A Phase 2 Study of VLX-1005 Versus Placebo in Suspected Heparin Induced Thrombocytopenia

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy and safety of VLX-1005, a 12-lipoxygenase (12-LOX) enzyme inhibitor in treating heparin induced thrombocytopenia (HIT). Participants with suspected HIT will receive the usual standard of care, and will be assigned randomly to either VLX-1005 or placebo treatment. The study will measure important outcomes including platelet count, stroke, pulmonary embolus (clot to the lungs) and bleeding.

Detailed Description
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Over 12 million patients are treated with heparin each year in the United States. Heparin induced thrombocytopenia (HIT) is a recognized complication of heparin therapy and is characterized by the formation of antibodies to heparin and platelet factor 4 (PF4). The scale of the clinical problem is illustrated by cardiopulmonary bypass patients, half of whom develop antibodies to PF4/heparin complexes. In a significant proportion of such seropositive HIT patients, these antibodies will bind to and activate platelets, resulting in a drop in the number of platelets (thrombocytopenia) and activation of the coagulation (clotting) system. Formation of clots in this manner can lead to stroke, heart attacks, damage to internal organs or to limbs, and even death. The current standard of care with anticoagulants such as argatroban or bivalirudin have not proven effective in reducing poor outcomes in HIT: major morbidity and death rates remain high (> 20%). In addition, these anticoagulants increase the risk of major bleeding ( 20%) which can prove to be a fatal complication of such therapy. VLX-1005 has been developed to address the major unmet clinical need for safer, more effective therapy for HIT. VLX-1005 is a drug that blocks the 12-lipoxygenase (12-LOX) pathway that is believed to be responsible for platelet activation in HIT. In animal models of HIT, VLX-1005 can prevent or treat HIT and halt the development of both thrombocytopenia and abnormal blood clots. The drug has not been associated with increased bleeding in either animals or healthy human volunteers. The current study will enroll patients suspected of having HIT by clinical measures (4T score) and by laboratory testing (heparin-PF4 immunoassay). Patients will be randomly assigned in a double-blind fashion to either VLX-1005 intravenously or placebo. All patients will receive current guideline mandated therapy for HIT that will include the standard of care anticoagulation: either argatroban or bivalirudin. Patients will be treated for 7 to 14 days until the platelet count has recovered into the normal range. The study will measure important outcomes including platelet count recovery time, stroke, pulmonary embolus, deep vein thrombosis, myocardial infarction, limb and organ injury, and major bleeding.

Official Title
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A Randomized, Double-Blind, Phase 2 Pilot Study of VLX-1005 Versus Placebo in Participants With Suspected Heparin Induced Thrombocytopenia Treated With Background Standard of Care

Conditions
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Thrombocytopenia, Immune, Heparin Induced Thrombocytopenia

Intervention / Treatment
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* Drug: VLX-1005
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult participants ≥ 18 years of age. Able to provide informed consent or have informed consent provided on their behalf by a primary caregiver prior to study-related activities being initiated. Recent unfractionated heparin or low-molecular-weight heparin exposure. Qualifying platelet count < 150 X 10^9/L and clinical 4T score of ≥ 4; candidate for argatroban or bivalirudin treatment. Positive PF4-immunoassay (eg, ELISA [≥ 1.0 optical density units], LIA [≥ 1.0 U/mL], CLIA [≥ 1.0 U/mL]). - Exclusion Criteria: Previous treatment with argatroban or bivalirudin for > 48 hr prior to randomization. Participants cannot receive other anti-coagulants, such as fondaparinux and danaparoid, or direct oral anti-coagulants, such as rivaroxaban as initial standard of care. QT interval corrected by the method of Fridericia (QTcF) > 450 msec for males, > 470 msec for females. History of hepatitis C antibody, hepatitis B surface antigen, or human immunodeficiency virus (HIV) antibody at screening. Current renal disease with a calculated creatinine clearance less than 30 mL/min. Participants with a history of substance abuse or dependency or history of recreational IV drug use (by self-declaration). Participant has a suspected history of alcohol abuse in the 6 months prior to screening. Participants who are unlikely to comply with the study protocol or, in the opinion of the investigator, would not be a suitable candidate for participation in the study. Participants with cancer, having a life expectancy of < 12 months. Current diagnosis of or any other clinically significant indication of active sepsis Pregnant or lactating women. Have participated in any other investigational drug trial within 30 days of dosing or 5 half-lives (whichever is longer) in the current study. -

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: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: VLX-1005<br>VLX-1005 200 mg given every 12 hours by intravenous infusion over 1 hour. | Drug: VLX-1005<br>* VLX-1005, a 12-LOX enzyme inhibitor<br>* Other names: 12-LOX enzyme inhibitor;|
| Placebo Comparator: Placebo<br>Placebo given every 12 hours by intravenous infusion over 1 hour. | Drug: Placebo<br>* Placebo matching VLX-1005<br>* Other names: Inactive substance similar in appearance to VLX-1005;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to recovery of platelet count to ≥ 150 X 10^9/L in patients with a positive serotonin release assay | Time to platelet count recovery; defined as the time from the first dose of study drug to the time of the first of 2 consecutive platelet count recoveries to ≥ 150 X 10^9/L in patients with positive serotonin release assay (SRA+) confirmed HIT. | Up to 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite of death, amputation, new thrombosis, stroke, systemic embolism, myocardial infarction, deep vein thrombosis or pulmonary embolism, skin necrosis, limb gangrene, organ ischemia or infarction | Proportion of participants with incidence of the composite of death, amputation, new thrombosis, stroke, systemic embolism, myocardial infarction, deep vein thrombosis or pulmonary embolism, skin necrosis, limb gangrene, organ ischemia or infarction | Up to14 days | 
| Incidence of death, amputation, new thrombosis, stroke, systemic embolism, myocardial infarction, deep vein thrombosis or pulmonary embolism, organ ischemia or infarction | Time from study drug initiation to any incidence of the composite of death, amputation, new thrombosis, stroke, systemic embolism, myocardial infarction, deep vein thrombosis or pulmonary embolism, skin necrosis, limb gangrene, organ ischemia or infarction | Up to14 days | 
| Time from the first dose of study drug to change to oral anti-coagulant treatment | Time from initiation of therapy to switching to oral treatment | Up to14 days | 
| Time from study drug initiation to each element of the composite as a separate endpoint: death, amputation, new thrombosis, stroke, systemic embolism, myocardial infarction, deep vein thrombosis or pulmonary embolism, organ ischemia or infarction | Measurement of important clinical outcomes by time to event | Up to14 days | 
| Proportion of participants with any element of the composite as a separate endpoint: death, amputation, new thrombosis, stroke, systemic embolism, myocardial infarction, deep vein thrombosis or pulmonary embolism, organ ischemia or infarction | Measurement of proportion of participants with important clinical outcomes | Up to14 days | 
| Time from study drug initiation to occurrence of any incidence of International Society on Thrombosis and Haemostasis (ISTH) major bleeding | Incidence of major bleeding by time to event | Up to14 days | 
| Proportion of participants with incidence of major bleeding as defined by ISTH criteria | Measurement of proportion of participants who develop major bleeding | Up to14 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Heparin, Thrombocytopenia, Platelets