Acute Non-cardioembolic Ischemic Stroke
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 antiplatelet therapy in patients following a recent non cardioembolic ischemic stroke which occurs when a blood clot that has not formed in the heart travelled to the brain. 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
Population Health Research Institute
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 and older at the time of signing the informed consent * Non-cardioembolic ischemic stroke with * persistent signs and symptoms of stroke lasting for ≥ 24 hours OR * acute brain infarction documented by computed tomography (CT) or MRI AND * with the intention to be treated with antiplatelet therapy during the study conduct * Imaging of brain (CT or MRI) ruling out hemorrhagic stroke or another pathology that could explain symptoms (e.g. brain tumor, abscess, vascular malformation) * Severity of index event nearest the time of randomization: * Part A: minor stroke (defined as National Institutes of Health Stroke Scale (NIHSS) ≤ 7) can be enrolled * Part B: participants with minor or moderate stroke and NIHSS ≤ 15 can be enrolled. Participants undergoing thrombolysis or endovascular therapy (mechanical thrombectomy) can be enrolled but at the earliest 24 hours after the intervention * Randomization within 48 hours after the onset of symptoms of the index event (or after patients were last known to be without symptoms in case of wake-up stroke) * Ability to conduct an MRI either before randomization or within 72 hours after randomization
Exclusion criteria
* Prior ischemic stroke within last 30 days of index event * History of atrial fibrillation or suspicion of cardioembolic source of stroke * Dysphagia with inability to safely swallow study medication * Contraindication to perform brain MRI * Part A only: thrombolysis or endovascular therapy (mechanical thrombectomy) performed for index event * Active bleeding; known bleeding disorder, history of major bleeding (intracranial, retroperitoneal, intraocular) or clinically significant gastrointestinal bleeding within last 6 months of randomization.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy-Number of Participants With Composite of Symptomatic Ischemic Stroke or Covert Brain Infarcts Detected by Magnetic Resonance Imaging (MRI) | From baseline up to 26 weeks | Ischemic stroke was defined as either of : 1) Rapid onset (or present on awakening) of a new focal neurological deficit with clinical (\>24 hours symptoms/signs) or imaging evidence of infarction that was not attributable to a non-ischemic cause; 2) Acute worsening of an existing focal neurological deficit that was judged to be attributable to a new infarction or extension of the previous infarction in the same vascular territory, based on persisting symptoms/signs or imaging evidence of infarction and no evidence of a non-ischemic etiology. If imaging was inconclusive, persistent symptoms/signs must be significant (worsening of NIHSS score of 4 or more) and sustained (duration of ≥24 hours or until death). Covert brain infarcts were defined as incident infarcts detected by serial MRI in the absence of an adjudicated stroke consistent with the location of the infarct. MRI criteria for brain infarction were available in the MRI procedures manual. |
| Safety-Number of Participants With Composite of International Society on Thrombosis and Hemostasis (ISTH) Major Bleeding and Clinically Relevant Non-major (CRNM) Bleeding | From baseline up to 52 weeks | 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 |
|---|---|---|
| Efficacy-Number of Participants With Composite of Symptomatic Ischemic Stroke and Covert Brain Infarcts Detected by MRI, Cardiovascular (CV) Death, Myocardial Infarction (MI) and Systemic Embolism. | From baseline up to 26 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. According to MI Universal Definition from 2018 the diagnosis of MI required the combination of: 1) Presence of acute myocardial injury, and 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. Systemic embolism was defined as abrupt vascular insufficiency associated with clinical or radiological evidence of arterial occlusion in the absence of other likely mechanisms (this did not include thromboembolism of the pulmonary vasculature or venous thrombosis). |
| Efficacy-Number of Participants With Symptomatic Ischemic Stroke | From baseline up to 52 weeks | Definition of symptomatic ischemic stroke can be referred to first Primary endpoint. |
| Efficacy-Number of Participants With Covert Brain Infarcts Detected by MRI | From baseline up to 26 weeks | Definition of covert brain infarcts can be referred to first Primary endpoint. |
| Efficacy-Number of Participants With Symptomatic Ischemic Stroke, CV Death, MI | From baseline up to 52 weeks | Definition of symptomatic ischemic stroke can be referred to first Primary endpoint. Definition of CV death and MI can be referred to first Second endpoint. |
| Efficacy-Number of Participants With Symptomatic Ischemic and Hemorrhagic Stroke | From baseline up to 52 weeks | Definition of symptomatic ischemic can be referred to fourth secondary endpoint. Hemorrhagic stroke was defined as an acute, atraumatic extravasation of blood into the brain parenchyma, intraventricular or subarachnoid space with associated neurological symptoms. This did not include microbleeds or hemorrhagic transformation of an ischemic stroke. |
| Safety-Number of Participants With ISTH CRNM Bleeding | From baseline up to 52 weeks | Definition of ISTH CRNM bleeding can be referred to second Primary endpoint. |
| Efficacy-Number of Participants With All-cause Mortality | From baseline up to 52 weeks | — |
| 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. |
| Safety-Number of Participants With ISTH Minor Bleeding | From baseline up to 52 weeks | All other overt bleeding episodes not meeting the above criteria for ISTH major or CRNM bleeding were classified as minor bleeding (e.g. bleeding from a minor wound that does not prompt a face-to-face evaluation for a physical examination or laboratory testing). |
| Safety-Number of Participants With Intracerebral Hemorrhage (Non-traumatic) | From baseline up to 52 weeks | Non-traumatic intracerebral hemorrhage was defined as a hemorrhagic stroke on the recurrent stroke CRF page that is in addition classified as a bleeding with bleeding site intracranial (-subarachnoid, -intraparenchymal \[excluding microbleeds\], or -intraventricular) and spontaneous causality of bleeding, excluding all symptomatic and hemorrhagic transformation (defined by the PT hemorrhagic transformation). |
| Efficacy-Number of Participants With Disabling Stroke (mRS≥4) | From baseline up to 52 weeks | Modified ranking score (mRS): 0-No symptoms at all; 1-No significant disability despite symptoms; despite symptoms, able to carry out all usual duties and activities; 2-Slight disability; unable to carry out all previous activities but able to look after own affairs without assistance; 3-Moderate disability; requiring some help, but able to walk without assistance; 4-Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance; 5-Severe disability; bedridden, incontinent and requiring constant nursing care and attention; 6-Death. |
| Safety-Number of Participants With ISTH Major Bleeding | From baseline up to 52 weeks | Definition of ISTH major bleeding can be referred to second Primary endpoint. |
Countries
Australia, Austria, Belgium, Bulgaria, China, Czechia, Denmark, Finland, France, Germany, Hungary, Italy, Japan, Netherlands, Poland, Portugal, Russia, Slovakia, Spain, Sweden, Switzerland, United Kingdom, United States
Participant flow
Recruitment details
Study was conducted at 197 centers in 23 countries or regions, between 15-Jun-2020 (first participant first visit) and 18-Feb-2022 (last participant last visit)
Pre-assignment details
1880 participants were screened. 72 participants were screening failures. 1808 participants were randomized in a 1:1:1:1 ratio to 4 treatment groups: 455, 450, and 447 participants to asundexian 10 mg, 20 mg and 50 mg groups, 456 participants to placebo group. 22 participants (10, 4, 4 and 4 in the asundexian 10 mg, 20 mg and 50 mg, and placebo groups) never administered.
Participants by arm
| Arm | Count |
|---|---|
| Asundexian 10 mg Participants received Asundexian (BAY2433334) 10 mg for 26 weeks at least and up to 52 weeks | 455 |
| Asundexian 20 mg Participants received Asundexian (BAY2433334) 20 mg for 26 weeks at least and up to 52 weeks | 450 |
| Asundexian 50 mg Participants received Asundexian (BAY2433334) 50 mg for 26 weeks at least and up to 52 weeks | 447 |
| Placebo Participants received Asundexian (BAY2433334) placebo for 26 weeks at least and up to 52 weeks | 456 |
| Total | 1,808 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 49 | 50 | 51 | 56 |
| Overall Study | Death | 6 | 1 | 8 | 5 |
| Overall Study | Logistical Difficulties | 2 | 2 | 3 | 2 |
| Overall Study | Lost to Follow-up | 1 | 5 | 2 | 3 |
| Overall Study | Missing Information | 1 | 2 | 1 | 3 |
| Overall Study | Non-compliance With Study Drug | 3 | 1 | 2 | 0 |
| Overall Study | Other | 7 | 6 | 5 | 4 |
| Overall Study | Physician Decision | 3 | 4 | 9 | 7 |
| Overall Study | Physician Decision: COVID-19 Pandemic Related | 1 | 0 | 0 | 0 |
| Overall Study | Study drug never administered | 10 | 4 | 4 | 4 |
| Overall Study | Subject Decision | 29 | 39 | 37 | 48 |
| Overall Study | Subject Decision: COVID-19 Pandemic Related | 0 | 1 | 0 | 2 |
| Overall Study | Switching To Other Therapy | 1 | 1 | 1 | 2 |
| Overall Study | Withdrawal by Subject | 7 | 5 | 11 | 6 |
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 | 296 Participants | 273 Participants | 269 Participants | 261 Participants | 1099 Participants |
| Age, Categorical Between 18 and 65 years | 154 Participants | 174 Participants | 186 Participants | 195 Participants | 709 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 67 Participants | 68 Participants | 67 Participants | 66 Participants | 268 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 8 Participants | 4 Participants | 3 Participants | 18 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 3 Participants | 3 Participants | 6 Participants | 14 Participants |
| Race (NIH/OMB) White | 377 Participants | 367 Participants | 381 Participants | 380 Participants | 1505 Participants |
| Sex: Female, Male Female | 150 Participants | 154 Participants | 161 Participants | 150 Participants | 615 Participants |
| Sex: Female, Male Male | 300 Participants | 293 Participants | 294 Participants | 306 Participants | 1193 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 / 445 | 6 / 446 | 17 / 443 | 10 / 452 |
| other Total, other adverse events | 126 / 445 | 127 / 446 | 136 / 443 | 136 / 452 |
| serious Total, serious adverse events | 90 / 445 | 83 / 446 | 93 / 443 | 98 / 452 |
Outcome results
Primary
Efficacy-Number of Participants With Composite of Symptomatic Ischemic Stroke or Covert Brain Infarcts Detected by Magnetic Resonance Imaging (MRI)
Ischemic stroke was defined as either of : 1) Rapid onset (or present on awakening) of a new focal neurological deficit with clinical (\>24 hours symptoms/signs) or imaging evidence of infarction that was not attributable to a non-ischemic cause; 2) Acute worsening of an existing focal neurological deficit that was judged to be attributable to a new infarction or extension of the previous infarction in the same vascular territory, based on persisting symptoms/signs or imaging evidence of infarction and no evidence of a non-ischemic etiology. If imaging was inconclusive, persistent symptoms/signs must be significant (worsening of NIHSS score of 4 or more) and sustained (duration of ≥24 hours or until death). Covert brain infarcts were defined as incident infarcts detected by serial MRI in the absence of an adjudicated stroke consistent with the location of the infarct. MRI criteria for brain infarction were available in the MRI procedures manual.
Time frame: From baseline up to 26 weeks
Population: FAS
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Asundexian 10 mg | Efficacy-Number of Participants With Composite of Symptomatic Ischemic Stroke or Covert Brain Infarcts Detected by Magnetic Resonance Imaging (MRI) | Symptomatic ischemic stroke | 24 Participants |
| Asundexian 10 mg | Efficacy-Number of Participants With Composite of Symptomatic Ischemic Stroke or Covert Brain Infarcts Detected by Magnetic Resonance Imaging (MRI) | Imputed infarcts seen in participants with incomplete MRI follow-up | 6 Participants |
| Asundexian 10 mg | Efficacy-Number of Participants With Composite of Symptomatic Ischemic Stroke or Covert Brain Infarcts Detected by Magnetic Resonance Imaging (MRI) | Imputed infarcts with the rule of Quan | 11 Participants |
| Asundexian 10 mg | Efficacy-Number of Participants With Composite of Symptomatic Ischemic Stroke or Covert Brain Infarcts Detected by Magnetic Resonance Imaging (MRI) | Covert brain infarct | 56 Participants |
| Asundexian 20 mg | Efficacy-Number of Participants With Composite of Symptomatic Ischemic Stroke or Covert Brain Infarcts Detected by Magnetic Resonance Imaging (MRI) | Imputed infarcts with the rule of Quan | 14 Participants |
| Asundexian 20 mg | Efficacy-Number of Participants With Composite of Symptomatic Ischemic Stroke or Covert Brain Infarcts Detected by Magnetic Resonance Imaging (MRI) | Symptomatic ischemic stroke | 25 Participants |
| Asundexian 20 mg | Efficacy-Number of Participants With Composite of Symptomatic Ischemic Stroke or Covert Brain Infarcts Detected by Magnetic Resonance Imaging (MRI) | Covert brain infarct | 57 Participants |
| Asundexian 20 mg | Efficacy-Number of Participants With Composite of Symptomatic Ischemic Stroke or Covert Brain Infarcts Detected by Magnetic Resonance Imaging (MRI) | Imputed infarcts seen in participants with incomplete MRI follow-up | 11 Participants |
| Asundexian 50 mg | Efficacy-Number of Participants With Composite of Symptomatic Ischemic Stroke or Covert Brain Infarcts Detected by Magnetic Resonance Imaging (MRI) | Imputed infarcts with the rule of Quan | 16 Participants |
| Asundexian 50 mg | Efficacy-Number of Participants With Composite of Symptomatic Ischemic Stroke or Covert Brain Infarcts Detected by Magnetic Resonance Imaging (MRI) | Imputed infarcts seen in participants with incomplete MRI follow-up | 7 Participants |
| Asundexian 50 mg | Efficacy-Number of Participants With Composite of Symptomatic Ischemic Stroke or Covert Brain Infarcts Detected by Magnetic Resonance Imaging (MRI) | Symptomatic ischemic stroke | 17 Participants |
| Asundexian 50 mg | Efficacy-Number of Participants With Composite of Symptomatic Ischemic Stroke or Covert Brain Infarcts Detected by Magnetic Resonance Imaging (MRI) | Covert brain infarct | 56 Participants |
| Placebo | Efficacy-Number of Participants With Composite of Symptomatic Ischemic Stroke or Covert Brain Infarcts Detected by Magnetic Resonance Imaging (MRI) | Symptomatic ischemic stroke | 23 Participants |
| Placebo | Efficacy-Number of Participants With Composite of Symptomatic Ischemic Stroke or Covert Brain Infarcts Detected by Magnetic Resonance Imaging (MRI) | Covert brain infarct | 55 Participants |
| Placebo | Efficacy-Number of Participants With Composite of Symptomatic Ischemic Stroke or Covert Brain Infarcts Detected by Magnetic Resonance Imaging (MRI) | Imputed infarcts seen in participants with incomplete MRI follow-up | 5 Participants |
| Placebo | Efficacy-Number of Participants With Composite of Symptomatic Ischemic Stroke or Covert Brain Infarcts Detected by Magnetic Resonance Imaging (MRI) | Imputed infarcts with the rule of Quan | 15 Participants |
Comparison: Dose-response testp-value: 0.7976MCP Mod
Comparison: Comparison of the Asundexian 10 mg group versus Placebo group.90% CI: [0.8105, 1.3478]
Comparison: Comparison of the Asundexian 20 mg group versus Placebo group.90% CI: [0.9281, 1.5428]
Comparison: Comparison of the Asundexian 50 mg group versus Placebo group.90% CI: [0.8082, 1.3619]
Primary
Safety-Number of Participants With Composite of International Society on Thrombosis and Hemostasis (ISTH) Major Bleeding and 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: From baseline up to 52 weeks
Population: SAF
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Asundexian 10 mg | Safety-Number of Participants With Composite of International Society on Thrombosis and Hemostasis (ISTH) Major Bleeding and Clinically Relevant Non-major (CRNM) Bleeding | 19 Participants |
| Asundexian 20 mg | Safety-Number of Participants With Composite of International Society on Thrombosis and Hemostasis (ISTH) Major Bleeding and Clinically Relevant Non-major (CRNM) Bleeding | 14 Participants |
| Asundexian 50 mg | Safety-Number of Participants With Composite of International Society on Thrombosis and Hemostasis (ISTH) Major Bleeding and Clinically Relevant Non-major (CRNM) Bleeding | 19 Participants |
| Placebo | Safety-Number of Participants With Composite of International Society on Thrombosis and Hemostasis (ISTH) Major Bleeding and Clinically Relevant Non-major (CRNM) Bleeding | 52 Participants |
| Placebo | Safety-Number of Participants With Composite of International Society on Thrombosis and Hemostasis (ISTH) Major Bleeding and Clinically Relevant Non-major (CRNM) Bleeding | 11 Participants |
Comparison: Comparison of the Asundexian 10 mg group versus Placebo groupp-value: =0.150790% CI: [0.924, 3.215]Log Rank
Comparison: Comparison of the Asundexian 20 mg group versus Placebo groupp-value: =0.533990% CI: [0.662, 2.494]Log Rank
Comparison: Comparison of the Asundexian 50 mg group versus Placebo groupp-value: =0.140190% CI: [0.938, 3.262]Log Rank
Comparison: Comparison of the Total Asundexian group versus Placebo groupp-value: =0.165390% CI: [0.918, 2.736]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 | 6 Participants |
| Asundexian 50 mg | Efficacy-Number of Participants With All-cause Mortality | 17 Participants |
| Placebo | Efficacy-Number of Participants With All-cause Mortality | 10 Participants |
Secondary
Efficacy-Number of Participants With Composite of Symptomatic Ischemic Stroke and Covert Brain Infarcts Detected by MRI, Cardiovascular (CV) Death, Myocardial Infarction (MI) and Systemic Embolism.
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. According to MI Universal Definition from 2018 the diagnosis of MI required the combination of: 1) Presence of acute myocardial injury, and 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. Systemic embolism was defined as abrupt vascular insufficiency associated with clinical or radiological evidence of arterial occlusion in the absence of other likely mechanisms (this did not include thromboembolism of the pulmonary vasculature or venous thrombosis).
Time frame: From baseline up to 26 weeks
Population: FAS
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Asundexian 10 mg | Efficacy-Number of Participants With Composite of Symptomatic Ischemic Stroke and Covert Brain Infarcts Detected by MRI, Cardiovascular (CV) Death, Myocardial Infarction (MI) and Systemic Embolism. | Ischemic Stroke | 24 Participants |
| Asundexian 10 mg | Efficacy-Number of Participants With Composite of Symptomatic Ischemic Stroke and Covert Brain Infarcts Detected by MRI, Cardiovascular (CV) Death, Myocardial Infarction (MI) and Systemic Embolism. | CV death | 3 Participants |
| Asundexian 10 mg | Efficacy-Number of Participants With Composite of Symptomatic Ischemic Stroke and Covert Brain Infarcts Detected by MRI, Cardiovascular (CV) Death, Myocardial Infarction (MI) and Systemic Embolism. | MI | 3 Participants |
| Asundexian 10 mg | Efficacy-Number of Participants With Composite of Symptomatic Ischemic Stroke and Covert Brain Infarcts Detected by MRI, Cardiovascular (CV) Death, Myocardial Infarction (MI) and Systemic Embolism. | Systemic embolism | 1 Participants |
| Asundexian 10 mg | Efficacy-Number of Participants With Composite of Symptomatic Ischemic Stroke and Covert Brain Infarcts Detected by MRI, Cardiovascular (CV) Death, Myocardial Infarction (MI) and Systemic Embolism. | Covert brain infarct | 56 Participants |
| Asundexian 10 mg | Efficacy-Number of Participants With Composite of Symptomatic Ischemic Stroke and Covert Brain Infarcts Detected by MRI, Cardiovascular (CV) Death, Myocardial Infarction (MI) and Systemic Embolism. | Imputed infarcts seen in participants with incomplete MRI follow-up | 6 Participants |
| Asundexian 20 mg | Efficacy-Number of Participants With Composite of Symptomatic Ischemic Stroke and Covert Brain Infarcts Detected by MRI, Cardiovascular (CV) Death, Myocardial Infarction (MI) and Systemic Embolism. | Imputed infarcts seen in participants with incomplete MRI follow-up | 11 Participants |
| Asundexian 20 mg | Efficacy-Number of Participants With Composite of Symptomatic Ischemic Stroke and Covert Brain Infarcts Detected by MRI, Cardiovascular (CV) Death, Myocardial Infarction (MI) and Systemic Embolism. | Systemic embolism | 0 Participants |
| Asundexian 20 mg | Efficacy-Number of Participants With Composite of Symptomatic Ischemic Stroke and Covert Brain Infarcts Detected by MRI, Cardiovascular (CV) Death, Myocardial Infarction (MI) and Systemic Embolism. | Ischemic Stroke | 25 Participants |
| Asundexian 20 mg | Efficacy-Number of Participants With Composite of Symptomatic Ischemic Stroke and Covert Brain Infarcts Detected by MRI, Cardiovascular (CV) Death, Myocardial Infarction (MI) and Systemic Embolism. | MI | 0 Participants |
| Asundexian 20 mg | Efficacy-Number of Participants With Composite of Symptomatic Ischemic Stroke and Covert Brain Infarcts Detected by MRI, Cardiovascular (CV) Death, Myocardial Infarction (MI) and Systemic Embolism. | CV death | 2 Participants |
| Asundexian 20 mg | Efficacy-Number of Participants With Composite of Symptomatic Ischemic Stroke and Covert Brain Infarcts Detected by MRI, Cardiovascular (CV) Death, Myocardial Infarction (MI) and Systemic Embolism. | Covert brain infarct | 57 Participants |
| Asundexian 50 mg | Efficacy-Number of Participants With Composite of Symptomatic Ischemic Stroke and Covert Brain Infarcts Detected by MRI, Cardiovascular (CV) Death, Myocardial Infarction (MI) and Systemic Embolism. | CV death | 6 Participants |
| Asundexian 50 mg | Efficacy-Number of Participants With Composite of Symptomatic Ischemic Stroke and Covert Brain Infarcts Detected by MRI, Cardiovascular (CV) Death, Myocardial Infarction (MI) and Systemic Embolism. | MI | 3 Participants |
| Asundexian 50 mg | Efficacy-Number of Participants With Composite of Symptomatic Ischemic Stroke and Covert Brain Infarcts Detected by MRI, Cardiovascular (CV) Death, Myocardial Infarction (MI) and Systemic Embolism. | Systemic embolism | 0 Participants |
| Asundexian 50 mg | Efficacy-Number of Participants With Composite of Symptomatic Ischemic Stroke and Covert Brain Infarcts Detected by MRI, Cardiovascular (CV) Death, Myocardial Infarction (MI) and Systemic Embolism. | Imputed infarcts seen in participants with incomplete MRI follow-up | 7 Participants |
| Asundexian 50 mg | Efficacy-Number of Participants With Composite of Symptomatic Ischemic Stroke and Covert Brain Infarcts Detected by MRI, Cardiovascular (CV) Death, Myocardial Infarction (MI) and Systemic Embolism. | Covert brain infarct | 56 Participants |
| Asundexian 50 mg | Efficacy-Number of Participants With Composite of Symptomatic Ischemic Stroke and Covert Brain Infarcts Detected by MRI, Cardiovascular (CV) Death, Myocardial Infarction (MI) and Systemic Embolism. | Ischemic Stroke | 17 Participants |
| Placebo | Efficacy-Number of Participants With Composite of Symptomatic Ischemic Stroke and Covert Brain Infarcts Detected by MRI, Cardiovascular (CV) Death, Myocardial Infarction (MI) and Systemic Embolism. | Covert brain infarct | 55 Participants |
| Placebo | Efficacy-Number of Participants With Composite of Symptomatic Ischemic Stroke and Covert Brain Infarcts Detected by MRI, Cardiovascular (CV) Death, Myocardial Infarction (MI) and Systemic Embolism. | Imputed infarcts seen in participants with incomplete MRI follow-up | 5 Participants |
| Placebo | Efficacy-Number of Participants With Composite of Symptomatic Ischemic Stroke and Covert Brain Infarcts Detected by MRI, Cardiovascular (CV) Death, Myocardial Infarction (MI) and Systemic Embolism. | CV death | 6 Participants |
| Placebo | Efficacy-Number of Participants With Composite of Symptomatic Ischemic Stroke and Covert Brain Infarcts Detected by MRI, Cardiovascular (CV) Death, Myocardial Infarction (MI) and Systemic Embolism. | Systemic embolism | 0 Participants |
| Placebo | Efficacy-Number of Participants With Composite of Symptomatic Ischemic Stroke and Covert Brain Infarcts Detected by MRI, Cardiovascular (CV) Death, Myocardial Infarction (MI) and Systemic Embolism. | Ischemic Stroke | 23 Participants |
| Placebo | Efficacy-Number of Participants With Composite of Symptomatic Ischemic Stroke and Covert Brain Infarcts Detected by MRI, Cardiovascular (CV) Death, Myocardial Infarction (MI) and Systemic Embolism. | MI | 3 Participants |
Secondary
Efficacy-Number of Participants With Covert Brain Infarcts Detected by MRI
Definition of covert brain infarcts can be referred to first Primary endpoint.
Time frame: From baseline up to 26 weeks
Population: FAS
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Asundexian 10 mg | Efficacy-Number of Participants With Covert Brain Infarcts Detected by MRI | 62 Participants |
| Asundexian 20 mg | Efficacy-Number of Participants With Covert Brain Infarcts Detected by MRI | 68 Participants |
| Asundexian 50 mg | Efficacy-Number of Participants With Covert Brain Infarcts Detected by MRI | 63 Participants |
| Placebo | Efficacy-Number of Participants With Covert Brain Infarcts Detected by MRI | 60 Participants |
Secondary
Efficacy-Number of Participants With Disabling Stroke (mRS≥4)
Modified ranking score (mRS): 0-No symptoms at all; 1-No significant disability despite symptoms; despite symptoms, able to carry out all usual duties and activities; 2-Slight disability; unable to carry out all previous activities but able to look after own affairs without assistance; 3-Moderate disability; requiring some help, but able to walk without assistance; 4-Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance; 5-Severe disability; bedridden, incontinent and requiring constant nursing care and attention; 6-Death.
Time frame: From baseline up to 52 weeks
Population: FAS
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Asundexian 10 mg | Efficacy-Number of Participants With Disabling Stroke (mRS≥4) | 5 Participants |
| Asundexian 20 mg | Efficacy-Number of Participants With Disabling Stroke (mRS≥4) | 5 Participants |
| Asundexian 50 mg | Efficacy-Number of Participants With Disabling Stroke (mRS≥4) | 1 Participants |
| Placebo | Efficacy-Number of Participants With Disabling Stroke (mRS≥4) | 3 Participants |
Secondary
Efficacy-Number of Participants With Symptomatic Ischemic and Hemorrhagic Stroke
Definition of symptomatic ischemic can be referred to fourth secondary endpoint. Hemorrhagic stroke was defined as an acute, atraumatic extravasation of blood into the brain parenchyma, intraventricular or subarachnoid space with associated neurological symptoms. This did not include microbleeds or hemorrhagic transformation of an ischemic stroke.
Time frame: From baseline up to 52 weeks
Population: FAS
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Asundexian 10 mg | Efficacy-Number of Participants With Symptomatic Ischemic and Hemorrhagic Stroke | 26 Participants |
| Asundexian 20 mg | Efficacy-Number of Participants With Symptomatic Ischemic and Hemorrhagic Stroke | 26 Participants |
| Asundexian 50 mg | Efficacy-Number of Participants With Symptomatic Ischemic and Hemorrhagic Stroke | 25 Participants |
| Placebo | Efficacy-Number of Participants With Symptomatic Ischemic and Hemorrhagic Stroke | 30 Participants |
Secondary
Efficacy-Number of Participants With Symptomatic Ischemic Stroke
Definition of symptomatic ischemic stroke can be referred to first Primary endpoint.
Time frame: From baseline up to 52 weeks
Population: FAS
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Asundexian 10 mg | Efficacy-Number of Participants With Symptomatic Ischemic Stroke | 26 Participants |
| Asundexian 20 mg | Efficacy-Number of Participants With Symptomatic Ischemic Stroke | 26 Participants |
| Asundexian 50 mg | Efficacy-Number of Participants With Symptomatic Ischemic Stroke | 22 Participants |
| Placebo | Efficacy-Number of Participants With Symptomatic Ischemic Stroke | 28 Participants |
Secondary
Efficacy-Number of Participants With Symptomatic Ischemic Stroke, CV Death, MI
Definition of symptomatic ischemic stroke can be referred to first Primary endpoint. Definition of CV death and MI can be referred to first Second endpoint.
Time frame: From baseline up to 52 weeks
Population: FAS
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Asundexian 10 mg | Efficacy-Number of Participants With Symptomatic Ischemic Stroke, CV Death, MI | 33 Participants |
| Asundexian 20 mg | Efficacy-Number of Participants With Symptomatic Ischemic Stroke, CV Death, MI | 30 Participants |
| Asundexian 50 mg | Efficacy-Number of Participants With Symptomatic Ischemic Stroke, CV Death, MI | 33 Participants |
| Placebo | Efficacy-Number of Participants With Symptomatic Ischemic Stroke, CV Death, MI | 35 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 | 37 Participants |
| Asundexian 20 mg | Safety-Number of Participants With All Bleeding | 48 Participants |
| Asundexian 50 mg | Safety-Number of Participants With All Bleeding | 48 Participants |
| Placebo | Safety-Number of Participants With All Bleeding | 44 Participants |
Secondary
Safety-Number of Participants With Intracerebral Hemorrhage (Non-traumatic)
Non-traumatic intracerebral hemorrhage was defined as a hemorrhagic stroke on the recurrent stroke CRF page that is in addition classified as a bleeding with bleeding site intracranial (-subarachnoid, -intraparenchymal \[excluding microbleeds\], or -intraventricular) and spontaneous causality of bleeding, excluding all symptomatic and hemorrhagic transformation (defined by the PT hemorrhagic transformation).
Time frame: From baseline up to 52 weeks
Population: SAF
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Asundexian 10 mg | Safety-Number of Participants With Intracerebral Hemorrhage (Non-traumatic) | 0 Participants |
| Asundexian 20 mg | Safety-Number of Participants With Intracerebral Hemorrhage (Non-traumatic) | 0 Participants |
| Asundexian 50 mg | Safety-Number of Participants With Intracerebral Hemorrhage (Non-traumatic) | 3 Participants |
| Placebo | Safety-Number of Participants With Intracerebral Hemorrhage (Non-traumatic) | 1 Participants |
Secondary
Safety-Number of Participants With ISTH CRNM Bleeding
Definition of ISTH CRNM bleeding can be referred 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 ISTH CRNM Bleeding | 15 Participants |
| Asundexian 20 mg | Safety-Number of Participants With ISTH CRNM Bleeding | 12 Participants |
| Asundexian 50 mg | Safety-Number of Participants With ISTH CRNM Bleeding | 12 Participants |
| Placebo | Safety-Number of Participants With ISTH CRNM Bleeding | 7 Participants |
Secondary
Safety-Number of Participants With ISTH Major Bleeding
Definition of ISTH major bleeding can be referred 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 ISTH Major Bleeding | 4 Participants |
| Asundexian 20 mg | Safety-Number of Participants With ISTH Major Bleeding | 3 Participants |
| Asundexian 50 mg | Safety-Number of Participants With ISTH Major Bleeding | 7 Participants |
| Placebo | Safety-Number of Participants With ISTH Major Bleeding | 4 Participants |
Secondary
Safety-Number of Participants With ISTH Minor Bleeding
All other overt bleeding episodes not meeting the above criteria for ISTH major or CRNM bleeding were classified as minor bleeding (e.g. bleeding from a minor wound that does not prompt a face-to-face evaluation for a physical examination or laboratory testing).
Time frame: From baseline up to 52 weeks
Population: SAF
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Asundexian 10 mg | Safety-Number of Participants With ISTH Minor Bleeding | 21 Participants |
| Asundexian 20 mg | Safety-Number of Participants With ISTH Minor Bleeding | 39 Participants |
| Asundexian 50 mg | Safety-Number of Participants With ISTH Minor Bleeding | 34 Participants |
| Placebo | Safety-Number of Participants With ISTH Minor Bleeding | 34 Participants |