A Study of Andexanet Alfa in Patients Requiring Urgent Surgery or Procedure (ANNEXA-RS)

A Randomized Study of Andexanet Alfa Compared to Usual Care in Patients Receiving a Factor Xa Inhibitor Who Require Urgent Surgery or Procedure (ANNEXA-RS)

The study will aim to find out if the drug andexanet alfa is safe and effective in preventing major bleeding during urgent surgery or invasive procedures. The study will compare the use of andexanet alfa to the usual care given at the study center.

Study Overview

• Status: Withdrawn
• Conditions: Urgent Surgery
• Intervention / Treatment: Drug: Andexanet alfa; Drug: Usual Care

Detailed Description

This study will be an open-label, randomised, controlled, prospective, multicenter study. The study will include patients requiring urgent surgery or procedure that needs to be performed within 15 hours of the last dose of blood-thinning drug (direct oral activated Factor X (FXa) inhibitor).

The study will comprise of the following periods:

• Screening, followed by surgery or procedure and study intervention.
• Follow-up period: there will be four follow-up visits over a duration of approximately 30 days.
• Follow-up visit for patients with positive anti-andexanet alfa antibody test: patients with a positive anti-andexanet alfa antibody response at day 30 will have a follow-up anti-andexanet alfa antibody test approximately 120 days post-surgery or procedure.

Patients will be randomised in the ratio of 1:1 to receive either andexanet alfa or usual care.

• Study Type: Interventional
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, 1425
    • Research Site
  • Córdoba, Argentina, X5000AOQ
    • Research Site
  • Mar del Plata, Argentina, B7602CBM
    • Research Site
  • Quilmes, Argentina, B1878GEG
    • Research Site
• Australia
  • Adelaide, Australia, 5000
    • Research Site
  • Concord, Australia, 2139
    • Research Site
  • Epping, Australia, 3076
    • Research Site
  • Fitzroy, Australia, 3065
    • Research Site
  • Garran, Australia, 2605
    • Research Site
  • Melbourne, Australia, 3004
    • Research Site
  • New Lambton Heights, Australia, 2305
    • Research Site
  • Sydney, Australia, NSW 2145
    • Research Site
• Austria
  • Graz, Austria, 8036
    • Research Site
• Belgium
  • Aalst, Belgium, 9300
    • Research Site
  • Ghent, Belgium, 9000
    • Research Site
  • Kortrijk, Belgium, 8500
    • Research Site
  • Leuven, Belgium, 3000
    • Research Site
• Brazil
  • Florianopolis, Brazil, 88015-231
    • Research Site
  • Ribeirão Preto, Brazil, 14048-900
    • Research Site
  • Salvador, Brazil, 40170-130
    • Research Site
  • Sao Paulo, Brazil, 05403-000
    • Research Site
• Bulgaria
  • Lom, Bulgaria, 3600
    • Research Site
  • Plovdiv, Bulgaria, 4002
    • Research Site
  • Sofia, Bulgaria, 1431
    • Research Site
  • Sofia, Bulgaria, 1527
    • Research Site
  • Sofia, Bulgaria, 1336
    • Research Site
  • Sofia, Bulgaria, 1606
    • Research Site
• Canada
  • Quebec
    • Montreal, Quebec, Canada, H1T 2M4
      • Research Site
• China
  • Beijing, China, 100037
    • Research Site
  • Beijing, China, 100044
    • Research Site
  • Haerbin, China, 150001
    • Research Site
  • Hangzhou, China, 310014
    • Research Site
  • Wuhan, China, 430060
    • Research Site
• Czechia
  • Brno, Czechia, 625 00
    • Research Site
  • Prague, Czechia, 12808
    • Research Site
  • Praha 10, Czechia, 10034
    • Research Site
  • Usti nad Labem, Czechia, 40113
    • Research Site
• Denmark
  • København NV, Denmark, 2400
    • Research Site
• Estonia
  • Tallinn, Estonia, 13419
    • Research Site
• Finland
  • Helsinki, Finland, 00290
    • Research Site
  • Tampere, Finland, FI-33521
    • Research Site
• France
  • Nantes cedex 1, France, 44093
    • Research Site
  • Nimes, France, 30006 Cedex 4
    • Research Site
• Georgia
  • Tbilisi, Georgia, 0112
    • Research Site
  • Tbilisi, Georgia, 0159
    • Research Site
• Germany
  • Aachen, Germany, 52074
    • Research Site
  • Dresden, Germany, 01307
    • Research Site
  • Lübeck, Germany, 23538
    • Research Site
  • Mainz, Germany, 55131
    • Research Site
  • Murnau, Germany, 82418
    • Research Site
  • Rostock, Germany, 18057
    • Research Site
• Greece
  • Athens, Greece, 15126
    • Research Site
  • Thessaloniki, Greece, 54642
    • Research Site
• Hungary
  • Budapest, Hungary, 1083
    • Research Site
  • Pécs, Hungary, 7624
    • Research Site
  • Székesfehérvár, Hungary, 8000
    • Research Site
  • Zalaegerszeg, Hungary, 8900
    • Research Site
• Israel
  • Ashdod, Israel, 7747629
    • Research Site
  • Jerusalem, Israel, 91031
    • Research Site
  • Petah Tikva, Israel, 49372
    • Research Site
  • Tel-Aviv, Israel, 6423906
    • Research Site
• Italy
  • Alessandria, Italy, 15100
    • Research Site
  • Catania, Italy, 95123
    • Research Site
  • Milano, Italy, 20142
    • Research Site
  • Parma, Italy, 43126
    • Research Site
  • Pisa, Italy, 56124
    • Research Site
  • Roma, Italy, 00168
    • Research Site
  • Varese, Italy, 21100
    • Research Site
• Japan
  • Bunkyo-ku, Japan, 113-8603
    • Research Site
  • Hiroshima-shi, Japan, 734-8551
    • Research Site
  • Kashihara-shi, Japan, 634-8522
    • Research Site
  • Kawasaki-shi, Japan, 216-8511
    • Research Site
  • Kumamoto-shi, Japan, 860-0008
    • Research Site
  • Kumamoto-shi, Japan, 861-8520
    • Research Site
  • Kurume, Japan, 830-8543
    • Research Site
  • Sakai-shi, Japan, 593-8304
    • Research Site
  • Sendai-shi, Japan, 980-8574
    • Research Site
• Korea, Republic of
  • Daegu, Korea, Republic of, 42472
    • Research Site
• Malaysia
  • Kuala Lumpur, Malaysia, 50586
    • Research Site
  • Kuantan, Malaysia, 25200
    • Research Site
• Mexico
  • Aguascalientes, Mexico, 20230
    • Research Site
  • Nuevo Leon, Mexico, 66278
    • Research Site
  • San Luis Río Colorado, Mexico, 83448
    • Research Site
• New Zealand
  • Auckland, New Zealand, 2025
    • Research Site
• Poland
  • Kraków, Poland, 31-826
    • Research Site
  • Lublin, Poland, 20-954
    • Research Site
  • Szczecin, Poland, 71-252
    • Research Site
  • Łódź, Poland, 92-213
    • Research Site
• Portugal
  • Amadora, Portugal, 2720-276
    • Research Site
  • Lisboa, Portugal, 1649-035
    • Research Site
  • Porto, Portugal, 4099-001
    • Research Site
• Romania
  • Bucuresti, Romania, 022328
    • Research Site
  • Bucuresti, Romania, 22328
    • Research Site
  • Timisoara, Romania, 300723
    • Research Site
• Serbia
  • Kragujevac, Serbia, 34000
    • Research Site
  • Nis, Serbia, 18000
    • Research Site
  • Novi Sad, Serbia, 21000
    • Research Site
  • Sremska Kamenica, Serbia, 21204
    • Research Site
• Singapore
  • Singapore, Singapore, 308433
    • Research Site
  • Singapore, Singapore, 119074
    • Research Site
• Slovakia
  • Bratislava, Slovakia, 833 01
    • Research Site
• Slovenia
  • Celje, Slovenia, 3000
    • Research Site
• Spain
  • Barcelona, Spain, 08036
    • Research Site
  • Elche, Spain, 03293
    • Research Site
  • L'Hospitalet de Llobregat, Spain, 08907
    • Research Site
  • Madrid, Spain, 28031
    • Research Site
  • Marbella (Málaga), Spain, 29600
    • Research Site
  • Sevilla, Spain, 41009
    • Research Site
  • Sevilla, Spain, 41013
    • Research Site
  • Valencia, Spain, 46010
    • Research Site
  • Valencia, Spain, 46026
    • Research Site
  • Valencia, Spain, 46015
    • Research Site
• Switzerland
  • Zurich, Switzerland, 8091
    • Research Site
• Taiwan
  • Tainan, Taiwan, 704
    • Research Site
• United Kingdom
  • London, United Kingdom, EC1A 7BE
    • Research Site
• United States
  • Arizona
    • Chandler, Arizona, United States, 85224
      • Research Site
  • Colorado
    • Aurora, Colorado, United States, 80012
      • Research Site
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Research Site
  • Florida
    • Jacksonville, Florida, United States, 32209
      • Research Site
    • Saint Cloud, Florida, United States, 34769
      • Research Site
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Research Site
  • Oklahoma
    • Tulsa, Oklahoma, United States, 74104
      • Research Site
  • Tennessee
    • Knoxville, Tennessee, United States, 37920
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• The patient requires, in the opinion of the Investigator, urgent surgery or procedure and requires reversal of direct oral FXa inhibition.
• The patient requires urgent surgery or procedure within 12 hours of informed consent.
• The patient requires urgent surgery or procedure that is expected to be associated with a high risk of bleeding or bleeding to occur into a critical organ.
• The patient has taken an oral FXa inhibitor (such as apixaban, rivaroxaban, or edoxaban) within 15 hours or more, prior to start of surgery or procedure.
• Female patients of childbearing potential must have a negative pregnancy test at Screening.
• Willingness to use highly effective methods of contraception (for male and female patients who are fertile).

Exclusion Criteria:

• The patient requires surgeries or procedures that have a very low chance of causing significant, uncontrollable bleeding, such as small skin procedures, cataract surgery, and minor dental procedures.
• The patient has acute life-threatening bleeding at the time of Screening.
• The patient will undergo a surgery or procedure which will require the use of heparin.
• Patient who is not expected to live for more than three months due to other health problems or has specifically requested not to be resuscitated if their heart stops beating.
• Prior to screening, the patient had either experienced low platelet count due to heparin use with or without blood clots or had a genetic condition that affects blood clotting.
• Patient has acute decompensated heart failure, cardiogenic shock, sepsis, or septic shock at the time of Screening.
• Patient has history of heparin-induced thrombocytopenia (with or without thrombosis) or inherited coagulopathy (eg, anti-thrombin III deficiency, anti-phospholipid antibody syndrome, protein C/S deficiency, Factor V Leiden) at the time of Screening.
• Previously diagnosed with a bleeding disorder (eg, platelet function disorder, hemophilia, Von Willebrand disease, or coagulation factor deficiency).
• Prior known hypersensitivity to andexanet alfa.
• Use of andexanet alfa 30 days prior to Screening.
• Patient diagnosed with dementia.
• Any prohibited medication as determined in the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Andexanet Alfa Group; Patients will receive andexanet alfa as IV bolus followed by an infusion.	Drug: Andexanet alfa; Andexanet is a recombinant version of human FXa; Other Names: Andexxa®, Ondexxya®
Active Comparator: Usual Care Group; Patients will receive treatment based on the Investigator's discretion, according to regional, local/institutional guidelines or practices.	Drug: Usual Care; As per the label of the chosen usual care product(s) and/or usual care standards.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients achieving effective intraoperative hemostasis	Intraoperative hemostasis will be assessed according to the categories as per 4-point hemostasis scale: Excellent - Normal hemostasis, Good - Mildly abnormal hemostasis (eg. slight oozing from surgical wounds), Moderate - Moderate abnormality in intraprocedural hemostasis (eg. controllable bleeding), Poor - Severe hemostatic abnormality (eg. severe refractory hemorrhage). Hemostasis will be considered to be effective if the intraoperative hemostasis category is 'excellent' or 'good', and ineffective if the intraoperative hemostasis category is 'moderate' or 'poor'.	From start to the end of surgery or procedure on Day 0

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from Baseline in anti-FXa activity measured through blood samples	The ability of andexanet alfa to rapidly reverse the anticoagulation effect of FXa inhibitors by reduction of anti-FXa activity when compared to usual care.	Baseline to start of surgery or procedure
Change from Baseline in anti-FXa activity measured through blood samples	The ability of andexanet alfa to sustainably reverse the anticoagulation effect of FXa inhibitors by reduction of anti-FXa activity when compared to usual care at two hours post start of surgery or procedure will be assessed.	Baseline to two hours post start of surgery or procedure

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients with adverse events	Safety and tolerability will be evaluated in terms of adverse events and serious adverse events.	Screening (Day -1 to Day 0) until follow-up visit (Day 30 or Day 120)

Collaborators and Investigators

• Sponsor: AstraZeneca

Study record dates

Study Major Dates

• Study Start (Estimated): August 2, 2024
• Primary Completion (Estimated): January 5, 2027
• Study Completion (Estimated): September 7, 2027

Study Registration Dates

• First Submitted: June 9, 2023
• First Submitted That Met QC Criteria: June 21, 2023
• First Posted (Actual): July 3, 2023

Study Record Updates

• Last Update Posted (Actual): October 26, 2024
• Last Update Submitted That Met QC Criteria: October 23, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: Andexanet alfa; Blood Thinners
• Other Study ID Numbers: D9604C00001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All requests will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com /ST/Submission/Disclosure.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

IPD Sharing Time Frame

AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please refer to our disclosure commitment at:

https://astrazenecagrouptrials.pharmacm.com /ST/Submission/Disclosure.

IPD Sharing Access Criteria

When a request has been approved AstraZeneca will provide access to the de-identified individual patientlevel data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at:

https://astrazenecagrouptrials.pharmacm.com /ST/Submission/Disclosure.

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No