Steering Committee:

The Steering Committee is responsible for the overall study supervision, assisting in developing the study protocol and preparing the final manuscript. All other study committees report to this committee. Its members are investigators trained in designing and conducting randomized clinical trials in critically ill patients

Advisory Board:

The Advisory Board is a committee of experts in the field that will advise the Steering Committee on different requested aspects, and will also promote and organize substudies.

Study Coordinating Center:

This Committee is the executive one, conducting the trial in all organizational, logistic, and procedural aspects, as well as controlling the DQT.

Data Safety Monitoring Board:

The DSMB is set up with independent epidemiologists and intensivists that supervises the trial. It also might provide recommendations for the SCC of continuing the study as planned or discontinuing the recruitment based on evidence that the intervention causes increased mortality in the experimental group as compared to the control group

Interim analyses will be conducted after recruitment of the first 200 patients and at 75% of the sample by the DSMB. The first Interim analysis will have two steps:

• A safety analysis where 28-day mortality will be compared between anonymized groups masked as A or B to detect potential risks associated with the intervention. According to the results the DSMB may 22recommended interruption of the Study for safety reasons.

• A second -blinded to outcome- analysis will be performed to compare the use of selected procedural interventions such as resuscitation fluids during the 6h study period between groups to demonstrate a gradient. If no difference or gradient is found the DSMB may recommend interruption of the Study for futility reasons.

The second interim analysis will focus on differences in the primary outcome between groups to potentially recommend an earlier interruption of the study in case of an already statistically significant difference

Study Centers

Around 80 centers will be recruited in Western Europe, Asia, North-America, and Latin-America. The process will start with a survey of professional and technical resources as well as processes of care. Centers will be contacted trying to make this process representative across public, private and university hospitals, different countries and cultures, and hospital size.

Funding

The Study is not supported by any major grant, but a fundraising campaign among involved universities both in Europe and Latin-America will provide the financial means to cover the costs which in particular will be insurances where required, and the logistics/human resources of the DQT.

Timeline

• 2021: Study design, ethics approval, site recruitment, funding application
• 2022: Protocol and registry training, first patient recruitment
• 2022-2024: Patient recruitment, interim analysis
• 2024: Reporting results