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)

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

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/Apixaban; Combination product: Placebo/Apixaban

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

• Study Type: Interventional
• Enrollment (Actual): 54
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Tempe, Arizona, United States, 85283

Participation Criteria

Eligibility Criteria

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

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

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Module 1 (90 mg bolus); 90 mg PRT064445 given as a single IV	Combination product: PRT064445/Apixaban; Other Names: Andexanet; Combination product: Placebo/Apixaban
Experimental: Module 1 (210 mg bolus); 210 mg PRT064445 given as a single IV bolus	Combination product: PRT064445/Apixaban; Other Names: Andexanet; Combination product: Placebo/Apixaban
Experimental: Module 1 (420 mg bolus); 420 mg PRT064445 given as a single IV bolus	Combination product: PRT064445/Apixaban; Other Names: Andexanet; Combination product: Placebo/Apixaban
Experimental: Module 1 (420 mg bolus + 180 mg infusion) 4 mg/min; 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)	Combination product: PRT064445/Apixaban; Other Names: Andexanet; Combination product: Placebo/Apixaban
Experimental: Module 1 (420 mg bolus + 180 mg bolus) 30mg/min; 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	Combination product: PRT064445/Apixaban; Other Names: Andexanet; Combination product: Placebo/Apixaban
Experimental: Module 1 (420 mg bolus + 480 mg infusion) 4mg/min; 900 mg PRT064445 given as follows: 420 mg IV, followed by a continuous infusion of 480 mg (4 mg/min over 120 minutes	Combination product: PRT064445/Apixaban; Other Names: Andexanet; Combination product: Placebo/Apixaban
Placebo Comparator: Module 1 Placebo; Placebo administered intravenously (IV) as a bolus, two bolus doses 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
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 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.
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. Cmax 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 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, calculated as Dose/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.
Efficacy: Percent Change From Baseline in Unbound Apixaban Plasma Concentration at 2 Mins Following 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.	Baseline to 2 minutes following the end of andexanet/placebo administration
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 electro chemiluminescent 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.

Collaborators and Investigators

• Sponsor: Portola Pharmaceuticals

Publications and helpful links

General Publications

• Siegal D, Lu G, Leeds JM, Karbarz M, Castillo J, Mathur V, Hutchaleelaha A, Sinha U, Kitt M, McClure M, Hollenbach SJ, Curnutte JT, Conley PB, Crowther M. Safety, pharmacokinetics, and reversal of apixaban anticoagulation with andexanet alfa. Blood Adv. 2017 Sep 22;1(21):1827-1838. doi: 10.1182/bloodadvances.2017007112. eCollection 2017 Sep 26.

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: December 18, 2012
• First Submitted That Met QC Criteria: December 31, 2012
• First Posted (Estimated): January 1, 2013

Study Record Updates

• Last Update Posted (Actual): August 7, 2023
• Last Update Submitted That Met QC Criteria: August 3, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Healthy volunteers
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Apixaban
• Other Study ID Numbers: 12-502 Module 1