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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\u2009weeks PMA.<\/jats:p><jats:p>Closed-loop automated control of the inspiratory fraction of oxygen (FiO<jats:sub>2<\/jats:sub>-C) reduces time outside the hemoglobin oxygen saturation (SpO<jats:sub>2<\/jats:sub>) target range, number and duration of hypo- and hyperoxemic episodes and caregivers\u2019 workload. Effects on clinically important outcomes in ELGANs such as ROP, BPD, NEC, NDI and mortality have not yet been studied.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>An outcome-assessor-blinded, randomized controlled, parallel-group trial was designed and powered to study the effect of FiO<jats:sub>2<\/jats:sub>-C (in addition to routine manual control (RMC) of FiO<jats:sub>2<\/jats:sub>), compared to RMC only, on death and severe complications related to hypoxemia and\/or hyperoxemia. 2340 ELGANS with a GA of 23\u2009+\u20090\/7 to 27\u2009+\u20096\/7\u2009weeks will be recruited in approximately 75 European tertiary care neonatal centers. Study participants are randomly assigned to RMC (control-group) or FiO<jats:sub>2<\/jats:sub>-C in addition to RMC (intervention-group). Central randomization is stratified for center, gender and PMA at birth (&lt;\u200926\u2009weeks and\u2009\u2265\u200926\u2009weeks).<\/jats:p><jats:p>FiO<jats:sub>2<\/jats:sub>-C is provided by commercially available and CE-marked ventilators with an FiO<jats:sub>2<\/jats:sub>-C algorithm intended for use in newborn infants. The primary outcome variable (composite of death, severe ROP, BPD or NEC) is assessed at 36\u2009weeks 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\u2009months corrected age.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Short-term studies on FiO<jats:sub>2<\/jats:sub>-C showed improved time ELGANs spent within their assigned SpO<jats:sub>2<\/jats:sub>target range, but effects of FiO<jats:sub>2<\/jats:sub>-C on clinical outcomes are yet unknown and will be addressed in the FiO<jats:sub>2<\/jats:sub>-C trial. This will ensure an appropriate assessment of safety and efficacy before FiO<jats:sub>2<\/jats:sub>-C may be implemented as standard therapy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Trial registration<\/jats:title><jats:p>The study is registered at www.ClinicalTrials.gov:<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/www.ClinicalTrials.gov\">NCT03168516<\/jats:ext-link>, May 30, 2017.<\/jats:p><\/jats:sec>","DOI":"10.1186\/s12887-019-1735-9","type":"journal-article","created":{"date-parts":[[2019,10,21]],"date-time":"2019-10-21T08:33:32Z","timestamp":1571646812000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Effects of closed-loop automatic control of the inspiratory fraction of oxygen (FiO2-C) on outcome of extremely preterm infants \u2013 study protocol of a randomized controlled parallel group multicenter trial for safety and efficacy"],"prefix":"10.1186","volume":"19","author":[{"name":"FiO2-C Study Group","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian A.","family":"Maiwald","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hendrik J.","family":"Niemarkt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian F.","family":"Poets","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael S.","family":"Urschitz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jochem","family":"K\u00f6nig","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helmut","family":"Hummler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dirk","family":"Bassler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Corinna","family":"Engel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5066-0857","authenticated-orcid":false,"given":"Axel R.","family":"Franz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2019,10,21]]},"reference":[{"issue":"2","key":"1735_CR1","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1016\/j.resp.2013.05.026","volume":"189","author":"JM Di Fiore","year":"2013","unstructured":"Di Fiore JM, Martin RJ, Gauda EB. 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Patients can only be enrolled into the study after informed written consent was given by both parents\/guardians (by the only parent\/guardian in case of single-parent\/guardian families). In case parents are less than 18\u2009years of age, the relevant legal guardian(s) of the child has\/have to sign the informed consent.At the time of publication, the FiO<sub>2<\/sub>-C trial is currently conducted in Germany and may expand to other countries, once ethical and (if appropriate) authority approval has been obtained.<i>Ethics: Ethics Committee at the University Hospital Tuebingen, reference no. 170\/2018AMG1, approved;<\/i><i>Authority: Bundesinstitut f\u00fcr Arzneimittel und Medizinprodukte (BfArM),<\/i> reference no. 4042695 approved conduct.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"C.F. Poets received speaker honoraria from Masimo Inc. and Sentec. All other contributors declare that they do not have competing interest.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"363"}}