A Phase III Randomized Controlled Trial of Plitidepsin, a Marine-Derived Compound, in Hospitalized Adults With Moderate COVID-19
Pedro Landete, Olga-Adriana Caliman-Sturdza, Jose A Lopez-Martin, Liliana Preotescu, Mihaela-Catalina Luca, Anastasia Kotanidou, Paula Villares, Shirley-Patricia Iglesias, Pablo Guisado-Vasco, Elena-Maria Saiz-Lou, Maria Del Carmen Farinas-Alvarez, Esperanza Merino De Lucas, Eduardo Perez-Alba, Jose-Miguel Cisneros, Vicente Estrada, Carmen Hidalgo-Tenorio, Garyfallia Poulakou, Miguel Torralba, Jesus Fortun, Paula Garcia-Ocana, Adrien Lemaignen, Miguel Marcos-Martin, Maria Molina, Roger Paredes, Maria Teresa Perez-Rodriguez, Dimitar Raev, Pablo Ryan, Fernanda Meira, Javier Gomez, Nadia Torres, Diego Lopez-Mendoza, Jose Jimeno, Jose-Felipe F Varona
Clinical Infectious Diseases, doi:10.1093/cid/ciae227
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 . 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.
Supplementary Data Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.
Notes Author contributions. O-A. C-S., L. P., M-C. L., A. K., P. V., S-P. I., P. G-V., M-C. F-A, E. M. L., E. P-A., J-M. C., V. E., C. H-T., G. P., M. T., J. F., P. G-O., A. L., M. M-M, M. M., R. P., M. T. P-R., D. R., P. R.: investigation, writing-review. P. L, J. F. V.: investigation, writing-review, validation. D. L-M.: supervision, project administration, and funding acquisition. E-M. S-L.: supervision, validation, and investigation. F. M.: supervision, validation. J. G.: software, methodology, formal analysis and writingreview, visualization. N. T.: software, data curation and validation. J. A. L-M: conceptualization, formal analysis, methodology and writing-original draft, review & editing, and visualization. J. J.: conceptualization, formal analysis, methodology and writing-original draft, review & editing, supervision, and funding acquisition. Acknowledgments. The authors thank the patients, and their relatives for their participation in this trial and also thank Timothy Silverstein for providing editorial support and Raquel Lloris for dedicated contributions to this trial. Data from this trial are not publicly available. Ethical Approval..
References
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Mahoney, Barthel, Functional evaluation: the Barthel Index, Md State Med J
Rodon, Munoz-Basagoiti, Perez-Zsolt, Identification of plitidepsin as potent inhibitor of SARS-CoV-2-induced cytopathic effect after a drug repurposing screen, Front Pharmacol
Souza, Carrasco, Rojas-Cortes, Effectiveness of nirmatrelvirritonavir for the treatment of patients with mild to moderate COVID-19 and at high risk of hospitalization: systematic review and meta-analyses of observational studies, PLoS One
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'abstract': '<jats:title>Abstract</jats:title>\n'
' <jats:sec>\n'
' <jats:title>Background</jats:title>\n'
' <jats:p>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.</jats:p>\n'
' </jats:sec>\n'
' <jats:sec>\n'
' <jats:title>Methods</jats:title>\n'
' <jats:p>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\u2005mg/day or 2.5\u2005mg/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.</jats:p>\n'
' </jats:sec>\n'
' <jats:sec>\n'
' <jats:title>Results</jats:title>\n'
' <jats:p>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\u2005mg vs control; hazard ratio, 1.06; 95% confidence interval, .73–1.53; P '
'= .78 for plitidepsin 2.5\u2005mg vs control). Plitidepsin was generally well '
'tolerated.</jats:p>\n'
' </jats:sec>\n'
' <jats:sec>\n'
' <jats:title>Conclusions</jats:title>\n'
' <jats:p>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.</jats:p>\n'
' <jats:p>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.</jats:p>\n'
' </jats:sec>',
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'resource': {'primary': {'URL': 'https://academic.oup.com/cid/article/79/4/910/7740910'}},
'subtitle': [],
'short-title': [],
'issued': {'date-parts': [[2024, 8, 26]]},
'references-count': 13,
'journal-issue': { 'issue': '4',
'published-online': {'date-parts': [[2024, 8, 26]]},
'published-print': {'date-parts': [[2024, 10, 15]]}},
'URL': 'http://dx.doi.org/10.1093/cid/ciae227',
'relation': {},
'ISSN': ['1058-4838', '1537-6591'],
'subject': [],
'published-other': {'date-parts': [[2024, 10, 15]]},
'published': {'date-parts': [[2024, 8, 26]]}}
