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Influence of Vorapaxar on Thrombin Generation and Coagulability

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ClinicalTrials.gov Identifier: NCT03207451
Recruitment Status : Completed
First Posted : July 2, 2017
Last Update Posted : August 22, 2018
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Inova Health Care Services

Brief Summary:
This investigation will be conducted in patients 18-75 years of age with multiple coronary artery disease risk factors (antiplatelet naïve patients) and patients with prior MI or PVD on antiplatelet therapy. Pharmacodynamics will be assessed at multiple time points to assess onset-, maintenance-, and offset-effect of vorapaxar on thrombin generation, platelet reactivity, and plasma/platelet endothelial and inflammatory biomarkers. Safety assessment will be assessed throughout the study.

Condition or disease Intervention/treatment Phase
Coronary Artery Disease Peripheral Vascular Disease Myocardial Infarction Drug: Vorapaxar Drug: Vorapaxar and Aspirin Drug: Vorapaxar and Clopidogrel Drug: Vorapaxar, Aspirin, and Clopidogrel Phase 4

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 90 participants
Allocation: Non-Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)
Primary Purpose: Health Services Research
Actual Study Start Date : January 1, 2016
Actual Primary Completion Date : July 1, 2018
Actual Study Completion Date : August 1, 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Vorapaxar
Subjects with multiple risk factors and antiplatelet naïve to receive Vorapaxar.
Drug: Vorapaxar
Vorapaxar is the principle study drug and will be given to all subjects.
Other Name: Group 1

Experimental: Vorapaxar and Clopidogrel
Subjects with 600 mg Load /75mg QD Clopidogrel QD for ≥ 7 days to receive Vorapaxar
Drug: Vorapaxar and Clopidogrel
Subjects in groups 2 will be on Clopidogrel when they begin Vorapaxar therapy.
Other Name: Group 2

Experimental: Vorapaxar and Aspirin
Subjects with 81mg QD Aspirin to receive Vorapaxar
Drug: Vorapaxar and Aspirin
Subjects in groups 3 will be on Aspirin when they begin Vorapaxar therapy.
Other Name: Group 3

Experimental: Vorapaxar, Aspirin, and Clopidogrel
Subjects with 81 mg QD Aspirin+75mg QD Clopidogrel to receive Vorapaxar.
Drug: Vorapaxar, Aspirin, and Clopidogrel
Subjects in groups 4 will be on both Aspirin and Clopidogrel when they begin Vorapaxar therapy.
Other Name: Group 4




Primary Outcome Measures :
  1. Effects of Vorapaxar on Platelet Aggregation as measured by Light Transmission Aggregometry. Final and Maximum percent of aggregation will be measured in response to ADP, Collagen, and Thrombin Receptor Activating Protein (TRAP or SFFLRN). [ Time Frame: 8 weeks ]
  2. Effects of Vorapaxar on Clot Formation as measured by thrombelastography. [ Time Frame: 8 weeks ]

Secondary Outcome Measures :
  1. Effects of Vorapaxar on Thrombin Generation as measured by Calibrated Automatic Thrombogram Assay. [ Time Frame: 8 weeks ]
  2. Effects of Vorapaxar on plasma C-reactive protein (CRP). [ Time Frame: 8 weeks ]
  3. Effects of Vorapaxar on plasma fibrinogen. [ Time Frame: 8 weeks ]
  4. Effects of Vorapaxar on plasma von Willebrand factor (vWF). [ Time Frame: 8 weeks ]
  5. Effects of Vorapaxar on plasma interleukin (IL)-6. [ Time Frame: 8 weeks ]
  6. Effects of Vorapaxar on plasma p-selectin. [ Time Frame: 8 weeks ]
  7. Effects of Vorapaxar on plasma plasminogen activator inhibitor (PAI)-1. [ Time Frame: 8 weeks ]
  8. Effects of Vorapaxar on plasma matrix metalloproteinase (MMP)-9. [ Time Frame: 8 weeks ]
  9. Effects of Vorapaxar on Urinary TxB2. [ Time Frame: 8 weeks ]


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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Subject may be of either sex and of any race, and must be between 18 and 75 years of age.
  2. Subject must have multiple risk factors of developing atherosclerosis, or evidence of a history of atherosclerosis involving the coronary or peripheral vascular systems as follows:

    1. Subject must present with multiple risk factors for CAD or PAD, such as high blood pressure, high cholesterol, diabetes, obesity, current smokers, or
    2. CAD as indicated by a history of presumed spontaneous MI (hospitalized with final diagnosis of MI, excluding periprocedural or definite secondary MI [e.g., due to profound anemia or hypertensive emergency, troponin increase in sepsis]) at least 1 month prior to enrollment, or
    3. PAD as indicated by a history of intermittent claudication and

    i. a resting ankle/brachial index (ABI) of <0.85, or ii. significant peripheral artery stenosis (>50%) documented by angiography or non-invasive testing by duplex ultrasound, or iii. previous limb or foot amputation for arterial vascular disease (excludes trauma), or iv. previous aorto-femoral bypass surgery, limb bypass surgery or percutaneous transluminal angioplasty of the iliac or infrainguinal arteries, or v. subjects with asymptomatic carotid artery disease ii. amputation, peripheral bypass, or peripheral angioplasty of the extremities secondary to ischemia

  3. Subject must be willing and able to give appropriate, informed consent.
  4. Women of childbearing potential must have a negative pregnancy test prior to enrollment and immediately before drug administration and agree to use at least two methods of medically approved barrier contraception, or a hormonal contraceptive to prevent pregnancy throughout the study.A woman of child-bearing potential who is currently sexually active must agree to use a medically accepted method of contraception prior to screening, while receiving protocol-specified medication, and for 2 months after stopping the medication.
  5. The subject is able to read and give written informed consent and has signed and dated an informed consent document and authorization permitting release of personal health information approved by the Investigator's Institutional Review Board (IRB).

Exclusion Criteria:

  1. Clinically unstable at the time of enrollment.
  2. Any planned coronary revascularization or peripheral intervention.
  3. Concurrent or anticipated treatment with warfarin (or derivatives, e.g., phenprocoumon), oral factor Xa inhibitor, or oral direct thrombin inhibitor after enrollment.
  4. Concurrent or anticipated treatment with a potent inducer (e.g., rifampin) or potent inhibitor (eg, ketoconazole, erythromycin) of CYP3A4 isoenzymes (but see note in text for exceptions). Make list of CYP3A4 inhibitors and inducers (appendix)
  5. History of a bleeding, or evidence of active abnormal bleeding.
  6. History at any time of intracranial hemorrhage, intracranial or spinal cord surgery, or a central nervous system tumor or aneurysm.
  7. Documented sustained severe hypertension (systolic blood pressure >200 mmHg or diastolic blood pressure >110 mmHg) at enrollment or within the previous 10 days.
  8. Severe valvular heart disease, as defined by the American College of Cardiology /American Heart Association.
  9. History within 30 days before enrollment ofof major invasive surgeries (other than mentioned above), is anticipating one during the course of their study participation, or is planning to have one within 1 month post dosing with the study drug.
  10. History within 30 days before enrollment or of TIA and ischemic (presumed thrombotic) stroke/CVA.
  11. Known platelet count <100,000/mm3 within 30 days before enrollment.
  12. Known active hepatobiliary disease, or known unexplained persistent increase in serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) activity to two times or more the upper limit of the reference range (upper limit of "normal" [2xULN]).
  13. Any serious illness or any condition that the investigator feels would (a) pose a significant hazard to the subject if investigational therapy were initiated, or (b) would limit the prognosis of the subject, regardless of investigational therapy.
  14. Any serious medical comorbidity (e.g., active malignancy) such that the subject's life expectancy is <24 months.
  15. Current participation in any other study of investigational therapy, or participation in such a study within the last 30 days.
  16. Known hypersensitivity to any component of the current investigational product.
  17. Subject is a woman who is breast-feeding, pregnant, or who intends to become pregnant.
  18. Subject is part of the staff personnel directly involved with this study, or is a family member of the investigational staff.
  19. Known current substance abuse at the time of enrollment.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03207451


Locations
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United States, Virginia
Inova Fairfax Hospital
Falls Church, Virginia, United States, 22207
Sponsors and Collaborators
Inova Health Care Services
Merck Sharp & Dohme Corp.
Investigators
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Principal Investigator: Paul Gurbel, MD Inova Health System
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Responsible Party: Inova Health Care Services
ClinicalTrials.gov Identifier: NCT03207451    
Obsolete Identifiers: NCT02629367
Other Study ID Numbers: 15-2051
First Posted: July 2, 2017    Key Record Dates
Last Update Posted: August 22, 2018
Last Verified: August 2018
Keywords provided by Inova Health Care Services:
Anti-Platelet Therapy
Additional relevant MeSH terms:
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Coronary Artery Disease
Myocardial Infarction
Vascular Diseases
Peripheral Vascular Diseases
Peripheral Arterial Disease
Infarction
Ischemia
Pathologic Processes
Necrosis
Coronary Disease
Myocardial Ischemia
Heart Diseases
Cardiovascular Diseases
Arteriosclerosis
Arterial Occlusive Diseases
Atherosclerosis
Aspirin
Clopidogrel
Vorapaxar
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action