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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03766581
Recruitment Status : Completed
First Posted : December 6, 2018
Results First Posted : June 12, 2023
Last Update Posted : June 12, 2023
Sponsor:
Collaborator:
Janssen, LP
Information provided by (Responsible Party):
Bristol-Myers Squibb

Study Description
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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.

Condition or disease Intervention/treatment Phase
Acute Ischemic Stroke Transient Ischemic Attack (TIA) Drug: BMS-986177 Other: Placebo Drug: Clopidogrel Drug: Aspirin Phase 2

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 2366 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: 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)
Actual Study Start Date : January 27, 2019
Actual Primary Completion Date : March 31, 2022
Actual Study Completion Date : March 31, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Ischemic Stroke

Arms and Interventions
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Arm Intervention/treatment
Placebo Comparator: BMS-986177 Placebo
Specified Dose on Specified Days
 Other: Placebo
Oral Administration

Drug: Clopidogrel
Oral administration

Drug: Aspirin
Oral administration
Experimental: Dose 1: BMS-986177 + Aspirin + Clopidogrel
Specified Dose on Specified Days
 Drug: BMS-986177
Oral administration

Drug: Clopidogrel
Oral administration

Drug: Aspirin
Oral administration
Experimental: Dose 2: BMS-986177 + Aspirin + Clopidogrel
Specified Dose on Specified Days
 Drug: BMS-986177
Oral administration

Drug: Clopidogrel
Oral administration

Drug: Aspirin
Oral administration
Experimental: Dose 3: BMS-986177 + Aspirin + Clopidogrel
Specified Dose on Specified Days
 Drug: BMS-986177
Oral administration

Drug: Clopidogrel
Oral administration

Drug: Aspirin
Oral administration
Experimental: Dose 4: BMS-986177 + Aspirin + Clopidogrel
Specified Dose on Specified Days
 Drug: BMS-986177
Oral administration

Drug: Clopidogrel
Oral administration

Drug: Aspirin
Oral administration
Experimental: Dose 5: BMS-986177 + Aspirin + Clopidogrel
Specified Dose on Specified Days
 Drug: BMS-986177
Oral administration

Drug: Clopidogrel
Oral administration

Drug: Aspirin
Oral administration
Experimental: Dose 6: BMS-986177 + Aspirin + Clopidogrel
Specified Dose on Specified Days
 Drug: BMS-986177
Oral administration

Drug: Clopidogrel
Oral administration

Drug: Aspirin
Oral administration
Experimental: Dose 7: BMS-986177 + Aspirin + Clopidogrel
Specified Dose on Specified Days
 Drug: BMS-986177
Oral administration

Drug: Clopidogrel
Oral administration

Drug: Aspirin
Oral administration


Outcome Measures
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Primary Outcome Measures :
  1. 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 [ Time Frame: 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 :
  1. Percent of Participants With Major Bleeding According to BARC Type 3 and 5 [ Time Frame: 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


  2. Number of Participants With Bleeding Based on BARC Types 1-5 [ Time Frame: 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.

  3. Number of Participants With Bleeding Based on ISTH-Defined Criteria [ Time Frame: 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.

  4. Number of Participants With Bleeding Based on PLATO-Defined Criteria [ Time Frame: 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

  5. 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 [ Time Frame: 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.

  6. Composite of Percent of Participants With New Ischemic Stroke, MI and All Cause Death [ Time Frame: 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.

  7. National Institutes of Health Stroke Scale (NIHSS) [ Time Frame: 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.

  8. Modified Rankin Scale (mRS) [ Time Frame: 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

  9. Montreal Cognitive Assessment (MoCA) [ Time Frame: 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

  10. Digit Symbol Substitution Test (DSST) [ Time Frame: 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.

  11. Number of Participants With Adverse Events (AEs) [ Time Frame: 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.

  12. Number of Participants With Clinically Significant Vital Sign Abnormalities [ Time Frame: 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.

  13. Number of Participants With Clinically Significant Physical Examination Abnormalities [ Time Frame: From first dose to up to 90 days after first dose ]
    Number of participants with clinically significant physical examination abnormalities.

  14. Number of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities [ Time Frame: From first dose to up to 90 days after first dose ]
    Number of participants with clinically significant ECG abnormalities.

  15. Number of Participants With Clinically Significant Laboratory Abnormalities - Liver [ Time Frame: 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)


  16. Percent Change From Baseline in aPTT Activity [ Time Frame: Baseline and day 90 ]
    Percent change from baseline in activated partial thromboplastin time (aPTT) activity via exposure response.

  17. Percent Change From Baseline in Factor XI Clotting Activity [ Time Frame: Baseline and day 90 ]
    Percent change from baseline in factor XI clotting activity via exposure response.

  18. Pharmacokinetic Parameter - Estimated Clearance (CL) [ Time Frame: 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.

  19. Pharmacokinetic Parameter - Volume of the Central Compartment (VC) [ Time Frame: 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.

  20. Volume of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI [ Time Frame: At day 90 ]
    Total volume of diffusion-weighted imaging (DWI) magnetic resonance imaging (MRI) infarcts on the DWI Sequence on day 90 MRI.

  21. Number of Incident Infarcts (New DWI+ or DWI- Lesions) by Participant on Day 90 MRI [ Time Frame: At day 90 ]
    Number of diffusion-weighted imaging (DWI) magnetic resonance imaging (MRI) infarcts on the DWI Sequence on day 90 MRI.


Other Outcome Measures:
  1. Percent of Participants With Ischemic Stroke Events [ Time Frame: 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.


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   40 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03766581


Locations
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Sponsors and Collaborators
Bristol-Myers Squibb
Janssen, LP
Investigators
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Study Director: Bristol-Myers Squibb Bristol-Myers Squibb
  Study Documents (Full-Text)

Documents provided by Bristol-Myers Squibb:
Study Protocol and Statistical Analysis Plan  [PDF] October 9, 2020

More Information
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Additional Information:

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Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT03766581    
Other Study ID Numbers: CV010-031
First Posted: December 6, 2018    Key Record Dates
Results First Posted: June 12, 2023
Last Update Posted: June 12, 2023
Last Verified: June 2023

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Stroke
Ischemic Stroke
Ischemic Attack, Transient
Ischemia
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
Pathologic Processes
Brain Ischemia
Aspirin
Clopidogrel
Anti-Inflammatory Agents, Non-Steroidal
 Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Platelet Aggregation Inhibitors
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Antipyretics
Purinergic P2Y Receptor Antagonists