Detailed statistical analysis plan for the SafeBoosC III trial: a multinational randomised clinical trial assessing treatment guided by cerebral oxygenation monitoring versus treatment as usual in extremely preterm infants
Mathias Lühr Hansen,
Adelina Pellicer,
Christian Gluud,
Eugene Dempsey,
Jonathan Mintzer,
Simon Hyttel-Sorensen,
Anne Marie Heuchan,
Cornelia Hagmann,
Gabriel Dimitriou,
Gerhard Pichler,
Gunnar Naulaers,
Guoqiang Cheng,
Ana Vilan,
Jakub Tkaczyk,
Karen B. Kreutzer,
Monica Fumagalli,
Olivier Claris,
Siv Fredly,
Tomasz Szczapa,
Theis Lange,
Janus Christian Jakobsen,
Gorm Greisen
Affiliations
Mathias Lühr Hansen
Department of Neonatology, Rigshospitalet, Copenhagen University Hospital
Adelina Pellicer
Department of Neonatology, La Paz University Hospital
Christian Gluud
Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital
Eugene Dempsey
Infant Centre and Department of Paediatrics and Child Health, University College Cork
Jonathan Mintzer
Division of Neonatal-Perinatal Medicine, Mountainside Medical Center
Simon Hyttel-Sorensen
Department of Neonatology, Rigshospitalet, Copenhagen University Hospital
Anne Marie Heuchan
Department of Neonatology, Royal Hospital for Children
Cornelia Hagmann
Department of Neonatology, Children’s University Hospital of Zürich
Gabriel Dimitriou
NICU, Department of Pediatrics, University General Hospital of Patras
Gerhard Pichler
Department of Pediatrics, Medical University of Graz
Gunnar Naulaers
Department of Neonatology, University Hospital Leuven
Guoqiang Cheng
Department of Neonatology, Children’s Hospital of Fudan University
Ana Vilan
Department of Neonatology, Centrohospitalar Universitário de São João
Jakub Tkaczyk
Department of Neonatology, University Hospital Motol
Karen B. Kreutzer
Department of Neonatology, University Children’s Hospital Tuebingen
Monica Fumagalli
Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico Milan
Olivier Claris
Department of Neonatology, Hospices Civil De Lyon
Siv Fredly
Department of Neonatology, Oslo University Hospital
Tomasz Szczapa
Department of Neonatology, Poznan University of Medical Sciences
Theis Lange
Section of Biostatistics, Department of Publich Health, Copenhagen University
Janus Christian Jakobsen
Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital
Gorm Greisen
Department of Neonatology, Rigshospitalet, Copenhagen University Hospital
Abstract Background Infants born extremely preterm are at high risk of dying or suffering from severe brain injuries. Treatment guided by monitoring of cerebral oxygenation may reduce the risk of death and neurologic complications. The SafeBoosC III trial evaluates the effects of treatment guided by cerebral oxygenation monitoring versus treatment as usual. This article describes the detailed statistical analysis plan for the main publication, with the aim to prevent outcome reporting bias and data-driven analyses. Methods/design The SafeBoosC III trial is an investigator-initiated, randomised, multinational, pragmatic phase III trial with a parallel group structure, designed to investigate the benefits and harms of treatment based on cerebral near-infrared spectroscopy monitoring compared with treatment as usual. Randomisation will be 1:1 stratified for neonatal intensive care unit and gestational age (lower gestational age (< 26 weeks) compared to higher gestational age (≥ 26 weeks)). The primary outcome is a composite of death or severe brain injury at 36 weeks postmenstrual age. Primary analysis will be made on the intention-to-treat population for all outcomes, using mixed-model logistic regression adjusting for stratification variables. In the primary analysis, the twin intra-class correlation coefficient will not be considered. However, we will perform sensitivity analyses to address this. Our simulation study suggests that the inclusion of multiple births is unlikely to significantly affect our assessment of intervention effects, and therefore we have chosen the analysis where the twin intra-class correlation coefficient will not be considered as the primary analysis. Discussion In line with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines, we have developed and published this statistical analysis plan for the SafeBoosC III trial, prior to any data analysis. Trial registration ClinicalTrials.org, NCT03770741. Registered on 10 December 2018.
