A Study on BMS-986177 for the Prevention of a Stroke in Patients Receiving Aspirin and Clopidogrel

Study Overview
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Brief Summary
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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.

Official Title
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A Global, Phase 2, Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study of BMS-986177, an Oral Factor XIa Inhibitor, for the Prevention of New Ischemic Stroke or New Covert Brain Infarction in Patients Receiving Aspirin and Clopidogrel Following Acute Ischemic Stroke or Transient Ischemic Attack (TIA)

Conditions
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Acute Ischemic Stroke, Transient Ischemic Attack (TIA)

Intervention / Treatment
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* Drug: BMS-986177
* Other: Placebo
* Drug: Clopidogrel
* Drug: Aspirin


Participation Criteria
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Eligibility Criteria
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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/exclusion criteria could apply

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: BMS-986177 Placebo<br>Specified Dose on Specified Days | Other: Placebo<br>* Oral Administration<br>Drug: Clopidogrel<br>* Oral administration<br>Drug: Aspirin<br>* Oral administration<br>|
| Experimental: Dose 1: BMS-986177 + Aspirin + Clopidogrel<br>Specified Dose on Specified Days | Drug: BMS-986177<br>* Oral administration<br>Drug: Clopidogrel<br>* Oral administration<br>Drug: Aspirin<br>* Oral administration<br>|
| Experimental: Dose 2: BMS-986177 + Aspirin + Clopidogrel<br>Specified Dose on Specified Days | Drug: BMS-986177<br>* Oral administration<br>Drug: Clopidogrel<br>* Oral administration<br>Drug: Aspirin<br>* Oral administration<br>|
| Experimental: Dose 3: BMS-986177 + Aspirin + Clopidogrel<br>Specified Dose on Specified Days | Drug: BMS-986177<br>* Oral administration<br>Drug: Clopidogrel<br>* Oral administration<br>Drug: Aspirin<br>* Oral administration<br>|
| Experimental: Dose 4: BMS-986177 + Aspirin + Clopidogrel<br>Specified Dose on Specified Days | Drug: BMS-986177<br>* Oral administration<br>Drug: Clopidogrel<br>* Oral administration<br>Drug: Aspirin<br>* Oral administration<br>|
| Experimental: Dose 5: BMS-986177 + Aspirin + Clopidogrel<br>Specified Dose on Specified Days | Drug: BMS-986177<br>* Oral administration<br>Drug: Clopidogrel<br>* Oral administration<br>Drug: Aspirin<br>* Oral administration<br>|
| Experimental: Dose 6: BMS-986177 + Aspirin + Clopidogrel<br>Specified Dose on Specified Days | Drug: BMS-986177<br>* Oral administration<br>Drug: Clopidogrel<br>* Oral administration<br>Drug: Aspirin<br>* Oral administration<br>|
| Experimental: Dose 7: BMS-986177 + Aspirin + Clopidogrel<br>Specified Dose on Specified Days | Drug: BMS-986177<br>* Oral administration<br>Drug: Clopidogrel<br>* Oral administration<br>Drug: Aspirin<br>* Oral administration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | From randomization to up to 90 days after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | From first dose to up to 107 days after first dose | 
| 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. | From first dose to up to 107 days after first dose | 
| 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. | From first dose to up to 107 days after first dose | 
| 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: 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) 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 Any Major: Any one of the above criteria Minor: Bleeding that does not meet criteria for PLATO Major bleeding, and requiring medical intervention | From first dose to up to 107 days after first dose | 
| 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. | From randomization to up to 90 days after randomization | 
| 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. | From randomization to up to 90 days after randomization | 
| 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. | At baseline, on Days 21 and 90, and at the time of a new stroke event | 
| 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 = No significant disability despite symptoms; able to carry out all usual duties and activities = Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance = Moderate disability; requiring some help, but able to walk without assistance = Moderately severe disability; unable to walk and attend to bodily needs without assistance = Severe disability; bedridden, incontinent and requiring constant nursing care and attention = Dead | At baseline, on Days 21 and 90, and at the time of a new stroke event | 
| 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 | At baseline, on Days 21 and 90, and at the time of a new stroke event | 
| 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. | At baseline, on Days 21 and 90, and at the time of a new stroke event | 
| 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. | From first dose to 2 days after last dose of study therapy (up to approximately 107 days) | 
| 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. | 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 physical examination abnormalities. | From first dose to up to 90 days after first dose | 
| Number of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities | Number of participants with clinically significant ECG abnormalities. | From first dose to up to 90 days after first dose | 
| 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) | From first dose to up to approximately 38 months | 
| Percent Change From Baseline in aPTT Activity | Percent change from baseline in activated partial thromboplastin time (aPTT) activity via exposure response. | Baseline and day 90 | 
| Percent Change From Baseline in Factor XI Clotting Activity | Percent change from baseline in factor XI clotting activity via exposure response. | Baseline and day 90 | 
| 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. | From first dose to up to 90 days after first dose | 
| 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. | From first dose to up to 90 days after first dose | 
| 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. | At day 90 | 
| 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. | At day 90 |