A Phase III Randomized Controlled Trial of Plitidepsin, a Marine-Derived Compound, in Hospitalized Adults With Moderate COVID-19.

Autor:	Landete P; Pneumology Department, Hospital Universitario La Princesa, Madrid, Spain.; Research Laboratory, Instituto de Investigación La Princesa (IIS Princesa), Madrid, Spain.; Department of Pneumology, Hospital Enfermera Isabel Zendal, Madrid SARS CoV2 Unit, Madrid, Spain.; Department of Pneumology, Universidad Autónoma de Madrid, Madrid, Spain., Caliman-Sturdza OA; Department of Infectious Diseases, Judetean de Urgenta 'Sf. Ioan cel Nou', Suceava, Romania.; Deparment of Internal Medicine, University of Suceava, Suceava, Romania., Lopez-Martin JA; Virology Unit, PharmaMar, Madrid, Spain., Preotescu L; Department of Internal Mecicine, Institutul National De Boli Infectioase 'Prof. Dr. Matei Bals', Bucharest, Romania.; Department of Internal Mecicine, University of Medicine and Pharmacy 'Carol Davila', Bucharest, Romania., Luca MC; Department of Internal Medicine, Spitalul Clinic De Boli Infecţioase 'Sf. Paraschev', Iasi, Romania.; Department of Internal Medicine, 'Grigore T. Popa' University, Iasi, Romania., Kotanidou A; Department of Internal Medicine, National and Kapodistrian University of Athens, Athens, Greece.; Pulmonary and Critical Care, Evagelismos General Hospital, Athens, Greece., Villares P; Internal Medicine, Hospital Universitario HM Sanchinarro, HM Hospitales Group, Madrid, Spain., Iglesias SP; Infectiology Department, Clinica de la Costa, Barranquilla, Colombia., Guisado-Vasco P; Internal Medicine, Hospital Universitario Quironsalud Madrid, Madrid, Spain.; Medical Research Center, Universidad Europea, Madrid, Spain., Saiz-Lou EM; Virology Unit, PharmaMar, Madrid, Spain., Del Carmen Farinas-Alvarez M; Infectious Diseases Department, Hospital Universitario 'Marqués de Valdecilla', Santander, Spain.; Department of Internal Medicine, Valdecilla Research Institute (IDIVAL), Santander, Spain.; Department of Medicine and Psychiatry, Universidad de Cantabria, Research Center, Santander, Spain., de Lucas EM; Unit of Infectious Diseases, Alicante General University Hospital, Alicante, Spain.; Department of Infectious Disease, Alicante Institute of Health and Biomedical Research (ISABIAL), Alicante, Spain., Perez-Alba E; Infectology Department, Hospital Universitario 'Dr. José Eleuterio González', Monterrey, Mexico.; Department of Infectious Diseases, Universidad Autónoma de Nuevo León, Monterrey, Mexico., Cisneros JM; Department of Research, Institute of Biomedicine of Seville (IBiS), Seville, Spain.; Department of Infectious Diseases, Virgen del Rocío' University Hospital, Seville, Spain., Estrada V; Infectious Diseases Unit, Hospital Universitario 'San Carlos', Madrid, Spain., Hidalgo-Tenorio C; Infectious Diseases Unit, Hospital Universitario 'Virgen de las Nieves', Granada, Spain., Poulakou G; 3rd Department of Internal Medicine and Laboratory, National Sotiria General Hospital, Athens, Greece., Torralba M; Internal Medicine, Guadalajara University Hospital, Guadalajara, Spain., Fortun J; Infectious Diseases Department, Hospital Universitario Ramon y Cajal, Madrid, Spain., Garcia-Ocana P; Infectious Diseases Unit, Hospital Universitario de Jerez de la Frontera, Cádiz, Spain., Lemaignen A; Department of Infectious Diseases, Centre Hospitalier Regional et Universitaire de Tours (CHRU Tours)-Hopital Bretonneaut, Tours, France., Marcos-Martin M; Department of Medicine, Hospital Universitario de Salamanca, Salamanca, Spain., Molina M; ILD Unit-Respiratory Department, University Hospital of Bellvitge, Barcelona, Spain.; Bellvitge Institute for Biomedical Reseach, IDIBELL, Barcelona, Spain.; Department of Research Center, CIBERES, Barcelona, Spain., Paredes R; Infectious Diseases Department, Hospital Universitari Germans Trial I Pujol, Badalona, Spain.; Department of Infectious Diseases, IrsiCaixa AIDS Research Institute, Badalona, Spain., Perez-Rodriguez MT; Infectious Diseases Unit, Internal Medicine Department, Complexo Hospitalario Universitario de Vigo . Vigo, Spain., Raev D; Cardiology and Internal Medicine, Internal Medicine Clinic, University Hospital UMHAT 'Sveta Anna', Sofia, Bulgaria., Ryan P; Infectious Diseases Hospital Infanta Leonor, Madrid, Spain., Meira F; Virology Unit, PharmaMar, Madrid, Spain., Gomez J; Department of Biostatistics, PharmaMar, Madrid, Spain., Torres N; Department of Data Management, PharmaMar, Madrid, Spain., Lopez-Mendoza D; Virology Unit, PharmaMar, Madrid, Spain., Jimeno J; Virology Unit, PharmaMar, Madrid, Spain., Varona JF; Department of Internal Medicine, Hospital Universitario HM Monteprincipe, HM Hospitales, Madrid, Spain.; Facultad HM de Ciencias de la Salud, Universidad Camilo Jose Cela, Madrid, Spain.
Jazyk:	angličtina
Zdroj:	Clinical infectious diseases : an official publication of the Infectious Diseases Society of America [Clin Infect Dis] 2024 Oct 15; Vol. 79 (4), pp. 910-919.
DOI:	10.1093/cid/ciae227
Abstrakt:	Background: Plitidepsin has shown potent preclinical activity against severe acute respiratory syndrome coronavirus 2 and was generally well tolerated in a phase I trial of hospitalized patients with coronavirus disease 2019 (COVID-19). NEPTUNO, a phase III, multicenter, randomized, controlled trial, was designed to evaluate the efficacy and safety of plitidepsin in the management of moderate COVID-19 in hospitalized adult patients. Methods: Included patients had documented severe acute respiratory syndrome coronavirus 2 infection, required oxygen therapy, and had adequate organ function. The planned sample size was 609 patients. Patients were randomized 1:1:1 to at least 3 days of dexamethasone plus either plitidepsin (1.5 mg/day or 2.5 mg/day, for 3 days) or standard of care (control). The primary endpoint was the time to sustained withdrawal of supplemental oxygen. Secondary endpoints included time to sustained hospital discharge, clinical status, duration of oxygen support, percentage of patients requiring admission to the intensive care unit, and safety. Results: After randomizing 205 patients, NEPTUNO was discontinued due to a notable drop in COVID-19-related hospitalizations. Available data suggest a 2-day improvement in the median time to sustained oxygen therapy discontinuation (5 vs 7 days) favoring both plitidepsin arms (hazard ratio, 1.37; 95% confidence interval, .96-1.96; P = .08 for plitidepsin 1.5 mg vs control; hazard ratio, 1.06; 95% confidence interval, .73-1.53; P = .78 for plitidepsin 2.5 mg vs control). Plitidepsin was generally well tolerated. Conclusions: Despite the trial limitations, these results suggest that plitidepsin may have a positive benefit-risk ratio in the management of patients requiring oxygen therapy. Further studies with plitidepsin, including those in immunosuppressed patients, are warranted.Results from this phase III trial suggest that plitidepsin, a first-in-class antiviral, may have a positive benefit-risk ratio in the management of hospitalized patients requiring oxygen therapy for moderate COVID-19. Competing Interests: Potential conflicts of interest. V. E. has received economic support for educational talks and advisory boards from Gilead Sciences and PharmaMar SA. M. M-M. has received grants and fees for scientific advice not related with this work; received in the past 36 months from Boehringer Ing, Roche, Ferrer, Chiesi. P. V. has received provision of study materials, travel support travel from PharmaMar SA, and payments from PharmaMar SA and GlaxoSmithKline (GSK). P. G-V. received speaker fees from FLS Science, PharmaMar SA (Madrid, Spain), Pfizer (Spain), and GSK (Spain); consulting fees from Angelini Pharma and PharmaMar SA; served as an advisory board member for Berlin Cures GmbH and PharmaMar SA; and received meeting grants from GSK and PharmaMar SA. A. L. has received occasional training fees from Gilead, is a member of a Data Monitoring Committee for a randomized controlled trial for Biophytis Biopharma. R. P. has received grants or contracts from MSD, ViiV Healthcare; consulting fees Pfizer, Gilead, AstraZeneca, PharmaMar SA, GSK, Atea. G. P. has received fees, as member advisory panels and consultancy, from Pfizer, MSD, Menarini, and Gilead. M. M. has received fees from Boehringer as scientific advisor and payments for lectures and educational events from GSK. J. F. has received grants and payments from Gilead, Pfizer, Shionogy, Astellas, and MSD, as well as travel support. P. R. has received fees and travel support from Gilead, Merck, VIV, and Gesida. D. L-M., E-M. S-L, F. M., J. G., and N. T. are a full-time employees of PharmaMar. J. J. holds stocks of Pangaea Oncology, has a nonremunerated role in the Scientific Advisory Board, and holds stocks of Promontory Therapeutics; is a full-time employee and shareholder of PharmaMar, S.A. (Madrid, Spain), and a co-inventor of 2 patents for Plitidepsin (WO99-42125). J. A. L.-M. is a full-time employee and shareholder of PharmaMar, S.A (Madrid, Spain), and a co-inventor of a patent for plitidepsin (WO2008135793A1). All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)
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