Protocol and statistical analysis plan for the mega randomised registry trial research program comparing conservative versus liberal oxygenation targets in adults receiving unplanned invasive mechanical ventilation in the ICU (Mega-ROX)

Background: The effect of conservative versus liberal oxygen therapy on 90-day in-hospital mortality in patients who require unplanned invasive mechanical ventilation in an intensive care unit (ICU) is uncertain and will be evaluated in the mega randomised registry trial research program (Mega-ROX). Objective: To summarise the protocol and statistical analysis plan for Mega-ROX. Design, setting and participants: Mega-ROX is a 40 000-patient parallel-group, registry-embedded clinical trial in which adults who require unplanned invasive mechanical ventilation in an ICU will be randomly assigned to conservative or liberal oxygen therapy. Within this overarching trial research program, three nested parallel randomised controlled trials will be conducted. These will include patients with suspected hypoxic ischaemic encephalopathy (HIE) following resuscitation from a cardiac arrest, patients with sepsis, and patients with non-HIE acute brain injuries or conditions. Main outcome measures: The primary outcome is in-hospital allcause mortality up to 90 days from the date of randomisation. Secondary outcomes include duration of survival, duration of mechanical ventilation, ICU length of stay, hospital length of stay, and proportion of patients discharged home. Results and conclusions: Mega-ROX will compare the effect of conservative versus liberal oxygen therapy on 90-day in-hospital mortality in critically ill adults who receive unplanned invasive mechanical ventilation in an ICU. The protocol and a pre-specified approach to analyses are reported here to mitigate analysis bias. Trial registration: Australian and New Zealand Clinical Trials Registry (ANZCTRN 12620000391976).