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

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03551743

Enrollment

Registered

2018-06-11

Start date

2012-12-31

Completion date

2015-09-30

Last updated

2023-02-21

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

Conditions

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 (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.

Interventions

COMBINATION_PRODUCTPRT064445/Edoxaban

COMBINATION_PRODUCTPlacebo/Edoxaban

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 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)

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 Edoxaban Plasma Concentration at 2 Mins Following Andexanet/Placebo Administration	Baseline to 2 minutes following the end of 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.
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. Maximum observed plasma concentration was taken directly from the raw data.
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.
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 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)	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.
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 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.

Participant flow

Recruitment details

Subject recruitment occurred at investigative site in the US between March 2014 through August 2015

Pre-assignment details

28 subjects were enrolled in Module 4. Edoxaban was administered 60 mg orally once daily for 6 days in an open label fashion. Andexanet/placebo was administered intravenously (IV) on Day 6 such that they ended at 3 hours (Cohorts 1 and 2) or 5 hours (Cohort 3) after the last dose of edoxaban.

Participants by arm

Arm	Count
Module 4 Placebo Placebo administered intravenously (IV) as a bolus or a bolus followed by continuous infusion.	10
Module 4 (600mg) 600 mg andexanet IV bolus administered over \ 20 minutes (\ 30 mg/min)	6
Module 4 (800 mg Bolus + 480 mg Infusion) 800 mg andexanet IV bolus over \ 27 minutes (\ 30 mg/min) followed immediately by a continuous infusion of 480 mg (8 mg/min over 60 min) \[total 1280 mg\]	6
Module 4 (800 mg) 800 mg andexanet IV bolus administered over \ 27 minutes (\ 30 mg/min)	6
Total	28

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003
Overall Study	Adverse Event	1	0	0	0
Overall Study	Withdrawal by Subject	1	0	0	0

Baseline characteristics

Characteristic	Module 4 Placebo	Module 4 (600mg)	Module 4 (800 mg Bolus + 480 mg Infusion)	Module 4 (800 mg)	Total
Age, Continuous	30.2 years STANDARD_DEVIATION 8.35	38.8 years STANDARD_DEVIATION 8.61	31.3 years STANDARD_DEVIATION 8.82	35.5 years STANDARD_DEVIATION 8.55	33.4 years STANDARD_DEVIATION 8.79
Sex: Female, Male Female	2 Participants	2 Participants	1 Participants	3 Participants	8 Participants
Sex: Female, Male Male	8 Participants	4 Participants	5 Participants	3 Participants	20 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —
other Total, other adverse events	3 / 8	5 / 6	3 / 6	3 / 6
serious Total, serious adverse events	0 / 8	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: 26 subjects who received andexanet or placebo were included in the pharmacodynamics (PD) analysis

Arm	Measure	Value (MEAN)	Dispersion
Module 4 Placebo	Efficacy: Percent Change From Baseline in Anti-fXa Activity at 2 Mins Following Andexanet/Placebo Administration	-27.64 Percent change in anti-fXa activity	Standard Deviation 13.091
Module 4 (600mg)	Efficacy: Percent Change From Baseline in Anti-fXa Activity at 2 Mins Following Andexanet/Placebo Administration	-51.71 Percent change in anti-fXa activity	Standard Deviation 15.95
Module 4 (800 mg Bolus + 480 mg Infusion)	Efficacy: Percent Change From Baseline in Anti-fXa Activity at 2 Mins Following Andexanet/Placebo Administration	-72.60 Percent change in anti-fXa activity	Standard Deviation 8.35
Module 4 (800 mg)	Efficacy: Percent Change From Baseline in Anti-fXa Activity at 2 Mins Following Andexanet/Placebo Administration	-82.04 Percent change in anti-fXa activity	Standard Deviation 6.66

p-value: 0.0344ANCOVA

p-value: 0.0014ANCOVA

p-value: 0.0002ANCOVA

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 electrochemiluminescent assay. t1/2 was determined by linear regression of the log concentration on the terminal portion of the plasma concentration-time curve.