Effects of closed-loop automatic control of the inspiratory fraction of oxygen (FiO₂-C) on outcome of extremely preterm infants - study protocol of a randomized controlled parallel group multicenter trial for safety and efficacy

Background: Most extremely low gestational age neonates (ELGANS, postmenstrual age at birth (PMA) < 28 completed weeks) require supplemental oxygen and experience frequent intermittent hypoxemic and hyperoxemic episodes. Hypoxemic episodes and exposure to inadequately high concentrations of oxygen are associated with an increased risk of retinopathy of prematurity (ROP), chronic lung disease of prematurity (BPD), necrotizing enterocolitis (NEC), neurodevelopmental impairment (NDI), and death beyond 36 weeks PMA. Closed-loop automated control of the inspiratory fraction of oxygen (FiO₂-C) reduces time outside the hemoglobin oxygen saturation (SpO₂) target range, number and duration of hypo- and hyperoxemic episodes and caregivers' workload. Effects on clinically important outcomes in ELGANs such as ROP, BPD, NEC, NDI and mortality have not yet been studied.

Methods: An outcome-assessor-blinded, randomized controlled, parallel-group trial was designed and powered to study the effect of FiO₂-C (in addition to routine manual control (RMC) of FiO₂), compared to RMC only, on death and severe complications related to hypoxemia and/or hyperoxemia. 2340 ELGANS with a GA of 23 + 0/7 to 27 + 6/7 weeks will be recruited in approximately 75 European tertiary care neonatal centers. Study participants are randomly assigned to RMC (control-group) or FiO₂-C in addition to RMC (intervention-group). Central randomization is stratified for center, gender and PMA at birth (< 26 weeks and ≥ 26 weeks). FiO₂-C is provided by commercially available and CE-marked ventilators with an FiO₂-C algorithm intended for use in newborn infants. The primary outcome variable (composite of death, severe ROP, BPD or NEC) is assessed at 36 weeks PMA (or, in case of ROP, until complete vascularization of the retina, respectively). The co-primary outcome variable (composite outcome of death, language/cognitive delay, motor impairment, severe visual impairment or hearing impairment) is assessed at 24 months corrected age.

Discussion: Short-term studies on FiO₂-C showed improved time ELGANs spent within their assigned SpO₂ target range, but effects of FiO₂-C on clinical outcomes are yet unknown and will be addressed in the FiO₂-C trial. This will ensure an appropriate assessment of safety and efficacy before FiO₂-C may be implemented as standard therapy.

Trial registration: The study is registered at www.ClinicalTrials.gov: NCT03168516 , May 30, 2017.