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140407 Synopsis_acs Dual Therapy_phase 2 Draft 7may2014 (2)

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  JNJ-39039039; BAY 59-7939 (rivaroxaban) Clinical Protocol Synopsis RIVAROXACS2002 7 May 2014 DRAFT  Page 1 of 10 SYNOPSIS A Randomized, Double-Blind, Double-Dummy, Active-controlled, Parallel-group, Multicenter Study to Compare the Safety of Rivaroxaban versus Acetylsalicylic Acid in Addition to Either Clopidogrel or Ticagrelor Therapy in Subjects with Acute Coronary Syndrome Rivaroxaban (JNJ-39039039; BAY 59-7939) is an oral, direct acting, Factor Xa (FXa) inhibitor anticoagulant which has been developed for the treatment of several thrombosis-mediated conditions. The mechanism of action of rivaroxaban is to selectively and directly inhibit FXa, which plays a central role in the cascade of blood coagulation by mediating thrombin formation. Rivaroxaban does not require metabolic conversion or a cofactor to exert its activity. Rivaroxaban is marketed under the trade name XARELTO ®  and has been approved for multiple indications worldwide. XARELTO co-administered with acetylsalicylic acid (ASA) alone or with ASA  plus clopidogrel or ticlopidine has been approved in the EU for the prevention of atherothrombotic events in adult patients after an acute coronary syndrome (ACS) with elevated cardiac biomarkers. The background therapy to be used in combination with the study drug rivaroxaban or the comparator ASA in this study is a single antiplatelet agent, either clopidogrel or ticagrelor, both of which work by inhibiting a receptor called P2Y12, an adenosine diphosphate chemoreceptor involved in platelet aggregation. OBJECTIVES AND HYPOTHESIS Primary Objective The primary objective of this study is to evaluate the bleeding risk of rivaroxaban compared with ASA in addition to a single antiplatelet agent (clopidogrel or ticagrelor) in subjects with recent ACS (including ST segment elevation myocardial infarction [STEMI], non-ST-segment elevation myocardial infarction [NSTEMI], or unstable angina [UA]). The primary bleeding outcome is TIMI clinically-significant bleeding events. Exploratory Analyses The exploratory analyses of the study are: ã   To evaluate the efficacy of rivaroxaban compared with ASA in addition to a single antiplatelet agent (clopidogrel or ticagrelor) in reducing the risk of the composite of cardiovascular death (CVD), myocardial infarction (MI), and ischemic stroke in subjects with recent ACS. Hypothesis The primary hypothesis of this study is that rivaroxaban 2.5 mg b.i.d. is non-inferior (NI) to ASA 81 mg daily in bleeding risk, when added onto the background treatment of a single antiplatelet agent, clopidogrel or ticagrelor, based on the analysis of time to the first treatment-emergent TIMI clinically significant bleeding event, and by a NI margin (ie, the upper bound of 95% confidence interval [CI]) of 2.0 for hazard ratio.  JNJ-39039039; BAY 59-7939 (rivaroxaban) Clinical Protocol Synopsis RIVAROXACS2002 7 May 2014 DRAFT  Page 2 of 10 OVERVIEW OF STUDY DESIGN This is a prospective, randomized, double-dummy, double-blind, active-controlled, parallel-group,   multicenter study of fixed duration of treatment to evaluate the safety and efficacy of rivaroxaban compared with ASA in addition to a single antiplatelet agent (clopidogrel or ticagrelor) treatment in subjects with a recent ACS (STEMI, NSTEMI, or UA). Eligible subjects are men or women, 18 years of age or older, who have had symptoms suggestive of ACS occurring within 24 hours before hospital presentation that lasted at least 10 minutes at rest and have a diagnosis of STEMI, a diagnosis of NSTEMI, or a diagnosis of UA with transient or persistent ST-segment deviation of 0.1 millivolt (mV) or greater in 1 or more ECG leads. Potential subjects who are 18 to 54 years of age must also have either diabetes mellitus or a prior MI in addition to the index ACS event. Subjects with prior stroke or TIA will be excluded from the study. Approximately 3,000 eligible subjects receiving maintenance treatment of ASA plus clopidogrel (A+C) or ASA plus ticagrelor (A+T), will be enrolled.   It is estimated that approximately 50% (range: 40-60%) of subjects will receive treatment with clopidogrel. Subjects should be randomized to receive study drug no later than 4 days after hospitalization for their ACS index event. Subjects in the A+C group will be randomly assigned at 1:1 ratio to either stay on ASA plus clopidogrel treatment (A+C), or to switch to rivaroxaban plus clopidogrel (R+C). Subjects in the A+T group will be randomly assigned at 1:1 ratio to either stay on ASA plus ticagrelor treatment (A+T), or to switch to rivaroxaban plus ticagrelor (R+T). The primary safety outcome of the study is TIMI clinically significant bleeding. Additional bleeding outcomes to be collected include bleeding events classified by other TIMI bleeding categories (including life-threatening bleeding) and bleeding events by Bleeding Academic Research Consortium (BARC) definitions. The principal efficacy endpoint is the composite of CVD, MI and ischemic stroke. Benefit-risk will also be assessed. This study will include 3 phases: a 4-day screening phase, a double-dummy, double-blind treatment phase of 6 months, and a 30-day follow-up phase. There are scheduled visits at Month 1, Month 3 and Month 6 of treatment. Subjects who experience any safety or efficacy endpoint events will continue to receive  blinded study drug unless a termination criteria arose and complete all assessments at all scheduled visits. Subjects who discontinue study drug prematurely will be bought in for scheduled visits until their 6-month enrollment period is complete, to capture key safety and clinical endpoint data as outlined in the Time and Events Schedule. For all subjects, approximately 30 days after the last dose of study drug, a  post-treatment follow-up visit will occur that will include assessment of any new or ongoing serious adverse events, ongoing adverse events that led to discontinuation of study drug prior to the completion of  JNJ-39039039; BAY 59-7939 (rivaroxaban) Clinical Protocol Synopsis RIVAROXACS2002 7 May 2014 DRAFT  Page 3 of 10 6-month treatment period, and adverse events of special interest. For subject who complete the 6-month treatment period, this follow-up visit is their End-of-Study visit will occur at approximately 30 days after Month 6. For subjects who discontinue study drug early, their Month 6 visit can serve as their End-of-Study visit. Subjects will be randomly assigned to double-dummy, double-blind rivaroxaban or ASA treatment up to 4 days after the subject has been hospitalized for the index ACS event when parenteral anticoagulant therapy would normally be discontinued. Enrollment should occur as early as possible after the initial treatments, including revascularization procedures for the index ACS event have been performed (note: for subjects who receive PCI, study drug should be given at least 12 hours after the arterial sheath has  been removed and the last dose of parenteral anticoagulant administered, whichever occurred later), but no later than 4 days after hospitalization for the index ACS event. Rivaroxaban 2.5 mg b.i.d. will be compared with ASA 81 mg daily, in addition to a single antiplatelet clopidogrel 75 mg daily or ticagrelor 90 mg b.i.d., given as background treatment. The selection of the antiplatelet agent will be left to the managing physician and the choice will be made at the time of the acute phase of ACS prior to randomization. The initial choice of clopidogrel or ticagrelor should be maintained throughout the study, except in cases where discontinuation is medically indicated. Subjects with known conditions that contraindicate anticoagulant therapy (e.g., history of intracranial hemorrhage), or requiring continued treatment with anticoagulant drugs including warfarin sodium, or meeting any of the other exclusion criteria, including a history of stroke or TIA, will be excluded. All subjects will receive guideline-directed medical therapy in accordance to the national or international guidelines and at the nationally- or locally- indicated dose. The ASA dose will be 81 mg per day. For clopidogrel, the daily maintenance dose must not exceed 75 mg per day, and for ticagrelor, the maintenance dose must not exceed 90 mg b.i.d.. An Operations Committee (OC) will be responsible for monitoring safety during the study. An Executive Committee (EC) will receive any recommendations regarding possible additional analyses or modifications to the study and decide whether to accept them. The EC will oversee the implementation of any modifications to the study. In addition, study conduct will be overseen by the OC. One interim analysis on the primary safety endpoint and the efficacy endpoint may be performed when approximately 80% of the expected total follow-up time will have passed. Formal statistical monitoring guidelines, stopping rules, and details of the statistical analyses will be incorporated in the Statistical Analysis Plan (SAP). SUBJECT POPULATION Screening for eligible subjects will be performed within 4 days after the subject has been hospitalized for the index ACS event. The inclusion and exclusion criteria for enrolling subjects in this study are described in the following 2 subsections. If there is a question about the inclusion or exclusion criteria below, the investigator should consult with the appropriate sponsor representative before enrolling a subject into this study. Inclusion Criteria: 1.   Man or woman 18 years of age or older. 2.   Received acute phase treatment including intravenous anticoagulant or antiplatelet, and currently receiving maintenance dual antiplatelet treatment with either clopidogrel and ASA, or ticagrelor and ASA.  JNJ-39039039; BAY 59-7939 (rivaroxaban) Clinical Protocol Synopsis RIVAROXACS2002 7 May 2014 DRAFT  Page 4 of 10 3.   Has been hospitalized for symptoms suggestive of ACS that lasted at least 10 minutes at rest, and occurred 24 hours or less before hospital presentation or developed ACS while being hospitalized for an indication other than ACS, and has a diagnosis of: −   STEMI:    Elevation of ST-segment more than 0.1 millivolt (mV) in 2 or more continuous ECG leads, or new left bundle branch block, or ST-segment depression 0.1 mV or greater in 2 of the precordial leads V1-V4 with evidence suggestive of true posterior infarction, all with elevated biomarkers of myocardial necrosis (creatinine kinase-muscle and brain isoenzyme [CK-MB] or troponin) −    NSTEMI:    Elevated biomarkers of myocardial necrosis (creatinine kinase muscle and brain isoenzyme [CK-MB] or troponin) plus 1 of the following:    Transient ST-segment elevation, or ST-segment depression, or Twave changes consistent with myocardial ischemia, or    Identification of a culprit lesion at coronary angiography demonstrating recent, active intracoronary athero-thrombosis (for example, thrombus or an ulcerated plaque) −   UA with the following:    Transient or persistent ST-segment deviation 0.1 mV or greater in 1 or more ECG leads 4.   Subjects who are 18 to 54 years of age inclusive must also have either diabetes mellitus or a  prior MI in addition to the presenting ACS event. 5.   Women must be: −    postmenopausal (for at least 2 years), or −   surgically sterile, (have had a hysterectomy or bilateral oophorectomy, tubal ligation, or otherwise be incapable of pregnancy), or −   abstinent (at the discretion of the investigator/per local regulations), or −   if sexually active, be practicing an effective method of birth control (eg, prescription oral contraceptives, contraceptive injections, contraceptive patch, intrauterine device, double- barrier method, male partner sterilization) as local regulations permit, before entry, and must agree to continue to use the same method of contraception throughout the study. −   Wo men of childbearing potential must have a negative urine β -human chorionic gonadotropin (β -hCG) pregnancy test at screening. Serum pregnancy testing may be  performed if required by local regulation. 6.   Subjects must have signed an informed consent document indicating that they understand the  purpose of and procedures required for the study and are willing to participate in the study
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