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

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01758432

Enrollment

Registered

2013-01-01

Start date

2012-12-31

Completion date

2015-09-30

Last updated

2023-08-07

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Healthy Volunteers

Keywords

Healthy volunteers

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

Interventions

COMBINATION_PRODUCTPRT064445/Apixaban

COMBINATION_PRODUCTPlacebo/Apixaban

DRUGPlacebo

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

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 7cohorts 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)

Eligibility

Sex/Gender

ALL

Age

18 Years to 45 Years

Healthy volunteers

Yes

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.

Design outcomes

Primary

Measure	Time frame	Description
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

Measure	Time frame	Description
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.
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.
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 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.
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.

Countries

United States

Participant flow

Recruitment details

Subject recruitment occurred at investigative site in the US between November 2012 through October 2013

Pre-assignment details

Apixaban was administered orally at 5 mg twice daily for 6 days to steady-state in an open label fashion. Subjects were then randomized to receive study treatment (andexanet:placebo, 6:3) intravenously at different doses/dose regimens on Day 6, all bolus doses administered such that they ended at 3 hours after the last dose of apixaban.

Participants by arm

Arm	Count
Module 1 Placebo Placebo was administered intravenously (IV) as a bolus, two bolus doses or a bolus followed by continuous infusion.	18
Module 1 ( 90 mg) 90 mg andexanet IV bolus administered over 3 minutes (\ 30 mg/min)	6
Module 1 (210 mg) 210 mg andexanet IV bolus administered over 10 minutes (\ 30 mg/min)	6
Module 1 (420 mg) 420 mg andexanet IV bolus administered over 15 minutes (\ 30 mg/min)	6
Module 1 (420 mg Bolus + 180 mg Infusion) 420 mg andexanet IV bolus administered over \ 14 minutes (\ 30 mg/min) followed immediately by a 180 mg continuous IV infusion (4 mg/min over 45 minutes) \[total 600 mg\]	6
Module 1 (420 mg Bolus + 180 mg Bolus) 420 mg andexanet/placebo IV bolus administered over \ 14 minutes (\ 30 mg/min) followed after 45 minutes by a second bolus of 180 mg over\ 6 minutes (\ 30 mg/min) \[total 600 mg\]	6
Module 1 (420 mg Bolus + 480 mg Infusion) 420 mg andexanet IV bolus administered over \ 14 minutes (\ 30 mg/min) followed immediately by a 480 mg continuous IV infusion (4 mg/min over 2 hours) \[total 900 mg\]	6
Total	54

Baseline characteristics

Characteristic	Module 1 Placebo	Module 1 ( 90 mg)	Module 1 (210 mg)	Module 1 (420 mg)	Module 1 (420 mg Bolus + 180 mg Infusion)	Module 1 (420 mg Bolus + 180 mg Bolus)	Module 1 (420 mg Bolus + 480 mg Infusion)	Total
Age, Continuous	33.4 years STANDARD_DEVIATION 7.69	33.7 years STANDARD_DEVIATION 8.48	35.0 years STANDARD_DEVIATION 7.32	33.8 years STANDARD_DEVIATION 5.78	31.7 years STANDARD_DEVIATION 9.5	32.5 years STANDARD_DEVIATION 8.6	31.8 years STANDARD_DEVIATION 6.97	33.2 years STANDARD_DEVIATION 7.42
Sex: Female, Male Female	1 Participants	0 Participants	1 Participants	0 Participants	3 Participants	3 Participants	0 Participants	8 Participants
Sex: Female, Male Male	17 Participants	6 Participants	5 Participants	6 Participants	3 Participants	3 Participants	6 Participants	46 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk	EG006 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —	— / —	— / —	— / —
other Total, other adverse events	14 / 18	3 / 6	3 / 6	5 / 6	4 / 6	2 / 6	3 / 6
serious Total, serious adverse events	0 / 18	0 / 6	0 / 6	0 / 6	0 / 6	0 / 6	0 / 6

Outcome results

Primary

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)

Time frame: Baseline to 2 minutes following the end of andexanet/placebo administration

Population: 54 subjects who received andexanet or placebo were included in the pharmacodynamics (PD) analysis

Arm	Measure	Value (MEAN)	Dispersion
Module 1 Placebo	Efficacy: Percent Change From Baseline in Anti-fXa Activity at 2 Mins Following Andexanet/Placebo Administration	-7.06 Percent change in anti-fXa activity	Standard Deviation 10.801
Module 1 ( 90 mg)	Efficacy: Percent Change From Baseline in Anti-fXa Activity at 2 Mins Following Andexanet/Placebo Administration	-67.79 Percent change in anti-fXa activity	Standard Deviation 7.731
Module 1 (210 mg)	Efficacy: Percent Change From Baseline in Anti-fXa Activity at 2 Mins Following Andexanet/Placebo Administration	-78.51 Percent change in anti-fXa activity	Standard Deviation 3.815
Module 1 (420 mg)	Efficacy: Percent Change From Baseline in Anti-fXa Activity at 2 Mins Following Andexanet/Placebo Administration	-95.04 Percent change in anti-fXa activity	Standard Deviation 1.375
Module 1 (420 mg Bolus + 180 mg Infusion)	Efficacy: Percent Change From Baseline in Anti-fXa Activity at 2 Mins Following Andexanet/Placebo Administration	-94.03 Percent change in anti-fXa activity	Standard Deviation 1.87
Module 1 (420 mg Bolus + 180 mg Bolus)	Efficacy: Percent Change From Baseline in Anti-fXa Activity at 2 Mins Following Andexanet/Placebo Administration	-93.07 Percent change in anti-fXa activity	Standard Deviation 1.765
Module 1 (420 mg Bolus + 480 mg Infusion)	Efficacy: Percent Change From Baseline in Anti-fXa Activity at 2 Mins Following Andexanet/Placebo Administration	-92.82 Percent change in anti-fXa activity	Standard Deviation 1.267

p-value: <0.0001ANCOVA

Secondary

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.