Detailed statistical analysis plan for a secondary Bayesian analysis of the SafeBoosC-III trial: a multinational, randomised clinical trial assessing treatment guided by cerebral oximetry monitoring versus usual care in extremely preterm infants
Authors: Olsen Markus Harboe , Hansen Mathias Lühr , Lange Theis , Gluud Christian , Thabane Lehana , Greisen Gorm , Jakobsen Janus Christian ,   the SafeBoosC-III Trial Group, Pellicer Adelina , El-Kuffash Afif , Bargiel Agata , Alarcon Ana , Hopper Andrew , Truttmann Anita , Hergenhan Anja , Klamer Anja , Curley Anna , Marie Anne , Smits Anne , Memisoglu Asli Cinar , Krolak-Olejnik Barbara , Rzepecka Beata , Gonzales Begona Loureiro , Yasa Beril , Urlesberger Berndt , Morales-Betancourt Catalina , Lecart Chantal , Knöepfli Claudia , Hagmann Cornelia , Healy David , Ergenekon Ebru , Hatzidaki Eleftheria , Bergon-Sendin Elena , Skylogianni Eleni , Rafinska-Wazny Elzbieta , Mastretta Emmanuele , Dempsey Eugene , Valverde Eva , Papathoma Evangelina , Mosca Fabio , Dimitriou Gabriel , Pichler Gerhard , Vento Giovanni , Hahn Gitte Holst , Naulaers Gunnar , Cheng Guoqiang , Fuchs Hans , Ozkan Hilal , De Las Cuevas Isabel , Serrano-Vinuales Itziar , Sadowska-Krawczenko Iwona , Kucera Jachym , Tkaczyk Jakub , Miletin Jan , Sirc Jan , Baumgartner Jana , Mintzer Jonathan , De Buyst Julie , McCall Karen , Tsoni Konstantina , Sarafidis Kosmas , Bender Lars , Lopez Laura Serrano , Wang Le , Thewissen Liesbeth , Huijia Lin , Chalak Lina , Yang Ling , Cornette Luc , Arruza Luis , Wilinska Maria , Baserga Mariana , Rasmussen Marie Isabel Skov , Ybarra Marta Mencia , Palacio Marta Teresa , Stocker Martin , Agosti Massimo , Cetinkaya Merih , Alsina Miguel , Fumagalli Monica , Kadri Munaf M. , Akin Mustafa Senol , Baş Münevver , Koksal Nilgun , Vaccarello Olalla Otero , Baud Olivier , Zafra Pamela , Agergaard Peter , Korcek Peter , Maton Pierre , Sanchez-Salmador Rebeca , del Rio Florentino Ruth , Lauterbach Ryszard , Borregas Salvador Piris , Nesargi Saudamini , Suna Serife , Rao Shashidhar Appaji , Zeng Shujuan , Pisoni Silvia , Hyttel-Sørensen Simon , Kersin Sinem Gulcan , Fredly Siv , Oguz Suna , Marciniak Sylwia , Karen Tanja , Szczapa Tomasz , Nordvik Tone , Karadyova Veronika , Gao Xiaoyan , Xu Xin , Vesoulis Zachary , Peng Zhang , Yin Zhaoqing 
Published: November 2023

Background

Extremely preterm infants have a high mortality and morbidity. Here, we present a statistical analysis plan for secondary Bayesian analyses of the pragmatic, sufficiently powered multinational, trial—SafeBoosC III—evaluating the benefits and harms of cerebral oximetry monitoring plus a treatment guideline versus usual care for such infants.

Methods

The SafeBoosC-III trial is an investigator-initiated, open-label, randomised, multinational, pragmatic, phase III clinical trial with a parallel-group design. The trial randomised 1601 infants, and the frequentist analyses were published in April 2023. The primary outcome is a dichotomous composite outcome of death or severe brain injury. The exploratory outcomes are major neonatal morbidities associated with neurodevelopmental impairment later in life: (1) bronchopulmonary dysplasia; (2) retinopathy of prematurity; (3) late-onset sepsis; (4) necrotising enterocolitis; and (5) number of major neonatal morbidities (count of bronchopulmonary dysplasia, retinopathy of prematurity, and severe brain injury). The primary Bayesian analyses will use non-informed priors including all plausible effects. The models will use a Hamiltonian Monte Carlo sampler with 1 chain, a sampling of 10,000, and at least 25,000 iterations for the burn-in period. In Bayesian statistics, such analyses are referred to as ‘posteriors’ and will be presented as point estimates with 95% credibility intervals (CrIs), encompassing the most probable results based on the data, model, and priors selected. The results will be presented as probability of any benefit or any harm, Bayes factor, and the probability of clinical important benefit or harm. Two statisticians will analyse the blinded data independently following this protocol.

Discussion

This statistical analysis plan presents a secondary Bayesian analysis of the SafeBoosC-III trial. The analysis and the final manuscript will be carried out and written after we publicise the primary frequentist trial report. Thus, we can interpret the findings from both the frequentists and Bayesian perspective. This approach should provide a better foundation for interpreting of our findings.

Trial registration

ClinicalTrials.org, NCT03770741. Registered on 10 December 2018.