Evaluation of Closed-Loop Automatic Control of Inspiratory Fraction of Oxygen on Outcomes in Extremely Preterm Infants: A Randomized Controlled Multicenter Trial

The primary objective of this study is to evaluate the **efficacy** of closed-loop automatic control of the inspiratory fraction of oxygen (FiO2-C) in extremely preterm infants. This is compared to manual adjustments of the inspired oxygen fraction (FiO2) during mechanical ventilation, continuous positive airway pressure (CPAP), or any other positive pressure respiratory support. The clinical relevance of this objective lies in its potential to improve outcomes in preterm infants by optimizing oxygen delivery, thereby reducing complications associated with prematurity such as retinopathy of prematurity (ROP), necrotizing enterocolitis (NEC), bronchopulmonary dysplasia (BPD), and mortality, as well as enhancing neurocognitive outcomes after 24 months.

Secondary objectives include assessing the **safety** of FiO2-C, which is crucial for ensuring that the automatic control system does not introduce additional risks to this vulnerable population.

The clinical trial involves a total of **217 participants**, specifically targeting **preterm infants** with a gestational age at birth ranging from 23+0/7 to 27+6/7 weeks. The study population includes both male and female subjects, and it is acknowledged as a vulnerable population due to the age and health status of the participants. The selection criteria focus on the gestational age at birth, ensuring that only infants within the specified range are included. The trial does not specify any particular lifestyle considerations such as diet or physical activity, as these factors are not applicable to the infant population. The sponsor has not provided additional information regarding the general health status or other lifestyle habits of the participants.

The clinical trial is designed to evaluate the **efficacy** and safety of closed-loop automatic control of the inspiratory fraction of oxygen (FiO2-C) in extremely preterm infants, compared to manual adjustments of the inspired oxygen fraction (FiO2). This is a randomized, controlled, parallel-group, multicenter trial. The trial aims to assess the impact of FiO2-C on primary endpoints, including mortality and complications such as severe retinopathy of prematurity, chronic lung disease, and necrotizing enterocolitis until hospital discharge, as well as neurodevelopmental outcomes at 24 months corrected age. The trial is expected to run from July 2018 to March 2026, with participant involvement lasting up to 24 months.

Participants will be preterm infants with a gestational age at birth between 23+0/7 and 27+6/7 weeks. The study will begin with a screening visit to confirm eligibility based on gestational age criteria. Following randomization, participants will undergo regular follow-up visits to monitor health outcomes and developmental progress. The end-of-study visit will occur at 24 months corrected age, where final assessments of neurodevelopmental status will be conducted. Conditions that may lead to early termination from the study include withdrawal of consent by the guardians or any adverse events that compromise the safety of the participant.

The trial will utilize **oxygen** as the active substance, administered via inhalation. The maximum daily and total dose is set at 100% volume/volume, with a maximum treatment period of 13 weeks. The primary outcomes will be evaluated through a composite of mortality and severe complications, while secondary outcomes will focus on individual components of the primary outcomes and developmental scores. The trial is categorized as a Phase III study, indicating its focus on efficacy and safety in a larger population. The study does not involve a low-intervention approach, ensuring rigorous monitoring and data collection throughout the trial duration.

The clinical trial involves the use of **OXYGEN PH.EUR.**, a medicinal gas, compressed, as the experimental medication. The active substance is **oxygen ph.eur.**, classified under Specified Substance Group 3. The pharmaceutical form of the medication is a compressed gas, intended for **inhalation use**. The dosage is expressed as a percentage volume/volume (% V/V), with a maximum daily dose and total dose amounting to 100% V/V. The maximum treatment period is set at 13 days. This product is of chemical origin and is not a paediatric formulation. The administration of the gas is facilitated through standard infant ventilators, with the aim of assessing the efficacy of closed-loop automatic control of the inspiratory fraction of oxygen (FiO2-C) in extremely preterm infants.

In addition to the experimental treatment, the study includes standard-of-care therapy, which involves manual adjustments of the inspired oxygen fraction (FiO2) during mechanical ventilation, continuous positive airway pressure (CPAP), or any other positive pressure respiratory support. This serves as the comparator treatment to evaluate the primary endpoints of the trial. Participant compliance with the dosing schedule and administration route is monitored to ensure adherence to the study protocol. The trial aims to determine the safety and efficacy of the closed-loop automatic control system compared to manual adjustments alone.

Efficacy in this clinical trial will be assessed by evaluating the effects of closed-loop automatic control of the inspiratory fraction of **oxygen** (FiO2-C) on extremely preterm infants. The primary endpoints for efficacy include two composite outcomes. The first primary outcome is a composite of death, severe retinopathy of prematurity, chronic lung disease of prematurity, and necrotizing enterocolitis until discharge from the hospital. The second primary outcome is a composite of death or neurodevelopmental impairment at 24 months corrected age, which includes motor disability, language or cognitive delay, and severe visual or hearing impairment.

Secondary endpoints will focus on the individual components of the primary outcome variables and developmental scores as measured by the Bayley Scales of Infant Development, 3rd edition. The trial will compare the efficacy of FiO2-C provided in standard infant ventilators, in addition to manual adjustments of the inspired oxygen fraction, against manual adjustments alone during mechanical ventilation, continuous positive airway pressure, or any other positive pressure respiratory support. The trial is designed as a randomized controlled parallel group multicenter study, with the estimated end date set for March 31, 2026.