This is a randomized, double-blind, study in healthy volunteers dosed to steady state with fXa inhibitors, designed to (1) demonstrate PK/PD comparability between andexanet manufactured by the Generation 1 and Generation 2 processes, (2) evaluate the degree to which the Generation 2 andexanet reverses fXa-inhibitor-induced anticoagulation in comparison to placebo, and (3) evaluate safety of Generation 2 andexanet.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
153
factor Xa inhibitor antidote
factor Xa inhibitor
factor Xa inhibitor
West Coast Clinical Trials
Cypress, California, United States
Pharmacokinetics
To evaluate the pharmacokinetics of Generation 2 process andexanet, as measured by AUC(0-∞)
Time frame: Day 1 through Day 7
Reversal
To evaluate reversal of fXa-inhibitor-mediated anticoagulation, as measured by anti-fXa activity
Time frame: Day 1 through Day 7
Safety will be evaluated by assessment of adverse events, venous thromboembolic events, physical exam findings, vital signs, oxygen saturation, fecal occult blood testing, and 12-lead ECGs.
Non-laboratory-based Endpoints
Time frame: Day 1 through Day 32
Safety will be evaluated by analyzing the following: • Hematology, chemistry & urinalysis.
Laboratory-based Endpoints
Time frame: Day 1 through Day 32
Safety will be evaluated by analyzing the following: • Antibodies to andexanet, fX, & fXa, and neutralizing antibodies
Laboratory-based Endpoints
Time frame: Day 1 through Day 32
Safety will be evaluated by analyzing the following: • TFPI, D-dimer, F1+2, thrombin-antithrombin III, and Russell's viper venom time
Laboratory-based Endpoints
Time frame: Day 1 through Day 32
Safety will be evaluated by analyzing the following: fX, fibrinogen, tissue-type plasminogen activator, plasmin-alpha2-antiplasmin complexes, thrombin activatable fibrinolysis inhibitor, beta-thromboglobulin, platelet factor 4 & soluble thrombomodulin
Laboratory-based Endpoints
Time frame: Day 1 through Day 32
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low molecular weight heparin
factor Xa inhibitor
factor Xa inhibitor antidote
factor Xa inhibitor antidote
factor Xa inhibitor
factor Xa inhibitor
To evaluate the pharmacokinetics of Generation 2 process andexanet, as measured by the following PK parameter: Total area under the plasma concentration-time curve from time 0 to infinity (AUC(0 ∞)
Pharmacokinetics
Time frame: Day 1 through Day 7
Reversal
To evaluate reversal of fXa-inhibitor-mediated anticoagulation, as measured by free fraction of the fXa inhibitor
Time frame: Day 1 through Day 7
Reversal
To evaluate reversal of fXa-inhibitor-mediated anticoagulation, as measured by restoration of thrombin generation
Time frame: Day 1 through Day 7
To evaluate the pharmacokinetics of Generation 2 process andexanet, as measured by the following PK parameter: Cmax - Maximum Observed Concentration
Pharmacokinetics
Time frame: Day 1 through Day 7
To evaluate the pharmacokinetics of Generation 2 process andexanet, as measured by the following PK parameter: Tmax - Time to maximum observed plasma concentration (Tmax)
Pharmacokinetics
Time frame: Day 1 through Day 7
To evaluate pharmacokinetics of Generation 2 process andexanet as measured by following PK parameter: t1/2 - Plasma t½, determined by linear regression of the log concentration on the distribution & terminal portion of the plasma concentration-time curve
Pharmacokinetics
Time frame: Day 1 through Day 7
To evaluate the pharmacokinetics of Generation 2 process andexanet, as measured by the following PK parameter: CL - Clearance
Pharmacokinetics
Time frame: Day 1 through Day 7
To evaluate the pharmacokinetics of Generation 2 process andexanet, as measured by the following PK parameter: Vss - Volume of distribution at steady state (Vss)
Pharmacokinetics
Time frame: Day 1 through Day 7
To evaluate the pharmacokinetics of Generation 2 process andexanet, as measured by the following PK parameter: lamda z - The terminal or elimination rate constant (lamda z)
Pharmacokinetics
Time frame: Day 1 through Day 7