A Phase 2 study of Factor XIa inhibitor to prevent New Ischemic Stroke
Research type
Research Study
Full 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) AXIOMATIC-SSP Antithrombotic treatment with factor XIa inhibition to Optimize Management of Acute Thromboembolic events in Secondary Stroke Prevention
IRAS ID
268970
Contact name
Jesse Dawson
Contact email
Sponsor organisation
Bristol-Myers Squibb International Corporation
Eudract number
2017-005029-19
Clinicaltrials.gov Identifier
Duration of Study in the UK
2 years, 2 months, days
Research summary
Summary of Research
Stroke is a leading cause of death and disability worldwide. Up to 87% of all strokes are attributed to ischemic stroke. The risk of recurrent cerebrovascular events is particularly high during the initial 90 days following an ischemic stroke or transient ischemic attack (TIA). Antiplatelet therapy with aspirin or clopidogrel has long been the standard of care therapy for the prevention of recurrent ischemic stroke after TIA or ischemic stroke due to large artery atherosclerosis. Recent clinical trial evidence supports the use of dual platelet inhibition (DAPT) with aspirin plus clopidogrel to further decrease the risk of a future stroke. However, the residual risk for a recurrent stroke remains high. Factor XIa inhibition has the potential to address this unmet medical need with a limited effect on bleeding.
This secondary stroke prevention trial testing a FXIa inhibitor on top of DAPT.The study will recruit participants >40 years with an acute ischemic stroke or TIA within 48 hrs of symptom onset. The study duration is 90 days and 75% of the participants will receive BMS-986177 and 25% placebo. All participants will take aspirin 100 mg + clopidogrel 300-mg single loading dose followed by clopidogrel 75 mg once daily for 21 days. From day 22-90, participants will only receive 100 mg aspirin with the study medication. Participants will be required to attend 3 clinic visits and 2 phone calls. The study involves a study-specific MRI at baseline and day 90. About 2350 participants are planned to take part in this study, with approximately 190 of them being in the UK.
A Data Monitoring Committee (DMC), who is independent of the sponsor, will assess safety data on an ongoing basis to ensure patient safety at all times.
Bristol-Myers Squibb is the sponsor of this study.
Summary of Results
The purpose of this study was to find out if milvexian, given in different doses with aspirin plus clopidogrel and then with aspirin only, is safe and effective in preventing a secondary (or new) stroke or silent stroke in participants who have recently had a stroke. Stroke is a condition where blood clots form in the vessels of the brain and can block blood circulation.
A silent stroke does not show symptoms, but a magnetic resonance imaging (MRI) scan shows evidence of stroke. At the start of the study, there were 7 milvexian dose groups (25 mg once daily, 50 mg once daily, 100 mg once daily, 25 mg twice daily, 50 mg twice daily, 100 mg twice daily, and 200 mg twice daily) and the placebo group. The placebo treatment looked the same as milvexian, but it did not have any “active ingredient” in it.
During the study, the sponsor decided to stop signing up participants in the 2 milvexian dose groups (50 mg and 100 mg once daily). The reason was to answer key questions for this study with a smaller total number of participants. It was not because of safety reasons with milvexian or its dose groups of 50 mg or 100 mg once daily. Participants who have been assigned to receive milvexian 50 mg or 100 mg once daily were able to finish the study.What were the overall results of this study?
This section describes the results for participants who took either milvexian (1 of 5 doses: 25 mg once daily and 25 mg, 50 mg, 100 mg, and 200 mg twice daily) or a placebo. In this study, milvexian or placebo was taken with aspirin plus clopidogrel and then with aspirin only.
Participants in the 2 milvexian dose groups (50 mg and 100 mg once daily) are not included in the answers to the main questions of this summary because of the smaller number of participants in these 2 groups.The main questions that researchers wanted to answer were:
1. Did milvexian given for up to 90 days with aspirin and clopidogrel help in preventing a new stroke or a new silent stroke?: Researchers checked the results of 2120 participants who were assigned to receive milvexian (1 of 5 dose groups) or a placebo.
Combined analysis of participants with either a new stroke or a new silent stroke The main analysis was designed to study the number of participants with either a new stroke or a new silent stroke (as seen on the MRI scan on Day 90 of the treatment period) when looked at together.Fewer participants who took milvexian 25 mg once daily or 50 mg to 100 mg twice daily (14% to 16%) had either a new stroke or a new silent stroke compared to those who took a placebo (17%).
However, researchers did not find evidence that increasing doses of milvexian, given with aspirin plus clopidogrel and then with aspirin only, lessened the number of participants with either a new stroke or a new silent stroke.
2. Did milvexian given for up to 90 days with aspirin and clopidogrel increase the number of bleeding events while in the study?: Researchers checked the results of 2295 participants who took at least 1 dose of milvexian (1 of 5 dose groups) or a placebo.
Researchers did not find evidence that increasing the dose of milvexian led to more bleeding events compared to a placebo. However, a larger study is needed to confirm these results because this study was not designed to compare these differences.
Why was this study done?
Researchers were looking for a different way to prevent secondary strokes.
Stroke and mini-stroke (also called a “transient ischemic attack”), are conditions where blood clots form in the vessels of the brain and can block blood circulation. This can result in serious disabilities or death.Patients who have had a stroke are at a higher risk of having another one (also known as secondary stroke or new stroke). The risk is high especially during the first 90 days after the stroke or mini-stroke.
A secondary stroke may or may not have symptoms such as sudden trouble seeing, walking, or speaking; confusion; or dizziness. A silent stroke does not show symptoms, but an MRI scan shows evidence of stroke.
Blood thinner drugs work to prevent blood clots from forming by stopping the clotting proteins from binding together or by stopping platelets (blood cells that help with clotting) from sticking to each other. However, blood thinner drugs have a risk of bleeding.
Aspirin and clopidogrel are blood thinner drugs called “antiplatelet agents”. Aspirin and clopidogrel are commonly given to prevent blood clots and to lessen the risk of a secondary stroke.Milvexian, the investigational or study medicine, is designed to block factor XIa (one of the components in the clotting process). It belongs to a class of blood thinner drugs called “anticoagulants”.
The purpose of this study was to find out if milvexian is safe and effective in preventing a secondary (or new) stroke when given daily for up to 90 days with aspirin plus clopidogrel and then with aspirin only. Researchers wanted to determine study questions that will be answered in larger studies of milvexian to be conducted in the future. Information on potential side effects while taking milvexian or a placebo were also collected.
Were there any side effects?
The safety of every participant is essential throughout the development and testing of potential treatments. The study doctors keep a record of all symptoms the participants have during the study.
Symptoms or abnormal findings that study doctors think may be related to treatment are called “side effects”.
This section describes the side effects that happened in 2334 participants who took at least 1 dose of milvexian or placebo.
The total milvexian group includes all 7 dose groups.
• It includes the 5 dose groups (25 mg once daily and 25 mg to 200 mg twice daily).
• It also includes the 2 dose groups (50 mg and 100 mg once daily) that were closed earlier than planned.Overall, 88 out of 2334 participants (4%) stopped taking the study medicine because of side effects they had during the study.
Did any of the participants have serious side effects?
A side effect that is life-threatening or causes a participant to be hospitalized or study doctors think is medically important is called a “serious side effect”.
Overall, 30 out of 2334 participants (1%) had at least 1 serious side effect in this study.
How has this study helped participants and researchers?
The information gained from this study was used to plan larger studies (Phase 3) of milvexian to confirm the results seen in this study.
Before a treatment can be approved, the results of many studies need to be reviewed to decide which treatments work and are safe. If you have questions about your study treatment, please speak with your study doctor or study team.REC name
East Midlands - Derby Research Ethics Committee
REC reference
19/EM/0328
Date of REC Opinion
6 Jan 2020
REC opinion
Further Information Favourable Opinion