INHALEd nebulised unfractionated HEParin for the treatment of
hospitalised patients with COVID-19 (INHALE-HEP): Protocol and
Statistical Analysis Plan for an investigator-initiated international
meta-trial of randomised studies
Abstract
Inhaled nebulised unfractionated heparin (UFH) has a strong scientific
and biological rationale that warrants urgent investigation of its
therapeutic potential in patients with COVID-19. UFH has antiviral
effects and prevents the SARS-CoV-2 virus’ entry into mammalian cells.
In addition, UFH has significant anti-inflammatory and anti-coagulant
properties, which limit progression of lung injury and vascular
pulmonary thrombosis. Methods and intervention The INHALEd nebulised
unfractionated HEParin for the treatment of hospitalised patients with
COVID-19 (INHALE-HEP) meta-trial is a prospective individual patient
data analysis of on-going randomised controlled trials and early phase
studies. Individual studies are being conducted in multiple countries.
Participating studies randomise adult patients admitted to the hospital
with confirmed SARS-CoV-2 infection, who do not require immediate
mechanical ventilation, to inhaled nebulised UFH or standard care. All
studies collect a minimum core dataset. The primary outcome for the
meta-trial is intubation (or death, for patients who died before
intubation) at day 28. The secondary outcomes are oxygenation, clinical
worsening and mortality, assessed in time-to-event analyses. Individual
studies may have additional outcomes. Analysis We use a Bayesian
approach to monitoring, followed by analysing individual patient data,
outcomes and adverse events. All analyses will follow the
intention-to-treat principle, considering all participants in the
treatment group to which they were assigned, except for cases lost to
follow-up or withdrawn. Trial registration, ethics and dissemination The
meta-trial is registered at ClinicalTrials.gov ID NCT04635241. Each
contributing study is individually registered and has received approval
of the relevant ethics committee or institutional review board.