Apixaban for Secondary Prevention of Thromboembolism Among Patients With AntiphosPholipid Syndrome

Study Overview
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Brief Summary
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This study is designed to compare the safety and effectiveness of two blood thinners, apixaban and warfarin, for the prevention of blood clots in patients who have a higher risk of blood clots than the general population, a condition called antiphospholipid syndrome.

Detailed Description
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This study is a prospective, open-label, blinded event, pilot study that will randomize patients with a history of venous thrombosis and antiphospholipid syndrome (APS) already receiving anticoagulation to either warfarin or apixaban. The study will assess the safety and efficacy of apixaban compared with adjusted dose warfarin for the prevention of recurrent thrombosis (defined as the aggregate of arterial or venous thrombosis) and vascular death. The primary efficacy outcome will be confirmed upon adjudication by a panel blinded to the treatment arm. The primary safety outcome will be major bleeding and clinically relevant non-major bleeding events. Patients who consent to study participation will be randomized to anticoagulation with adjusted dose warfarin sodium or apixaban 5 mg by mouth twice daily. This pilot study will also provide information and experience identifying, recruiting, enrolling and randomizing patients with APS and a history of venous thrombosis to anticoagulation with apixaban or warfarin for the prevention of recurrent thrombosis.

Official Title
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Apixaban for the Secondary Prevention of Thromboembolism: a Prospective Randomized Outcome Pilot Study Among Patients With the AntiphosPholipid Syndrome

Conditions
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Thrombosis, Antiphospholipid Syndrome

Intervention / Treatment
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* Drug: Apixaban
* Drug: Warfarin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be ≥ 18 years of age Have a clinical diagnosis of the antiphospholipid syndrome (APS) and a history of venous thrombosis only (excluding arterial thrombosis as recommended by the Data Safety Monitoring Board (DSMB)) for which the patient is receiving anticoagulation therapy for the prevention of recurrent thrombosis; Anticoagulation is defined as warfarin sodium titrated at the discretion of the clinician to a target INR (International Normalized Ratio) 2.5 (range 2-3), 3.0 (range 2.5-3.5), or 3.5 (range 3-4). Should the patient be receiving some other form of anticoagulation (apixaban, rivaroxaban, edoxaban, dabigatran etexilate, low-molecular weight heparin) and is willing to be randomized to warfarin with a target INR 2.5 or apixaban 5 mg by mouth twice daily and meets all other inclusion criteria. Able to undergo magnetic resonance imaging (MRI) of the brain; Have completed at least 6 months of anticoagulation for the indication of venous thrombosis and be without symptoms or signs consistent with acute thrombosis for a minimum of 6 months; Be willing to provide informed consent to contact the subjects anticoagulation provider for INRs and dosing as well as details regarding any adverse events; A woman of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of hCG (Human Chorionic Gonadotropin) within 24 hours prior to the start of study drug; Women must not be breastfeeding; A WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug apixaban plus 5 half-lives of study drug apixaban (3 days) plus 30 days (duration of ovulatory cycle) for a total of 33 days post-treatment completion; Males who are sexually active with any WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug apixaban plus 5 half-lives of the study drug apixaban (3 days) plus 90 days (duration of sperm turnover) for a total of 93 days post-treatment completion; Azoospermic males and women who are continuously not heterosexually active are exempt from contraceptive requirements. However, a WOCBP must still undergo pregnancy testing as described above; If they are actively receiving a strong dual inhibitor of cytochrome P450 3A4 (CYP3A4) and P-gp, such as ketoconazole, itraconazole, ritonavir, and are agreeable to taking apixaban 2.5 mg twice daily. Exclusion Criteria: A history of arterial thromboembolism (e.g., stroke, myocardial infarction, or other arterial thrombosis); Another indication for long-term anticoagulation for which no FDA (Food & Drug Administration) approval of apixaban exists (e.g., mechanical heart valve); A life expectancy of less than 1 year; Is unable to attend follow-up appointments; Is participating in a clinical trial or has participated in a trial within the last 30 days; Is receiving concomitant dual antiplatelet therapy; Requires aspirin dose of greater than 165 mg daily; Requires clopidogrel, ticagrelor, prasugrel, or another P2Y12 inhibitor; A hemoglobin level of less than 8 mg per deciliter; A platelet count of less than 50,000 per cubic millimeter; Serum creatinine level of more than 2.5 mg per deciliter or a calculated creatinine clearance of less than 25 ml per minute; Alanine aminotransferase or aspartate aminotransferase level greater than 2 times the upper limit of the normal range; A total bilirubin more than 1.5 times the upper limit of the normal range; Have active cancer for which treatment (chemotherapy/radiation therapy) is being delivered or has been delivered within the last 3 months; Are actively taking a strong dual inducer of CYP3A4 and P-gp, such as: rifampin carbamazepine phenytoin St.John's wort Intend pregnancy or breastfeeding within the next year; Have a known allergy to apixaban, rivaroxaban, or edoxaban; Have experienced thrombosis while receiving warfarin at a target INR of 2 to 3 and have been assigned a higher target INR at the discretion of the treating clinician; Have active pathological bleeding; Have a history of catastrophic APS (CAPS) as defined by clinical routine; At the discretion of the investigator, are not considered to be good candidates secondary to a safety concern. Patients who meet the above inclusion & exclusion criteria will be offered participation in the study. After informed consent is obtained, the patient will be consented for Magnetic Resonance Imaging (MRI). A brain MRI without contrast including weighted imaging and fluid-attenuated inversion recovery (FLAIR) will be performed as a study procedure to rule out prior stroke. If the patient has radiographic evidence of prior stroke on this MRI, then the patient will not be randomized, and will not be included in future study procedures or study analyses.

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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Apixaban<br>Subjects will receive apixaban 5 mg tablets taken twice daily for the duration of the study. | Drug: Apixaban<br> <br> * Other names: Eliquis;|
| Active Comparator: Warfarin<br>Subjects will receive warfarin for the duration of the study, with the dose and frequency adjusted per clinician discretion to achieve an INR (International Normalized Ratio) between 2 and 4. | Drug: Warfarin<br> <br> * Other names: Coumadin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate (number divided by duration) of clinically overt thromboses (arterial and/or venous) or vascular death |  | From time of first dose of study drug through 2 days after receiving the last dose of study drug at the end of 12 months of treatment | 
| Rate (number divided by duration) of occurrence of major (including fatal) and clinically relevant non-major bleeding | Major bleeding is clinically overt bleeding accompanied by one or more of the following: a decrease in the hemoglobin level of 2 g per deciliter or more, transfusion of 2 or more units of packed red cells, bleeding at a critical site (intracranial, intraspinal, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome, or retroperitoneal), or fatal bleeding. Clinically relevant non-major bleeding is defined as clinically overt bleeding that does not satisfy the criteria for major bleeding and that led to hospital admission, physician-guided medical or surgical treatment, or a change in antithrombotic therapy. | From time of first dose of study drug through 2 days after receiving the last dose of study drug at the end of 12 months of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Net clinical benefit (combination of occurrence of thrombosis and bleeding rates) | Sum of number of thrombosis and bleeding events divided by duration | From time of first dose of study drug through 2 days after receiving the last dose of study drug at the end of 12 months of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Apixaban, Eliquis