Phase IIB, Randomized, Double‐Blind, Placebo‐Controlled Clinical Trial of Intravenous Defibrotide for the Prevention and Treatment of Respiratory Distress and Cytokine Release Syndrome in COVID-19
et al., European Journal of Haematology, doi:10.1111/ejh.70214, NCT04348383, May 2026
RCT 150 hospitalized COVID-19 patients with respiratory failure showing no significant benefit with continuous IV defibrotide versus placebo.
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risk of death, 22.7% higher, RR 1.23, p = 0.56, treatment 27 of 100 (27.0%), control 11 of 50 (22.0%), day 60.
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risk of death, 4.5% higher, RR 1.05, p = 1.00, treatment 23 of 100 (23.0%), control 11 of 50 (22.0%), day 30.
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ECMO, 200.0% higher, RR 3.00, p = 0.14, treatment 12 of 100 (12.0%), control 2 of 50 (4.0%).
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risk of ICU admission, no change, RR 1.00, p = 1.00, treatment 72 of 100 (72.0%), control 36 of 50 (72.0%).
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hospitalization time, 17.9% higher, relative time 1.18, p = 0.41, treatment median 16.5 IQR 24.6 n=74, control median 14.0 IQR 10.0 n=39, length of stay for survivors.
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recovery time, 33.3% higher, relative time 1.33, p = 0.10, treatment median 15.0 IQR 24.0 n=100, control median 20.0 IQR 16.0 n=50, cumulative days alive between first achievement of improvement (≥ 1 category) on the WHO scale and day 30.
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dialysis requirement, 33.3% higher, RR 1.33, p = 0.75, treatment 8 of 100 (8.0%), control 3 of 50 (6.0%).
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any serious AE, 5.6% lower, RR 0.94, p = 0.86, treatment 34 of 100 (34.0%), control 18 of 50 (36.0%), NNT 50.
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| Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates |
Jara Rubio et al., 12 May 2026, Double Blind Randomized Controlled Trial, placebo-controlled, Spain, peer-reviewed, median age 61.0, 39 authors, study period 14 April, 2020 - 29 June, 2021, trial NCT04348383 (history).
Contact: paul_richardson@dfci.harvard.edu, jmoraled@um.es.
Abstract:
Phase IIB, Randomized, Double- Blind, Placebo- Controlled Clinical Trial of Intravenous Defibrotide for the Prevention and Treatment of Respiratory Distress and Cytokine Release Syndrome in COVID- 19
Ruben Jara Rubio 1 | Antonio José Martinez-Mellado 2 | Jonathan Kiwitt-Cárdenas 3 | José G. Clavel 4 | Bartolomé García-Perez 5 | Pedro Castro 6 | Maribel Diaz-Ricart 7 | Andrés Carrillo-Alcaraz 8 | Amparo López-Bernús 9 | Enrique Bernal Morell 10 | Aychel Roura 11 | Sonia Marín 11 | Francisco-José Ruiz-López 12 | Elena Solana-Martinez 12 | Domingo Martinez-Baño 1 | Carlos L. Albacete Moreno 1 | Enriqueta Andreu Soler 1 | Adrián Tellez Santoyo 6 | Sara Fernández Méndez 6 | Jose A. Noguera Velasco 13 | Iria Cebreiros Lopez 13 | Andrés Parrilla 14 | Alberto Espuny-Miró 15 | David García-Bernal 16 | Miguel Blanquer 2 | Andrés Sánchez-Salinas 2 | Francisca Iniesta 16 | Cristina Hernandez Garcia 16 | Manuel Muro 17 | Alfredo Minguela Puras 17 | Antonio Moreno-Docón 18 | Alberto M. Torres-Cantero 3 | Maria Munoz Garcia 19 | Manuel Serrano 20 | Massimo Iacobelli 21 | Carmelo Carlo-Stella 22,23 | Lee-Jen Wei 24 | Paul G. Richardson 25 | José M. Moraleda 16
1 Intensive Care Service, University Hospital Virgen de la Arrixaca, IMIB- Pascual Parrilla, University of Murcia, Murcia, Spain | 2 Hematology Department, University Hospital Virgen de la Arrixaca, IMIB- Pascual Parrilla, University of Murcia, Murcia, Spain | 3 Preventive Medicine Department, University Hospital Virgen de la Arrixaca, IMIB- Pascual Parrilla, University of Murcia, Murcia, Spain | 4 Department of Quantitative Methods, Faculty of Economics and Business, University of Murcia, Murcia, Spain | 5 Internal Medicine Department, University Hospital Virgen de la Arrixaca, IMIBPascual Parrilla, University of Murcia, Murcia, Spain | 6 Medical Intensive Care Unit, Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain | 7 Hematopathology, Pathology Department, Centre of Biomedical Diagnosis (CDB), Hospital Clinic, University of Barcelona, Barcelona, Spain | 8 Intensive Care Service, University Hospital Morales Meseguer, IMIB- Pascual Parrilla, University of Murcia, Murcia, Spain | 9 Internal Medicine Department, University Clinical Hospital, Salamanca, Spain | 10 Infectious Disease Department, University Hospital Reina Sofia, IMIB- Pascual Parrilla, University of Murcia, Murcia, Spain | 11 Infectious Disease Service, University Hospital Virgen de la Arrixaca, IMIB- Pascual Parrilla, University of Murcia, Murcia, Spain | 12 Pulmonology Department, University Hospital Virgen de la Arrixaca, IMIB- Pascual Parrilla, University of Murcia, Murcia, Spain | 13 Clinical Laboratory Service, University Hospital Virgen de la Arrixaca, IMIB- Pascual Parrilla, University of Murcia, Murcia, Spain | 14 Image Diagnostic Service, University Hospital Virgen de la Arrixaca, Murcia, Spain | 15 Pharmacy Department, University Hospital Virgen de la Arrixaca, IMIBPascual Parrilla, University of Murcia, Murcia, Spain | 16 Hematopoietic Transplant and Cellular Therapy Unit, University Hospital Virgen de la Arrixaca, IMIB- Pascual Parrilla, University of Murcia, Murcia, Spain | 17 Immunology Department, University Hospital Virgen de la Arrixaca, IMIB- Pascual Parrilla, Murcia, Spain | 18 Virology Laboratory, University Hospital Virgen de la Arrixaca, IMIB- Pascual Parrilla, University of..
DOI record:
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"abstract": "<jats:title>ABSTRACT</jats:title>\n <jats:sec>\n <jats:title>Introduction</jats:title>\n <jats:p>Endothelial dysfunction is key in COVID‐19 pathogenesis. This randomized, double‐blind phase IIb trial investigated continuous intravenous infusion of defibrotide in patients hospitalized with SARS‐CoV‐2 infection and respiratory failure.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Methods</jats:title>\n <jats:p>One‐hundred and fifty patients were randomized (2:1) to defibrotide or placebo, stratified by disease severity (WHO COVID‐19 severity scale 4/5 vs. 6). The primary endpoint was clinical improvement time (days from first improvement through Day 30).</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Results</jats:title>\n <jats:p>\n Median clinical improvement time was not significantly different with defibrotide versus placebo (15.0 [IQR: 0–24] vs. 20.0 [IQR: 9–25] days;\n <jats:italic>p</jats:italic>\n = 0.10). Day‐30 (23.0% vs. 22.0%) and Day‐60 (26.0% vs. 22.0%) mortality, reduction in mean fraction of inspired oxygen during treatment, and median duration of hospitalization did not differ with defibrotide versus placebo. Defibrotide demonstrated favorable safety, with no differences versus placebo in serious adverse events (34.0% vs. 36.0%), hypotension (16.0% vs. 12.0%), or hemorrhage (13.0% vs. 8.0%). Exploratory pre‐specified biomarker analyses showed greater early\n <jats:sc>d</jats:sc>\n ‐dimer reduction and lymphocyte recovery with defibrotide, although these results require validation.\n </jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Conclusion</jats:title>\n <jats:p>Continuous intravenous infusion of defibrotide was safe but did not improve clinical outcomes in severe COVID‐19. Further analyses will explore mechanistic actions and pharmacokinetics of defibrotide and the pathophysiology of endothelial dysfunction in COVID‐19.</jats:p>\n <jats:p>\n <jats:bold>Trial Registration:</jats:bold>\n EudraCT identifier: 2020‐001409‐21. Clinicaltrials.gov identifier: NCT04348383\n </jats:p>\n </jats:sec>",
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Late treatment
is less effective
is less effective
