Atrial Fibrillation (AF)
Conditions
Brief summary
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.
Interventions
DRUGBAY2433334
Tablet, taken orally once a day.
DRUGApixaban
Capsule, taken orally twice a day.
Tablet, taken orally once a day.
Capsule, taken orally twice a day.
Sponsors
Bayer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
45 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Composite of International Society on Thrombosis and Hemostasis (ISTH) Major Bleeding or Clinically Relevant Non-major (CRNM) 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) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With All 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) | 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). |
| Number of Participants With ISTH Major 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) | 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. |
| Number of Participants of ISTH Clinically Relevant Non-major (CRNM) 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) | 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. |
| Number of Participants With ISTH 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) | All other overt bleeding episodes not meeting ISTH Major Bleeding criteria or clinically relevant non major bleeding were classified as minor bleeding. |
Countries
Austria, Belgium, Canada, Czechia, France, Hungary, Italy, Japan, Latvia, Netherlands, Spain, Sweden, Switzerland, United Kingdom
Participant flow
Recruitment details
Study was conducted at 94 centers in 14 countries or regions, between 30-Jan-2020 (first participant first visit) and 08-Oct-2021 (last participant last visit)
Pre-assignment details
862 participants were screened. 107 participants were screening failures. 755 participants were randomized in a 1:1:1 ratio to 3 treatment groups: 251 participants to the asundexian 20 mg group, 254 participants to the asundexian 50 mg group and 250 participants to the apixaban group. 2 participants of asundexian 20 mg group never administered drug.
Participants by arm
| Arm | Count |
|---|---|
| Asundexian 20 mg Participants received Asundexian (BAY2433334) 20 mg and Apixaban placebo for 12 weeks | 249 |
| Asundexian 50 mg Participants received Asundexian (BAY2433334) 50 mg and Apixaban placebo for 12 weeks | 254 |
| Apixaban Participants received Asundexian (BAY2433334) placebo and Apixaban for 12 weeks | 250 |
| Total | 753 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 13 | 14 | 11 |
| Overall Study | Death | 1 | 2 | 3 |
| Overall Study | Non-compliance with study drug | 0 | 0 | 1 |
| Overall Study | Other | 7 | 5 | 14 |
| Overall Study | Physician Decision | 1 | 3 | 2 |
| Overall Study | Study drug never administered | 2 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 3 | 1 |
Baseline characteristics
| Characteristic | Total | Asundexian 20 mg | Asundexian 50 mg | Apixaban |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 643 Participants | 216 Participants | 211 Participants | 216 Participants |
| Age, Categorical Between 18 and 65 years | 110 Participants | 33 Participants | 43 Participants | 34 Participants |
| Race/Ethnicity, Customized Asian | 119 Participants | 39 Participants | 40 Participants | 40 Participants |
| Race/Ethnicity, Customized Black or African American | 3 Participants | 1 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Not reported | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 630 Participants | 209 Participants | 212 Participants | 209 Participants |
| Sex: Female, Male Female | 308 Participants | 102 Participants | 97 Participants | 109 Participants |
| Sex: Female, Male Male | 445 Participants | 147 Participants | 157 Participants | 141 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 4 / 254 | 2 / 249 | 5 / 250 |
| other Total, other adverse events | 116 / 254 | 110 / 249 | 113 / 250 |
| serious Total, serious adverse events | 20 / 254 | 22 / 249 | 20 / 250 |
Outcome results
Primary
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.
Time frame: 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)
Population: Safety analysis set (SAF)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Asundexian 20 mg | Number of Participants With Composite of International Society on Thrombosis and Hemostasis (ISTH) Major Bleeding or Clinically Relevant Non-major (CRNM) Bleeding | 3 Participants |
| Asundexian 50 mg | Number of Participants With Composite of International Society on Thrombosis and Hemostasis (ISTH) Major Bleeding or Clinically Relevant Non-major (CRNM) Bleeding | 1 Participants |
| Asundexian Pooled | Number of Participants With Composite of International Society on Thrombosis and Hemostasis (ISTH) Major Bleeding or Clinically Relevant Non-major (CRNM) Bleeding | 4 Participants |
| Apixaban | Number of Participants With Composite of International Society on Thrombosis and Hemostasis (ISTH) Major Bleeding or Clinically Relevant Non-major (CRNM) Bleeding | 6 Participants |
Comparison: Comparison of the Asundexian pooled group (Asundexian 20 mg group and Asundexian 50 mg group) versus Apixaban group in ISTH major bleeding or CRNM bleeding90% CI: [0.09, 0.97]Other
Secondary
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.
Time frame: 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)
Population: Safety analysis set (SAF)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Asundexian 20 mg | Number of Participants of ISTH Clinically Relevant Non-major (CRNM) Bleeding | 3 Participants |
| Asundexian 50 mg | Number of Participants of ISTH Clinically Relevant Non-major (CRNM) Bleeding | 1 Participants |
| Asundexian Pooled | Number of Participants of ISTH Clinically Relevant Non-major (CRNM) Bleeding | 4 Participants |
| Apixaban | Number of Participants of ISTH Clinically Relevant Non-major (CRNM) Bleeding | 6 Participants |
Comparison: Comparison of the Asundexian pooled group (Asundexian 20 mg group and Asundexian 50 mg group) versus Apixaban group in ISTH CRNM bleeding90% CI: [0.09, 0.97]
Secondary
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).
Time frame: 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)
Population: Safety analysis set (SAF)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Asundexian 20 mg | Number of Participants With All Bleeding | 12 Participants |
| Asundexian 50 mg | Number of Participants With All Bleeding | 10 Participants |
| Asundexian Pooled | Number of Participants With All Bleeding | 22 Participants |
| Apixaban | Number of Participants With All Bleeding | 26 Participants |
Comparison: Comparison of the Asundexian pooled group (Asundexian 20 mg group and Asundexian 50 mg group) versus Apixaban group in all bleeding90% CI: [0.26, 0.67]
Secondary
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.
Time frame: 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)
Population: Safety analysis set (SAF)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Asundexian 20 mg | Number of Participants With ISTH Major Bleeding | 0 Participants |
| Asundexian 50 mg | Number of Participants With ISTH Major Bleeding | 0 Participants |
| Asundexian Pooled | Number of Participants With ISTH Major Bleeding | 0 Participants |
Secondary
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.
Time frame: 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)
Population: Safety analysis set (SAF)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Asundexian 20 mg | Number of Participants With ISTH Minor Bleeding | 10 Participants |
| Asundexian 50 mg | Number of Participants With ISTH Minor Bleeding | 9 Participants |
| Asundexian Pooled | Number of Participants With ISTH Minor Bleeding | 19 Participants |
| Apixaban | Number of Participants With ISTH Minor Bleeding | 20 Participants |
Comparison: Comparison of the Asundexian pooled group (Asundexian 20 mg group and Asundexian 50 mg group) versus Apixaban group in ISTH minor bleeding90% CI: [0.28, 0.83]