Evaluation of Conservative Versus Conventional Oxygen Administration on ICU Mortality in Mechanically Ventilated Critically Ill Adults Using Nitrous Oxide and Oxygen

The primary objective of this study is to verify the hypothesis that the strict maintenance of **normoxia** improves survival in a wide population of mechanically ventilated critically ill patients compared to the application of conventional, more liberal strategies of oxygen administration. Survival will be measured at ICU discharge. This objective is clinically relevant as it aims to determine whether a conservative approach to oxygen administration can enhance patient outcomes in critical care settings.

Secondary objectives include verifying the hypothesis that strict maintenance of normoxia reduces 90-day mortality, the onset of new organ failures (respiratory, cardiovascular, renal, and hepatic) after 48 hours from ICU admission, and the occurrence of nosocomial infections during ICU stay. Additionally, the study will assess the length of mechanical ventilation, vasopressor use, ICU stay, and the occurrence of ICU-acquired weakness and cognitive dysfunction. Confirmation of the efficacy of a conservative strategy for oxygen administration could lead to a significant revision of current clinical practices and recommendations, potentially impacting other clinical scenarios such as emergency departments.

The clinical trial involves **adult critically ill patients** who require either non-invasive or invasive mechanical ventilation. The study population includes both male and female participants aged 18 years and older, without restrictions on ethnicity. Participants are selected based on their admission to participating intensive care units (ICUs) and are expected to have an ICU stay of more than 72 hours, with a need for respiratory support lasting at least 6 hours. The trial does not focus on a vulnerable population. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet, physical activity, or habits are not specified in the trial data. Key inclusion criteria include the requirement for respiratory support and the acquisition of informed consent. The trial aims to assess the impact of maintaining normoxia on survival rates at ICU discharge compared to conventional oxygen administration strategies.

The clinical trial is designed to evaluate the effects of **oxygen** administration strategies on ICU mortality in adult critically ill patients requiring non-invasive or invasive mechanical ventilation. This is a multicenter, randomized, open-label trial with an estimated duration from November 2019 to January 2025. The trial aims to verify whether strict maintenance of normoxia improves survival compared to conventional, more liberal oxygen administration strategies. The primary endpoint is the ICU mortality rate, defined as the number of deaths for any cause occurring strictly during the ICU stay, censored at day 90. Secondary endpoints include 90-day mortality, new organ dysfunction, infections, ICU free days, cognitive dysfunction, and ICU-acquired weakness.

Participants will be randomly assigned to either a conservative or conventional oxygen administration group. The trial will include an initial screening visit to confirm eligibility, which requires critically ill patients admitted to participant ICUs, aged 18 years or older, with an expected ICU stay of more than 72 hours and requiring respiratory support for at least 6 hours. Informed consent must be obtained. Follow-up visits will be conducted to monitor the participants' health status and adherence to the oxygen administration protocol. The end-of-study visit will assess the primary and secondary endpoints, including survival and health outcomes at ICU discharge.

The expected length of participant involvement is up to 90 days, with the possibility of early termination if the participant withdraws consent, experiences adverse events, or if the investigator deems it necessary for safety reasons. The trial is not categorized as low intervention and is classified as a Phase III study. The study will utilize **nitrous oxide** and oxygen as medicinal gases, administered orally, with a maximum daily and total dose of 100% for a treatment period of up to 12 weeks. The trial's findings will contribute to understanding the optimal oxygen administration strategy for improving survival in critically ill patients.

The clinical trial involves the administration of a **medicinal gas** composed of **nitrous oxide** and **oxygen**. The experimental medication is delivered in a pharmaceutical form identified as PHF763. The active substances, **nitrous oxide** and **oxygen**, are both of chemical origin. **Nitrous oxide**, also known by synonyms such as **nitrogen dioxide**, **dinitrogenii oxidum**, **nitrogen monoxide**, and **laughing gas**, is combined with **oxygen**, also referred to as **oxygenium**. The administration route for this medicinal gas is **oral use**. The dosage is expressed in percentage terms, with a maximum daily dose and total dose amounting to 100% each. The maximum treatment period is set at 12 weeks.

In this study, the experimental treatment is compared against conventional oxygen administration strategies. The trial aims to assess the effects of strict maintenance of normoxia on survival rates in critically ill patients in intensive care units (ICUs). The study does not involve any pediatric formulations, and the medicinal gas is not classified as an orphan drug. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed treatment regimen.

Efficacy in this clinical trial will be assessed by evaluating the primary and secondary endpoints. The primary endpoint is the **ICU mortality rate**, defined as the number of deaths from any cause occurring strictly during the ICU stay, with data censored at day 90. Secondary endpoints include 90-day mortality, the occurrence of new organ dysfunction defined by a SOFA score of 3 or more for the corresponding organ occurring 48 hours after ICU admission, and the incidence of bloodstream, respiratory, and surgical site infections. Additional secondary endpoints are ventilator-free hours (VFHs) and vasopressor-free hours (VasoFHs) during the ICU stay, ICU-free days at 28-day and 90-day intervals, cognitive dysfunction at ICU discharge assessed by the Mini-Mental State Examination (MMSE), and ICU-acquired weakness at ICU discharge evaluated using the Medical Research Council (MRC) Scale.