Clinical Trial

. 2024 Jan;23(1):46-59.

doi: 10.1016/S1474-4422(23)00403-9.

Safety and efficacy of factor XIa inhibition with milvexian for secondary stroke prevention (AXIOMATIC-SSP): a phase 2, international, randomised, double-blind, placebo-controlled, dose-finding trial

Mukul Sharma¹, Carlos A Molina², Kazunori Toyoda³, Daniel Bereczki⁴, Shrikant I Bangdiwala⁵, Scott E Kasner⁶, Helmi L Lutsep⁷, Georgios Tsivgoulis⁸, George Ntaios⁹, Anna Czlonkowska¹⁰, Ashfaq Shuaib¹¹, Pierre Amarenco¹², Matthias Endres¹³, Byung-Woo Yoon¹⁴, David Tanne¹⁵, Danilo Toni¹⁶, Laetitia Yperzeele¹⁷, Paul von Weitzel-Mudersbach¹⁸, Gisele Sampaio Silva¹⁹, Alvaro Avezum²⁰, Jesse Dawson²¹, Daniel Strbian²², Turgut Tatlisumak²³, Jens Eckstein²⁴, Sebastián F Ameriso²⁵, Joerg R Weber²⁶, Else Charlotte Sandset²⁷, Nana Goar Pogosova²⁸, Pablo M Lavados²⁹, Antonio Arauz³⁰, David Gailani³¹, Hans-Christoph Diener³², Richard A Bernstein³³, Charlotte Cordonnier³⁴, Anja Kahl³⁵, Grigor Abelian³⁵, Mark Donovan³⁵, Chahin Pachai³⁵, Danshi Li³⁵, Graeme J Hankey³⁶

Affiliations

¹ Population Health Research Institute, McMaster University, Hamilton, ON, Canada. Electronic address: mike.sharma@phri.ca.
² Hospital Universitari Vall d'Hebron, Barcelona, Spain.
³ National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
⁴ Semmelweis University, Budapest, Hungary.
⁵ Population Health Research Institute, McMaster University, Hamilton, ON, Canada; Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada.
⁶ Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA.
⁷ Department of Neurology, Oregon Health & Science University, Portland, OR, USA.
⁸ Second Department of Neurology, National and Kapodistrian University of Athens, Attikon University Hospital, Athens, Greece.
⁹ Department of Internal Medicine, University of Thessaly, Larissa, Greece.
¹⁰ 2nd Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland.
¹¹ Division of Neurology, Department of Medicine, University of Alberta Hospital, Edmonton, AB, Canada.
¹² Population Health Research Institute, McMaster University, Hamilton, ON, Canada; Department of Neurology and Stroke Center, University of Paris, Bichat Hospital, Paris, France.
¹³ Department of Neurology and Center for Stroke Research Berlin, Charité-Universitätsmedizin Berlin, Berlin, Germany.
¹⁴ Uijeongbu Eulji Medical Center, Eulji University, Gyeonggi-do, South Korea.
¹⁵ Stroke and Cognition Institute, Rambam Health Care Campus, Haifa, Technion, Israel.
¹⁶ Emergency Department Stroke Unit, Department of Human Neurosciences, Sapienza University of Rome, Rome, Italy.
¹⁷ Stroke Unit and Neurovascular Center Antwerp, Department of Neurology, Antwerp University Hospital, Antwerp (Edegem), Belgium.
¹⁸ Department of Neurology, Aarhus University Hospital, Aarhus, Denmark.
¹⁹ Universidade Federal de São Paulo/UNIFESP and Hospital Israelita Albert Einstein, São Paulo, Brazil.
²⁰ Centro Internacional de Pesquisa, Hospital Alemão Oswaldo Cruz, São Paulo, Brazil.
²¹ School of Cardiovascular and Metabolic Health, College of Medical, Veterinary & Life Sciences, Queen Elizabeth University Hospital, Glasgow, UK.
²² Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland.
²³ Department of Clinical Neuroscience/Neurology, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg and Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden.
²⁴ Department of Internal Medicine and Department of Digitalization & ICT, University Hospital Basel, Basel, Switzerland.
²⁵ Servicio de Neurología Vascular, Departamento de Neurología, FLENI, Buenos Aires, Argentina.
²⁶ Department of Neurology, Klinikum Klagenfurt, Austria.
²⁷ Department of Neurology, Oslo University Hospital and The Norwegian Air Ambulance Foundation, Oslo, Norway.
²⁸ National Medical Research Center of Cardiology after E Chazov, Moscow, Russia.
²⁹ Departamento de Neurología y Psiquiatría, Unidad de Investigación y Ensayos Clínicos, Clínica Alemana, Universidad del Desarrollo, Santiago, Chile.
³⁰ Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, México City, México.
³¹ Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
³² Department of Neuroepidemiology, Institute for Medical Informatics, Biometry and Epidemiology (IMIBE), University Duisburg-Essen, Essen, Germany.
³³ Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
³⁴ University of Lille, Lille, Inserm, CHU Lille, U1172 - LiINCog - Lille Neuroscience & Cognition, F-59000, Lille, France.
³⁵ Bristol Myers Squibb, Princeton, NJ, USA.
³⁶ Medical School, Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, Perth, WA, Australia; Perron Institute for Neurological and Translational Science, Perth, Australia.

PMID: 38101902
PMCID: PMC10822143
DOI: 10.1016/S1474-4422(23)00403-9

Clinical Trial

Safety and efficacy of factor XIa inhibition with milvexian for secondary stroke prevention (AXIOMATIC-SSP): a phase 2, international, randomised, double-blind, placebo-controlled, dose-finding trial

Mukul Sharma et al. Lancet Neurol. 2024 Jan.

. 2024 Jan;23(1):46-59.

doi: 10.1016/S1474-4422(23)00403-9.

Authors

Affiliations

¹ Population Health Research Institute, McMaster University, Hamilton, ON, Canada. Electronic address: mike.sharma@phri.ca.
² Hospital Universitari Vall d'Hebron, Barcelona, Spain.
³ National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
⁴ Semmelweis University, Budapest, Hungary.
⁵ Population Health Research Institute, McMaster University, Hamilton, ON, Canada; Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada.
⁶ Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA.
⁷ Department of Neurology, Oregon Health & Science University, Portland, OR, USA.
⁸ Second Department of Neurology, National and Kapodistrian University of Athens, Attikon University Hospital, Athens, Greece.
⁹ Department of Internal Medicine, University of Thessaly, Larissa, Greece.
¹⁰ 2nd Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland.
¹¹ Division of Neurology, Department of Medicine, University of Alberta Hospital, Edmonton, AB, Canada.
¹² Population Health Research Institute, McMaster University, Hamilton, ON, Canada; Department of Neurology and Stroke Center, University of Paris, Bichat Hospital, Paris, France.
¹³ Department of Neurology and Center for Stroke Research Berlin, Charité-Universitätsmedizin Berlin, Berlin, Germany.
¹⁴ Uijeongbu Eulji Medical Center, Eulji University, Gyeonggi-do, South Korea.
¹⁵ Stroke and Cognition Institute, Rambam Health Care Campus, Haifa, Technion, Israel.
¹⁶ Emergency Department Stroke Unit, Department of Human Neurosciences, Sapienza University of Rome, Rome, Italy.
¹⁷ Stroke Unit and Neurovascular Center Antwerp, Department of Neurology, Antwerp University Hospital, Antwerp (Edegem), Belgium.
¹⁸ Department of Neurology, Aarhus University Hospital, Aarhus, Denmark.
¹⁹ Universidade Federal de São Paulo/UNIFESP and Hospital Israelita Albert Einstein, São Paulo, Brazil.
²⁰ Centro Internacional de Pesquisa, Hospital Alemão Oswaldo Cruz, São Paulo, Brazil.
²¹ School of Cardiovascular and Metabolic Health, College of Medical, Veterinary & Life Sciences, Queen Elizabeth University Hospital, Glasgow, UK.
²² Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland.
²³ Department of Clinical Neuroscience/Neurology, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg and Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden.
²⁴ Department of Internal Medicine and Department of Digitalization & ICT, University Hospital Basel, Basel, Switzerland.
²⁵ Servicio de Neurología Vascular, Departamento de Neurología, FLENI, Buenos Aires, Argentina.
²⁶ Department of Neurology, Klinikum Klagenfurt, Austria.
²⁷ Department of Neurology, Oslo University Hospital and The Norwegian Air Ambulance Foundation, Oslo, Norway.
²⁸ National Medical Research Center of Cardiology after E Chazov, Moscow, Russia.
²⁹ Departamento de Neurología y Psiquiatría, Unidad de Investigación y Ensayos Clínicos, Clínica Alemana, Universidad del Desarrollo, Santiago, Chile.
³⁰ Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, México City, México.
³¹ Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
³² Department of Neuroepidemiology, Institute for Medical Informatics, Biometry and Epidemiology (IMIBE), University Duisburg-Essen, Essen, Germany.
³³ Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
³⁴ University of Lille, Lille, Inserm, CHU Lille, U1172 - LiINCog - Lille Neuroscience & Cognition, F-59000, Lille, France.
³⁵ Bristol Myers Squibb, Princeton, NJ, USA.
³⁶ Medical School, Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, Perth, WA, Australia; Perron Institute for Neurological and Translational Science, Perth, Australia.

PMID: 38101902
PMCID: PMC10822143
DOI: 10.1016/S1474-4422(23)00403-9

Abstract

Background: People with factor XI deficiency have lower rates of ischaemic stroke than the general population and infrequent spontaneous bleeding, suggesting that factor XI has a more important role in thrombosis than in haemostasis. Milvexian, an oral small-molecule inhibitor of activated factor XI, added to standard antiplatelet therapy, might reduce the risk of non-cardioembolic ischaemic stroke without increasing the risk of bleeding. We aimed to estimate the dose-response of milvexian for recurrent ischaemic cerebral events and major bleeding in patients with recent ischaemic stroke or transient ischaemic attack (TIA).

Methods: AXIOMATIC-SSP was a phase 2, randomised, double-blind, placebo-controlled, dose-finding trial done at 367 hospitals in 27 countries. Eligible participants aged 40 years or older, with acute (<48 h) ischaemic stroke or high-risk TIA, were randomly assigned by a web-based interactive response system in a 1:1:1:1:1:2 ratio to receive one of five doses of milvexian (25 mg once daily, 25 mg twice daily, 50 mg twice daily, 100 mg twice daily, or 200 mg twice daily) or matching placebo twice daily for 90 days. All participants received clopidogrel 75 mg daily for the first 21 days and aspirin 100 mg daily for the first 90 days. Investigators, site staff, and participants were masked to treatment assignment. The primary efficacy endpoint was the composite of ischaemic stroke or incident covert brain infarct on MRI at 90 days, assessed in all participants allocated to treatment who completed a follow-up MRI brain scan, and the primary analysis assessed the dose-response relationship with Multiple Comparison Procedure-Modelling (MCP-MOD). The main safety outcome was major bleeding at 90 days, assessed in all participants who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov (NCT03766581) and the EU Clinical Trials Register (2017-005029-19).

Findings: Between Jan 27, 2019, and Dec 24, 2021, 2366 participants were randomly allocated to placebo (n=691); milvexian 25 mg once daily (n=328); or twice-daily doses of milvexian 25 mg (n=318), 50 mg (n=328), 100 mg (n=310), or 200 mg (n=351). The median age of participants was 71 (IQR 62-77) years and 859 (36%) were female. At 90 days, the estimates of the percentage of participants with either symptomatic ischaemic stroke or covert brain infarcts were 16·8 (90·2% CI 14·5-19·1) for placebo, 16·7 (14·8-18·6) for 25 mg milvexian once daily, 16·6 (14·8-18·3) for 25 mg twice daily, 15·6 (13·9-17·5) for 50 mg twice daily, 15·4 (13·4-17·6) for 100 mg twice daily, and 15·3 (12·8-19·7) for 200 mg twice daily. No significant dose-response was observed among the five milvexian doses for the primary composite efficacy outcome. Model-based estimates of the relative risk with milvexian compared with placebo were 0·99 (90·2% CI 0·91-1·05) for 25 mg once daily, 0·99 (0·87-1·11) for 25 mg twice daily, 0·93 (0·78-1·11) for 50 mg twice daily, 0·92 (0·75-1·13) for 100 mg twice daily, and 0·91 (0·72-1·26) for 200 mg twice daily. No apparent dose-response was observed for major bleeding (four [1%] of 682 participants with placebo, two [1%] of 325 with milvexian 25 mg once daily, two [1%] of 313 with 25 mg twice daily, five [2%] of 325 with 50 mg twice daily, five [2%] of 306 with 100 mg twice daily, and five [1%] of 344 with 200 mg twice daily). Five treatment-emergent deaths occurred, four of which were considered unrelated to the study drug by the investigator.

Interpretation: Factor XIa inhibition with milvexian, added to dual antiplatelet therapy, did not substantially reduce the composite outcome of symptomatic ischaemic stroke or covert brain infarction and did not meaningfully increase the risk of major bleeding. Findings from our study have informed the design of a phase 3 trial of milvexian for the prevention of ischaemic stroke in patients with acute ischaemic stroke or TIA.

Funding: Bristol Myers Squibb and Janssen Research & Development.

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Conflict of interest statement

Declaration of interests MS has received consulting fees from Janssen, HLS Therapeutics, and Bayer; and has served in a leadership or fiduciary role for the Canadian Stroke Consortium. CAM has received honoraria from Bristol Myers Squibb and Boehringer Ingelheim. KT has received honoraria from Bayer, Daiichi Sankyo, Bristol Myers Squibb, Otsuka, Novartis, and Abbott Medical. DB has received consulting fees from Bristol Myers Squibb, Bayer, Ipsen, and Boehringer Ingelheim; and has received honoraria from Novo Nordisk, HUMAN BioPlazma, and Parexel. SEK has received grants or contracts from Bristol Myers Squibb; and has received consulting fees from Bristol Myers Squibb. HL has received consulting fees from Bristol Myers Squibb; has participated on steering committees or advisory boards for Bristol Myers Squibb, the US National Institute of Neurological Disorders and Stroke, and Coherex Medical; and is on the Editorial Board for Medscape Neurology. GT has received consulting fees from Bristol Myers Squibb. GN has received financial support from Bristol Myers Squibb. AC has participated on a steering committee for Bristol Myers Squibb; has received grants or contracts from Bristol Myers Squibb; and has previously served as the President of the Cerebrovascular Section of Polish Neurological Society, honorary president of the Polish Neurological Society, and in a leadership role for the Angels Initiative— Poland. PA has participated on a steering committee for Bristol Myers Squibb and Janssen; has received grants or contracts from Sanofi, Bristol Myers Squibb, AstraZeneca, Pfizer, Merck, AltheraPharm, and the French Government; has received consulting fees from Bayer, Novartis, and Novo Nordisk; has received honoraria from Viatris and Sanofi; and has participated in an advisory board for Novartis. ME has received grants or contracts from Bayer; has received consulting fees from Bayer; has received honoraria from Abbott, Boehringer Ingelheim, Pfizer, Amgen, GSK, Sanofi, and Novartis; has participated on data safety monitoring boards or advisory boards for Bristol Myers Squibb, Bayer, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Amgen, and Covidien; has served in a leadership or fiduciary role for the European Academy of Neurology, German Neurological Society (DGN), International Society for Cerebral Blood Flow and Metabolism, American Heart Association/American Stroke Association, European Stroke Organisation, World Stroke Organization, German Center for Cardiovascular Research (DZHK), and German Center for Neurodegenerative Diseases (DZNE); and has been a recipient of materials from Amgen. DTa has received consulting fees from QuantaIX Neuroscience, Babylink, and Pi-cardia, and for being a national leader in a randomised controlled trial. DTo has received honoraria from Abbott, Alexion, AstraZeneca, Bayer, Boehringer Ingelheim, Medtronic, and Pfizer. LY has participated in steering committees for Bristol Myers Squibb and Janssen Research & Development; has received honoraria from Bayer, Bristol Myers Squibb, Pfizer, Boehringer Ingelheim, and Daiichi Sankyo; and has received support for attendance at the World Stroke Congress from the World Stroke Organization Future Stroke Leaders Program. PvWM has received contracts and support for attending an investigator meeting from Bristol Myers Squibb; and has served as a national leader and member of a steering committee for Bristol Myers Squibb. GSS has received support from and participated on a steering committee for Bristol Myers Squibb; has received grants or contracts from Boehringer Ingelheim; has received consulting fees from Bristol Myers Squibb and Boehringer Ingelheim; and has participated in an advisory board for Bristol Myers Squibb. AAv has received grants and honoraria from Bayer. JD has received support from Bristol Myers Squibb; has received grants from Pfizer; and has received honoraria from Pfizer, Daiichi Sankyo, and AstraZeneca. DS has received contracts, support for attending a steering committee meeting, and materials and drugs for performing the trial from Bristol Myers Squibb. TT has received grants from the University of Gothenburg, Sahlgrenska University Hospital, and Wennerstrom's Foundation; and has received consulting fees from Bayer, Inventiva Pharma, Bristol Myers Squibb, and Portola Pharmaceuticals. JE has received travel support from Bristol Myers Squibb for attending steering committee meetings. SFA has received grants from Bayer and Boehringer Ingelheim; and has received honoraria from Novo Nordisk and Abbott. JRW has served as President Elect of the Austrian Society of Neurology. ECS has received honoraria from Bristol Myers Squibb, Daiichi Sankyo, and Boston Scientific. NGP has served as the President of the Russian National Society of Preventive Cardiology. PML has received grants from Bristol Myers Squibb and Janssen; has received honoraria from Boehringer Ingelheim and Pfizer; has received support for attending the Global Stroke Alliance; has participated on a data safety monitoring board or advisory board for RapidAI; and has served as the President of the Chilean Stroke Association. DG has received grants or contracts, or both, from the US National Heart, Lung and Blood Institute and the US National Institutes of Health; has received consulting fees from Bristol Myers Squibb, Ionis, Janssen, and Anthos Therapeutics; and has participated on a steering committee for Bristol Myers Squibb. HCD has received support from Bristol Myers Squibb; has received grants from Boehringer Ingelheim and AstraZeneca; has received honoraria from Boehringer Ingelheim, Pfizer, Sanofi, and Bristol Myers Squibb; has received support for attending meetings or travel, or both, from Boehringer Ingelheim; and has participated on data safety monitoring boards or advisory boards for Actelion, the German Research Council, and the ELAN Study. RAB has received consulting fees from and has participated on a steering committee for Bristol Myers Squibb. CC has received honoraria from Bristol Myers Squibb and Amgen; and has participated on data safety monitoring boards or advisory boards for AstraZeneca and Biogen. GA, MD, and CP are employees and shareholders of Bristol Myers Squibb. AK and DL are employees and shareholders of Bristol Myers Squibb; and have a pending patent application related to this study. GJH has received consulting fees from Bristol Myers Squibb, Janssen Research & Development, and Bayer; has received honoraria from Janssen Medical Affairs; has received honoraria for participating on a data safety monitoring board for AC Immune; and has received honoraria from the American Heart Association for serving as an Associate Editor for Circulation. SIB, AS, BWY, and AAr declare no competing interests.

Figures

**Figure 1:. Trial profile**
The shaded boxes show dose groups that were terminated early. The outcome event of stroke was also counted as an adverse event. *The primary analysis population comprised all patients with a primary endpoint event up to day 90 or an evaluable MRI from the day 90 visit.

**Figure 2:. BARC type 3 and type 5 bleeding events**
BARC type 3 bleeding events: haemoglobin drop 3 g/dL, requiring transfusion or surgery, or intracerebral haemorrhage. No type 5 (ie, fatal) bleeding events were observed. The figure includes all patients who received at least one dose of study drug, except for those in the dose groups that were terminated early. BARC=Bleeding Academic Research Consortium. RR=relative risk.

See this image and copyright information in PMC

Comment in

Anticoagulants to prevent recurrent non-cardioembolic stroke.
Khatri P. Khatri P. Lancet Neurol. 2024 Jan;23(1):3-5. doi: 10.1016/S1474-4422(23)00464-7. Lancet Neurol. 2024. PMID: 38101895 No abstract available.

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Safety and efficacy of factor XIa inhibition with milvexian for secondary stroke prevention (AXIOMATIC-SSP): a phase 2, international, randomised, double-blind, placebo-controlled, dose-finding trial

Affiliations

Safety and efficacy of factor XIa inhibition with milvexian for secondary stroke prevention (AXIOMATIC-SSP): a phase 2, international, randomised, double-blind, placebo-controlled, dose-finding trial

Authors

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Abstract

Conflict of interest statement

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Associated data

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