Acute Myocardial Infarction
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 on top of a dual antiplatelet therapy (acetylsalicylic acid +/- clopidogrel) in patients following a recent heart attack (myocardial infarction) that happens when a blood vessel in the heart suddenly becomes blocked. 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.
Interventions
DRUGBAY2433334
Tablet, taken orally once a day.
Tablet, taken orally once 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
* Participants must be 45 years of age or older, at the time of signing the informed consent * Acute myocardial infarction (excluding MI associated with PCI or CABG revascularization procedures) with: * clinical symptoms of acute myocardial infarction AND * elevated biomarkers of myocardial necrosis (creatine kinase-muscle and brain isoenzyme \[CK-MB\] or cardiac troponins) AND * at least one of the following risk factors need to be fulfilled: * Age ≥ 65 years * Prior MI (before the index AMI event) * Prior peripheral arterial disease * Diabetes Mellitus * Prior coronary artery bypass grafting (CABG) AND * initial angiography and revascularization procedures, either PCI or CABG, as treatment for the index event performed before randomization. (Note: a planned, staged PCI procedure can be performed after randomization) * Plan for dual antiplatelet therapy (ASA + P2Y12 inhibitor) after hospital discharge for the index AMI * Randomization during hospitalization for the index AMI event and latest within 5 days of hospital admission * Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Written informed consent has to be signed before any study-specific procedure.
Exclusion criteria
* Hemodynamically significant ventricular arrhythmias or cardiogenic shock at time of randomization * Active bleeding; known bleeding disorder, history of major bleeding (intracranial, retroperitoneal, intraocular) or clinically significant gastrointestinal bleeding within last 6 months of randomization * Planned use or requirement of full dose and long term anticoagulation therapy during study conduct.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy - Number of Participants With Composite of CV Death, MI, Stroke and Stent Thrombosis (ST) | From baseline up to 52 weeks | CV death included death due to stroke, MI, heart failure or cardiogenic shock, sudden death or any other death due to other cardiovascular causes. Death due to non-traumatic hemorrhage was included. Acute MI was used when there was evidence of myocardial necrosis in a clinical setting consistent with acute myocardial ischemia. Stroke was defined as an acute episode of focal or global neurological dysfunction caused by an injury of the brain, spinal cord, or retina as a result of hemorrhage or infarction. ST was defined incorporating diagnostic certainty as well as timing: Definite ST: The highest level of certainty. Either angiographic or pathological confirmation of stent thrombosis. Probable ST: Regardless of the time after the index procedure, any MI that is related to documented acute ischemia in the territory of the implanted stent without angiographic confirmation of stent thrombosis and in the absence of any other obvious cause |
| Safety - Number of Participants With BARC Bleeding Definition Type 2, 3 and 5 | From baseline up to 52 weeks | Type 2: any overt, actionable sign of hemorrhage that doesn't fit the criteria for type 3 or 5 but meets at least one of the following criteria: 1) requires nonsurgical, med intervention by a HCP, 2) leads to hospital or rise in level of care, or 3) prompt eval. Type 3a: 1) overt bleed + Hg drop of 3 to \<5 g/dl (provided Hg drop is related to bleed); 2 any transfusion with overt bleed. Type 3b: 1) overt bleed + Hg drop ≥5 g/dL (provided Hg drop is related to bleed); 2) cardiac tamponade; 3) bleed requiring surgical intervention for control (exclude dental/nasal /skin/hemorrhoid); 4) bleed requiring IV vasoactive agents. Type 3c: 1) ICH hemorrhage (doesn't include microbleeds or HT, does include intraspinal); subcategories confirmed by autopsy or imaging or LP; 2) intraocular bleed compromising vision. Type 5: fatal bleed. Type 5a: probable fatal bleed; no autopsy or image confirmation but clinical suspicion. Type 5b: definite fatal bleed; overt bleed or autopsy or image confirmation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy - Number of Participants With Stroke | From baseline up to 52 weeks | Stroke was defined as an acute episode of focal or global neurological dysfunction caused by an injury of the brain, spinal cord, or retina as a result of hemorrhage or infarction. |
| Efficacy - Number of Participants With Stent Thrombosis | From baseline up to 52 weeks | ST was defined incorporating diagnostic certainty as well as timing: Definite ST: The highest level of certainty. Either angiographic or pathological confirmation of stent thrombosis. Probable ST: Regardless of the time after the index procedure, any MI that is related to documented acute ischemia in the territory of the implanted stent without angiographic confirmation of stent thrombosis and in the absence of any other obvious cause |
| Efficacy - Number of Participants With All Cause Mortality | From baseline up to 52 weeks | — |
| Efficacy - Number of Participants With CV Death | From baseline up to 52 weeks | CV death included death due to stroke, MI, heart failure or cardiogenic shock, sudden death or any other death due to other cardiovascular causes. Death due to non-traumatic hemorrhage was included. |
| Safety - Number of Participants With BARC Bleeding Definition Type 3, 5 | From baseline up to 52 weeks | Type 3a: 1) overt bleed + Hg drop of 3 to \<5 g/dl (provided Hg drop is related to bleed); 2 any transfusion with overt bleed. Type 3b: 1) overt bleed + Hg drop ≥5 g/dL (provided Hg drop is related to bleed); 2) cardiac tamponade; 3) bleed requiring surgical intervention for control (exclude dental/nasal /skin/hemorrhoid); 4) bleed requiring IV vasoactive agents. Type 3c: 1) ICH hemorrhage (doesn't include microbleeds or HT, does include intraspinal); subcategories confirmed by autopsy or imaging or LP; 2) intraocular bleed compromising vision. Type 5: fatal bleed. Type 5a: probable fatal bleed; no autopsy or image confirmation but clinical suspicion. Type 5b: definite fatal bleed; overt bleed or autopsy or image confirmation. |
| Safety - Number of Participants With BARC Bleeding Definition Type 1,2,3,5 | From baseline up to 52 weeks | Type 1: bleeding that is not actionable and does not cause the patient to seek unscheduled performance of studies, hospitalization, or treatment by a healthcare professional; may include episodes leading to self-discontinuation of medical therapy by the patient without consulting a healthcare professional. For BARC bleeding definition 2,3 and 5, please refer to second primary endpoint. |
| Safety - Number of Participants With All Bleeding | From baseline up to 52 weeks | All bleeding events occurred from first intake of study intervention until 2 days after the last intake of study intervention |
| Efficacy - Number of Participants With MI | From baseline up to 52 weeks | Acute MI was used when there was evidence of myocardial necrosis in a clinical setting consistent with acute myocardial ischemia. According to MI Universal Definition from 2018 the diagnosis of MI requires combination of: 1. Presence of acute myocardial injury. 2. Evidence of acute myocardial ischemia derived from the clinical presentation, electrocardiographic changes, or the results of myocardial or coronary artery imaging, or in case of post-mortem pathological findings irrespective of biomarker values. |
Countries
Austria, Belgium, Czechia, Germany, Hungary, Italy, Japan, Netherlands, Poland, Spain, Sweden, Switzerland, United Kingdom, United States
Participant flow
Recruitment details
Study was conducted at 157 centers in 14 countries or regions, between 17-Jun-2020 (first participant first visit) and 21-Feb-2022 (last participant last visit)
Pre-assignment details
1664 participants were screened, 63 participants were screening failures. 1601 participants were randomized in a 1:1:1:1 ratio to 4 treatment groups: 397, 401, and 402 participants to the asundexian 10 mg, 20 mg and 50 mg groups and 401 participants to the placebo group
Participants by arm
| Arm | Count |
|---|---|
| Asundexian 10 mg Participants received Asundexian (BAY2433334) 10 mg | 397 |
| Asundexian 20 mg Participants received Asundexian (BAY2433334) 20 mg | 401 |
| Asundexian 50 mg Participants received Asundexian (BAY2433334) 50 mg | 402 |
| Placebo Participants received placebo | 401 |
| Total | 1,601 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 35 | 40 | 39 | 44 |
| Overall Study | Death | 7 | 2 | 4 | 3 |
| Overall Study | Lost to Follow-up | 0 | 1 | 2 | 3 |
| Overall Study | Non-Compliance with study drug | 0 | 1 | 1 | 1 |
| Overall Study | Physician Decision | 4 | 9 | 9 | 5 |
| Overall Study | Subject Decision | 34 | 25 | 25 | 26 |
| Overall Study | Subject decision COVID-19 pandemic related | 1 | 0 | 1 | 0 |
| Overall Study | Technical Problems | 2 | 2 | 3 | 4 |
| Overall Study | Unspecific | 4 | 2 | 2 | 2 |
| Overall Study | Withdrawal by Subject | 7 | 2 | 7 | 4 |
Baseline characteristics
| Characteristic | Asundexian 20 mg | Asundexian 50 mg | Asundexian 10 mg | Placebo | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 278 Participants | 284 Participants | 275 Participants | 265 Participants | 1102 Participants |
| Age, Categorical Between 18 and 65 years | 123 Participants | 118 Participants | 122 Participants | 136 Participants | 499 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 50 Participants | 50 Participants | 53 Participants | 50 Participants | 203 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 2 Participants | 3 Participants | 1 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 2 Participants | 1 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 1 Participants | 5 Participants | 9 Participants | 17 Participants |
| Race (NIH/OMB) White | 345 Participants | 347 Participants | 334 Participants | 339 Participants | 1365 Participants |
| Sex: Female, Male Female | 87 Participants | 100 Participants | 93 Participants | 90 Participants | 370 Participants |
| Sex: Female, Male Male | 314 Participants | 302 Participants | 304 Participants | 311 Participants | 1231 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 10 / 397 | 7 / 401 | 10 / 402 | 7 / 401 |
| other Total, other adverse events | 89 / 395 | 118 / 397 | 94 / 402 | 107 / 399 |
| serious Total, serious adverse events | 74 / 395 | 82 / 397 | 67 / 402 | 82 / 399 |
Outcome results
Primary
Efficacy - Number of Participants With Composite of CV Death, MI, Stroke and Stent Thrombosis (ST)
CV death included death due to stroke, MI, heart failure or cardiogenic shock, sudden death or any other death due to other cardiovascular causes. Death due to non-traumatic hemorrhage was included. Acute MI was used when there was evidence of myocardial necrosis in a clinical setting consistent with acute myocardial ischemia. Stroke was defined as an acute episode of focal or global neurological dysfunction caused by an injury of the brain, spinal cord, or retina as a result of hemorrhage or infarction. ST was defined incorporating diagnostic certainty as well as timing: Definite ST: The highest level of certainty. Either angiographic or pathological confirmation of stent thrombosis. Probable ST: Regardless of the time after the index procedure, any MI that is related to documented acute ischemia in the territory of the implanted stent without angiographic confirmation of stent thrombosis and in the absence of any other obvious cause
Time frame: From baseline up to 52 weeks
Population: FAS
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Asundexian 10 mg | Efficacy - Number of Participants With Composite of CV Death, MI, Stroke and Stent Thrombosis (ST) | 27 Participants |
| Asundexian 20 mg | Efficacy - Number of Participants With Composite of CV Death, MI, Stroke and Stent Thrombosis (ST) | 24 Participants |
| Asundexian 50 mg | Efficacy - Number of Participants With Composite of CV Death, MI, Stroke and Stent Thrombosis (ST) | 22 Participants |
| Placebo | Efficacy - Number of Participants With Composite of CV Death, MI, Stroke and Stent Thrombosis (ST) | 22 Participants |
Comparison: Comparison of the Asundexian 20 mg group and 50 mg group versus Placebo groupp-value: =0.843990% CI: [0.687, 1.612]Log Rank
Comparison: Comparison of the Asundexian 20 mg group versus Placebo groupp-value: =0.756290% CI: [0.674, 1.781]Log Rank
Comparison: Comparison of the Asundexian 50 mg group versus Placebo groupp-value: =0.97890% CI: [0.614, 1.656]Log Rank
Primary
Safety - Number of Participants With BARC Bleeding Definition Type 2, 3 and 5
Type 2: any overt, actionable sign of hemorrhage that doesn't fit the criteria for type 3 or 5 but meets at least one of the following criteria: 1) requires nonsurgical, med intervention by a HCP, 2) leads to hospital or rise in level of care, or 3) prompt eval. Type 3a: 1) overt bleed + Hg drop of 3 to \<5 g/dl (provided Hg drop is related to bleed); 2 any transfusion with overt bleed. Type 3b: 1) overt bleed + Hg drop ≥5 g/dL (provided Hg drop is related to bleed); 2) cardiac tamponade; 3) bleed requiring surgical intervention for control (exclude dental/nasal /skin/hemorrhoid); 4) bleed requiring IV vasoactive agents. Type 3c: 1) ICH hemorrhage (doesn't include microbleeds or HT, does include intraspinal); subcategories confirmed by autopsy or imaging or LP; 2) intraocular bleed compromising vision. Type 5: fatal bleed. Type 5a: probable fatal bleed; no autopsy or image confirmation but clinical suspicion. Type 5b: definite fatal bleed; overt bleed or autopsy or image confirmation.
Time frame: From baseline up to 52 weeks
Population: SAF
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Asundexian 10 mg | Safety - Number of Participants With BARC Bleeding Definition Type 2, 3 and 5 | 30 Participants |
| Asundexian 20 mg | Safety - Number of Participants With BARC Bleeding Definition Type 2, 3 and 5 | 32 Participants |
| Asundexian 50 mg | Safety - Number of Participants With BARC Bleeding Definition Type 2, 3 and 5 | 42 Participants |
| Placebo | Safety - Number of Participants With BARC Bleeding Definition Type 2, 3 and 5 | 36 Participants |
| Pooled Asundexian | Safety - Number of Participants With BARC Bleeding Definition Type 2, 3 and 5 | 104 Participants |
Comparison: Comparison of the Pooled Asundexian group versus Placebo groupp-value: =0.915890% CI: [0.713, 1.347]Log Rank
Comparison: Comparison of the Asundexian 10 mg group versus Placebo groupp-value: =0.563390% CI: [0.577, 1.302]Log Rank
Comparison: Comparison of the Asundexian 20 mg group versus Placebo groupp-value: =0.58490% CI: [0.587, 1.306]Log Rank
Comparison: Comparison of the Asundexian 50 mg group versus Placebo groupp-value: =0.41790% CI: [0.828, 1.747]Log Rank
Secondary
Efficacy - Number of Participants With All Cause Mortality
Time frame: From baseline up to 52 weeks
Population: FAS
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Asundexian 10 mg | Efficacy - Number of Participants With All Cause Mortality | 10 Participants |
| Asundexian 20 mg | Efficacy - Number of Participants With All Cause Mortality | 7 Participants |
| Asundexian 50 mg | Efficacy - Number of Participants With All Cause Mortality | 10 Participants |
| Placebo | Efficacy - Number of Participants With All Cause Mortality | 7 Participants |
Comparison: Comparison of the Asundexian 20 mg group and Asundexian 50 mg group versus Placebo groupp-value: =0.601690% CI: [0.603, 2.658]Log Rank
Comparison: Comparison of the Asundexian 20 mg group versus Placebo groupp-value: =0.994590% CI: [0.414, 2.401]Log Rank
Comparison: Comparison of the Asundexian 50 mg group versus Placebo groupp-value: =0.408590% CI: [0.667, 3.405]Log Rank
Secondary
Efficacy - Number of Participants With CV Death
CV death included death due to stroke, MI, heart failure or cardiogenic shock, sudden death or any other death due to other cardiovascular causes. Death due to non-traumatic hemorrhage was included.
Time frame: From baseline up to 52 weeks
Population: FAS
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Asundexian 10 mg | Efficacy - Number of Participants With CV Death | 7 Participants |
| Asundexian 20 mg | Efficacy - Number of Participants With CV Death | 4 Participants |
| Asundexian 50 mg | Efficacy - Number of Participants With CV Death | 5 Participants |
| Placebo | Efficacy - Number of Participants With CV Death | 2 Participants |
Comparison: Comparison of the Asundexian 20 mg group and Asundexian 50 mg group versus Placebo group90% CI: [0.322, 5.05]
Comparison: Comparison of the Asundexian 50 mg group versus Placebo group90% CI: [0.479, 8.273]
Secondary
Efficacy - Number of Participants With MI
Acute MI was used when there was evidence of myocardial necrosis in a clinical setting consistent with acute myocardial ischemia. According to MI Universal Definition from 2018 the diagnosis of MI requires combination of: 1. Presence of acute myocardial injury. 2. Evidence of acute myocardial ischemia derived from the clinical presentation, electrocardiographic changes, or the results of myocardial or coronary artery imaging, or in case of post-mortem pathological findings irrespective of biomarker values.
Time frame: From baseline up to 52 weeks
Population: FAS
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Asundexian 10 mg | Efficacy - Number of Participants With MI | 18 Participants |
| Asundexian 20 mg | Efficacy - Number of Participants With MI | 20 Participants |
| Asundexian 50 mg | Efficacy - Number of Participants With MI | 18 Participants |
| Placebo | Efficacy - Number of Participants With MI | 17 Participants |
Comparison: Comparison of the Asundexian 20 mg group and Asundexian 50 mg versus Placebo group90% CI: [0.696, 1.819]
Comparison: Comparison of the Asundexian 20 mg group versus Placebo group90% CI: [0.686, 2.031]
Comparison: Comparison of the Asundexian 50 mg group versus Placebo group90% CI: [0.613, 1.866]
Secondary
Efficacy - Number of Participants With Stent Thrombosis
ST was defined incorporating diagnostic certainty as well as timing: Definite ST: The highest level of certainty. Either angiographic or pathological confirmation of stent thrombosis. Probable ST: Regardless of the time after the index procedure, any MI that is related to documented acute ischemia in the territory of the implanted stent without angiographic confirmation of stent thrombosis and in the absence of any other obvious cause
Time frame: From baseline up to 52 weeks
Population: FAS
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Asundexian 10 mg | Efficacy - Number of Participants With Stent Thrombosis | 4 Participants |
| Asundexian 20 mg | Efficacy - Number of Participants With Stent Thrombosis | 5 Participants |
| Asundexian 50 mg | Efficacy - Number of Participants With Stent Thrombosis | 4 Participants |
| Placebo | Efficacy - Number of Participants With Stent Thrombosis | 4 Participants |
Secondary
Efficacy - Number of Participants With Stroke
Stroke was defined as an acute episode of focal or global neurological dysfunction caused by an injury of the brain, spinal cord, or retina as a result of hemorrhage or infarction.
Time frame: From baseline up to 52 weeks
Population: FAS
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Asundexian 10 mg | Efficacy - Number of Participants With Stroke | 4 Participants |
| Asundexian 20 mg | Efficacy - Number of Participants With Stroke | 3 Participants |
| Asundexian 50 mg | Efficacy - Number of Participants With Stroke | 0 Participants |
| Placebo | Efficacy - Number of Participants With Stroke | 2 Participants |
Secondary
Safety - Number of Participants With All Bleeding
All bleeding events occurred from first intake of study intervention until 2 days after the last intake of study intervention
Time frame: From baseline up to 52 weeks
Population: SAF
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Asundexian 10 mg | Safety - Number of Participants With All Bleeding | 70 Participants |
| Asundexian 20 mg | Safety - Number of Participants With All Bleeding | 75 Participants |
| Asundexian 50 mg | Safety - Number of Participants With All Bleeding | 82 Participants |
| Placebo | Safety - Number of Participants With All Bleeding | 85 Participants |
Secondary
Safety - Number of Participants With BARC Bleeding Definition Type 1,2,3,5
Type 1: bleeding that is not actionable and does not cause the patient to seek unscheduled performance of studies, hospitalization, or treatment by a healthcare professional; may include episodes leading to self-discontinuation of medical therapy by the patient without consulting a healthcare professional. For BARC bleeding definition 2,3 and 5, please refer to second primary endpoint.
Time frame: From baseline up to 52 weeks
Population: SAF
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Asundexian 10 mg | Safety - Number of Participants With BARC Bleeding Definition Type 1,2,3,5 | 70 Participants |
| Asundexian 20 mg | Safety - Number of Participants With BARC Bleeding Definition Type 1,2,3,5 | 75 Participants |
| Asundexian 50 mg | Safety - Number of Participants With BARC Bleeding Definition Type 1,2,3,5 | 82 Participants |
| Placebo | Safety - Number of Participants With BARC Bleeding Definition Type 1,2,3,5 | 85 Participants |
Secondary
Safety - Number of Participants With BARC Bleeding Definition Type 3, 5
Type 3a: 1) overt bleed + Hg drop of 3 to \<5 g/dl (provided Hg drop is related to bleed); 2 any transfusion with overt bleed. Type 3b: 1) overt bleed + Hg drop ≥5 g/dL (provided Hg drop is related to bleed); 2) cardiac tamponade; 3) bleed requiring surgical intervention for control (exclude dental/nasal /skin/hemorrhoid); 4) bleed requiring IV vasoactive agents. Type 3c: 1) ICH hemorrhage (doesn't include microbleeds or HT, does include intraspinal); subcategories confirmed by autopsy or imaging or LP; 2) intraocular bleed compromising vision. Type 5: fatal bleed. Type 5a: probable fatal bleed; no autopsy or image confirmation but clinical suspicion. Type 5b: definite fatal bleed; overt bleed or autopsy or image confirmation.
Time frame: From baseline up to 52 weeks
Population: SAF
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Asundexian 10 mg | Safety - Number of Participants With BARC Bleeding Definition Type 3, 5 | 5 Participants |
| Asundexian 20 mg | Safety - Number of Participants With BARC Bleeding Definition Type 3, 5 | 3 Participants |
| Asundexian 50 mg | Safety - Number of Participants With BARC Bleeding Definition Type 3, 5 | 3 Participants |
| Placebo | Safety - Number of Participants With BARC Bleeding Definition Type 3, 5 | 5 Participants |