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

Abstract

BackgroundInfants 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/designThe 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.DiscussionIn 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 registrationClinicalTrials.org, NCT03770741. Registered on 10 December 2018.

Hemodynamic management of the micropreemie: When inotropes are not enough

“…Additionally, the treatment guided by NIRS reduced the cerebral burden of hypoxia without affecting the EEG or the selected blood biomarkers [17]. This study supports the concept of utilizing end organ perfusion for hemodynamic management of a micropreemie and is now being tested in a large RCT of 1600 infants in >50 NICUs in the SafeBOOSC III study [18,31]. The inclusion allows recruitment up to 6 h of age and the primary outcome is a composite of either death or severe brain injury detected by cranial ultrasound scans.…”

Effects of Freshly Irradiated vs Irradiated and Stored Red Blood Cell Transfusion on Cerebral Oxygenation in Preterm Infants

“…In this physiological study, the clinical significance of the small changes in cerebral oxygenation kinetics was not fully understood. Currently, there are ongoing trials to determine whether reduction in cerebral hypoxia and hyperoxia burdens could improve long-term outcomes in preterm infants . A mean increase in cerebral oxygenation over the 5 days after transfusion by about 2.0% was smaller than the anticipated change of 5.0%.…”

Cerebral near-infrared spectroscopy monitoring versus treatment as usual for extremely preterm infants. A protocol for the SafeBoosC randomised clinical phase III trial

“…The details of how the twin issue will be statistically accounted for iswill be outlined in thea later publication of the SafeBoosC. III statistical and data analysis plan (23). (41,42).…”

“…Full dDetails regarding statistical considerations and detailed statistical plan and data analysis arewill be outlined in a separate report (23), which will be published before the analysis phase begins, without knowledge of any data collected.…”

“…Only one interim analysis is planned, after one-third of trial participants have been randomised. Additional analyses will be decided by the data monitoring and safety committee members (23). Based on primarily safety considerations, the data monitoring and safety committee will make recommendations to the steering group to continue, change, hold, or terminate the trial.…”