Study to Gather Information About the Proper Dosing of the Oral FXIa Inhibitor BAY 2433334 and to Compare the Safety of the Study Drug to Apixaban, a Non-vitamin K Oral Anticoagulant (NOAC) in Patients With Irregular Heartbeat (Atrial Fibrillation) That Can Lead to Heart-related Complications. (PACIFIC-AF)

Multicenter, Randomized, Active Comparator-controlled, Double-blind, Double-dummy, Parallel Group, Dose-finding Phase 2 Study to Compare the Safety of the Oral FXIa Inhibitor BAY2433334 to Apixaban in Patients With Atrial Fibrillation

The purpose of this study is to try to find the best dose of the new drug BAY 2433334 to give to participants and to look at how well BAY 2433334 works in patients with irregular heartbeat (atrial fibrillation) that can lead to blood clots, stroke and other heart-related complications. In addition researchers want to compare the safety of the study drug to apixaban, a non-vitamin K oral anticoagulant (NOAC) in patients with atrial fibrillation. This study is also done to learn how the drug in this study moves into, through and out of the body. BAY 2433334, works by blocking a step of the blood clotting process in our body and thins the blood and is a so called oral FXIa inhibitor.

Apixaban, works by reducing the production of blood clotting factors in our body and thins the blood and is a so called non-vitamin K oral anticoagulant (NOAC). Thinning the blood can prevent you from blood clots which can cause a stroke.

Study Overview

• Status: Completed
• Conditions: Atrial Fibrillation (AF)
• Intervention / Treatment: Drug: BAY2433334; Other: BAY2433334 matching placebo; Other: Apixaban matching placebo; Drug: Apixaban

• Study Type: Interventional
• Enrollment (Actual): 755
• Phase: Phase 2

Contacts and Locations

Study Locations

• Austria
  • Salzburg, Austria, 5020
    • Uniklinikum Salzburg - Landeskrankenhaus
  • Wien, Austria, 1090
    • Universitätsklinikum AKH Wien
  • Wien, Austria, 1210
    • Klinik Floridsdorf - Krankenhaus Nord
  • Oberösterreich
    • Braunau, Oberösterreich, Austria, 5280
      • Krankenhaus St. Josef Braunau
    • Linz, Oberösterreich, Austria, 4020
      • Ordensklinikum Linz GmbH Elisabethinen
  • Steiermark
    • Graz, Steiermark, Austria, 8036
      • Medizinische Universität Graz
  • Tirol
    • Innsbruck, Tirol, Austria, 6020
      • Medizinische Universität Innsbruck
  • Vorarlberg
    • Feldkirch, Vorarlberg, Austria, 6807
      • Landeskrankenhaus Feldkirch
• Belgium
  • Bonheiden, Belgium, 2820
    • Imeldaziekenhuis - St-Elisabethkliniek
  • Brugge, Belgium, 8000
    • AZ St-Jan Brugge Oostende AV
  • Edegem, Belgium, 2650
    • UZ Antwerpen
  • Hasselt, Belgium, 3500
    • Jessa Ziekenhuis
  • Mechelen, Belgium, 2800
    • VZW Emmaus
  • Roeselare, Belgium, 8800
    • AZ Delta
  • Vlaams Brabant
    • Leuven, Vlaams Brabant, Belgium, 3000
      • UZ Leuven Gasthuisberg
• Canada
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 3A7
      • Queen Elizabeth II Health Sciences Centre
  • Quebec
    • Montreal, Quebec, Canada, H1T 1C8
      • Montreal Heart Institute
    • Montreal, Quebec, Canada, H1T 3Y7
      • Clinique Sante Cardio MC
    • Ste-Foy, Quebec, Canada, G1V 4G5
      • Institut Universitaire de Cardiologie et de Pneumologie
• Czechia
  • Plzen, Czechia, 304 60
    • Fakultni nemocnice Plzen - Lochotin
  • Praha 10, Czechia, 100 34
    • Fakultni nemocnice Kralovske Vinohrady
  • Praha 4, Czechia, 140 21
    • Institut Klinicke A Experimentalni Mediciny
  • Praha 5, Czechia, 150 06
    • Fakultni nemocnice v Motole
  • Slany, Czechia, 274 01
    • Nemocnice Slany
  • Zlin, Czechia, 762 75
    • Krajská nemocnice T. Bati, a.s.
• France
  • Creteil, France, 94010
    • Hopital Henri Mondor
  • La Roche Sur Yon Cedex, France, 85025
    • Centre Hospitalier Departemental Vendée
  • Le Coudray, France, 28630
    • Centre Hospitalier Louis Pasteur
  • Paris, France, 75018
    • Hopital Bichat - Paris
  • Saint Brieuc, France, 22000
    • Centre Hospitalier Régional - Saint Brieuc
  • Toulouse, France, 31403
    • Hôpital de Rangueil - Toulouse
  • Valenciennes Cedex, France, 59322
    • Centre Hospitalier - Valenciennes Cedex
• Hungary
  • Balatonfured, Hungary, 8230
    • Tagore Medical Center
  • Budapest, Hungary
    • Magyar Honvedseg Egeszsegugyi Kozpont
  • Budapest, Hungary, 1122
    • University of Semmelweis/ Semmelweis Egyetem
  • Nagykanizsa, Hungary, 8800
    • Kanizsai Dorottya Hospital
  • Nyiregyhaza, Hungary, 4400
    • Medifarma-98 Egeszsegugyi, Kereskedelmi es Szolgaltato Kft.
  • Pecs, Hungary, 7624
    • Pecsi Tudomanyegyetem Klinikai Kozpont
  • Szekszard, Hungary, 7100
    • Tolna Megyei Balassa János Kórház
  • Szentes, Hungary, 6600
    • Csongrad-Csanad Megyei Dr. Bugyi Istvan Korhaz
• Italy
  • Lazio
    • Roma, Lazio, Italy, 00161
      • A.O.U. Policlinico Umberto I
  • Liguria
    • Genova, Liguria, Italy, 16132
      • IRCCS Ospedale Policlinico San Martino
  • Lombardia
    • Brescia, Lombardia, Italy, 25123
      • ASST Spedali Civili di Brescia
  • Marche
    • Ascoli Piceno, Marche, Italy, 63074
      • ASUR Marche - Area Vasta 5
  • Toscana
    • Arezzo, Toscana, Italy, 52044
      • AUSL Toscana Sud-Est
    • Arezzo, Toscana, Italy, 52100
      • AUSL Toscana Sud-Est
  • Umbria
    • Perugia, Umbria, Italy, 06129
      • A.O. di Perugia
• Japan
  • Fukuoka
    • Itoshima, Fukuoka, Japan, 819-1104
      • Nakamura Cardiovascular Clinic
  • Hyogo
    • Himeji, Hyogo, Japan, 670-8560
      • Hyogo Prefectural Harima-Himeji General Medical Center
  • Kanagawa
    • Miura-gun, Kanagawa, Japan, 240-0116
      • Hayama Heart Center
  • Osaka
    • Kishiwada, Osaka, Japan, 596-0042
      • Kishiwada Tokushukai Hospital
    • Yao, Osaka, Japan, 581-0011
      • Yao Tokushukai General Hospital
  • Tokyo
    • Adachi-ku, Tokyo, Japan, 123-0845
      • Nishiarai Heart Central Clinic
    • Hachioji, Tokyo, Japan, 192-0918
      • Minamino Cardiovascular Hospital
    • Hachioji, Tokyo, Japan, 193-0811
      • Tokyo Angel Hospital
    • Koto-ku, Tokyo, Japan, 136-0072
      • Koto Hospital
• Latvia
  • Daugavpils, Latvia, LV-5417
    • Daugavpils Regional Hospital
  • Daugavpils, Latvia, LV-5401
    • Doctor's Practice in Cardiology
  • Liepaja, Latvia, LV-3414
    • Liepaja Regional Hospital
  • Riga, Latvia, LV-1002
    • P. Stradins Clinical University Hospital
  • Riga, Latvia, LV-1001
    • 1st Riga Clinical Hospital
  • Riga, Latvia, LV-1038
    • Riga East Clinical University Hospital "Gailezers"
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Academisch Medisch Centrum (AMC)
  • Arnhem, Netherlands, 6815 AD
    • Ziekenhuis Rijnstate
  • Breda, Netherlands, 4818 CK
    • Amphia Ziekenhuis, locatie Molengracht
  • Dordrecht, Netherlands, 3318 AT
    • Albert Schweitzer Ziekenhuis, Dordwijk
  • Enschede, Netherlands, 7511 JX
    • Medisch Spectrum Twente
  • Groningen, Netherlands, 9728 NT
    • Martini Ziekenhuis, Locatie van Swieten
  • Haarlem, Netherlands, 2035 RC
    • Spaarne Gasthuis - locatie Zuid
  • Maastricht, Netherlands, 6229 HX
    • Maastricht UMC
• Spain
  • Barcelona, Spain, 08035
    • Ciutat Sanitaria i Universitaria de la Vall d'Hebron
  • Barcelona, Spain, 08041
    • Hospital de la Santa Creu i de Sant Pau | Cardiología
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de Octubre
  • Málaga, Spain, 29010
    • Hospital Virgen de la Victoria
  • Barcelona
    • L'Hospitalet de Llobregat, Barcelona, Spain, 08907
      • Ciutat Sanitaria i Universitaria de Bellvitge
• Sweden
  • Falun, Sweden, 791 82
    • Falu Lasarett
  • Lund, Sweden, 222 21
    • Clemenstorget Hjärtmottagning
  • Skellefteå, Sweden, 931 86
    • Skellefteå lasarett
  • Stockholm, Sweden, 182 88
    • Danderyds Sjukhus
  • Stockholm, Sweden, 118 83
    • Södersjukhuset AB
  • Örebro, Sweden, 703 62
    • Avdelningen för kliniska prövningar AKP
  • Östersund, Sweden, 831 83
    • Ostersunds sjukhus
• Switzerland
  • Bern, Switzerland, 3010
    • Inselspital Universitätsspital Bern
  • Genève, Switzerland, 1211
    • Hopital Cantonal Universitaire de Geneve
  • Lugano, Switzerland, 6900
    • Ospedale Regionale di Lugano
  • Aargau
    • Aarau, Aargau, Switzerland, 5001
      • Kantonsspital Aarau
  • Basel-Stadt
    • Basel, Basel-Stadt, Switzerland, 4031
      • Universitätsspital Basel
  • Sankt Gallen
    • St. Gallen, Sankt Gallen, Switzerland, 9007
      • Kantonsspital St. Gallen
• United Kingdom
  • Liverpool, United Kingdom, L14 3PE
    • Heart and Chest Hospital
  • Cambridgeshire
    • Ely, Cambridgeshire, United Kingdom, CB7 5SQ
      • Staploe Medical Centre
  • Hertfordshire
    • Welwyn Garden City, Hertfordshire, United Kingdom, AL7 4HQ
      • Queen Elizabeth II Hospital
  • London
    • Harrow, London, United Kingdom, HA1 3UJ
      • Northwick Park Hospital
  • West Sussex
    • Chichester, West Sussex, United Kingdom, PO19 6SE
      • St Richard's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Participant must be 45 years of age or older at the time of signing the informed consent.

• Participant with AF documented by ECG evidence with

  • CHA2DS2-VASc score ≥ 2 if male or CHA2DS2-VASc score ≥ 3 if female

  • Indication for treatment with an oral anticoagulant in

    • any participant currently not treated with an oral anticoagulant (e.g. treatment naïve) or alternatively,
    • participant on a NOAC in case of at least one bleeding risk feature (history of a prior bleed within the last 12 months requiring medical attention and / or moderate renal dysfunction with eGFR 30-50 ml/min and / or current clinically indicated antiplatelet therapy with Acetylsalicylic acid(ASA) ≤ 100 mg)
• Written informed consent

Exclusion Criteria:

• Mechanical heart valve prosthesis
• Any degree of rheumatic mitral stenosis or moderate-to-severe, non-rheumatic mitral stenosis
• Atrial fibrillation due to a reversible cause, participants in sinus rhythm after successful ablation, or plan for cardioversion or ablation during study conduct
• Requirement for chronic anticoagulation (for a different indication than AF) or antiplatelet therapy (up to 100 mg ASA is allowed). Anticipated need for chronic therapy with Nonsteroidal anti-inflammatory drugs (NSAIDs)
• Treated with a Vitamin K antagonist in the 30 days prior to screening

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: BAY2433334 50mg+Apixaban matching placebo	Drug: BAY2433334; Tablet, taken orally once a day.; Other: Apixaban matching placebo; Capsule, taken orally twice a day.
Experimental: BAY2433334 20mg+Apixaban matching placebo	Drug: BAY2433334; Tablet, taken orally once a day.; Other: Apixaban matching placebo; Capsule, taken orally twice a day.
Active Comparator: BAY2433334 matching placebo+Apixaban; Apixaban usual dose is 5 mg, reduced to 2.5 mg for participants with any 2 of the following criteria: age 80 years or older, body weight less than 60 kg, or serum creatinine level of 1.5 mg per dL or more.	Other: BAY2433334 matching placebo; Tablet, taken orally once a day.; Drug: Apixaban; Capsule, taken orally twice a day.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Composite of International Society on Thrombosis and Hemostasis (ISTH) Major Bleeding or Clinically Relevant Non-major (CRNM) Bleeding	ISTH Major Bleeding criteria: 1. Fatal bleeding, and/or 2. Symptomatic bleeding in a critical area or organ (intracranial, intraocular, intraspinal, pericardial, retroperitoneal, intraarticular, or intramuscular with compartment syndrome), and/or 3. Clinically overt bleeding associated with a recent decrease in the hemoglobin level of ≥ 2 g/dL (20 g/L; 1.24 mmol/L) compared to the most recent hemoglobin value available before the event, and/or 4. Clinically overt bleeding leading to transfusion of 2 or more units of packed red blood cells or whole blood. ISTH Clinically Relevant Non-Major Bleeding is considered any sign or symptom of hemorrhage that does not fit the criteria for the ISTH definition of major bleeding, but does meet at least one of the following criteria 1. requiring medical intervention by a healthcare professional. 2. leading to hospitalization or increased level of care. 3. prompting a face to face (i.e. not just a telephone or electronic communication) evaluation.	After the first administration of study intervention with an average administration of 12 weeks (but not starting after more than 2 days after the last administration)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With All Bleeding	Adjudication of all bleeding events was performed by members of the Clinical events committee (CEC) who reviewed events in a blinded fashion and adjudicated and classified the following events in a consistent and unbiased manner according to the following classifications: ISTH (major, clinically relevant non-major and minor); Thrombolysis in myocardial infarction (TIMI major, minor, requiring medical attention, minimal); Bleeding Academic Research Consortium (BARC type 1, 2, 3, 5).	After the first administration of study intervention with an average administration of 12 weeks (but not starting after more than 2 days after the last administration)
Number of Participants With ISTH Major Bleeding	ISTH Major Bleeding criteria: 1. Fatal bleeding, and/or 2. Symptomatic bleeding in a critical area or organ (intracranial, intraocular, intraspinal, pericardial, retroperitoneal, intraarticular, or intramuscular with compartment syndrome), and/or 3. Clinically overt bleeding associated with a recent decrease in the hemoglobin level of ≥ 2 g/dL (20 g/L; 1.24 mmol/L) compared to the most recent hemoglobin value available before the event, and/or 4. Clinically overt bleeding leading to transfusion of 2 or more units of packed red blood cells or whole blood.	After the first administration of study intervention with an average administration of 12 weeks (but not starting after more than 2 days after the last administration)
Number of Participants of ISTH Clinically Relevant Non-major (CRNM) Bleeding	ISTH Clinically Relevant Non-Major Bleeding is considered any sign or symptom of hemorrhage that does not fit the criteria for the ISTH definition of major bleeding, but does meet at least one of the following criteria 1. requiring medical intervention by a healthcare professional. 2. leading to hospitalization or increased level of care. 3. prompting a face to face (i.e. not just a telephone or electronic communication) evaluation.	After the first administration of study intervention with an average administration of 12 weeks (but not starting after more than 2 days after the last administration)
Number of Participants With ISTH Minor Bleeding	All other overt bleeding episodes not meeting ISTH Major Bleeding criteria or clinically relevant non major bleeding were classified as minor bleeding.	After the first administration of study intervention with an average administration of 12 weeks (but not starting after more than 2 days after the last administration)

Collaborators and Investigators

• Sponsor: Bayer

Publications and helpful links

General Publications

• Piccini JP, Caso V, Connolly SJ, Fox KAA, Oldgren J, Jones WS, Gorog DA, Durdil V, Viethen T, Neumann C, Mundl H, Patel MR; PACIFIC-AF Investigators. Safety of the oral factor XIa inhibitor asundexian compared with apixaban in patients with atrial fibrillation (PACIFIC-AF): a multicentre, randomised, double-blind, double-dummy, dose-finding phase 2 study. Lancet. 2022 Apr 9;399(10333):1383-1390. doi: 10.1016/S0140-6736(22)00456-1. Epub 2022 Apr 3.

Helpful Links

• Click here to find information about studies related to Bayer Healthcare products conducted in Europe
• Click here to find information for studies related to Bayer products. To find this study enter the ClinicalTrials.gov identifier (NCT) number or Bayer Study Identifier (ID) in the search field.

Study record dates

Study Major Dates

• Study Start (Actual): January 30, 2020
• Primary Completion (Actual): October 8, 2021
• Study Completion (Actual): October 8, 2021

Study Registration Dates

• First Submitted: January 2, 2020
• First Submitted That Met QC Criteria: January 2, 2020
• First Posted (Actual): January 6, 2020

Study Record Updates

• Last Update Posted (Actual): October 27, 2022
• Last Update Submitted That Met QC Criteria: October 26, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Atrial Fibrillation; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Apixaban
• Other Study ID Numbers: 19765; 2019-002365-35 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

IPD Plan Description

Availability of this study's data will later be determined according to Bayer's commitment to the EFPIA/PhRMA "Principles for responsible clinical trial data sharing". This pertains to scope, timepoint and process of data access.

As such, Bayer commits to sharing upon request from qualified researchers patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials in patients for medicines and indications approved in the US and EU as necessary for conducting legitimate research. This applies to data on new medicines and indications that have been approved by the EU and US regulatory agencies on or after January 01, 2014.

Interested researchers can use www.clinicalstudydatarequest.com to request access to anonymized patient-level data and supporting documents from clinical studies to conduct research. Information on the Bayer criteria for listing studies and other relevant information is provided in the Study sponsors section of the portal.

Drug and device information, study documents

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