUDY MEDICATION AND ADMINISTRATION TREATMENT GROUPS AND REGIMENS Method of treatment allocation Rivaroxaban group Enoxaparin/VKA group FORMULATION AND DOSE Rivaroxaban Enoxaparin/VKA PACKAGING, LABELING, AND STORAGE DRUG ACCOUNTABILITY AND TREATMENT COMPLIANCE VKA treatment monitoring STUDY PROCEDURES SCREENING STUDY DRUG TREATMENT PERIOD Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 2 of 88

4 6.2.1 Patient booklet Patient contacts Assessment of clinical outcomes Suspected recurrent PE or DVT Suspected bleeding Deaths Vascular events Observational period EFFICACY OUTCOMES SAFETY OUTCOMES Bleeding definitions MEASURES TO MINIMIZE BIAS ADVERSE EVENTS (AE) AE monitoring AE definitions AE Serious adverse event (SAE) Unexpected AEs Relationship of AE to study drugs Severity of the AE AE documentation Reporting of SAE/pregnancy Study specific exceptions to the (S)AE reporting APPROACH TO THE BLEEDING PATIENT CENTRALIZED LABORATORY ASSESSMENTS Liver function testing Pharmacodynamics Sample collection, processing and storage PE DOSE CONFIRMATION PHASE HEALTHCARE RESOURCE UTILIZATION ASSESSMENT OF TREATMENT SATISFACTION PREMATURE DISCONTINUATION Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 3 of 88

5 8. DATA QUALITY ASSURANCE DATA QUALITY DOCUMENTATION STUDY COMMITTEES Executive committee Study management and coordination committee (SMCC) Central independent adjudication committee (CIAC) Data safety monitoring board (DSMB) The dose confirmation committee ETHICAL AND LEGAL ASPECTS ETHICS COMMITTEE (EC)/INSTITUTIONAL REVIEW BOARD (IRB) ETHICAL CONDUCT OF THE STUDY REGULATORY AUTHORITY APPROVALS/AUTHORIZATIONS SUBJECT INFORMATION AND CONSENT INSURANCE CONFIDENTIALITY ARCHIVING OF DATA STATISTICAL AND ANALYTICAL METHODS STATISTICAL ANALYSIS PLAN ANALYSIS POPULATIONS STUDY POPULATION/DEMOGRAPHICS AND PATIENT CHARACTERISTICS EFFICACY ANALYSIS Primary efficacy analysis Secondary efficacy analyses SAFETY ANALYSIS Principal safety analysis Additional safety analyses INTERIM ANALYSIS Einstein-DVT evaluation Einstein-PE evaluation SAMPLE SIZE CALCULATION EINSTEIN-DVT EVALUATION Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 4 of 88

6 10.8 DOSE CONFIRMATION ANALYSIS AND SAMPLE SIZE CALCULATION EINSTEIN-PE EVALUATION Dose confirmation analysis Sample size calculation META-ANALYSIS NAME AND ADDRESS OF PRINCIPAL INVESTIGATOR USE OF DATA AND PUBLICATION APPENDICES CALCULATION OF THE CREATININE CLEARANCE (CLCR) PACKAGE INSERT EXAMPLES CONTACT REPORT HEALTH CARE RESOURCE UTILIZATION (HCRU) ANTI-CLOT TREATMENT SCALE TREATMENT SATISFACTION QUESTIONNAIRE (TSQ) NON-INFERIORITY MARGIN REFERENCES LIST OF ABBREVIATIONS Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 5 of 88

7 Study Synopsis Product, rivaroxaban Title: Oral direct factor Xa inhibitor rivaroxaban in patients with acute symptomatic deep-vein thrombosis or pulmonary embolism. Investigators/ study location: Involving approximately 300 centers worldwide in over 30 countries. Clinical phase: III Study objectives 1) For the Einstein-DVT evaluation. The primary efficacy objective is to evaluate whether rivaroxaban is at least as effective as enoxaparin/vka in the treatment of patients with acute symptomatic deep-vein thrombosis (DVT) without symptomatic pulmonary embolism (PE) for the prevention of recurrent venous thromboembolic events. 2) For the Einstein-PE evaluation. The primary efficacy objective is to evaluate whether rivaroxaban is at least as effective as enoxaparin/vka in the treatment of patients with acute symptomatic PE with or without symptomatic DVT for the prevention of recurrent venous thromboembolic events. Study design This is a multicenter, randomized, open-label, assessor-blind, event-driven, non-inferiority program for efficacy with a study treatment duration of 3, 6, or 12 months. The program consists of two independent evaluations: 1) one in patients with confirmed acute symptomatic DVT without symptomatic PE (Einstein-DVT), and 2) one in patients with confirmed acute symptomatic PE with or without symptomatic DVT (Einstein-PE). The Einstein-DVT and Einstein-PE evaluations are integrated in a single protocol since the Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 6 of 88

8 patients groups are fully complimentary, and are recruited in the same centers. In addition, all essential design features of both evaluations are identical, including further eligibility criteria, experimental and comparator treatment, outcome definitions and outcome assessments, as well as follow-up schedule. Moreover, both evaluations are supervised and guided by the same study committees and a pre-specified meta-analysis is planned. Pre-randomization treatment is allowed up to a maximum of 36 hours. In addition, a single pre-randomization VKA dose is allowed. Pre-randomization treatment is allowed up to a maximum of 48 hours. In addition, a single pre-randomization VKA dose is allowed. After randomization, patients allocated to rivaroxaban will receive rivaroxaban 15 mg twice-daily for a total of 3 weeks followed by rivaroxaban 20 mg once-daily. Patients allocated to the comparator will receive enoxaparin twice-daily for at least 5 days in combination with VKA (overlap 4 to 5 days) and will continue with VKA if the INR has been 2 on two consecutive measurements at least 24 hours apart. Only warfarin and acenocoumarol are allowed as VKAs. Allocation to treatment will be done centrally by interactive voice response system for Einstein-DVT and Einstein-PE, separately, and will be stratified by 1) country and 2) by intended treatment duration. The decision to treat for 3, 6 or 12 months will be based on the risk profile of the patient, and local preferences, and will be made by the investigator at the time of randomization. All patients will have a 30-day observational period after cessation of treatment. The primary efficacy outcome is symptomatic recurrent VTE, i.e., the composite of (recurrent) DVT or fatal or non-fatal PE. The primary efficacy analysis is based on the time to the first symptomatic recurrent VTE event during the 3-, 6-, and 12- month study treatment periods. In Einstein-PE, a dose confirmation phase will be implemented. For this dose confirmation phase, the initial 400 patients will have repeat lung imaging (i.e., perfusion lung scan (PLS) or spiral computed tomography (sct)) at 3 weeks. After completion of the 3-week repeat imaging in these patients, a dose confirmation analysis will be performed based on the composite of asymptomatic deterioration on PLS or sct and the primary efficacy outcome at 3 weeks. Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 7 of 88

9 The principal safety outcome is the combination of major and clinically relevant non-major bleeding. All suspected recurrent VTE, deaths, as well as all episodes of bleeding and vascular events will be evaluated by a central, blinded, independent adjudication committee (CIAC). Adjudication results will be the basis for the final analyses. An independent data and safety monitoring board (DSMB) will monitor the patients safety and give recommendations to the executive committee. A separate independent dose confirmation committee will perform the dose confirmation analysis in Einstein-PE and give recommendations to the executive committee. The program is event driven and requires 88 confirmed recurrent VTE for the Einstein- DVT- and the Einstein-PE-evaluation, separately. To obtain this number of events, the number of patients needed is approximately 2900 for each evaluation. In Einstein-PE, an additional 400 patients is required for the dose confirmation phase. In Einstein-PE, an additional 400 patients is required for the dose confirmation phase. To obtain this number of events, the number of patients needed is approximately 2930 for each evaluation. A 24-hour emergency telephone service will be available throughout the program. Repeat lung imaging (PLS, sct) at week 3 in the initial 400 PE patients. Inclusion criteria 1. a. For Einstein-DVT: confirmed acute symptomatic proximal DVT without symptomatic PE, or b. For Einstein-PE: confirmed acute symptomatic PE with or without symptomatic Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 8 of 88

10 DVT 2. Written informed consent Exclusion criteria 1. Legal lower age limitations (country specific) 2. Thrombectomy, insertion of a caval filter, or use of a fibrinolytic agent to treat the current episode of DVT and/or PE 3. Other indication for VKA than DVT and/or PE 4. More than 36 hours pre-randomization treatment with therapeutic dosages of anticoagulant treatment or more than a single dose of VKA prior to randomization More than 48 hours pre-randomization treatment with therapeutic dosages of anticoagulant treatment or more than a single dose of VKA prior to randomization. 5. Participation in another pharmacotherapeutic study within 30 days 6. Creatinine clearance < 30 ml/min 7. Significant liver disease (e.g. acute hepatitis, chronic active hepatitis, cirrhosis) or ALAT > 3 x ULN 8. Bacterial endocarditis 9. Life expectancy <3 months 10. Active bleeding or high risk for bleeding contraindicating treatment with enoxaparin or VKA 11. Systolic blood pressure >180 mmhg or diastolic blood pressure >110 mmhg 12. Childbearing potential without proper contraceptive measures, pregnancy or breast feeding 13. Any other contraindication listed in the local labeling of enoxaparin, warfarin, or acenocoumarol 14. Concomitant use of strong CYP3A4 inhibitors (e.g., HIV protease inhibitors, systemic ketoconazole) or strong CYP 3A4 inducers like rifampicin Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 9 of 88

11 Number of patients Einstein-DVT: approximately 2900 patients (1450 per treatment arm) Einstein-PE: approximately 3300 patients (1650 per treatment arm) Einstein-DVT: approximately 2930 patients (1465 per treatment arm) Einstein-PE: approximately 2930 patients (1465 per treatment arm) Study medication Formulation Rivaroxaban: HDPE-bottles containing tablets Enoxaparin: containers or pre-filled syringes as registered for DVT and/or PE treatment Warfarin or acenocoumarol according to marketed packaging Mode of administration Rivaroxaban: per os Enoxaparin: subcutaneous injections Warfarin, acenocoumarol: per os Dose regimen Pre-randomization treatment with any anticoagulant is allowed for a maximum duration of 36 hours. However, only a single pre-randomization dose of VKA is allowed. Prerandomization treatment with any anticoagulant is allowed for a maximum duration of 48 hours. However, only a single pre-randomization dose of VKA is allowed. Rivaroxaban arm in Einstein-DVT and Einstein-PE The first rivaroxaban tablet should be administered as soon as possible after randomization. If pre-randomization treatment was given, randomization should be planned 4 hours after bolus injection or stopping the infusion with UFH or within 6 to 12 hours after the last injection of LMWH with a twice-daily regimen, or within 12 to 24 hours after the last injection of LMWH with a once-daily regimen, or 12 to 24 hours after last injection of fondaparinux. During the first 3 weeks, patients will receive 15 mg rivaroxaban twice- Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 10 of 88

12 daily. Thereafter, patients will receive rivaroxaban 20 mg once-daily. Rivaroxaban will be administered orally and should be taken with food. Comparator arm in Einstein-DVT and Einstein-PE Enoxaparin, 1.0 mg/kg twice-daily with a minimal duration of 5 days. This 5 day treatment period could include the period up to 36 hr before randomization if enoxaparin twice-daily was used. Enoxaparin, 1.0 mg/kg twice-daily with a minimal duration of 5 days. This 5 day treatment period could include the period up to 48 hr before randomization if enoxaparin twice-daily was used. VKA should be started as soon as possible but not later than 48 hours after randomization. Enoxaparin should continue until the INR is 2.0 on two consecutive measurements at least 24 hours apart with an advised overlap with VKA for 4 to 5 days. VKA dosages will be adjusted to maintain the INR within the therapeutic range (target 2.5, range ). The INR should initially be measured every 2 to 3 days and when stable at least once-monthly. Evaluation criteria Efficacy The primary efficacy outcome for Einstein-DVT and Einstein-PE is symptomatic recurrent VTE, i.e., the composite of DVT or fatal or non-fatal PE. Definitions The following definitions are applied by the CIAC to confirm a suspected episode of recurrent PE/DVT: 1. Suspected (recurrent) PE with one of the following findings a (new) intraluminal filling defect in segmental or more proximal branches on sct, a (new) intraluminal filling defect or an extension of an existing defect or a new sudden cut-off of vessels more than 2.5 mm in diameter on the pulmonary angiogram, a (new) perfusion defect of at least 75% of a segment with a local normal ventilation result (high-probability) on ventilation/perfusion lung scintigraphy Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 11 of 88

13 inconclusive sct, pulmonary angiography or lung scintigraphy with demonstration of DVT in the lower extremities by compression ultrasound or venography. 2. Suspected (recurrent) DVT with one of the following findings if there were no previous DVT investigations: abnormal compression ultrasound (CUS), an intraluminal filling defect on venography. if there was a DVT investigation at screening: abnormal CUS where compression had been normal or, if non-compressible during screening, a substantial increase (4 mm or more) in diameter of the thrombus during full compression, an extension of an intraluminal filling defect, or a new intraluminal filling defect or an extension of non-visualization of veins in the presence of a sudden cut-off on venography. 3. Fatal PE PE based on objective diagnostic testing, autopsy, or death which can not be attributed to a documented cause and for which PE/DVT can not be ruled out (unexplained death). In the absence of objective testing, a suspected episode of DVT or PE will be considered as confirmed if it led to a change in anticoagulant treatment at therapeutic dosages for more than 48 hours. Safety The principal safety outcome is clinically relevant bleeding (i.e., major bleeding and other clinically relevant non-major bleeding). Other safety outcomes include all deaths and other vascular events. Definitions The following criteria are applied by the CIAC to classify bleeding Major bleeding is defined as overt bleeding associated with: a fall in hemoglobin of 2 g/dl Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 12 of 88

14 or more, or leading to a transfusion of 2 or more units of packed red blood cells or whole blood, or bleeding that occurs in a critical site: intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, retroperitoneal, or contributing to death. Clinically relevant non-major bleeding is defined as overt bleeding not meeting the criteria for major bleeding but associated with medical intervention, an unscheduled contact (visit or telephone call) with a physician, (temporary) cessation of study treatment, or associated with discomfort for the patient such as pain, or impairment of activities of daily life. Substudies Health economics: Key parameters of health care resource utilization will be documented for all patients of both studies and compared between the treatment groups Anti-Clot Treatment Scale (ACTS): Patients satisfaction with treatment will be measured with the ACTS in a subset of the patient population Pharmacodynamics (PD): Trough and peak levels of rivaroxaban will be evaluated by measurement of prothrombin time (PT) and prothrombinase induced clotting time (PICT) Statistical considerations A dose confirmation analysis will be performed in the initial 400 PE patients based on the combination of symptomatic recurrent venous thromboembolism and asymptomatic deterioration on repeat lung imaging at 3 weeks. The incidence of this combined outcome will be compared amongst control and rivaroxaban patients. The one-sided 95% interval of the absolute difference of the observed incidences will be calculated. If the one-sided 95% CI of this difference does not exceed 8.0%, inclusion of PE patients will be continued as planned. For this purpose, it is necessary to include 200 PE patients in each treatment group based on a combined event rate of 4% and a one-sided type I error of 5% and a power of 90%. For the primary analysis of Einstein-DVT and Einstein-PE, the time to the first event of the Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 13 of 88

15 composite primary efficacy outcome will be analyzed using a stratified Cox s proportional hazard model. The rivaroxaban-to-comparator hazard ratio will be computed with 95% CI (two-sided testing), based on this model. Rivaroxaban will be considered at least as effective as the comparator if the upper limit of the CI is less than 2.0. If in one of the evaluations rivaroxaban is at least as effective as the comparator, the time (person time free from complication) to the principal safety outcome will be compared between those treatment groups, using a stratified Cox s proportional hazard model. If the difference is statistically significant in favor of rivaroxaban (at a two-sided significance level of 0.05), time to major bleeding only will also be tested at the same significance level. A total of 88 events for the Einstein-DVT and Einstein-PE evaluations will give a power of 90% to demonstrate that rivaroxaban is at least as effective as the comparator, considering a relative non-inferiority upper CI margin for the hazard ratio of 2.0 (two-sided α=0.05), assuming equal efficacy. Based on the observation that most recurrent events occur in the first month after the initial event, an incidence of recurrent VTE of 2.5% at 3 months, 3% at 6 months and 3.5% at 12 months is expected. Hence, a mean incidence for the primary efficacy outcome of 3% for both treatment groups is expected and approximately 1450 patients per group would be needed (i.e., 2900 DVT and 2900 PE patients). However, to correct for the exclusion of the 400 patients of the dose confirmation phase in the secondary efficacy analysis in Einstein-PE, the sample size for Einstein-PE will be adjusted to 1650 per group to obtain 88 events among the patients not participating in the dose confirmation phase, thereby ensuring a power of 90% for this secondary analysis. Hence, a mean incidence for the primary efficacy outcome of 3% for both treatment groups is expected and approximately 1465 patients per group would be needed (i.e., 2930 DVT and 2930 PE patients). The number of patients in Einstein-DVT and Einstein-PE will be adjusted based on the observed overall incidence of symptomatic recurrent VTE. Study duration per patient The study duration is 3, 6 or 12 months followed by a 30-day observational period. Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 14 of 88

16 Anticipated study duration Approximately 31 months: 24 months recruitment, 6 months treatment for the last patients, and a 30-day observational period. If the number of events is reached before all patients have completed the intended study treatment duration, then the study will be stopped. The last included patients will be allowed to be treated for at least 6 months. New Flowchart Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 15 of 88

17 Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 16 of 88

18 New flowchart Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 17 of 88

19 New flowchart Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 18 of 88

20 1. Introduction and rationale The classical management of VTE consists of an initial treatment with adjusted-dose intravenous UFH, bodyweight-adjusted subcutaneous LMWH, or bodyweight-adjusted subcutaneous fondaparinux followed by long-term treatment with a VKA. (1) Patients should receive (LMW)Heparin/fondaparinux for at least five days. Heparin therapy may be discontinued when the INR is equal or above 2 for two or more measurements at least 24 hours apart. VKA therapy should be continued for at least three months. The dose of VKA needs to be adjusted to maintain the INR in the therapeutic range (target 2.5, range ). VKA therapy has several unsatisfying aspects, including a slow onset and offset of action, a narrow therapeutic window, necessity of frequent INR monitoring, and dose adjustments, caused by food and drug interactions. (2) An oral anticoagulant drug that requires no monitoring of its effect, with a rapid onset of action and a high benefit-risk ratio is of considerable interest. Rivaroxaban is a novel, direct oral factor Xa-inhibitor which plays its role at the intersection of the extrinsic and the intrinsic pathways for thrombin generation. Selective inhibition of factor Xa by rivaroxaban is expected to terminate the burst of thrombin generation, to result in improved inhibition of thrombus formation with an improved safety profile. The antithrombotic effect of rivaroxaban was demonstrated in different thrombosis models at doses of mg/kg with a comparable antithrombotic/bleeding risk ratio in rats and rabbits in comparison to enoxaparin. In human safety pharmacology studies and in different animal models, rivaroxaban showed a dose-dependent inhibition of blood coagulation, linear pharmacokinetic, up to 30 mg, a bioavailability of 60% to 86%, excretion mainly via the renal route, and no induction of cytochrome P450. Rivaroxaban was tested for point mutations and for Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 19 of 88

21 clastogenicity and all tests were negative. Drug-drug interaction between rivaroxaban and strong CYP3A4 inhibitors showed significant effects on the rivaroxaban turnover rate in vitro. In healthy volunteers, single doses up to 80 mg and multiple doses of 30 mg for 5 days were well tolerated and inhibition of factor Xa was dose-dependent. Clotting parameters (PT, aptt, HepTest, factor Xa inhibition) showed expected changes with a dose dependent prolongation or increase in inhibition. No effects of rivaroxaban on factor IIa or antithrombin were observed. Bleeding time was not prolonged to a clinically relevant extent. Apart from clotting parameters, only isolated laboratory values showed minor deviation from normal without any consistent pattern. No accumulation of rivaroxaban was observed at doses of up to 30 mg bid. The pharmacokinetic profile of rivaroxaban was dose proportional up to 10 mg and dose-dependent, but less than proportional above this dose. Rivaroxaban was rapidly absorbed after oral treatment both as a solution (Cmax after approximately 30 minutes) and as a tablet (Cmax after 2-4 hours). The terminal half-life was between 9 to 12 hours. This relatively long half-life would allow a once-daily dosing schedule. After a single 30 mg dose of rivaroxaban, thrombin generation was still significantly reduced at 24 hours. Rivaroxaban has been evaluated in an extensive phase II program in patients undergoing hip and knee replacement surgery. A once-daily 10 mg dose of rivaroxaban was found to be associated with the most optimal efficacy-safety profile as compared with standard prophylaxis. Therefore, the 10 mg dose of rivaroxaban was selected for further evaluation in the patient phase III thromboprophylaxis program. A once-daily rivaroxaban regimen has been evaluated in a dose ranging phase II study (Einstein Phase II, IMP 11528) in 543 patients with acute symptomatic DVT. Patients Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 20 of 88

22 received once daily 20, 30 or 40 mg oral rivaroxaban or an initial course of (LMW)Heparin followed by VKA and were treated for 3 months. The primary efficacy outcome was the composite of symptomatic recurrent DVT or symptomatic fatal or non-fatal PE at 12 weeks and deterioration in thrombotic burden, as assessed by CUS and PLS, at baseline and at 12 weeks. The principal safety outcome was the combination of major and clinically relevant non-major bleeding. Each of the 3 dose regimens was shown to be equally effective and safe compared to standard treatment. Symptomatic recurrent VTE occurred in 2.6%, 3.6% and 1.7% in the once-daily 20, 30 or 40 mg rivaroxaban groups respectively versus 6.9 % in the comparator group. Deterioration in thrombotic burden or symptomatic recurrent VTE occurred in 6.1%, 5.4% and 6.6% in the once-daily 20, 30 or 40 mg rivaroxaban groups respectively versus 9.9 % in the comparator group. There was 1 major bleed in the 20 mg group, 2 in the 30 mg and none in the 40 mg group versus 2 in the comparator group. Clinically relevant non-major bleed occurred in 2.2 to 5.2% in the rivaroxaban groups versus 7.3% in the comparator group. Treatment with rivaroxaban was not associated with liver toxicity. Similar results at 12 weeks were obtained in another dose ranging phase II study (ODIXA-DVT, IMP 11223) in 613 patients with acute symptomatic DVT. Patients received 10, 20, or 30 mg rivaroxaban twice-daily or 40 mg once-daily versus standard treatment (initial course of enoxaparin followed by VKA) and were treated for 3 months. This study also evaluated the composite of symptomatic recurrent DVT or symptomatic fatal or non-fatal PE and asymptomatic deterioration in thrombotic burden, as assessed by repeat CUS and PLS at 3 weeks. Although symptomatic VTE and asymptomatic deterioration in thrombotic burden occurred rarely in all treatment arms at 3 weeks, asymptomatic thrombus resolution on repeat CUS and PLS was lowest (58%) for the 40 mg once-daily treatment arm in comparison to the 3 twicedaily treatment arms (72%, 69%, and 68%, respectively) and enoxaparin/vka arm Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 21 of 88

23 (61%). Although this small difference is likely based on chance alone, it can also be hypothesized that the higher Ctrough levels observed for the twice-daily regimens as compared to the once-daily regimen represented a more intensified anticoagulant effect that could be beneficial especially in the acute treatment phase. In conclusion, 20 mg rivaroxaban daily is the lowest effective dose associated with a safety profile at least as good as standard treatment with (LMW)Heparin followed by VKA. The combined analysis of both dose-finding studies indicates that the optimal regimen consists of a twice-daily administration of 15 mg for the initial 3-week treatment phase followed by once-daily administration of 20 mg for the subsequent treatment period. The proposed phase III VTE treatment program consists of two independent evaluations 1) one in patients with symptomatic DVT without symptomatic PE (Einstein-DVT) and 2) one in patients with symptomatic PE with or without symptomatic DVT (Einstein-PE). Both evaluations are integrated in one protocol since the patients groups are fully complimentary, and are recruited in the same centers. In addition, all essential design features are identical, including further eligibility criteria, experimental and comparator treatment, outcome definitions and assessments, as well as follow-up schedule. Moreover, both evaluations are supervised and guided by the same study committees and a pre-specified meta-analysis is planned. Both Einstein-DVT and Einstein-PE will evaluate rivaroxaban 15 mg twice-daily for 3 weeks followed by 20 mg once-daily versus standard treatment with enoxaparin/vka. Patients will be randomized to one of these treatment arms and followed up to document the incidence of recurrent VTE. Since the rivaroxaban dose selection was only done in patients with symptomatic DVT without symptomatic PE (although 70% of these patients had asymptomatic PE), the obtained results do not have to be automatically applicable also for patients with symptomatic PE. Therefore, before Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 22 of 88

24 exposing a large series of patients with PE to the selected rivaroxaban regimen, a dose confirmation phase will be performed in Einstein-PE. In this PE dose confirmation phase, patients with symptomatic PE with or without DVT will have repeat PLS or sct at 3 weeks. After inclusion of approximately 400 patients with PE, the independent dose confirmation committee will perform the analysis. Further detailed information on rivaroxaban can be found in the investigator s brochure. 2. Study objectives a) For the Einstein-DVT evaluation. The primary efficacy objective is to evaluate whether rivaroxaban is at least as effective as enoxaparin/vka in the treatment of patients with acute symptomatic deep-vein thrombosis (DVT) without symptomatic pulmonary embolism (PE) for the prevention of recurrent venous thromboembolic events. b) For the Einstein-PE evaluation. The primary efficacy objective is to evaluate whether rivaroxaban is at least as effective as enoxaparin/vka in the treatment of patients with acute symptomatic PE with or without symptomatic DVT for the prevention of recurrent venous thromboembolic events. 3. Study design This is a multicenter, randomized, open-label, assessor-blind, event-driven, noninferiority program for efficacy with a study treatment duration of 3, 6, or 12 months. The program consists of two independent evaluations: 1) one in patients with confirmed acute symptomatic DVT without symptomatic PE (Einstein-DVT), and 2) one in patients with confirmed acute symptomatic PE with or without symptomatic DVT (Einstein-PE). In patients with symptomatic PE, a dose confirmation phase will be implemented. 3.1 Description of the study Patients with confirmed acute symptomatic DVT and/or PE are eligible for Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 23 of 88

25 inclusion. Pre-randomization treatment with any anticoagulant is allowed for a maximum duration of 36 hours. Pre-randomization treatment with any anticoagulant is allowed for a maximum duration of 48 hours. However, only a single prerandomization dose of VKA is allowed. After randomization, patients allocated to the rivaroxaban arm will receive rivaroxaban 15 mg twice-daily for a total of 3 weeks followed by rivaroxaban 20 mg once-daily. Patients allocated to the comparator arm will receive enoxaparin twice-daily for at least 5 days in combination with VKA (overlap 4 to 5 days) and will continue with VKA only if the INR has been 2 on two consecutive measurements at least 24 hours apart. Warfarin and acenocoumarol are allowed as VKAs. Allocation to treatment will be done centrally by IVRS separately for 1) patients with DVT without symptomatic PE (Einstein-DVT) and 2) patients with PE with or without symptomatic DVT (Einstein-PE). Allocation will be stratified by 1) country and 2) by intended treatment duration. The decision to treat for 3, 6 or 12 months will be based on the risk profile of the patient, and local preferences, and will be made by the investigator at the time of randomization. All patients will have a 30-day observational period after cessation of treatment. The primary efficacy outcome is symptomatic recurrent VTE, i.e., the composite of recurrent DVT or fatal or non-fatal PE. The primary efficacy analysis is based on the time to the first symptomatic recurrent VTE event during the 3-, 6,- and 12- month study treatment periods. For the PE dose confirmation phase, the initial 400 PE patients will have repeat lung imaging (perfusion lung scan (PLS) or spiral computed tomography (sct)) at 3 weeks. After inclusion of these patients, randomization of PE patients will be temporarily interrupted and an analysis will be performed based on the composite of asymptomatic deterioration on PLS or sct and the primary efficacy outcome at 3 weeks. If the potential efficacy of rivaroxaban is confirmed, randomization of Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 24 of 88

26 PE patients will be resumed. The principal safety outcome is the combination of major and clinically relevant non-major bleeding. All suspected recurrent VTEs, deaths, as well as all episodes of bleeding and other vascular events will be evaluated by a central, blinded, independent adjudication committee. Adjudication results will be the basis for the final analyses. The DSMB will monitor the patients safety during the study and give recommendations to the executive committee (ExCie). A separate independent dose confirmation committee will perform the dose confirmation analysis for the PE dose confirmation phase and give recommendations to the executive committee (ExCie). For all patients, contacts (visits or phone calls) are scheduled at regular time points (see flow-chart). Randomized patients not treated or with premature discontinuation of study drug, will at least be seen at the end of the respective treatment periods, i.e., at month 3, 6 or 12. Each treatment period will be followed by an observational period of 30 days regardless the duration of study drug administration. During all contacts, the treatment and clinical course of the patient will be evaluated using a contact report (Appendix 14.3). Patients with suspected efficacy or safety outcomes will undergo confirmatory testing. Key parameters of health care resource utilization will be documented for all patients and compared between 2 treatment groups and patients satisfaction with treatment will be measured with the ACTS in a subset of the patient population. 4. Study population 4.1 Planned number of patients Both the Einstein-DVT and the Einstein-PE evaluations are event-driven and will require each 88 confirmed recurrent VTE. The expected number of patients Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 25 of 88

27 required per evaluation is approximately In Einstein-PE, an additional 400 patients will be required for the dose confirmation phase. The expected number of patients required per evaluation is approximately Inclusion criteria 1. a For Einstein-DVT: confirmed acute symptomatic proximal DVT without symptomatic PE, or b. For Einstein-PE: confirmed acute symptomatic PE with or without symptomatic DVT 2. Written informed consent 4.3 Exclusion criteria 1. Legal lower age limitations (country specific) 2. Thrombectomy, insertion of a caval filter, or use of a fibrinolytic agent to treat the current episode of DVT and/or PE 3. Other indication for VKA than DVT and/or PE 4. More than 48 hours pre-randomization treatment with therapeutic dosages of (LMW)Heparin/fondaparinux or more than a single dose of VKA prior to randomization. More than 36 hours pre-randomization treatment with therapeutic dosages of (LMW)Heparin/fondaparinux or more than a single dose of VKA prior to randomization 5. Participation in another pharmacotherapeutic study within 30 days 6. Creatinine clearance < 30 ml/min, 7. Significant liver disease (e.g. acute hepatitis, chronic active hepatitis, cirrhosis) or ALAT > 3 x ULN 8. Bacterial endocarditis 9. Life expectancy <3 months 10. Active bleeding or high risk for bleeding contraindicating treatment with enoxaparin or VKA Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 26 of 88

28 11. Systolic blood pressure >180 mmhg or diastolic blood pressure >110 mmhg 12. Childbearing potential without proper contraceptive measures, pregnancy or breast feeding 13. Any other contraindication listed in the local labeling of warfarin, acenocoumarol, or enoxaparin 14. Concomitant use of strong CYP3A4 inhibitors (e.g., HIV protease inhibitors, systemic ketoconazole) or CYP 3A4 inducers like rifampicin. 4.4 Prior and concomitant medication Medication prior to randomization Therapeutic dosages of (LMW)Heparin/fondaparinux are allowed up to a maximum of 36 hours prior to randomization. Therapeutic dosages of (LMW)Heparin/fondaparinux are allowed up to a maximum of 48 hours prior to randomization. The duration of prophylactic dosages of (LMW)Heparin is not restricted. A single pre-randomization dose of VKA is also allowed Concomitant medication Non-steroid anti-inflammatory drugs (NSAIDs) and antiplatelet agents are discouraged. However if indicated, aspirin up to a dosage of 100 mg/day as well as clopidogrel (75 mg/day) are allowed. Concomitant use of strong CYP3A4 inhibitors (e.g. HIV protease inhibitors, systemic ketoconazole) are not allowed at any time during active treatment period. Instead, concomitant use of strong CYP 3A4 inducers is allowed for no more than two days; in case treatment with CYP 3A4 inducers is needed for more than two days, the patient will withdraw from the study treatment. Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 27 of 88

29 5. Study medication and administration 5.1 Treatment groups and regimens Method of treatment allocation Allocation to treatment will be done centrally by IVRS separately for 1) patients with DVT without symptomatic PE and 2) patients with PE with or without symptomatic DVT. Allocation will be stratified by 1) country and 2) by intended treatment duration. At randomization, the investigator provides the IVRS with: clinical presentation (i.e., DVT or PE), the patient s date of birth, study center identification, and intended treatment duration. A fax will be sent by the IVRS to confirm treatment allocation. The fax will also provide a calendar with dates of pre-scheduled contacts. When patients treated for 6 or 12 month return for their 3-month visit, the IVRS will be called to confirm that study treatment is continued or was prematurely discontinued Rivaroxaban group The first rivaroxaban dose should be administered as soon as possible after randomization. Randomization should be planned 4 hours after bolus injection or stopping the infusion with UFH or within 6 to 12 hours after the last injection of LMWH with a twice-daily regimen, or within 12 to 24 hours after the last injection of LMWH with a once-daily regimen, or 12 to 24 hours after last injection of fondaparinux. The first 3 weeks patients will receive rivaroxaban 15 mg twice-daily followed by rivaroxaban 20 mg once-daily. In patients where, the first day of study treatment, the first dose of 15 mg is taken in the afternoon or in the evening, the second dose of 15 mg will be taken in the evening of the same day. Two 15 mg doses can be taken at once, if patient can take the first dose only in the evening. From day 2 to day 21 included one 15mg dose will be taken in the morning and one in the evening. Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 28 of 88

30 This will ensure that the 15 mg dose is taken twice daily from day 1 to 21 inclusive. The patient then will start their once daily 20mg tablet on Day 22. Patients will be treated for 3, 6 or 12 months. For patients treated for 6 or 12 month, study medication supply will take place at 3-month intervals. After the final assessment, study drug is discontinued. If a rivaroxaban dose was missed, it can only be taken the same day. Double dosing on a single day is not allowed Enoxaparin/VKA group Enoxaparin, 1.0 mg/kg twice-daily. Minimal duration of treatment with enoxaparin is 5 days. This 5-day treatment period could include the period up to 36 hr before randomization if enoxaparin twice-daily was used. This 5-day treatment period could include the period up to 48 hr before randomization if enoxaparin twice-daily was used. Warfarin and acenocoumarol are the only allowed VKAs and should be started not later than 48 hours after randomization. Enoxaparin should continue until the INR is 2.0 on two consecutive measurements at least 24 hours apart with an advised overlap with VKA for 4 to 5 days. VKA dosages will be adjusted to maintain the INR within the therapeutic range (target 2.5, range ). The INR should initially be measured every 2 to 3 days and when stable at least once-monthly. Each center has to specify a priori to the study which VKA compound (warfarin or acenocoumarol) will be used during the study. 5.2 Formulation and dose Rivaroxaban Rivaroxaban will be provided by Bayer as 15 mg and 20 mg tablets for oral use and should be taken with food. Since patients with a creatinine clearance below 30mL/min are excluded from the study, a dose adaptation is not indicated. In patients with moderate renal impairment (creatinine clearance between Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 29 of 88

31 ml/min), a dose adaptation is not indicated because of the wide therapeutic window of rivaroxaban and the potential risk for undertreatment with rivaroxaban dosages below 20mg per day Enoxaparin/VKA Enoxaparin and the pre-specified VKA will be used according to approved formulations. 5.3 Packaging, labeling, and storage For the initial 3 weeks, rivaroxaban will be provided in a HDPE-bottles containing 42 tablets of 15 mg covering the 3 week period. For the rest of the treatment period, rivaroxaban will be provided in a HDPE-bottles containing 95 tablets (to cover 3 month periods). Drug labeling will be according to national law and GMP ruling Annex It is recommended to store rivaroxaban at room temperature. Enoxaparin and VKA will be stored according to their package inserts. 5.4 Drug accountability and treatment compliance Study medication should be used in accordance with the protocol, under the responsibility of the investigator. The hospital pharmacist or any authorized person should maintain a complete and accurate record of the receipt of all study medication supplied to the site by the sponsor. These records should include dates of receipt, batches and quantities received. The dispensing of study medication provided by the sponsor should include subject number, the date, quantity and batch numbers of the dispensed and returned medication and the dispenser. All non dispensed medication supplied to the site by the sponsor should be kept securely in the original containers in a designated locked container until retrieved/dispensed. Subjects should be instructed to return all used, partially used, or unused medication packaging to the site. If enoxaparin syringes were Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 30 of 88

32 dispensed to the subject only the unused syringes in the original packaging should be returned. A log should be kept, by subject number of the date, quantity and batch numbers returned (the dispensing and the return log may be combined).for medication supplied by the sponsor the total amount of medication used and unused should equal the amount received, any discrepancies should be explained in writing. All unused medication will be destroyed and records of shipment/receipt and or destruction will be maintained VKA treatment monitoring Compliance with VKA administration will be ensured by the use of a target INR of 2.5 (range 2-3) with a minimum of once-monthly monitoring. The investigator has to record all information concerning the VKA treatment, including the date of first and last intake with specifications of the brand and all INR values and the actual measurement dates. This information will be obtained directly from the patient file or transmitted by the INR-monitoring physician or laboratory. 6. Study procedures 6.1 Screening Patients are potentially eligible if the diagnosis of DVT/PE is based on either one of the following: For PE An intraluminal filling defect in segmental or more proximal branches on sct scan. An intraluminal filling defect or a sudden cutoff of vessels more than 2.5 mm in diameter on the pulmonary angiogram. A perfusion defect of at least 75% of a segment with a local normal ventilation result (high-probability) on ventilation/perfusion lung scintigraphy. Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 31 of 88

33 Inconclusive sct, pulmonary angiography or lung scintigraphy with demonstration of DVT in the lower extremities by compression ultrasound or venography. For DVT A non-compressible proximal vein on compression ultrasonography. An intraluminal filling defect in the proximal veins on venography. Proximal veins are the iliac vein, common femoral vein, superficial femoral vein and the popliteal vein. The index event will be adjudicated. The adjudication package will contain films or images of one of the above tests which was used to confirm the diagnosis only. No systematic search for other sites of thrombosis is required. Description of the procedures for these tests will be provided in the diagnostic test manual. Due to logistical constraints, adjudication will be performed after randomization hence the adjudication result is not used to assign the patient to the PE or DVT evaluation but only for the assignment of patients to the perprotocol population. In patients with acute symptomatic DVT/PE, confirmed by one of the above diagnostic tests, eligibility will be assessed by the absence of the exclusion criteria. Eligible patients will be asked to provide written informed consent. Demographics, medical history, anticoagulant/antiplatelet medication will be recorded. Blood samples are taken for hemoglobin, platelet count, INR, aptt, ALAT, serum creatinine and central lab assessment (liver function tests), including a retention sample. The creatinine clearance will be calculated (see appendix 13.1). A pregnancy test is performed in all women of child-bearing potential. Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 32 of 88

34 Thereafter, the treatment duration will be determined. A 3 month treatment duration is often employed for patients with only transient risk factors such as: Recent surgery or trauma Immobilization Use of estrogen containing drugs Puerperium A 6 month or a 12-month treatment duration is often employed for patients with idiopathic VTE, or with permanent risk factors such as: Active cancer Previous episodes of PE/DVT Known thrombophilic condition (e.g. deficiency of AT-III, protein S or C, factor V or prothrombin gene mutations, or antiphospholipid antibodies) The final decision to treat a patient for 3 or 6 to 12 months is at the investigator s discretion and is based on the above risk assessments as well as the potential for bleeding. This intended treatment duration must be specified at randomization and patients will be stratified accordingly. The patients will then be randomized using the IVRS. 6.2 Study drug treatment period This is the period between randomization (Day 1) and final assessment at month 3, month 6 or month Patient booklet Patients will receive a booklet detailing symptoms suggestive for recurrent PE/DVT and bleeding. Patients will be asked to immediately contact the investigator if these symptoms occur. Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 33 of 88

35 The booklet will contain the following information for both treatment groups: The study outline in layman s terms The local medical contact person and emergency telephone number The visit schedule provided by the IVRS (fax with dates of telephone and/or hospital visits) How to recognize and report signs and symptoms of possible recurrent symptomatic PE/DVT or bleeding Instructions to keep empty medication packages For the rivaroxaban treatment group How to take rivaroxaban For the enoxaparin VKA treatment group How to use enoxaparin/vka The planned dates of blood collections for the next INR control Instruction to insert the INR monitoring cards (if available) Patient contacts For all randomized patients, there will be contacts (visits or telephone calls) at various time points (see flow-chart). During each patient contact, the following will be systematically checked (Appendix 13.3 contact report): occurrence, worsening, or recurrence of symptoms of PE or DVT, (S)AE, including bleeding events. Concomitant medication Compliance with rivaroxaban treatment or enoxaparin/vka treatment and monitoring In addition, on various time points blood samples will be obtained for central laboratory assessment (see flow-chart). Health care resource utilization data (HCRU) will be reported and in a subset of patients the patient satisfaction Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 34 of 88

36 questionnaire (ACTS) will be collected (see flow-chart and sections 6.10, 6.11) Assessment of clinical outcomes All suspected clinical outcomes i.e., recurrent PE/DVT, bleeding, death and vascular events), will be notified expedited (notification fax or within 24 hours of awareness). The adjudication package should be assembled and sent within 2 weeks after occurrence of the event for assessment by the central blinded and independent adjudication committee (CIAC) Suspected recurrent PE or DVT Patients with suspected recurrent PE/DVT will undergo objective testing to assess the recurrent episode. In all patients, the INR, aptt and a platelet count will be obtained. The following documentation should be sent for adjudication: Films/images of objective testing The recurrent PE/DVT clinical summary form Suspected bleeding Patients with a suspected bleeding will undergo confirmatory testing, if applicable, and a (S)AE form will be completed. In patients with unusual overt bleeding, Hb, aptt, INR, and platelet count are obtained. However, whether or not a bleeding is an unusual overt bleeding is up to the discretion of the investigator. The following documentation should be sent for adjudication: Results/films/images of confirmatory testing The bleeding clinical summary form Deaths Autopsy should be requested in patients who die, and an SAE form should be completed. The following documentation should be sent for adjudication: Results/films/images of confirmatory testing, if applicable The bleeding, recurrent PE/DVT, or vascular event clinical summary form, if Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 35 of 88

37 applicable The death clinical summary form Vascular events Patients with a suspected acute coronary syndrome (STEMI, NSTEMI, UA), ischemic stroke, transient ischemic attack (TIA), non-cns systemic embolism or vascular death (see also section ) will undergo confirmatory testing, if applicable, and a (S)AE form will be completed. The documents to be sent for adjudication are: Results/films/images of confirmatory testing The vascular event clinical summary form Observational period All patients will have an observational period after cessation of study treatment. The length of this period will be 30 days starting the day after the last intake of study medication. At the end of this observational period, a contact is planned for all included patients to record: (S)AEs, including suspected bleeding and vascular events Suspected recurrent PE/DVT Anticoagulant medication and any medication given in case of a suspected thrombotic or bleeding event, including death or (S)AE All suspected outcome events will be investigated and adjudicated in the same way as during the treatment period. All events that occur in the observational period will be described, no formal analyses will be performed. Also for those patients who discontinued study medication prematurely, the same observation period applies. 6.3 Efficacy outcomes The primary efficacy outcome is symptomatic recurrent VTE, i.e., the composite of Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 36 of 88

38 recurrent DVT or fatal or non-fatal PE occurring during the 3-, 6,- and 12-month study treatment periods. The following definitions are applied by the CIAC to confirm a suspected episode of symptomatic recurrent PE/DVT. (3;4) 1. Suspected (recurrent) PE with one of the following findings a (new) intraluminal filling defect in segmental or more proximal branches or on spiral CT scan a (new) intraluminal filling defect or an extension of an existing defect or a new sudden cutoff of vessels more than 2.5 mm in diameter on the pulmonary angiogram a (new) perfusion defect of at least 75% of a segment with a local normal ventilation result (high-probability) on ventilation/perfusion lung scan (VPLS) inconclusive sct, pulmonary angiography or VPLS with demonstration of DVT in the lower extremities by compression ultrasound or venography. 2. Suspected (recurrent) DVT with one of the following findings if there were no previous DVT investigations: abnormal compression ultrasound (CUS) an intraluminal filling defect on venography if there was a DVT investigation at screening: abnormal CUS where compression had been normal or, if non-compressible during screening, a substantial increase (4 mm or more) in diameter of the thrombus during full compression an extension of an intraluminal filling defect, or a new intraluminal filling defect or an extension of non-visualization of veins in the presence of a sudden cut-off on venography Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 37 of 88

39 3. Fatal PE PE based on objective diagnostic testing, autopsy, or death which can not be attributed to a documented cause and for which PE/DVT can not be ruled out (unexplained death). In the absence of objective testing, a suspected episode of DVT or PE will be considered as confirmed if it led to a change in anticoagulant treatment at therapeutic dosages for more than 48 hours. 6.4 Safety outcomes The principal safety outcome is clinically relevant bleeding (i.e., major bleeding and clinically relevant non-major bleeding). Additional safety outcomes include all deaths and other vascular events. Definitions for vascular events ( ) will be according to international accepted standards and will be specified in the adjudication manual Bleeding definitions All suspected bleedings will be reported as either AE or SAE and will be classified by the CIAC as major, clinically relevant non-major, trivial, or no bleeding. Major bleeding is defined as overt bleeding and: associated with a fall in hemoglobin of 2 g/dl or more, or leading to a transfusion of 2 or more units of packed red blood cells or whole blood, or occurring in a critical site: intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, retroperitoneal, or contributing to death Other clinically relevant bleeding is defined as overt bleeding not meeting the criteria for major bleeding but associated with medical intervention, Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 38 of 88

40 unscheduled contact (visit or telephone call) with a physician, (temporary) cessation of study treatment, or associated with any other discomfort such as pain, or impairment of activities of daily life. Examples of these bleeding are: epistaxis if it lasts for more than 5 minutes, if it is repetitive (i.e., 2 or more episodes of true bleeding, i.e. not spots on a handkerchief, within 24 hours), or leads to an intervention (packing, electrocoagulation etc), or gingival bleeding if it occurs spontaneously (i.e. unrelated to tooth brushing or eating), or if it lasts for more than 5 minutes, or hematuria if it is macroscopic, and either spontaneous or lasts for more than 24 hours after instrumentation (e.g., catheter placement or surgery) or the urogenital tract, or macroscopic gastro-intestinal hemorrhage: at least one episode of melena/hematemesis, if clinically apparent, or rectal blood loss, if more than a few spots, or hemoptysis, if more than a few speckles in the sputum, or intramuscular hematoma, or subcutaneous hematoma if the size is larger than 25 cm2, or larger than 100 cm2 if provoked, or multiple source bleeding All other overt bleeding episodes not meeting the criteria for clinically relevant bleeding will be classified as trivial bleed. 6.5 Measures to minimize bias A series of measures will be implemented to minimize the potential for bias in this open label design. These measures include: Patients will be informed on the signs and symptoms of efficacy and safety outcomes and will be instructed to immediately contact the study site if these signs or symptoms occur. Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 39 of 88

41 Patients in both treatment arms will have a contact with the site with a fixed frequency (see flow-chart). During each contact, all patients will be interviewed using a standardized outcome form for efficacy as well as for bleeding events. Recurrent thromboembolic complications need to be documented carefully in all patients using accepted objective diagnostic testing. All suspected events will be reported to and interpreted by the adjudication committee that is blinded to treatment assignment. The adjudication committee will objectively and consistently adjudicate these events. Rules of adjudication will be pre-defined by the committee in an adjudication manual before the study start Every effort will be made to follow each patient up to the planned end of the study, including those who will discontinue the study drug prematurely. A per-protocol analysis will be performed in addition to the primary intentionto-treat (ITT) analysis and the outcome of both analyses will be presented. Sites will be monitored closely for non-compliance to the protocol and possible bias. If this is the case, rapid intervention will be planned. 6.6 Adverse events (AE) AE monitoring Subjects must be carefully monitored for AEs. AEs should be assessed in terms of their seriousness, severity, and relationship to the study drug AE definitions AE An AE is any untoward medical occurrence in a subject or clinical investigation subject administered with a pharmaceutical product. The AE does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 40 of 88

42 unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of an investigational product, whether or not considered related to the medicinal product. AE associated with the use of a drug in humans, whether or not considered drug related, include the following: An AE occurring in the course of the use of a drug product in professional practice. An AE occurring from an overdose whether accidental or intentional. An AE occurring from drug abuse. An AE occurring from drug withdrawal. An AEs where there is a reasonable possibility that the event occurred purely as a result of the subjects participation in the study (e.g., AE or serious AE due to discontinuation of anti-hypertensive drugs during wash-out phase) must also be reported as an AE even if it is not related to the investigational product. The clinical manifestation of any failure of expected pharmacological action is not recorded as an AE if it is already reflected as a data point captured in the CRF. If, however, the event fulfills any of the criteria for a serious AE, it must be recorded and reported as such Serious adverse event (SAE) A SAE is any untoward medical occurrence that at any dose: Results in death. Is life-threatening, i.e., an AE in which the subject was at risk of death at the time of the event. It does not refer to an AE which hypothetically might have caused death if it were more severe. Requires in-patient hospitalization or prolongation of existing hospitalization unless at least one of the following exceptions are met: the admission results in a hospital stay of less than 12 hours, or the admission is pre-planned (i.e., elective Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 41 of 88

43 or scheduled surgery arranged prior to the start of the study), or the admission is not associated with an AE (e.g., social hospitalization for purposes of respite care). However, it should be noted that invasive treatment during any hospitalization may fulfill the criteria of medically important and as such may be reportable as a SAE dependent on clinical judgment. In addition, where local regulatory authorities specifically require a more stringent definition, the local regulation takes precedent. Results in persistent or significant disability or incapacity i.e., a substantial disruption of a person s ability to conduct normal life s functions. Is a congenital anomaly or birth defect. Is an important medical event because it may jeopardize the subject and may require intervention to prevent another serious condition. As guidance for determination of important medical events refer to the WHO adverse reaction terminology critical terms list. These terms either refer to or might be indicative of a serious disease state. Such reported events warrant special attention because of their possible association with a serious disease state and may lead to more decisive action than reports on other terms Unexpected AEs An unexpected AE is any adverse drug event, the specificity or severity of which is not consistent with the current investigator brochure (or package insert for marketed products). Also, reports which add significant information on specificity or severity of a known, already documented AE constitute unexpected AEs. For example, an event more specific or more severe than described in the Investigator Brochure would be considered unexpected. Specific examples would be 1) acute renal failure as a labeled adverse event with a subsequent new report of interstitial nephritis and 2) hepatitis with a first report of fulminant hepatitis. Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 42 of 88

44 Relationship of AE to study drugs The assessment of the relationship of an AE to the administration of study drug is a clinical decision based on all available information at the time of the completion of the CRF. An assessment of No would include: The existence of a clear alternative explanation e.g., bleeding at surgical site, or Non-plausibility e.g., the subject is struck by an automobile when there is no indication that the drug caused disorientation that may have caused the event; cancer developing a few days after the first drug administration. An assessment of Yes indicates that there is a reasonable suspicion that the AE is associated with the use of the investigational drug. Factors to be considered in assessing the relationship of the AE to study drugs include: The temporal sequence from drug administration: The event should occur after the drug is given. The length of time from drug exposure to event should be evaluated in the clinical context of the event. Recovery on discontinuation (de-challenge), recurrence on reintroduction (rechallenge): Subject s response after drug discontinuation (de-challenge) or subjects response after drug re-introduction (re-challenge) should be considered in the view of the usual clinical course of the event in question. Underlying, concomitant, undercurrent diseases: Each report should be evaluated in the context of the natural history and course of the disease being treated and any other disease the subject may have. Concomitant medication or treatment: The other drugs the subject is taking or the treatment the subject receives should be examined to determine whether any of them may be suspected to cause the event in question. The pharmacokinetic properties (absorption, distribution, metabolism and Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 43 of 88

45 excretion) of the study drug(s), coupled with the individual subject s pharmacodynamics should be considered Severity of the AE The severity of AEs should be graded as follows: Mild usually transient in nature and generally not interfering with normal activities. Moderate sufficiently discomforting to interfere with normal activities. Severe prevents normal activities AE documentation All AEs occurring after the subject has signed the informed consent must be fully recorded in the CRF. Documentation must be supported by an entry in the subject s file. A laboratory test abnormality considered clinically relevant, e.g., causing the subject to withdraw from the study, requiring treatment or causing apparent clinical manifestations, or judged relevant by the investigator, should be reported as an AE. Each event should be described in detail along with start and stop dates, severity, relationship to study drug, action taken and outcome Reporting of SAE/pregnancy SAEs, including laboratory test abnormalities fulfilling the definition of serious, after signing the informed consent, during the treatment period and until 1 month after the last dose, must immediately (within 24 hours of the investigator s awareness) be reported to the person detailed in the study file. A SAE form must also be completed within 24 hours of the investigator awareness (as complete as possible and tick on the form whether or not the SAE is suspected to be a bleeding) and forwarded to the designated person as detailed in the study file. Each SAE must be followed up until resolution or stabilization by submission of updated reports to the designated person. When required, and according to local Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 44 of 88

46 law and regulations, SAEs must be reported to the ethics committee and regulatory authorities. Pregnancy occurring during the study, although not considered a SAE, must be reported within the same timelines as a SAE on a pregnancy monitoring form. The outcome of a pregnancy should be followed up carefully and any abnormal outcome of the mother or the child should be reported Study specific exceptions to the (S)AE reporting The study efficacy outcomes DVT and non-fatal PE will not be reported as (S)AE. Transfer of patients to a rehabilitation unit as a standard practice will not be considered as a prolonged hospitalization and should not be reported as an SAE. However, if this transfer is part of treatment of a medical complication, it should be considered prolonged hospitalization and the event should be reported as a SAE. In order to collect additional information about clinically important laboratory abnormalities, any laboratory abnormality that required cessation of the study drug (see also 6.6.1) will be captured as a SAE. 6.7 Approach to the bleeding patient If a patient has a serious bleed during study treatment, the following routine measures could be considered. Delay the next enoxaparin, rivaroxaban, or VKA administration or discontinue treatment if indicated If the patient is treated with VKA, consider vitamin K administration If the patient is treated with enoxaparin, consider protamine sulfate administration Consider usual treatment for bleeding, including blood transfusion, and fresh frozen plasma If bleeding can not be controlled, consider administration of one of the following Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 45 of 88

47 procoagulants (both according to the dosages advised in the package insert): recombinant factor VIIa (NovoSeven ) 4-factor concentrate Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. 6.8 Centralized laboratory assessments Centralized laboratory assessments will involve liver function testing, amylase and pharmacodynamics Liver function testing Liver function tests (LFT), i.e., bilirubin (total, conjugated) and ALAT, ASAT and alkaline phosphatase (AP) will be assessed centrally. The blood samples will be collected at regular time intervals (see flow-chart). In addition, a pre-randomization retention blood sample will be collected. This sample could be used for hepatitis assessment if indicated for the evaluation of clinically important liver function abnormalities (e.g., hepatitis, liver necrosis) occurring during the study. Any LFT value not evaluated centrally will also be recorded in the CRF together with the reference ranges. The central laboratory will report LFT values to the investigator within 24 to 48 hours. Elevated LFT as defined below will also be reported to the liver emergency consultant for appropriate assistance. ALAT will be done in all patients before randomization (at the local laboratory) and patients with ALAT >3x limit of normal (ULN) will be excluded from the study. All included patients will also have a central laboratory LFT assessment (+ amylase) prior to start of study medication and thereafter will have post randomization sampling as follows: 3-month stratum: week 2, month 1, 2, 3 (+ amylase) and 1 month after stop study treatment 6-month stratum: week 2, month 1, 2, 3, 4, 5, 6 (+ amylase) and 1 month after stop study treatment Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 46 of 88

48 12-month stratum: week 2, month 1, 2, 3, 4, 5, 6 (+ amylase), 7, 8, 9, 10, 11, 12 (+ amylase), and 1 month after stop study treatment If at any of these post-randomization assessments: ALAT >3x ULN but < 5x ULN or total bilirubin >2x ULN with a ratio of direct to total bilirubin of 50%: Contact liver emergency consultant Repeat LFT at least weekly (central laboratory) until ALAT falls below 2x ULN and total bilirubin <2x ULN Evaluate patient for liver disease by reviewing alcohol intake, concomitant medication, concomitant diseases and/or further (laboratory) assessments, if appropriate If after 4 weeks of testing, values improve but ALAT >2x ULN and the cause of the LFT rise is not study drug related according to the investigator and the liver emergency consultant, the monitoring frequency may be decreased (e.g., every 2 weeks for 2 months and then return to the routine monthly tests (see flow-chart) based upon mutual agreement. If after 4 weeks of testing there is persistent elevation of ALAT >3x ULN or total bilirubin >2x ULN with a ratio of direct to total bilirubin of 50% Or, if at any time there is: elevation of ALAT >3x ULN and total bilirubin >2x ULN with a ratio of direct to total bilirubin of 50%, or elevation of ALAT >5 x ULN, or a patient develops clinical manifestations of liver injury (e.g., jaundice) - Contact liver emergency consultant - Stop rivaroxaban medication and it is up to the investigator s clinical judgment to discontinue enoxaparin/vka antagonist therapy. For both groups report as SAE Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 47 of 88

49 - Evaluate alcohol intake, concomitant medication, and concomitant disease - Perform hepatitis screen, if appropriate (anti-hav, HBsAg, anti-hbc, anti- HBs and anti-hcv) - Obtain relevant specialist consultation, including diagnostic imaging of liver and hepatobiliary system and other diagnostic tests (e.g., additional laboratory), if appropriate - Serial LFT, if appropriate (frequency of monitoring will be planned in mutual agreement with the investigator and liver emergency consultant). If liver function values have normalized and liver function values rise is not study drug related, study medication may be resumed after specialist consultation and assessment of the case by the liver advisory panel. The liver emergency consultant will discuss relevant abnormal LFT results and case assessment with the investigator. In addition, clinically relevant abnormal results of other LFT will be discussed with the investigator and summarized in a laboratory issue log Pharmacodynamics Prothrombin time (PT) and prothrombinase induced clotting time (PICT) will be used to assess the peak and trough levels of rivaroxaban. Blood sampling will occur at regular time points (see flow-chart) and patients in the rivaroxaban group will be instructed to come to the hospital prior to intake of medication (trough level) or 2 hours after the intake (peak level) Sample collection, processing and storage The blood samples will be collected in specific tubes which will be provided by MDS Pharma Service (central lab). Further details on collection, labeling, storage and shipping of samples plasma are provided in a separate laboratory manual. 6.9 PE dose confirmation phase In the PE dose confirmation phase, the initial consecutive 400 patients with symptomatic PE (with or without DVT) will have repeat lung imaging (PLS or sct, Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 48 of 88

50 depending on the test used for confirmation of the index event) at 3 weeks (Day 21). If the diagnostic tests to confirm the index event was made using pulmonary angiography, a PLS or sct needs to be obtained within 36 hours of randomization. After obtaining the repeat PLS or sct at 3 weeks, original hard copies of the baseline and repeat tests need to be sent for central adjudication in an expedited manner. The paired sets of lung imaging tests will be assessed for deterioration of thrombotic burden (i.e., extension of perfusion defect for PLS or new intraluminal filling defect for sct). After inclusion of the initial 400 PE patients, randomization of PE patients will be temporarily interrupted (organized through the IVRS system) and a dose confirmation analysis will be performed. This analysis will be based on the composite of asymptomatic deterioration on PLS or sct and the primary efficacy outcome at 3 weeks. If the potential efficacy of rivaroxaban is confirmed, randomization of PE patients will be resumed Healthcare resource utilization Key parameters of health care resource utilization (HCRU) will be collected at several time points (see flow-chart) for all patients and compared between the treatment groups. The data collected will include duration of hospital stay and visits to health care providers for study outcomes, used diagnostic procedures in relation to outcomes (Appendix 13.4) and INR monitoring. The statistical analysis plan for the HCRU will be specified before starting enrolment. The HCRU-data will be described by country and analysed by treatment group with appropriate statistical methods: categorical variables by frequency tables and continuous variables by sample statistics and t-tests Assessment of treatment satisfaction The anti-clot treatment scale (ACTS) (see Appendix 13.5) will be done in all patients of some of the participating countries (US, UK, Canada, Germany, France, Italy, the Netherlands,) using country-specific translations of the questionnaire. The Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 49 of 88

51 ACTS will be completed at regular time points (see flow-chart). In patients who discontinue treatment for reasons other than a bleeding or a venous thrombotic complication, the ACTS will be completed close to the day of discontinuation. The reproducibility of the ACTS will be determined in a subsample of 150 patients at the 3-months visit. In addition, the treatment satisfaction questionnaire for medication (TSQM, Appendix 13.6) will be completed at various time points (see flow-chart).an analysis plan of the psychometric properties of the ACTS will be specified before database lock. After database lock, the psychometric analysis will be carried out without knowledge of treatment assignment. Hereafter, still without knowledge of treatment assignment, an analysis plan will be specified to compare the ACTS results between the treatment groups. 7. Premature discontinuation Subjects may be withdrawn from the study for the following reasons: At their own request or at the request of their legally acceptable representative. If, in the investigator s opinion, continuation in the study would be detrimental to the subject s well-being. At the specific request of Bayer. However, early permanent discontinuation of study drug is discouraged wherever possible. The single most important reason for premature discontinuation should be marked on the appropriate CRF and in the subject medical records. Discontinued patients will not be replaced. In some situations, it might be necessary to interrupt study medication temporarily (e.g. while contraindicated medication is taken). Patients should be encouraged to restart study drug after a short interruption (1 to 7 days) except when absolutely contraindicated. Patients who discontinue drug prematurely will at least be seen at the end of the respective treatment periods i.e. at month 3, 6 or 12 and data on clinical outcomes, HCRU and ACTS (if applicable) will be collected. A decision to stop recruitment and/or study treatment can be taken by the executive committee following an advise on safety aspects of the study by the DSMB. The ethics committee/ Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 50 of 88

52 institutional review board will be informed of this decision. Stopping guidelines will be defined prior to the start of the study. Bayer has the right to close this study, and the investigator/bayer has the right to close a centre, at any time, although this should occur only after consultation between involved parties and the executive committee. The ethics committee/ institutional review board must be informed. Should the study/center be closed prematurely, all study materials (except documentation that has to remain stored at site) must be returned to Bayer. The investigator will retain all other documents until notification given by Bayer for destruction. If the number of events is reached before all patients have completed the intended study treatment duration, then the study will be stopped. The last included patients will be treated for at least 6 months. 8. Data quality assurance 8.1 Data quality Monitoring and auditing procedures defined/agreed by Bayer will be followed, in order to comply with GCP guidelines. Each center will be monitored at regular intervals to ensure compliance with the protocol, GCP and legal aspects. This will include on-site checking of the CRF for completeness and clarity, cross-checking with source documents, and clarification of administrative matters. 8.2 Documentation Entries made in the CRF must be either verifiable against source documents, or have been directly entered into the CRF, in which case the entry in the CRF will be considered as the source data. The source data parameter to be verified and the identification of the source document must be documented. The study file and all source data should be retained until notification given by Bayer for destruction. 8.3 Study committees Executive committee The executive committee has the overall scientific responsibility of the study. Its tasks and responsibilities are: Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 51 of 88

53 To create and approve the final protocol To co-author protocol amendments whenever necessary To ensure a scientifically sound and safe conduct of the study To decide on the DSMB recommendations To review and approve the statistical analysis plan To guarantee the integrity of data collection and analyses To decide on the publication- and presentation policy of the final results and ancillary studies Study management and coordination committee (SMCC) The SMCC has the overall clinical responsibility of the study. Its tasks and responsibilities are: To review the protocol To review the CRF To select the investigators network To support and organize the national logistics in the initiation and conduct of the study To monitor progress of study enrollment To address/resolve study management problems To assist in the analysis and presentation of the results Central independent adjudication committee (CIAC) All suspected recurrent PE/DVT, bleeding, vascular events and all deaths during the study period and the observational period will be evaluated by an independent and blinded central adjudication committee (CIAC). The CIAC will be provided with all relevant documentation related to the events. The procedures followed by the CIAC will be described in an adjudication manual. Adjudication results will be the basis for the final analyses Data safety monitoring board (DSMB) This committee has the responsibility to provide the executive committee with Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 52 of 88

54 recommendations related to the protection of the patients safety, including stopping recruitment and study treatment. For that purpose, the DSMB will, during the study, regularly review all incidences of SAEs, recurrent PE/DVT and bleeding, also those not yet adjudicated. A-priori agreed guidelines to assess the patients safety as well as, stopping guidelines, organizational aspects, responsibilities, and processes will be described in the DSMB charter for this trial The dose confirmation committee This committee has the responsibility to perform the analysis on the initial 400 PE patients. The analysis will be performed according to the procedures described in section of the protocol. They will provide the executive committee with recommendations to continue the PE evaluation or not. 9. Ethical and legal aspects 9.1 Ethics committee (EC)/institutional review board (IRB) Documented approval from appropriate ECs/IRBs will be obtained for all participating centers/countries prior to study start, according to GCP, local laws, regulations and organizations. When necessary, an extension, amendment or renewal of the EC/IRB approval must be obtained and also forwarded to Bayer. The EC/IRB must supply to Bayer, upon request, a list of the EC//IRB members involved in the vote and a statement to confirm that the EC//IRB is organized and operates according to GCP and applicable laws and regulations. 9.2 Ethical conduct of the study The procedures set out in this protocol, pertaining to the conduct, evaluation, and documentation of this study, are designed to ensure that Bayer and investigator abide by GCP Guidelines and under the guiding principles detailed in the declaration of Helsinki. The study will also be carried out in keeping with applicable local law(s) and regulation(s). This may include an inspection by Bayer representatives and/or regulatory authority representatives at any time. The investigator must agree to the inspection of study-related records by the regulatory Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 53 of 88

55 authority/bayer representatives, and must allow direct access to source documents to the regulatory authority/bayer representatives. Modifications to the protocol will not be implemented by either Bayer or the investigator without agreement by both parties. However, the investigator may implement a deviation from, or a change of, the protocol to eliminate an immediate hazard(s) to the trial subjects without prior EC/IRB/Bayer approval/favorable opinion. As soon as possible, the implemented deviation or change, the reasons for it and if appropriate the proposed protocol amendment should be submitted to the EC/IRB/Bayer. Any deviations from the protocol must be fully explained and documented by the investigator. Any change to the study should be written and filed as an amendment to this protocol. Such amendments will be a joined effort of the executive committee and Bayer. 9.3 Regulatory authority approvals/authorizations Regulatory authority approvals/authorizations notifications, where required, must be in place and fully documented prior to study start. 9.4 Subject information and consent A core information and informed consent form will be provided. Prior to the beginning of the study, the investigator must have the EC s/irb s written approval of the written informed consent form and any other written information to be provided to subjects. The written approval of the EC/IRB together with the approved subject information/informed consent forms must be filed in the study files. Written informed consent must be obtained before any study specific procedure takes place. Participation in the study and date of informed consent given by the subject should be documented appropriately in the subject s files. 9.5 Insurance All subjects participating in the study will have insurance coverage by Bayer, which is in line with applicable laws and/or regulations. 9.6 Confidentiality All records identifying the subject will be kept confidential and, to the extent permitted by the applicable laws and/or regulations, will not be made publicly Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 54 of 88

56 available. Subject names will not be supplied to Bayer. Only the subject number will be recorded in the CRF, and if the subject name appears on any other document (e.g., pathologist report), it must be obliterated before a copy of the document is supplied to Bayer. Study findings stored on a computer will be stored in accordance with local data protection laws. The subjects will be informed in writing that representatives of Bayer, EC/IRB, or regulatory authorities may inspect their records to verify the information collected, and that all personal information made available for inspection will be handled in strictest confidence and in accordance with local data protection laws. If the results of the study are published, the subject s identity will remain confidential. The investigator will maintain a list to enable subjects records to be identified. 9.7 Archiving of data The investigator should arrange for the retention of the study documentation file and the raw data from the hospital for the longest of the following periods of time: At least 15 years after completion/discontinuation of the study. Patient hospital files and other source data should be kept for the maximum period of time permitted by the hospital, institution or private practice, but not less than 15 years. At least 5 years after receipt of any applicable FDA notification for this product. Data on SAEs should always be included in the study documentation file. All data and documents should be made available if requested by relevant authorities. Records should be maintained to verify the existence of each patient in the study, and should contain the full name, last known address, telephone number, and other pertinent information of each patient. Not withstanding the foregoing, the investigator should contact Bayer to obtain written permission to dispose study-related records including information on the method of such disposal, or, at Bayer s sole discretion, the archiving of such records by Bayer. Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 55 of 88

57 10. Statistical and analytical methods 10.1 Statistical analysis plan Separate statistical reports will be generated for the Einstein-DVT (report a), Einstein-PE (report b) evaluations, and the meta-analysis (report c). The plan described in the following sections will be detailed in three separate Statistical Analysis Plans (SAP) that will be finalized before the first patient is entered. However, the SAPs will accommodate protocol amendments or unexpected issues in study execution or data that affect planned analyses. Any revision will be clearly identified in the final SAPs, issued prior to data base lock. If not stated otherwise, the following statistical specifications apply to all three statistical reports Analysis populations The intention-to-treat (ITT) population will consist of all patients who have been randomized (i.e., when the patient number and allocated treatment are recorded in the IVRS data base). Patients will be analyzed in the treatment group assigned by IVRS. The valid-for-safety-analysis population will consist of all patients who were randomized and received at least one dose of anticoagulant treatment after randomization (i.e., enoxaparin, warfarin, acenocoumarol, rivaroxaban). The perprotocol-population (PP) will consist of all randomized patients without any major deviation from the protocol. The following deviations will lead to exclusion from the PP population: For the Einstein-DVT evaluation: patients in whom the presence of DVT at baseline can not be confirmed by the CIAC For the Einstein-PE evaluation: patients in whom the presence of PE at baseline can not be confirmed by the CIAC Patients not receiving the appropriate treatment as allocated by IVRS or no treatment at all Patients not treated adequately with the study drug (detailed criteria will be specified in the SAPs) Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 56 of 88

58 10.3 Study population/demographics and patient characteristics The number of patients in each population will be presented by strata and treatment group. Patients excluded from the analysis populations will be listed and summarized by strata, treatment group and reason for exclusion. The number and percentage of randomized patients who discontinued treatment prematurely will be tabulated by main reason for discontinuation and treatment group. Demographic and baseline characteristics (including risk factors) will be summarized by treatment group using descriptive statistics. No statistical tests will be performed. For the comparator groups, an INR plot (% of time in the therapeutic range) will be given Efficacy analysis All efficacy analyses will be performed on the ITT population. Additionally, a supportive analysis of the primary efficacy outcome will be carried out based on the PP population Primary efficacy analysis For the primary analysis, the time to the first event of the composite primary efficacy outcome will be analyzed using a stratified Cox s proportional hazard model, with intended treatment duration as stratum and adjusted for the baseline presence of malignancy. (5) For the ITT analysis, patients who did not have a VTE event during the time of the predefined treatment duration, or patients lost to followup or patients who died because of other reasons than DVT/PE or patients who withdrew informed consent before the end of the predefined treatment duration and who did not have a primary efficacy outcome will be censored at the last day the patient had a complete assessment for study outcomes within the intended treatment duration. Further details will be specified in the SAPs. The rivaroxaban-tocomparator hazard ratio will be computed with 95% CI (two-sided testing) for Einstein-DVT and Einstein-PE, separately. Based on this model rivaroxaban will be considered at least as effective as the comparator if the upper limit of the CI is less than 2.0. In Einstein-PE, the primary efficacy analysis will be based on all patients, including those who were part of the dose confirmation analysis. The assumption of Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 57 of 88

59 proportional hazards will be checked using graphical methods as log(-log)-plots and plots of scaled Schoenfeld residuals. The impact of baseline covariates (location of DVT, renal clearance, age, sex, mobility at randomization, cancer, pulmonary disease, cardiac disease) on the primary efficacy outcome will be described by calculating adjusted hazard ratios and corresponding 95% confidence intervals of the treatment effect. The frequencies of the separate components contributing to the primary efficacy outcome will be described Secondary efficacy analyses The secondary efficacy analyses will be done as the primary efficacy analysis, using a 95% CI, for the time to the primary efficacy outcome for patients with active cancer at entry and separately for the subgroups of patients that used acenocoumarol or warfarin. For Einstein-PE, an analysis similar to the primary efficacy analysis, but excluding those patients who were part of the dose confirmation analysis, will be carried out Safety analysis All safety analyses will be performed on the valid-for-safety-analysis population. The analysis of bleeding events will primarily focus on those events which occurred during treatment or within 2 days after stop of treatment. Bleeding events observed later will be described separately. In addition, the analysis of bleeding events and mortality will be performed in the ITT population Principal safety analysis To maintain a two sided error of 0.05 for the primary efficacy analysis and the principal safety analysis, a closed testing procedure will be applied using a stepwise testing approach for the principal safety analysis. If the primary efficacy analysis shows that rivaroxaban is at least as effective as the comparator, the time (person time free from complication) to the principal safety outcome will be compared between treatment groups, using a stratified Cox s proportional hazard model with stratum and covariate as in the primary efficacy analysis. If the difference is statistically significant in favor of rivaroxaban (at a two-sided significance level of Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 58 of 88

60 0.05), time to major bleeding only will also be tested at the same significance level Additional safety analyses Other safety outcomes include all deaths and other vascular events. AEs will be coded using the MedDRA Dictionary. Treatment emergent adverse events will be defined as AEs occurring or worsening after randomization but not more than 7 days after stop of study medication. Events occurring during the 30 day follow up period will be described. Further safety analyses (e.g., laboratory data) will be described in the SAP Interim analysis Einstein-DVT evaluation No formal interim analysis is planned. Risk-benefit will be evaluated by the DSMB, which will give regular recommendation to the executive committee. Access to interim tabular risk benefit data will be restricted. The procedures of the DSMB will be described in a separate manual Einstein-PE evaluation The dose confirmation analysis will be performed (see section ) by the independent dose confirmation committee. Risk-benefit will be evaluated by the DSMB, which will give regular recommendation to the executive committee. Access to interim tabular risk benefit data will be restricted. The procedures of the DSMB will be described in a separate manual Sample size calculation Einstein-DVT evaluation Assuming equal efficacy, a total of 88 events will give a power of 90% to demonstrate that rivaroxaban is at least as effective as the comparator, considering a relative non-inferiority upper CI margin for the hazard ratio of 2.0 (two-sided α=0.05) (see appendix 13.7). Based on the observation that most recurrent events occur in the first month after the initial event, we expect an incidence of recurrent VTE of 2.5% at 3 months, 3% at 6 months and 3.5 % at 12 months. Hence, a mean incidence for the primary efficacy outcome of 3% for both treatment groups is expected and at least 1465 patients per group would be needed. This number of Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 59 of 88

61 patients will be adjusted based on the observed overall incidence of symptomatic recurrent VTE. Since the outcomes are clinical events, loss to follow-up is expected to be negligible. Therefore, no further adjustment of sample size is considered. The decision to stop recruitment when the required number of events will be reached will be taken by the executive committee and will be based on the observed overall incidence of confirmed outcomes Dose confirmation analysis and sample size calculation Einstein-PE evaluation Dose confirmation analysis A dose confirmation analysis will be performed in the initial 400 PE patients based on the combination of symptomatic recurrent venous thromboembolism and asymptomatic deterioration at repeat lung imaging at 3 weeks. The incidence of this combined outcome will be compared amongst the control and rivaroxaban patients, who had a 3 week lung imaging test performed or who had a symptomatic recurrent VTE before the planned repeat lung imaging test at 3 weeks. The one-sided 95% interval of the absolute difference between observed incidences will be calculated using the exact methods. If the one-sided 95% CI of the difference of the observed incidences does not exceed 8.0%, Einstein-PE will be continued as planned. For this purpose, it is necessary to include 200 PE patients in each treatment group based on an event rate of 4%, i.e., 2% symptomatic recurrent VTE plus 2% asymptomatic deterioration at repeat lung imaging at 3 weeks, an one-sided type I error of 5% and a power of 90% Sample size calculation Assuming equal efficacy, a total of 88 events will give a power of 90% to demonstrate that rivaroxaban is at least as effective as the comparator, considering a relative non-inferiority upper CI margin for the hazard ratio of 2.0 (two-sided α=0.05) (justification of non-inferiority margin appendix 13.7). Based on the observation that most recurrent events occur in the first month after the initial event, we expect an incidence of recurrent VTE of 2.5% at 3 months, 3% at 6 months and 3.5% at 12 months. Hence, a mean incidence for the primary efficacy outcome of Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 60 of 88

62 3% for both treatment groups is expected and approximately 1465 patients per group would be needed. However, in Einstein-PE it is proposed to perform a noninferiority dose confirmation analysis. The statistical properties of this analysis, based on an outcome that is partly related to the primary outcome, are uncertain. Hence, it is conservatively proposed to accumulate 88 events in the patients who did not participate in the dose confirmation part (approximately 1665 patients per group) to allow for 90% power in the proposed sensitivity analysis. However, 1465 patients per group will be considered the minimum number of patients to be included to allow for sufficient power in case higher incidence rates of the primary outcome necessitate analyses based on absolute margins. This number of patients will be adjusted based on the observed overall incidence of symptomatic recurrent VTE. Since the outcomes are clinical events, loss to follow-up is expected to be negligible. Therefore, no further adjustment of sample size is considered. The decision to stop recruitment when the required number of events will be reached will be taken by the executive committee and will be based on the observed overall incidence of confirmed outcomes Meta-analysis 1. A combined estimate of relative efficacy with regard to the primary outcome, stratified for DVT/PE and intended treatment duration and adjusted for baseline presence of malignancy. This analysis will have a power of more than 90% (other assumptions according to the primary sample size analyses for the individual studies) to exclude a HR margin of 1.75 (justification of noninferiority margin appendix 13.6). To test for interaction, treatment by study term will be introduced in this model. Combined results will be only presented if interaction is absent. 2. A combined estimate of relative efficacy with regard to the primary efficacy outcome, excluding unexplained death, stratified for study and intended treatment duration and baseline presence of malignancy. 3. A combined estimate of relative efficacy with regard to the primary outcome, Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 61 of 88

63 stratified for study and intended treatment duration and adjusted for baseline presence of malignancy, for the following subgroups: patients with and without malignancy (without adjustment for baseline presence of malignancy); male and female patients; patients below and above 60 years of age, patients with low (<50 kg) medium and high (>100 kg) body weight, patients with normal, or moderately (<50 ml/min ) impaired renal function. 4. Similar analyses will be conducted with regard to the primary safety outcome. 11. Name and address of principal investigator Name: Dr Harry R. Büller Address: Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands Tel n : Fax n : Information regarding additional key personnel will be found in the study files. 12. Use of data and publication All data and results and all intellectual property rights in the data and results derived from the study will be the property of Bayer, who may utilize the data in various ways, such as for submission to government regulatory authorities or disclosure to other investigators. The investigator, whilst free to utilize data derived from the study for scientific purposes, must discuss any publication with Bayer prior to release and obtain written consent of Bayer on the intended publication. Bayer recognizes the right of the investigator to publish the results upon completion of the study. However, the investigator must send a draft manuscript of the publication or abstract to Bayer thirty days in advance of submission in order to obtain approval prior to submission of the final version for publication. This will be reviewed promptly and approval will not be withheld unreasonably. In case of a difference of opinion between Bayer and the investigator(s), the contents of the publication will be discussed in order to find a solution which satisfies both parties. The executive Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 62 of 88

64 committee will be responsible for the publication and presentation strategy. All publications will be based on data released or agreed by Bayer, verified by the executive committee. 13. Appendices 13.1 Calculation of the creatinine clearance (CLCR) The creatinine clearance (CLCR, expressed as ml/min), is yielded by the Cockcroft and Gault formulas, relating serum creatinine, with age (in years) and body weight (in Kg). According to the units used for serum creatinine (µmol/l, or mg/dl) and gender, the formula is as follows: CLCR for men (140 - age) x (weight) x (creatinine concentration, µmol/) CLCR for women (140 - age) x (weight) x x (creatinine concentration, µmol/l) CLCR for men (140 - age) x (weight) 72 x (creatinine concentration, mg/dl) CLCR for women (140 - age) x (weight) x x (creatinine concentration, mg/dl) 13.2 Package insert examples Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 63 of 88

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78 13.3 Contact report 1. Date of contact Day Month Year 2. Please ask the patient systematically the following questions and tick the No/Yes box. Since the last contact did you experience new, or increased: Dyspnea Chest pain Cough Hemoptysis Syncope Tachypnea Tachycardia Cyanosis Fever If PE is clinically suspected, perform objective testing, complete the adjudication package as described in section of the protocol and reply to the additional questions related to HCRU. No Yes 3. Please ask the patient systematically the following question and tick the No/Yes box for each symptom listed below. Since the last contact did you experience new, or increased: Calf pain or tenderness Collateral superficial veins Tenderness along deep veins Swelling of entire leg Pitting edema Appearance of collateral superficial veins or increase in collateral veins If DVT is clinically suspected, perform objective testing and complete the adjudication package as described in section of the protocol and reply to the additional questions related to HCRU. No Yes 4. Did the patient experience any bleeding? No Yes If yes, complete the (S)AE form, the adjudication package as described in section , and reply to the additional questions related to HCRU. Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 77 of 88

79 13.4 Health Care resource utilization (HCRU) If there is a suspected outcome (DVT, PE or bleeding), please answer the questions below. Did the patient pay visits to another health care provider in relation to this suspected outcome No Yes If yes, please indicate the care providers: a. General practitioner b. Medical specialist Radiologist Pulmonologist Cardiologist Emergency Room Other please specify Was the patient hospitalized for the suspected outcome? No Yes If yes, date of admission date of discharge Which diagnostic test(s) was (were) performed for suspected PE/DVT 1. = Perfusion/Ventilation lung scan 2. = Pulmonary angiography 3. = Spiral CT-scan 4. = Ultrasound 5. = Venography Which diagnostic test(s) was (were) performed for bleeding 6. = Other (please describe test below) 7. = Laboratory 8. = CT-scan 9. = Endoscopy 6. = Other (please describe test below Diagnostic test Date of test Number: Day Month Year Number: Day Month Year Number: Day Month Year Number: Day Month Year Number: Day Month Year Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 78 of 88

80 13.5 Anti-Clot Treatment scale We are interested in your experiences of anti-clot treatment. We would be grateful if you could help us by filling out this questionnaire. The questions below ask about your experiences of anti-clot treatment during the past 4 weeks. All of the information you provide is Completely confidential. Please be sure to answer all questions. Instructions: We are interested in your experiences of anti-clot treatment during the past 4 weeks. Please circle the number in the box that best describes your views. During the past 4 weeks.. Not at all A little Moderately Quite a bit Extremely 1. How much does the possibility of bleeding as a result of anti-clot treatment limit you from taking part in vigorous physical activities? (e.g. exercise, sports, dancing, etc.) 2. How much does the possibility of bleeding as a result of anti-clot treatment limit you from taking part in your usual activities? (e.g. work, shopping, housework etc.) How bothered are you by the possibility of bruising as a result of anti-clot treatment? How bothered are you by having to avoid other medicines (e.g. aspirin) as a result of anti-clot treatment? How much does anti-clot treatment limit your diet? (e.g. food or drink, including alcohol) 6. How much of a hassle (inconvenience) are the daily aspects of anti-clot treatment? (e.g. remembering to take your medicine at a certain time, taking the correct dose of your medicine, following a diet, limiting alcohol, etc.) 7. How much of a hassle (inconvenience) are the occasional aspects of anti-clot treatment? (e.g. the need for blood tests, going to or contacting the clinic/doctor, making arrangements for treatment while travelling etc.) Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 79 of 88

81 Now I want to ask you about daily and occasional aspects of your ACT during the past 4 week. Not at all A little Moderately Quite a bit Extremely 8. How difficult is it to follow your anti-clot treatment? How time-consuming is your anti-clot treatment? How much do you worry about your anti-clot treatment? How frustrating is your anti-clot treatment? How much of a burden is your anti-clot treatment? Overall, how much of a negative impact has your anti-clot treatment had on your life? 14. How confident are you that your anticlot treatment will protect your health? (e.g. prevent blood clots, stroke, heart attack, DVT, embolism) How reassured do you feel because of your anti-clot treatment? How satisfied are you with your anticlot treatment? Overall, how much of a positive impact has your anti-clot treatment had on your life? Thank you for your help! Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 80 of 88

82 13.6 Treatment Satisfaction Questionnaire (TSQ) Instructions: Please take some time to think about your level of satisfaction or dissatisfaction with the medication you are taking in this clinical trial. We are interested in your evaluation of the effectiveness, side effects, and convenience of the medication over the last two to three weeks, or since you last used it. For each question, please place a single check mark next to the response that most closely corresponds to your own experiences. 1.How satisfied or dissatisfied are you with the ability of the medication to prevent or treat the condition? 1Extremely Dissatisfied 2 Very Dissatisfied 3 Dissatisfied 4 Somewhat Satisfied 5 Satisfied 6 Very Satisfied 7 Extremely Satisfied 2. How satisfied or dissatisfied are you with the way the medication relieves symptoms? 1 Extremely Dissatisfied 2 Very Dissatisfied 3 Dissatisfied 4 Somewhat Satisfied 5 Satisfied 6 Very Satisfied 7 Extremely Satisfied 3. As a result of taking this medication, do you experience any side effects at all? 1 Yes 0 No 4. How dissatisfied are you by side effects that interfere with your physical health and ability to function (e.g., strength, energy levels)? 1 Extremely Dissatisfied 2 Very Dissatisfied 3 Somewhat Dissatisfied 4 Slightly Dissatisfied 5 Not at all Dissatisfied 5. How dissatisfied are you by side effects that interfere with your mental function (e.g., ability to think clearly, stay awake)? 1 Extremely Dissatisfied 2 Very Dissatisfied 3 Somewhat Dissatisfied 4 Slightly Dissatisfied 5 Not at all Dissatisfied 6. How dissatisfied are you by side effects that interfere with your mood or emotions (e.g., anxiety/fear, sadness, irritation/anger)? 1 Extremely Dissatisfied 2 Very Dissatisfied 3 Somewhat Dissatisfied Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 81 of 88

83 4 Slightly Dissatisfied 5 Not at all Dissatisfied 7. How satisfied or dissatisfied are you with how easy the medication is to use? 1 Extremely Dissatisfied 2 Very Dissatisfied 3 Dissatisfied 4 Somewhat Satisfied 5 Satisfied 6 Very Satisfied 7 Extremely Satisfied 8. How satisfied or dissatisfied are you with how easy it is to plan when you will use the medication each time? 1 Extremely Dissatisfied 2 Very Dissatisfied 3 Dissatisfied 4 Somewhat Satisfied 5 Satisfied 6 Very Satisfied 7 Extremely Satisfied 9. How satisfied or dissatisfied are you by how often you are expected to use/take the medication? 1 Extremely Dissatisfied 2 Very Dissatisfied 3 Dissatisfied 4 Somewhat Satisfied 5 Satisfied 6 Very Satisfied 7 Extremely Satisfied 10. How satisfied are you that the good things about this medication outweigh the bad things? 1 Extremely Dissatisfied 2 Very Dissatisfied 3 Dissatisfied 4 Somewhat Satisfied 5 Satisfied 6 Very Satisfied 7 Extremely Satisfied 11. Taking all things into account, how satisfied or dissatisfied are you with this medication? 1 Extremely Dissatisfied 2 Very Dissatisfied 3 Dissatisfied 4 Somewhat Satisfied 5 Satisfied 6 Very Satisfied 7 Extremely Satisfied Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 82 of 88

84 13.7 Non-inferiority margin The statistical methodology proposed for defining the margin is based on the indirect confidence interval comparison (ICIC) method. This method focuses on identifying the maximally acceptable loss of control effect assessed as the difference between the currently recommended and approved standard of care in the field and placebo or no-treatment. Quantification of the effect of active control relative to placebo is derived from historical studies. However, as will be documented below, placebo or no-treatment studies are rare for the initial 3 months of treatment and are generally old. However, studies that continued anticoagulant treatment beyond 3 months and compared with placebo and no treatment are available. Therefore, the non-inferiority margin will be chosen conservatively based on the combination of the abovementioned trial results and should reflect that more than 50% of the observed effect is retained for the entire study population. Literature search The search was conducted to identify studies that compared the currently recommended initial UFH/LMWH followed by VKA for 3 to 12 months with placebo treatment, no treatment or less effective treatment. Studies that applied this comparison for only part of the 3 to 12 months period were also included and only data of the appropriate comparative period were used for this analysis. The search relied on titles, abstracts, and multiple database descriptors and was not restricted by language. Selection of non-inferiority margin The criteria listed below were applied to refine the literature search to studies appropriate for inclusion in the non-inferiority margin estimation: 1. inclusion of patients with acute DVT, and/or PE 2. use of objective diagnostic methods to document the index event 3. randomized clinical trial 4. report of objectively confirmed symptomatic VTE recurrence The design of each of the selected studies is described below. The early study of Barritt and Jordan is in fact the only no-treatment controlled study and treated patients only for 14 days. (6) Other early studies dated between 1979 and 1993 addressed mainly the initial 3 months of treatment and used inferior therapy for the initial 7 to 10 days, or for the period of VKA treatment after the 7 to 10 day period. Studies published hereafter addressed mainly the need for continuation of VKA therapy and compared this therapy to no treatment or placebo treatment after the initial 6 weeks to 6 months. A summary of the design elements of the identified studies including patient, treatment, and endpoint characteristics of each is provided in Table 1. Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 83 of 88

85 Table 1 Summary of design elements for studies supporting background VTE recurrence rates Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 84 of 88

86 Data synthesis The incidences of symptomatic VTE recurrence in each of the 14 studies identified to support estimation of the non-inferiority margin are summarized in the next Table. Table 2 Number (%) of patients with symptomatic VTE recurrence in studies identified for non-inferiority margin estimation From these data, the overall estimated difference between more effective therapy in comparison to less effective therapy was calculated using the random effect model on log odds ratio. For Integrated Protocol /Study number 11702/Version no 3.0/13Jul2010, incl Amend 2, 3, 4, 5 Page 85 of 88