Venous Thromboembolism
Conditions
Keywords
Anti-factor XI (FXI) monoclonal antibody, Deep Vein Thrombosis, Unilateral total knee arthroplasty (TKA),
Brief summary
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
Interventions
DRUGREGN9933
Participants will receive a single dose of REGN9933 by IV infusion
DRUGEnoxaparin
Participants will receive enoxaparin by SC administration daily through the time of venography (or day 12, whichever is earlier)
DRUGApixiban
Participants will receive apixaban orally twice a day through the time of venography (or day 12, whichever is earlier)
Sponsors
Regeneron Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Confirmed, Adjudicated Venous Thromboembolism (VTE) (REGN9933 vs Enoxaparin) | Through Day 12 | Composite endpoint that includes: asymptomatic deep DVT (deep venous thrombosis) 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With at Least One Treatment Emergent Adverse Event (TEAE) | Up to Day 75 | A TEAE is any untoward medical occurrence in a participant administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment. |
| Percentage of Participants With Major VTE (REGN9933 vs Enoxaparin) | Through Day 12 | Major VTE is a composite endpoint that includes: proximal DVT; confirmed symptomatic DVT of either leg; confirmed fatal or nonfatal PE including unexplained death for which PE cannot be ruled out |
| Percentage of Participants With DVT (REGN9933 vs Enoxaparin) | Through Day 12 | DVT measured by venography of the operated leg |
| Total REGN9933 Concentrations in Serum | Days 0.0625 (post-dose), 4, 9, 29, and 74 | The concentrations of REGN9933 over time were summarized by descriptive statistics by study arm for the overall population |
| Number of Participants With Major Bleeding and Clinically Relevant Non-major (CRNM) Bleeding | Through Day 12 | International Society on Thrombosis and Hemostasis (ISTH) criteria for Major Bleeding and CRNM Bleeding as described in the protocol |
| Fold Change From Baseline in Prothrombin Time (PT) | Days 1, 5, 10, 30, and 75 | PT is a measure of extrinsic and/or common pathway function. Fold change is based on the follow-up value/baseline value within an arm. |
| Number of Participants With Anti-REGN9933 Antibodies by Status | Through Day 75 | Immunogenicity characterized by anti-drug antibody (ADA) status |
| Number of Participants With Treatment-Emergent or Treatment-Boosted Anti-REGN13335 Antibodies by Maximum Titer Level | Through Day 75 | Immunogenicity characterized per drug molecule by ADA status |
| Percentage of Participants With Confirmed, Adjudicated VTE (Enoxaparin vs Apixaban) | Through Day 12 | 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. |
| Fold Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Days 1, 5, 10, 30, and 75 | aPTT was used to measure the anticipated anticoagulant effect of REGN9933. Fold change is based on the follow-up value/baseline value within an arm. |
Countries
Belgium, Bulgaria, Canada, Hungary, Latvia, Lithuania, Poland
Participant flow
Pre-assignment details
A total of 450 participants were screened for study eligibility, and 77 participants discontinued during the screening period. 373 participants met eligibility criteria and were randomized into 1 of 3 treatment groups.
Participants by arm
| Arm | Count |
|---|---|
| REGN9933 REGN9933 was administered by intravenous (IV) infusion | 123 |
| Enoxaparin Enoxaparin was administered by subcutaneous (SC) administration | 125 |
| Apixaban Apixaban was administered orally twice a day | 125 |
| Total | 373 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 3 | 1 | 3 |
Baseline characteristics
| Characteristic | REGN9933 | Enoxaparin | Apixaban | Total |
|---|---|---|---|---|
| Age, Continuous | 66.5 Years STANDARD_DEVIATION 7.73 | 66.6 Years STANDARD_DEVIATION 7.61 | 66.5 Years STANDARD_DEVIATION 7.69 | 66.5 Years STANDARD_DEVIATION 7.66 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 2 Participants | 4 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 120 Participants | 121 Participants | 121 Participants | 362 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 123 Participants | 125 Participants | 125 Participants | 373 Participants |
| Sex: Female, Male Female | 95 Participants | 104 Participants | 89 Participants | 288 Participants |
| Sex: Female, Male Male | 28 Participants | 21 Participants | 36 Participants | 85 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 123 | 0 / 125 | 0 / 125 |
| other Total, other adverse events | 9 / 123 | 11 / 125 | 16 / 125 |
| serious Total, serious adverse events | 4 / 123 | 1 / 125 | 2 / 125 |
Outcome results
Primary
Percentage of Participants With Confirmed, Adjudicated Venous Thromboembolism (VTE) (REGN9933 vs Enoxaparin)
Composite endpoint that includes: asymptomatic deep DVT (deep venous thrombosis) 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
Time frame: Through Day 12
Population: Randomized participants in the REGN9933 and enoxaparin arms that had either an evaluable venogram, a confirmed episode of venous thromboembolism, or both.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| REGN9933 | Percentage of Participants With Confirmed, Adjudicated Venous Thromboembolism (VTE) (REGN9933 vs Enoxaparin) | 17.2 percentage of participants |
| Enoxaparin | Percentage of Participants With Confirmed, Adjudicated Venous Thromboembolism (VTE) (REGN9933 vs Enoxaparin) | 22.2 percentage of participants |
90% CI: [0.47, 1.32]
Secondary
Fold Change From Baseline in Activated Partial Thromboplastin Time (aPTT)
aPTT was used to measure the anticipated anticoagulant effect of REGN9933. Fold change is based on the follow-up value/baseline value within an arm.
Time frame: Days 1, 5, 10, 30, and 75
Population: All randomized participants who received any study drug and who had at least 1 non-missing pharmacodynamic (PD) result following the first dose of study drug and who were evaluable at time points specified for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| REGN9933 | Fold Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Day 5 | 2.26 Fold Change | Standard Deviation 0.309 |
| REGN9933 | Fold Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Day 75 | 1.01 Fold Change | Standard Deviation 0.132 |
| REGN9933 | Fold Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Day 1 | 1.84 Fold Change | Standard Deviation 0.245 |
| REGN9933 | Fold Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Day 10 | 2.17 Fold Change | Standard Deviation 0.443 |
| REGN9933 | Fold Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Day 30 | 1.56 Fold Change | Standard Deviation 0.385 |
| Enoxaparin | Fold Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Day 10 | 1.04 Fold Change | Standard Deviation 0.114 |
| Enoxaparin | Fold Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Day 75 | 1.01 Fold Change | Standard Deviation 0.119 |
| Enoxaparin | Fold Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Day 5 | 1.11 Fold Change | Standard Deviation 0.143 |
| Enoxaparin | Fold Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Day 30 | 1.01 Fold Change | Standard Deviation 0.149 |
| Apixaban | Fold Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Day 75 | 1.03 Fold Change | Standard Deviation 0.12 |
| Apixaban | Fold Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Day 5 | 1.16 Fold Change | Standard Deviation 0.163 |
| Apixaban | Fold Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Day 10 | 1.10 Fold Change | Standard Deviation 0.117 |
| Apixaban | Fold Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Day 30 | 1.04 Fold Change | Standard Deviation 0.129 |
Secondary
Fold Change From Baseline in Prothrombin Time (PT)
PT is a measure of extrinsic and/or common pathway function. Fold change is based on the follow-up value/baseline value within an arm.
Time frame: Days 1, 5, 10, 30, and 75
Population: All randomized participants who received any study drug and who had at least 1 non-missing pharmacodynamic (PD) result following the first dose of study drug and who were evaluable at time points specified for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| REGN9933 | Fold Change From Baseline in Prothrombin Time (PT) | Day 5 | 0.96 Fold Change | Standard Deviation 0.086 |
| REGN9933 | Fold Change From Baseline in Prothrombin Time (PT) | Day 75 | 0.94 Fold Change | Standard Deviation 0.145 |
| REGN9933 | Fold Change From Baseline in Prothrombin Time (PT) | Day 1 | 1.01 Fold Change | Standard Deviation 0.075 |
| REGN9933 | Fold Change From Baseline in Prothrombin Time (PT) | Day 10 | 0.95 Fold Change | Standard Deviation 0.108 |
| REGN9933 | Fold Change From Baseline in Prothrombin Time (PT) | Day 30 | 0.99 Fold Change | Standard Deviation 0.22 |
| Enoxaparin | Fold Change From Baseline in Prothrombin Time (PT) | Day 10 | 0.94 Fold Change | Standard Deviation 0.073 |
| Enoxaparin | Fold Change From Baseline in Prothrombin Time (PT) | Day 75 | 0.93 Fold Change | Standard Deviation 0.092 |
| Enoxaparin | Fold Change From Baseline in Prothrombin Time (PT) | Day 5 | 0.94 Fold Change | Standard Deviation 0.064 |
| Enoxaparin | Fold Change From Baseline in Prothrombin Time (PT) | Day 30 | 0.97 Fold Change | Standard Deviation 0.122 |
| Apixaban | Fold Change From Baseline in Prothrombin Time (PT) | Day 75 | 0.94 Fold Change | Standard Deviation 0.073 |
| Apixaban | Fold Change From Baseline in Prothrombin Time (PT) | Day 5 | 1.02 Fold Change | Standard Deviation 0.091 |
| Apixaban | Fold Change From Baseline in Prothrombin Time (PT) | Day 10 | 1.00 Fold Change | Standard Deviation 0.089 |
| Apixaban | Fold Change From Baseline in Prothrombin Time (PT) | Day 30 | 0.99 Fold Change | Standard Deviation 0.183 |
Secondary
Number of Participants With Anti-REGN9933 Antibodies by Status
Immunogenicity characterized by anti-drug antibody (ADA) status
Time frame: Through Day 75
Population: All participants who received study drug REGN9933 and had at least 1 non-missing ADA result following the first dose of study drug
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| REGN9933 | Number of Participants With Anti-REGN9933 Antibodies by Status | Negative | 118 Participants |
| REGN9933 | Number of Participants With Anti-REGN9933 Antibodies by Status | Pre-existing Immunoreactivity | 1 Participants |
| REGN9933 | Number of Participants With Anti-REGN9933 Antibodies by Status | Treatment-emergent (TE) Response | 0 Participants |
| REGN9933 | Number of Participants With Anti-REGN9933 Antibodies by Status | Treatment-boosted (TB) Response | 0 Participants |
Secondary
Number of Participants With Major Bleeding and Clinically Relevant Non-major (CRNM) Bleeding
International Society on Thrombosis and Hemostasis (ISTH) criteria for Major Bleeding and CRNM Bleeding as described in the protocol
Time frame: Through Day 12
Population: Randomized participants that had either an evaluable venogram, a confirmed episode of venous thromboembolism, or both.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| REGN9933 | Number of Participants With Major Bleeding and Clinically Relevant Non-major (CRNM) Bleeding | 0 Participants |
| Enoxaparin | Number of Participants With Major Bleeding and Clinically Relevant Non-major (CRNM) Bleeding | 0 Participants |
| Apixaban | Number of Participants With Major Bleeding and Clinically Relevant Non-major (CRNM) Bleeding | 0 Participants |
Secondary
Number of Participants With Treatment-Emergent or Treatment-Boosted Anti-REGN13335 Antibodies by Maximum Titer Level
Immunogenicity characterized per drug molecule by ADA status
Time frame: Through Day 75
Population: All participants who received study drug REGN9933 and had at least 1 non-missing ADA result following the first dose of study drug
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| REGN9933 | Number of Participants With Treatment-Emergent or Treatment-Boosted Anti-REGN13335 Antibodies by Maximum Titer Level | Low (<1,000) | 0 Participants |
| REGN9933 | Number of Participants With Treatment-Emergent or Treatment-Boosted Anti-REGN13335 Antibodies by Maximum Titer Level | Moderate (1,000 to 10,000) | 0 Participants |
| REGN9933 | Number of Participants With Treatment-Emergent or Treatment-Boosted Anti-REGN13335 Antibodies by Maximum Titer Level | High (>10,000) | 0 Participants |
Secondary
Percentage of Participants With at Least One Treatment Emergent Adverse Event (TEAE)
A TEAE is any untoward medical occurrence in a participant administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment.
Time frame: Up to Day 75
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| REGN9933 | Percentage of Participants With at Least One Treatment Emergent Adverse Event (TEAE) | 22.0 percentage of participants |
| Enoxaparin | Percentage of Participants With at Least One Treatment Emergent Adverse Event (TEAE) | 20.8 percentage of participants |
| Apixaban | Percentage of Participants With at Least One Treatment Emergent Adverse Event (TEAE) | 24.8 percentage of participants |
Secondary
Percentage of Participants With Confirmed, Adjudicated VTE (Enoxaparin vs Apixaban)
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.
Time frame: Through Day 12
Population: Randomized participants in the enoxaparin and apixaban arms that had either an evaluable venogram, a confirmed episode of venous thromboembolism, or both.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| REGN9933 | Percentage of Participants With Confirmed, Adjudicated VTE (Enoxaparin vs Apixaban) | 22.2 percentage of participants |
| Enoxaparin | Percentage of Participants With Confirmed, Adjudicated VTE (Enoxaparin vs Apixaban) | 12.4 percentage of participants |
90% CI: [0.32, 0.95]
Secondary
Percentage of Participants With DVT (REGN9933 vs Enoxaparin)
DVT measured by venography of the operated leg
Time frame: Through Day 12
Population: Randomized participants in the REGN9933 and enoxaparin arms that had either an evaluable venogram, a confirmed episode of venous thromboembolism, or both.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| REGN9933 | Percentage of Participants With DVT (REGN9933 vs Enoxaparin) | 17.2 percentage of participants |
| Enoxaparin | Percentage of Participants With DVT (REGN9933 vs Enoxaparin) | 22.2 percentage of participants |
90% CI: [0.47, 1.32]
Secondary
Percentage of Participants With Major VTE (REGN9933 vs Enoxaparin)
Major VTE is a composite endpoint that includes: proximal DVT; confirmed symptomatic DVT of either leg; confirmed fatal or nonfatal PE including unexplained death for which PE cannot be ruled out
Time frame: Through Day 12
Population: Randomized participants in the REGN9933 and enoxaparin arms that had either an evaluable venogram, a confirmed episode of venous thromboembolism, or both.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| REGN9933 | Percentage of Participants With Major VTE (REGN9933 vs Enoxaparin) | 0 percentage of participants |
| Enoxaparin | Percentage of Participants With Major VTE (REGN9933 vs Enoxaparin) | 2.6 percentage of participants |
90% CI: [0.16, 1.61]
Secondary
Total REGN9933 Concentrations in Serum
The concentrations of REGN9933 over time were summarized by descriptive statistics by study arm for the overall population
Time frame: Days 0.0625 (post-dose), 4, 9, 29, and 74
Population: All participants in the REGN9933 treatment group who received study drug and who had at least 1 non-missing result following the first dose of study drug and who were evaluable at time points specified for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| REGN9933 | Total REGN9933 Concentrations in Serum | Day 0.0625 (post-dose) | 65.6 milligrams/Liter (mg/L) | Standard Deviation 18.2 |
| REGN9933 | Total REGN9933 Concentrations in Serum | Day 4 | 34.9 milligrams/Liter (mg/L) | Standard Deviation 9.65 |
| REGN9933 | Total REGN9933 Concentrations in Serum | Day 9 | 23.7 milligrams/Liter (mg/L) | Standard Deviation 7.15 |
| REGN9933 | Total REGN9933 Concentrations in Serum | Day 29 | 5.51 milligrams/Liter (mg/L) | Standard Deviation 3.47 |
| REGN9933 | Total REGN9933 Concentrations in Serum | Day 74 | 0.140 milligrams/Liter (mg/L) | Standard Deviation 0.107 |