Phase 2 Healthy Volunteer Study to Evaluate the Ability of PRT064445 to Reverse the Effects of Several Blood Thinner Drugs on Laboratory Tests (Module 4 of 4)
- Conditions
- Healthy Volunteers
- Interventions
- Combination Product: PRT064445/EdoxabanDrug: PlaceboCombination Product: Placebo/Edoxaban
- Registration Number
- NCT03551743
- 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
- 28
- 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 4 (600 mg bolus) Placebo/Edoxaban 600 mg PRT064445 given as a single IV bolus Module 4 (800 mg bolus + 480 mg infusion) 8mg/min PRT064445/Edoxaban 1280 mg PRT064445: 800 mg IV at \~30 mg/min, followed by a continuous infusion of 480 mg (4 mg /min over 60 minutes) Module 4 (800 mg bolus) PRT064445/Edoxaban 800 mg PRT064445 as a single IV bolus Module 4 (600 mg bolus) PRT064445/Edoxaban 600 mg PRT064445 given as a single IV bolus Module 4 (800 mg bolus) Placebo/Edoxaban 800 mg PRT064445 as a single IV bolus Module 4 Placebo Placebo Placebo administered intravenously (IV) as a bolus or a bolus followed by continuous infusion. Module 4 (800 mg bolus + 480 mg infusion) 8mg/min Placebo/Edoxaban 1280 mg PRT064445: 800 mg IV at \~30 mg/min, followed by a continuous infusion of 480 mg (4 mg /min over 60 minutes)
- 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 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 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. Maximum observed plasma concentration was taken directly from the raw data.
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 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.
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 Edoxaban Plasma Concentration at 2 Mins Following Andexanet/Placebo Administration Baseline to 2 minutes following the end of andexanet/placebo administration Unbound edoxaban concentrations was measured immediately prior to (Baseline) and at 2 mins following andexanet/placebo administration. Unbound plasma concentrations for edoxaban was determined by a rapid equilibrium dialysis method followed by Liquid chromatography- Mass Spectrometry.
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 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.