Calf Deep Vein Thrombosis Treatment Trial

Study Overview
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Brief Summary
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The primary objective is to evaluate whether apixaban is more effective in treating patients with isolated calf vein thrombosis (DVT) than serial imaging of the DVT for preventing thrombus spread, pulmonary embolism (PE) and/or recurring DVTs.

Detailed Description
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This is a randomized double-blind placebo controlled superiority clinical trial. Patients will be identified at the time of the diagnosis of acute calf deep vein thrombosis and approached at that time. If they agree they would be randomly assigned to placebo or apixaban treatment for three months. Along with this they will also undergo repeat ultrasounds at 7, 14, and 90 days along with telephone follow-up at 30 and 60 days.

Official Title
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A Phase IV, Randomized, Double Blind Study Evaluating the Safety and Efficacy of Apixaban in Subjects With Calf Vein Thrombosis

Conditions
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Deep Vein Thrombosis

Intervention / Treatment
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* Drug: Apixaban
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Age range: ≥ 18 years. Both males and females Confirmed acute calf vein thrombosis confined to either the deep (posterior tibial, anterior tibial, or peroneal) or muscular (gastrocnemius or soleal) veins. Negative serum or urine pregnancy test done (within 2 weeks) prior to randomization, for women of childbearing potential only. Note: A woman of childbearing potential (WOCBP) is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) and is not postmenopausal. Menopause is defined as 12 months of amenorrhea in a woman over age 45 years in the absence of other biological or physiological causes. Ability to provide written informed consent. Exclusion criteria Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown: Pregnant women Nursing women Men or women of childbearing potential who are unwilling to employ adequate contraception Note: Women of child bearing potential must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug(s) plus 33 days after finishing the last dose. Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug(s) plus 93 days after finishing the last dose. Azoospermic males and WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements. However they must still undergo pregnancy testing as described in this section. Note: Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on the importance of pregnancy prevention and the implications of an unexpected pregnancy Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on the use of highly effective methods of contraception. Highly effective methods of contraception have a failure rate of < 1% when used consistently and correctly. At a minimum, subjects must agree to the use of one method of highly effective contraception as listed below: HIGHLY EFFECTIVE METHODS OF CONTRACEPTION Male condoms with spermicide Hormonal methods of contraception including combined oral contraceptive pills, vaginal ring, injectables, implants and intrauterine devices (IUDs) such as Mirena® by WOCBP subject or male subject's WOCBP partner. Female partners of male subjects participating in the study may use hormone based contraceptives as one of the acceptable methods of contraception since they will not be receiving study drug, IUDs such as ParaGard®, Tubal ligation Vasectomy. Complete Abstinence* *Complete abstinence is defined as complete avoidance of heterosexual intercourse and is an acceptable form of contraception for all study drugs. Acceptable alternate methods of highly effective contraception must be discussed in the event that the subject chooses to forego complete abstinence Acute co-existing proximal DVT (popliteal, femoral, iliac veins or IVC), pulmonary embolism, splanchnic vein thrombosis, cerebral venous sinus thrombosis within the past 3 months for whom anticoagulation therapy is indicated. Age < 18 years. Continuous treatment with therapeutic anticoagulant for more than 72 hours pre-randomization. Contraindication to anticoagulant therapy Significant kidney disease. Creatinine clearance < 25 ml/min using the Cockcroft-Gault equation: glomerular filtration rate (GFR) = (140-age) * (Wt in kg) * (0.85 if female) / (72 * Cr). (within last four weeks) Significant liver disease (e.g. acute hepatitis, chronic active hepatitis, cirrhosis) or alanine transaminase (ALT) (or AST) > 3 x upper limit of normal (ULN). (within last four weeks) Platelet count < 50 x109/L.(within last four weeks) Life expectancy < 12 months. Current active bleeding. Concomitant use of strong CYP3A4 inhibitors (e.g., HIV protease inhibitors, systemic ketoconazole) or strong CYP3A4 inducers like rifampicin. Active cancer defined as any evidence of cancer on cross-sectional imaging or cancer treatments within the past 6 months (chemotherapy, radiation therapy or cancer related surgery). . Anticipated need for urgent/emergent surgery or major invasive procedure. Dual antiplatelet therapy (thienopyridine plus aspirin) and/or aspirin greater than 165 mg while on study medication.

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: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: Multicenter, randomized, double blind, placebo-controlled, superiority clinical trial.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Apixaban<br>Apixaban 5mg (10 mg twice daily for 7 days followed by 5 mg twice daily for 3 months). | Drug: Apixaban<br>* Active anticoagulation with apixaban 10 mg twice daily for 7 days followed by 5 mg twice daily to complete a total of 3 months treatment.<br>* Other names: Eliquis;|
| Placebo Comparator: Placebo<br>Patients will receive matching placebo. | Other: Placebo<br>* apixaban matching placebo 2 tablets twice daily for 7 days followed by one tablet twice daily to complete a total of 3 months.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects Who Experience a Composite Venous Thromboembolism (VTE) Event Within 3 Months | The composite VTE event will include thrombus propagation either within the calf veins or into proximal deep veins (popliteal, femoral or iliac veins), symptomatic or incidental VTE recurrence or all-cause mortality within 3 months of therapy initiation. All suspected VTE events will be evaluated by a central, blinded, independent adjudication committee. | Within 3 months of therapy initiation | 
| Number of Subjects Who Experience Either Major Bleeding or Clinically Relevant Non-major Bleeding Within 3 Months | Major bleeding is defined as overt bleeding plus a hemoglobin decrease of ≥ 2 g/dL or transfusion of ≥ 2 units of packed red blood cells, or bleeding at a critical site: intracranial, intraspinal, intraocular, retroperitoneal, pericardial intra-articular, intramuscular with compartment syndrome, or fatal bleeding. Clinically relevant non-major bleeding is defined as any overt, actionable sign of hemorrhage meeting at least one of the following criteria: (i) requiring nonsurgical, medical intervention by a healthcare professional, (ii) leading to hospitalization or increased level of care, or (iii) prompting evaluation. All patients who received at least one dose of study medication will be included in the safety analysis. All suspected bleeding events will be evaluated by a central, blinded, independent adjudication committee. | Within 3 months of therapy initiation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Time of Thrombus Propagation | The timing of thrombus propagation for those individuals who have suffered such an event. The date of thrombus propagation confirmation will be compared to the date of the original Deep Vein Thrombosis (DVT) diagnosis for this purpose. | Within 3 months of therapy initiation | 
| Net Clinical Benefit or Harm for the Two Strategies | The outcome of net clinical benefit or harm will be assessed as the composite of the primary efficacy outcome or the principal safety outcome up to day 90. The difference in the incidences of the combined endpoint at 3 months between treatment arms will be estimated and tested using a normal approximation of the binomial distribution. All tests will be conducted at the two-sided 0.05 significance level. | Within 3 months of therapy initiation. |