BleedingPhase 3NCT02220725

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

A Phase 3 study testing Andexanet in people with Bleeding, run by Portola Pharmaceuticals at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Trial summary

The purpose of this study is to evaluate the ability of Andexanet Alfa to reverse the anticoagulation effect of Rivaroxaban. Read more about this study

Who is it for?: Ages 50 to 75 yearsHealthy volunteers can take part
Conditions the study is for: Bleeding
What is being tested?: Andexanet
Type of treatment: Injection or infusion
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 80 participants
Where: 1 siteUnited States
Study dates: May 2014to Aug 2015
Phase: Phase 3
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 50 to 75 years
All sexes
Healthy volunteers accepted
Adult, Older adult

Who may be able to join

Reasonably healthy men and women aged 50 to 75

Who cannot join

History of abnormal bleeding, active bleeding or risk factors for bleeding
History of thrombosis or risk factors for thrombosis
History of adult asthma or use of inhaled medications

Trial locations and contacts

1 site in 1 country.

United States1 site

West Coast Clinical Trials
Cypress, California, 90630

Other trials in United States

About this study

Official title: A Phase 3 Randomized, Double-blind, Placebo-controlled Study in Older Subjects to Assess Safety and the Reversal of Rivaroxaban Anticoagulation With Intravenously Administered Andexanet Alpha

The purpose of this study is to evaluate the ability of Andexanet Alfa to reverse the anticoagulation effect of Rivaroxaban.

Conditions: Bleeding
Being tested: Andexanet, Placebo
Keywords: Andexanet alpha, Anticoagulation, Antidote, Rivaroxaban, Anti-fXa inhibitor, PRT4445, Xarelto, Reversal agent
Medical subject headings: Hemorrhage

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

AndexanetBiological
Also called Andexanet alpha, PRT4445
PlaceboOther

Study groups in NCT02220725
Study group	Role	What they receive
Andexanet 800mg bolus (Part I)	Experimental	Andexanet (antidote) - 800 mg bolus Receives: Biological: Andexanet; Other: Placebo
Andexanet 800mg + 960mg (Part II)	Experimental	800 mg bolus + 960 mg infusion (8 mg/min) Receives: Biological: Andexanet; Other: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

Efficacy: Percent Change From Baseline in Anti-fXa Activity at the Nadir (Parts I and II)
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.
Measured: 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)

Secondary outcomes (5)

Efficacy: Percent Change in Anti-fXa Activity (Part II)
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
Measured: Baseline to +2 minutes or +5 minutes following the end of andexanet/placebo bolus (Part II)
Efficacy: Number of Participants With ≥80% Reduction in the Anti-fXa Activity From Baseline to Nadir
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
Measured: 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)
Efficacy: Change From Baseline in Free Rivaroxaban Concentration at the Nadir
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.
Measured: 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)
Efficacy: Change in Thrombin Generation (ETP) From Baseline to Its Peak [Parts I and II]
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.
Measured: 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)
Efficacy: Number of Participants With Thrombin Generation (ETP) Above the Lower Limit of the Derived Normal Range at Its Peak (mITT Population)
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
Measured: 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)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

May 2014Aug 2015

First posted20 Aug 2014 (estimated)
Study startMay 2014
Primary completionAug 2015
Study completionAug 2015

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (1)Papers the sponsor has linked to this study.
Other trials for BleedingStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 3
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Quadruple blind
Who is masked: Participant, Care provider, Investigator, Outcomes assessor
Enrolment: 80 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT02220725
Sponsor's protocol ID: 14-504
Status last verified: Feb 2023
First submitted: 18 Aug 2014
Last updated: 10 Feb 2023
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes

Publications

Siegal DM, Curnutte JT, Connolly SJ, Lu G, Conley PB, Wiens BL, Mathur VS, Castillo J, Bronson MD, Leeds JM, Mar FA, Gold A, Crowther MA. Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. N Engl J Med. 2015 Dec 17;373(25):2413-24. doi: 10.1056/NEJMoa1510991. Epub 2015 Nov 11.
PubMed 26559317

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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Study at a glance

From the registry record, last updated by the sponsor on 10 Feb 2023. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: A Phase 3 Randomized, Double-blind, Placebo-controlled Study in Older Subjects to Assess Safety and the Reversal of Rivaroxaban Anticoagulation With Intravenously Administered Andexanet Alpha
ClinicalTrials.gov ID: NCT02220725
Acronym / sponsor ID: 14-504
Conditions: Bleeding
Keywords: Andexanet alpha, Anticoagulation, Antidote, Rivaroxaban, Anti-fXa inhibitor, PRT4445, Xarelto, Reversal agent
Phase: Phase 3
Study type: Interventional
Recruitment status: Completed
Enrolment: 80 participants (actual)
Lead sponsor: Portola PharmaceuticalsIndustry (pharma, biotech, devices)
Study start: May 2014
Primary completion: Aug 2015 (actual)
Study completion: Aug 2015 (actual)
First posted: 20 Aug 2014 (estimated)
Results: Posted 25 Sep 2018

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

The purpose of this study is to evaluate the ability of Andexanet Alfa to reverse the anticoagulation effect of Rivaroxaban.

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Quadruple blind (participant, care provider, investigator, outcomes assessor)
Number of arms: 2

Arm	Type	Receives
Andexanet 800mg bolus (Part I)	Experimental	Biological: Andexanet, Other: PlaceboAndexanet (antidote) - 800 mg bolus
Andexanet 800mg + 960mg (Part II)	Experimental	Biological: Andexanet, Other: Placebo800 mg bolus + 960 mg infusion (8 mg/min)

Who may qualify

Ages: 50 to 75 years
Sex: All
Healthy volunteers: Accepted
Age groups: Adult, Older adult

Key inclusion criteria (1 listed)

Reasonably healthy men and women aged 50 to 75

Key exclusion criteria (3 listed)

History of abnormal bleeding, active bleeding or risk factors for bleeding
History of thrombosis or risk factors for thrombosis
History of adult asthma or use of inhaled medications

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
AndexanetAlso: Andexanet alpha, PRT4445	Biological	Andexanet 800mg + 960mg (Part II), Andexanet 800mg bolus (Part I)
Placebo	Other	Andexanet 800mg + 960mg (Part II), Andexanet 800mg bolus (Part I)

Primary outcome

Efficacy: Percent Change From Baseline in Anti-fXa Activity at the Nadir (Parts I and II)
Time frame: 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)
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.

5 secondary outcomes

Efficacy: Percent Change in Anti-fXa Activity (Part II)
Time frame: Baseline to +2 minutes or +5 minutes following the end of andexanet/placebo bolus (Part II)
Efficacy: Number of Participants With ≥80% Reduction in the Anti-fXa Activity From Baseline to Nadir
Time frame: 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)
Efficacy: Change From Baseline in Free Rivaroxaban Concentration at the Nadir
Time frame: 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)
Efficacy: Change in Thrombin Generation (ETP) From Baseline to Its Peak [Parts I and II]
Time frame: 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)
Efficacy: Number of Participants With Thrombin Generation (ETP) Above the Lower Limit of the Derived Normal Range at Its Peak (mITT Population)
Time frame: 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)

Results and safety

Results posted to the registry on 25 Sep 2018, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Placebo (Part I)	14	14
Andexanet (Part I)	27	27
Placebo (Part II)	13	13
Andexanet (Part II)	26	24

Primary outcome: Efficacy: Percent Change From Baseline in Anti-fXa Activity at the Nadir (Parts I and II)

Time frame: 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). Mean (Standard Deviation). Unit: Percent change in anti-fXa activity

Measure	Placebo (Part I) n = 14	Andexanet (Part I) n = 27	Placebo (Part II) n = 13	Andexanet (Part II) n = 26
Value	-18.39 (14.662)	-92.22 (10.697)	-44.75 (11.749)	-96.72 (1.838)

Placebo (Part I) vs Andexanet (Part I): Hodges-Lehman estimate of shift: -70.14 (95% CI -85.43 to -65.91), p <0.0001, 2-sided test exact Wilcoxon rank-sum tes
Placebo (Part II) vs Andexanet (Part II): Hodges-Lehman estimate of shift: -51.87 (95% CI -57.95 to -47.03), p <0.0001, 2-sided test exact Wilcoxon rank-sum tes

Population analysed: 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).

5 secondary outcomes are reported in the full results.

Adverse events

Time frame: ~8 to 12 weeks. Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Placebo (Part I)	0 of 14 (0%)	0 of 14 (0%)	Not reported
Andexanet (Part I)	0 of 27 (0%)	5 of 27 (18.5%)	Not reported
Placebo (Part II)	0 of 13 (0%)	2 of 13 (15.4%)	Not reported
Andexanet (Part II)	0 of 26 (0%)	5 of 26 (19.2%)	Not reported

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 10 Feb 2023.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Derived from this study: PubMed 26559317Siegal DM, Curnutte JT, Connolly SJ, Lu G, Conley PB, Wiens BL, Mathur VS, Castillo J, Bronson MD, Leeds JM, Mar FA, Gold A, Crowther MA. Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. N Engl J Med. 2015 Dec 17;373(25):2413-24. doi: 10.1056/NEJMoa1510991. Epub 2015 Nov 11.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Vandana Mathur, M.D. study director

Portola Pharmaceuticals

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Andexanet in people with Bleeding, run by Portola Pharmaceuticals at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 1 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 10 Feb 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 25 Sep 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Efficacy: Percent Change From Baseline in Anti-fXa Activity at the Nadir (Parts I and II) (time frame: 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)). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02220725, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Feb 2023.