A Trial to Learn How Well REGN9933 Works for Preventing Blood Clots After Knee Replacement Surgery in Adult Participants

Study Overview
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Brief Summary
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The primary objective of the study is to evaluate the efficacy of REGN9933 for the prevention of venous thromboembolism (VTE) after unilateral total knee arthroplasty (TKA), compared to enoxaparin The secondary objectives of the study are: To evaluate the bleeding risk (ie, major and clinically relevant non-major [CRNM] bleeding) of REGN9933 after unilateral TKA through time of venography, compared to enoxaparin To assess overall safety and tolerability of REGN9933 in participants undergoing TKA To evaluate the efficacy of REGN9933 in prevention of clinically relevant VTE, compared to enoxaparin To evaluate the efficacy of REGN9933 in prevention of deep venous thrombosis (DVT) detected by venography, compared to enoxaparin To evaluate the pharmacokinetics (PK) of REGN9933 after single intravenous (IV) administration To assess pharmacodynamic (PD) effects of REGN9933 on intrinsic and extrinsic coagulation pathways To assess immunogenicity following a single dose of REGN9933 over time To compare the efficacy of enoxaparin and apixaban in prevention of VTE after unilateral TKA

Official Title
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A Phase 2, Multicenter, Randomized, Open-Label, Active-Control Study of REGN9933, a Factor XI Monoclonal Antibody, for Prevention of Venous Thromboembolism After Elective, Unilateral, Total Knee Arthroplasty

Conditions
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Venous Thromboembolism

Intervention / Treatment
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* Drug: REGN9933
* Drug: Enoxaparin
* Drug: Apixiban


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Undergoing elective unilateral TKA Has a body weight ≤130 kg at screening visit Is judged by the investigator to be in good health based on medical history, physical examination, vital sign measurements, and Electrocardiograms (ECG) performed at screening and/or prior to administration of initial dose of study drug Is in good health based on laboratory safety testing obtained during the screening period as described in the protocol Key Exclusion Criteria: History of bleeding in the past 6 months requiring hospitalization or transfusion; history of intracranial or intraocular bleeding, excessive operative or post-operative bleeding, and traumatic spinal or epidural anesthesia; history of bleeding diathesis. History of thromboembolic disease or thrombophilia History of major surgery, including brain, spinal, or ocular, within approximately the past 6 months. History of major trauma within approximately the past 6 months. Hospitalized (>24 hours) for any reason within 30 days of the screening visit Using the Modification of Diet in Renal Disease equation, has an estimated glomerular filtration rate as described in the protocol Note: Other protocol-defined Inclusion/ Exclusion Criteria apply

Ages Eligible for Study
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Minimum Age: 50 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: REGN9933<br>REGN9933 will be administered by intravenous (IV) infusion | Drug: REGN9933<br>* Participants will receive a single dose of REGN9933 by IV infusion<br>|
| Active Comparator: Enoxaparin<br>Enoxaparin will be administered by subcutaneous (SC) administration | Drug: Enoxaparin<br>* Participants will receive enoxaparin by SC administration daily through the time of venography (or day 12, whichever is earlier)<br>* Other names: Lovenox;|
| Active Comparator: Apixaban<br>Apixaban will be administered orally twice a day | Drug: Apixiban<br>* Participants will receive apixaban orally twice a day through the time of venography (or day 12, whichever is earlier)<br>* Other names: Eliquis;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of confirmed, adjudicated venous thromboembolism (VTE) | Asymptomatic deep DVT detected by unilateral venography of the operated leg; confirmed symptomatic DVT of either leg; confirmed fatal or nonfatal pulmonary embolism (PE) including unexplained death for which PE cannot be ruled out (REGN9933 vs enoxaparin) | Through Day 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of major bleeding | International Society on Thrombosis and Hemostasis (ISTH) criteria for Major Bleeding as described in the protocol | Up to approximately Day 12 | 
| Incidence of clinically relevant non-major (CRNM) bleeding | International Society on Thrombosis and Hemostasis (ISTH) criteria for Clinically Relevant Non-Major Bleeding as described in the protocol | Up to approximately Day 12 | 
| Incidence of treatment emergent adverse events (TEAEs) | A TEAE is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment | Through end of study; approximately Day 75 | 
| Incidence of major VTE | Major VTE is defined as: proximal DVT; confirmed symptomatic DVT of either leg; confirmed fatal or nonfatal PE including unexplained death for which PE cannot be ruled out | Through Day 12 | 
| Incidence of DVT | DVT will be measured by venography of the operated leg | Approximately Day 12 | 
| Concentrations of REGN9933 in serum | The concentrations of REGN9933 over time will be summarized by descriptive statistics by study arm for the overall population | Through end of study; approximately Day 75 | 
| Change in activated partial thromboplastin time (aPTT) | aPTT will be used to measure the anticipated anticoagulant effect of REGN9933 | Baseline to end of study; approximately Day 75 | 
| Change in prothrombin time (PT) | PT is a measure of extrinsic and/or common pathway function. | Baseline to end of study; approximately Day 75 | 
| Incidence of anti-drug antibodies (ADA) to REGN9933 | Immunogenicity will be characterized per drug molecule by ADA status | Through end of study; approximately Day 75 | 
| Titer of anti-drug antibodies to REGN9933 | Immunogenicity will be characterized per drug molecule by ADA status. | Through end of study; approximately Day 75 | 
| Incidence of confirmed, adjudicated VTE | Asymptomatic deep DVT detected by unilateral venography of the operated leg; confirmed symptomatic DVT of either leg; confirmed fatal or nonfatal pulmonary embolism (PE) including unexplained death for which PE cannot be ruled out (enoxaparin vs apixaban) | Baseline through Day 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anti-factor XI (FXI) monoclonal antibody, Deep Vein Thrombosis, Unilateral total knee arthroplasty (TKA),