Trial Outcomes & Findings for A Study in Older Subject to Evaluate the Safety and Ability of Andexanet Alfa to Reverse the Anticoagulation Effect of Rivaroxaban (NCT NCT02220725)

Results Overview

In Part 1, the primary endpoint was percent change from baseline in anti-fXa activity at the nadir, when nadir was defined as the smaller value for anti-fXa activity at the +2 minutes or +5 minutes time point following the end of the bolus. In Part 2, the primary endpoint was the percent change from baseline in anti-fXa activity from its baseline to nadir, when nadir was defined as the smaller value for anti-fXa activity between the 110-minute time point (10 minutes prior to the end of the continuous infusion) and the 5-minute time point after the end of the continuous infusion. The baseline for the primary endpoint in both parts was the anti-fXa activity just prior to administration of andexanet, 4 hours following the Day 4 dose of rivaroxaban. Anti-fXa activity was measured by a modified chromogenic assay.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

80 participants

Primary outcome timeframe

Baseline to +2 minutes or +5 minutes following the end of andexanet/placebo bolus (Part I), or 10 minutes prior to end of andexanet/placebo continuous infusion or 5 minutes after the end of andexanet/placebo continuous infusion (Part II)

Results posted on

2023-02-10

Participant Flow

Subject recruitment occurred at investigative site in the US between May 2014 through June 2015

Rivaroxaban was administered orally at 20 mg once daily for 4 days followed by andexanet as a bolus (800 mg; Part I) or as a bolus followed by an infusion (800 mg bolus followed by 8 mg/min infusion for 120 minutes, 1760 mg total dose; Part II). Bolus was started 4 hours after the last rivaroxaban dose.

Participant milestones

Participant milestones
Measure	Placebo (Part I) Vehicle Control	Andexanet (Part I) 800 mg bolus	Placebo (Part II) Vehicle Control	Andexanet (Part II) 800 mg bolus + 960 mg infusion (8 mg/min)
Overall Study STARTED	14	27	13	26
Overall Study COMPLETED	14	27	13	24
Overall Study NOT COMPLETED	0	0	0	2

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo (Part I) Vehicle Control	Andexanet (Part I) 800 mg bolus	Placebo (Part II) Vehicle Control	Andexanet (Part II) 800 mg bolus + 960 mg infusion (8 mg/min)
Overall Study Lost to Follow-up	0	0	0	1
Overall Study Withdrawal by Subject	0	0	0	1

Baseline Characteristics

A Study in Older Subject to Evaluate the Safety and Ability of Andexanet Alfa to Reverse the Anticoagulation Effect of Rivaroxaban

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo (Part I) n=14 Participants Vehicle Control	Andexanet (Part I) n=27 Participants 800 mg bolus	Placebo (Part II) n=13 Participants Vehicle Control	Andexanet (Part II) n=26 Participants 800 mg bolus + 960 mg infusion (8 mg/min)	Total n=80 Participants Total of all reporting groups
Age, Continuous	54.4 years STANDARD_DEVIATION 3.84 • n=5 Participants	55.6 years STANDARD_DEVIATION 3.79 • n=7 Participants	58.1 years STANDARD_DEVIATION 5.45 • n=5 Participants	57.0 years STANDARD_DEVIATION 5.08 • n=4 Participants	56.2 years STANDARD_DEVIATION 4.61 • n=21 Participants
Sex: Female, Male Female	6 Participants n=5 Participants	9 Participants n=7 Participants	6 Participants n=5 Participants	11 Participants n=4 Participants	32 Participants n=21 Participants
Sex: Female, Male Male	8 Participants n=5 Participants	18 Participants n=7 Participants	7 Participants n=5 Participants	15 Participants n=4 Participants	48 Participants n=21 Participants

PRIMARY outcome

Timeframe: Baseline to +2 minutes or +5 minutes following the end of andexanet/placebo bolus (Part I), or 10 minutes prior to end of andexanet/placebo continuous infusion or 5 minutes after the end of andexanet/placebo continuous infusion (Part II)

Population: Modified Intent-to-Treat Population included all subjects receiving andexanet/placebo with anti-fXa activity baseline value at ≥1 timepoints: 2 or 5 minute after the end of the bolus (Part I; N = 41); 110 minute during continuous infusion, 2 minute before or 5 minute after the end of continuous infusion (Part II; N = 39).

In Part 1, the primary endpoint was percent change from baseline in anti-fXa activity at the nadir, when nadir was defined as the smaller value for anti-fXa activity at the +2 minutes or +5 minutes time point following the end of the bolus. In Part 2, the primary endpoint was the percent change from baseline in anti-fXa activity from its baseline to nadir, when nadir was defined as the smaller value for anti-fXa activity between the 110-minute time point (10 minutes prior to the end of the continuous infusion) and the 5-minute time point after the end of the continuous infusion. The baseline for the primary endpoint in both parts was the anti-fXa activity just prior to administration of andexanet, 4 hours following the Day 4 dose of rivaroxaban. Anti-fXa activity was measured by a modified chromogenic assay.

Outcome measures

Outcome measures
Measure	Placebo (Part I) n=14 Participants Placebo was administered intravenously (IV) as a bolus (Part I). The bolus was started 4 hours after the last rivaroxaban dose (at the approximate steady state Cmax for rivaroxaban)	Andexanet (Part I) n=27 Participants Andexanet administered IV as a bolus of 800 mg at a target rate of approximately 30 mg/minute (over approximately 27 minutes) (Part 1). The bolus was started 4 hours after the last rivaroxaban dose (at the approximate steady state Cmax for rivaroxaban)	Placebo (Part II) n=13 Participants Placebo was administered IV as a bolus followed by a continuous infusion for 120 minutes (Part II). The bolus was started 4 hours after the last rivaroxaban dose (at the approximate steady state Cmax for rivaroxaban)	Andexanet (Part II) n=26 Participants Andexanet was administered IV as a bolus of 800 mg at a target rate of approximately 30 mg/minute (over approximately 27 minutes) followed by a continuous infusion of 960 mg at 8 mg/minute for 120 minutes (Part II). The bolus was started 4 hours after the last rivaroxaban dose (at the approximate steady state Cmax for rivaroxaban).
Efficacy: Percent Change From Baseline in Anti-fXa Activity at the Nadir (Parts I and II)	-18.39 Percent change in anti-fXa activity Standard Deviation 14.662	-92.22 Percent change in anti-fXa activity Standard Deviation 10.697	-44.75 Percent change in anti-fXa activity Standard Deviation 11.749	-96.72 Percent change in anti-fXa activity Standard Deviation 1.838

SECONDARY outcome

Timeframe: Baseline to +2 minutes or +5 minutes following the end of andexanet/placebo bolus (Part II)

Population: mITT; 41 and 39 subjects who received andexanet or placebo were included in the pharmacodynamics (PD) analysis in Part I and II, respectively.

The percent change from baseline in anti-fXa activity at the nadir, following the bolus, when nadir was defined as the smaller value for anti-fXa activity at the +2 minute or +5 minute time point after the completion of the andexanet bolus (Part II). Baseline was the last assessment obtained prior to the first dose of andexanet or placebo

Outcome measures

Outcome measures
Measure	Placebo (Part I) n=13 Participants Placebo was administered intravenously (IV) as a bolus (Part I). The bolus was started 4 hours after the last rivaroxaban dose (at the approximate steady state Cmax for rivaroxaban)	Andexanet (Part I) n=26 Participants Andexanet administered IV as a bolus of 800 mg at a target rate of approximately 30 mg/minute (over approximately 27 minutes) (Part 1). The bolus was started 4 hours after the last rivaroxaban dose (at the approximate steady state Cmax for rivaroxaban)	Placebo (Part II) Placebo was administered IV as a bolus followed by a continuous infusion for 120 minutes (Part II). The bolus was started 4 hours after the last rivaroxaban dose (at the approximate steady state Cmax for rivaroxaban)	Andexanet (Part II) Andexanet was administered IV as a bolus of 800 mg at a target rate of approximately 30 mg/minute (over approximately 27 minutes) followed by a continuous infusion of 960 mg at 8 mg/minute for 120 minutes (Part II). The bolus was started 4 hours after the last rivaroxaban dose (at the approximate steady state Cmax for rivaroxaban).
Efficacy: Percent Change in Anti-fXa Activity (Part II)	-23.62 Percent change in anti-fXa activity Standard Deviation 10.309	-95.34 Percent change in anti-fXa activity Standard Deviation 1.611	—	—

SECONDARY outcome

Timeframe: Baseline to +2 minutes or +5 minutes following the end of andexanet/placebo bolus (Part I), or 10 minutes prior to end of andexanet/placebo continuous infusion or 5 minutes after the end of andexanet/placebo continuous infusion (Part II)

Population: mITT; 41 and 39 subjects who received andexanet or placebo were included in the PD analysis in Part I and II, respectively.

Number of participants with ≥80% reduction in anti-fXa activity from its baseline to nadir, when nadir was defined as the smaller value for anti-fXa activity at the +2 minute or +5 minute time point after the completion of the andexanet bolus (Part I) or between the 110-minute time point (10 minutes prior to the end of the continuous infusion) and the 5-minute time point after the end of the continuous infusion (inclusive) {Part II\]. Baseline was the last assessment obtained prior to the first dose of andexanet or placebo

Outcome measures

Outcome measures
Measure	Placebo (Part I) n=14 Participants Placebo was administered intravenously (IV) as a bolus (Part I). The bolus was started 4 hours after the last rivaroxaban dose (at the approximate steady state Cmax for rivaroxaban)	Andexanet (Part I) n=27 Participants Andexanet administered IV as a bolus of 800 mg at a target rate of approximately 30 mg/minute (over approximately 27 minutes) (Part 1). The bolus was started 4 hours after the last rivaroxaban dose (at the approximate steady state Cmax for rivaroxaban)	Placebo (Part II) n=13 Participants Placebo was administered IV as a bolus followed by a continuous infusion for 120 minutes (Part II). The bolus was started 4 hours after the last rivaroxaban dose (at the approximate steady state Cmax for rivaroxaban)	Andexanet (Part II) n=26 Participants Andexanet was administered IV as a bolus of 800 mg at a target rate of approximately 30 mg/minute (over approximately 27 minutes) followed by a continuous infusion of 960 mg at 8 mg/minute for 120 minutes (Part II). The bolus was started 4 hours after the last rivaroxaban dose (at the approximate steady state Cmax for rivaroxaban).
Efficacy: Number of Participants With ≥80% Reduction in the Anti-fXa Activity From Baseline to Nadir	0 Participants	26 Participants	0 Participants	26 Participants

SECONDARY outcome

Timeframe: Baseline to +2 minutes or +5 minutes following the end of andexanet/placebo bolus (Part I), or 10 minutes prior to end of andexanet/placebo continuous infusion or 5 minutes after the end of andexanet/placebo continuous infusion (Part II)

Population: 54 subjects who received rivaroxaban were included in the rivaroxaban pharmacokinetics (PK) analysis

Change from baseline in free rivaroxaban concentration (ng/mL) at the nadir, when nadir was defined as the smaller value for free rivaroxaban at the +2 minute or +5 minute time point after the completion of the andexanet bolus (Part I) or between the 110-minute time point (10 minutes prior to the end of the continuous infusion) and the 5-minute time point after the end of the continuous infusion (inclusive) \[Part II\]. Free plasma concentrations of rivaroxaban was determined using a validated method that involved analysis of citrated human plasma with high-throughput equilibrium dialysis followed by liquid chromatography mass spectrometry.

Outcome measures

Outcome measures
Measure	Placebo (Part I) n=14 Participants Placebo was administered intravenously (IV) as a bolus (Part I). The bolus was started 4 hours after the last rivaroxaban dose (at the approximate steady state Cmax for rivaroxaban)	Andexanet (Part I) n=27 Participants Andexanet administered IV as a bolus of 800 mg at a target rate of approximately 30 mg/minute (over approximately 27 minutes) (Part 1). The bolus was started 4 hours after the last rivaroxaban dose (at the approximate steady state Cmax for rivaroxaban)	Placebo (Part II) n=13 Participants Placebo was administered IV as a bolus followed by a continuous infusion for 120 minutes (Part II). The bolus was started 4 hours after the last rivaroxaban dose (at the approximate steady state Cmax for rivaroxaban)	Andexanet (Part II) n=26 Participants Andexanet was administered IV as a bolus of 800 mg at a target rate of approximately 30 mg/minute (over approximately 27 minutes) followed by a continuous infusion of 960 mg at 8 mg/minute for 120 minutes (Part II). The bolus was started 4 hours after the last rivaroxaban dose (at the approximate steady state Cmax for rivaroxaban).
Efficacy: Change From Baseline in Free Rivaroxaban Concentration at the Nadir	-4.155 ng/mL Standard Deviation 2.8914	-23.347 ng/mL Standard Deviation 6.2229	-12.063 ng/mL Standard Deviation 5.2510	-30.296 ng/mL Standard Deviation 8.1451

SECONDARY outcome

Timeframe: Baseline to +2 minutes or +10 minutes following the end of andexanet/placebo bolus (Part I), or 10 minutes prior to end of andexanet/placebo continuous infusion or 5 minutes after the end of andexanet/placebo continuous infusion (Part II)

Population: mITT; 41 and 39 subjects who received andexanet or placebo were included in the PD analysis in Part I and II, respectively.

Change in ETP from baseline to its peak, where peak was defined as the largest value for ETP between the +2 minute time point and the +10 minute time point after the end of the andexanet bolus (inclusive) {Part I\] or between the 110-minute time point (10 minutes prior to the end of the continuous infusion) and the 5-minute time point after the end of the continuous infusion (inclusive) \[Part II\]. Baseline was the last assessment obtained prior to the first dose of andexanet or placebo. ETP was measured using a tissue factor-initiated thrombin generation assay.

Outcome measures

Outcome measures
Measure	Placebo (Part I) n=14 Participants Placebo was administered intravenously (IV) as a bolus (Part I). The bolus was started 4 hours after the last rivaroxaban dose (at the approximate steady state Cmax for rivaroxaban)	Andexanet (Part I) n=27 Participants Andexanet administered IV as a bolus of 800 mg at a target rate of approximately 30 mg/minute (over approximately 27 minutes) (Part 1). The bolus was started 4 hours after the last rivaroxaban dose (at the approximate steady state Cmax for rivaroxaban)	Placebo (Part II) n=13 Participants Placebo was administered IV as a bolus followed by a continuous infusion for 120 minutes (Part II). The bolus was started 4 hours after the last rivaroxaban dose (at the approximate steady state Cmax for rivaroxaban)	Andexanet (Part II) n=26 Participants Andexanet was administered IV as a bolus of 800 mg at a target rate of approximately 30 mg/minute (over approximately 27 minutes) followed by a continuous infusion of 960 mg at 8 mg/minute for 120 minutes (Part II). The bolus was started 4 hours after the last rivaroxaban dose (at the approximate steady state Cmax for rivaroxaban).
Efficacy: Change in Thrombin Generation (ETP) From Baseline to Its Peak [Parts I and II]	173.861 nmol/min Standard Deviation 104.2528	1314.193 nmol/min Standard Deviation 331.1670	264.424 nmol/min Standard Deviation 140.6792	1510.368 nmol/min Standard Deviation 344.7691

SECONDARY outcome

Timeframe: Baseline to +2 minutes or +10 minutes following the end of andexanet/placebo bolus (Part I), or 10 minutes prior to end of andexanet/placebo continuous infusion or 5 minutes after the end of andexanet/placebo continuous infusion (Part II)

Population: mITT; 41 and 39 subjects who received andexanet or placebo were included in the PD analysis in Part I and II, respectively.

Number of participants with ETP above the lower limit of the normal range at its peak, between the +2 minute time point and the +10 minute time point after the end of the andexanet bolus (inclusive) \[Part I\] or between the 110-minute time point (10 minutes prior to the end of the continuous infusion) and the 5-minute time point after the end of the continuous infusion (inclusive) \[Part II\]. ETP was measured using a tissue factor-initiated thrombin generation assay

Outcome measures

Outcome measures
Measure	Placebo (Part I) n=14 Participants Placebo was administered intravenously (IV) as a bolus (Part I). The bolus was started 4 hours after the last rivaroxaban dose (at the approximate steady state Cmax for rivaroxaban)	Andexanet (Part I) n=27 Participants Andexanet administered IV as a bolus of 800 mg at a target rate of approximately 30 mg/minute (over approximately 27 minutes) (Part 1). The bolus was started 4 hours after the last rivaroxaban dose (at the approximate steady state Cmax for rivaroxaban)	Placebo (Part II) n=13 Participants Placebo was administered IV as a bolus followed by a continuous infusion for 120 minutes (Part II). The bolus was started 4 hours after the last rivaroxaban dose (at the approximate steady state Cmax for rivaroxaban)	Andexanet (Part II) n=26 Participants Andexanet was administered IV as a bolus of 800 mg at a target rate of approximately 30 mg/minute (over approximately 27 minutes) followed by a continuous infusion of 960 mg at 8 mg/minute for 120 minutes (Part II). The bolus was started 4 hours after the last rivaroxaban dose (at the approximate steady state Cmax for rivaroxaban).
Efficacy: Number of Participants With Thrombin Generation (ETP) Above the Lower Limit of the Derived Normal Range at Its Peak (mITT Population)	1 Participants	26 Participants	0 Participants	26 Participants

Adverse Events

Placebo (Part I)

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Andexanet (Part I)

Serious events: 0 serious events

Other events: 5 other events

Deaths: 0 deaths

Placebo (Part II)

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

Andexanet (Part II)

Serious events: 0 serious events

Other events: 5 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	Placebo (Part I) n=14 participants at risk Vehicle Control	Andexanet (Part I) n=27 participants at risk 800 mg bolus	Placebo (Part II) n=13 participants at risk Vehicle Control	Andexanet (Part II) n=26 participants at risk 800 mg bolus + 960 mg infusion (8 mg/min)
Injury, poisoning and procedural complications Infusion Related Reaction	0.00% 0/14 • ~8 to 12 weeks The Safety Analysis Population consisted of all subjects randomized and treated with study drug (andexanet or placebo)	18.5% 5/27 • ~8 to 12 weeks The Safety Analysis Population consisted of all subjects randomized and treated with study drug (andexanet or placebo)	0.00% 0/13 • ~8 to 12 weeks The Safety Analysis Population consisted of all subjects randomized and treated with study drug (andexanet or placebo)	0.00% 0/26 • ~8 to 12 weeks The Safety Analysis Population consisted of all subjects randomized and treated with study drug (andexanet or placebo)
Musculoskeletal and connective tissue disorders Muscle Spasms	0.00% 0/14 • ~8 to 12 weeks The Safety Analysis Population consisted of all subjects randomized and treated with study drug (andexanet or placebo)	0.00% 0/27 • ~8 to 12 weeks The Safety Analysis Population consisted of all subjects randomized and treated with study drug (andexanet or placebo)	7.7% 1/13 • ~8 to 12 weeks The Safety Analysis Population consisted of all subjects randomized and treated with study drug (andexanet or placebo)	11.5% 3/26 • ~8 to 12 weeks The Safety Analysis Population consisted of all subjects randomized and treated with study drug (andexanet or placebo)
Gastrointestinal disorders Constipation	0.00% 0/14 • ~8 to 12 weeks The Safety Analysis Population consisted of all subjects randomized and treated with study drug (andexanet or placebo)	0.00% 0/27 • ~8 to 12 weeks The Safety Analysis Population consisted of all subjects randomized and treated with study drug (andexanet or placebo)	7.7% 1/13 • ~8 to 12 weeks The Safety Analysis Population consisted of all subjects randomized and treated with study drug (andexanet or placebo)	7.7% 2/26 • ~8 to 12 weeks The Safety Analysis Population consisted of all subjects randomized and treated with study drug (andexanet or placebo)

Additional Information

Head of Clinical Development

Portola Pharmaceuticals, Inc.

Phone: 650-246-7000

Results disclosure agreements

Principal investigator is a sponsor employee Conducted in healthy volunteers at Clinical Research Organization.
Publication restrictions are in place

Restriction type: OTHER