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

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

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.

Study Overview

• Status: Completed
• Conditions: Myocardial Infarction; Myocardial Ischemia; Atherosclerosis
• Intervention / Treatment: Drug: Vorapaxar; Drug: Aspirin; Drug: Clopidogrel; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 120
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

5

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Goto S, Yamaguchi T, Ikeda Y, Kato K, Yamaguchi H, Jensen P. Safety and exploratory efficacy of the novel thrombin receptor (PAR-1) antagonist SCH530348 for non-ST-segment elevation acute coronary syndrome. J Atheroscler Thromb. 2010 Feb 26;17(2):156-64. doi: 10.5551/jat.3038. Epub 2010 Feb 3.

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2006
• Primary Completion (Actual): October 1, 2007
• Study Completion (Actual): October 1, 2007

Study Registration Dates

• First Submitted: May 22, 2008
• First Submitted That Met QC Criteria: May 22, 2008
• First Posted (Estimate): May 26, 2008

Study Record Updates

• Last Update Posted (Actual): May 5, 2017
• Last Update Submitted That Met QC Criteria: March 31, 2017
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Necrosis; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Myocardial Infarction; Infarction; Myocardial Ischemia; Ischemia; Atherosclerosis; Acute Coronary Syndrome; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Aspirin; Clopidogrel; Vorapaxar
• Other Study ID Numbers: P04772

Plan for Individual participant data (IPD)

Study Data/Documents

1. CSR Synopsis