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
Authors: König Jochem , Stauch Anette , Engel Corinna , Urschitz Michael S. , Franz Axel R. ,   for the FiO2-C study group, Poets Christian F. , Hummler Helmut , Niemarkt Hendrik J. , Bassler Dirk , Maiwald Christian A. , Bergmann Iris , Weiss Monika , Eichhorn Andreas , Raubuch Michael , Roth Michael , Schuler Birgit , Rötsch Kai , Bai Ruimiao , Fiedler Andreas , Kapp Sonja , Völkl Thomas M. K. , Horsinka Sibylle C. , Hammond Edmondo N. L. , von Buch Christoph , Körner Hans Thorsten , Tröger Birte , Rüdiger Mario , Seipolt Barbara , Mense Lars , Hoehn Thomas , Lohmeier Klaus , Bittrich Hans-Jörg , Roefke Kathrin , Niethammer Klaus , Brenner Britta , Raecke Olaf , Fuchs Hans , Klotz Daniel , Koluch Anna , Idel Sandra , Lübking Laura , Bohnhorst Bettina , Peter Corinna , Jacobi Christoph , Gille Christian , Beedgen Bernd , Heinzmann Tina , Meyer Sascha , Kühr Joachim , Holz Sandra , Welcker Silvia , Thome Ulrich H. , Ackermann Benjamin W. , Gebauer Corinna , Flemmer Andreas W. , Herber-Jonat Susanne , Kley Adelheid , Krüger Marcus , Reber Daniela , Krüger Marcus , Brickmann Christian , Ackermann Kilian , Sandkötter Julia , Masjosthusmann Katja , Schroth Michael , Grillhösl Christian , Kittel Jochen , Michel Holger , Schneider Hans-Christoph , Mayer Anja , Lode Hans-Martin , Lorenz Daniel , Bosk Axel T. , Gausepohl Hans-Jürgen , Lindner Torben , Vochem Matthias , Strahleck Thomas , Neuberger Patrick , Maiwald Christian A. , Arand Jörg , Ehrhardt Harald , Mendler Marc R. , Essers Jochen , Bender Christian , Beckmann Jessica , Mammodova Narmina , Rauch Ralf , Bernbeck Ulrich , Niemarkt Hendrik J. , Mohns Thilo , Mulder Estelle E. M. , van Straaten Henrica L. M. , Hütten Matthias , van Westering-Kroon Elke , Nair Vrinda 
Published: November 2024

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.