Cerebral oximetry monitoring versus usual care for extremely preterm infants: a detailed statistical analysis plan for the 2-year follow-up of the participants of the SafeBoosC-III randomised clinical trial

Marie Isabel S Rasmussen; Mathias Lühr Hansen; Adelina Pellicer; Christian Gluud; Eugene Dempsey; Jonathan Mintzer; Simon Hyttel-Sørensen; Anne Marie Heuchan; Cornelia Hagmann; Ebru Ergenekon; Gabriel Dimitriou; Gerhard Pichler; Gunnar Naulaers; Jakub Tkaczyk; Hans Fuchs; Monica Fumagalli; Saudamini Nesargi; Siv Fredly; Tomasz Szczapa; Anne Mette Plomgaard; Bo Mølholm Hansen; Markus Harboe Olsen; Janus Christian Jakobsen; Gorm Greisen

doi:10.1186/s13063-025-09392-7

Cerebral oximetry monitoring versus usual care for extremely preterm infants: a detailed statistical analysis plan for the 2-year follow-up of the participants of the SafeBoosC-III randomised clinical trial

Marie Isabel S Rasmussen^*, Mathias Lühr Hansen, Adelina Pellicer, Christian Gluud, Eugene Dempsey, Jonathan Mintzer, Simon Hyttel-Sørensen, Anne Marie Heuchan, Cornelia Hagmann, Ebru Ergenekon, Gabriel Dimitriou, Gerhard Pichler, Gunnar Naulaers, Jakub Tkaczyk, Hans Fuchs, Monica Fumagalli, Saudamini Nesargi, Siv Fredly, Tomasz Szczapa, Anne Mette PlomgaardBo Mølholm Hansen, Markus Harboe Olsen, Janus Christian Jakobsen, Gorm Greisen

^*Corresponding author af dette arbejde

Abstract

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.

Originalsprog	Engelsk
Tidsskrift	Trials
Vol/bind	27
Udgave nummer	1
Sider (fra-til)	100
ISSN	1745-6215
DOI	https://doi.org/10.1186/s13063-025-09392-7
Status	Udgivet - 5 jan. 2026

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10.1186/s13063-025-09392-7

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Citationsformater

Rasmussen, M. I. S., Hansen, M. L., Pellicer, A., Gluud, C., Dempsey, E., Mintzer, J., Hyttel-Sørensen, S., Heuchan, A. M., Hagmann, C., Ergenekon, E., Dimitriou, G., Pichler, G., Naulaers, G., Tkaczyk, J., Fuchs, H., Fumagalli, M., Nesargi, S., Fredly, S., Szczapa, T., ... Greisen, G. (2026). Cerebral oximetry monitoring versus usual care for extremely preterm infants: a detailed statistical analysis plan for the 2-year follow-up of the participants of the SafeBoosC-III randomised clinical trial. Trials, 27(1), 100. https://doi.org/10.1186/s13063-025-09392-7

Cerebral oximetry monitoring versus usual care for extremely preterm infants: a detailed statistical analysis plan for the 2-year follow-up of the participants of the SafeBoosC-III randomised clinical trial. / Rasmussen, Marie Isabel S ; Hansen, Mathias Lühr; Pellicer, Adelina et al.
I: Trials, Bind 27, Nr. 1, 05.01.2026, s. 100.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Rasmussen, MIS , Hansen, ML, Pellicer, A, Gluud, C, Dempsey, E, Mintzer, J, Hyttel-Sørensen, S, Heuchan, AM, Hagmann, C, Ergenekon, E, Dimitriou, G, Pichler, G, Naulaers, G, Tkaczyk, J, Fuchs, H, Fumagalli, M, Nesargi, S, Fredly, S, Szczapa, T, Plomgaard, AM , Hansen, BM , Olsen, MH , Jakobsen, JC & Greisen, G 2026, 'Cerebral oximetry monitoring versus usual care for extremely preterm infants: a detailed statistical analysis plan for the 2-year follow-up of the participants of the SafeBoosC-III randomised clinical trial', Trials, bind 27, nr. 1, s. 100. https://doi.org/10.1186/s13063-025-09392-7

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title = "Cerebral oximetry monitoring versus usual care for extremely preterm infants: a detailed statistical analysis plan for the 2-year follow-up of the participants of the SafeBoosC-III randomised clinical trial",

abstract = "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.",

keywords = "Humans, Infant, Extremely Premature, Oximetry/methods, Infant, Newborn, Randomized Controlled Trials as Topic, Time Factors, Gestational Age, Neurodevelopmental Disorders/diagnosis, Child, Preschool, Female, Male, Follow-Up Studies, Cerebrovascular Circulation, Child Development, Treatment Outcome, Infant",

author = "Rasmussen, {Marie Isabel S} and Hansen, {Mathias L{\"u}hr} and Adelina Pellicer and Christian Gluud and Eugene Dempsey and Jonathan Mintzer and Simon Hyttel-S{\o}rensen and Heuchan, {Anne Marie} and Cornelia Hagmann and Ebru Ergenekon and Gabriel Dimitriou and Gerhard Pichler and Gunnar Naulaers and Jakub Tkaczyk and Hans Fuchs and Monica Fumagalli and Saudamini Nesargi and Siv Fredly and Tomasz Szczapa and Plomgaard, {Anne Mette} and Hansen, {Bo M{\o}lholm} and Olsen, {Markus Harboe} and Jakobsen, {Janus Christian} and Gorm Greisen",

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day = "5",

doi = "10.1186/s13063-025-09392-7",

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pages = "100",

journal = "Trials",

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TY - JOUR

T1 - Cerebral oximetry monitoring versus usual care for extremely preterm infants

T2 - a detailed statistical analysis plan for the 2-year follow-up of the participants of the SafeBoosC-III randomised clinical trial

AU - Rasmussen, Marie Isabel S

AU - Hansen, Mathias Lühr

AU - Pellicer, Adelina

AU - Gluud, Christian

AU - Dempsey, Eugene

AU - Mintzer, Jonathan

AU - Hyttel-Sørensen, Simon

AU - Heuchan, Anne Marie

AU - Hagmann, Cornelia

AU - Ergenekon, Ebru

AU - Dimitriou, Gabriel

AU - Pichler, Gerhard

AU - Naulaers, Gunnar

AU - Tkaczyk, Jakub

AU - Fuchs, Hans

AU - Fumagalli, Monica

AU - Nesargi, Saudamini

AU - Fredly, Siv

AU - Szczapa, Tomasz

AU - Plomgaard, Anne Mette

AU - Hansen, Bo Mølholm

AU - Olsen, Markus Harboe

AU - Jakobsen, Janus Christian

AU - Greisen, Gorm

PY - 2026/1/5

Y1 - 2026/1/5

N2 - 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.

AB - 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.

KW - Humans

KW - Infant, Extremely Premature

KW - Oximetry/methods

KW - Infant, Newborn

KW - Randomized Controlled Trials as Topic

KW - Time Factors

KW - Gestational Age

KW - Neurodevelopmental Disorders/diagnosis

KW - Child, Preschool

KW - Female

KW - Male

KW - Follow-Up Studies

KW - Cerebrovascular Circulation

KW - Child Development

KW - Treatment Outcome

KW - Infant

U2 - 10.1186/s13063-025-09392-7

DO - 10.1186/s13063-025-09392-7

M3 - Journal article

C2 - 41491571

SN - 1745-6215

VL - 27

SP - 100

JO - Trials

JF - Trials

IS - 1

ER -