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)

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

NCT03578146

Enrollment

Registered

2018-07-06

Start date

2012-12-31

Completion date

2015-09-30

Last updated

2023-02-22

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/Rivaroxaban

COMBINATION_PRODUCTPlacebo/Rivaroxaban

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 Rivaroaxaban Plasma Concentration at 2 Mins Following Andexanet/Placebo Administration	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)	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 )	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, calculated as Dose/AUC0-inf
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 2013 through April 2014

Pre-assignment details

Rivaroxaban was administered orally at 20 mg once daily for 6 days to steady-state in an open label fashion. Subjects were then randomized to receive study treatment (andexanet or placebo) 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 rivaroxaban.

Participants by arm

Arm	Count
Module 2 Placebo Placebo administered intravenously (IV) as a bolus or a bolus followed by continuous infusion	16
Module 2 (210 mg) 210 mg andexanet IV bolus administered over 7 minutes (\ 30 mg/min)	6
Module 2 (420 mg) 420 mg andexanet IV bolus administered over 14 minutes (\ 30 mg/min)	6
Module 2 (600 mg) 600 mg andexanet IV bolus administered over 20 minutes (\ 30 mg/min)	6
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)	6
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 \[8 mg/min over 120 min\]	8
Total	48

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004	FG005
Overall Study	Did Not Receive Treatment	1	0	0	0	0	2
Overall Study	Lost to Follow-up	0	1	1	0	0	1

Baseline characteristics

Characteristic	Module 2 Placebo	Module 2 (210 mg)	Module 2 (420 mg)	Module 2 (600 mg)	Module 2 (720 mg Bolus + 240 mg Infusion)	Module 2 (800 mg Bolus + 960 mg Infusion)	Total
Age, Continuous	38.2 years STANDARD_DEVIATION 6.69	35.7 years STANDARD_DEVIATION 3.33	35.7 years STANDARD_DEVIATION 9.07	34.2 years STANDARD_DEVIATION 7.25	35.2 years STANDARD_DEVIATION 5.04	32.9 years STANDARD_DEVIATION 8.1	35.8 years STANDARD_DEVIATION 6.79
Sex: Female, Male Female	3 Participants	0 Participants	1 Participants	4 Participants	0 Participants	1 Participants	9 Participants
Sex: Female, Male Male	13 Participants	6 Participants	5 Participants	2 Participants	6 Participants	7 Participants	39 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
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —	— / —	— / —
other Total, other adverse events	12 / 15	4 / 6	3 / 6	5 / 6	5 / 6	5 / 6
serious Total, serious adverse events	0 / 15	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: 45 subjects who received andexanet or placebo were included in the pharmacodynamics (PD) analysis

Arm	Measure	Value (MEAN)	Dispersion
Module 2 Placebo	Efficacy: Percent Change From Baseline in Anti-fXa Activity at 2 Mins Following Andexanet/Placebo Administration	22.37 Percent change in anti-fXa activity	Standard Deviation 42.247
Module 2 (210 mg)	Efficacy: Percent Change From Baseline in Anti-fXa Activity at 2 Mins Following Andexanet/Placebo Administration	-18.09 Percent change in anti-fXa activity	Standard Deviation 23.922
Module 2 (420 mg)	Efficacy: Percent Change From Baseline in Anti-fXa Activity at 2 Mins Following Andexanet/Placebo Administration	-50.59 Percent change in anti-fXa activity	Standard Deviation 22.056
Module 2 (600 mg)	Efficacy: Percent Change From Baseline in Anti-fXa Activity at 2 Mins Following Andexanet/Placebo Administration	-75.26 Percent change in anti-fXa activity	Standard Deviation 19.072
Module 2 (720 mg Bolus + 240 mg Infusion)	Efficacy: Percent Change From Baseline in Anti-fXa Activity at 2 Mins Following Andexanet/Placebo Administration	-88.91 Percent change in anti-fXa activity	Standard Deviation 6.098
Module 2 (800 mg Bolus + 960 mg Infusion)	Efficacy: Percent Change From Baseline in Anti-fXa Activity at 2 Mins Following Andexanet/Placebo Administration	-92.72 Percent change in anti-fXa activity	Standard Deviation 3.084

p-value: 0.0121ANCOVA

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