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)

A Randomized, Double-Blind, Vehicle-Controlled Multiple Dose 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

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.

Study Overview

• Status: Completed
• Conditions: Healthy Volunteers
• Intervention / Treatment: Drug: Placebo; Combination product: PRT064445/Edoxaban; Combination product: Placebo/Edoxaban

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.

• Study Type: Interventional
• Enrollment (Actual): 28
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy men or women between the ages of 18 and 45 years old

Exclusion Criteria:

• 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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Module 4 (600 mg bolus); 600 mg PRT064445 given as a single IV bolus	Combination product: PRT064445/Edoxaban; Other Names: Andexanet; Combination product: Placebo/Edoxaban
Experimental: Module 4 (800 mg bolus + 480 mg infusion) 8mg/min; 1280 mg PRT064445: 800 mg IV at ~30 mg/min, followed by a continuous infusion of 480 mg (4 mg /min over 60 minutes)	Combination product: PRT064445/Edoxaban; Other Names: Andexanet; Combination product: Placebo/Edoxaban
Experimental: Module 4 (800 mg bolus); 800 mg PRT064445 as a single IV bolus	Combination product: PRT064445/Edoxaban; Other Names: Andexanet; Combination product: Placebo/Edoxaban
Placebo Comparator: Module 4 Placebo; Placebo administered intravenously (IV) as a bolus or a bolus followed by continuous infusion.	Drug: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy: Percent Change From Baseline in Anti-fXa Activity at 2 Mins Following 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)	Baseline to 2 minutes following the end of andexanet/placebo administration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy: Percent Change From Baseline in Thrombin Generation at 2 Mins Following 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.	Baseline to 2 minutes following the end of andexanet/placebo administration
Efficacy: Percent Change From Baseline in Unbound Edoxaban Plasma Concentration at 2 Mins Following 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.	Baseline to 2 minutes following the end of andexanet/placebo administration
Andexanet Maximum Observed Plasma Concentration (Cmax)	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.	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.
Andexanet Area Under the Drug Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC0-inf )	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	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.
Andexanet Time of Maximum Observed Plasma Concentration (Tmax)	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.	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.
Andexanet Apparent Terminal Elimination Half-life (t1/2)	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.	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.
Andexanet Total Systemic Clearance (CL)	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.	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.
Andexanet Total Volume of Distribution (Vss)	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.	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.

Collaborators and Investigators

• Sponsor: Portola Pharmaceuticals

Publications and helpful links

General Publications

• Lu G, Conley PB, Leeds JM, Karbarz MJ, Levy GG, Mathur VS, Castillo J, Crowther M, Curnutte JT. A phase 2 PK/PD study of andexanet alfa for reversal of rivaroxaban and edoxaban anticoagulation in healthy volunteers. Blood Adv. 2020 Feb 25;4(4):728-739. doi: 10.1182/bloodadvances.2019000885.

Study record dates

Study Major Dates

• Study Start: December 1, 2012
• Primary Completion (Actual): September 1, 2015
• Study Completion (Actual): September 1, 2015

Study Registration Dates

• First Submitted: May 15, 2018
• First Submitted That Met QC Criteria: June 7, 2018
• First Posted (Actual): June 11, 2018

Study Record Updates

• Last Update Posted (Estimate): February 21, 2023
• Last Update Submitted That Met QC Criteria: February 17, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Edoxaban
• Other Study ID Numbers: 12-502 Module 4