BACKGROUND: The SafeBoosC-III trial investigated treatment guided by cerebral oximetry monitoring for the first 72 h after birth in extremely preterm infants (born below 28 weeks gestational age) and showed no effects on mortality or severe brain injury at 36 weeks' postmenstrual age versus usual care. As severe brain injury in the neonatal period is not a strong predictor of long-term neurodevelopmental outcomes, the prospectively planned SafeBoosC-III follow-up study aims to assess the long-term benefits and harms of the experimental intervention versus usual care at 2 years of corrected age. The statistical analysis plan presented here was defined before data collection was complete and outlines our approach for analysing outcomes in the SafeBoosC-III follow-up study. METHODS: The co-primary outcomes were (1) a composite of death or moderate-to-severe neurodevelopmental disability and (2) the mean Bayley-III/IV cognitive score. We employed a 3-tier data model, incorporating routine clinical follow-up, parental questionnaires, and informal assessments to minimise missing data. All randomised participants with available data were included in all analyses. Mixed-effect linear and logistic regression was used to analyse the dichotomous and continuous co-primary outcomes, respectively. Sensitivity analyses were conducted to address missing data and assess the robustness of our findings. DISCUSSION: This statistical analysis plan aimed to ensure transparency and reduce the risk of outcome reporting bias. By including dichotomous and continuous co-primary outcomes, we aimed to provide a comprehensive evaluation of the intervention's effect on long-term benefits and harms. TRIAL REGISTRATION: ClinicalTrials.gov NCT05134116 . Registered on November 24, 2021.

2 Department of Neonatology Poznan University of Medical Sciences Poznań Poland

Centre for Clinical Intervention Research The Capital Region Copenhagen Trial Unit 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 Gazi University Hospital Yenimahalle Ankara Turkey

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 Neuroanaesthesiology The Neuroscience Centre Copenhagen University Hospital Rigshospitalet Copenhagen Denmark

Department of Paediatrics and Adolescent Medicine Copenhagen University Hospital Hilleroed Denmark

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

Department of Pediatrics Hvidovre University Hospital Hvidovre Denmark

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

NICU Department of Pediatrics University General Hospital of Patras Patras Greece

St Johns Medical College Hospital Bengaluru India

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NCT05134116