Phase 2 Healthy Volunteer Study to Evaluate the Ability of PRT064445 to Reverse the Effects of Several Blood Thinner Drugs on Laboratory Tests (Module 2 of 4)
- Conditions
- Healthy Volunteers
- Interventions
- Combination Product: PRT064445/RivaroxabanDrug: PlaceboCombination Product: Placebo/Rivaroxaban
- Registration Number
- NCT03578146
- Lead Sponsor
- Portola Pharmaceuticals
- Brief Summary
The purpose of this study is to evaluate the ability of PRT064445 to reverse the effects of several blood thinner drugs on laboratory tests. The study also is evaluating the blood levels of PRT064445 given at different doses.
- Detailed Description
A randomized, double-blind, vehicle-controlled study to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of intravenously administered PRT064445 after dosing to steady state with one of four direct/indirect factor Xa (fXa) inhibitors in healthy volunteers.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 48
- Healthy men or women between the ages of 18 and 45 years old
- History (including family history) or symptoms of, or risk factors for bleeding
- History (including family history) of or risk factors for a hypercoagulable or thrombotic condition
- Absolute/relative contraindication to anticoagulation or treatment with specific anticoagulants
- History of major surgery, severe trauma or bone fracture within 3 months prior to dosing; or planned surgery within 1 month after dosing.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Module 2 (720 mg bolus + 240 mg infusion) PRT064445/Rivaroxaban 720 mg IV bolus administered over 24 minutes \[\~30 mg/min\] followed by 240 mg continuous IV infusion \[4 mg/min over 60 min) Module 2 (800 mg bolus + 960 mg infusion) Placebo/Rivaroxaban 800 mg IV bolus administered over 26.7 minutes \[\~30 mg/min\] followed by 960 mg continuous IV infusion \[8 mg/min over 120 min\] Module 2 (420 mg) Placebo/Rivaroxaban 420 mg andexanet IV bolus administered over 14 minutes (\~30 mg/min) Module 2 (600 mg) Placebo/Rivaroxaban 600 mg andexanet IV bolus administered over 20 minutes (\~30 mg/min) Module 2 (720 mg bolus + 240 mg infusion) Placebo/Rivaroxaban 720 mg IV bolus administered over 24 minutes \[\~30 mg/min\] followed by 240 mg continuous IV infusion \[4 mg/min over 60 min) Module 2 Placebo Placebo Placebo administered intravenously (IV) as a bolus or a bolus followed by continuous fusion. Module 2 (210 mg) Placebo/Rivaroxaban 210 mg andexanet IV bolus administered over 7 minutes (\~30 mg/min) Module 2 (420 mg) PRT064445/Rivaroxaban 420 mg andexanet IV bolus administered over 14 minutes (\~30 mg/min) Module 2 (800 mg bolus + 960 mg infusion) PRT064445/Rivaroxaban 800 mg IV bolus administered over 26.7 minutes \[\~30 mg/min\] followed by 960 mg continuous IV infusion \[8 mg/min over 120 min\] Module 2 (210 mg) PRT064445/Rivaroxaban 210 mg andexanet IV bolus administered over 7 minutes (\~30 mg/min) Module 2 (600 mg) PRT064445/Rivaroxaban 600 mg andexanet IV bolus administered over 20 minutes (\~30 mg/min)
- Primary Outcome Measures
Name Time Method Efficacy: Percent Change From Baseline in Anti-fXa Activity at 2 Mins Following Andexanet/Placebo Administration Baseline to 2 minutes following the end of andexanet/placebo administration Anti-fXa activity was measured immediately prior to (Baseline) and at 2 mins following andexanet/placebo administration. Anti-fXa activity was measured using a commercial kit (Coamatic Heparin-82 33 9363, DiaPharma)
- Secondary Outcome Measures
Name Time Method Efficacy: Percent Change From Baseline in Thrombin Generation at 2 Mins Following Andexanet/Placebo Administration Baseline to 2 minutes following the end of andexanet/placebo administration Thrombin generation was measured immediately prior to (Baseline) and at 2 mins following andexanet/placebo administration. Thrombin generation was measured using a TF-initiated thrombin generation assay.
Efficacy: Percent Change From Baseline in Unbound Rivaroaxaban Plasma Concentration at 2 Mins Following Andexanet/Placebo Administration Baseline to 2 minutes following the end of andexanet/placebo administration Unbound rivaroxaban concentrations was measured immediately prior to (Baseline) and at 2 mins following andexanet/placebo administration. Unbound plasma concentrations for rivaroxaban were determined by a rapid equilibrium dialysis method followed by Liquid Chromatography-Mass Spectometry assay.
Andexanet Maximum Observed Plasma Concentration (Cmax) Blood was collected at predose, 0.033, 0.2, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4.5, 5.5, 6.5, 7.5, 8.5 and 14.5 hours postdose. Plasma concentrations of andexanet was determined using a validated method that involved analysis of citrated human plasma by an electrochemiluminescent assay.
Andexanet Area Under the Drug Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC0-inf ) Blood was collected at predose, 0.033, 0.2, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4.5, 5.5, 6.5, 7.5, 8.5 and 14.5 hours postdose. Plasma concentrations of andexanet was determined using a validated method that involved analysis of citrated human plasma by an electrochemiluminescent assay. AUC0-inf was calculated using a non-compartmental approach
Andexanet Time of Maximum Observed Plasma Concentration (Tmax) Blood was collected at predose, 0.033, 0.2, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4.5, 5.5, 6.5, 7.5, 8.5 and 14.5 hours postdose. Plasma concentrations of andexanet was determined using a validated method that involved analysis of citrated human plasma by an electrochemiluminescent assay. Tmax was taken directly from the raw data.
Andexanet Apparent Terminal Elimination Half-life (t1/2) Blood was collected at predose, 0.033, 0.2, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4.5, 5.5, 6.5, 7.5, 8.5 and 14.5 hours postdose. Plasma concentrations of andexanet was determined using a validated method that involved analysis of citrated human plasma by an electrochemiluminescent assay. t1/2 was determined by linear regression of the log concentration on the terminal portion of the plasma concentration-time curve.
Andexanet Total Systemic Clearance (CL) Blood was collected at predose, 0.033, 0.2, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4.5, 5.5, 6.5, 7.5, 8.5 and 14.5 hours postdose. Plasma concentrations of andexanet was determined using a validated method that involved analysis of citrated human plasma by an electrochemiluminescent assay. CL was calculated using a non-compartmental approach, calculated as Dose/AUC0-inf
Andexanet Total Volume of Distribution (Vss) Blood was collected at predose, 0.033, 0.2, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4.5, 5.5, 6.5, 7.5, 8.5 and 14.5 hours postdose. Plasma concentrations of andexanet was determined using a validated method that involved analysis of citrated human plasma by an electrochemiluminescent assay. Vss was calculated using a non-compartmental approach.