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)

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ClinicalTrials.gov Identifier: NCT03578146

Recruitment Status : Completed

First Posted : July 6, 2018

Results First Posted : September 5, 2018

Last Update Posted : October 2, 2018

Sponsor:

Information provided by (Responsible Party):

Portola Pharmaceuticals

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Healthy Volunteers	Combination Product: PRT064445/Rivaroxaban Combination Product: Placebo/Rivaroxaban Drug: Placebo	Phase 2

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 Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	48 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Intervention Model Description:	This study has four modules with a total of 21 cohorts, each module was reported and submitted separately. Module 1, NCT01758432 (54 subjects with 7 cohorts including placebo); Module 2, NCT03578146 (48 subjects with 6 cohorts including placebo); Module 3, NCT03551730 (27 subjects with 4 cohorts including placebo); Module 4, NCT03551743 (28 subjects with 4 cohorts including placebo)
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
Official Title:	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
Study Start Date :	December 2012
Actual Primary Completion Date :	September 2015
Actual Study Completion Date :	September 2015

Resource links provided by the National Library of Medicine

Drug Information available for: Rivaroxaban Andexanet alfa

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Experimental: Module 2 (210 mg) 210 mg andexanet IV bolus administered over 7 minutes (~30 mg/min)	Combination Product: PRT064445/Rivaroxaban Other Name: Andexanet Combination Product: Placebo/Rivaroxaban
Experimental: Module 2 (420 mg) 420 mg andexanet IV bolus administered over 14 minutes (~30 mg/min)	Combination Product: PRT064445/Rivaroxaban Other Name: Andexanet Combination Product: Placebo/Rivaroxaban
Experimental: Module 2 (600 mg) 600 mg andexanet IV bolus administered over 20 minutes (~30 mg/min)	Combination Product: PRT064445/Rivaroxaban Other Name: Andexanet Combination Product: Placebo/Rivaroxaban
Experimental: Module 2 (720 mg bolus + 240 mg infusion) 720 mg IV bolus administered over 24 minutes [~30 mg/min] followed by 240 mg continuous IV infusion [4 mg/min over 60 min)	Combination Product: PRT064445/Rivaroxaban Other Name: Andexanet Combination Product: Placebo/Rivaroxaban
Experimental: Module 2 (800 mg bolus + 960 mg infusion) 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]	Combination Product: PRT064445/Rivaroxaban Other Name: Andexanet Combination Product: Placebo/Rivaroxaban
Experimental: Module 2 Placebo Placebo administered intravenously (IV) as a bolus or a bolus followed by continuous fusion.	Drug: Placebo

Outcome Measures

Primary Outcome Measures :

Efficacy: Percent Change From Baseline in Anti-fXa Activity at 2 Mins Following Andexanet/Placebo Administration [ Time Frame: 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 :

Efficacy: Percent Change From Baseline in Thrombin Generation at 2 Mins Following Andexanet/Placebo Administration [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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 ) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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.

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:	18 Years to 45 Years (Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	Yes

Criteria

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.

Contacts and Locations

No Contacts or Locations Provided

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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Responsible Party:	Portola Pharmaceuticals
ClinicalTrials.gov Identifier:	NCT03578146
Other Study ID Numbers:	12-502 Module 2
First Posted:	July 6, 2018 Key Record Dates
Results First Posted:	September 5, 2018
Last Update Posted:	October 2, 2018
Last Verified:	September 2015

Additional relevant MeSH terms:

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Rivaroxaban Factor Xa Inhibitors Antithrombins Serine Proteinase Inhibitors	Protease Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Anticoagulants

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