BackgroundInhaled nebulised unfractionated heparin (UFH) has a strong rationale as a treatment for severe respiratory infections, including COVID-19, due to its antiviral, anti-inflammatory, and anti-coagulant properties, which may prevent viral entry, lung injury progression, and pulmonary thrombosis. We aimed to evaluate the efficacy of inhaled nebulised UFH to prevent intubation or death in hospitalised COVID-19 patients.MethodsIn this prospective, a priori set up and defined, collaborative meta-trial of six randomised clinical studies, adult hospitalised but not intubated COVID-19 patients were randomly assigned to inhaled nebulised UFH on top of standard of care or standard of care alone. The dose and method of nebulisation was specific to each study. The primary outcome was intubation or death, assessed at the longest follow-up after randomisation. The meta-trial was registered at ClinicalTrials.gov ID NCT04635241.FindingsBetween June 2020 and December 2022, 478 patients from 10 hospitals in six countries (Argentina, Brazil, Egypt, Indonesia, Ireland and USA) were enrolled. The odds ratio (OR) for intubation or death was 0.43 (0.26-0.73, p = 0.001); the OR for in-hospital mortality was 0.26 (0.13-0.54, p < 0.001) with inhaled nebulised UFH compared to standard of care alone. There were no safety issues reported, including no instances of pulmonary or systemic bleeding in the nebulised UFH group.InterpretationIn patients hospitalised but not intubated for COVID-19, inhaled nebulised UFH prevented intubation and reduced mortality, without causing pulmonary or systemic bleeding.FundingThe Sponsor of the meta-trial was the INHALE-HEP Collaborative Research Group (CRG); investigators of each contributing study were members of the INHALE-HEP CRG. No funding was received for the meta-trial. The Brazilian study was funded by The J.R. Moulton Charity Trust. The Irish study was funded by a Grant from Science Foundation Ireland to Cúram, the SFI's Centre for Research in Medical Devices (Research Centre Award Reference: 13/RC/2073).