Phase 2 Healthy Volunteer Study to Evaluate the Ability of PRT064445 to Reverse the Effects of Several Blood Thinner Drugs on Laboratory Tests (Module 1 of 4)
- Conditions
- Healthy Volunteers
- Interventions
- Combination Product: PRT064445/ApixabanDrug: PlaceboCombination Product: Placebo/Apixaban
- Registration Number
- NCT01758432
- 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, and pharmacodynamics of intravenously administered PRT064445 after dosing to steady state with one of four direct/indirect fXa inhibitors in healthy volunteers
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 54
- 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 1 (210 mg bolus) Placebo/Apixaban 210 mg PRT064445 given as a single IV bolus Module 1 (90 mg bolus) PRT064445/Apixaban 90 mg PRT064445 given as a single IV Module 1 (420 mg bolus + 180 mg infusion) 4 mg/min PRT064445/Apixaban 600 mg PRT064445 given as follows: 420 mg IV over \~14 minutes (\~30 mg/min), followed by a continuous infusion of 180 mg (4 mg/min over 45 minutes) Module 1 (90 mg bolus) Placebo/Apixaban 90 mg PRT064445 given as a single IV Module 1 (210 mg bolus) PRT064445/Apixaban 210 mg PRT064445 given as a single IV bolus Module 1 (420 mg bolus + 180 mg bolus) 30mg/min PRT064445/Apixaban 600 mg PRT064445 given as follows: up to 420 mg IV over \~14 minutes (\~30 mg/min), followed by a second bolus of 180 mg IV over \~6 minutes (\~30 mg/min), 45 minutes after completion of the bolus Module 1 (420 mg bolus + 480 mg infusion) 4mg/min PRT064445/Apixaban 900 mg PRT064445 given as follows: 420 mg IV, followed by a continuous infusion of 480 mg (4 mg/min over 120 minutes Module 1 Placebo Placebo Placebo administered intravenously (IV) as a bolus, two bolus doses or a bolus followed by continuous infusion. Module 1 (420 mg bolus) PRT064445/Apixaban 420 mg PRT064445 given as a single IV bolus Module 1 (420 mg bolus + 180 mg infusion) 4 mg/min Placebo/Apixaban 600 mg PRT064445 given as follows: 420 mg IV over \~14 minutes (\~30 mg/min), followed by a continuous infusion of 180 mg (4 mg/min over 45 minutes) Module 1 (420 mg bolus) Placebo/Apixaban 420 mg PRT064445 given as a single IV bolus Module 1 (420 mg bolus + 180 mg bolus) 30mg/min Placebo/Apixaban 600 mg PRT064445 given as follows: up to 420 mg IV over \~14 minutes (\~30 mg/min), followed by a second bolus of 180 mg IV over \~6 minutes (\~30 mg/min), 45 minutes after completion of the bolus Module 1 (420 mg bolus + 480 mg infusion) 4mg/min Placebo/Apixaban 900 mg PRT064445 given as follows: 420 mg IV, followed by a continuous infusion of 480 mg (4 mg/min over 120 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 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.
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
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 Apixaban Plasma Concentration at 2 Mins Following Andexanet/Placebo Administration Baseline to 2 minutes following the end of andexanet/placebo administration Unbound apixaban concentrations was measured immediately prior to (Baseline) and at 2 mins following andexanet/placebo administration. Unbound plasma concentrations for apixaban 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. Cmax 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, calculated as Dose/AUC0-inf
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 electro chemiluminescent assay. t1/2 was determined by linear regression of the log concentration on the terminal portion of the plasma concentration-time curve.