Acute Ischemic Stroke, Transient Ischemic Attack (TIA)
Conditions
Brief summary
The purpose of this clinical study is to determine whether the addition of an oral Factor XIa Inhibitor to Aspirin and Clopidogrel is more effective than standard therapy in secondary stroke prevention.
Interventions
DRUGBMS-986177
Oral administration
OTHERPlacebo
Oral Administration
DRUGClopidogrel
Oral administration
DRUGAspirin
Oral administration
Sponsors
Janssen, LP
Bristol-Myers Squibb
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male and Female ≥40 years of age * Acute Ischemic Stroke or Transient Ischemic Attack * Intracranial or Extracranial Atherosclerotic Plaque proximal to the affected brain area
Exclusion criteria
* Predicted inability to swallow study medication * Any condition that, in the opinion of the Investigator, contraindicates anticoagulant therapy or would have an unacceptable risk of bleeding * Use of thrombolytic therapy or mechanical thrombectomy for treatment of index stroke Other protocol defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent of Participants With Model Based Assessment of Composite of New Ischemic Stroke During Treatment and New Covert Brain Infarction (FLAIR + DWI) Detected by MRI by Day 90 | From randomization to up to 90 days after randomization | Model based assessment estimate for composite event is a customized statistical analysis called MCP-MOD (Multiple Comparison Procedures, MODel) estimation, which is used to check for dose-response relationship. 95% confidence interval (CI) for composite event based on bootstrap (10000 samples). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent of Participants With Major Bleeding According to BARC Type 3 and 5 | From first dose to up to 107 days after first dose | Percent of participants with major bleeding based on the Bleeding Academic Research Consortium (BARC) Types 3 and 5 definitions. BARC bleeding types: 3a = Overt bleeding plus hemoglobin drop of 3 to \< 5 g/dL transfusion with overt bleeding 3b = Overt bleeding plus hemoglobin drop ≥5 g/dL; cardiac tamponade; bleeding requiring surgical intervention for control; bleeding requiring IV vasoactive agents 3c = Intracranial hemorrhage, 5a = Probable fatal bleeding 5b = Definite fatal bleeding |
| Number of Participants With Bleeding Based on BARC Types 1-5 | From first dose to up to 107 days after first dose | Number of participants with bleeding based on Bleeding Academic Research Consortium (BARC) Type 1 to 5. BARC bleeding types: 0=No bleeding. 1=Not actionable bleeding. 2=Overt, actionable sign of hemorrhage requiring nonsurgical, medical intervention by a health-care professional, leading to hospitalization or increased level of care, or prompting evaluation. 3a=Overt bleeding plus hemoglobin drop of 3 to \< 5 g/dL. 3b=Overt bleeding plus hemoglobin drop ≥5 g/dL; cardiac tamponade; bleeding requiring surgical intervention; bleeding requiring IV vasoactive agents. 3c=Intracranial hemorrhage; intraocular bleed compromising vision. 4=CABG-related bleeding, perioperative intracranial bleeding within 48 hours, reoperation after closure of sternotomy to control bleeding, transfusion of ≥5 U whole blood or packed red blood cells within a 48-hour period, chest tube output more than or equal to 2L within a 24-hour period. 5a=Probable fatal bleeding. 5b=Definite fatal bleeding. |
| Number of Participants With Bleeding Based on ISTH-Defined Criteria | From first dose to up to 107 days after first dose | Number of participants with bleeding based on International Society on Thrombosis and Hemostasis (ISTH). ISTH Bleeding Types: 1) Fatal bleeding and/or 2) Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with compartment syndrome and/or 3) Bleeding causing a fall in hemoglobin level of ≥2 g/dL, or leading to transfusion of ≥2 units of whole blood or red cells. |
| Number of Participants With Bleeding Based on PLATO-Defined Criteria | From first dose to up to 107 days after first dose | Number of participants with bleeding based on Platelet Inhibition and Patient Outcomes (PLATO) defined criteria. PLATO bleeding definitions: 1. Major Life-threatening: Fatal, Intracranial, Intrapericardial with cardiac tamponade, Resulting in hypovolemic shock or severe hypotension that requires pressors or surgery, Clinically overt or apparent bleeding associated with decrease in hemoglobin \>5 g/dL, Requiring transfusion of ≥4 U whole blood or packed red blood cells (PRBCs) 2. Other Major: Significantly disabling (eg, intraocular with permanent vision loss), Associated drop in hemoglobin of 3 to 5 g/dL, Requiring transfusion of 2 to 3 U whole blood or PRBCs 3. Any Major: Any one of the above criteria 4. Minor: Bleeding that does not meet criteria for PLATO Major bleeding, and requiring medical intervention |
| Percent of Participants With Descriptive Assessment of Composite of New Ischemic Stroke During Treatment and New Covert Brain Infarction (FLAIR + DWI) Detected by MRI by Day 90 | From randomization to up to 90 days after randomization | Descriptive Assessment of Composite of New Ischemic Stroke During Treatment and New Covert Brain Infarction (FLAIR + DWI) Detected by MRI by Day 90. |
| Composite of Percent of Participants With New Ischemic Stroke, MI and All Cause Death | From randomization to up to 90 days after randomization | Composite of percent of participants of new ischemic stroke, (Myocardial Infarction) MI and all cause death. |
| National Institutes of Health Stroke Scale (NIHSS) | At baseline, on Days 21 and 90, and at the time of a new stroke event | The NIHSS is an 11-item neurologic examination stroke scale used to evaluate the effect of acute cerebral infarction on the levels of consciousness, language, neglect, visual-field loss, extraocular movement, motor strength, ataxia, dysarthria, and sensory loss. A trained observer rates the patent's ability to answer questions and perform activities. The score for each ability is a number between 0 and 4, 0 being normal functioning and 4 being completely impaired. The patient's NIHSS score is calculated by adding the number for each element of the scale; 42 is the highest score possible. In the NIHSS, the higher the score, the more impaired a stroke participant is. |
| Modified Rankin Scale (mRS) | At baseline, on Days 21 and 90, and at the time of a new stroke event | The Modified Rankin Score (mRS) is a 6-point disability scale with possible scores ranging from 0 to 6. 0 = No symptoms at all 1. = No significant disability 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 and attend to bodily needs without assistance 5. = Severe disability; bedridden, incontinent and requiring constant nursing care and attention 6. = Dead |
| Montreal Cognitive Assessment (MoCA) | At baseline, on Days 21 and 90, and at the time of a new stroke event | The Montreal Cognitive Assessment (MoCA) is a survey with a summed score. MoCA score ranges between a lowest score of 0 to a highest score of 30. A score of: * ≥26 points: indicates normal cognitive function * 18-25 points: Mild cognitive impairment * 10-17 points: Moderate cognitive impairment * fewer than 10 points: Severe cognitive impairment |
| Digit Symbol Substitution Test (DSST) | At baseline, on Days 21 and 90, and at the time of a new stroke event | The Descriptive Summary of the Digit Symbol Substitution Test (DSST) is a scale item, with a lowest score of 0 and highest total score of 135. Higher score indicates better cognitive functioning. |
| Number of Participants With Clinically Significant Vital Sign Abnormalities | From first dose to up to 90 days after first dose | Number of participants with clinically significant vital sign abnormalities. Vital signs included heart rate and diastolic and systolic blood pressure. |
| Number of Participants With Clinically Significant Physical Examination Abnormalities | From first dose to up to 90 days after first dose | Number of participants with clinically significant physical examination abnormalities. |
| Number of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities | From first dose to up to 90 days after first dose | Number of participants with clinically significant ECG abnormalities. |
| Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | From first dose to up to approximately 38 months | The number of treated participants who experienced a laboratory abnormality of the liver during the course of the study. Aspartate aminotransferase (AST) Alanine aminotransferase (ALT) Upper Limit of Normal (ULN) Results reported in International System of Units (SI) |
| Percent Change From Baseline in aPTT Activity | Baseline and day 90 | Percent change from baseline in activated partial thromboplastin time (aPTT) activity via exposure response. |
| Percent Change From Baseline in Factor XI Clotting Activity | Baseline and day 90 | Percent change from baseline in factor XI clotting activity via exposure response. |
| Pharmacokinetic Parameter - Estimated Clearance (CL) | From first dose to up to 90 days after first dose | Pharmacokinetic Parameter - Estimated Clearance (CL). CL is derived from plasma concentration versus time data. PK parameters were generated using a Population Pharmacokinetics (PPK) model. Summary statistics for these individual predicted PK parameters and exposures were stratified by dose. The PPK model analysis was based on combined PK data collected on days 1, 21, and 90. |
| Pharmacokinetic Parameter - Volume of the Central Compartment (VC) | From first dose to up to 90 days after first dose | Pharmacokinetic Parameter - Volume of the Central Compartment (VC). VC is derived from plasma concentration versus time data. PK parameters were generated using a Population Pharmacokinetics (PPK) model. Summary statistics for these individual predicted PK parameters and exposures were stratified by dose. The PPK model analysis was based on combined PK data collected on days 1, 21, and 90. |
| Volume of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | At day 90 | Total volume of diffusion-weighted imaging (DWI) magnetic resonance imaging (MRI) infarcts on the DWI Sequence on day 90 MRI. |
| Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | At day 90 | Number of diffusion-weighted imaging (DWI) magnetic resonance imaging (MRI) infarcts on the DWI Sequence on day 90 MRI. |
| Number of Participants With Adverse Events (AEs) | From first dose to 2 days after last dose of study therapy (up to approximately 107 days) | AE: include all non-serious adverse events with onset on or after first dose date and within 2 days after the last dose of study treatment. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Percent of Participants With Ischemic Stroke Events | From randomization to up to 90 days after randomization | Secondary analysis of symptomatic ischemic stroke events. Clinical events are included up to day 90. Wald 95% CI within group. Undetermined stroke is included. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Canada, Chile, China, Czechia, Denmark, Finland, France, Germany, Greece, Hong Kong, Hungary, Israel, Italy, Japan, Mexico, Norway, Poland, Russia, South Korea, Spain, Sweden, Switzerland, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Placebo + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Placebo + Aspirin 100 mg QD on days 22-90. All administered orally. | 691 |
| Milvexian 25 mg QD Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 25 mg QD + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 25 mg QD + Aspirin 100 mg QD on days 22-90. All administered orally. | 328 |
| Milvexian 25 mg BID Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 25 mg BID + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 25 mg BID + Aspirin 100 mg QD on days 22-90. All administered orally. | 318 |
| Milvexian 50 mg BID Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 50 mg BID + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 50 mg BID + Aspirin 100 mg QD on days 22-90. All administered orally. | 328 |
| Milvexian 100 mg BID Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 100 mg BID + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 100 mg BID + Aspirin 100 mg QD on days 22-90. All administered orally. | 310 |
| Milvexian 200 mg BID Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 200 mg BID + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 200 mg BID + Aspirin 100 mg QD on days 22-90. All administered orally. | 351 |
| Milvexian 50 mg QD Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 50 mg QD + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 50 mg QD + Aspirin 100 mg QD on days 22-90. All administered orally. | 22 |
| Milvexian 100 mg QD Loading dose of Clopidogrel 300 mg + Aspirin 100 mg followed by Milvexian 100 mg QD + Aspirin 100 mg QD + Clopidogrel 75 mg QD on days 1-21 and Milvexian 100 mg QD + Aspirin 100 mg QD on days 22-90. All administered orally. | 18 |
| Total | 2,366 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Randomization | Other reasons | 2 | 1 | 0 | 1 | 0 | 0 | 0 | 0 |
| Randomization | Participant no longer meets study criteria | 5 | 3 | 4 | 0 | 2 | 3 | 0 | 1 |
| Randomization | Participant request to discontinue study treatment | 1 | 0 | 0 | 0 | 1 | 2 | 0 | 0 |
| Randomization | Participant withdrew consent | 1 | 0 | 1 | 2 | 1 | 1 | 0 | 0 |
| Treatment | Adverse Event | 82 | 44 | 47 | 46 | 50 | 77 | 5 | 2 |
| Treatment | Death | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Treatment | Lost to Follow-up | 1 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Treatment | Other reasons | 13 | 8 | 3 | 7 | 3 | 3 | 0 | 0 |
| Treatment | Participant no longer meets study criteria | 9 | 1 | 5 | 4 | 4 | 4 | 2 | 0 |
| Treatment | Participant request to discontinue treatment | 34 | 6 | 10 | 10 | 14 | 15 | 0 | 1 |
| Treatment | Participant withdrew consent | 11 | 4 | 5 | 5 | 4 | 4 | 0 | 0 |
| Treatment | Poor/Non compliance | 2 | 2 | 1 | 1 | 1 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo | Total | Milvexian 100 mg QD | Milvexian 50 mg QD | Milvexian 200 mg BID | Milvexian 100 mg BID | Milvexian 50 mg BID | Milvexian 25 mg BID | Milvexian 25 mg QD |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 69.1 Years STANDARD_DEVIATION 10.58 | 69.6 Years STANDARD_DEVIATION 10.81 | 65.4 Years STANDARD_DEVIATION 11.65 | 65.7 Years STANDARD_DEVIATION 10.64 | 69.5 Years STANDARD_DEVIATION 11.11 | 69.7 Years STANDARD_DEVIATION 10.59 | 69.3 Years STANDARD_DEVIATION 10.69 | 70.1 Years STANDARD_DEVIATION 11.34 | 70.9 Years STANDARD_DEVIATION 10.66 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 10 Participants | 22 Participants | 1 Participants | 1 Participants | 1 Participants | 2 Participants | 1 Participants | 2 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 62 Participants | 197 Participants | 7 Participants | 7 Participants | 27 Participants | 29 Participants | 23 Participants | 22 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 619 Participants | 2147 Participants | 10 Participants | 14 Participants | 323 Participants | 279 Participants | 304 Participants | 294 Participants | 304 Participants |
| Race/Ethnicity, Customized Asian | 35 Participants | 109 Participants | 0 Participants | 0 Participants | 17 Participants | 11 Participants | 13 Participants | 21 Participants | 12 Participants |
| Race/Ethnicity, Customized Asian Indian | 2 Participants | 6 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian Other | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 15 Participants | 48 Participants | 3 Participants | 3 Participants | 5 Participants | 3 Participants | 8 Participants | 6 Participants | 5 Participants |
| Race/Ethnicity, Customized Chinese | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Japanese | 84 Participants | 290 Participants | 0 Participants | 0 Participants | 40 Participants | 39 Participants | 41 Participants | 40 Participants | 46 Participants |
| Race/Ethnicity, Customized Malay | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 5 Participants | 24 Participants | 0 Participants | 1 Participants | 1 Participants | 5 Participants | 4 Participants | 2 Participants | 6 Participants |
| Race/Ethnicity, Customized White | 549 Participants | 1884 Participants | 15 Participants | 18 Participants | 288 Participants | 251 Participants | 260 Participants | 246 Participants | 257 Participants |
| Sex: Female, Male Female | 254 Participants | 859 Participants | 10 Participants | 7 Participants | 128 Participants | 112 Participants | 121 Participants | 118 Participants | 109 Participants |
| Sex: Female, Male Male | 437 Participants | 1507 Participants | 8 Participants | 15 Participants | 223 Participants | 198 Participants | 207 Participants | 200 Participants | 219 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 5 / 691 | 4 / 328 | 0 / 22 | 0 / 18 | 3 / 318 | 3 / 328 | 5 / 310 | 5 / 351 |
| other Total, other adverse events | 178 / 682 | 81 / 325 | 6 / 22 | 11 / 17 | 83 / 313 | 92 / 325 | 82 / 306 | 90 / 344 |
| serious Total, serious adverse events | 94 / 682 | 37 / 325 | 5 / 22 | 3 / 17 | 39 / 313 | 41 / 325 | 42 / 306 | 54 / 344 |
Outcome results
Primary
Percent of Participants With Model Based Assessment of Composite of New Ischemic Stroke During Treatment and New Covert Brain Infarction (FLAIR + DWI) Detected by MRI by Day 90
Model based assessment estimate for composite event is a customized statistical analysis called MCP-MOD (Multiple Comparison Procedures, MODel) estimation, which is used to check for dose-response relationship. 95% confidence interval (CI) for composite event based on bootstrap (10000 samples).
Time frame: From randomization to up to 90 days after randomization
Population: All randomized participants who experienced a new ischemic stroke by day 90, or an evaluable day 90 MRI regardless of when the MRI was collected. Dose -response model-based endpoint that was pre-specified for data to be collected only in the Placebo, 25 mg QD, and BID dose regimens.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percent of Participants With Model Based Assessment of Composite of New Ischemic Stroke During Treatment and New Covert Brain Infarction (FLAIR + DWI) Detected by MRI by Day 90 | 16.8 Percentage of participants |
| Milvexian 25 mg QD | Percent of Participants With Model Based Assessment of Composite of New Ischemic Stroke During Treatment and New Covert Brain Infarction (FLAIR + DWI) Detected by MRI by Day 90 | 16.7 Percentage of participants |
| Milvexian 25 mg BID | Percent of Participants With Model Based Assessment of Composite of New Ischemic Stroke During Treatment and New Covert Brain Infarction (FLAIR + DWI) Detected by MRI by Day 90 | 16.6 Percentage of participants |
| Milvexian 50 mg BID | Percent of Participants With Model Based Assessment of Composite of New Ischemic Stroke During Treatment and New Covert Brain Infarction (FLAIR + DWI) Detected by MRI by Day 90 | 15.6 Percentage of participants |
| Milvexian 100 mg BID | Percent of Participants With Model Based Assessment of Composite of New Ischemic Stroke During Treatment and New Covert Brain Infarction (FLAIR + DWI) Detected by MRI by Day 90 | 15.4 Percentage of participants |
| Milvexian 200 mg BID | Percent of Participants With Model Based Assessment of Composite of New Ischemic Stroke During Treatment and New Covert Brain Infarction (FLAIR + DWI) Detected by MRI by Day 90 | 15.3 Percentage of participants |
Comparison: Milvexian 25 mg QD over Placebo95% CI: [0.87, 1.1]MCP-MOD
Comparison: Milvexian 25 mg BID over Placebo95% CI: [0.83, 1.15]MCP-MOD
Comparison: Milvexian 50 mg BID over Placebo95% CI: [0.76, 1.16]MCP-MOD
Comparison: Milvexian 100 mg BID over Placebo95% CI: [0.73, 1.18]MCP-MOD
Comparison: Milvexian 200 mg BID over Placebo95% CI: [0.69, 1.31]MCP-MOD
Secondary
Composite of Percent of Participants With New Ischemic Stroke, MI and All Cause Death
Composite of percent of participants of new ischemic stroke, (Myocardial Infarction) MI and all cause death.
Time frame: From randomization to up to 90 days after randomization
Population: All randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Composite of Percent of Participants With New Ischemic Stroke, MI and All Cause Death | 6.1 Percentage of participants |
| Milvexian 25 mg QD | Composite of Percent of Participants With New Ischemic Stroke, MI and All Cause Death | 5.2 Percentage of participants |
| Milvexian 25 mg BID | Composite of Percent of Participants With New Ischemic Stroke, MI and All Cause Death | 4.7 Percentage of participants |
| Milvexian 50 mg BID | Composite of Percent of Participants With New Ischemic Stroke, MI and All Cause Death | 4.9 Percentage of participants |
| Milvexian 100 mg BID | Composite of Percent of Participants With New Ischemic Stroke, MI and All Cause Death | 5.2 Percentage of participants |
| Milvexian 200 mg BID | Composite of Percent of Participants With New Ischemic Stroke, MI and All Cause Death | 9.4 Percentage of participants |
| Milvexian 50 mg QD | Composite of Percent of Participants With New Ischemic Stroke, MI and All Cause Death | 18.2 Percentage of participants |
| Milvexian 100 mg QD | Composite of Percent of Participants With New Ischemic Stroke, MI and All Cause Death | 5.6 Percentage of participants |
Secondary
Digit Symbol Substitution Test (DSST)
The Descriptive Summary of the Digit Symbol Substitution Test (DSST) is a scale item, with a lowest score of 0 and highest total score of 135. Higher score indicates better cognitive functioning.
Time frame: At baseline, on Days 21 and 90, and at the time of a new stroke event
Population: All randomized participants with a complete DSST assessment
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Digit Symbol Substitution Test (DSST) | Baseline | 34.9 Score on a scale | Standard Deviation 22.36 |
| Placebo | Digit Symbol Substitution Test (DSST) | Day 21 | 41.2 Score on a scale | Standard Deviation 22.14 |
| Placebo | Digit Symbol Substitution Test (DSST) | Day 90 | 42.8 Score on a scale | Standard Deviation 21.18 |
| Placebo | Digit Symbol Substitution Test (DSST) | First recurrent stroke | 36.3 Score on a scale | Standard Deviation 13.56 |
| Milvexian 25 mg QD | Digit Symbol Substitution Test (DSST) | First recurrent stroke | 28.0 Score on a scale | Standard Deviation 20.95 |
| Milvexian 25 mg QD | Digit Symbol Substitution Test (DSST) | Day 21 | 38.9 Score on a scale | Standard Deviation 19.27 |
| Milvexian 25 mg QD | Digit Symbol Substitution Test (DSST) | Baseline | 31.2 Score on a scale | Standard Deviation 18.87 |
| Milvexian 25 mg QD | Digit Symbol Substitution Test (DSST) | Day 90 | 41.7 Score on a scale | Standard Deviation 21.66 |
| Milvexian 25 mg BID | Digit Symbol Substitution Test (DSST) | Baseline | 32.9 Score on a scale | Standard Deviation 22.89 |
| Milvexian 25 mg BID | Digit Symbol Substitution Test (DSST) | First recurrent stroke | 42.0 Score on a scale | Standard Deviation 4.36 |
| Milvexian 25 mg BID | Digit Symbol Substitution Test (DSST) | Day 21 | 40.2 Score on a scale | Standard Deviation 21.6 |
| Milvexian 25 mg BID | Digit Symbol Substitution Test (DSST) | Day 90 | 41.3 Score on a scale | Standard Deviation 20.29 |
| Milvexian 50 mg BID | Digit Symbol Substitution Test (DSST) | Baseline | 37.2 Score on a scale | Standard Deviation 25.67 |
| Milvexian 50 mg BID | Digit Symbol Substitution Test (DSST) | Day 21 | 45.1 Score on a scale | Standard Deviation 25.77 |
| Milvexian 50 mg BID | Digit Symbol Substitution Test (DSST) | Day 90 | 45.2 Score on a scale | Standard Deviation 21.86 |
| Milvexian 50 mg BID | Digit Symbol Substitution Test (DSST) | First recurrent stroke | 40.5 Score on a scale | Standard Deviation 2.12 |
| Milvexian 100 mg BID | Digit Symbol Substitution Test (DSST) | First recurrent stroke | 23.0 Score on a scale | — |
| Milvexian 100 mg BID | Digit Symbol Substitution Test (DSST) | Day 90 | 45.5 Score on a scale | Standard Deviation 23.44 |
| Milvexian 100 mg BID | Digit Symbol Substitution Test (DSST) | Day 21 | 41.2 Score on a scale | Standard Deviation 22.87 |
| Milvexian 100 mg BID | Digit Symbol Substitution Test (DSST) | Baseline | 33.7 Score on a scale | Standard Deviation 21.89 |
| Milvexian 200 mg BID | Digit Symbol Substitution Test (DSST) | First recurrent stroke | 27.5 Score on a scale | Standard Deviation 16.96 |
| Milvexian 200 mg BID | Digit Symbol Substitution Test (DSST) | Day 90 | 41.4 Score on a scale | Standard Deviation 21.97 |
| Milvexian 200 mg BID | Digit Symbol Substitution Test (DSST) | Day 21 | 39.1 Score on a scale | Standard Deviation 21.35 |
| Milvexian 200 mg BID | Digit Symbol Substitution Test (DSST) | Baseline | 31.7 Score on a scale | Standard Deviation 19.15 |
| Milvexian 50 mg QD | Digit Symbol Substitution Test (DSST) | First recurrent stroke | 9.0 Score on a scale | — |
| Milvexian 50 mg QD | Digit Symbol Substitution Test (DSST) | Baseline | 47.1 Score on a scale | Standard Deviation 29.34 |
| Milvexian 50 mg QD | Digit Symbol Substitution Test (DSST) | Day 90 | 47.5 Score on a scale | Standard Deviation 27.48 |
| Milvexian 50 mg QD | Digit Symbol Substitution Test (DSST) | Day 21 | 54.6 Score on a scale | Standard Deviation 32.73 |
| Milvexian 100 mg QD | Digit Symbol Substitution Test (DSST) | Day 21 | 37.1 Score on a scale | Standard Deviation 20.13 |
| Milvexian 100 mg QD | Digit Symbol Substitution Test (DSST) | Day 90 | 40.7 Score on a scale | Standard Deviation 17.46 |
| Milvexian 100 mg QD | Digit Symbol Substitution Test (DSST) | First recurrent stroke | 47.0 Score on a scale | — |
| Milvexian 100 mg QD | Digit Symbol Substitution Test (DSST) | Baseline | 29.2 Score on a scale | Standard Deviation 18.16 |
Secondary
Modified Rankin Scale (mRS)
The Modified Rankin Score (mRS) is a 6-point disability scale with possible scores ranging from 0 to 6. 0 = No symptoms at all 1. = No significant disability 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 and attend to bodily needs without assistance 5. = Severe disability; bedridden, incontinent and requiring constant nursing care and attention 6. = Dead
Time frame: At baseline, on Days 21 and 90, and at the time of a new stroke event
Population: All randomized participants with a complete mRS assessment
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Modified Rankin Scale (mRS) | Baseline | 0.5 Score on a scale | Standard Deviation 0.87 |
| Placebo | Modified Rankin Scale (mRS) | Day 21 | 1.0 Score on a scale | Standard Deviation 1.18 |
| Placebo | Modified Rankin Scale (mRS) | Day 90 | 0.7 Score on a scale | Standard Deviation 1.04 |
| Placebo | Modified Rankin Scale (mRS) | First recurrent stroke | 3.0 Score on a scale | Standard Deviation 1.6 |
| Milvexian 25 mg QD | Modified Rankin Scale (mRS) | First recurrent stroke | 2.7 Score on a scale | Standard Deviation 1.03 |
| Milvexian 25 mg QD | Modified Rankin Scale (mRS) | Day 21 | 1.0 Score on a scale | Standard Deviation 1.13 |
| Milvexian 25 mg QD | Modified Rankin Scale (mRS) | Baseline | 0.6 Score on a scale | Standard Deviation 0.95 |
| Milvexian 25 mg QD | Modified Rankin Scale (mRS) | Day 90 | 0.8 Score on a scale | Standard Deviation 1.04 |
| Milvexian 25 mg BID | Modified Rankin Scale (mRS) | Baseline | 0.6 Score on a scale | Standard Deviation 0.96 |
| Milvexian 25 mg BID | Modified Rankin Scale (mRS) | First recurrent stroke | 2.6 Score on a scale | Standard Deviation 1.35 |
| Milvexian 25 mg BID | Modified Rankin Scale (mRS) | Day 21 | 0.9 Score on a scale | Standard Deviation 1.15 |
| Milvexian 25 mg BID | Modified Rankin Scale (mRS) | Day 90 | 0.8 Score on a scale | Standard Deviation 1.07 |
| Milvexian 50 mg BID | Modified Rankin Scale (mRS) | Baseline | 0.5 Score on a scale | Standard Deviation 0.86 |
| Milvexian 50 mg BID | Modified Rankin Scale (mRS) | Day 21 | 0.9 Score on a scale | Standard Deviation 1.15 |
| Milvexian 50 mg BID | Modified Rankin Scale (mRS) | Day 90 | 0.7 Score on a scale | Standard Deviation 1.01 |
| Milvexian 50 mg BID | Modified Rankin Scale (mRS) | First recurrent stroke | 2.3 Score on a scale | Standard Deviation 1.62 |
| Milvexian 100 mg BID | Modified Rankin Scale (mRS) | First recurrent stroke | 2.9 Score on a scale | Standard Deviation 1.64 |
| Milvexian 100 mg BID | Modified Rankin Scale (mRS) | Day 90 | 0.7 Score on a scale | Standard Deviation 1.01 |
| Milvexian 100 mg BID | Modified Rankin Scale (mRS) | Day 21 | 1.0 Score on a scale | Standard Deviation 1.17 |
| Milvexian 100 mg BID | Modified Rankin Scale (mRS) | Baseline | 0.5 Score on a scale | Standard Deviation 0.89 |
| Milvexian 200 mg BID | Modified Rankin Scale (mRS) | First recurrent stroke | 1.8 Score on a scale | Standard Deviation 1.72 |
| Milvexian 200 mg BID | Modified Rankin Scale (mRS) | Day 90 | 0.8 Score on a scale | Standard Deviation 1.05 |
| Milvexian 200 mg BID | Modified Rankin Scale (mRS) | Day 21 | 0.9 Score on a scale | Standard Deviation 1.19 |
| Milvexian 200 mg BID | Modified Rankin Scale (mRS) | Baseline | 0.6 Score on a scale | Standard Deviation 0.95 |
| Milvexian 50 mg QD | Modified Rankin Scale (mRS) | First recurrent stroke | 2.0 Score on a scale | Standard Deviation 0 |
| Milvexian 50 mg QD | Modified Rankin Scale (mRS) | Baseline | 0.2 Score on a scale | Standard Deviation 0.53 |
| Milvexian 50 mg QD | Modified Rankin Scale (mRS) | Day 90 | 0.6 Score on a scale | Standard Deviation 1.05 |
| Milvexian 50 mg QD | Modified Rankin Scale (mRS) | Day 21 | 0.9 Score on a scale | Standard Deviation 1.27 |
| Milvexian 100 mg QD | Modified Rankin Scale (mRS) | Day 21 | 1.3 Score on a scale | Standard Deviation 1.14 |
| Milvexian 100 mg QD | Modified Rankin Scale (mRS) | Day 90 | 1.0 Score on a scale | Standard Deviation 1.11 |
| Milvexian 100 mg QD | Modified Rankin Scale (mRS) | First recurrent stroke | 1.0 Score on a scale | — |
| Milvexian 100 mg QD | Modified Rankin Scale (mRS) | Baseline | 0.7 Score on a scale | Standard Deviation 0.99 |
Secondary
Montreal Cognitive Assessment (MoCA)
The Montreal Cognitive Assessment (MoCA) is a survey with a summed score. MoCA score ranges between a lowest score of 0 to a highest score of 30. A score of: * ≥26 points: indicates normal cognitive function * 18-25 points: Mild cognitive impairment * 10-17 points: Moderate cognitive impairment * fewer than 10 points: Severe cognitive impairment
Time frame: At baseline, on Days 21 and 90, and at the time of a new stroke event
Population: All randomized participants with a complete MoCA assessment
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Montreal Cognitive Assessment (MoCA) | Baseline | 22.3 Score on a scale | Standard Deviation 5.06 |
| Placebo | Montreal Cognitive Assessment (MoCA) | Day 21 | 24.0 Score on a scale | Standard Deviation 4.77 |
| Placebo | Montreal Cognitive Assessment (MoCA) | Day 90 | 24.6 Score on a scale | Standard Deviation 4.54 |
| Placebo | Montreal Cognitive Assessment (MoCA) | First recurrent stroke | 23.2 Score on a scale | Standard Deviation 6.63 |
| Milvexian 25 mg QD | Montreal Cognitive Assessment (MoCA) | First recurrent stroke | 17.3 Score on a scale | Standard Deviation 6.11 |
| Milvexian 25 mg QD | Montreal Cognitive Assessment (MoCA) | Day 21 | 23.9 Score on a scale | Standard Deviation 5.01 |
| Milvexian 25 mg QD | Montreal Cognitive Assessment (MoCA) | Baseline | 21.6 Score on a scale | Standard Deviation 5.59 |
| Milvexian 25 mg QD | Montreal Cognitive Assessment (MoCA) | Day 90 | 24.0 Score on a scale | Standard Deviation 4.69 |
| Milvexian 25 mg BID | Montreal Cognitive Assessment (MoCA) | Baseline | 22.0 Score on a scale | Standard Deviation 5.18 |
| Milvexian 25 mg BID | Montreal Cognitive Assessment (MoCA) | First recurrent stroke | 25.3 Score on a scale | Standard Deviation 2.31 |
| Milvexian 25 mg BID | Montreal Cognitive Assessment (MoCA) | Day 21 | 24.0 Score on a scale | Standard Deviation 4.7 |
| Milvexian 25 mg BID | Montreal Cognitive Assessment (MoCA) | Day 90 | 24.2 Score on a scale | Standard Deviation 4.8 |
| Milvexian 50 mg BID | Montreal Cognitive Assessment (MoCA) | Baseline | 22.5 Score on a scale | Standard Deviation 4.82 |
| Milvexian 50 mg BID | Montreal Cognitive Assessment (MoCA) | Day 21 | 24.3 Score on a scale | Standard Deviation 4.57 |
| Milvexian 50 mg BID | Montreal Cognitive Assessment (MoCA) | Day 90 | 24.4 Score on a scale | Standard Deviation 4.48 |
| Milvexian 50 mg BID | Montreal Cognitive Assessment (MoCA) | First recurrent stroke | 19.0 Score on a scale | Standard Deviation 8.49 |
| Milvexian 100 mg BID | Montreal Cognitive Assessment (MoCA) | First recurrent stroke | 3.0 Score on a scale | — |
| Milvexian 100 mg BID | Montreal Cognitive Assessment (MoCA) | Day 90 | 24.5 Score on a scale | Standard Deviation 4.36 |
| Milvexian 100 mg BID | Montreal Cognitive Assessment (MoCA) | Day 21 | 23.6 Score on a scale | Standard Deviation 4.48 |
| Milvexian 100 mg BID | Montreal Cognitive Assessment (MoCA) | Baseline | 22.4 Score on a scale | Standard Deviation 5.04 |
| Milvexian 200 mg BID | Montreal Cognitive Assessment (MoCA) | First recurrent stroke | 23.1 Score on a scale | Standard Deviation 7.08 |
| Milvexian 200 mg BID | Montreal Cognitive Assessment (MoCA) | Day 90 | 24.2 Score on a scale | Standard Deviation 5.05 |
| Milvexian 200 mg BID | Montreal Cognitive Assessment (MoCA) | Day 21 | 24.0 Score on a scale | Standard Deviation 4.96 |
| Milvexian 200 mg BID | Montreal Cognitive Assessment (MoCA) | Baseline | 22.1 Score on a scale | Standard Deviation 5.31 |
| Milvexian 50 mg QD | Montreal Cognitive Assessment (MoCA) | First recurrent stroke | 11.0 Score on a scale | — |
| Milvexian 50 mg QD | Montreal Cognitive Assessment (MoCA) | Baseline | 24.4 Score on a scale | Standard Deviation 3.84 |
| Milvexian 50 mg QD | Montreal Cognitive Assessment (MoCA) | Day 90 | 25.0 Score on a scale | Standard Deviation 4.72 |
| Milvexian 50 mg QD | Montreal Cognitive Assessment (MoCA) | Day 21 | 26.4 Score on a scale | Standard Deviation 2.61 |
| Milvexian 100 mg QD | Montreal Cognitive Assessment (MoCA) | Day 21 | 24.1 Score on a scale | Standard Deviation 4.7 |
| Milvexian 100 mg QD | Montreal Cognitive Assessment (MoCA) | Day 90 | 26.4 Score on a scale | Standard Deviation 1.69 |
| Milvexian 100 mg QD | Montreal Cognitive Assessment (MoCA) | First recurrent stroke | 22.0 Score on a scale | — |
| Milvexian 100 mg QD | Montreal Cognitive Assessment (MoCA) | Baseline | 22.0 Score on a scale | Standard Deviation 4.59 |
Secondary
National Institutes of Health Stroke Scale (NIHSS)
The NIHSS is an 11-item neurologic examination stroke scale used to evaluate the effect of acute cerebral infarction on the levels of consciousness, language, neglect, visual-field loss, extraocular movement, motor strength, ataxia, dysarthria, and sensory loss. A trained observer rates the patent's ability to answer questions and perform activities. The score for each ability is a number between 0 and 4, 0 being normal functioning and 4 being completely impaired. The patient's NIHSS score is calculated by adding the number for each element of the scale; 42 is the highest score possible. In the NIHSS, the higher the score, the more impaired a stroke participant is.
Time frame: At baseline, on Days 21 and 90, and at the time of a new stroke event
Population: All randomized participants with a complete NIHSS assessment
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | National Institutes of Health Stroke Scale (NIHSS) | Baseline | 1.6 Score on a scale | Standard Deviation 1.87 |
| Placebo | National Institutes of Health Stroke Scale (NIHSS) | Day 21 | 0.9 Score on a scale | Standard Deviation 2.11 |
| Placebo | National Institutes of Health Stroke Scale (NIHSS) | Day 90 | 0.5 Score on a scale | Standard Deviation 1.4 |
| Placebo | National Institutes of Health Stroke Scale (NIHSS) | First recurrent stroke | 6.2 Score on a scale | Standard Deviation 5.01 |
| Milvexian 25 mg QD | National Institutes of Health Stroke Scale (NIHSS) | First recurrent stroke | 4.6 Score on a scale | Standard Deviation 6.79 |
| Milvexian 25 mg QD | National Institutes of Health Stroke Scale (NIHSS) | Day 21 | 0.8 Score on a scale | Standard Deviation 1.35 |
| Milvexian 25 mg QD | National Institutes of Health Stroke Scale (NIHSS) | Baseline | 1.7 Score on a scale | Standard Deviation 1.68 |
| Milvexian 25 mg QD | National Institutes of Health Stroke Scale (NIHSS) | Day 90 | 0.6 Score on a scale | Standard Deviation 1.06 |
| Milvexian 25 mg BID | National Institutes of Health Stroke Scale (NIHSS) | Baseline | 1.6 Score on a scale | Standard Deviation 1.73 |
| Milvexian 25 mg BID | National Institutes of Health Stroke Scale (NIHSS) | First recurrent stroke | 5.4 Score on a scale | Standard Deviation 3.17 |
| Milvexian 25 mg BID | National Institutes of Health Stroke Scale (NIHSS) | Day 21 | 0.8 Score on a scale | Standard Deviation 1.43 |
| Milvexian 25 mg BID | National Institutes of Health Stroke Scale (NIHSS) | Day 90 | 0.6 Score on a scale | Standard Deviation 1.51 |
| Milvexian 50 mg BID | National Institutes of Health Stroke Scale (NIHSS) | Baseline | 1.6 Score on a scale | Standard Deviation 1.79 |
| Milvexian 50 mg BID | National Institutes of Health Stroke Scale (NIHSS) | Day 21 | 0.8 Score on a scale | Standard Deviation 1.58 |
| Milvexian 50 mg BID | National Institutes of Health Stroke Scale (NIHSS) | Day 90 | 0.6 Score on a scale | Standard Deviation 1.14 |
| Milvexian 50 mg BID | National Institutes of Health Stroke Scale (NIHSS) | First recurrent stroke | 4.6 Score on a scale | Standard Deviation 4.3 |
| Milvexian 100 mg BID | National Institutes of Health Stroke Scale (NIHSS) | First recurrent stroke | 7.1 Score on a scale | Standard Deviation 4.68 |
| Milvexian 100 mg BID | National Institutes of Health Stroke Scale (NIHSS) | Day 90 | 0.6 Score on a scale | Standard Deviation 1.32 |
| Milvexian 100 mg BID | National Institutes of Health Stroke Scale (NIHSS) | Day 21 | 0.8 Score on a scale | Standard Deviation 1.48 |
| Milvexian 100 mg BID | National Institutes of Health Stroke Scale (NIHSS) | Baseline | 1.8 Score on a scale | Standard Deviation 1.81 |
| Milvexian 200 mg BID | National Institutes of Health Stroke Scale (NIHSS) | First recurrent stroke | 4.4 Score on a scale | Standard Deviation 4.6 |
| Milvexian 200 mg BID | National Institutes of Health Stroke Scale (NIHSS) | Day 90 | 0.6 Score on a scale | Standard Deviation 1.29 |
| Milvexian 200 mg BID | National Institutes of Health Stroke Scale (NIHSS) | Day 21 | 0.9 Score on a scale | Standard Deviation 1.88 |
| Milvexian 200 mg BID | National Institutes of Health Stroke Scale (NIHSS) | Baseline | 1.6 Score on a scale | Standard Deviation 1.79 |
| Milvexian 50 mg QD | National Institutes of Health Stroke Scale (NIHSS) | First recurrent stroke | 5.3 Score on a scale | Standard Deviation 3.06 |
| Milvexian 50 mg QD | National Institutes of Health Stroke Scale (NIHSS) | Baseline | 1.1 Score on a scale | Standard Deviation 1.44 |
| Milvexian 50 mg QD | National Institutes of Health Stroke Scale (NIHSS) | Day 90 | 0.3 Score on a scale | Standard Deviation 0.72 |
| Milvexian 50 mg QD | National Institutes of Health Stroke Scale (NIHSS) | Day 21 | 0.8 Score on a scale | Standard Deviation 1.9 |
| Milvexian 100 mg QD | National Institutes of Health Stroke Scale (NIHSS) | Day 21 | 0.9 Score on a scale | Standard Deviation 1.39 |
| Milvexian 100 mg QD | National Institutes of Health Stroke Scale (NIHSS) | Day 90 | 0.6 Score on a scale | Standard Deviation 1.45 |
| Milvexian 100 mg QD | National Institutes of Health Stroke Scale (NIHSS) | First recurrent stroke | 1.0 Score on a scale | — |
| Milvexian 100 mg QD | National Institutes of Health Stroke Scale (NIHSS) | Baseline | 2.0 Score on a scale | Standard Deviation 1.7 |
Secondary
Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI
Number of diffusion-weighted imaging (DWI) magnetic resonance imaging (MRI) infarcts on the DWI Sequence on day 90 MRI.
Time frame: At day 90
Population: All randomized participants with an evaluable MRI
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | 4 | 1 Participants |
| Placebo | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | 5 | 1 Participants |
| Placebo | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | 2 | 11 Participants |
| Placebo | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | >0 | 82 Participants |
| Placebo | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | 1 | 57 Participants |
| Placebo | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | 3 | 8 Participants |
| Placebo | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | >5 | 4 Participants |
| Milvexian 25 mg QD | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | >5 | 0 Participants |
| Milvexian 25 mg QD | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | 4 | 1 Participants |
| Milvexian 25 mg QD | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | 1 | 26 Participants |
| Milvexian 25 mg QD | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | 2 | 8 Participants |
| Milvexian 25 mg QD | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | 3 | 5 Participants |
| Milvexian 25 mg QD | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | >0 | 40 Participants |
| Milvexian 25 mg QD | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | 5 | 0 Participants |
| Milvexian 25 mg BID | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | 4 | 2 Participants |
| Milvexian 25 mg BID | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | >5 | 2 Participants |
| Milvexian 25 mg BID | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | 3 | 4 Participants |
| Milvexian 25 mg BID | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | 1 | 36 Participants |
| Milvexian 25 mg BID | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | >0 | 49 Participants |
| Milvexian 25 mg BID | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | 5 | 0 Participants |
| Milvexian 25 mg BID | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | 2 | 5 Participants |
| Milvexian 50 mg BID | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | 3 | 1 Participants |
| Milvexian 50 mg BID | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | >5 | 1 Participants |
| Milvexian 50 mg BID | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | 1 | 26 Participants |
| Milvexian 50 mg BID | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | 5 | 0 Participants |
| Milvexian 50 mg BID | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | 2 | 5 Participants |
| Milvexian 50 mg BID | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | >0 | 36 Participants |
| Milvexian 50 mg BID | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | 4 | 3 Participants |
| Milvexian 100 mg BID | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | 3 | 2 Participants |
| Milvexian 100 mg BID | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | >0 | 35 Participants |
| Milvexian 100 mg BID | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | 1 | 24 Participants |
| Milvexian 100 mg BID | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | 2 | 3 Participants |
| Milvexian 100 mg BID | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | 4 | 2 Participants |
| Milvexian 100 mg BID | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | 5 | 1 Participants |
| Milvexian 100 mg BID | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | >5 | 3 Participants |
| Milvexian 200 mg BID | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | 3 | 2 Participants |
| Milvexian 200 mg BID | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | >5 | 0 Participants |
| Milvexian 200 mg BID | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | 4 | 2 Participants |
| Milvexian 200 mg BID | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | 2 | 6 Participants |
| Milvexian 200 mg BID | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | 5 | 2 Participants |
| Milvexian 200 mg BID | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | 1 | 23 Participants |
| Milvexian 200 mg BID | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | >0 | 35 Participants |
| Milvexian 50 mg QD | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | 1 | 1 Participants |
| Milvexian 50 mg QD | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | >0 | 3 Participants |
| Milvexian 50 mg QD | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | 5 | 0 Participants |
| Milvexian 50 mg QD | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | 4 | 0 Participants |
| Milvexian 50 mg QD | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | >5 | 0 Participants |
| Milvexian 50 mg QD | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | 2 | 2 Participants |
| Milvexian 50 mg QD | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | 3 | 0 Participants |
| Milvexian 100 mg QD | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | >5 | 0 Participants |
| Milvexian 100 mg QD | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | 3 | 0 Participants |
| Milvexian 100 mg QD | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | 5 | 0 Participants |
| Milvexian 100 mg QD | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | >0 | 3 Participants |
| Milvexian 100 mg QD | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | 2 | 0 Participants |
| Milvexian 100 mg QD | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | 4 | 1 Participants |
| Milvexian 100 mg QD | Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | 1 | 2 Participants |
Secondary
Number of Participants With Adverse Events (AEs)
AE: include all non-serious adverse events with onset on or after first dose date and within 2 days after the last dose of study treatment.
Time frame: From first dose to 2 days after last dose of study therapy (up to approximately 107 days)
Population: All treated participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Adverse Events (AEs) | 399 Participants |
| Milvexian 25 mg QD | Number of Participants With Adverse Events (AEs) | 190 Participants |
| Milvexian 25 mg BID | Number of Participants With Adverse Events (AEs) | 186 Participants |
| Milvexian 50 mg BID | Number of Participants With Adverse Events (AEs) | 192 Participants |
| Milvexian 100 mg BID | Number of Participants With Adverse Events (AEs) | 193 Participants |
| Milvexian 200 mg BID | Number of Participants With Adverse Events (AEs) | 211 Participants |
| Milvexian 50 mg QD | Number of Participants With Adverse Events (AEs) | 11 Participants |
| Milvexian 100 mg QD | Number of Participants With Adverse Events (AEs) | 13 Participants |
Secondary
Number of Participants With Bleeding Based on BARC Types 1-5
Number of participants with bleeding based on Bleeding Academic Research Consortium (BARC) Type 1 to 5. BARC bleeding types: 0=No bleeding. 1=Not actionable bleeding. 2=Overt, actionable sign of hemorrhage requiring nonsurgical, medical intervention by a health-care professional, leading to hospitalization or increased level of care, or prompting evaluation. 3a=Overt bleeding plus hemoglobin drop of 3 to \< 5 g/dL. 3b=Overt bleeding plus hemoglobin drop ≥5 g/dL; cardiac tamponade; bleeding requiring surgical intervention; bleeding requiring IV vasoactive agents. 3c=Intracranial hemorrhage; intraocular bleed compromising vision. 4=CABG-related bleeding, perioperative intracranial bleeding within 48 hours, reoperation after closure of sternotomy to control bleeding, transfusion of ≥5 U whole blood or packed red blood cells within a 48-hour period, chest tube output more than or equal to 2L within a 24-hour period. 5a=Probable fatal bleeding. 5b=Definite fatal bleeding.
Time frame: From first dose to up to 107 days after first dose
Population: All treated participants
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 5A | 0 Participants |
| Placebo | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 2 | 9 Participants |
| Placebo | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 5B | 0 Participants |
| Placebo | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 3A | 2 Participants |
| Placebo | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 4 | 0 Participants |
| Placebo | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 3C | 2 Participants |
| Placebo | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 3B | 0 Participants |
| Placebo | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 1 | 41 Participants |
| Milvexian 25 mg QD | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 4 | 0 Participants |
| Milvexian 25 mg QD | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 5B | 0 Participants |
| Milvexian 25 mg QD | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 1 | 26 Participants |
| Milvexian 25 mg QD | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 2 | 7 Participants |
| Milvexian 25 mg QD | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 3A | 1 Participants |
| Milvexian 25 mg QD | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 3B | 1 Participants |
| Milvexian 25 mg QD | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 3C | 0 Participants |
| Milvexian 25 mg QD | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 5A | 0 Participants |
| Milvexian 25 mg BID | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 2 | 9 Participants |
| Milvexian 25 mg BID | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 5A | 0 Participants |
| Milvexian 25 mg BID | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 5B | 0 Participants |
| Milvexian 25 mg BID | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 3B | 1 Participants |
| Milvexian 25 mg BID | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 3C | 0 Participants |
| Milvexian 25 mg BID | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 3A | 1 Participants |
| Milvexian 25 mg BID | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 1 | 16 Participants |
| Milvexian 25 mg BID | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 4 | 0 Participants |
| Milvexian 50 mg BID | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 1 | 28 Participants |
| Milvexian 50 mg BID | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 5B | 0 Participants |
| Milvexian 50 mg BID | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 3C | 3 Participants |
| Milvexian 50 mg BID | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 2 | 7 Participants |
| Milvexian 50 mg BID | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 5A | 0 Participants |
| Milvexian 50 mg BID | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 3A | 1 Participants |
| Milvexian 50 mg BID | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 3B | 1 Participants |
| Milvexian 50 mg BID | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 4 | 0 Participants |
| Milvexian 100 mg BID | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 3C | 0 Participants |
| Milvexian 100 mg BID | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 5A | 0 Participants |
| Milvexian 100 mg BID | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 3A | 2 Participants |
| Milvexian 100 mg BID | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 3B | 3 Participants |
| Milvexian 100 mg BID | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 1 | 25 Participants |
| Milvexian 100 mg BID | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 5B | 0 Participants |
| Milvexian 100 mg BID | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 4 | 0 Participants |
| Milvexian 100 mg BID | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 2 | 10 Participants |
| Milvexian 200 mg BID | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 5A | 0 Participants |
| Milvexian 200 mg BID | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 3B | 1 Participants |
| Milvexian 200 mg BID | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 2 | 8 Participants |
| Milvexian 200 mg BID | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 4 | 0 Participants |
| Milvexian 200 mg BID | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 3A | 3 Participants |
| Milvexian 200 mg BID | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 3C | 1 Participants |
| Milvexian 200 mg BID | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 5B | 0 Participants |
| Milvexian 200 mg BID | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 1 | 22 Participants |
| Milvexian 50 mg QD | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 5A | 0 Participants |
| Milvexian 50 mg QD | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 3B | 0 Participants |
| Milvexian 50 mg QD | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 4 | 0 Participants |
| Milvexian 50 mg QD | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 1 | 5 Participants |
| Milvexian 50 mg QD | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 5B | 0 Participants |
| Milvexian 50 mg QD | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 3A | 0 Participants |
| Milvexian 50 mg QD | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 3C | 0 Participants |
| Milvexian 50 mg QD | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 2 | 1 Participants |
| Milvexian 100 mg QD | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 5B | 0 Participants |
| Milvexian 100 mg QD | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 1 | 2 Participants |
| Milvexian 100 mg QD | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 2 | 1 Participants |
| Milvexian 100 mg QD | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 3A | 0 Participants |
| Milvexian 100 mg QD | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 3B | 0 Participants |
| Milvexian 100 mg QD | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 3C | 0 Participants |
| Milvexian 100 mg QD | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 4 | 0 Participants |
| Milvexian 100 mg QD | Number of Participants With Bleeding Based on BARC Types 1-5 | Type 5A | 0 Participants |
Secondary
Number of Participants With Bleeding Based on ISTH-Defined Criteria
Number of participants with bleeding based on International Society on Thrombosis and Hemostasis (ISTH). ISTH Bleeding Types: 1) Fatal bleeding and/or 2) Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with compartment syndrome and/or 3) Bleeding causing a fall in hemoglobin level of ≥2 g/dL, or leading to transfusion of ≥2 units of whole blood or red cells.
Time frame: From first dose to up to 107 days after first dose
Population: All treated participants
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Bleeding Based on ISTH-Defined Criteria | Major | 4 Participants |
| Placebo | Number of Participants With Bleeding Based on ISTH-Defined Criteria | Minor Bleed | 43 Participants |
| Placebo | Number of Participants With Bleeding Based on ISTH-Defined Criteria | Major or CRNM | 11 Participants |
| Placebo | Number of Participants With Bleeding Based on ISTH-Defined Criteria | Clinically Relevant Non-Major (CRNM) | 7 Participants |
| Milvexian 25 mg QD | Number of Participants With Bleeding Based on ISTH-Defined Criteria | Major | 2 Participants |
| Milvexian 25 mg QD | Number of Participants With Bleeding Based on ISTH-Defined Criteria | Major or CRNM | 10 Participants |
| Milvexian 25 mg QD | Number of Participants With Bleeding Based on ISTH-Defined Criteria | Clinically Relevant Non-Major (CRNM) | 8 Participants |
| Milvexian 25 mg QD | Number of Participants With Bleeding Based on ISTH-Defined Criteria | Minor Bleed | 25 Participants |
| Milvexian 25 mg BID | Number of Participants With Bleeding Based on ISTH-Defined Criteria | Clinically Relevant Non-Major (CRNM) | 9 Participants |
| Milvexian 25 mg BID | Number of Participants With Bleeding Based on ISTH-Defined Criteria | Major or CRNM | 11 Participants |
| Milvexian 25 mg BID | Number of Participants With Bleeding Based on ISTH-Defined Criteria | Minor Bleed | 16 Participants |
| Milvexian 25 mg BID | Number of Participants With Bleeding Based on ISTH-Defined Criteria | Major | 2 Participants |
| Milvexian 50 mg BID | Number of Participants With Bleeding Based on ISTH-Defined Criteria | Clinically Relevant Non-Major (CRNM) | 7 Participants |
| Milvexian 50 mg BID | Number of Participants With Bleeding Based on ISTH-Defined Criteria | Minor Bleed | 28 Participants |
| Milvexian 50 mg BID | Number of Participants With Bleeding Based on ISTH-Defined Criteria | Major or CRNM | 12 Participants |
| Milvexian 50 mg BID | Number of Participants With Bleeding Based on ISTH-Defined Criteria | Major | 5 Participants |
| Milvexian 100 mg BID | Number of Participants With Bleeding Based on ISTH-Defined Criteria | Minor Bleed | 26 Participants |
| Milvexian 100 mg BID | Number of Participants With Bleeding Based on ISTH-Defined Criteria | Major | 6 Participants |
| Milvexian 100 mg BID | Number of Participants With Bleeding Based on ISTH-Defined Criteria | Clinically Relevant Non-Major (CRNM) | 8 Participants |
| Milvexian 100 mg BID | Number of Participants With Bleeding Based on ISTH-Defined Criteria | Major or CRNM | 14 Participants |
| Milvexian 200 mg BID | Number of Participants With Bleeding Based on ISTH-Defined Criteria | Major or CRNM | 13 Participants |
| Milvexian 200 mg BID | Number of Participants With Bleeding Based on ISTH-Defined Criteria | Major | 5 Participants |
| Milvexian 200 mg BID | Number of Participants With Bleeding Based on ISTH-Defined Criteria | Minor Bleed | 22 Participants |
| Milvexian 200 mg BID | Number of Participants With Bleeding Based on ISTH-Defined Criteria | Clinically Relevant Non-Major (CRNM) | 8 Participants |
| Milvexian 50 mg QD | Number of Participants With Bleeding Based on ISTH-Defined Criteria | Clinically Relevant Non-Major (CRNM) | 1 Participants |
| Milvexian 50 mg QD | Number of Participants With Bleeding Based on ISTH-Defined Criteria | Major or CRNM | 1 Participants |
| Milvexian 50 mg QD | Number of Participants With Bleeding Based on ISTH-Defined Criteria | Major | 0 Participants |
| Milvexian 50 mg QD | Number of Participants With Bleeding Based on ISTH-Defined Criteria | Minor Bleed | 5 Participants |
| Milvexian 100 mg QD | Number of Participants With Bleeding Based on ISTH-Defined Criteria | Minor Bleed | 2 Participants |
| Milvexian 100 mg QD | Number of Participants With Bleeding Based on ISTH-Defined Criteria | Major | 0 Participants |
| Milvexian 100 mg QD | Number of Participants With Bleeding Based on ISTH-Defined Criteria | Clinically Relevant Non-Major (CRNM) | 1 Participants |
| Milvexian 100 mg QD | Number of Participants With Bleeding Based on ISTH-Defined Criteria | Major or CRNM | 1 Participants |
Secondary
Number of Participants With Bleeding Based on PLATO-Defined Criteria
Number of participants with bleeding based on Platelet Inhibition and Patient Outcomes (PLATO) defined criteria. PLATO bleeding definitions: 1. Major Life-threatening: Fatal, Intracranial, Intrapericardial with cardiac tamponade, Resulting in hypovolemic shock or severe hypotension that requires pressors or surgery, Clinically overt or apparent bleeding associated with decrease in hemoglobin \>5 g/dL, Requiring transfusion of ≥4 U whole blood or packed red blood cells (PRBCs) 2. Other Major: Significantly disabling (eg, intraocular with permanent vision loss), Associated drop in hemoglobin of 3 to 5 g/dL, Requiring transfusion of 2 to 3 U whole blood or PRBCs 3. Any Major: Any one of the above criteria 4. Minor: Bleeding that does not meet criteria for PLATO Major bleeding, and requiring medical intervention
Time frame: From first dose to up to 107 days after first dose
Population: All treated participants
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Bleeding Based on PLATO-Defined Criteria | MAJOR LIFE-THREATENING | 2 Participants |
| Placebo | Number of Participants With Bleeding Based on PLATO-Defined Criteria | MINIMAL | 43 Participants |
| Placebo | Number of Participants With Bleeding Based on PLATO-Defined Criteria | MINOR | 7 Participants |
| Placebo | Number of Participants With Bleeding Based on PLATO-Defined Criteria | ANY MAJOR | 4 Participants |
| Placebo | Number of Participants With Bleeding Based on PLATO-Defined Criteria | OTHER MAJOR BLEEDING | 2 Participants |
| Milvexian 25 mg QD | Number of Participants With Bleeding Based on PLATO-Defined Criteria | OTHER MAJOR BLEEDING | 1 Participants |
| Milvexian 25 mg QD | Number of Participants With Bleeding Based on PLATO-Defined Criteria | MINOR | 6 Participants |
| Milvexian 25 mg QD | Number of Participants With Bleeding Based on PLATO-Defined Criteria | MINIMAL | 27 Participants |
| Milvexian 25 mg QD | Number of Participants With Bleeding Based on PLATO-Defined Criteria | ANY MAJOR | 2 Participants |
| Milvexian 25 mg QD | Number of Participants With Bleeding Based on PLATO-Defined Criteria | MAJOR LIFE-THREATENING | 1 Participants |
| Milvexian 25 mg BID | Number of Participants With Bleeding Based on PLATO-Defined Criteria | OTHER MAJOR BLEEDING | 1 Participants |
| Milvexian 25 mg BID | Number of Participants With Bleeding Based on PLATO-Defined Criteria | MINIMAL | 18 Participants |
| Milvexian 25 mg BID | Number of Participants With Bleeding Based on PLATO-Defined Criteria | MAJOR LIFE-THREATENING | 1 Participants |
| Milvexian 25 mg BID | Number of Participants With Bleeding Based on PLATO-Defined Criteria | MINOR | 7 Participants |
| Milvexian 25 mg BID | Number of Participants With Bleeding Based on PLATO-Defined Criteria | ANY MAJOR | 2 Participants |
| Milvexian 50 mg BID | Number of Participants With Bleeding Based on PLATO-Defined Criteria | ANY MAJOR | 5 Participants |
| Milvexian 50 mg BID | Number of Participants With Bleeding Based on PLATO-Defined Criteria | MINIMAL | 28 Participants |
| Milvexian 50 mg BID | Number of Participants With Bleeding Based on PLATO-Defined Criteria | MAJOR LIFE-THREATENING | 4 Participants |
| Milvexian 50 mg BID | Number of Participants With Bleeding Based on PLATO-Defined Criteria | OTHER MAJOR BLEEDING | 1 Participants |
| Milvexian 50 mg BID | Number of Participants With Bleeding Based on PLATO-Defined Criteria | MINOR | 7 Participants |
| Milvexian 100 mg BID | Number of Participants With Bleeding Based on PLATO-Defined Criteria | ANY MAJOR | 5 Participants |
| Milvexian 100 mg BID | Number of Participants With Bleeding Based on PLATO-Defined Criteria | MAJOR LIFE-THREATENING | 3 Participants |
| Milvexian 100 mg BID | Number of Participants With Bleeding Based on PLATO-Defined Criteria | OTHER MAJOR BLEEDING | 2 Participants |
| Milvexian 100 mg BID | Number of Participants With Bleeding Based on PLATO-Defined Criteria | MINOR | 9 Participants |
| Milvexian 100 mg BID | Number of Participants With Bleeding Based on PLATO-Defined Criteria | MINIMAL | 26 Participants |
| Milvexian 200 mg BID | Number of Participants With Bleeding Based on PLATO-Defined Criteria | ANY MAJOR | 5 Participants |
| Milvexian 200 mg BID | Number of Participants With Bleeding Based on PLATO-Defined Criteria | MINOR | 9 Participants |
| Milvexian 200 mg BID | Number of Participants With Bleeding Based on PLATO-Defined Criteria | OTHER MAJOR BLEEDING | 3 Participants |
| Milvexian 200 mg BID | Number of Participants With Bleeding Based on PLATO-Defined Criteria | MAJOR LIFE-THREATENING | 2 Participants |
| Milvexian 200 mg BID | Number of Participants With Bleeding Based on PLATO-Defined Criteria | MINIMAL | 21 Participants |
| Milvexian 50 mg QD | Number of Participants With Bleeding Based on PLATO-Defined Criteria | ANY MAJOR | 0 Participants |
| Milvexian 50 mg QD | Number of Participants With Bleeding Based on PLATO-Defined Criteria | MAJOR LIFE-THREATENING | 0 Participants |
| Milvexian 50 mg QD | Number of Participants With Bleeding Based on PLATO-Defined Criteria | OTHER MAJOR BLEEDING | 0 Participants |
| Milvexian 50 mg QD | Number of Participants With Bleeding Based on PLATO-Defined Criteria | MINIMAL | 6 Participants |
| Milvexian 50 mg QD | Number of Participants With Bleeding Based on PLATO-Defined Criteria | MINOR | 0 Participants |
| Milvexian 100 mg QD | Number of Participants With Bleeding Based on PLATO-Defined Criteria | MINIMAL | 2 Participants |
| Milvexian 100 mg QD | Number of Participants With Bleeding Based on PLATO-Defined Criteria | MINOR | 1 Participants |
| Milvexian 100 mg QD | Number of Participants With Bleeding Based on PLATO-Defined Criteria | MAJOR LIFE-THREATENING | 0 Participants |
| Milvexian 100 mg QD | Number of Participants With Bleeding Based on PLATO-Defined Criteria | ANY MAJOR | 0 Participants |
| Milvexian 100 mg QD | Number of Participants With Bleeding Based on PLATO-Defined Criteria | OTHER MAJOR BLEEDING | 0 Participants |
Secondary
Number of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities
Number of participants with clinically significant ECG abnormalities.
Time frame: From first dose to up to 90 days after first dose
Population: All treated participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities | 0 Participants |
| Milvexian 25 mg QD | Number of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities | 0 Participants |
| Milvexian 25 mg BID | Number of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities | 0 Participants |
| Milvexian 50 mg BID | Number of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities | 0 Participants |
| Milvexian 100 mg BID | Number of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities | 0 Participants |
| Milvexian 200 mg BID | Number of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities | 0 Participants |
| Milvexian 50 mg QD | Number of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities | 0 Participants |
| Milvexian 100 mg QD | Number of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities | 0 Participants |
Secondary
Number of Participants With Clinically Significant Laboratory Abnormalities - Liver
The number of treated participants who experienced a laboratory abnormality of the liver during the course of the study. Aspartate aminotransferase (AST) Alanine aminotransferase (ALT) Upper Limit of Normal (ULN) Results reported in International System of Units (SI)
Time frame: From first dose to up to approximately 38 months
Population: All treated participants with at least one clinically significant liver laboratory abnormality
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | Total Bilirubin > 1.5x ULN | 10 Participants |
| Placebo | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | ALT > 20x ULN | 0 Participants |
| Placebo | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | Total Bilirubin > 2x ULN | 3 Participants |
| Placebo | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | ALT > 10x ULN | 1 Participants |
| Placebo | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | ALT > 3x ULN | 4 Participants |
| Placebo | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | AST > 5x ULN | 3 Participants |
| Placebo | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | AST > 10x ULN | 1 Participants |
| Placebo | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | AST > 20x ULN | 0 Participants |
| Placebo | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | Concurrent ALT/AST Elevation > 3x ULN with total bilirubin >2x ULN | 0 Participants |
| Placebo | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | ALT > 5x ULN | 1 Participants |
| Placebo | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | ALP > 2x ULN | 4 Participants |
| Placebo | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | AST > 3x ULN | 6 Participants |
| Milvexian 25 mg QD | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | AST > 20x ULN | 0 Participants |
| Milvexian 25 mg QD | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | AST > 10x ULN | 0 Participants |
| Milvexian 25 mg QD | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | Concurrent ALT/AST Elevation > 3x ULN with total bilirubin >2x ULN | 0 Participants |
| Milvexian 25 mg QD | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | ALT > 5x ULN | 0 Participants |
| Milvexian 25 mg QD | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | Total Bilirubin > 2x ULN | 1 Participants |
| Milvexian 25 mg QD | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | ALT > 10x ULN | 0 Participants |
| Milvexian 25 mg QD | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | ALT > 20x ULN | 0 Participants |
| Milvexian 25 mg QD | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | ALT > 3x ULN | 2 Participants |
| Milvexian 25 mg QD | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | Total Bilirubin > 1.5x ULN | 6 Participants |
| Milvexian 25 mg QD | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | AST > 3x ULN | 5 Participants |
| Milvexian 25 mg QD | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | ALP > 2x ULN | 5 Participants |
| Milvexian 25 mg QD | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | AST > 5x ULN | 2 Participants |
| Milvexian 25 mg BID | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | Concurrent ALT/AST Elevation > 3x ULN with total bilirubin >2x ULN | 0 Participants |
| Milvexian 25 mg BID | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | AST > 5x ULN | 1 Participants |
| Milvexian 25 mg BID | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | ALP > 2x ULN | 1 Participants |
| Milvexian 25 mg BID | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | AST > 10x ULN | 0 Participants |
| Milvexian 25 mg BID | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | AST > 20x ULN | 0 Participants |
| Milvexian 25 mg BID | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | Total Bilirubin > 2x ULN | 1 Participants |
| Milvexian 25 mg BID | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | ALT > 5x ULN | 0 Participants |
| Milvexian 25 mg BID | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | ALT > 10x ULN | 0 Participants |
| Milvexian 25 mg BID | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | ALT > 20x ULN | 0 Participants |
| Milvexian 25 mg BID | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | AST > 3x ULN | 1 Participants |
| Milvexian 25 mg BID | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | Total Bilirubin > 1.5x ULN | 2 Participants |
| Milvexian 25 mg BID | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | ALT > 3x ULN | 0 Participants |
| Milvexian 50 mg BID | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | Total Bilirubin > 1.5x ULN | 7 Participants |
| Milvexian 50 mg BID | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | ALT > 20x ULN | 0 Participants |
| Milvexian 50 mg BID | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | AST > 5x ULN | 0 Participants |
| Milvexian 50 mg BID | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | ALT > 5x ULN | 0 Participants |
| Milvexian 50 mg BID | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | AST > 10x ULN | 0 Participants |
| Milvexian 50 mg BID | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | AST > 3x ULN | 4 Participants |
| Milvexian 50 mg BID | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | Concurrent ALT/AST Elevation > 3x ULN with total bilirubin >2x ULN | 0 Participants |
| Milvexian 50 mg BID | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | ALP > 2x ULN | 6 Participants |
| Milvexian 50 mg BID | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | AST > 20x ULN | 0 Participants |
| Milvexian 50 mg BID | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | ALT > 10x ULN | 0 Participants |
| Milvexian 50 mg BID | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | ALT > 3x ULN | 2 Participants |
| Milvexian 50 mg BID | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | Total Bilirubin > 2x ULN | 2 Participants |
| Milvexian 100 mg BID | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | AST > 20x ULN | 1 Participants |
| Milvexian 100 mg BID | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | ALT > 3x ULN | 3 Participants |
| Milvexian 100 mg BID | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | ALT > 5x ULN | 2 Participants |
| Milvexian 100 mg BID | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | ALT > 10x ULN | 1 Participants |
| Milvexian 100 mg BID | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | ALT > 20x ULN | 1 Participants |
| Milvexian 100 mg BID | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | AST > 3x ULN | 3 Participants |
| Milvexian 100 mg BID | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | AST > 5x ULN | 2 Participants |
| Milvexian 100 mg BID | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | AST > 10x ULN | 1 Participants |
| Milvexian 100 mg BID | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | ALP > 2x ULN | 4 Participants |
| Milvexian 100 mg BID | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | Total Bilirubin > 1.5x ULN | 5 Participants |
| Milvexian 100 mg BID | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | Total Bilirubin > 2x ULN | 2 Participants |
| Milvexian 100 mg BID | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | Concurrent ALT/AST Elevation > 3x ULN with total bilirubin >2x ULN | 1 Participants |
| Milvexian 200 mg BID | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | ALT > 10x ULN | 1 Participants |
| Milvexian 200 mg BID | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | AST > 5x ULN | 1 Participants |
| Milvexian 200 mg BID | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | ALT > 20x ULN | 0 Participants |
| Milvexian 200 mg BID | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | ALT > 3x ULN | 3 Participants |
| Milvexian 200 mg BID | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | Concurrent ALT/AST Elevation > 3x ULN with total bilirubin >2x ULN | 0 Participants |
| Milvexian 200 mg BID | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | Total Bilirubin > 1.5x ULN | 2 Participants |
| Milvexian 200 mg BID | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | AST > 20x ULN | 0 Participants |
| Milvexian 200 mg BID | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | AST > 3x ULN | 3 Participants |
| Milvexian 200 mg BID | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | Total Bilirubin > 2x ULN | 1 Participants |
| Milvexian 200 mg BID | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | ALP > 2x ULN | 2 Participants |
| Milvexian 200 mg BID | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | AST > 10x ULN | 0 Participants |
| Milvexian 200 mg BID | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | ALT > 5x ULN | 2 Participants |
| Milvexian 50 mg QD | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | AST > 5x ULN | 1 Participants |
| Milvexian 50 mg QD | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | AST > 20x ULN | 0 Participants |
| Milvexian 50 mg QD | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | AST > 3x ULN | 1 Participants |
| Milvexian 50 mg QD | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | ALP > 2x ULN | 0 Participants |
| Milvexian 50 mg QD | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | ALT > 20x ULN | 0 Participants |
| Milvexian 50 mg QD | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | ALT > 10x ULN | 0 Participants |
| Milvexian 50 mg QD | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | Total Bilirubin > 1.5x ULN | 0 Participants |
| Milvexian 50 mg QD | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | ALT > 5x ULN | 0 Participants |
| Milvexian 50 mg QD | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | Concurrent ALT/AST Elevation > 3x ULN with total bilirubin >2x ULN | 0 Participants |
| Milvexian 50 mg QD | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | Total Bilirubin > 2x ULN | 0 Participants |
| Milvexian 50 mg QD | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | ALT > 3x ULN | 0 Participants |
| Milvexian 50 mg QD | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | AST > 10x ULN | 0 Participants |
| Milvexian 100 mg QD | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | AST > 10x ULN | 0 Participants |
| Milvexian 100 mg QD | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | Concurrent ALT/AST Elevation > 3x ULN with total bilirubin >2x ULN | 0 Participants |
| Milvexian 100 mg QD | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | AST > 5x ULN | 0 Participants |
| Milvexian 100 mg QD | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | Total Bilirubin > 2x ULN | 0 Participants |
| Milvexian 100 mg QD | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | ALT > 10x ULN | 0 Participants |
| Milvexian 100 mg QD | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | ALT > 3x ULN | 0 Participants |
| Milvexian 100 mg QD | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | AST > 20x ULN | 0 Participants |
| Milvexian 100 mg QD | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | Total Bilirubin > 1.5x ULN | 0 Participants |
| Milvexian 100 mg QD | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | ALT > 20x ULN | 0 Participants |
| Milvexian 100 mg QD | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | ALT > 5x ULN | 0 Participants |
| Milvexian 100 mg QD | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | AST > 3x ULN | 0 Participants |
| Milvexian 100 mg QD | Number of Participants With Clinically Significant Laboratory Abnormalities - Liver | ALP > 2x ULN | 0 Participants |
Secondary
Number of Participants With Clinically Significant Physical Examination Abnormalities
Number of participants with clinically significant physical examination abnormalities.
Time frame: From first dose to up to 90 days after first dose
Population: All treated participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Clinically Significant Physical Examination Abnormalities | 0 Participants |
| Milvexian 25 mg QD | Number of Participants With Clinically Significant Physical Examination Abnormalities | 0 Participants |
| Milvexian 25 mg BID | Number of Participants With Clinically Significant Physical Examination Abnormalities | 0 Participants |
| Milvexian 50 mg BID | Number of Participants With Clinically Significant Physical Examination Abnormalities | 0 Participants |
| Milvexian 100 mg BID | Number of Participants With Clinically Significant Physical Examination Abnormalities | 0 Participants |
| Milvexian 200 mg BID | Number of Participants With Clinically Significant Physical Examination Abnormalities | 0 Participants |
| Milvexian 50 mg QD | Number of Participants With Clinically Significant Physical Examination Abnormalities | 0 Participants |
| Milvexian 100 mg QD | Number of Participants With Clinically Significant Physical Examination Abnormalities | 0 Participants |
Secondary
Number of Participants With Clinically Significant Vital Sign Abnormalities
Number of participants with clinically significant vital sign abnormalities. Vital signs included heart rate and diastolic and systolic blood pressure.
Time frame: From first dose to up to 90 days after first dose
Population: All treated participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Clinically Significant Vital Sign Abnormalities | 0 Participants |
| Milvexian 25 mg QD | Number of Participants With Clinically Significant Vital Sign Abnormalities | 0 Participants |
| Milvexian 25 mg BID | Number of Participants With Clinically Significant Vital Sign Abnormalities | 0 Participants |
| Milvexian 50 mg BID | Number of Participants With Clinically Significant Vital Sign Abnormalities | 0 Participants |
| Milvexian 100 mg BID | Number of Participants With Clinically Significant Vital Sign Abnormalities | 0 Participants |
| Milvexian 200 mg BID | Number of Participants With Clinically Significant Vital Sign Abnormalities | 0 Participants |
| Milvexian 50 mg QD | Number of Participants With Clinically Significant Vital Sign Abnormalities | 0 Participants |
| Milvexian 100 mg QD | Number of Participants With Clinically Significant Vital Sign Abnormalities | 0 Participants |
Secondary
Percent Change From Baseline in aPTT Activity
Percent change from baseline in activated partial thromboplastin time (aPTT) activity via exposure response.
Time frame: Baseline and day 90
Population: All participants with at least one aPTT pharmacodynamic endpoint assessed after first dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in aPTT Activity | 2.47 Percent change | Standard Error 0.768 |
| Milvexian 25 mg QD | Percent Change From Baseline in aPTT Activity | 38.72 Percent change | Standard Error 2.264 |
| Milvexian 25 mg BID | Percent Change From Baseline in aPTT Activity | 58.30 Percent change | Standard Error 3.195 |
| Milvexian 50 mg BID | Percent Change From Baseline in aPTT Activity | 97.32 Percent change | Standard Error 3.601 |
| Milvexian 100 mg BID | Percent Change From Baseline in aPTT Activity | 140.76 Percent change | Standard Error 5.154 |
| Milvexian 200 mg BID | Percent Change From Baseline in aPTT Activity | 193.64 Percent change | Standard Error 7.041 |
| Milvexian 50 mg QD | Percent Change From Baseline in aPTT Activity | 48.48 Percent change | Standard Error 11.243 |
| Milvexian 100 mg QD | Percent Change From Baseline in aPTT Activity | 118.06 Percent change | Standard Error 13.84 |
Secondary
Percent Change From Baseline in Factor XI Clotting Activity
Percent change from baseline in factor XI clotting activity via exposure response.
Time frame: Baseline and day 90
Population: All participants with at least one factor XI clotting pharmacodynamic endpoint assessed after first dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Factor XI Clotting Activity | 4.48 Percent change | Standard Error 3.455 |
| Milvexian 25 mg QD | Percent Change From Baseline in Factor XI Clotting Activity | -8.88 Percent change | Standard Error 1.28 |
| Milvexian 25 mg BID | Percent Change From Baseline in Factor XI Clotting Activity | -17.67 Percent change | Standard Error 1.9 |
| Milvexian 50 mg BID | Percent Change From Baseline in Factor XI Clotting Activity | -37.20 Percent change | Standard Error 1.655 |
| Milvexian 100 mg BID | Percent Change From Baseline in Factor XI Clotting Activity | -61.52 Percent change | Standard Error 1.869 |
| Milvexian 200 mg BID | Percent Change From Baseline in Factor XI Clotting Activity | -70.25 Percent change | Standard Error 3.043 |
| Milvexian 50 mg QD | Percent Change From Baseline in Factor XI Clotting Activity | 3.86 Percent change | Standard Error 13.754 |
| Milvexian 100 mg QD | Percent Change From Baseline in Factor XI Clotting Activity | -44.27 Percent change | Standard Error 6.501 |
Secondary
Percent of Participants With Descriptive Assessment of Composite of New Ischemic Stroke During Treatment and New Covert Brain Infarction (FLAIR + DWI) Detected by MRI by Day 90
Descriptive Assessment of Composite of New Ischemic Stroke During Treatment and New Covert Brain Infarction (FLAIR + DWI) Detected by MRI by Day 90.
Time frame: From randomization to up to 90 days after randomization
Population: All randomized participants who experienced a new ischemic stroke by day 90, or an evaluable day 90 MRI regardless of when the MRI was collected.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percent of Participants With Descriptive Assessment of Composite of New Ischemic Stroke During Treatment and New Covert Brain Infarction (FLAIR + DWI) Detected by MRI by Day 90 | 16.6 Percentage of participants |
| Milvexian 25 mg QD | Percent of Participants With Descriptive Assessment of Composite of New Ischemic Stroke During Treatment and New Covert Brain Infarction (FLAIR + DWI) Detected by MRI by Day 90 | 16.2 Percentage of participants |
| Milvexian 25 mg BID | Percent of Participants With Descriptive Assessment of Composite of New Ischemic Stroke During Treatment and New Covert Brain Infarction (FLAIR + DWI) Detected by MRI by Day 90 | 18.5 Percentage of participants |
| Milvexian 50 mg BID | Percent of Participants With Descriptive Assessment of Composite of New Ischemic Stroke During Treatment and New Covert Brain Infarction (FLAIR + DWI) Detected by MRI by Day 90 | 14.1 Percentage of participants |
| Milvexian 100 mg BID | Percent of Participants With Descriptive Assessment of Composite of New Ischemic Stroke During Treatment and New Covert Brain Infarction (FLAIR + DWI) Detected by MRI by Day 90 | 14.8 Percentage of participants |
| Milvexian 200 mg BID | Percent of Participants With Descriptive Assessment of Composite of New Ischemic Stroke During Treatment and New Covert Brain Infarction (FLAIR + DWI) Detected by MRI by Day 90 | 16.4 Percentage of participants |
| Milvexian 50 mg QD | Percent of Participants With Descriptive Assessment of Composite of New Ischemic Stroke During Treatment and New Covert Brain Infarction (FLAIR + DWI) Detected by MRI by Day 90 | 19.0 Percentage of participants |
| Milvexian 100 mg QD | Percent of Participants With Descriptive Assessment of Composite of New Ischemic Stroke During Treatment and New Covert Brain Infarction (FLAIR + DWI) Detected by MRI by Day 90 | 18.8 Percentage of participants |
Secondary
Percent of Participants With Major Bleeding According to BARC Type 3 and 5
Percent of participants with major bleeding based on the Bleeding Academic Research Consortium (BARC) Types 3 and 5 definitions. BARC bleeding types: 3a = Overt bleeding plus hemoglobin drop of 3 to \< 5 g/dL transfusion with overt bleeding 3b = Overt bleeding plus hemoglobin drop ≥5 g/dL; cardiac tamponade; bleeding requiring surgical intervention for control; bleeding requiring IV vasoactive agents 3c = Intracranial hemorrhage, 5a = Probable fatal bleeding 5b = Definite fatal bleeding
Time frame: From first dose to up to 107 days after first dose
Population: All treated participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percent of Participants With Major Bleeding According to BARC Type 3 and 5 | 0.6 Percentage of participants |
| Milvexian 25 mg QD | Percent of Participants With Major Bleeding According to BARC Type 3 and 5 | 0.6 Percentage of participants |
| Milvexian 25 mg BID | Percent of Participants With Major Bleeding According to BARC Type 3 and 5 | 0.6 Percentage of participants |
| Milvexian 50 mg BID | Percent of Participants With Major Bleeding According to BARC Type 3 and 5 | 1.5 Percentage of participants |
| Milvexian 100 mg BID | Percent of Participants With Major Bleeding According to BARC Type 3 and 5 | 1.6 Percentage of participants |
| Milvexian 200 mg BID | Percent of Participants With Major Bleeding According to BARC Type 3 and 5 | 1.5 Percentage of participants |
| Milvexian 50 mg QD | Percent of Participants With Major Bleeding According to BARC Type 3 and 5 | 0 Percentage of participants |
| Milvexian 100 mg QD | Percent of Participants With Major Bleeding According to BARC Type 3 and 5 | 0 Percentage of participants |
Secondary
Pharmacokinetic Parameter - Estimated Clearance (CL)
Pharmacokinetic Parameter - Estimated Clearance (CL). CL is derived from plasma concentration versus time data. PK parameters were generated using a Population Pharmacokinetics (PPK) model. Summary statistics for these individual predicted PK parameters and exposures were stratified by dose. The PPK model analysis was based on combined PK data collected on days 1, 21, and 90.
Time frame: From first dose to up to 90 days after first dose
Population: All treated participants with at least one post-dose PK sample. Pre-specified for data to be collected only in the 25 mg QD, and BID dose regimens.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Pharmacokinetic Parameter - Estimated Clearance (CL) | 8.15 L/h | Geometric Coefficient of Variation 34 |
| Milvexian 25 mg QD | Pharmacokinetic Parameter - Estimated Clearance (CL) | 8.01 L/h | Geometric Coefficient of Variation 34.3 |
| Milvexian 25 mg BID | Pharmacokinetic Parameter - Estimated Clearance (CL) | 7.54 L/h | Geometric Coefficient of Variation 32.8 |
| Milvexian 50 mg BID | Pharmacokinetic Parameter - Estimated Clearance (CL) | 7.08 L/h | Geometric Coefficient of Variation 31.3 |
| Milvexian 100 mg BID | Pharmacokinetic Parameter - Estimated Clearance (CL) | 7.43 L/h | Geometric Coefficient of Variation 32.9 |
Secondary
Pharmacokinetic Parameter - Volume of the Central Compartment (VC)
Pharmacokinetic Parameter - Volume of the Central Compartment (VC). VC is derived from plasma concentration versus time data. PK parameters were generated using a Population Pharmacokinetics (PPK) model. Summary statistics for these individual predicted PK parameters and exposures were stratified by dose. The PPK model analysis was based on combined PK data collected on days 1, 21, and 90.
Time frame: From first dose to up to 90 days after first dose
Population: All treated participants with at least one post-dose PK sample. Pre-specified for data to be collected only in the 25 mg QD, and BID dose regimens.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Pharmacokinetic Parameter - Volume of the Central Compartment (VC) | 34.9 L | Geometric Coefficient of Variation 152 |
| Milvexian 25 mg QD | Pharmacokinetic Parameter - Volume of the Central Compartment (VC) | 31.4 L | Geometric Coefficient of Variation 138 |
| Milvexian 25 mg BID | Pharmacokinetic Parameter - Volume of the Central Compartment (VC) | 30.9 L | Geometric Coefficient of Variation 145 |
| Milvexian 50 mg BID | Pharmacokinetic Parameter - Volume of the Central Compartment (VC) | 28.9 L | Geometric Coefficient of Variation 149 |
| Milvexian 100 mg BID | Pharmacokinetic Parameter - Volume of the Central Compartment (VC) | 31.6 L | Geometric Coefficient of Variation 181 |
Secondary
Volume of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI
Total volume of diffusion-weighted imaging (DWI) magnetic resonance imaging (MRI) infarcts on the DWI Sequence on day 90 MRI.
Time frame: At day 90
Population: All randomized participants with an evaluable MRI
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Volume of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | 2.3492 mL | Standard Deviation 11.40906 |
| Milvexian 25 mg QD | Volume of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | 0.8976 mL | Standard Deviation 1.96342 |
| Milvexian 25 mg BID | Volume of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | 2.9902 mL | Standard Deviation 8.28993 |
| Milvexian 50 mg BID | Volume of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | 1.2682 mL | Standard Deviation 2.72452 |
| Milvexian 100 mg BID | Volume of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | 1.4727 mL | Standard Deviation 3.78795 |
| Milvexian 200 mg BID | Volume of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | 1.2711 mL | Standard Deviation 4.05035 |
| Milvexian 50 mg QD | Volume of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | 8.8960 mL | Standard Deviation 13.85294 |
| Milvexian 100 mg QD | Volume of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI | 1.4503 mL | Standard Deviation 1.89112 |
Other Pre-specified
Percent of Participants With Ischemic Stroke Events
Secondary analysis of symptomatic ischemic stroke events. Clinical events are included up to day 90. Wald 95% CI within group. Undetermined stroke is included.
Time frame: From randomization to up to 90 days after randomization
Population: All randomized participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Percent of Participants With Ischemic Stroke Events | Ischemic stroke | 5.5 Percentage of participants |
| Placebo | Percent of Participants With Ischemic Stroke Events | Undetermined stroke | 0 Percentage of participants |
| Milvexian 25 mg QD | Percent of Participants With Ischemic Stroke Events | Undetermined stroke | 0 Percentage of participants |
| Milvexian 25 mg QD | Percent of Participants With Ischemic Stroke Events | Ischemic stroke | 4.6 Percentage of participants |
| Milvexian 25 mg BID | Percent of Participants With Ischemic Stroke Events | Ischemic stroke | 3.8 Percentage of participants |
| Milvexian 25 mg BID | Percent of Participants With Ischemic Stroke Events | Undetermined stroke | 0 Percentage of participants |
| Milvexian 50 mg BID | Percent of Participants With Ischemic Stroke Events | Undetermined stroke | 0 Percentage of participants |
| Milvexian 50 mg BID | Percent of Participants With Ischemic Stroke Events | Ischemic stroke | 4.0 Percentage of participants |
| Milvexian 100 mg BID | Percent of Participants With Ischemic Stroke Events | Undetermined stroke | 0 Percentage of participants |
| Milvexian 100 mg BID | Percent of Participants With Ischemic Stroke Events | Ischemic stroke | 3.5 Percentage of participants |
| Milvexian 200 mg BID | Percent of Participants With Ischemic Stroke Events | Ischemic stroke | 7.7 Percentage of participants |
| Milvexian 200 mg BID | Percent of Participants With Ischemic Stroke Events | Undetermined stroke | 0 Percentage of participants |
| Milvexian 50 mg QD | Percent of Participants With Ischemic Stroke Events | Ischemic stroke | 13.6 Percentage of participants |
| Milvexian 50 mg QD | Percent of Participants With Ischemic Stroke Events | Undetermined stroke | 0 Percentage of participants |
| Milvexian 100 mg QD | Percent of Participants With Ischemic Stroke Events | Undetermined stroke | 0 Percentage of participants |
| Milvexian 100 mg QD | Percent of Participants With Ischemic Stroke Events | Ischemic stroke | 5.6 Percentage of participants |
Comparison: Milvexian 25 mg QD over Placebo95% CI: [0.46, 1.49]Wald Confidence Limits
Comparison: Milvexian 25 mg BID over Placebo95% CI: [0.36, 1.3]Wald Confidence Limits
Comparison: Milvexian 50 mg BID over Placebo95% CI: [0.39, 1.33]Wald Confidence Limits
Comparison: Milvexian 100 mg BID over Placebo95% CI: [0.33, 1.25]Wald Confidence Limits
Comparison: Milvexian 200 mg BID95% CI: [0.87, 2.25]Wald Confidence Limits
Comparison: Milvexian 50 mg QD over Placebo95% CI: [0.83, 7.42]Wald Confidence Limits
Comparison: Milvexian 100 mg QD over Placebo95% CI: [0.15, 6.96]Wald Confidence Limits