Independent Data Monitoring Committee (IDMC) recommendation to stop the study

Researchers are looking for a better way to treat people with atrial fibrillation (AF) and prevent stroke or systemic embolism (blood clots travelling through the blood stream to plug another vessel).

Atrial fibrillation is a condition of having irregular and often rapid heartbeat. It can lead to the formation of blood clots in the heart which can travel through the blood stream to plug another vessel, and like this lead to serious and life-threatening conditions, such as a stroke. A stroke occurs because the brain tissue beyond the blockage no longer receives nutrients and oxygen so that brain cells die. As strokes arising from atrial fibrillation can involve extensive areas of the brain, it is important to prevent them.

Blood clots are formed in a process known as coagulation. Medications are already available to prevent the formation of blood clots. When taken by mouth (orally), they are known as oral anticoagulants (OACs) including apixaban. OACs decrease the risk of the above-mentioned serious and life-threatening conditions. The main side effect of OACs is an increase of the risk of bleeding.

The study treatment asundexian is a new type of anticoagulant currently under development to provide further treatment options. Asundexian aims to further improve the standard of care with regard to the risk of bleeding.

The main purpose of this study is to collect more data about how well asundexian works to prevent stroke and systemic embolism and how safe it is compared to apixaban in people with atrial fibrillation and at high risk for stroke.

To see how well the study treatment asundexian works researchers compare:

• how long asundexian works well and
• how long apixaban works well after the start of the treatment. Working well means that the treatments can prevent the following from happening:
• stroke and/or
• systemic embolism. The study will keep collecting data until a certain number of strokes or embolisms happen in the study.

To see how safe asundexian is, the researchers will compare how often major bleedings occur after taking the study treatments asundexian and apixaban, respectively. Major bleedings are bleedings that have a serious or even life-threatening impact on a person's health.

The study participants will be randomly (by chance) assigned to 1 of 2 treatment groups, A and B. Dependent on the treatment group, the participants will either take the study treatment asundexian by mouth once a day or apixaban by mouth twice a day for approximately 9 - 33 months.

Each participant will be in the study for approximately 9 - 34 months. There will be visits to the study site every 3 to 6 months and up to 7 phone calls. Those participants who do not want or are unable to have visits to the study site may join the study remotely in selected locations. The location name contains the abbreviation - DCT in such cases.

During the study, the study team will:

• take blood samples
• do physical examinations
• examine heart health using an electrocardiogram (ECG)
• check vital signs such as blood pressure and heart rate
• do pregnancy tests
• ask the participants questions about their quality of life
• ask the participants questions about how they are feeling and what adverse events they are having.

An adverse event is any medical problem that a participant has during a study. Doctors keep track of all adverse events that happen in studies, even if they do not think the adverse events might be related to the study treatments.

Inclusion Criteria:

• 18 years of age or older

• The patient willing and able to understand the Patient information Sheet and provide written informed consent

• Atrial fibrillation with an indication for indefinite treatment with an oral anticoagulant

• CHA2DS2-VASc score ≥ 3 if male or ≥ 4 if female, OR CHA2DS2-VASc score of 2 if male or 3 if female and at least one of the following enrichment criteria:

  • age ≥ 70
  • previous stroke, transient ischemic attack, or systemic embolism
  • renal dysfunction with eGFR < 50 ml/min within 14 days prior to randomization
  • prior episode of non-traumatic major bleeding
  • current single agent antiplatelet therapy planned to continue for at least 6 months after randomization
  • ≤ 6 consecutive weeks of treatment with oral anticoagulant prior to randomization.

Exclusion Criteria:

• Mechanical heart valve prosthesis

• Moderate-to-severe mitral stenosis at the time of study inclusion.

• Atrial fibrillation only due to reversible cause.

• Participants after successful ablation therapy without documented recurrent AF or participants after left atrial appendage occlusion / exclusion or plan for ablation or Left atrial appendage (LAA) occlusion / exclusion within the next 6 months.

• Recent ischemic stroke (within 7 days prior to randomization).

• Active non-trivial bleeding; known chronic bleeding disorder ; history of non-traumatic intracranial hemorrhage.

• Known significant liver disease or known hepatic insufficiency classified as Child-Pugh B or C at randomization.

• Estimated glomerular filtration rate (eGFR) < 25 mL/min/1.73 m2 within 14 days prior to randomization or on dialysis or expected to be started on dialysis within the next 12 months starting from randomization.

• Major surgery during the last 30 days prior to randomization.

• Known allergy, intolerance or hypersensitivity to either of the study interventions.

• Any contraindication for the use of an anticoagulant or listed in the local labelling for apixaban.

• Requirement for chronic anticoagulation for a different indication than AF, e.g. mechanical heart valve or left ventricular cardiac thrombus (atrial thrombus is allowed), or dual antiplatelet therapy (single agent therapy is allowed).

• Treatment with Vitamin K antagonist (VKA) in the 10 days prior to randomization.

• Concomitant use of or anticipated need for:

  • daily or near daily (> 5 days per week) therapy with nonsteroidal anti-inflammatory drugs (NSAIDs) for more than 4 weeks during the study
  • herbal or traditional medicine, and / or supplements with known anticoagulant and / or antiplatelet effect
  • combined P-glycoprotein (P-gp) and strong cytochrome P450 isoenzyme 3A4 (CYP3A4) inhibitors
  • combined P-gp and strong / moderate CYP3A4 inducers Respective substances (apart from NSAIDs) must be stopped - in case of combined inhibitors / inducers of CYP3A4 and P-gp for at least 14 days before randomization.

• Previous (within 30 days or 5 half-lives of the investigational drug, whichever is longer) or concomitant participation in another clinical study with investigational medicinal product(s) or device(s). Registries and observational studies are allowed.

• Known current alcohol and / or illicit drug abuse.

• Close affiliation with the investigational site.

• Any other history, condition or therapy, or uncontrolled intercurrent illness which would make the participant unsuitable for the study vulnerable or life expectancy < 12 months.

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.vivli.org 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 member section of the portal.