Trial to Assess the Effects of Vorapaxar (SCH 530348; MK-5348) in Preventing Heart Attack and Stroke in Particpants With Acute Coronary Syndrome (TRA•CER) (Study P04736)

Study Overview
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Brief Summary
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The study is designed to determine whether vorapaxar, when added to the existing standard of care (eg, aspirin, clopidogrel) for preventing heart attack and stroke in patients with acute coronary syndrome, will yield additional benefit over the existing standard of care in preventing heart attack and stroke. The study is also designed to assess risk of bleeding with vorapaxar added to the standard of care versus the standard of care alone.

Official Title
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A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of SCH 530348 in Addition to Standard of Care in Subjects With Acute Coronary Syndrome: Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRA•CER)

Conditions
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Atherosclerosis, Myocardial Ischemia, Myocardial Infarction

Intervention / Treatment
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* Drug: Vorapaxar
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women at least 18 years old with current clinical manifestation of non-ST-segment-elevation myocardial infarction (heart attack) according to the following three criteria: current symptoms of cardiac ischemia (chest pain leading to cardiac ischemia or heart attack) AND either of the following: concurrent elevation of troponin I or T, or of creatine kinase - myocardial band (CK-MB) to a level above the upper limit of normal, OR concurrent appropriate electrocardiographic evidence AND any one (or more) of the following: age >= 55 years documented history of prior heart attack or coronary revascularization (eg, angioplasty [PCI], coronary artery replacement [CABG]) diabetes (documented use of insulin or oral hypoglycemic[s]) documented history of peripheral arterial disease Exclusion Criteria: history of intracranial hemorrhage or of central nervous system (CNS) surgery, tumor, or aneurysm any bleeding disorder or abnormality sustained severe hypertension or valvular heart disease current or recent platelet count <100,000 mm^3 planned or ongoing treatment with a blood thinning medication pregnancy any significant medical or physiological condition or abnormality that could put the subject at increased risk or limit the subject's ability to participate for the duration of the study

Ages Eligible for Study
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Minimum Age: 18 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Loading oral dose of one 40 mg vorapaxar placebo tablet on Day 1, then one 2.5 mg vorapaxar placebo tablet daily, orally for at least 1 year in addition to current treatment of acute coronary syndrome, which will be continued to be administered as per current stand of care. | Drug: Placebo<br>* oral tablets; matching placebo for vorapaxar; loading and maintenance dosing; once daily for at least 1 year<br>|
| Experimental: Vorapaxar<br>Loading oral dose of one 40 mg vorapaxar tablet on Day 1, then one 2.5 mg vorapaxar tablet daily, orally for at least 1 year in addition to current treatment of acute coronary syndrome, which will be continued to be administered as per current stand of care. | Drug: Vorapaxar<br>* oral tablets; 40-mg loading dose on first day, followed by 2.5 mg once daily for at least 1 year<br>* Other names: MK-5348;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Kaplan-Meier Estimate of the Percentage of Participants Who Experienced Cardiovascular Death, Myocardial Infarction, Stroke, Recurrent Ischemia With Re-hospitalization, and/or Urgent Coronary Revascularization Within 2 Years From Randomization | The time (in days) from study start to the first occurrence of any of the following clinical outcomes was recorded: cardiovascular (CV) death, myocardial infarction (MI), stroke, recurrent ischemia with re-hospitalization (RIR), and/or urgent coronary revascularization (UCR). A Clinical Endpoints Committee (CEC) reviewed and adjudicated each suspected efficacy endpoint event while blinded to treatment. Participants who did not have any endpoint event until last visit or participants who were lost to follow-up and had no event were censored at the time of last available information (last study visit). If a participant had a fatal event that was not part of a specific endpoint for analysis, they were censored at the time of death. The Kaplan-Meier estimate reports the percentage of participants who experienced at least 1 of the components of the primary composite efficacy endpoint within 2 years from randomization. | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Kaplan-Meier Estimate of the Percentage of Participants Who Experienced Cardiovascular Death, Myocardial Infarction, and/or Stroke Within 2 Years From Randomization | The time (in days) from study start to the first occurrence of any of the following clinical outcomes was recorded: cardiovascular (CV) death, myocardial infarction (MI), and/or stroke. A CEC reviewed and adjudicated each suspected efficacy endpoint event while blinded to treatment. Participants who did not have any endpoint event until last visit or participants who were lost to follow-up and had no event were censored at the time of last available information (last study visit). If a participant had a fatal event that was not part of a specific endpoint for analysis, they were censored at the time of death. The Kaplan-Meier estimate reports the percentage of participants who experienced at least 1 of the components of the secondary composite efficacy endpoint within 2 years from randomization. | up to 2 years | 
| Kaplan-Meier Estimate of the Percentage of Participants Who Met Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries (GUSTO) Moderate or Severe Bleeding Criteria Within 2 Years From Randomization | Adverse events were categorized as bleeding events if the intensity of the event was other or more than would be normally expected in the given situation (eg, mild nosebleed in a person who does not normally have nosebleeds, greater bruising than expected for a given injury, greater volume of blood loss than expected for a given procedure). The investigator graded the intensity of bleeding events according to the GUSTO cooperative group criteria as follows: Mild , Moderate or Severe and the grading was adjudicated by the CEC. The Kaplan-Meier estimate reports the percentage of participants who experienced GUSTO moderate or severe bleeding within 2 years from randomization. | Up to 2 years | 
| Kaplan-Meier Estimate of the Percentage of Participants Who Experienced Clinically Significant Bleeding Within 2 Years From Randomization | Adverse events were categorized as bleeding events if the intensity of the event was other or more than would be normally expected in the given situation (eg, mild nosebleed in a person who does not normally have nosebleeds, greater bruising than expected for a given injury, greater volume of blood loss than expected for a given procedure). The investigator graded the intensity of bleeding events according to the Thrombolysis in Myocardial Infarction (TIMI) Study Group criteria as major, minor or other. Clinically Significant Bleeding was defined as the composite of TIMI Major bleeding, TIMI Minor bleeding, or bleeding that required unplanned medical or surgical treatment or unplanned laboratory evaluation even if it did not meet the criteria for TIMI major or minor bleeding. The Kaplan-Meier estimate reports the percentage of participants who experienced clinically significant bleeding within 2 years from randomization. | Up to 2 years | 
| Kaplan-Meier Estimate of the Percentage of Participants Who Experienced CV Death, MI, Stroke, or UCR Within 2 Years From Randomization | The time (in days) from study start to the first occurrence of any of the following clinical outcomes was recorded: CV death, MI, stroke, or UCR. A CEC reviewed and adjudicated each suspected efficacy endpoint event while blinded to treatment. Participants who did not have any endpoint event until last visit or participants who were lost to follow-up and had no event were censored at the time of last available information (last study visit). If a participant had a fatal event that was not part of a specific endpoint for analysis, they were censored at the time of death. The Kaplan-Meier estimate reports the percentage of participants who experienced CV death, MI, stroke, or UCR within 2 years from randomization. | Up to 2 years | 
| Kaplan-Meier Estimate of the Percentage of Participants Who Experienced CV Death or MI Within 2 Years From Randomization | The time (in days) from study start to the first occurrence of any of the following clinical outcomes was recorded: CV death or MI. A CEC reviewed and adjudicated each suspected efficacy endpoint event while blinded to treatment. Participants who did not have any endpoint event until last visit or participants who were lost to follow-up and had no event were censored at the time of last available information (last study visit). If a participant had a fatal event that was not part of a specific endpoint for analysis, they were censored at the time of death. The Kaplan-Meier estimate reports the percentage of participants who experienced CV death or MI within 2 years from randomization. | Up to 2 years | 
| Kaplan-Meier Estimate of the Percentage of Participants Who Experienced All-cause Death, MI, Stroke, RIR, or UCR Within 2 Years From Randomization | The time (in days) from study start to the first occurrence of any of the following clinical outcomes was recorded: all-cause death, MI, stroke, RIR, or UCR. A CEC reviewed and adjudicated each suspected efficacy endpoint event while blinded to treatment. Participants who did not have any endpoint event until last visit or participants who were lost to follow-up and had no event were censored at the time of last available information (last study visit). The Kaplan-Meier estimate reports the percentage of participants who experienced all-cause death, MI, stroke, RIR, or UCR within 2 years from randomization. | Up to 2 years | 
| Kaplan-Meier Estimate of the Percentage of Participants Who Experienced All-cause Death, MI, Stroke, or UCR Within 2 Years From Randomization | The time (in days) from study start to the first occurrence of any of the following clinical outcomes was recorded: all-cause death, MI, stroke, or UCR. A CEC reviewed and adjudicated each suspected efficacy endpoint event while blinded to treatment. Participants who did not have any endpoint event until last visit or participants who were lost to follow-up and had no event were censored at the time of last available information (last study visit). The Kaplan-Meier estimate reports the percentage of participants who experienced all-cause Death, MI, stroke, or UCR I within 2 years from randomization. | Up to 2 years | 
| Kaplan-Meier Estimate of the Percentage of Participants Who Experienced CV Death Within 2 Years From Randomization | The time (in days) from study start to the CV death (if reported) was recorded. A CEC reviewed and adjudicated each suspected efficacy endpoint event while blinded to treatment. Participants who did not have any endpoint event until last visit or participants who were lost to follow-up and had no event were censored at the time of last available information (last study visit). If a participant had a fatal event that was not part of a specific endpoint for analysis, they were censored at the time of death. The Kaplan-Meier estimate reports the percentage of participants who experienced CV death within 2 years from randomization. | Up to 2 years | 
| Kaplan-Meier Estimate of the Percentage of Participants Who Experienced an MI Within 2 Years From Randomization | The time (in days) from study start to the first occurrence of an MI was recorded. A CEC reviewed and adjudicated each suspected efficacy endpoint event while blinded to treatment. Participants who did not have any endpoint event until last visit or participants who were lost to follow-up and had no event were censored at the time of last available information (last study visit). If a participant had a fatal event that was not part of a specific endpoint for analysis, they were censored at the time of death. The Kaplan-Meier estimate reports the percentage of participants who experienced an MI within 2 years from randomization. | Up to 2 years | 
| Kaplan-Meier Estimate of the Percentage of Participants Who Experienced RIR Within 2 Years From Randomization | The time (in days) from study start to the first occurrence of RIR was recorded. A CEC reviewed and adjudicated each suspected efficacy endpoint event while blinded to treatment. Participants who did not have any endpoint event until last visit or participants who were lost to follow-up and had no event were censored at the time of last available information (last study visit). If a participant had a fatal event that was not part of a specific endpoint for analysis, they were censored at the time of death. The Kaplan-Meier estimate reports the percentage of participants who experienced RIR within 2 years from randomization. | Up to 2 years | 
| Kaplan-Meier Estimate of the Percentage of Participants Who Experienced UCR Within 2 Years From Randomization | The time (in days) from study start to the first occurrence of UCR was recorded. A CEC reviewed and adjudicated each suspected efficacy endpoint event while blinded to treatment. Participants who did not have any endpoint event until last visit or participants who were lost to follow-up and had no event were censored at the time of last available information (last study visit). If a participant had a fatal event that was not part of a specific endpoint for analysis, they were censored at the time of death. The Kaplan-Meier estimate reports the percentage of participants who experienced UCR within 2 years from randomization. | Up to 2 years | 
| Kaplan-Meier Estimate of the Percentage of Participants Who Died From Any Cause Within 2 Years From Randomization | The time (in days) from study start to death from any cause was recorded. A CEC reviewed and adjudicated each suspected efficacy endpoint event while blinded to treatment. Participants who did not have any endpoint event until last visit or participants who were lost to follow-up and had no event were censored at the time of last available information (last study visit). The Kaplan-Meier estimate reports the percentage of participants who died from any cause within 2 years from randomization. | Up to 2 years | 
| Kaplan-Meier Estimate of the Percentage of Participants Who Experienced a Stroke Within 2 Years From Randomization | The time (in days) from study start to first experience of a stroke was recorded. A CEC reviewed and adjudicated each suspected efficacy endpoint event while blinded to treatment. Participants who did not have any endpoint event until last visit or participants who were lost to follow-up and had no event were censored at the time of last available information (last study visit). If a participant had a fatal event that was not part of a specific endpoint for analysis, they were censored at the time of death. The Kaplan-Meier estimate reports the percentage of participants who experienced a stroke within 2 years from randomization. | Up to 2 years |