Precision Medicine Platform for Novel Oral Anticoagulants

Study Overview
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Brief Summary
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The anticoagulants have been developed with new generation for FDA-approved indications including treatment and prevention of venous, pulmonary, and systemic thromboembolism. While the prescription of new oral anticoagulants (NOAC) has increasingly and largely replaced warfarin in accordance of better efficacy and safety, there are still adverse effects, including incidental minor and major bleeding, and inefficacy in thrombosis prevention. The overarching goal of this study is to develop a Pharmacogenomics Platform that is specifically designed for NOACs, in order to optimize and personalize the prescription and to facilitate the precision medicine.

Detailed Description
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Pharmaceutical companies have developed new oral anticoagulants (NOACs) to replace warfarin for prevention of systemic thrombo-embolization and embolic stroke in patients with atrial fibrillation or other thromboembolism diseases. The sale of NOACs has been increasing globally as the prevalence of atrial fibrillation increases in countries with aging population. Patients with high thromboembolism risk are also at high risk for major bleeding. The conservative strategy is not good for that more patients on reduced dose of NOACs had stroke. The clinical dilemma is how to justify the efficacy of NOACs in stroke prevention without encountering the incidental major bleeding from side effects. In order to solve this dilemma, the comprehensive evaluation of risk for thromboembolism, risk of bleeding, and genetic background on related to drug pharmacokinetics and response is essential. The primary goal of this project is to combine the clinical data and genetic information to develop a drug response evaluation platform to facilitate personalized and precision medicine for NOACs prescription. Pharmacogenomics elucidates the drug response and side effect on the basis of individual genetic background. This proposed project will enroll clinical patients who have atrial fibrillation and indications for the prescription of NOACs. The information will be collected for clinical demographics, medical history of embolic stroke, thromboembolism events, any bleeding events, and concurrent use of other medicines. Peak level of NOAC in use, and post-drug coagulation test will be performed. The above data will be integrated for the pharmacogenomic analysis with multiple genes (CES1, ABCB1, SLCO1B1, CYP2C9*2, CYP2C9*3, VKORC, CYP3A4, MMP-9, ALOX5AP, MTHFR, FGB and eNOs). The single nucleotide polymorphism (SNPs) of gene clusters will be derived from this clinical study. These output results will be used to optimize the gene-array product that is specifically-designed for NOACs prescription. The NOACs-specific gene-array for a precision prescription will be developed to help physicians to choose the right NOAC and the best dose for individualized patients. This tool will maximize thromboembolism prevention from the NOACs prescription along with the minimization of NOACs side effects. The product will be commercialized with great potential for the global market.

Official Title
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Development of Precision Medicine Platform for Pharmacogenomics of Novel Oral Anticoagulants (NOACs)

Conditions
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Anticoagulant Adverse Reaction

Intervention / Treatment
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* Diagnostic Test: Pharmacogenomics


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Long-term indication for use of dabigatran Long-term indication for use of rivaroxaban Long-term indication for use of apixaban Long-term indication for use of edoxaban Exclusion Criteria: Any contraindication for use of anticoagulants Prisoners pregnancy mental disorders history of any mechanical or prosthetic valve replacement hemodialysis or other renal replacement therapy congenital coagulation abnormalities autoimmune diseases

Ages Eligible for Study
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Minimum Age: 20 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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Dabigatran<br>Subjects who are receiving long-term Dabigatran for certain clinical conditions, and without any contraindication are enrolled for this cohort group. | Diagnostic Test: Pharmacogenomics<br>* Subjects enrolled in this study are providing blood samples for completing a set of laboratory testing and pharmacogenomic analyses. They are requested to comply a Pharmacist interview and complete of assisted questionnaires.<br>* Other names: Prothrombin time (PT), activated partial thromboplastin time (aPTT), Ecarin-based assay (for dabigatran), chromogenic anti-Xa assays (for rivaroxaban, apixaban, and edoxaban);|
| Rivaroxaban<br>Subjects who are receiving long-term Rivaroxaban for certain clinical conditions, and without any contraindication are enrolled for this cohort group. | Diagnostic Test: Pharmacogenomics<br>* Subjects enrolled in this study are providing blood samples for completing a set of laboratory testing and pharmacogenomic analyses. They are requested to comply a Pharmacist interview and complete of assisted questionnaires.<br>* Other names: Prothrombin time (PT), activated partial thromboplastin time (aPTT), Ecarin-based assay (for dabigatran), chromogenic anti-Xa assays (for rivaroxaban, apixaban, and edoxaban);|
| Apixaban<br>Subjects who are receiving long-term Apixaban for certain clinical conditions, and without any contraindication are enrolled for this cohort group. | Diagnostic Test: Pharmacogenomics<br>* Subjects enrolled in this study are providing blood samples for completing a set of laboratory testing and pharmacogenomic analyses. They are requested to comply a Pharmacist interview and complete of assisted questionnaires.<br>* Other names: Prothrombin time (PT), activated partial thromboplastin time (aPTT), Ecarin-based assay (for dabigatran), chromogenic anti-Xa assays (for rivaroxaban, apixaban, and edoxaban);|
| Edoxaban<br>Subjects who are receiving long-term Edoxaban for certain clinical conditions, and without any contraindication are enrolled for this cohort group. | Diagnostic Test: Pharmacogenomics<br>* Subjects enrolled in this study are providing blood samples for completing a set of laboratory testing and pharmacogenomic analyses. They are requested to comply a Pharmacist interview and complete of assisted questionnaires.<br>* Other names: Prothrombin time (PT), activated partial thromboplastin time (aPTT), Ecarin-based assay (for dabigatran), chromogenic anti-Xa assays (for rivaroxaban, apixaban, and edoxaban);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of major bleeding events during any NOAC treatment | Any gastrointestinal, retroperitoneal, urinary tract, abnormal uterine bleeding, intracranial, intra-ocular or intra-spinal bleeding events that are noted in medical records or examination reports, or demonstrated by images studies including a computer tomography scan or a magnetic resonance imaging, or a sonography or an ophthalmoscope; or bleeding requiring surgery; or transfusion of ≥ 2 units (i.e. ≥ 500 mL) of packed red blood cells) or associated with a decrease in hemoglobin of ≥ 2.0 g/L episodes. | From date of enrollment until the date of first major bleeding events of any type or date of death, whichever came first, assessed up to 36 months. | 
| Number of minor bleeding events during any NOAC treatment | Any gastrointestinal, urinary tract, abnormal uterine, soft tissue, skin, conjunctival, nasopharyngeal, oral cavity bleeding events that are noted in medical records or examination reports, or demonstrated by images studies including an endoscopic examination, or a sonography or an ophthalmoscope; or requirement of blood transfusion of < 2 units (i.e. less than 500 mL) of packed red blood cells or associated with a decrease in hemoglobin of < 2.0 g/L episodes. | From date of enrollment until the date of first major bleeding events of any type or date of death, whichever came first, assessed up to 36 months. | 
| Number of thromboembolism events during any NOAC treatment | Any clinical evident events of venous, pulmonary, or systemic thromboembolism that are noted in medical records or examination records, or demonstrated by images of an angiography, or a sonography, or a computer tomography scan, or an isotope phlebography. | From date of enrollment until the date of first thromboembolism events of any type or date of death, whichever came first, assessed up to 36 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Thromboembolism, Oral anticoagulants, Adverse events, Pharmacogenomics, Precision Medicine