Phase <scp>IIB</scp> , Randomized, Double‐Blind, Placebo‐Controlled Clinical Trial of Intravenous Defibrotide for the Prevention and Treatment of Respiratory Distress and Cytokine Release Syndrome in <scp>COVID</scp> ‐19

INTRODUCTION: 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. METHODS: 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). RESULTS: Median clinical improvement time was not significantly different with defibrotide versus placebo (15.0 [IQR: 0-24] vs. 20.0 [IQR: 9-25] days; p = 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 d-dimer reduction and lymphocyte recovery with defibrotide, although these results require validation. CONCLUSION: 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. TRIAL REGISTRATION: EudraCT identifier: 2020-001409-21. CLINICALTRIALS: gov identifier: NCT04348383.

Authors

Institutions

Publication Details

Journal
European Journal Of Haematology
Published
2026-05-12
DOI
https://doi.org/10.1111/ejh.70214
Primary Topic
COVID-19 Clinical Research Studies
Type
article
Field-Weighted Citation Impact
0.00

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

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

Sonia Marı́n, Antonio José Martínez-Mellado, Adrián Téllez Santoyo, Bartolomé García‐Pérez et al.
European Journal Of Haematology
COVID-19 Clinical Research Studies
article

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

Sonia Marı́n, Antonio José Martínez-Mellado, Adrián Téllez Santoyo, Bartolomé García‐Pérez, Alberto Espuny-Miró, Rubén Jara Rubio, Enriqueta Andreu Soler, Carmelo Carlo‐Stella, Paul Gerard Guy Richardson, L. J. Wei, Sara Fernández Méndez, David García‐Bernal, Elena Solana-Martínez, Cristina Hernández García, MC Santiago García, José M. Moraleda, Jonathan Kiwitt-Cárdenas, Massimo Iacobelli, Andrés Sánchez‐Salinas, Antonio Moreno‐Docón, Alberto M. Torres‐Cantero, Amparo López‐Bernús, Francisca Iniesta, Iria Cebreiros López, Carlos L. Albacete Moreno, Manuel Muro, Enrique Bernal Morell, Andrés Parrilla, José G. Clavel, Alfredo Minguela Puras, Domingo Martinez‐Baño, Jose A. Noguera Velasco, Pedro Castro, Aychel Roura, Miguel Blanquer, Manuel Serrano, Andrés Carrillo‐Alcaraz, Maribel Diaz‐Ricart, Francisco‐José Ruiz‐López
article en

Abstract

INTRODUCTION: 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. METHODS: 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). RESULTS: Median clinical improvement time was not significantly different with defibrotide versus placebo (15.0 [IQR: 0-24] vs. 20.0 [IQR: 9-25] days; p = 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 d-dimer reduction and lymphocyte recovery with defibrotide, although these results require validation. CONCLUSION: 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. TRIAL REGISTRATION: EudraCT identifier: 2020-001409-21. CLINICALTRIALS: gov identifier: NCT04348383.

European Journal Of Haematology
Humanitas University (IT), Harvard University (US), Universidad de La Laguna (ES), Universidad de Salamanca (ES), Hospital General Universitario Morales Meseguer (ES), Techint (Italy) (IT), Hospital Clínic de Barcelona (ES), Dana-Farber Cancer Institute (US), Hospital Reina Sofía de Murcia (ES), Instituto Murciano de Investigación Biosanitaria (ES), Hospital Universitario Virgen de la Arrixaca (ES), IRCCS Humanitas Research Hospital (IT), Universitat de Barcelona (ES), Universidad de Murcia (ES)
Fundación Séneca, Jazz Pharmaceuticals, Instituto de Salud Carlos III
Good health and well-being
Openalex Percentile: Top 5%
COVID-19 Clinical Research Studies
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.