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

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

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

Study Overview

• Status: Active, not recruiting
• Conditions: Venous Thromboembolism
• Intervention / Treatment: Drug: REGN9933; Drug: Enoxaparin; Drug: Apixiban

• Study Type: Interventional
• Enrollment (Actual): 373
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Limburg
    • Genk, Limburg, Belgium, 3600
      • Ziekenhuis Oost-Limburg- Campus Sint-Jan
• Bulgaria
  • Pleven, Bulgaria, 5800
    • MBAL Heart and Brain Hospital
• Canada
  • Ontario
    • Ajax, Ontario, Canada, L1S 7K7
      • Durham Bone and Joint Specialists
• Hungary
  • Kaposvar, Hungary, 7400
    • Department of Orthopedics, Somogy County Mór Kaposi Teaching Hospital
  • Jász-Nagykun-Szolnok
    • Szolnok, Jász-Nagykun-Szolnok, Hungary, 5000
      • MÁV Kórház és Rendelointézet Szolnok
• Latvia
  • Liepaja, Latvia, LV3414
    • Liepaja Regional Hospital
  • Riga, Latvia, LV-1004
    • Riga's 2nd Hospital
  • Riga, Latvia, LV-1002
    • Vidzemes Hospital
  • Riga, Latvia, LV1005
    • Hospital of Traumatology and Orthopaedics
• Lithuania
  • Kaunas, Lithuania, LT-44320
    • Lietuvos Sveikatos Mokslu Universiteto Kauno Ligoninė
  • Kauno Apskritis
    • Kaunas, Kauno Apskritis, Lithuania, LT-50009
      • Lietuvos sveikatos mokslų universiteto ligoninė Kauno klinik
  • Klaipedos Apskritis
    • Klaipeda, Klaipedos Apskritis, Lithuania, LT-92288
      • Klaipeda university hospital
• Poland
  • Lodz, Poland, 90-153
    • SP ZOZ Centralny Szpital Kliniczny UM w Lodzi
  • Lublin, Poland, 20-954
    • Samodzielny Publiczny Szpital Kliniczny nr 4 w Lublinie
  • Radzyn Podlaski, Poland, 21-300
    • Samodzielny Publiczny Zaklad Opieki Zdrowotnej w Radzyniu Podlaskim
  • Malopolskie
    • Tarnow, Malopolskie, Poland, 33-100
      • Specjalistyczny Szpital im. E. Szczeklika w Tarnowie

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

1. Undergoing elective unilateral TKA
2. Has a body weight ≤130 kg at screening visit
3. 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
4. Is in good health based on laboratory safety testing obtained during the screening period as described in the protocol

Key Exclusion Criteria:

1. 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.
2. History of thromboembolic disease or thrombophilia
3. History of major surgery, including brain, spinal, or ocular, within approximately the past 6 months.
4. History of major trauma within approximately the past 6 months.
5. Hospitalized (>24 hours) for any reason within 30 days of the screening visit
6. 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Regeneron Pharmaceuticals
• Investigators: Study Director: Clinical Trial Management, Regeneron Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): May 24, 2023
• Primary Completion (Estimated): May 29, 2024
• Study Completion (Estimated): May 29, 2024

Study Registration Dates

• First Submitted: November 8, 2022
• First Submitted That Met QC Criteria: November 8, 2022
• First Posted (Actual): November 16, 2022

Study Record Updates

• Last Update Posted (Actual): April 8, 2024
• Last Update Submitted That Met QC Criteria: April 5, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Deep Vein Thrombosis; Anti-factor XI (FXI) monoclonal antibody; Unilateral total knee arthroplasty (TKA),
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Embolism and Thrombosis; Thromboembolism; Venous Thromboembolism; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Anticoagulants; Enoxaparin
• Other Study ID Numbers: R9933-DVT-2230; 2022-501470-18-00 (Other Identifier: EU CT)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All Individual Patient Data (IPD) that underlie publicly available results will be considered for sharing
• IPD Sharing Time Frame: When Regeneron has received marketing authorization from major health authorities (e.g., FDA, European Medicines Agency (EMA), Pharmaceuticals and Medical Devices Agency (PMDA), etc.) for the product and indication, has made the study results publicly available (e.g., scientific publication, scientific conference, clinical trial registry), has the legal authority to share the data, and has ensured the ability to protect participant privacy.
• IPD Sharing Access Criteria: Qualified researchers can submit a proposal for access to individual patient or aggregate level data from a Regeneron-sponsored clinical trial through Vivli. Regeneron's Independent Research Request Evaluation Criteria can be found at: https://www.regeneron.com/sites/default/files/Regeneron-External-Data-Sharing-Policy-and-Independent-Research-Request-Evaluation-Criteria.pdf
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No