Rivaroxaban in Combination With Aspirin Alone or With Aspirin and a Thienopyridine in Patients With Acute Coronary Syndromes (The ATLAS ACS TIMI 46 Trial)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety of rivaroxaban in patients with recent acute coronary syndrome (ACS) and to assess the ability of rivaroxaban to reduce the occurrence of death, myocardial infarction (heart attack), repeat myocardial infarctions, stroke, and ischemia (inadequate blood supply to a local area) in patients with recent ACS.

Detailed Description
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This is a randomized (patients will be assigned to study treatment by chance), double-blind (neither the patient nor the study doctor will know the identity of the assigned study treatment) study to evaluate the safety and efficacy of rivaroxaban (study drug) compared to placebo (a tablet identical in appearance to study drug but contains no active drug) in patients with acute coronary syndrome (ACS [a condition where blood flow in a blood vessel in the heart is restricted because of a blood clot]). Rivaroxaban is a drug that acts as a blood thinner and is being tested to see if it will be safe and effective in patients diagnosed ACS. The goal of this study is to identify the dose and dosing schedule (once-a-day or twice-a-day dosing) of rivaroxaban that will be safe and effective in preventing adverse cardiovascular outcomes such as death, myocardial infarctions (MI) including repeat myocardial infarction (reMI), stroke, or ischemia (inadequate blood supply to a local area) requiring revascularization (ie, the re-establishment of blood supply to a part or an organ) in patients with ACS who are receiving antiplatelet therapy (ie, aspirin alone or aspirin plus an approved thienopyridine, a type of drug such as clopidogrel that acts to inhibit the formation of blood clots). Approximately 3500 patients are planned to participate in the study for approximately 7 months. At study entry, all patients who are currently receiving treatment for ACS with antiplatelet therapy will be permitted to continue this therapy during the study. Patients will be enrolled and randomized to receive placebo, rivaroxaban administered as a once-daily dose, or rivaroxaban administered as a twice-daily dose at each dose level of rivaroxaban tested. Patients randomized at each dose level will continue to receive the same treatment for 6 months. Near the end of enrollment at the first dose level, available safety and efficacy data from patients will be assessed by an Operations Committee before enrolling and randomizing additional patients to the next higher dose level of rivaroxaban. Increasing dose levels of rivaroxaban are planned; however, progression to each higher dose level will be at the discretion of the Operations Committee. Patient safety will be monitored by evaluating adverse events reported, results from clinical laboratory tests, findings from electrocardiograms (ECGs) and vital signs measurements, findings from physical examinations, and the number of patients with protocol-defined major or minor bleeding, or bleeding requiring medical attention. All patients will take study drug or placebo tablets orally (by mouth) twice daily for 6 months starting at an initial total daily dose of 5 mg. Both once- and twice-daily dosing regimens will be tested at each rivaroxaban dose level planned.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Dose-Escalation and Dose-Confirmation Study to Evaluate the Safety and Efficacy of Rivaroxaban in Combination With Aspirin Alone or With Aspirin and a Thienopyridine in Subjects With Acute Coronary Syndromes

Conditions
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Acute Coronary Syndrome

Intervention / Treatment
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* Drug: Rivaroxaban/Placebo
* Drug: Placebo
* Drug: Rivaroxaban


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have symptoms suggestive of ACS that lasted at least 10 minutes at rest occurring within 7 days of randomization Have a diagnosis of ST-elevation myocardial infarction or non-ST elevation myocardial infarction/unstable angina (ie, chest pain or discomfort) (ST elevation is an abnormal finding from an ECG test) with at least 1 protocol-defined high risk feature Exclusion Criteria: Active bleeding or high risk of bleeding or intracranial hemorrhage (bleeding within the skull enclosing the brain) Need for continued anticoagulant therapy Significantly impaired renal (kidney) or hepatic (liver) function Severe concomitant diseases such as cardiogenic shock (heart damage that results in insufficient blood supply to other parts or organs of the body), refractory ventricular arrhythmias (irregular contractions of the heart unresponsive to treatment), or any severe condition that would limit life expectancy of the patient to less than 6 months

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 001<br>Rivaroxaban 1 rivaroxaban tablet twice daily for 6 months. Safety at each dose level will be confirmed before additional patients are randomized to the next higher dose level. | Drug: Rivaroxaban<br>* 1 rivaroxaban tablet twice daily for 6 months. Safety at each dose level will be confirmed before additional patients are randomized to the next higher dose level.<br>|
| Experimental: 002<br>Rivaroxaban/Placebo 1 rivaroxaban tablet once daily (and 1 placebo tablet once daily) for 6 months. Safety at each dose level will be confirmed before additional patients are randomized to the next higher dose level. | Drug: Rivaroxaban/Placebo<br>* 1 rivaroxaban tablet once daily (and 1 placebo tablet once daily) for 6 months. Safety at each dose level will be confirmed before additional patients are randomized to the next higher dose level.<br>|
| Placebo Comparator: 003<br>Placebo 1 placebo tablet twice daily for 6 months. | Drug: Placebo<br>* 1 placebo tablet twice daily for 6 months.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Thrombolysis in Myocardial Infarction (TIMI) Clinically Significant Bleeding Events (Primary Safety) | The number of patients with a first occurrence of a TIMI clinically significant bleeding event that occurred from the time of randomization to the time of the last patient contact. TIMI clinically significant bleeding events included TIMI minor bleeding events, TIMI major bleeding events, or any bleeding that required medical attention. | Day 1 to Day 210 | 
| The Composite Endpoint of All Cause Death, Myocardial Infarction (MI) (Including Repeat MI), Stroke (Ischemic, Hemorrhagic or Unknown), or Severe Recurrent Ischemia Requiring Revascularization (Primary Efficacy) | The number of patients who died due to any cause or had a first occurrence of MI (including repeat MI) or stroke (ischemic, hemorrhagic or unknown) or severe recurrent ischemia requiring revascularization from the time of randomization to the last date of patient contact. | Day 1 to Day 210 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Composite Endpoint of Death (All Cause), Myocardial Infarction (MI) (or Repeat MI), or Stroke | The number of patients who died due to any cause or had a first occurrence of MI (or repeat MI) or stroke from the time of randomization to the last date of patient contact. | Day 1 to Day 210 | 
| The Composite Endpoint of Cardiovascular Death, Myocardial Infarction (MI), or Stroke | The number of patients with the composite endpoint of cardiovascular death or MI or stroke that occurred from the time of randomization to the last date of patient contact. | Day 1 to Day 210 | 
| The Number of Deaths (All Cause) | The number of patients who died due to any cause from the time of randomization to the last date of patient contact. | Day 1 to Day 210 | 
| The Composite Endpoint of Death (All Cause), MI (or reMI), Stroke, Severe Recurrent Ischemia Requiring Revascularization, or Thrombolysis in Myocardial Infarction (TIMI) (Major or Minor Bleeding) to Assess the Net Clinical Benefit | The number of patients who died due to any cause or had a first occurrence of MI (or repeat MI), or stroke, or severe recurrent ischemia requiring revascularization, or TIMI (major or minor bleeding) from the time of randomization to the last date of patient contact to assess the net clinical benefit of rivaroxaban. | Day 1 to Day 210 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Coronary Syndrome (ACS), Myocardial Ischemia, Rivaroxaban (BAY59-7939), Anti-platelet agents, Aspirin, Thienopyridine, Clopidogrel