Efficacy and Safety of Apixaban in the Treatment of Heparin Induced Thrombocytopenia (HIT)

Study Overview
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Brief Summary
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This research study is studying a drug as a possible treatment for heparin induced thrombocytopenia (HIT) or Heparin-induced Thrombocytopenia and Thrombosis (HITT). The drug involved in this study is apixaban.

Detailed Description
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This research study is a Phase II clinical trial. The FDA (the U.S. Food and Drug Administration) has not approved apixaban as a treatment option for this specific disease but it has been approved for other uses. HIT and HITT are common and severe complications of heparin therapy. Once patients are diagnosed with either one of these, they are typically switched to a non-heparin anticoagulant (a type of drug that thins your blood). As of now the only drug that is FDA approved for HIT or HITT is argatroban, which is administered continuously through an IV over multiple days and is extremely costly. In this research study, the investigators are researching the activity and tolerability of apixaban in participants with HIT or HITT. The investigators believe that apixaban will work just as well as argatroban and will be more convenient for this population. The oral route of apixaban allows for the potential outpatient treatment of HIT or HITT which is both convenient and less expensive than treatment with argatroban.

Official Title
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A Phase II Study to Evaluate the Efficacy and Safety of Apixaban in the Treatment of Heparin Induced Thrombocytopenia (HIT)

Conditions
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Heparin-induced Thrombocytopenia, Heparin-induced Thrombocytopenia and Thrombosis

Intervention / Treatment
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* Drug: Apixaban


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Hospitalized patients at MGH and participating Dana Farber/Harvard Cancer Center (DF/HCC) sites. Patient must have a diagnosis of HIT or high clinical suspicion of HIT, with a 4 T score of ≥ 5 as calculated by the following criteria: Thrombocytopenia Platelet count fall >50 percent and nadir ≥20,000/microL - 2 points Platelet count fall 30 to 50 percent or nadir 10 to 19,000/microL - 1 points Platelet count fall <30 percent or nadir <10,000/microL - 0 points Timing of platelet count fall Clear onset between days 5 and 10 or platelet count fall at ≤1 day if prior heparin exposure within the last 30 days - 2 points Consistent with fall at 5 to 10 days but unclear (eg, missing platelet counts), onset after day 10, or fall ≤1 day with prior heparin exposure within 30 to 100 days - 1 point Platelet count fall at <4 days without recent exposure - 0 points Thrombosis or other sequelae Confirmed new thrombosis, skin necrosis, or acute systemic reaction after intravenous unfractionated heparin bolus - 2 points Progressive or recurrent thrombosis, non-necrotizing (erythematous) skin lesions, or suspected thrombosis that has not been proven - 1 point None - 0 points Other causes for thrombocytopenia None apparent - 2 points Possible - 1 point Definite - 0 points Prior to or immediately subsequent to enrollment, the patient must have the diagnosis confirmed by Heparin-PF4 EIA or other accepted confirmatory test to remain on study. Patients can be treated with argatroban, bivalirudin or fondaparinux for up to 72 hours prior to enrollment. Age 18 years or older. ECOG performance status ≤2 (Karnofsky ≥60%) Participants must have organ and marrow function as defined below: absolute neutrophil count ≥1,500/mcL AST(SGOT) and ALT(SGPT) ≤2.5 × institutional upper limit of normal creatinine clearance ≥25 mL/min as was used in the AMPLIFY trial16 The effects of apixaban on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study entry, for the duration of the study participation, and 4 months after completion of apixaban administration. Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: Patient requires anticoagulation for a mechanical heart valve. Patient requires: anticoagulation for another indication for long-term anticoagulation therapy, dual antiplatelet therapy, treatment with aspirin at a dose of more than 162 mg daily Patient has signs of active or ongoing clinically significant hemorrhage. Patient has hereditary or acquired coagulopathy or bleeding disorder. Patient has a contraindication to apixaban. Participants receiving any medications or substances that are inhibitors or inducers of cytochrome P-450 3A4 or p-glycoprotein are ineligible. Because this list of these agents are constantly changing, it is important to regularly consult a frequently-updated list. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product. Patient has severe renal insufficiency (CrCl <25 ml/min-as used in the AMPLIFY trial) Patient has hepatic disease (including Child-Pugh B and C) associated with coagulopathy or clinically relevant bleeding risk. Recent (previous seven days), or complicated lumbar puncture or epidural catheter placement or removal. Patient has high potential need to undergo a surgical or major invasive procedure in the near future. Patient has a history of uncorrected cerebral aneurysm, intracranial tumor or hemorrhagic cerebrovascular accident. Patient refuses to receive transfused blood products should this intervention become clinically indicated. Patient is taking or has been taking an investigational drug within the previous 30 days prior to enrollment. In the judgment of the investigator, any disease or circumstance that would interfere with the objectives of the study. Participants with known brain metastases. History of allergic reactions attributed to compounds of similar chemical or biologic composition to apixaban. Uncontrolled intercurrent illness. Pregnant women are excluded; breastfeeding should be discontinued if the mother is treated with apixaban. Prior treatment with a non-heparin anticoagulant while awaiting study enrollment is not an exclusion.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Apixaban for HIT<br>Patients with Heparin Induced Thrombocytopenia (HIT) will receive Apixaban, at an initial dose of 10 mg orally twice a day for 7 days followed by 5 mg twice a day for a total of 30 days. | Drug: Apixaban<br>* Apixaban is an anticoagulant that works by inhibiting the coagulation factor, Factor Xa.<br>|
| Experimental: Apixaban for HITT<br>Patients with Heparin Induced Thrombocytopenia with Thrombosis (HITT) will receive Apixaban, at an initial dose of 10 mg orally twice a day for 7 days followed by 5 mg twice a day for a total of 3 months. | Drug: Apixaban<br>* Apixaban is an anticoagulant that works by inhibiting the coagulation factor, Factor Xa.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative Incidence of New Symptomatic Thromboembolic Complications (TEC) Within 30 Days of the Initiation of Apixaban | New TEC | 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite Cumulative Incidence of All-cause Mortality, Limb Amputation and New TEC | Composite cumulative incidence | From the start of treatment until 30 days after the end of treatment, up to 60 days total for participants with HIT and up to 120 days total for participants with HITT | 
| Composite Cumulative Incidence of New TEC and Major Bleeding | Composite cumulative incidence | From the start of treatment until 30 days after the end of treatment, up to 60 days total for participants with HIT and up to 120 days total for participants with HITT | 
| Cumulative Incidence of Major Bleeding | Major Bleeding | From the start of treatment until 30 days after the end of treatment, up to 60 days total for participants with HIT and up to 120 days total for participants with HITT | 
| Time to Platelet Recovery | The time to platelet recovery serves as a surrogate index of the activity of apixaban. | From the start of treatment until time of platelet recovery, up to 60 days total for participants with HIT and up to 120 days total for participants with HITT | 
| Cumulative Incidence of All Cause Mortality | Death due to any cause during treatment or the follow-up period following treatment. | From the start of treatment until the time of death or until 30 days after the end of treatment, up to 60 days total for participants with HIT and up to 120 days total for participants with HITT | 
| Cumulative Incidence of Limb Amputation |  | From the start of treatment until 30 days after the end of treatment, up to 60 days total for participants with HIT and up to 120 days total for participants with HITT | 
| Cumulative Incidence of New Thromboembolic Complications (TEC) | New TEC during the study. | From the start of treatment until 30 days after the end of treatment, up to 60 days total for participants with HIT and up to 120 days total for participants with HITT | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Heparin-induced Thrombocytopenia