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Prospective, Open-Label Study of Andexanet Alfa in Patients Receiving a Factor XA Inhibitor Who Have Acute Major Bleeding (Annexa-4), Amendment 6 - Annexa-4

Trial Profile

Prospective, Open-Label Study of Andexanet Alfa in Patients Receiving a Factor XA Inhibitor Who Have Acute Major Bleeding (Annexa-4), Amendment 6 - Annexa-4

Status: Completed
Phase of Trial: Phase III/IV

Latest Information Update: 17 May 2021

At a glance

  • Drugs Andexanet alfa (Primary)
  • Indications Gastrointestinal haemorrhage; Haemorrhage; Intracranial haemorrhages
  • Focus Registrational; Therapeutic Use
  • Acronyms ANNEXA-4
  • Sponsors Portola Pharmaceuticals
  • Most Recent Events

    • 17 May 2021 Results (n=22) of sub-study analysis assessing the safety and efficacy of andexanet alfa for acute bleeding during treatment with enoxaparin, presented at the 70th Annual Scientific Session of the American College of Cardiology.
    • 10 May 2021 For the modified Rankin Scale score, baseline was first defined as 3 h before the start of bolus. After protocol amendment, it was assessed 15 min before bolus.
    • 10 May 2021 Results (n=227) of sub-study assessing efficacy and safety of andexanet in patients with ICrH published in the Stroke

Trial Overview

Purpose

This phase IIIb/IV study is designed to evaluate andexanet alfa in patients who present with an acute major bleed while receiving apixaban, rivaroxaban, edoxaban or enoxaparin.
This multi-center cohort study is not randomized and all participants received andexanet alfa given as a bolus dose over 20-30 minutes followed by a two-hour (120 minute) infusion. Patients received a low or high dose infusion depending on which Factor Xa inhibitor they received and the time since they received the last dose. Patients were evaluated for 30 days following andexanet alfa administration.

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

The two primary endpoints are:

1)The percent change from baseline (pre-treatment with andexanet) in anti-fXa activity

The percent change from baseline (pre-treatment with andexanet) in anti-fXa activity to the nadir from the evaluation period (where the evaluation period starts 5 minutes following the end of the andexanet bolus and ends 10 minutes after the end of the andexanet infusion).

2) The achievement of haemostatic efficacy.

The primary endpoints, including the evaluation of hemostatic efficacy in specific study populations against specific comparators, will be ordered in a fixed sequence multiple comparisons (i.e., hierarchical) fashion as delineated in the SAP.
Timepoint: Patients receive andexanet as an IV bolus administered over ~15–30 minutes, followed immediately by a continuous infusion administered over ~120 minutes. Primary endpoint 1: Sample for anti-fXa activity is drawn at 2 timepoints; one at (or within 30 minutes after) the end of the bolus, and another at (or within 30 minutes prior to) the end of the infusion. Primary Endpoint 2: Haemostatic efficacy: MRI/CT; GCS , mRS and NIHSS for ICH (pre-bolus and at 1hr, 12hr, +7d after end of infusion (EI). Transfusion-corrected haemoglobin and haematocrit for non-visible bleeding (at 12hr); Echocardiogram for pericardial bleed (pre-bolus and at 12hr EI). Ultrasound or CT/MRI scan for intraspinal bleeding (pre-bolus and at 1hr, 12hr, +7d EI).

Other Endpoints

Secondary Endpoints:
The secondary efficacy objective is to assess the relationship between the two primary efficacy endpoints. No additional efficacy endpoint is defined to support the secondary efficacy objective.
Exploratory Endpoints:
• The number of patients receiving one or more red blood cell transfusions from the start of the andexanet bolus through 12 hours after the end of andexanet infusion.
• For patients receiving apixaban, rivaroxaban, or edoxaban, to evaluate the decrease in free fraction of the fXa inhibitor following andexanet administration.
• The number of red blood cell units transfused per patient from the start of the andexanet bolus through 12 hours after the end of the andexanet infusion.
• The use of non-study-prescribed blood products and/or hemostatic agents.
• The occurrence of re-bleeding following andexanet treatment. Re-bleeding is defined as follows: bleeding from the same anatomical site in patients within 24 hours of initial andexanet treatment and after achieving initial good/excellent hemostasis.
• Andexanet reversal of anticoagulant effect as measured through TG parameters (with, endogenous thrombin potential (ETP) as the primary measure), for both the Tissue Factor (TF)-initiated assay and the non-TF-initiated assay.
• TFPI levels, both free and total, pre- and post-administration of andexanet.
• ATIII levels, pre- and post-administration of andexanet.
• Anti-factor IIa levels, pre- and post-administration of andexanet (enoxaparin patients only).
• The achievement of hemostatic efficacy in ICH patients at high risk of hematoma expansion.
• Change from baseline in GCS (for ICH patients only).
• Change from baseline in mRS (for ICH patients only).
• Change from baseline in NIHSS (for ICH patients only).
Safety Measurements:
-Survival status, AEs, vital signs, and clinical laboratory measurements
-Centrally-adjudicated Treatment-Emergent Adverse Events
-Antibodies to andexanet, fX, and fXa
Timepoint: Exploratory: -No. of red blood cell units transfused, use of non-study-prescribed hemostatic agents (start of bolus through 12 hr) -Free fraction of the direct fXa inhibitor (pre-bolus and 4hr, 8hr 12hr) -Re-bleeding within 24 hours -TG parameters (with ETP as primary measure), for both the TF-initiated and non-TF-initiated assay (pre-bolus, end of bolus, end of infusion, 4hr, 8hr 12hr 24, 48, 72hr, +7days) -ATIII and TFPI levels, pre- and post-administration of andexanet (-30 min EI, 4hr, 8hr 12hr 24, 48, 72hr, +7days) -Anti-factor IIa levels, pre- and post-administration -GCS, mRS and NIHSS (pre-bolus and at 1 hr, 12 hrs, and 30 days (for ICH only)). Safety: Antibodies to andexanet, fX, and fXa (pre-bolus and +7 days) AEs (followed through Study Day 30 post-treatment visit. [1]

Diseases Treated

Indication Qualifiers Patient Segments
Gastrointestinal haemorrhage treatment -
Haemorrhage treatment -
Intracranial haemorrhages treatment -

Subjects

  • Subject Type patients
  • Number

    Planned: 500

    Actual: 479

  • Sex male & female
  • Age Group ≥ 18 years; adult; elderly

Patient Inclusion Criteria

1. Acute major bleeding episode requiring urgent reversal of anticoagulation; defined by at least one of the following:
Acute bleeding that is potentially life-threatening, OR
Acute bleeding associated with a fall in hemoglobin level by ≥2 g/dL, OR
Acute bleeding associated with a hemoglobin level of ≤8 g/dL if no baseline hemoglobin is available, OR
Acute bleeding in a critical area or organ such as intraspinal, pericardial, or intracranial.

2. If bleeding is intracranial or intraspinal, the patient must have undergone a head CT or MRI scan demonstrating the bleeding.
3. Patient received or is believed to have received one of the following within 18 hours prior to andexanet administration: apixaban, rivaroxaban, edoxaban or enoxaparin.
4. For patients with intracranial bleeding, there must be a reasonable expectation that andexanet treatment will commence within 2 hours of the baseline imaging evaluation.

Patient Exclusion Criteria

Inclusion: 1. Acute major bleeding episode requiring urgent reversal of anticoagulation; defined by at least one of the following: - Acute bleeding that is potentially life-threatening, OR - Acute bleeding associated with a fall in hemoglobin level by ≥2 g/dL, OR - Acute bleeding associated with a hemoglobin level of ≤8 g/dL if no baseline hemoglobin is available, OR - Acute bleeding in a critical area or organ such as intraspinal, pericardial, or intracranial. 2. If bleeding is intracranial or intraspinal, the patient must have undergone a head CT or MRI scan demonstrating the bleeding. 3. Patient received or is believed to have received one of the following within 18 hours prior to andexanet administration: apixaban, rivaroxaban, edoxaban or enoxaparin. 4. For patients with intracranial bleeding, there must be a reasonable expectation that andexanet treatment will commence within 2 hours of the baseline imaging evaluation. Exclusion: 1. The patient is scheduled to undergo surgery in less than 12 hours, with the exception of minimally invasive surgery/procedures. 2. A patient with an intracerebral hemorrhage has any of the following: - Glasgow coma score < 7, OR - Intracerebral hematoma > 60 cc as assessed by CT or MRI 3. Patients with visible, musculoskeletal or intra-articular bleeding as their qualifying bleed. 4. Expected survival of less than 1 month 5. Recent history (within 2 weeks) of a diagnosed thrombotic event (TE) as follows: venous thromboembolism, myocardial infarction, disseminated intravascular coagulation (DIC), cerebral vascular accident, transient ischemic attack, unstable angina pectoris hospitalization or severe peripheral vascular disease within 2 weeks prior to screening. 6. Severe sepsis or septic shock at the time of Screening. 7. Pregnant or a lactating female. 8. Patient has received any of the following drugs or blood products within 7 days of Screening: - Vitamin K antagonist (VKA) - Dabigatran - Prothrombin Complex Concentrate products (PCC) or recombinant factor VIIa (rfVIIa) - Whole blood, plasma fractions 9. Treated with an investigational drug <30 days prior to Screening 10. Planned administration of PCC, fresh frozen plasma (FFP) or rfVIIa from Screening until within 12 hours after the end of the andexanet infusion.

Trial Details

Identifiers

Identifier Owner
NCT02329327 ClinicalTrials.gov: US National Institutes of Health
EudraCT2015-001785-26 European Clinical Trials Database
DRKS00012316 German Clinical Trials Register
14-505 -
EK421102015 -

Organisations

  • Sponsors Portola Pharmaceuticals
  • Affiliations Portola Pharmaceuticals

Trial Dates

  • Initiation Dates

    Planned : 01 Jan 2015

    Actual : 01 Jan 2015

  • Primary Completion Dates

    Planned : 24 Sep 2020

    Actual : 24 Sep 2020

  • End Dates

    Planned : 24 Sep 2020

    Actual : 24 Sep 2020

Substudies/Extensions

ANNEXA-4 sub-study: This sub-study assessed the occurrence of thrombotic events (TEs).

Other Details

  • Design multicentre; open; prospective
  • Phase of Trial Phase III/IV
  • Location Belgium; Canada; England; France; Germany; Japan; Netherlands; Spain; United Kingdom; USA; Wales
  • Focus Registrational; Therapeutic Use

Interventions

Drugs Route Formulation
Andexanet alfaPrimary Drug Intravenous Infusion

Andexanet

Biological: Andexanet
Description: All participants received andexanet alfa given as a bolus dose over 20-30 minutes followed by a two-hour (120 minute) infusion. Patients received a low or high dose infusion depending on which Factor Xa inhibitor they received and the time since they received the last dose. Patients were evaluated for 30 days following andexanet alfa administration.

Results

Therapeutic efficacy

Results from IIIb/IV ANNEXA-4 study showed that andexanet alfa rapidly and substantially reversed anti-Factor Xa activity, and these levels were sustained for the duration of administration. Excellent or good haemostasis was observed in 87.5% of patients and in 80% of those with intracranial haemorrhage. In 22 patients (mean age 68.0 years, 54.5% male and 63.6% with venous thromboembolism as primary indication) with acute major bleeding on enoxaparin, median anti-factor Xa activity decreased from 0.48 ([IQR] 0.41, -0.61) IU/mL at baseline to 0.14 (IQR 0.10, 0.17) IU/mL at the end of andexanet bolus administration (median decrease of 75.0%, 95% CI: 66.7-79.2%) in 17 patients. Excellent or good haemostasis at 12 hrs was achieved in 14 of 16 (87.5%, 95% CI: 61.7-98.4%) cases of the efficacy population in whom this could be assessed, and in 8 of 10 (80.0%, 95% CI: 44.4-97.5%) cases with intracranial haemorrhage. Earlier results showed that the median anti-Factor Xa activity decreased by 90% from baseline for patients on rivaroxaban and by 93% for patients on apixaban following the bolous dose, and sustained this reversal when followed by a 120-minute infusion. Additionally, 37 of 47 patients (79%) achieved excellent or good haemostasis over a 12-hour period following infusion. Haemostatic efficacy was similar for patients on apixaban (75%) and rivaroxaban (81%). The efficacy population included only those 47 patients whose bleed severity met the specific inclusion criteria. Updated data from 228 patients (of which 132 were adjudicated for efficacy) showed rapid and significant reversal of anti-Factor Xa activity was observed in andexanet alfa treated patients when administered as a bolus with a sustained reversal observed when followed by a 120-minute infusion. Excellent or good haemostasis achieved in 83 percent of andexanet alfa patients over a 12-hour period. Data from adjudicated efficacy population of 132 patients also demonstrated that andexanet alfa rapidly and substantially reversed anti-Factor Xa activity, and these levels were sustained for the duration of administration. The co-primary efficacy endpoint of the trial, anti-Factor Xa activity decreased by a median of greater than 90 percent for both apixaban and rivaroxaban following the bolus dose, which was sustained at similar levels for the duration of the two-hour infusion. 83% of the adjudicated efficacy patients achieved effective haemostasis. In patients with gastrointestinal bleeding, 86 percent had effective haemostasis, as did 81 percent of patients with intracranial bleeding. Both apixaban and rivaroxaban treated patients showed similar haemostatic efficacy of 82 and 83 percent respectively. The prospective, open-label trial evaluated the haemostatic efficacy of andexanet alfa in patients receiving a factor Xa inhibitor who have acute major bleeding. Updated results from 352 patients (249 of which were evaluable for efficacy) showed that rapid and significantly reversal of anti-Factor Xa activity (a measure of the anticoagulant activity of apixaban, rivaroxaban, edoxaban and enoxaparin, the anticoagulants studied in the trial) when administered as a bolus was observed and the reversal was sustained this reversal when followed by a 120-minute infusion. Excellent or good hemostasis (stoppage of bleeding) was achieved over the 12-hour period following treatment with andexanet alfa, as determined by an independent adjudication committee in 204 of 249 (82%) evaluable patients for efficacy. Among 98 evaluable patients in the subset, the median increase in haematoma volume from baseline to 12 hours, was 0.06 milliliters. Further, 71 patients in the subset experienced a spontaneous, single-compartment, intracerebral hemorrhage, which allows for the most precise measurement of hematoma volume. Of the patients that achieved excellent or good haemostatic efficacy within one hour post andexanet alfa treatment, 55 out of 56 patients (98%) maintained excellent or good hemostatic control for 12 hours, following the treatment. New exploratory analysis data showed that among 352 patients, 90 (26%) acute GI bleeding and 62 (18%) were evaluable for hemostatic efficacy. Bleeding was stopped in 82% (n = 51/62) of patients in the treatment arm over a period of 12 hours following treatment with andexxa alfa, which was consistent with the full study results. In 327 patients, who received apixaban or rivaroxaban, thrombine generation (TG) as measured by the endogenous thrombin potential (ETP) at 8 hr post end of infusion (ETP-8H) was increased post bolus and maintained through out infusion. ETP was decreased post infusion, however it was maintained in reference range for 18 hr. There was no difference in ETP-8H in patients with or without thrombotic complications (p = 0.610) and effective hemostasis (p = 0.544). In this analysis, ETP-8H failed to predict effective hemostasis (p = 0.491) or thrombotic events (p = 0.743). Also, ETP-8H did not predict hematoma growth in patients with ICH (p = 0.349). The prospective, open-label trial evaluated the haemostatic efficacy of andexanet alfa in patients receiving a factor Xa inhibitor who have acute major bleeding [2] [3] [4] [5] [6] [7] .

Adverse events

Phase IIIb/IV: Results from a phase IIIB/IV trial in non-vitamin K oral anticoagulant (Noac) related bleeding demonstrated that the 30 day mortality was lower in patients receiving andexanet alfa treatment. Updated results showed that Within 30 days, of 22 patients, one patient (4.5%) with acute major bleeding on enoxaparin, who received andexanet experienced a thromboembolic event and two (9.1%) patients died. Previous data from 322 enrolled patients showed 65% and 67%of intracranial haemorrhage (ICH) and a 25% and 29% of gastrointestinal bleeding in the andexanet and PCC cohorts respectively. Results showed that 67 patients who received andexanet alfa showed that the antidote was not associated with any infusion reactions, and no patients developed antibodies to Factor Xa or Factor X or neutralizing antibodies. Thrombotic events occurred in 14 patients with spontaneous intracranial hemorrhage (10.9%) and death occurred in 24 patients (18.8%), during the trial. Among 18 patients, who re-started oral anti-coagulation therapy within 30 days, no thrombotic events were observed. However, the majority of thrombotic events occurred in patients who delayed or did not re-start anti-coagulation therapy, with a Factor Xa inhibitor, during the follow-up period. The interim results from ANNEXA-4 study included safety data from 67 patients who experienced life-threatening gastrointestinal bleeding (49%), intracranial bleeding (42%) or bleeding at another site (9%) within 18 hours of administration of apixaban (31 patients), rivaroxaban (32 patients) or enoxaparin (4 patients). The occurrence of rate of events were in the range of expected in the study population given the severity of the bleeding, the study population advanced age and underlying thrombotic risk, and the percentage who restarted anticoagulant therapy (57%) following their bleeding episode. Infusion reaction was observed in two of the 228 patients. No patient developed antibodies to Factor Xa or Factor X or neutralizing antibodies to andexanet alfa. Final results from 352 patients showed that 227 were treated for intracranial hemorrhage (ICH) and 90 were treated for a gastrointestinal bleed. Thrombotic events (TEs) occurred in 34 patients and death was reported in 49 patients, consistent with previously reported trial results and with the high background thrombotic risk of the enrolled patient population. Before restart of any (full or prophylactic) anticoagulation, 26 (76.4%) patients showed TEs (n=34). The majority of thrombotic events occurred in patients who delayed or did not re-start anticoagulation therapy with a Factor Xa inhibitor during the follow-up period. No thrombotic events were observed among the 100 patients who re-started oral anticoagulation therapy. An infusion reaction was reported in two patients and none of the patient developed antibodies to Factor Xa or Factor X or neutralizing antibodies to the drug. The prospective, open-label trial evaluated the haemostatic efficacy of andexanet alfa in patients receiving a factor Xa inhibitor who have acute major bleeding. New exploratory analysis involving 352 patients showed that, of the 90 patients evaluable for safety study, TEs were reported in six patients (7%) and death occurred in 10 patients (11%). TEs were not reported in 40 patients (44%) who re-started oral anticoagulation therapy. The most common TEs observed were stroke and deep vein thrombosis. Patients with venous TEs were more anticoagulated for venous thromboembolism, in comparison with patients with arterial TEs. Median time to first TE was reported as 10.5 days, however time to event was longer for venous TEs, in comparison with arterial TEs. For most patients, the TEs were nonfatal [2] [8] [9] [4] [5] [7] [6] .

Immunogenicity

Low titers of anti- andexanet alfa antibodies were observed in 17% of healthy participants, of which 6% and 14% had low titers on day 30 and through days 44 to 48 respectively. Both healthy volunteers and patients of the ANNEXA-4 trial had a similar pattern of antibody response with 6% of the patients having antibodies against andexanet alfa. None of these anti-andexanet alfa antibodies were neutralizing and they showed no cross-reaction with FX or FXa in either healthy volunteers or in bleeding patients. The results were obtained from a total of 98 patients and 145 healthy volunteers [10] .

Publications

  1. van Haaps TF, Benz AP, Xu L, Coppens M, Eikelboom JW, Milling Jr TJ, et al. Andexanet Alfa for Acute Bleeding During Treatment with Enoxaparin. ACC-2021 2021; abstr. N/A.

    Available from: URL: https://www.sciencedirect.com/science/article/pii/S0735109721032125
  2. Coppens M, Xu L, Bavalia R, Middeldorp S, Verhamme P, Eikelboom JW, et al. Effects of Andexanet Alfa on Thrombin Generation in Bleeding Associated with Factor Xa Inhibitors. ASH-Hem-2019 2019; abstr. 711.

    Available from: URL: https://ash.confex.com/ash/2019/webprogram/Paper124596.html
  3. Portola Pharmaceuticals. Portola Pharmaceuticals Presents New Analysis from the ANNEXA-4 Study of its Factor Xa Inhibitor Reversal Agent Andexxa(Rm) in Patients with Acute Gastrointestinal Bleeding. Media-Rel 2019;.

    Media Release
  4. Portola Pharmaceuticals. Portola Pharmaceuticals Announces Interim Results from Ongoing Phase 3b/4 ANNEXXA-4(Tm) Study of Factor Xa Inhibitor Antidote AndexXa(Tm) (andexanet alfa) in Patients with Acute Major Bleeding. Media-Rel 2016;.

    Media Release
  5. Portola Pharmaceuticals. Portola Pharmaceuticals Announces New Interim Results from Ongoing ANNEXA-4 Study of Factor Xa Inhibitor Reversal Agent AndexXa(R)(Andexanet Alfa) in Patients with Life-Threatening Bleeding. Media-Rel 2018;.

    Media Release
  6. Portola Pharmaceuticals. Portola Pharmaceuticals Announces Full Results from the ANNEXA-4 Study of the Factor Xa Inhibitor Reversal Agent Andexxa(Rm) in Patients with Life-Threatening Bleeding. Media-Rel 2019;.

    Media Release
  7. Cohen AT, Lewis M, Connor A, Connolly S, Yue P, Curnutte J, et al. 30 Day Mortality Following Andexanet Alfa in Annexa-4 Compared with Prothrombin Complex Concentrate (Pcc) Therapy in the Orange Study for Life Threatening Non-Vitamin K Oral Anticoagulant (Noac) Related Bleeding. ACC-WCC-2020 2020; abstr. 1213-209.

    Available from: URL: https://www.sciencedirect.com/science/article/pii/S0735109720328692
  8. Beyer-Westendorf J, Yue P, Crowther M, Eikelboom JW, Gibson CM, Milling TJ, et al. Thrombotic events in bleeding patients treated with andexanet alfa: an ANNEXA-4 sub-study. ESC-Card-2019 2019; abstr. 288.

    Available from: URL: http://link.adisinsight.com/k5QCn
  9. Connolly SJ, Milling TJ Jr, Eikelboom JW, Gibson CM, Curnutte JT, Gold A, et al. Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors. N-Engl-J-Med 2016;.

    PubMed | CrossRef Fulltext
  10. Benz AP, Xu L, Eikelboom JW, Middeldorp S, Milling Jr TJ, Crowther M, et al. Andexanet Alfa for Acute Bleeding During Treatment With Edoxaban. ISC-2021 2021; abstr. P3.

    Available from: URL: https://www.abstractsonline.com/pp8/9216/presentation/2838
  11. Portola Pharmaceuticals. Portola Pharmaceuticals Announces New Analysis from the ANNEXA-4 Study of its Factor Xa Inhibitor Reversal Agent Andexxa(R) in Patients with Spontaneous (Non-Traumatic) Intracranial Hemorrhage. Media-Rel 2019;.

    Media Release
  12. Demchuk AM, Yue P, Zotova E, Nakamya J, Xu L, Milling TJ Jr, et al. Hemostatic Efficacy and Anti-FXa (Factor Xa) Reversal With Andexanet Alfa in Intracranial Hemorrhage: ANNEXA-4 Substudy. . Stroke 2021;STROKEAHA120030565.

    PubMed | CrossRef Fulltext
  13. Connolly SJ, Milling TJ, Eikelboom JW, Gibson CM, Curnutte JT, Gold A, et al. Andexanet Alfa for the Management of Acute Major Bleeding Associated with FXa Inhibitors. AAN-2017 2017; abstr. 3055.

    Available from: URL: http://submissions.mirasmart.com/AAN2017/itinerary/login.asp
  14. 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
  15. Momin JH, Hughes GJ. Andexanet alfa (Andexxa) for the reversal of direct oral anticoagulants. PT 2019;44(9):530-549.

    PubMed | CrossRef Fulltext
  16. Leeds JM, Xiong Y, Lovern M, Der K, Mandema JW, Lu G, et al. Effect of Covariates in the Pharmacokinetic/Pharmacodynamic Model of Andexanet Alfa Used to Predict the Regimen for Reversal of Anticoagulation by Fxa Inhibitors in Patients with Acute Major Bleeding. EHA-2018 2018; abstr. S839.

    Available from: URL: https://learningcenter.ehaweb.org/eha/2018/stockholm/214457/janet.m.leeds.effect.of.covariates.in.the.pharmacokinetic.pharmacodynamic.html?f=menu=6*ce_id=1346*ot_id=19074*media=3*marker=170
  17. Siegal D, Beyer-Westendorf J, Yue P, Souza S, Nakamya J, Connolly SJ, et al. The Efficacy and Safety of Andexanet Alfa in Patients With Acute Gastrointestinal Bleeding While Taking Factor Xa Inhibitors: An ANNEXA-4 Sub-Analysis. ACG-2019 2019; abstr. 579.

    Available from: URL: https://journals.lww.com/ajg/Fulltext/2019/10001/The_Efficacy_and_Safety_of_Andexanet_Alfa_in.579.aspx

Authors

Author Total Publications First Author Last Author
Albaladejo P 3 - -
Bavalia R 1 - -
Benz AP 2 1 -
Beyer-Westendorf J 4 1 -
Bronson MD 1 - -
Cohen AT 5 1 -
Conley P 1 - -
Conley PB 6 - 1
Connolly S 1 - -
Connolly SJ 9 2 4
Connor A 1 - -
Coppens M 2 1 -
Crowther M 9 - 3
Curnutte J 1 - -
Curnutte JT 5 - -
Demchuk AM 2 1 -
Der K 1 - -
Eikelboom JW 7 - -
Finks SW 1 - 1
Gibson CM 3 - -
Gold A 2 - -
Goldstein JN 1 - -
Goodman S 2 - -
Green L 1 - 1
Hughes GJ 1 - 1
Leeds J 1 - -
Leeds JM 2 1 -
Lewis M 1 - -
Lim WT 2 - -
Lopez-Sendon J 2 - -
Lopez-Sendon JL 1 - -
Lovern M 1 - -
Lu G 6 - -
MacCallum P 1 - -
Mandema JW 1 - -
Meeks B 1 - -
Middeldorp S 7 - 1
Milling Jr TJ 2 - -
Milling TJ 3 - -
Milling TJ Jr 2 - -
Momin JH 1 1 -
Nakamya J 4 - -
Ohara T 1 - -
Portola Pharmaceuticals 5 5 5
Rogers KC 1 1 -
Schmidt J 3 - -
Sendon JL? 1 - -
Siegal D 1 1 -
Siegal DM 2 - -
Souza S 1 - -
Tan J 1 - -
van Haaps TF 1 1 -
Verhamme P 5 - -
Westendorf JB? 1 - -
Wiens BL 1 - -
Xiong Y 1 - -
Xu L 4 - -
Yue P 8 - -
Zotova E 3 - -

Trial Centres

Investigators

Investigator Centre Name Trial Centre Country
Clinical Development
270 East Grand Avenue,
South San Francisco
Postcode: CA 94080
United States
Telephone: 0016502467039
pyue1@Portola.com
show details
Portola Pharmaceuticals USA
Jim Farmer
650.246.7000
fXaantidoe@portola.com
show details
Portola Pharmaceuticals USA

Centres

Centre Name Location Trial Centre Country
- Altenburg Germany
- Amsterdam Netherlands
- Annapolis, Maryland USA
- Asheville, North Carolina USA
- Augsburg Germany
- Austin, Texas USA
- Barcelona Spain
- Berlin Germany
- Boston, Massachusetts USA
- Bremen Germany
- Bruxelles Belgium
- Caceres Spain
- Cardiff United-Kingdom
- Celle Germany
- Chapel Hill, North Carolina USA
- Chemnitz Germany
- Cincinnati, Ohio USA
- Clermont-Ferrand France
- Cleveland, Ohio USA
- Coburg Germany
- Detmold Germany
- Detroit, Michigan USA
- Dresden Germany
- Essen Germany
- Fort Lauderdale, Florida USA
- Fort Worth, Texas USA
- Göttingen Germany
- Genk Belgium
- Greifswald Germany
- Grenoble France
- Halle Germany
- Hamburg Germany
- Hamilton, Ontario Canada
- Hannover Germany
- Heidelberg Germany
- Hessen Germany
- Huntington, West Virginia USA
- Jacksonville, Florida USA
- Jena Germany
- Konstanz Germany
- Leipzig Germany
- Leuven Belgium
- Limoges France
- London United-Kingdom
- Long Beach, California USA
- Los Angeles, California USA
- Lubeck Germany
- Ludwigshafen Germany
- Lyon France
- Münster Germany
- Madrid Spain
- Mainz Germany
- Minden Germany
- Montreal, Quebec Canada
- Munich Germany
- Orange, California USA
- Osnabrück Germany
- Pittsburgh, Pennsylvania USA
- Poitiers France
- Raleigh, North Carolina USA
- Regensburg Germany
- Rochester, New York USA
- Royal Oak, Michigan USA
- Saint Louis, Missouri USA
- Sande Germany
- Sarasota, Florida USA
- Stoke on Trent United-Kingdom
- Tübingen Germany
- Tampa, Florida USA
- Trier Germany
- Troy, Michigan USA
- Ulm Germany
- Würzburg Germany
Brain Attack Center Ota Memorial Hospital Hiroshima Japan
Center Hospital of the National Center for Global Health and Medicine Tokyo Japan
Hitachi General Hospital, Hitachi, Ltd. Ibaraki Japan
Institute of Brain and Blood Vessels Mihara Memorial Hospital Gunma Japan
Iwate Medical University Hospital Shiwa-gun Japan
Japanese Red Cross Kumamoto Hospital Kumamoto Japan
Kobe City Medical Center General Hospital, Local Independent Administrative Agency Kobe Japan
National Cerebral and Cardiovascular Center Suita Japan
National Hospital Organization Nagoya Medical Center Nagoya Japan
National Hospital Organization Sendai Medical Center Sendai Japan
Nippon Medical School Hospital Tokyo Japan
Population Health Research Institute
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Population Health Research Institute
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Portola Pharmaceuticals
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Portola Pharmaceuticals San Francisco USA
Rinku General Medical Center Izumisano Japan
Saiseikai Kumamoto Hospital, Social Welfare Organization Imperial Gift Foundation, Inc. Kumamoto Japan
Steel Memorial Yawata Hospital Fukuoka Japan
Teikyo University Hospital Tokyo Japan
Worldwide Clinical Trials
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Yamaguchi University Hospital Yamaguchi Japan
Yokosuka Kyosai Hospital Yokosuka Japan

Trial History

Event Date Event Type Comment
17 May 2021 Results Results (n=22) of sub-study analysis assessing the safety and efficacy of andexanet alfa for acute bleeding during treatment with enoxaparin, presented at the 70th Annual Scientific Session of the American College of Cardiology. Updated 04 Jul 2021
10 May 2021 Protocol amendment For the modified Rankin Scale score, baseline was first defined as 3 h before the start of bolus. After protocol amendment, it was assessed 15 min before bolus. Updated 20 May 2021
10 May 2021 Results Results (n=227) of sub-study assessing efficacy and safety of andexanet in patients with ICrH published in the Stroke Updated 18 May 2021
19 Mar 2021 Results Results (n=36) assessing safety and efficacy of Andexanet Alfa in patients with acute bleeding on edoxaban, presented at the International Stroke Conference 2021 Updated 26 Apr 2021
15 Dec 2020 Other trial event Last checked against European Clinical Trials Database record. Updated 15 Dec 2020
13 Nov 2020 Other trial event Last checked against German Clinical Trials Register record. Updated 13 Nov 2020
08 Oct 2020 Other trial event Last checked against ClinicalTrials.gov record. Updated 08 Oct 2020
05 Oct 2020 Status change - completed Status changed from active, no longer recruiting to completed. Updated 08 Oct 2020
17 Sep 2020 Completion date Planned End Date changed from 1 Nov 2022 to 24 Sep 2020. Updated 21 Sep 2020
17 Sep 2020 Other trial event Planned primary completion date changed from 1 Nov 2022 to 24 Sep 2020. Updated 21 Sep 2020
17 Sep 2020 Status change - active, no longer recruiting Status changed from recruiting to active, no longer recruiting. Updated 21 Sep 2020
27 Aug 2020 Other trial event This trial is completed in Germany, according to European Clinical Trials Database record. Updated 27 Aug 2020
30 Mar 2020 Results Results (n=410) assessing NOAC related major bleeding by conducting indirect comparison using data ANNEXA-4 and ORANGE studies, presented at the 2020 Annual Scientific Session of the American College of Cardiology and World Congress of Cardiology Updated 23 May 2020
16 Mar 2020 Other trial event According to a Portola Pharmaceuticals media release, data from this study will be presented at the American College of Cardiology's Annual Scientific Session together with the World Congress of Cardiology (ACC.20/WCC) Updated 18 Mar 2020
06 Nov 2019 Results Results released in the 61st Annual Meeting and Exposition of the American Society of Hematology. Updated 04 Dec 2019
30 Oct 2019 Results Results (n=352) of sub analysis of ANNEXA-4 evaluating Efficacy and Safety of Andexanet Alfa in Patients With Acute Gastrointestinal Bleeding While Taking Factor Xa Inhibitors, presented at the American College of Gastroenterology Annual Scientific Meeting and Postgraduate Course 2019 Updated 19 Feb 2020
28 Oct 2019 Interim results Results from the exploratory analysis of the study, presented in a Portola Pharmaceuticals media release. Updated 05 Nov 2019
28 Oct 2019 Other trial event According to a Portola Pharmaceuticals media release, data from the study will be presented at the American College of Gastroenterology (ACG) 2019 Annual Scientific Meeting. Updated 05 Nov 2019
04 Sep 2019 Results Results of a secondary analysis (sub-study; n=352) assessing the occurrence of thrombotic events (TEs), were presented at the ESC Congress 2019: Annual Congress of the European Society of Cardiology. Updated 02 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
22 May 2019 Results According to a Portola Pharmaceuticals media release, results of a new analysis of data from an important subgroup of this study (n=352) are being featured in an oral presentation today at the 5thEuropean Stroke Organisation Conference(ESOC 2019) in Milan, Italy. Updated 02 Jan 2020
22 May 2019 Results Results of a new analysis of data from an important subgroup of (n=352) presented in a Portola Pharmaceuticals media release. Updated 02 Jan 2020
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
07 Feb 2019 Results According to a Portola Pharmaceuticals media release, data are being presented at the International Stroke Conference 2019 and Published in The New England Journal of Medicine (NEJM). Updated 14 Feb 2019
07 Feb 2019 Results Results (n=352) presented in a Portola Pharmaceuticals media release. Updated 14 Feb 2019
30 Jan 2019 Other trial event According to a Portola Pharmaceuticals media release, data will be presented at the International Stroke Conference (ISC) 2019, and has also been submitted for simultaneous publication in a peer-reviewed medical journal. Updated 04 Feb 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
05 Sep 2018 Other trial event This trial has been completed in France. Updated 10 Sep 2018
16 Aug 2018 Other trial event Planned number of patients changed from 350 to 500. Updated 21 Aug 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
17 Jun 2018 Interim results First interim analysis presented at the 23rd Congress of the European Haematology Association Updated 24 Jul 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
12 Mar 2018 Interim results Interim results (n=228) presented at the American College of Cardiology's 67th Annual Scientific Session Expo 2018, according to a Portola Pharmaceuticals media release. Updated 15 Mar 2018
12 Mar 2018 Interim results Interim results (n=228) presented in a Portola Pharmaceuticals media release. Updated 15 Mar 2018
22 Jan 2018 Other trial event According to a Portola Pharmaceuticals media release, interim results from this trial will be presented at the American College of Cardiology's 67th Annual Scientific Session & Expo (ACC.18). Updated 24 Jan 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
12 Dec 2017 Other trial event New source identified and integrated (German Clinical Trials Register;DRKS00012316) Updated 12 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) for 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
28 Apr 2017 Interim results Interim results assessing the efficacy and safety, presented at the 69th Annual Meeting of the American Academy of Neurology. Updated 11 May 2017
03 Apr 2017 Other trial event Planned number of patients changed from 270 to 350. Updated 10 Apr 2017
28 Feb 2017 Other trial event According to a Portola Pharmaceuticals media release, the Data and Safety Monitoring Board (DSMB) has successfully completed its third review for this trial.- Updated 02 Mar 2017
01 Nov 2016 Other trial event As part of the updated agreement with Daiichi Sankyo , company will expand this study in bleeding patients in Germany, as reported by a Portola Pharmaceuticals media release. Updated 13 Nov 2016
13 Oct 2016 Other trial event According to a Portola Pharmaceuticals media release, the company expects to resubmit a Biologics License Application (BLA), for AndexXa in 2017. Updated 17 Nov 2016
30 Aug 2016 Interim results Interim results (n=67) published in the New England Journal of Medicine (2016). Updated 17 Oct 2016
30 Aug 2016 Other trial event According to a Portola Pharmaceuticals media release, interim data from this study will be discussed in a webcast on 30th August 2016. Updated 19 Sep 2016
30 Aug 2016 Interim results According to a Portola Pharmaceuticals media release, interim results were published online by The New England Journal of Medicine (NEJM) Updated 18 Sep 2016
30 Aug 2016 Interim results According to a Portola Pharmaceuticals media release, were presented orally in a Late-Breaking Science Hot Line session at the European Society of Cardiology (ESC) 2016 Congress in Rome Updated 18 Sep 2016
30 Aug 2016 Interim results Interim preliminary results (n=67) published in the Media Release Updated 18 Sep 2016
26 Aug 2016 Other trial event According to a Portola Pharmaceuticals media release, the interim results from this study will be presented at the European Society of Cardiology (ESC) 2016 Congress. Updated 11 Sep 2016
19 Aug 2016 Other trial event According to a Portola Pharmaceuticals media release, based on data from two Phase III studies (see profile 238727 and 242840) 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
02 Mar 2016 Other trial event New source identified and integrated (European Clinical Trials Database EudraCT2015-001785-26). Updated 10 Mar 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
05 Mar 2015 Status change - recruiting Status changed from not yet recruiting to recruiting as reported by ClinicalTrials.gov record. Updated 10 Mar 2015
12 Jan 2015 Other trial event According to a Portola Pharmaceuticals media release, the company initiated this study to support US FDA approval under Accelerated Approval pathway. Portola 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 phase III studies- ANNEXA-A and ANNEXA-R [see CTP 700238727 and 700242840]. Updated 20 Sep 2016
05 Jan 2015 New trial record New trial record Updated 05 Jan 2015
13 Aug 2014 Other trial event According to a Portola Pharmaceuticals media release, the company plans to initiate this study at the end of 2014 or the beginning of 2015. Updated 20 Sep 2016

References

  1. European Clinical Trials Database. Trial-Reg 2021;.

    Available from: URL: https://www.clinicaltrialsregister.eu
  2. van Haaps TF, Benz AP, Xu L, Coppens M, Eikelboom JW, Milling Jr TJ, et al. Andexanet Alfa for Acute Bleeding During Treatment with Enoxaparin. ACC-2021 2021; abstr. N/A.

    Available from: URL: https://www.sciencedirect.com/science/article/pii/S0735109721032125
  3. Coppens M, Xu L, Bavalia R, Middeldorp S, Verhamme P, Eikelboom JW, et al. Effects of Andexanet Alfa on Thrombin Generation in Bleeding Associated with Factor Xa Inhibitors. ASH-Hem-2019 2019; abstr. 711.

    Available from: URL: https://ash.confex.com/ash/2019/webprogram/Paper124596.html
  4. Portola Pharmaceuticals. Portola Pharmaceuticals Presents New Analysis from the ANNEXA-4 Study of its Factor Xa Inhibitor Reversal Agent Andexxa(Rm) in Patients with Acute Gastrointestinal Bleeding. Media-Rel 2019;.

    Media Release
  5. Portola Pharmaceuticals. Portola Pharmaceuticals Announces Interim Results from Ongoing Phase 3b/4 ANNEXXA-4(Tm) Study of Factor Xa Inhibitor Antidote AndexXa(Tm) (andexanet alfa) in Patients with Acute Major Bleeding. Media-Rel 2016;.

    Media Release
  6. Portola Pharmaceuticals. Portola Pharmaceuticals Announces New Interim Results from Ongoing ANNEXA-4 Study of Factor Xa Inhibitor Reversal Agent AndexXa(R)(Andexanet Alfa) in Patients with Life-Threatening Bleeding. Media-Rel 2018;.

    Media Release
  7. Portola Pharmaceuticals. Portola Pharmaceuticals Announces Full Results from the ANNEXA-4 Study of the Factor Xa Inhibitor Reversal Agent Andexxa(Rm) in Patients with Life-Threatening Bleeding. Media-Rel 2019;.

    Media Release
  8. Cohen AT, Lewis M, Connor A, Connolly S, Yue P, Curnutte J, et al. 30 Day Mortality Following Andexanet Alfa in Annexa-4 Compared with Prothrombin Complex Concentrate (Pcc) Therapy in the Orange Study for Life Threatening Non-Vitamin K Oral Anticoagulant (Noac) Related Bleeding. ACC-WCC-2020 2020; abstr. 1213-209.

    Available from: URL: https://www.sciencedirect.com/science/article/pii/S0735109720328692
  9. Beyer-Westendorf J, Yue P, Crowther M, Eikelboom JW, Gibson CM, Milling TJ, et al. Thrombotic events in bleeding patients treated with andexanet alfa: an ANNEXA-4 sub-study. ESC-Card-2019 2019; abstr. 288.

    Available from: URL: http://link.adisinsight.com/k5QCn
  10. 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
  11. Portola Pharmaceuticals. Portola Pharmaceuticals Announces Presentation of Interim Results from Phase 3b/4 ANNEXA(TM)-4 Study of AndexXa(TM) (andexanet alfa) at European Society of Cardiology 2016 Congress. Media-Rel 2016;.

    Media Release
  12. 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
  13. Portola Pharmaceuticals. Portola Pharmaceuticals to Present Full Results from the ANNEXA-4 Study of Andexxa During a Late-Breaking Oral Presentation at the International Stroke Conference 2019. Media-Rel 2019;.

    Media Release
  14. Portola Pharmaceuticals. Portola Pharmaceuticals Announces Results Demonstrating Andexxa(R) was Associated with Lowest Rate of Mortality in Patients with Multiple Types of Factor Xa Inhibitor-Related Bleeds. Media-Rel 2020;.

    Media Release
  15. Connolly SJ, Milling TJ Jr, Eikelboom JW, Gibson CM, Curnutte JT, Gold A, et al. Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors. N-Engl-J-Med 2016;.

    PubMed | CrossRef Fulltext
  16. Portola Pharmaceuticals. Portola Pharmaceuticals Expands Clinical Collaboration Agreement with Daiichi Sankyo Worth Up to $25 Million to Develop AndexXa(TM) (andexanet alfa) in Germany. Media-Rel 2016;.

    Media Release
  17. Benz AP, Xu L, Eikelboom JW, Middeldorp S, Milling Jr TJ, Crowther M, et al. Andexanet Alfa for Acute Bleeding During Treatment With Edoxaban. ISC-2021 2021; abstr. P3.

    Available from: URL: https://www.abstractsonline.com/pp8/9216/presentation/2838
  18. Portola Pharmaceuticals. Portola Pharmaceuticals Reports Fourth Quarter and Year-End 2013 Financial Results and Provides Corporate Update. Media-Rel 2014;.

    Media Release
  19. Portola Pharmaceuticals. Portola Pharmaceuticals Reports First Quarter 2016 Financial Results and Provides Corporate Update. Media-Rel 2016;.

    Media Release
  20. Portola Pharmaceuticals. Portola Pharmaceuticals Announces Acceptance of Late-Breaker Abstract Highlighting New Data for Andexanet Alfa at ACC.18. Media-Rel 2018;.

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

    Media Release
  22. Portola Pharmaceuticals. Portola Pharmaceuticals Announces New Analysis from the ANNEXA-4 Study of its Factor Xa Inhibitor Reversal Agent Andexxa(R) in Patients with Spontaneous (Non-Traumatic) Intracranial Hemorrhage. Media-Rel 2019;.

    Media Release
  23. 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
  24. 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
  25. Demchuk AM, Yue P, Zotova E, Nakamya J, Xu L, Milling TJ Jr, et al. Hemostatic Efficacy and Anti-FXa (Factor Xa) Reversal With Andexanet Alfa in Intracranial Hemorrhage: ANNEXA-4 Substudy. . Stroke 2021;STROKEAHA120030565.

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    Available from: URL: http://submissions.mirasmart.com/AAN2017/itinerary/login.asp
  27. Portola Pharmaceuticals. Portola Pharmaceuticals Announces Resubmission of Biologics License Application for AndexXa(R) (Andexanet Alfa). Media-Rel 2017;.

    Media Release
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    Available from: URL: http://clinicaltrials.gov
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  30. Portola Pharmaceuticals. Portola Pharmaceuticals Reports Fourth Quarter and Year-End 2016 Financial Results and Provides Corporate Update. Media-Rel 2017;.

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

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

    Media Release
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    Available from: URL: https://drks-neu.uniklinik-freiburg.de/drks%5fweb
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  37. 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;.

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