Trial to Assess the Safety and Effects of Vorapaxar in Japanese Subjects With Acute Coronary Syndrome (P04772; MK-5348-016)

Study Overview
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Brief Summary
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The study is designed to assess safety and effects of vorapaxar, when added to standard of care (aspirin and clopidigrel), in Japanese subjects with acute coronary syndrome. The study may also provide information about the effect of vorapaxar on preventing heart attack and stroke in this subject population.

Detailed Description
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The study drug (loading dose) is administered at least 1 hour before catheterization for diagnostic imaging or percutaneous coronary interventions (PCI). The incidence of bleeding is thought to be an important index to assess the safety of this drug, therefore thrombolysis in myocardial infarction (TIMI) is evaluated.

Official Title
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Phase II Study of SCH 530348 in Subjects With Acute Coronary Syndrome

Conditions
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Atherosclerosis, Myocardial Ischemia, Myocardial Infarction

Intervention / Treatment
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* Drug: Vorapaxar
* Drug: Placebo
* Drug: Aspirin
* Drug: Clopidogrel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women aged 18 years or more with history of cardiac ischemia related chest discomfort of > 10 minutes duration < 24 hours prior to randomization, and having at least 1 of the following A or B. Participants who are planned to undergo PCI will be the target participants. A: Positive biomarkers [Elevated troponin I or creatinine kinase MB isozyme greater than the site's upper limit of normal (ULN)] at or before registration B: Electrocardiogram (ECG) changes: ST segment depression >= 0.1 mV (>=1 mm), or transient (<30 minutes) ST segment elevation >= 0.1 mV (>=1 mm) in at least 2 contiguous leads Willing to give appropriate informed consent and complete all study-related procedures, and able to adhere to dosing and all visit schedules. Women of child-bearing potential (all postmenarchal women who are <1 years menopausal or who have not had surgical sterilization or a hysterectomy are considered to be women of child-bearing potential) must agree to use a medically accepted method of contraception while receiving protocol-specified medication, and for 60 days after stopping the medication. Exclusion Criteria: Pregnant and nursing mothers (premenopausal women should have a negative pregnancy test result confirmed before enrollment) Any serious illness or any condition that the investigator feels would pose a significant hazard to the participant if investigational therapy were initiated known hypersensitivity to any component of the current investigational product; Participation in a study of experimental therapy or use of any investigational drug within 30 days before enrollment Member of the staff personnel directly involved with this study; Family member of the investigational study staff; History of a bleeding diathesis, or evidence of active abnormal bleeding within 30 days before enrollment History of a hemorrhagic stroke at any time Severe hypertension (systolic blood pressure >200 mm Hg or diastolic blood pressure >110 mm Hg) while receiving therapy; Major surgery within 2 weeks prior to enrollment Known platelet count <100,000/mm^3 Uncontrolled cardiac arrhythmia; Known impairment of renal function (serum creatinine >2.0 mg/dL [>176.8 umol/L]), dysproteinemia, nephrotic syndrome, or other renal disease; Active or chronic hepatobiliary or hepatic disease, or aspartate aminotransferase (AST) or alanine aminotransferase (ALT) activity more than two times greater than the upper limit of the laboratory reference range Anticipated staged PCI Concurrent or anticipated treatment with warfarin, factor Xa inhibitor, direct thrombin inhibitor, or antiplatelet agents except aspirin and ticlopidine after enrollment Anticipated intracoronary brachytherapy

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vorapaxar 20 mg/1 mg<br>Vorapaxar 20 mg loading dose + daily 1 mg maintenance dose + standard of care (Aspirin + Ticlopidine) | Drug: Vorapaxar<br>* Oral tablets; single 20-mg or 40-mg loading dose on first day followed by daily 1-mg or 2.5-mg maintenance dose for 59 days<br>Drug: Aspirin<br>* Loading dose of 75-325 mg on Day 1, then 75-100 mg once daily for 60 days.<br>* Other names: ASA, acetylsalicylic acid;Drug: Clopidogrel<br>* 100 mg two or three times daily for 60 days.<br>|
| Experimental: Vorapaxar 20 mg/2.5 mg<br>Vorapaxar 20 mg loading dose + daily 2.5 mg maintenance dose + standard of care (Aspirin + Ticlopidine) | Drug: Vorapaxar<br>* Oral tablets; single 20-mg or 40-mg loading dose on first day followed by daily 1-mg or 2.5-mg maintenance dose for 59 days<br>Drug: Aspirin<br>* Loading dose of 75-325 mg on Day 1, then 75-100 mg once daily for 60 days.<br>* Other names: ASA, acetylsalicylic acid;Drug: Clopidogrel<br>* 100 mg two or three times daily for 60 days.<br>|
| Experimental: Vorapaxar 40 mg/1 mg<br>Vorapaxar 40 mg loading dose + daily 1 mg maintenance dose + standard of care (Aspirin + Ticlopidine) | Drug: Vorapaxar<br>* Oral tablets; single 20-mg or 40-mg loading dose on first day followed by daily 1-mg or 2.5-mg maintenance dose for 59 days<br>Drug: Aspirin<br>* Loading dose of 75-325 mg on Day 1, then 75-100 mg once daily for 60 days.<br>* Other names: ASA, acetylsalicylic acid;Drug: Clopidogrel<br>* 100 mg two or three times daily for 60 days.<br>|
| Experimental: Vorapaxar 40 mg/2.5 mg<br>Vorapaxar 40 mg loading dose + daily 2.5 mg maintenance dose + standard of care (Aspirin + Ticlopidine) | Drug: Vorapaxar<br>* Oral tablets; single 20-mg or 40-mg loading dose on first day followed by daily 1-mg or 2.5-mg maintenance dose for 59 days<br>Drug: Aspirin<br>* Loading dose of 75-325 mg on Day 1, then 75-100 mg once daily for 60 days.<br>* Other names: ASA, acetylsalicylic acid;Drug: Clopidogrel<br>* 100 mg two or three times daily for 60 days.<br>|
| Placebo Comparator: Placebo<br>Placebo loading dose + daily placebo maintenance dose + standard of care (Aspirin + Ticlopidine) | Drug: Placebo<br>* Oral tablets; matching placebo for SCH 530348 loading and maintenance doses for 59 days<br>Drug: Aspirin<br>* Loading dose of 75-325 mg on Day 1, then 75-100 mg once daily for 60 days.<br>* Other names: ASA, acetylsalicylic acid;Drug: Clopidogrel<br>* 100 mg two or three times daily for 60 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Experiencing Adverse Events (AEs) Who Underwent Percutaneous Coronary Interventions (PCI) | An AE is any unfavorable and unintended change in the structure, function or chemistry of the body temporally associated with study drug administration, whether or not considered related to the study drug. | Up to Day 60 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Experiencing Non-Major Adverse Cardiac Events (MACE) Who Underwent PCI | An AE is any unfavorable and unintended change in the structure, function or chemistry of the body temporally associated with study drug administration, whether or not considered related to the study drug. MACE events were defined as nonfatal myocardial infarction (MI), nonfatal stroke, hospitalization due to recurrent ischemia, or urgent coronary revascularization performed ≥ 30 days after administration of the loading dose (Day 1). All MACE events were excluded from this analysis. Analysis of data was by loading/maintenance dose group. | Up to Day 121 | 
| Number of Participants With Major, Minor, and Non-Thrombolysis in Myocardial Infarction Cooperative Group (TIMI) Bleeding Events Among Participants Who Underwent PCI | Major TIMI bleeding was defined as any intracranial bleeding (excluding microhemorrhages <10 mm evident only on gradient-echo magnetic resonance imaging [MRI]), clinically overt signs of hemorrhage associated with a drop in hemoglobin of ≥5 g/dL, or fatal bleeding (bleeding that directly results in death within 7 days). Minor TIMI bleeding was defined as any clinically overt bleeding resulting in hemoglobin drop of 3 to <5 g/dL. Non-TIMI bleeding included all bleeding events not covered under Major TIMI bleeding or Minor TIMI bleeding. Analysis of data was by maintenance dose group. | Up to Day 60 | 
| Number of Participants Who Underwent PCI With Inhibition of Platelet Aggregation By Study Visit | Blood samples were collected from participants at Baseline and Days 30, 60, 74, 90, and 121 to determine the extent of inhibition of platelet aggregation induced by thrombin-receptor agonist peptide (TRAP). Analysis of data was by maintenance dose group. | Baseline, Day 30, Day 60, Day 74, Day 90, Day 121 | 
| Median High-Sensitivity C-Reactive Protein (Hs-CRP) Levels Among Participants Who Underwent PCI By Study Visit | Participant blood samples were collected at Baseline and on Days 30 and 60 to evaluate the median level of hs-CRP. hs-CRP is a protein marker in the blood associated with inflammation with higher values indicating a greater degree of inflammation. Analysis of data was by maintenance dose group. | Baseline, Day 30, Day 60 | 
| Mean CD40 Ligand Levels Among Participants Who Underwent PCI | Participant blood samples were collected at Baseline and Days 30 and 60 to evaluate the mean level of CD40 ligand present. CD40 ligand is a protein primarily found on activated T-cells, with higher levels indicating better immunological health. Analysis of data was by maintenance dose group. | Baseline, Day 30, Day 60 | 
| Mean Membrane-Bound P-Selectin Levels Among Participants Who Underwent PCI | Participant blood samples were collected at Baseline and Days 30 and 60 to evaluate the mean level of membrane-bound P-selectin. Membrane-bound P-selectin was measured using flow cytometry and a monoclonal antibody to P-selectin. Intensity levels are reported in arbitrary units 0 (dark) to 1023 (bright). Higher values correspond to greater membrane-bound P-Selectin levels. Analysis of data was by maintenance dose group. | Baseline, Day 30, Day 60 | 
| Number of Participants Who Underwent PCI With Clinically Important Bleeding Events During Treatment and After Hospital Discharge | Clinically important bleeding events were defined as intracranial hemorrhage, bleeding requiring hospitalization, or TIMI major bleeding. Analysis of data was by loading/maintenance dose group. | Up to Day 121 | 
| Number of Participants With Major, Minor, and Non-TIMI Bleeding Events Among Participants Who Did Not Undergo PCI | Major TIMI bleeding was defined as any intracranial bleeding (excluding microhemorrhages <10 mm evident only on gradient-echo MRI), clinically overt signs of hemorrhage associated with a drop in hemoglobin of ≥5 g/dL, or fatal bleeding (bleeding that directly results in death within 7 days). Minor TIMI bleeding was defined as any clinically overt bleeding resulting in hemoglobin drop of 3 to <5 g/dL. Non-TIMI bleeding included all bleeding events not covered under Major TIMI bleeding or Minor TIMI bleeding. Analysis of data was by loading dose group. | Up to Day 60 | 
| Number of Participants Experiencing Non-MACE AEs Among Participants Who Did Not Undergo PCI | An AE is any unfavorable and unintended change in the structure, function or chemistry of the body temporally associated with study drug administration, whether or not considered related to the study drug. MACE events were defined as nonfatal MI, nonfatal stroke, hospitalization due to recurrent ischemia, or urgent coronary revascularization performed ≥ 30 days after administration of the loading dose (Day 1). All MACE events were excluded from this analysis. Analysis of data was by loading dose group. | Up to Day 121 | 
| Number of Participants Who Did Not Undergo PCI But Had Coronary Artery Bypass Graft (CABG) Who Experienced Bleeding Events | Bleeding events were evaluated up to 10 hours post-CABG among participants who did not undergo PCI. | Up to 10 Hours Post-CABG | 
| Number of Participants Who Did Not Undergo PCI But Had Bleeding Events That Required Transfusion | Bleeding events were evaluated among participants that did not undergo PCI to determine the number of participants that required blood transfusion. Analysis of data was by loading dose group. | Up to Day 60 | 
| Number of Participants Who Did Not Undergo PCI But Had Bleeding Events That Required Subsequent Hospitalization | Bleeding events were evaluated among participants that did not undergo PCI to determine the number of participants who required a subsequent hospitalization. Analysis of data was by loading dose group. | Up to Day 30 | 
| Median Hs-CRP Levels Among Participants Who Did Not Undergo PCI | Participant blood samples were collected at baseline and at the time of hospital discharge to determine the median serum level of hs-CRP. Analysis of data was by loading dose group. | Baseline Up To Day 60 | 
| Mean CD40 Ligand Levels Among Participants Who Did Not Undergo PCI | Participant blood samples were collected at baseline and at the time of hospital discharge to determine the mean serum level of CD40 ligand. Analysis of data was by loading dose group. | Baseline Up To Day 60 | 
| Number of Participants Who Did Not Undergo PCI That Had Clinically Important Bleeding Events | Clinically important bleeding events were defined as intracranial hemorrhage, bleeding requiring blood transfusion, bleeding requiring hospitalization, and TIMI major bleeding. Analysis of data was by loading dose group. | Baseline Up To Day 60 |