Tecarfarin Anti-Coagulation Trial (TACT)

Study Overview
=================
Brief Summary
-----------------
TACT is a real world randomized controlled trial of tecarfarin, a novel vitamin K antagonist, vs. warfarin. The quality of anticoagulation control will be compared for the two groups of subjects who require chronic oral anticoagulation for a broad panel of indications.

Detailed Description
-----------------
This will be a randomized, parallel-arm, open-label study comparing the safety and efficacy of tecarfarin and warfarin in approximately 1000 subjects who have an indication for chronic oral anticoagulation. The study will be fully enriched with subjects who are taking at least one CYP2C9-interacting medication and have either chronic kidney disease stage 3 or 4 and/or a genetic variant allele for CYP2C9. The study will be conducted at approximately 140 sites with experience in the management of anticoagulation subjects. Eligible subjects will be randomized to receive either tecarfarin or warfarin for a period ranging from 6 months to a maximum of approximately 24 months.

Official Title
-----------------
A Real-World, Randomized, Open-Label, Study on the Efficacy, Safety, and Tolerability of Tecarfarin (ATI-5923) a Novel Vitamin K Antagonist, Versus Warfarin in Subjects Requiring Chronic Anticoagulation

Conditions
-----------------
Thromboembolism, Thrombosis

Intervention / Treatment
-----------------
* Drug: Warfarin
* Drug: tecarfarin


Participation Criteria
=================
Eligibility Criteria
-----------------
General Screening Inclusion Criteria Is male or female and at least 18 years of age. Is able and willing to sign an IRB-approved written informed consent. Is able and willing to follow instructions, to comply with protocol requirements, and to attend required study visits. Is taking a CYP2C9-interacting medication (inhibitor, substrate, or inducer; see list in Appendix A) at the time of randomization and is expected to receive this medication chronically for the duration of the trial. Has either Chronic kidney disease stage 3 or 4 (eGFR ≥ 15 to <60 mL/min/1.73 m2 at Screening based on central laboratory) and/or A CYP2C9 genotype variant allele (Only for warfarin experienced patients) Patient is considered poorly controlled on warfarin therapy as judged by the investigator, e.g. has at least 2 INR values out of target range within previous 12 months Anticoagulation-Related Inclusion Criteria Requires chronic anticoagulation therapy. Is willing to receive chronic anticoagulation investigational therapy for the duration of the study or, for warfarin-naïve DVT subjects, treating physician prescribed at least a 6-month treatment period with an oral anticoagulation agent. Has one or more of the following indications for chronic oral anticoagulation: Atrial fibrillation/flutter (paroxysmal, persistent or permanent), not due to a reversible cause, documented by electrocardiography (ECG) Aortic and/or mitral prosthetic HV History of venous thromboembolic disease History of myocardial infarction or cardiomyopathy Any another indication for which warfarin is approved or recommended, with Sponsor approval Conforms to the following restrictions regarding vitamin-K containing dietary supplements: If taking at Baseline (Visit 2), is willing to continue with consistent doses throughout the study If not taking at Baseline (Visit 2), is willing to abstain from such supplements throughout the study General Exclusion Criteria Is pregnant, nursing, or a woman of childbearing potential who cannot assure that they will not become pregnant for the duration of the study. Has been treated with an investigational drug within 30 days or 5 half-lives, whichever is longer, at time of screening. Safety-Related Exclusion Criteria Has a life expectancy <1 year Is age >85 years Has severe end-organ disease, such as: Estimated GFR (eGFR) < 15 mL/min/1.73 m2 at Screening per the central laboratory Is on dialysis Is expected to be on dialysis or receive kidney transplant within 6 months of screening Advanced pulmonary disease requiring home oxygen NYHA class IV heart failure Severe psychiatric disorder such as advanced dementia Has a history of ischemic stroke without residual neurologic deficit within the last 3 months, prior major ischemic stroke with residual neurologic deficit, or any history of intracranial bleeding Is an ongoing alcohol or substance abuser Has anemia (screening hemoglobin <9 g/dL) For subjects who have received a MHV within 4 weeks of Screening, who have no active bleeding, and whose hemoglobin is stable, a Screening hemoglobin as low as 8 g/dL is allowed. For subjects with severe CKD (eGFR ≥ 15 to <30 mL/min/1.73 m2), who have no active bleeding, and whose hemoglobin is stable, a Screening hemoglobin as low as 8 g/dL is allowed. Has thrombocytopenia (screening platelet count <90,000 x 103/microL) Has a history of or presence of any illness or condition, which, in the judgment of the Investigator, may compromise the safety of the subject during Study Drug administration. Anticoagulation-related Exclusion Criteria Has active bleeding or lesions at risk of bleeding such as gastric ulceration, colonic or cerebral arterio-venous malformations, cerebral or aortic aneurysms, pericarditis or endocarditis Except for MHV replacement surgery and related or concurrent procedures, has recently (<14 days from Screening) undergone non-thromboembolic surgery or other invasive procedures such as lumbar puncture. Has blood dyscrasias or inherited disorders of hemostasis. Has a history of hemorrhagic tendencies or prior serious hemorrhagic events such as hemorrhage within the cranium, eye, spinal cord, retroperitoneum. Has active gross hematuria or gastrointestinal bleeding Has a history of gross hematuria or gastrointestinal bleeding within the past 6 months prior to Screening. (Note: Investigators may enroll patients with such bleeding episodes if they are resolved at least 4 weeks prior to screening and if the benefits of anticoagulation outweigh the risks using accepted risk stratification methods such as HASBLED.) Has received concomitant therapy with other anticoagulant or antiplatelet agents, such as clopidogrel, prasugrel, ticlopidine, dipyridamole, heparin or low molecular weight heparin (LMWH), or nonsteroidal anti-inflammatory drugs (NSAIDs) that cannot be discontinued prior to initiating tecarfarin/warfarin dosing, unless use of such drugs is necessary as part of bridging/transitioning during the first several days of Study Drug administration. Daily use of 81 - 100 mg aspirin and intermittent or chronic use of the selective COX-2 inhibitors celecoxib and valdecoxib is allowed. Has congenital or acquired coagulant inhibitors present which would interfere with the use of the INR, eg: Antiphospholipid antibody syndrome or positive lupus anticoagulant Abnormally prolonged prothrombin time, in the absence of therapeutic anticoagulation, due to an endogenous inhibitor

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tecarfarin<br>Tecarfarin will be administered and dose adjusted by the investigator. Dose adjustments will be made in accordance with a target INR range pre-specified by the investigator. | Drug: tecarfarin<br>* Tecarfarin is an oral vitamin K antagonist anticoagulant<br>* Other names: ATI-5923;|
| Active Comparator: Warfarin<br>Warfarin will be administered and dose adjusted by the investigator. Dose adjustments will be made in accordance with a target INR range pre-specified by the investigator. | Drug: Warfarin<br>* Warfarin is an oral vitamin K antagonist anticoagulant.<br>* Other names: Coumadin;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of time in the therapeutic range (TTR) for tecarfarin vs. warfarin for each treatment group in the randomized population | Interpolated and observed TTR will be calculated for the two treatment groups | From the date of randomization until study termination, up to 24 months (1st month not included) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage TTR for tecarfarin vs. warfarin in the sub-population of patients who are taking a CYP2C9-interacting medication and have a CYP2C9 genotype variant allele | Interpolated and observed TTR will be calculated for the two treatment groups | From the date of randomization until study termination, up to 24 months (1st month not included) | 
| Percentage TTR for tecarfarin vs warfarin for the sub-population of patients who are taking a CYP2C9-interacting medication and have chronic kidney disease stage 3 or 4 (eGFR ≥ 15 to <60 mL/min/1.73 m2) | Interpolated and observed TTR will be calculated for the two treatment groups | From the date of randomization until study termination, up to 24 months (1st month not included) | 
| Percentage of patients with INR > 4.0 for tecarfarin vs. warfarin | Percentage of observations of patients with INR > 4.0 will be calculated for the two treatment groups | From the date of randomization until study termination, up to 24 months (1st month not included) | 
| Percentage of patients with INR > 5.0 | Percentage of observations of patients with INR > 5.0 will be calculated for the two treatment groups | From the date of randomization until study termination, up to 24 months (1st month not included) | 
| Time to first embolic event for tecarfarin vs. warfarin | Time from enrollment until any embolic event (CVA, pulmonary embolism, peripheral embolism) while enrolled will be calculated for the two groups | From the date of randomization until study termination, up to 24 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
chronic anticoagulation, vitamin K antagonist, mechanical heart valve, CYP2C9, warfarin, tecarfarin, chronic kidney disease