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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

Trial Profile

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

Status: Completed
Phase of Trial: Phase III

Latest Information Update: 14 Jan 2020

At a glance

  • Drugs Andexanet alfa (Primary) ; Rivaroxaban
  • Indications Haemorrhage
  • Focus Registrational; Therapeutic Use
  • Acronyms ANNEXA-R
  • Sponsors Portola Pharmaceuticals
  • Most Recent Events

    • 26 Apr 2019 According to a Portola Pharmaceuticals media release, based on results of ANNEXA-R, ANNEXA-A and ANNEXA-4 (n=352), studies, the European Commission (EC) has granted conditional Marketing Authorization of Ondexxya (andexanet alfa) for the treatment of the adult patients with the Factor Xa inhibitor apixaban or rivaroxaban when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding.
    • 01 Mar 2019 According to a Portola Pharmaceuticals media release, the CHMP has recommended that the European Commission (EC) grant Ondexxya conditional approval for the reversal of the anticoagulant effects of the Factor Xa inhibitors apixaban or rivaroxaban in patients experiencing uncontrolled or life-threatening bleeding. The EC is expected to issue a decision in early May 2019.
    • 01 Mar 2019 According to a Portola Pharmaceuticals media release, based on results of this study, the Committee for Medicinal Products for Human Use (CHMP) of the EMA has adopted a positive opinion on the marketing authorization application (MAA) for Ondexxya (andexanet alfa).

Trial Overview

Outcome

Primary endpoint met - positive

Purpose

This pivotal trial investigating the efficacy, safety and tolerability of andexanet alfa for the reversal of rivaroxaban-induced anticoagulation in healthy older volunteers. The study was in two parts; in the first part, 41 participants received rivaroxaban 20mg once daily for 4 days and were then randomised to receive either placebo (n = 14) or an IV bolus of andexanet alfa 800mg (n = 27); in the second part, approximately 40 participants received rivaroxaban 20mg once daily for 4 days were then randomised to receive either placebo or andexanet alfa as an IV bolus of 800mg followed by continuous infusion of 8 mg/min for 120 minutes.

Comments

According to a Portola Pharmaceuticals media release, based on results of ANNEXA-R, ANNEXA-A and ANNEXA-4 (n=352), studies, the European Commission (EC) has granted conditional Marketing Authorization of Ondexxya (andexanet alfa) for the treatment of the adult patients with the Factor Xa inhibitor apixaban or rivaroxaban when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding.

Based on the results of ANNEXA-R, ANNEXA-A and interim data from ANNEXA-4 (n=185), the U.S. Food and Drug Administration (FDA) has approved Andexxa, the first and only antidote for patients treated with rivaroxaban and apixaban, in reversing the anticoagulant activity of the Factor Xa inhibitors.

Primary Endpoints

Met on 06 May 2015

Reversal of Rivaroxaban anticoagulation effect as measured by anti-factor Xa activity

safety_issue: No
time_frame: 43 Days
description: To compare reversal of Rivaroxaban anticoagulation between Andexanet Alpha and placebo measured by anti-fXa activity for bolus followed by continuous infusion [1]

Other Endpoints

Efficacy: Percent Change in Anti-fXa Activity (Part II)

description: 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 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

description: 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 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

description: 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. 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]

description: 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. 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)

description: 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 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) [2]

Diseases Treated

Indication Qualifiers Patient Segments
Haemorrhage prevention -

Biomarker

NCT Number Biomarker Name Biomarker Function
NCT02220725 Thrombin Outcome Measure
For more detail, check out BiomarkerBase: the leading source of information about biomarkers used in drug development and diagnostic tests, tracking a comprehensive list of biomarker uses worldwide by over 800 companies

Subjects

  • Subject Type volunteers
  • Number

    Planned: 80

    Actual: 80

  • Sex male & female
  • Age Group 50-75 years; adult; elderly

Patient Inclusion Criteria

- Reasonably healthy men and women aged 50 to 75

Patient Exclusion Criteria

- 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 Details

Identifiers

Identifier Owner
NCT02220725 ClinicalTrials.gov: US National Institutes of Health
14-504 -

Organisations

  • Sponsors Portola Pharmaceuticals
  • Affiliations Bayer HealthCare; Janssen Pharmaceuticals; Portola Pharmaceuticals

Trial Dates

  • Initiation Dates

    Planned : 01 Jun 2014

    Actual : 01 May 2014

  • Primary Completion Dates

    Planned : 01 Nov 2014

    Actual : 01 Aug 2015

  • End Dates

    Planned : 01 Dec 2014

    Actual : 01 Aug 2015

Other Details

  • Design double-blind; multicentre; parallel; prospective; randomised
  • Phase of Trial Phase III
  • Location USA
  • Focus Registrational; Therapeutic Use

Interventions

Drugs Route Formulation
Andexanet alfaPrimary Drug Intravenous Infusion
Rivaroxaban
-
-

Andexanet 800mg + 960mg (Part II)

800 mg bolus + 960 mg infusion (8 mg/min) Biological: Andexanet Other Name: Andexanet alpha, PRT4445 Other: Placebo

Andexanet 800mg bolus (Part I)

Andexanet (antidote) - 800 mg bolus Biological: Andexanet Other Name: Andexanet alpha, PRT4445 Other: Placebo

Results

Pharmacodynamics

Phase III: Andexanet alfa 800mg, reduced anti-Factor Xa activity of rivaroxaban by > 92% from baseline (p < 0.0001) during the first part of the phase III ANNEXA-R trial in healthy volunteers. Unbound rivaroxaban concentration from baseline, was reduced significantly by andexanet alfa, versus placebo (p < 0.0001). Endogenous thrombin potential increased 96% from baseline to peak in the andexanet alfa cohort, relative to placebo (p < 0.0001). After 10 minutes of the end of the bolus administration, 26 subjects administered andexanet alfa returned to the normal range of thrombin generation. Andexanet alfa 800mg, reduced anti-Factor Xa activity of rivaroxaban by 97% and sustained it for 1 to 2 hours after completion of the infusion, reduced mean plasma concentration of unbound rivaroxaban (p < 0.0001) and restored thrombin generation to normal in all volunteers (p < 0.0001), during the second part of the trial in healthy volunteers. The double-blind phase III trial, subdivided in two parts, recruited 41 healthy volunteers in the first part and 39 healthy volunteers in the second part. In the first part, healthy volunteers received rivaroxaban 20mg, qd, for four days, 2:1 to receive at Cmax, either andexanet alfa (n = 27) or placebo (n = 14). In the second part healthy volunteers received rivaroxaban 20mg once daily, for four days and were then randomised 2:1 ratio to andexanet alfa 800 mg IV bolus followed by continuous infusion of 8 mg/min for 120mins (n = 26) or placebo (n = 13) [3] [4] [5] .

In the first part of the ANNEXA-A phase III trial, single IV dose of andexanet alfa reversed the anticoagulant activity of apixaban, by 94%, two to five minutes after the dosing, thereby achieving the primary endpoint with statistical significance (p < 0.0001). Between 90-96% reversal of the anticoagulant activity was observed in each volunteer treated with andexanet alfa. Additionally, andexanet alfa restored thrombin generation to baseline normal levels (prior to Eliquis therapy). In the second part of the trial, an IV bolus dose of andexanet alfa reversed the anticoagulant activity of apixaban by 92% (p<0.0001), with persisting reversal for 1-2 hours. In addition, anti-Factor Xa activity was reversed by at least 80% in all 23 subjects who received andexanet alfa (p<0.0001). Plasma levels of free unbound apixaban were significantly reduced with andexanet alfa (p=0.0002). Thrombin generation at the end of infusion was restored to the normal range in all subjects who received andexanet alfa, and thrombin generation above the lower limit of normal occurred in all subjects who received andexanet alfa (p<0.0001). The double blind phase III trial, subdivided in two parts, recruited 33 healthy volunteers aged 50-73 years in the first part, and 31 healthy volunteers in the second part. In the first part, healthy volunteers received apixaban 5mg bid for four hours and then were randomised in a 3 : 1 ratio to andexanet alfa 400mg IV bolus (n = 24) or placebo (n = 9). In the second part healthy volunteers received apixaban 5 mg bid for four hours and were then randomised to 3 : 1 ratio to andexanet alfa 400 mg IV bolus followed by continuous infusion of 4 mg/min for 120mins or placebo [3] .

Publications

  1. Portola Pharmaceuticals. The New England Journal of Medicine Publishes Results of Portola Pharmaceuticals Phase 3 ANNEXA Studies of Andexanet Alfa. Media-Rel 2015;.

    Media Release
  2. Portola Pharmaceuticals. Portola Pharmaceuticals Announces Second Part of Phase 3 ANNEXA(TM)-R Study: Andexanet Alfa and Rivaroxaban Meets Primary and Secondary Endpoints. Media-Rel 2015;.

    Media Release
  3. Portola Pharmaceuticals. Portola Announces Full Results From Positive Phase 3 ANNEXA(Tm)-R Study Demonstrating That Andexanet Alfa Rapidly and Significantly Reversed Anticoagulant Effect of Factor Xa Inhibitor XARELTO(Rm). Media-Rel 2015;.

    Media Release
  4. Crowther M, Gold AM, Lu G, Leeds JM, Wiens BL, Mathur V, et al. Andexanet Alfa, a Universal Antidote for Reversal of Anticoagulation of Factor Xa Inhibitors in Healthy Human Volunteers. ISC-2016 2016; abstr. A212.

    Available from: URL: http://stroke.ahajournals.org/content/47/Suppl_1/A212.abstract?sid=f62e60b5-7da6-4a2a-b286-4d2e500f47d547/Suppl_1/A212#cited-by
  5. Lu G, Lin J, Bronson M, Crowther M, Conley PB, Curnutte JT. Reversal of apixaban and rivaroxaban anticoagulation by andexanet alfa in ANNEXA-A&R as assessed by non-tissue factor (TF)-initiated thrombin generation independent of TF pathway inhibitor (TFPI). ESC-Card-2018 2018; abstr. 5069.

    Available from: URL: http://link.adisinsight.com/w8PJo
  6. Siegal DM, Curnutte JT, Connolly SJ, Lu G, Conley PB, Wiens BL, et al. Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. N-Engl-J-Med 2015;.

    PubMed | CrossRef Fulltext
  7. Gold AM, Crowther M, Levy G, Lu G, Leeds J, Barron L, et al. Annexatm-R: A phase 3 randomized, double-blind, placebo-controlled trial, demonstrating reversal of rivaroxaban-induced anticoagulation in older subjects by andexanet alfa (PRT064445), a universal antidote for factor xa (fXa) inhibitors. ACC-2015 2015; abstr. 71833080.

    Available from: URL: http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=emed13&AN=71833080
  8. Rogers KC, Finks SW. A New Option for Reversing the Anticoagulant Effect of Factor Xa Inhibitors: Andexanet alfa (Andexxa(R)). Am-J-Med 2018;.

    PubMed | CrossRef Fulltext
  9. Momin JH, Hughes GJ. Andexanet alfa (Andexxa) for the reversal of direct oral anticoagulants. PT 2019;44(9):530-549.

    PubMed | CrossRef Fulltext
  10. Portola Pharmaceuticals. Portola Announces Phase 3 ANNEXA-R Study of Andexanet Alfa and Factor Xa Inhibitor XARELTO(Rm) (rivaroxaban) Met Primary Endpoint With High Statistical Significance. Media-Rel 2015;.

    Media Release

Authors

Author Total Publications First Author Last Author
Barron L 1 - -
Bronson M 1 - -
Bronson MD 1 - -
Castillo J 3 - -
Conely PB 1 - -
Conley P 1 - -
Conley PB 2 - -
Connolly S 1 - 1
Connolly SJ 2 - -
Crowther M 3 1 -
Crowther MA 1 - 1
Curnutte J 1 - -
Curnutte JT 3 - 2
Finks SW 1 - 1
Gold A 1 - -
Gold AM 2 1 -
Hughes GJ 1 - 1
Leeds J 1 - -
Leeds JM 2 - -
Levy G 1 - -
Lin J 1 - -
Lu G 4 1 -
Mar FA 1 - -
Mathur V 1 - -
Mathur VS 1 - -
Momin JH 1 1 -
Portola Pharmaceuticals 4 4 4
Rogers KC 1 1 -
Siegal DM 1 1 -
Wiens BL 2 - -

Trial Centres

Investigators

Investigator Centre Name Trial Centre Country
Gallia Levy, MD, PhD
Phone: 650.246.7000
fXaantidoe@portola.com
show details
Portola Pharmaceuticals USA
Khanh Vo
714-252-0700 x1115
show details
West Coast Clinical Trials USA

Centres

Centre Name Location Trial Centre Country
Portola Pharmaceuticals South San Francisco, California USA
West Coast Clinical Trials Cypress, California USA

Trial History

Event Date Event Type Comment
14 Jan 2020 Other trial event Last checked against ClinicalTrials.gov record. Updated 14 Jan 2020
01 Sep 2019 Results Results (from ANNEXA-A, ANNEXA-R and ANNEXA-4) published in the P and T Updated 22 Nov 2019
26 Apr 2019 Other trial event According to a Portola Pharmaceuticals media release, based on results of ANNEXA-R, ANNEXA-A and ANNEXA-4 (n=352), studies, the European Commission (EC) has granted conditional Marketing Authorization of Ondexxya (andexanet alfa) for the treatment of the adult patients with the Factor Xa inhibitor apixaban or rivaroxaban when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding. Updated 03 May 2019
01 Mar 2019 Other trial event According to a Portola Pharmaceuticals media release, the CHMP has recommended that the European Commission (EC) grant Ondexxya conditional approval for the reversal of the anticoagulant effects of the Factor Xa inhibitors apixaban or rivaroxaban in patients experiencing uncontrolled or life-threatening bleeding. The EC is expected to issue a decision in early May 2019. Updated 08 Mar 2019
01 Mar 2019 Other trial event According to a Portola Pharmaceuticals media release, based on results of this study, the Committee for Medicinal Products for Human Use (CHMP) of the EMA has adopted a positive opinion on the marketing authorization application (MAA) for Ondexxya (andexanet alfa). Updated 08 Mar 2019
11 Dec 2018 Other trial event According to a Portola Pharmaceuticals media release, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has extended the review period for the Companys marketing authorization application (MAA) for Ondexxya (andexanet alfa), and cancelled the Oral Explanation scheduled for Wednesday, 12th Dec 2018. An opinion is now expected by 28th Feb 2019. Updated 24 Dec 2018
11 Dec 2018 Other trial event According to a Portola Pharmaceuticals media release, the CHMP informed Portola Pharmaceuticals that it will provide a list of outstanding questions related to the data package the Company submitted for Ondexxya last quarter, which will require additional responses from the Company. The preliminary timetable provided to the Company by the CHMP sets a deadline of 29th Jan 2019 for responses to the questions followed by a 30-day assessment period for the CHMP to review the Companys responses. Updated 24 Dec 2018
31 Aug 2018 Biomarker Update Biomarkers information updated Updated 10 Oct 2017
29 Aug 2018 Results Results assessing reversal of apixaban and rivaroxaban anticoagulation by andexanet alfa in ANNEXA-A&R as assessed by non-tissue factor (TF)-initiated thrombin generation independent of TF pathway inhibitor, presented at the ESC Congress 2018: Annual Congress of the European Society of Cardiology Updated 14 Sep 2018
24 Jul 2018 Results Results (from ANNEXA-A, ANNEXA-R and ANNEXA-4) published in the American Journal of Medicine Updated 02 Aug 2018
03 May 2018 Other trial event According to a Portola Pharmaceuticals media release, based on the results of ANNEXA-R, ANNEXA-A and interim data from ANNEXA-4 (n=185), the U.S. Food and Drug Administration (FDA) has approved Andexxa, the first and only antidote for patients treated with rivaroxaban and apixaban, in reversing the anticoagulant activity of the Factor Xa inhibitors. Updated 10 May 2018
03 May 2018 Other trial event Based on the results of ANNEXA-R, ANNEXA-A and interim data from ANNEXA-4, the Marketing Authorization Application (MAA) has been submitted to the European Medicines Agency (EMA) for andexanet alfa is under review. The Committee for Medicinal Products for Human Use (CHMP) communicated a positive trend vote on the MAA in February 2018. A formal opinion from the CHMP is expected by the end of 2018, and the European Commission is expected to issue a decision in early 2019. Updated 10 May 2018
22 Dec 2017 Other trial event According to a Portola Pharmaceuticals media release, the U.S. Food and Drug Administration (FDA) will extend its review of the Biologics License Application (BLA) for AndexXa (andexanet alfa) by 90 days. The company recently submitted additional data requested by the agency for the ongoing ANNEXA-4 study as part of the continuing review process. The FDA communicated that the action date will move from February 3, 2018 to May 4, 2018. Updated 28 Dec 2017
15 Aug 2017 Other trial event According to a Portola Pharmaceuticals media release, the U.S. Food and Drug Administration (FDA) has found its resubmitted Biologics License Application (BLA) of AndexXa (andexanet alfa) to be acceptable for review, with an action due date of February 2, 2018. Updated 18 Aug 2017
03 Aug 2017 Other trial event According to a Portola Pharmaceuticals media release, the company resubmitted a Biologics License Application (BLA) to the Center for Biologics Evaluation and Research (CBER) of the U.S. FDA for of AndexXa (andexanet alfa). The resubmission includes supplemental information primarily related to manufacturing, as requested by the FDA in a complete response letter (CRL) issued to Portola in August 2016. Updated 10 Aug 2017
13 Oct 2016 Other trial event According to a Portola Pharmaceuticals media release, the company expects to resubmit a Biologics License Application (BLA), AndexXa in 2017. Updated 27 Oct 2016
19 Aug 2016 Other trial event According to a Portola Pharmaceuticals media release, based on data from this and other study (see profile 238727) Marketing Authorization Application (MAA) has been submitted to the European Medicines Agency (EMA), completed the validation period, and has been accepted for review. The MAA also included limited adjudicated efficacy and safety data from initial patients of ANNEXA-4 study. Updated 14 Sep 2016
17 Aug 2016 Other trial event According to a Portola Pharmaceuticals media release, company has received a Complete Response Letter (CRL) from the U.S. Food and Drug Administration (FDA) regarding its Biologics License Application (BLA) for AndexXa (andexanet alfa). Updated 12 Sep 2016
19 Feb 2016 Results Pooled analysis (n=298) of 3 trials [see ANNEXA-A, ANNEXA-R and CTP 700238713] were presented at the 41st International Stroke Conference. Updated 12 Apr 2016
17 Feb 2016 Other trial event According to a Portola Pharmaceuticals media release, the Center for Biologics Evaluation and Research (CBER) of the U.S FDA has accepted the Biologics License Application (BLA) for andexanet alfa for filing under a priority review. The FDA is expected to take action on the application by the Prescription Drug User Fee Act (PDUFA) action date of August 17, 2016. Updated 23 Feb 2016
18 Dec 2015 Other trial event According to Portola media release, submission of BLA to the US FDA was completed based upon the inputs from this trial. Updated 22 Dec 2015
11 Nov 2015 Results Results of ANNEXA-A and ANNEXA-R studies published in the New England Journal of Medicine Updated 18 Nov 2015
11 Nov 2015 Results According to a Portola Pharmaceuticals media release,full results of Part 2 of of this trial were presented at the American Heart Associations (AHA) Scientific Sessions 2015. Updated 18 Nov 2015
11 Nov 2015 Results According to a Portola Pharmaceuticals media release, pooled results of 2 studies including data from this trial and other study (see CTP 700238727) were published in The New England Journal of Medicine. Updated 18 Nov 2015
11 Nov 2015 Results Pooled results of 2 studies including data from this trial and other study (see CTP 700238727) were published in a Portola Pharmaceuticals media release. Updated 18 Nov 2015
09 Nov 2015 Other trial event According to a Portola Pharmaceuticals media release, full data from part II of this trial will be presented during a Late-Breaking Clinical Trial oral session at the upcoming American Heart Association (AHA) Scientific Sessions. Updated 10 Nov 2015
01 Oct 2015 Status change - completed Status changed from recruiting to completed as per ClinicalTrials.gov record. Updated 07 Oct 2015
15 Sep 2015 Results Topline results from part II published in the Portola Pharmaceuticals media release. Updated 17 Sep 2015
15 Sep 2015 Other trial event Full data from Part 2 of the ANNEXA-R study have been accepted for presentation during a Late Breaking Clinical Trial session at the American Heart Association's (AHA) Scientific Sessions 2015 in November, as reported in Portola Pharmaceuticals media release. Updated 17 Sep 2015
06 May 2015 Results According to a Portola Pharmaceuticals media release, results from this trial were presented at the American College of Cardiology's 64th Annual Scientific Session. Updated 08 May 2015
06 May 2015 Endpoint met Primary endpoint has been met for the bolus-only part. (Reversal of Rivaroxaban anticoagulation effect as measured by anti-factor Xa activity) Updated 08 May 2015
16 Mar 2015 Results Results of part 1 presented at the 64th Annual Scientific Session of the American College of Cardiology. Updated 09 Sep 2015
02 Mar 2015 Results Results for the first part of the trial published in a Portola Pharmaceuticals media release. Updated 26 May 2015
02 Mar 2015 Other trial event Results from the second part of the trial are expected in mid-2015, according to a Portola Pharmaceuticals media release. Updated 26 May 2015
02 Mar 2015 Other trial event The first part of the ANNEXA-R study has been completed and the results will be presented at the 64th Annual Scientific Session of the American College of Cardiology (ACC); the second part of the study, evaluating a continuous infusion of andexanet alfa, is ongoing according to a Janssen media release. Updated 25 May 2015
12 Jan 2015 Other trial event According to a Portola Pharmaceuticals media release, the company plans to submit a Biologics Licence Application (BLA) to US FDA of Andexanet Alfa for the reversal of Factor Xa inhibitor anticoagulation in patients with major bleeding, by the end of 2015. The BLA will be submitted on the basis of this study and 2 other studies [see CTP 700238727 and 700248217]. Updated 04 Aug 2015
09 Jan 2015 Results Topline results from the first part of the trial published in Portola Pharmaceuticals media release. Updated 03 Aug 2015
22 Aug 2014 Other trial event New source identified and integrated (ClinicalTrials.gov record; NCT02220725). Updated 22 Aug 2014
06 Aug 2014 Other trial event Portola Pharmaceuticals plans to report full data from ANNEXA-A (see CT profile 700238727) and ANNEXA-R studies in the first half of 2015. Updated 30 Sep 2014
12 May 2014 Status change - recruiting Status changed from planning to recruiting, as reported by a Portola Pharmaceuticals media release. Updated 14 May 2014
27 Feb 2014 Other trial event Portola Pharmaceuticals plans to report phase 3 data in the fourth quarter of 2014 and additional data in the first half of 2015. Updated 13 Aug 2014
03 Feb 2014 Other trial event Phase III trials of andexanet alfa for reversal of rivaroxaban-induced anticoagulation are expected to begin in the first half of 2014 according to a Portola Pharmaceuticals media release. Updated 07 Apr 2014
18 Nov 2013 New trial record New trial record Updated 07 Apr 2014

References

  1. Portola Pharmaceuticals. Portola Pharmaceuticals Reports First Quarter 2015 Financial Results and Provides Corporate Update. Media-Rel 2015;.

    Media Release
  2. ClinicalTrials.gov: US National Institutes of Health. Trial-Reg 2016;.

    Available from: URL: http://clinicaltrials.gov
  3. Portola Pharmaceuticals. The New England Journal of Medicine Publishes Results of Portola Pharmaceuticals Phase 3 ANNEXA Studies of Andexanet Alfa. Media-Rel 2015;.

    Media Release
  4. Portola Pharmaceuticals. Portola Pharmaceuticals Announces Second Part of Phase 3 ANNEXA(TM)-R Study: Andexanet Alfa and Rivaroxaban Meets Primary and Secondary Endpoints. Media-Rel 2015;.

    Media Release
  5. Portola Pharmaceuticals. Portola Announces Full Results From Positive Phase 3 ANNEXA(Tm)-R Study Demonstrating That Andexanet Alfa Rapidly and Significantly Reversed Anticoagulant Effect of Factor Xa Inhibitor XARELTO(Rm). Media-Rel 2015;.

    Media Release
  6. Portola Pharmaceuticals. Portola Pharmaceuticals Announces Validation of Marketing Authorization Application (MAA) by European Medicines Agency (EMA) for IndexXa(TM) (andexanet alfa), a Factor Xa Inhibitor Antidote. Media-Rel 2016;.

    Media Release
  7. Portola Pharmaceuticals. U.S. FDA Approves Portola Pharmaceuticals Andexxa(R), First and Only Antidote for the Reversal of Factor Xa Inhibitors. Media-Rel 2018;.

    Media Release
  8. Portola Pharmaceuticals. Portola Pharmaceuticals Begins Enrollment in Phase 3 Study of FDA-Designated Breakthrough Therapy Andexanet Alfa and Factor Xa Inhibitor XARELTO(Rm). Media-Rel 2014;.

    Media Release
  9. Portola Pharmaceuticals. Portola Pharmaceuticals Announces New Topline Data From Phase 3 ANNEXA-A(Tm) Trial Part 2: Breakthrough Designated Andexanet Alfa Successfully Meets Primary Endpoint for Prolonged Reversal of Factor Xa Inhibitor Eliquis (apixaban). Media-Rel 2015;.

    Media Release
  10. Crowther M, Gold AM, Lu G, Leeds JM, Wiens BL, Mathur V, et al. Andexanet Alfa, a Universal Antidote for Reversal of Anticoagulation of Factor Xa Inhibitors in Healthy Human Volunteers. ISC-2016 2016; abstr. A212.

    Available from: URL: http://stroke.ahajournals.org/content/47/Suppl_1/A212.abstract?sid=f62e60b5-7da6-4a2a-b286-4d2e500f47d547/Suppl_1/A212#cited-by
  11. Portola Pharmaceuticals. Portola Pharmaceuticals Reports Fourth Quarter and Year-End 2013 Financial Results and Provides Corporate Update. Media-Rel 2014;.

    Media Release
  12. Portola Pharmaceuticals. Portola Pharmaceuticals Supports World Thrombosis Day Campaign to Increase Awareness of Risks of Blood Clots. Media-Rel 2016;.

    Media Release
  13. Portola Pharmaceuticals. Portola Pharmaceuticals Initiates Phase 4 Study to Support Accelerated Approval of Andexanet Alfa -- Its Breakthrough-Designated Factor Xa Inhibitor Antidote. Media-Rel 2015;.

    Media Release
  14. Lu G, Lin J, Bronson M, Crowther M, Conley PB, Curnutte JT. Reversal of apixaban and rivaroxaban anticoagulation by andexanet alfa in ANNEXA-A&R as assessed by non-tissue factor (TF)-initiated thrombin generation independent of TF pathway inhibitor (TFPI). ESC-Card-2018 2018; abstr. 5069.

    Available from: URL: http://link.adisinsight.com/w8PJo
  15. Portola Pharmaceuticals. Portola Pharmaceuticals Completes BLA Submission to U.S. Food and Drug Administration for Andexanet Alfa. Media-Rel 2015;.

    Media Release
  16. Portola Pharmaceuticals. Portola Pharmaceuticals Announces AndexXa(R) (Andexanet Alfa) Biologics License Application Resubmission Accepted for Review by U.S. FDA. Media-Rel 2017;.

    Media Release
  17. Portola Pharmaceuticals Inc. Portola Pharmaceuticals Announces Additional Positive Phase 2 Proof-of-Concept Data for Andexanet Alfa (PRT4445*). Media-Rel 2013;.

    Media Release
  18. Portola Pharmaceuticals. Portola Pharmaceuticals Announces Resubmission of Biologics License Application for AndexXa(R) (Andexanet Alfa). Media-Rel 2017;.

    Media Release
  19. Siegal DM, Curnutte JT, Connolly SJ, Lu G, Conley PB, Wiens BL, et al. Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. N-Engl-J-Med 2015;.

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  20. Gold AM, Crowther M, Levy G, Lu G, Leeds J, Barron L, et al. Annexatm-R: A phase 3 randomized, double-blind, placebo-controlled trial, demonstrating reversal of rivaroxaban-induced anticoagulation in older subjects by andexanet alfa (PRT064445), a universal antidote for factor xa (fXa) inhibitors. ACC-2015 2015; abstr. 71833080.

    Available from: URL: http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=emed13&AN=71833080
  21. Rogers KC, Finks SW. A New Option for Reversing the Anticoagulant Effect of Factor Xa Inhibitors: Andexanet alfa (Andexxa(R)). Am-J-Med 2018;.

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  22. Portola Pharmaceuticals. Portola Pharmaceuticals Announces Biologics License Application for Andexanet Alfa Accepted for Review by FDA. Media-Rel 2016;.

    Media Release
  23. Portola Pharmaceuticals. Portola Pharmaceuticals Announces Phase 3 ANNEXA(TM)-R Part 2 Study Results to be Presented at American Heart Association Scientific Sessions 2015. Media-Rel 2015;.

    Media Release
  24. Janssen. Findings to be Presented at Annual Scientific Session of the American College of Cardiology (ACC) About an Additional Potential Reversal Strategy for and Real-World Safety Performance of XARELTO(Rm). Media-Rel 2015;.

    Media Release
  25. Momin JH, Hughes GJ. Andexanet alfa (Andexxa) for the reversal of direct oral anticoagulants. PT 2019;44(9):530-549.

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  26. Portola Pharmaceuticals. European CHMP Adopts Positive Opinion on Ondexxya(T) (andexanet alfa) Portola Pharmaceuticals Factor Xa Inhibitor Reversal Agent. Media-Rel 2019;.

    Media Release
  27. Portola Pharmaceuticals. Portola Announces Phase 3 ANNEXA-R Study of Andexanet Alfa and Factor Xa Inhibitor XARELTO(Rm) (rivaroxaban) Met Primary Endpoint With High Statistical Significance. Media-Rel 2015;.

    Media Release
  28. Portola Pharmaceuticals. Portola Pharmaceuticals Receives Complete Response Letter from FDA for Biologics License Application for AndexXa(TM) (andexanet alfa). Media-Rel 2016;.

    Media Release
  29. Portola Pharmaceuticals. CHMP Extends Review Period for Portola Pharmaceuticals Ondexxya(Tm) (andexanet alfa). Media-Rel 2018;.

    Media Release
  30. Portola Pharmaceuticals. European Commission Grants Conditional Marketing Authorization for Portola Pharmaceuticals' Ondexxya(Tm) (andexanet alfa), the First and Only Antidote for the Reversal of Factor Xa Inhibitors. Media-Rel 2019;.

    Media Release
  31. Portola Pharmaceuticals. Portola Pharmaceuticals Provides Update on Biologics License Application (BLA) for AndexXa(R) (andexanet alfa). Media-Rel 2017;.

    Media Release
  32. Portola Pharmaceuticals. Portola Pharmaceuticals Enters Into Clinical Collaboration Agreement With Bayer and Janssen for Phase 3 Studies of Andexanet Alfa*, Investigational Factor Xa Inhibitor Reversal Agent, and XARELTO(Rm). Media-Rel 2014;.

    Media Release
  33. Portola Pharmaceuticals. Portola Pharmaceuticals Reports Second Quarter Financial Results and Provides Corporate Update. Media-Rel 2014;.

    Media Release
  34. Portola Pharmaceuticals. Portola Pharmaceuticals Announces Commercial Supply Agreement for Andexanet Alfa With Lonza. Media-Rel 2014;.

    Media Release
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