Trial to Assess the Safety of Vorapaxar in Japanese Subjects With Cerebral Infarction (P05005; MK-5348-017)

Study Overview
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Brief Summary
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The study is designed to assess safety of Vorapaxar when added to standard of care (aspirin) in Japanese subjects with cerebral infarction. The study will assess incidence and tolerability of bleeding, major adverse cardiac events, all adverse events, and effect on expression of markers of inflammation.

Official Title
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Phase II Study of SCH 530348 in Subjects With Cerebral Infarction

Conditions
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Cerebral Infarction

Intervention / Treatment
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* Drug: Vorapaxar 2.5 mg
* Drug: Vorapaxar 1 mg
* Drug: Placebo
* Drug: Aspirin 75-150 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women at least 18 years old with last cerebral infarction (excluding cardiogenic cerebral embolism) having occurred from 14 days to less than 1 year after onset (at the time of obtaining consent), with stable nervous system for more than 24 hours and known course of disease. Participants confirmed to have cerebral infarction lesion by brain computerized tomography (CT) or magnetic resonance imaging (MRI). Both of in-participant and out-participant Willing to give appropriate informed consent and complete all study-related procedures and able to adhere to dosing and visit schedules. Women of child-bearing potential (all postmenopausal women who are <1 year 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 study drug, and for 60 days after completion or discontinuation of the medication. Exclusion Criteria: Pregnancy and nursing patients (premenopausal women should have a negative pregnancy test result confirmed before enrollment) Participant with any serious complication or any condition that the investigator feels that would cause a significant hazard to the participant if the study drug is administered. Known hypersensitivity to any component of the study drug. Participation in a study or use of an investigational study drug within 30 days before obtaining consent. Member of the staff personnel directly involved with this study Family member of the study staff. History of a bleeding diathesis, or evidence of active abnormal bleeding within 30 days before obtaining consent. History of cerebral hemorrhage. Severe hypertension (systolic blood pressure >200 mmHg or diastolic blood pressure >110 mmHg). Major surgery within 2 weeks before obtaining consent. Known platelet count <100,000/mm^3 Participants confirmed to have cerebral bleeding or any causes of cerebral bleeding by brain CT or MRI. Participants with transient ischemic attack (TIA), progressive stroke or cardiogenic cerebral embolism. 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 system or hepatic disease, or aspartate aminotransferase (GOT) or alanine aminotransferate (GPT) activity more than two times greater than the upper limit of the laboratory normal range. Participants with contraindictation to aspirin. Scheduled to have PCI (peripheral coronary intervention), peripheral interventional event, carotid endarterectomy, intra- and extra- cranial bypass surgery and intravascular surgery (angioplasty) during the study period. Combination therapy with unfractionated heparin, tissue plasminogen activator, urokinase, warfarin, factor Xa inhibitor, direct thrombin inhibitor or antiplatelet agents other than aspirin after obtaining consent, or scheduled to have the above combination therapy. Any serious impairment which would make detection of new ischemic events difficult (eg, bedridden participants, participants with total nursing care, dementia participants, etc.) or consciousness disturbance which may cause aspiration of the study drug.

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 2.5 mg + Aspirin<br>Vorapaxar oral tablets; once daily for 60 days + Aspirin. | Drug: Vorapaxar 2.5 mg<br>* Oral tablets; once daily for 60 days.<br>Drug: Aspirin 75-150 mg<br>* oral tablets; once daily for 60 days<br>|
| Experimental: Vorapaxar 1 mg + Aspirin<br>Vorapaxar oral tablets; once daily for 60 days + Aspirin. | Drug: Vorapaxar 1 mg<br>* Oral tablets; once daily for 60 days<br>Drug: Aspirin 75-150 mg<br>* oral tablets; once daily for 60 days<br>|
| Placebo Comparator: Placebo + Aspirin<br>Placebo oral tablets; once daily for 60 days + Aspirin | Drug: Placebo<br>* oral tablets; once daily for 60 days<br>Drug: Aspirin 75-150 mg<br>* oral tablets; once 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 Non-Major Adverse Cardiac Events (Non-MACE) | An adverse event (AE) is any unfavorable and unintended change in the structure, function, or chemistry of the body temporarily associated with study drug administration, whether or not considered related to study drug. MACE events were defined as nonfatal myocardial infarction (MI), nonfatal stroke, hospitalization due to recurrent ischemia, or urgent coronary revascularization. All MACE events were excluded from this analysis. | Up to Day 121 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Paticipants Experiencing Thrombolysis in Myocardial Infarction (TIMI) Major, Minor, and Non-TIMI Bleeding Events | Major TIMI bleeding was defined as any intracranial bleeding (excluding micohemorrhages <10 mm evident on magnetic resonance imaging [MRI]), clinical over signs of hemorrhge associated with a drop in hemoglobin >=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 a hemoglobin drop of 3 to <5 g/dL. Non-TIMI bleeding included all bleeding events not covered under Major TIMI or Minor TIMI bleeding. | Up to Day 60 | 
| Number of Participants With MACE or Death | The number of participants experiencing major cardiac events or death was evaluated up to Day 121. Major cardiac events were defined as nonfatal stroke, hospitalization due to recurrent ischemia, or urgent coronary revascularization. | Up to Day 121 | 
| Median High-Sensitivity C-Reactive Protein (Hs-CRP) Levels By Study Visit | Participant blood samples were collected to determine the median serum level of hs-CRP. hs-cRP levels reflect the underlying level of inflammation. The higher the level, the greater the disease burden. | Up to Day 60 | 
| Mean CD40 Ligand Levels By Study Visit | Participant blood samples were collected to determine the mean serum level of CD40 ligand. CD40 ligand values represent the level of disease activation with a higher level of CD40 ligand indicating a greater underlying risk. | Up to Day 60 | 
| Mean Membrane-Bound P-Selectin Levels By Study Visit | Participant blood samples were collected at Baseline, Day 30, and Day 60 to determine the mean level of membrane-bound p-selectin in the serum. Membrane-bound P-selectin levels reflect the underlying level of inflammation. Intensity levels are reported in arbitrary units 0 (dark) to 1023 (bright). Higher values correspond to greater membrane-bound P-Selectin levels. | Up to Day 60 |