BACKGROUND: The SafeBoosC project aims to test the clinical value of non-invasive cerebral oximetry by near-infrared spectroscopy in newborn infants. The purpose is to establish whether cerebral oximetry can be used to save newborn infants' lives and brains or not. Newborns contribute heavily to total childhood mortality and neonatal brain damage is the cause of a large part of handicaps such as cerebral palsy. The objective of the SafeBoosC-IIIv trial is to evaluate the benefits and harms of cerebral oximetry added to usual care versus usual care in mechanically ventilated newborns. METHODS/DESIGN: SafeBoosC-IIIv is an investigator-initiated, multinational, randomised, pragmatic phase-III clinical trial. The inclusion criteria will be newborns with a gestational age more than 28 + 0 weeks, postnatal age less than 28 days, predicted to require mechanical ventilation for at least 24 h, and prior informed consent from the parents or deferred consent or absence of opt-out. The exclusion criteria will be no available cerebral oximeter, suspicion of or confirmed brain injury or disorder, or congenital heart disease likely to require surgery. A total of 3000 participants will be randomised in 60 neonatal intensive care units from 16 countries, in a 1:1 allocation ratio to cerebral oximetry versus usual care. Participants in the cerebral oximetry group will undergo cerebral oximetry monitoring during mechanical ventilation in the neonatal intensive care unit for as long as deemed useful by the treating physician or until 28 days of life. The participants in the cerebral oximetry group will be treated according to the SafeBoosC treatment guideline. Participants in the usual care group will not receive cerebral oximetry and will receive usual care. We use two co-primary outcomes: (1) a composite of death from any cause or moderate to severe neurodevelopmental disability at 2 years of corrected age and (2) the non-verbal cognitive score of the Parent Report of Children's Abilities-Revised (PARCA-R) at 2 years of corrected age. DISCUSSION: There is need for a randomised clinical trial to evaluate cerebral oximetry added to usual care versus usual care in mechanically ventilated newborns. TRIAL REGISTRATION: The protocol is registered at www. CLINICALTRIALS: gov (NCT05907317; registered 18 June 2023).

2 Department of Neonatology Neonatal Biophysical Monitoring and Cardiopulmonary Therapies Research Unit Poznan University of Medical Sciences Poznan Poland

Copenhagen Trial Unit Centre for Clinical Intervention Research The Capital Region Copenhagen University Hospital ─ Rigshospitalet Copenhagen Denmark

Department of Clinical Sciences and Community Health University of Milan Milan Italy

Department of Intensive Care Copenhagen University Hospital Rigshospitalet Copenhagen Denmark

Department of Neonatology Children's University Hospital of Zürich Zurich Switzerland

Department of Neonatology Copenhagen University Hospital ─ Rigshospitalet Copenhagen Denmark

Department of Neonatology La Paz University Hospital Madrid Spain

Department of Neonatology Oslo University Hospital Oslo Norway

Department of Neonatology Royal Hospital for Children Glasgow UK

Department of Neonatology University Hospital Leuven Louvain Belgium

Department of Neonatology University Hospital Motol Prague Czech Republic

Department of Pediatrics Medical University of Graz Graz Austria

Department of Regional Health Research The Faculty of Health Sciences University of Southern Denmark Odense Denmark

Division of Neonatology and Pediatric Intensive Care Medicine Center for Pediatrics and Adolescents Medicine Medical Center ─ University of Freiburg Freiburg Germany

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milan Milan Italy

Infant Centre and Department of Paediatrics and Child Health University College Cork Cork Ireland

NICU Department of Paediatrics University General Hospital of Patras Patras Greece

St Johns Medical College Hospital Bengaluru India

The Department of Pediatrics Division of Newborn Medicine Mountainside Medical Center Montclair NJ USA

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NCT05907317