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

Phase 2

Completed

Conditions: Acute Ischemic Stroke
Transient Ischemic Attack (TIA)

Interventions: Other: Placebo
Drug: BMS-986177
Drug: Clopidogrel
Drug: Aspirin

Registration Number: NCT03766581

Lead Sponsor: Bristol-Myers Squibb

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 2366

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
BMS-986177 Placebo	Placebo	Specified Dose on Specified Days
Dose 2: BMS-986177 + Aspirin + Clopidogrel	BMS-986177	Specified Dose on Specified Days
Dose 1: BMS-986177 + Aspirin + Clopidogrel	BMS-986177	Specified Dose on Specified Days
Dose 3: BMS-986177 + Aspirin + Clopidogrel	Clopidogrel	Specified Dose on Specified Days
Dose 4: BMS-986177 + Aspirin + Clopidogrel	Aspirin	Specified Dose on Specified Days
Dose 5: BMS-986177 + Aspirin + Clopidogrel	BMS-986177	Specified Dose on Specified Days
Dose 5: BMS-986177 + Aspirin + Clopidogrel	Clopidogrel	Specified Dose on Specified Days
Dose 7: BMS-986177 + Aspirin + Clopidogrel	BMS-986177	Specified Dose on Specified Days
Dose 3: BMS-986177 + Aspirin + Clopidogrel	BMS-986177	Specified Dose on Specified Days
Dose 4: BMS-986177 + Aspirin + Clopidogrel	BMS-986177	Specified Dose on Specified Days
Dose 6: BMS-986177 + Aspirin + Clopidogrel	BMS-986177	Specified Dose on Specified Days
BMS-986177 Placebo	Clopidogrel	Specified Dose on Specified Days
Dose 1: BMS-986177 + Aspirin + Clopidogrel	Clopidogrel	Specified Dose on Specified Days
BMS-986177 Placebo	Aspirin	Specified Dose on Specified Days
Dose 1: BMS-986177 + Aspirin + Clopidogrel	Aspirin	Specified Dose on Specified Days
Dose 2: BMS-986177 + Aspirin + Clopidogrel	Clopidogrel	Specified Dose on Specified Days
Dose 2: BMS-986177 + Aspirin + Clopidogrel	Aspirin	Specified Dose on Specified Days
Dose 3: BMS-986177 + Aspirin + Clopidogrel	Aspirin	Specified Dose on Specified Days
Dose 4: BMS-986177 + Aspirin + Clopidogrel	Clopidogrel	Specified Dose on Specified Days
Dose 5: BMS-986177 + Aspirin + Clopidogrel	Aspirin	Specified Dose on Specified Days
Dose 7: BMS-986177 + Aspirin + Clopidogrel	Clopidogrel	Specified Dose on Specified Days
Dose 6: BMS-986177 + Aspirin + Clopidogrel	Clopidogrel	Specified Dose on Specified Days
Dose 6: BMS-986177 + Aspirin + Clopidogrel	Aspirin	Specified Dose on Specified Days
Dose 7: BMS-986177 + Aspirin + Clopidogrel	Aspirin	Specified Dose on Specified Days

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.
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
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 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.
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 Clinically Significant Electrocardiogram (ECG) Abnormalities	From first dose to up to 90 days after first dose	Number of participants with clinically significant ECG abnormalities.
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.
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
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
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.
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 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.
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.
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 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.
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.
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.
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.

Trial Locations

Locations (361): Local Institution - 0029
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Birmingham, Alabama, United States
Local Institution - 0007
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Glendale, California, United States
Local Institution - 0006
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Long Beach, California, United States
Kaiser Permanente Los Angeles Medical Center
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Los Angeles, California, United States
Local Institution - 0231
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Los Angeles, California, United States
Local Institution - 0376
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Sacramento, California, United States
Local Institution - 0004
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Stanford, California, United States
Local Institution - 0042
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Torrance, California, United States
Local Institution - 0340
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Newark, Delaware, United States
Local Institution - 0075
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Gainesville, Florida, United States
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Local Institution - 0029
🇺🇸Birmingham, Alabama, United States