The purpose of this study is to characterize andexanet posology and interaction between andexanet and enoxaparin post infusion in healthy participants.
This is a single-blind, placebo-controlled study. The study has 4 modules, which is then divided into 2 parts. Part A of the study will focus on further characterization of andexanet posology and Part B of the study will evaluate a re-institution of anticoagulation with enoxaparin. Module 1, 2 and 4 - rivaroxaban, apixaban and enoxaparin: These modules are designed to determine the pharmacodynamic (PD) effect of andexanet by assessing its reversal effects on rivaroxaban and apixaban anticoagulation, or assessing its effects in the absence of anticoagulants, and to identify the time interval after andexanet administration at which andexanet shows no impact on enoxaparin. Module 3 - rivaroxaban and apixaban: This Module is designed to determine the PD effect of bolus only andexanet by assessing its reversal effect on rivaroxaban and apixaban anticoagulation. All the Modules will comprise: * A Screening/Enrollment Period of maximum 28 days. * An in-house stay comprising of a safety baseline lab period (Day -3 to Day -1) * Treatment period (Day 1 to Day 2) * Safety follow-up period (Day 3 to Day 5) * A final Follow-up Visit within 30 days (+7 days) after the last andexanet/placebo administration.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
186
Andexanet alfa will be administered as an intravenous bolus followed by an infusion, however, in Module 3, only a bolus will be given.
Rivaroxaban will be administered as an oral tablet.
Apixaban will be administered as an oral tablet.
Research Site
Berlin, Germany
RECRUITINGResearch Site
Harrow, United Kingdom
RECRUITINGAnti-Factor (F) Xa activity
To determine the pharmacodynamic (PD) effect of andexanet doses by assessing reversal of rivaroxaban or apixaban anticoagulation measured by chromogenic enzymatic anti-FXa activity assays.
Time frame: Day 1 post dose
Change from baseline in anti-FXa activity
To determine the PD effect of andexanet doses by assessing reversal of rivaroxaban or apixaban anticoagulation measured by chromogenic enzymatic anti-FXa activity assays.
Time frame: Day 1 post dose
Thrombin generation potential
To determine the PD effect of andexanet doses by assessing reversal of rivaroxaban or apixaban anticoagulation measured as thrombin generation potential (including Endogenous Thrombin Potential \[ETP\]).
Time frame: Day 1 post dose
Change from pre-direct oral anticoagulants (DOAC) in thrombin generation potential
To determine the PD effect of andexanet doses by assessing reversal of rivaroxaban or apixaban anticoagulation measured as thrombin generation potential (including ETP).
Time frame: Day 1 post dose
Change from baseline in thrombin generation potential
To determine the PD effect of andexanet doses by assessing reversal of rivaroxaban or apixaban anticoagulation measured as thrombin generation potential (including ETP).
Time frame: Day 1 post dose
Time to onset of coagulation
To determine the PD effect of andexanet doses by assessing reversal of rivaroxaban or apixaban anticoagulation measured as time to onset of coagulation.
Time frame: Day 1 post dose
Change from pre-DOAC in time to onset of coagulation
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Enoxaparin will be administered as a subcutaneous injection.
Placebo will replace andexanet and be given as an IV bolus plus infusion in Modules 1 and 2; in Module 3, placebo will be IV bolus only. In Module 4, an oral placebo tablet will replace rivaroxaban and apixaban.
To determine the PD effect of andexanet doses by assessing reversal of rivaroxaban or apixaban anticoagulation measured as time to onset of coagulation.
Time frame: Day 1 post dose
Change from baseline in time to onset of coagulation
To determine the PD effect of andexanet doses by assessing reversal of rivaroxaban or apixaban anticoagulation measured as time to onset of coagulation.
Time frame: Day 1 post dose
Anti-FXa activity following enoxaparin dosing
To determine anticoagulation by enoxaparin at different time points after andexanet treatment measured by chromogenic enzymatic anti-FXa activity assays.
Time frame: From Day 1 to Day 2
Thrombin generation potential following enoxaparin dosing
To determine anticoagulation by enoxaparin at different time points after andexanet treatment measured as thrombin generation potential (including ETP).
Time frame: From Day 1 to Day 2
Module 3: Anti-FXa activity
To describe the PD effect of andexanet bolus by assessing reversal of rivaroxaban or apixaban anticoagulation, as measured by chromogenic enzymatic anti-FXa activity assays.
Time frame: Day 1 post dose
Module 3: Change from baseline in anti-FXa activity
To describe the PD effect of andexanet bolus by assessing reversal of rivaroxaban or apixaban anticoagulation, as measured by chromogenic enzymatic anti-FXa activity assays.
Time frame: Day 1 post dose
Module 3: Thrombin generation potential
To describe the PD effect of andexanet bolus by assessing reversal of rivaroxaban or apixaban anticoagulation, as measured by thrombin generation potential (including ETP).
Time frame: Day 1 post dose
Module 3: Change from baseline in thrombin generation potential
To describe the PD effect of andexanet bolus by assessing reversal of rivaroxaban or apixaban anticoagulation, as measured by thrombin generation potential (including ETP).
Time frame: Day 1 post dose
Module 3: Change from pre-DOAC in thrombin generation potential
To describe the PD effect of andexanet bolus by assessing reversal of rivaroxaban or apixaban anticoagulation, as measured by thrombin generation potential (including ETP).
Time frame: Day 1 post dose
Module 3: Time to onset of coagulation
To describe the PD effect of andexanet bolus by assessing reversal of rivaroxaban or apixaban anticoagulation, as measured by time to onset of coagulation.
Time frame: Day 1 post dose
Module 3: Change from pre-DOAC in time to onset of coagulation
To describe the PD effect of andexanet bolus by assessing reversal of rivaroxaban or apixaban anticoagulation, as measured by time to onset of coagulation.
Time frame: Day 1 post dose
Module 3: Change from baseline in time to onset of coagulation
To describe the PD effect of andexanet bolus by assessing reversal of rivaroxaban or apixaban anticoagulation, as measured by time to onset of coagulation.
Time frame: Day 1 post dose
Tissue factor pathway inhibitor (TFPI) activity
To describe additional PD effects of andexanet doses by assessing reversal of rivaroxaban or apixaban anticoagulation on levels of TFPI activity measured by enzymatic TFPI activity assay.
Time frame: Up to Day 4
Antithrombin 3 (AT3)
To describe additional PD effects of andexanet doses by assessing reversal of rivaroxaban or apixaban anticoagulation on levels of AT3 measured by an AT3 enzyme-linked immunosorbent assay (ELISA).
Time frame: Up to Day 4
Thrombinantithrombin complex (TAT)
To describe additional PD effects of andexanet doses by assessing reversal of rivaroxaban or apixaban anticoagulation on levels of TAT.
Time frame: Up to Day 4
Fibrin degradation fragment (D-dimer)
To describe additional PD effects of andexanet doses by assessing reversal of rivaroxaban or apixaban anticoagulation on levels of D-dimer.
Time frame: Up to Day 4
Prothrombin fragment 1+2 (F1+2)
To describe additional PD effects of andexanet doses by assessing reversal of rivaroxaban or apixaban anticoagulation on levels of F1+2.
Time frame: Up to Day 4