XAVINT registration study: new indication in the Instruction for use for the drug Xavron

The aim of the registration multicenter, double-blind, randomized, placebo-controlled XAVINT study was to evaluate the efficacy and safety of edaravone (Xavron, Yuria-Pharm LLC) as part of standard therapy in hospitalized patients with coronavirus disease (COVID-19) and systemic inflammatory response syndrome.

Object and methods of the research. A total of 150 patients were enrolled and randomized into the Xavron and placebo groups.

Results. Treatment with Xavron significantly reduced the duration of oxygen therapy by 17 hours (p=0.016), accelerated clinical improvement by 1 point on the WHO scale (p=0.012), and increased the rate of clinical recovery on day 7 (p=0.021). Greater efficacy was observed in subgroups of patients aged ≥50 years, with body mass index ≥25 kg/m², SpO₂ <93%, and interleukin-6 ≥12 pg/mL. Early administration of the drug (within 4 days from symptom onset) enhanced the therapeutic effect. Xavron demonstrated good tolerability and contributed to a reduction in oxidative stress markers.

Conclusion. The results of the XAVINT study confirmed the efficacy and safety of edaravone in the treatment of patients with COVID-19 and systemic inflammatory response, leading to the registration of a new therapeutic indication for the drug.

References

1. Wang C., Horby P.W., Hayden F.G., Gao G.F. (2020) A novel coronavirus outbreak of global health concern. Lancet, 395(10223): 470–473.
2. Lippi G., Sanchis-Gomar F., Henry B.M. (2020) Coronavirus disease 2019 (COVID-19): the portrait of a perfect storm. Ann. Transl. Med., 8(7): 497.
3. Adhanom Ghebreyesus T. (2020) WHO Director-General’s opening remarks at the media briefing on COVID-19.
4. Berlin D.A., Gulick R.M., Martinez F.J. (2020) Severe Covid-19. N. Engl. J. Med., 383(25): 2451–2460. doi: 10.1056/NEJMcp2009575.
5. Beltrán-García J., Osca-Verdega l.R., Pallardó F.V. et al. (2020) Sepsis and Coronavirus Disease 2019: Common Features and Anti-Inflammatory Therapeutic Approaches. Crit. Care Med., 48(12): 1841–1844.
6. Li H., Liu L., Zhang D. et al. (2020) SARS-CoV-2 and viral sepsis: observations and hypotheses. Lancet, 395(10235): 1517–1520.
7. Tang N., Li D., Wang X., Sun Z. (2020) Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J. Thromb. Haemost., 18(4): 844–847. doi: 10.1111/jth.14768.
8. Zhang C., Shi L., Wang F.S. (2020) Liver injury in COVID-19: management and challenges. Lancet Gastroenterol. Hepatol., 5(5): 428–430.
9. Cecchini R., Cecchini A.L. (2020) SARS-CoV-2 infection pathogenesis is related to oxidative stress as a response to aggression. Med. Hypotheses., 143: 110102.
10. Alam M.S., Czajkowsky D.M. (2022) SARS-CoV-2 infection and oxidative stress: Pathophysiological insight into thrombosis and therapeutic opportunities. Cytokine Growth Factor Rev., 63: 44–57. doi: 10.1016/j.cytogfr.2021.11.001.
11. Li M.Y., Li L., Zhang Y., Wang X.S. (2020) Expression of the SARS-CoV-2 cell receptor gene ACE2 in a wide variety of human tissues. Infect. Dis. Poverty, 9(1): 45.
12. Delgado-Roche L., Mesta F. (2020) Oxidative Stress as Key Player in Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) Infection. Arch. Med. Res., 51(5): 384–387. doi: 10.1016/j.arcmed.2020.04.019.
13. Насонов Е.Л., Бекетова Т.В., Решетняк Т.М. та ін. (2020) Коронавірусних хвороба 2019 (COVID-19) і імунозапальні ревматичні захворювання: на перехресті проблем тромбозапалення і аутоімунітету. Науково-практична ревматологія, 58(4): 353–367.
14. Bodro M., Compta Y., Sánchez-Valle R. (2020) Presentations and mechanisms of CNS disorders related to COVID-19. Neurol Neuroimmunol Neuroinflamm., 8(1): e923.
15. Zhao K., Li G.Z., Nie L.Y. et al. (2022) Edaravone for Acute Ischemic Stroke: A Systematic Review and Meta-analysis. Clin. Ther., 44(12): e29–e38. doi: 10.1016/j.clinthera.2022.11.005.
16. Abe K., Yuki S., Kogure K. (1988) Strong attenuation of ischemic and postischemic brain edema in rats by a novel free radical scavenger. Stroke, 19(4): 480–485.
17. Miyamoto S., Ogasawara K., Kuroda S. et al.; Committee for Stroke Guideline 2021, the Japan Stroke Society (2022) Japan Stroke Society Guideline 2021 for the Treatment of Stroke. Int. J. Stroke, 17(9): 1039–1049. doi: 10.1177/17474930221090347.
18. Iso H. (2021) Cardiovascular disease, a major global burden: Epidemiology of stroke and ischemic heart disease in Japan. Glob. Health Med., 3(6): 358–364.
19. Lapchak P.A. (2010) A critical assessment of edaravone acute ischemic stroke efficacy trials: is edaravone an effective neuroprotective therapy? Expert Opin Pharmacother., 11(10): 1753–1763. doi: 10.1517/14656566.2010.493558.
20. Feng S., Yang Q., Liu M. et al. (2011) Edaravone for acute ischaemic stroke. Cochrane Database Syst. Rev., 12: CD007230. doi: 10.1002/14651858.CD007230.pub2.
21. Miyaji Y., Yoshimura S., Sakai N. et al. (2015) Effect of edaravone on favorable outcome in patients with acute cerebral large vessel occlusion: subanalysis of RESCUE-Japan Registry. Neurol. Med. Chir. (Tokyo), 55(3): 241–247.
22. Bhandari R., Kuhad A., Kuhad A. (2018) Edaravone: a new hope for deadly amyotrophic lateral sclerosis. Drugs Today (Barc), 54(6): 349–360.
23. Kausar S., Wang F., Cui H. (2018) The Role of Mitochondria in Reactive Oxygen Species Generation and Its Implications for Neurodegenerative Diseases. Cells, 7: 274.
24. Yamashita T., Abe K. (2024) Update on Antioxidant Therapy with Edaravone: Expanding Applications in Neurodegenerative Diseases. Int. J. Mol. Sci., 25(5): 2945.
25. Abe K., Itoyama Y., Sobue G. et al.; Edaravone ALS Study Group (2014) Confirmatory double-blind, parallel-group, placebo-controlled study of efficacy and safety of edaravone (MCI-186) in amyotrophic lateral sclerosis patients. Amyotroph. Lateral. Scler. Frontotemporal. Degener, 15(7–8): 610–617.
26. Chiò A., Logroscino G., Traynor B.J. et al. (2013) Global epidemiology of amyotrophic lateral sclerosis: a systematic review of the published literature. Neuroepidemiology, 41(2): 118–30. doi: 10.1159/000351153.
27. http://www.fda.gov/news-events/press-announcements/fda-approves-drug-treat-als.
28. Schultheiß C., Willscher E., Paschold L. et al. (2022) The IL-1β, IL-6, and TNF cytokine triad is associated with post-acute sequelae of COVID-19. Cell Rep. Med., 3(6): 100663. doi: 10.1016/j.xcrm.2022.100663.
29. Queiroz M.A.F., Neves P.F.M.D., Lima S.S. et al. (2022) Cytokine Profiles Associated With Acute COVID-19 and Long COVID-19 Syndrome. Front. Cell Infect. Microbiol., 12: 922422. doi: 10.3389/fcimb.2022.922422.
30. Yin J.X., Agbana Y.L., Sun Z.S. et al. (2023) Increased interleukin-6 is associated with long COVID-19: a systematic review and meta-analysis. Infect. Dis. Poverty, 12: 43.
31. Xu Z., Shi L., Wang Y. et al. (2020) Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir. Med., 8(4): 420–422.
32. Kappelmann N., Dantzer R., Khandaker G.M. (2021) Interleukin-6 as potential mediator of long-term neuropsychiatric symptoms of COVID-19. Psychoneuroendocrinology, 131: 105295. doi: 10.1016/j.psyneuen.2021.105295.
33. Watanabe T., Tahara M., Todo S. (2008) The novel antioxidant edaravone: from bench to bedside. Cardiovasc. Ther., 26(2): 101–14. doi: 10.1111/j.1527-3466.2008.00041.x.
34. Kikuchi K., Takeshige N., Miura N. et al. (2012) Beyond free radical scavenging: Beneficial effects of edaravone (Radicut) in various diseases (Review). Exp. Ther. Med., 3(1): 3–8. doi: 10.3892/etm.2011.352.
35. Kikuchi K., Tancharoen S., Takeshige N. et al. (2013) The efficacy of edaravone (radicut), a free radical scavenger, for cardiovascular disease. Int. J. Mol. Sci., 14(7): 13909–13930. doi: 10.3390/ijms140713909.
36. Зайков С.В. (2020) COVID‑19 і коморбідні хронічні захворювання. INFUSION & CHEMOTHERAPY, 3: 5–10. doi: 10.32902/2663-0338-2020-3-5-10.
37. Wang X., Lai R., Su X. et al. (2018) Edaravone attenuates lipopolysaccharide-induced acute respiratory distress syndrome associated early pulmonary fibrosis via amelioration of oxidative stress and transforming growth factor-β1/Smad3 signaling. Biochem. Biophys. Res. Commun., 495(1): 706–712.
38. Наказ МОЗ України від 28.03.2020 р. № 722 «Організація надання медичної допомоги хворим на коронавірусну хворобу (COVID-19)».