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. 2024 Nov 12;25(1):756.
doi: 10.1186/s13063-024-08615-7.

Statistical analysis plan for the FiO2-C trial: effects of closed-loop automatic control of the inspiratory fraction of oxygen (FiO2-C) on outcomes of extremely preterm infants-a randomized-controlled parallel group multicentre trial for safety and efficacy

Jochem König #  1 , Anette Stauch #  2 , Corinna Engel  2 , Michael S Urschitz #  1 , Axel R Franz #  3   4 ; FiO2-C study group
Collaborators, Affiliations

Statistical analysis plan for the FiO2-C trial: effects of closed-loop automatic control of the inspiratory fraction of oxygen (FiO2-C) on outcomes of extremely preterm infants-a randomized-controlled parallel group multicentre trial for safety and efficacy

Jochem König et al. Trials. .

Abstract

Background: Extremely low gestational age neonates (ELGANs, i.e. those born before 28 weeks postmenstrual age (PMA)) often require supplemental oxygen and frequently experience intermittent hypo- and hyperoxemic episodes. Exposure to episodes with inadequate oxygen concentrations has been shown to be associated with an increased risk of retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), neurodevelopmental impairment (NDI) and death. Closed-loop automatic control of the inspiratory fraction of oxygen (FiO2-C) reduces number and duration of hypo- and hyperoxemic episodes in ELGANs. Its impacts on clinically important short- and long-term outcomes such as ROP, BPD, NEC, NDI and mortality have not yet been studied.

Methods: An outcome-assessor-blinded, multicentre, randomized-controlled, parallel-group trial for superiority was designed to study the effects of FiO2-C (provided by standard infant ventilators) in addition to routine manual control (RMC) during respiratory support, compared to RMC only, on short- and long-term clinical outcomes in ELGANs. Two co-primary composite outcomes were defined: (i) death, severe ROP, BPD or NEC, assessed at 36 weeks PMA or, in case of ROP, until complete vascularization of the retina; (ii) death or NDI (defined as language/cognitive delay, motor impairment, severe visual impairment or hearing impairment), assessed at 2 years corrected age.

Results: Primary outcomes will be compared between the two intervention groups using a Cochran-Mantel-Haenszel test. The factors considered for randomization (centre, sex and gestational age at birth (< 26 weeks and ≥ 26 weeks)) will be used to define strata. Results will be presented as adjusted odds ratios with two-sided 95% and 97.5% confidence intervals and two-sided p values.

Conclusions: The statistical analyses for the FiO2-C trial were defined in the study protocol and specified in detail in this statistical analysis plan published prior to any statistical analysis. This is in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines.

Trial registration: ClinicalTrials.gov NCT03168516. Registered on May 30, 2017.

Keywords: Closed-loop automatic control of the inspiratory fraction of oxygen (FiO2-C); Infant; Intermittent hypoxemia and hyperoxemia; Oxygen; Premature.

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Conflict of interest statement

Declarations Ethics approval and consent to participate The FiO2-C trial was performed in accordance with the Declaration of Helsinki and the guidelines of Good Clinical Practice. Parents or guardians of the participating infants were informed about the trial and their written informed consent was required before inclusion.The study was approved by all ethics committees of the participating institutions; it was also approved by the German authority BfArM (Bundesinstitut für Arzneimittel und Medizinprodukte) as it was conducted as pharmaceutical trial in Germany with the investigational medicinal product ‘oxygen’. The study was also a medicinal product study within the intended use of studied devices.Ethics:• Ethics Committee of Northwest Woman and Children Hospital, Xi’an, China; Document No. 21-041—18th Oct 2021• Ethics Committee at the University Hospital Tübingen, reference no. 170/2018AMG1, approved; Adviescommissie Onderzoek Máxima Medisch Centrum, Veldhoven, the Netherlands METC-No. w18.061, CCMO-No.: N165766.015.l8—1 April 2019• West of Scotland Research Ethics Service, Paisley, UK; IRAS Project ID: 317261, REC-reference 22/WS/0143—22 November 2022, Health Research Authority approval IRAS Project ID: 317261—25 November 2022Authority:• BfArM, reference no. 4042695 approved conduct Consent for publication All authors and collaborators gave consent for publication. No personal data of participants is presented here. Competing interests All contributors declare that they do not have competing interests.

References

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