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Abstract Background SafeBoosC-III is a pragmatic, multinational clinical trial evaluating cerebral oximetry-guided treatment for extremely preterm infants. In total, 1601 infants were randomised across 70 sites in Asia, Europe, and USA. To enhance data quality and patient care, a web-based training program was implemented for staff. We now report on the processes. Methods All training modules consisted of initial learning material followed by a case-based quiz, with elaborate responses to correct as well as to wrong answers. Modules covered trial introduction, cerebral oximetry monitoring, treatment guidelines, cerebral ultrasound, and Good Clinical Practice. The introduction module was accessible in eight languages on an online platform, while language versions varied for other modules, due to different needs. Certification was earned upon module completion, relevant to the staff category. The training was not mandatory, but for motivational purposes, principal investigators continuously received local certification rate reports. Results A total of 926 out of 2347 staff (39%) obtained certification. Amongst 295 staff who completed the evaluation, 83% rated the program as overall good and 94% found it relevant to clinical practice. Sites exhibited varying certification rates, with 10 at 0%, 43 between 0.1 and 79.9%, and 17 exceeding 80%. There was no correlation between the rate of certification in individual sites and how often the clinical management was changed due to cerebral hypoxia nor a correlation to site-specific estimates of the intervention effect. Conclusion Despite language barriers and a low budget, our web-based training and certification program proved feasible. Only a minority of sites reached 80% certification of staff and an impact on the trial could not be detected. Trial registration The SafeBoosC-III trial is registered at ClinicalTrials.gov NCT03770741. The first participant was randomised in June 2019 and recruitment was completed in December 2021.

Abstract Background The process of obtaining prior informed consent for experimental treatment does not fit well into the clinical reality of acute and intensive care. The therapeutic window of interventions is often short, which may reduce the validity of the consent and the rate of enrolled participants, to delay trial completion and reduce the external validity of the results. Deferred consent and ‘opt-out’ are alternative consent methods. The SafeBoosC-III trial was a randomised clinical trial investigating the benefits and harms of cerebral oximetry monitoring in extremely preterm infants during the first 3 days after birth, starting within the first 6 h after birth. Prior, deferred and opt-out consent were all allowed by protocol. This study aimed to evaluate the use of different consent methods in the SafeBoosC-III trial, Furthermore, we aimed to describe and analyse concerns or complaints that arose during the first 6 months of trial conduct. Methods All 70 principal investigators were invited to join this descriptive ancillary study. Each principal investigator received a questionnaire on the use of consent methods in their centre during the SafeBoosC-III trial, including the possibility to describe any concerns related to the consent methods used during the first 6 months of the trial, as raised by the parents or the clinical staff. Results Data from 61 centres were available. In 43 centres, only prior informed consent was used: in seven, only deferred consent. No centres used the opt-out method only, but five centres used prior and deferred, five used prior, deferred and opt-out (all possibilities) and one used both deferred and opt-out. Six centres applied to use the opt-out method by their local research ethics committee but were denied using it. One centre applied to use deferred consent but was denied. There were only 23 registered concerns during the execution of the trial. Conclusions Consent by opt-out was allowed by the protocol in this multinational trial but only a few investigators opted for it and some research ethics boards did not accept its use. It is likely to need promotion by the clinical research community to unfold its potential.

Abstract 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.

Abstract Background The SafeBoosC project aims to test the clinical value of non-invasive cerebral oximetry by near-infrared spectroscopy in newborn infants. The purpose is to establish whether cerebral oximetry can be used to save newborn infants’ lives and brains or not. Newborns contribute heavily to total childhood mortality and neonatal brain damage is the cause of a large part of handicaps such as cerebral palsy. The objective of the SafeBoosC-IIIv trial is to evaluate the benefits and harms of cerebral oximetry added to usual care versus usual care in mechanically ventilated newborns. Methods/design SafeBoosC-IIIv is an investigator-initiated, multinational, randomised, pragmatic phase-III clinical trial. The inclusion criteria will be newborns with a gestational age more than 28 + 0 weeks, postnatal age less than 28 days, predicted to require mechanical ventilation for at least 24 h, and prior informed consent from the parents or deferred consent or absence of opt-out. The exclusion criteria will be no available cerebral oximeter, suspicion of or confirmed brain injury or disorder, or congenital heart disease likely to require surgery. A total of 3000 participants will be randomised in 60 neonatal intensive care units from 16 countries, in a 1:1 allocation ratio to cerebral oximetry versus usual care. Participants in the cerebral oximetry group will undergo cerebral oximetry monitoring during mechanical ventilation in the neonatal intensive care unit for as long as deemed useful by the treating physician or until 28 days of life. The participants in the cerebral oximetry group will be treated according to the SafeBoosC treatment guideline. Participants in the usual care group will not receive cerebral oximetry and will receive usual care. We use two co-primary outcomes: (1) a composite of death from any cause or moderate to severe neurodevelopmental disability at 2 years of corrected age and (2) the non-verbal cognitive score of the Parent Report of Children’s Abilities-Revised (PARCA-R) at 2 years of corrected age. Discussion There is need for a randomised clinical trial to evaluate cerebral oximetry added to usual care versus usual care in mechanically ventilated newborns. Trial registration The protocol is registered at www.clinicaltrials.gov (NCT05907317; registered 18 June 2023).

Abstract Background In the SafeBoosC-III trial, treatment guided by cerebral oximetry monitoring for the first 72 hours after birth did not reduce the incidence of death or severe brain injury in extremely preterm infants at 36 weeks’ postmenstrual age, as compared with usual care. Despite an association between severe brain injury diagnosed in the neonatal period and later neurodevelopmental disability, this relationship is not always strong. The objective of the SafeBoosC-III follow-up study is to assess mortality, neurodevelopmental disability, or any harm in trial participants at 2 years of corrected age. One important challenge is the lack of funding for local costs for a trial-specific assessment. Methods Of the 1601 infants randomised in the SafeBoosC-III trial, 1276 infants were alive at 36 weeks’ postmenstrual age and will potentially be available for the 2-year follow-up. Inclusion criteria will be enrollment in a neonatal intensive care unit taking part in the follow-up study and parental consent if required by local regulations. We aim to collect data from routine follow-up programmes between the ages of 18 and 30 months of corrected age. If no routine follow-up has been conducted, we will collect informal assessments from other health care records from the age of at least 12 months. A local co-investigator blinded to group allocation will classify outcomes based on these records. We will supplement this with parental questionnaires including the Parent Report of Children’s Abilities—Revised. There will be two co-primary outcomes: the composite of death or moderate or severe neurodevelopmental disability and mean Bayley-III/IV cognitive score. We will use a 3-tier model for prioritisation, based on the quality of data. This approach has been chosen to minimise loss to follow-up assuming that little data is better than no data at all. Discussion Follow-up at the age of 2 years is important for intervention trials in the newborn period as only time can show real benefits and harms later in childhood. To decrease the risk of generalisation and data-driven biased conclusions, we present a detailed description of the methodology for the SafeBoosC-III follow-up study. As funding is limited, a pragmatic approach is necessary. Trial registration ClinicalTrials.gov NCT05134116 . Registered on 24 November 2021.

Introduction It is essential to choose a realistic anticipated intervention effect when calculating a sample size for a randomised clinical trial. Unfortunately, anticipated intervention effects are often inflated, when compared with the ‘true’ intervention effects. This is documented for mortality in critical care trials. A similar pattern might exist across different medical specialties. This study aims to estimate the range of observed intervention effects for all-cause mortality in trials included in Cochrane Reviews, within each Cochrane Review Group.Methods and analysis We will include randomised clinical trials assessing all-cause mortality as an outcome. Trials will be identified from Cochrane Reviews published in the Cochrane Database of Systematic Reviews. Cochrane Reviews will be clustered according to the registered Cochrane Review Group (eg, Anaesthesia, Emergency and Critical Care) and the statistical analyses will be conducted for each Cochrane Review Group and overall. The median relative risk and IQR for all-cause mortality and the proportion of trials with a relative all-cause mortality risk within seven different ranges will be reported (relative risk below 0.70, 0.70–0.79, 0.80–0.89, 0.90–1.09, 1.10–1.19, 1.20–1.30 and above 1.30). Subgroup analyses will explore the effects of original design, sample size, risk of bias, disease, intervention type, follow-up length, participating centres, funding type, information size and outcome hierarchy.Ethics and dissemination Since we will use summary data from trials already approved by relevant ethical committees, this study does not require ethical approval. Regardless of our findings, the results will be published in an international peer-reviewed journal.

Abstract Background Data monitoring of clinical trials is a tool aimed at reducing the risks of random errors (e.g. clerical errors) and systematic errors, which include misinterpretation, misunderstandings, and fabrication. Traditional ‘good clinical practice data monitoring’ with on-site monitors increases trial costs and is time consuming for the local investigators. This paper aims to outline our approach of time-effective central data monitoring for the SafeBoosC-III multicentre randomised clinical trial and present the results from the first three central data monitoring meetings. Methods The present approach to central data monitoring was implemented for the SafeBoosC-III trial, a large, pragmatic, multicentre, randomised clinical trial evaluating the benefits and harms of treatment based on cerebral oxygenation monitoring in preterm infants during the first days of life versus monitoring and treatment as usual. We aimed to optimise completeness and quality and to minimise deviations, thereby limiting random and systematic errors. We designed an automated report which was blinded to group allocation, to ease the work of data monitoring. The central data monitoring group first reviewed the data using summary plots only, and thereafter included the results of the multivariate Mahalanobis distance of each centre from the common mean. The decisions of the group were manually added to the reports for dissemination, information, correcting errors, preventing furture errors and documentation. Results The first three central monitoring meetings identified 156 entries of interest, decided upon contacting the local investigators for 146 of these, which resulted in correction of 53 entries. Multiple systematic errors and protocol violations were identified, one of these included 103/818 randomised participants. Accordingly, the electronic participant record form (ePRF) was improved to reduce ambiguity. Discussion We present a methodology for central data monitoring to optimise quality control and quality development. The initial results included identification of random errors in data entries leading to correction of the ePRF, systematic protocol violations, and potential protocol adherence issues. Central data monitoring may optimise concurrent data completeness and may help timely detection of data deviations due to misunderstandings or fabricated data.

Abstract Background Multiple clinical conditions are associated with cerebral hypoxia/ischaemia and thereby an increased risk of hypoxic-ischaemic brain injury. Cerebral near-infrared spectroscopy monitoring (NIRS) is a tool to monitor brain oxygenation and perfusion, and the clinical uptake of NIRS has expanded over recent years. Specifically, NIRS is used in the neonatal, paediatric, and adult perioperative and intensive care settings. However, the available literature suggests that clinical benefits and harms of cerebral NIRS monitoring are uncertain. As rates of clinically significant hypoxic-ischaemic brain injuries are typically low, it is difficult for randomised clinical trials to capture a sufficiently large number of events to evaluate the clinical effect of cerebral NIRS monitoring, when focusing on specific clinical settings. The aim of this systematic review will be to evaluate the benefits and harms of clinical care with access to cerebral NIRS monitoring versus clinical care without cerebral NIRS monitoring in children and adults across all clinical settings. Methods We will conduct a systematic review with meta-analysis and trial sequential analysis. We will only include randomised clinical trials. The primary outcomes are all-cause mortality, moderate or severe persistent cognitive or neurological deficit, and proportion of participants with one or more serious adverse events. We will search CENTRAL, EMBASE, MEDLINE, and the Science Citation Index Expanded from their inception and onwards. Two reviewers will independently screen all citations, full-text articles, and extract data. The risk of bias will be appraised using the Cochrane risk of bias tool version 2.0. If feasible, we will conduct both random-effects meta-analysis and fixed-effect meta-analysis of outcome data. Additional analysis will be conducted to explore the potential sources of heterogeneity (e.g. risk of bias, clinical setting). Discussion As we include trials across multiple clinical settings, there is an increased probability of reaching a sufficient information size. However, heterogeneity between the included trials may impair our ability to interpret results to specific clinical settings. In this situation, we may have to depend on subgroup analyses with inherent increased risks of type I and II errors. Systematic review registration PROSPERO CRD42020202986 . This systematic review protocol has been submitted for registration in the International Prospective Register of Systematic Reviews (PROSPERO) (http://www.crd.york.ac.uk/prospero) on the 12th of October 2020 and published on the 12th of November 2020 (registration ID CRD42020202986 ).

Abstract Background SafeBoosC-III is an international randomised clinical trial to evaluate the effect of treatment of extremely preterm infants during the first 3 days of life based on cerebral near-infrared spectroscopy (NIRS) monitoring versus treatment and monitoring as usual. To ensure high quality of the trial intervention as well as of patient care, we have developed a multilingual web-based training program to train relevant staff and test their competence. As we enter an under-explored area of e-learning, we have conducted a pilot study on the first of the five modules comprising the web-based training program to test the feasibility of developing such a program for an international trial with limited resources. Methods The module in this study focuses on the principles and practice of NIRS monitoring. The pedagogical idea was to integrate training and certification. One-hundred doctors and nurses from five Neonatal Intensive Care Units across China, Spain and Denmark were invited to participate in the pilot study. Upon completion of the NIRS module, participants were invited to evaluate their experience by completing an online survey. Data from closed-ended questions were analysed using descriptive statistics while data from open-ended questions underwent thematic analysis. Results In total, 81 of 100 invited staff members entered the training module and completed the online survey. The median time and the number of questions to pass the module was 15 minutes and seven questions, respectively. Most staff found the academic level of the learning material and quiz appropriate (85% and 93% of all staff members, respectively), as well as agreeing that the module was relevant to prepare them to ‘use the NIRS device’ (90%). Thematic analysis revealed issues such as a discrepancy between learning material and quiz questions, lack of clarity, and technical issues. Conclusion We provide evidence of the feasibility of developing a multilingual web-based training program for an international trial, despite challenges such as low budget, language barriers and possibly differences in the clinical training of staff. Exploring the integration of training and certification for international trials, the positive results of this study motivate further developments. Trial registration ClinicalTrial.gov, NCT03770741 . Registered 10 December 2018.

The Safeguarding the Brains of our smallest Children (SafeBoosC) project was initially established to test the patient-relevant benefits and harms of cerebral oximetry in extremely preterm infants in the setting of a randomized clinical trial. Extremely preterm infants constitute a small group of patients with a high risk of death or survival with brain injury and subsequent neurodevelopmental disability. Several cerebral oximeters are approved for clinical use, but the use of additional equipment may disturb and thereby possibly harm these vulnerable, immature patients. Thus, the mission statement of the consortium is “do not disturb—unless necessary.” There may also be more tangible risks such as skin breakdown, displacement of tubes and catheters due to more complicated nursing care, and mismanagement of cerebral oxygenation as a physiological variable. Other monitoring modalities have relevance for reducing the risk of hypoxic-ischemic brain injury occurring during acute illness and have found their place in routine clinical care without evidence from randomized clinical trials. In this manuscript, we discuss cerebral oximetry, pulse oximetry, non-invasive electric cardiometry, and invasive monitoring of blood pressure. We discuss the reliability of the measurements, the pathophysiological rationale behind the clinical use, the evidence of benefit and harms, and the costs. By examining similarities and differences, we aim to provide our perspective on the use or non-use of cerebral oximetry in newborn infants during intensive care.

Objective: To evaluate if the number of admitted extremely preterm (EP) infants (born before 28 weeks of gestational age) differed in the neonatal intensive care units (NICUs) of the SafeBoosC-III consortium during the global lockdown when compared to the corresponding time period in 2019.Design: This is a retrospective, observational study. Forty-six out of 79 NICUs (58%) from 17 countries participated. Principal investigators were asked to report the following information: (1) Total number of EP infant admissions to their NICU in the 3 months where the lockdown restrictions were most rigorous during the first phase of the COVID-19 pandemic, (2) Similar EP infant admissions in the corresponding 3 months of 2019, (3) the level of local restrictions during the lockdown period, and (4) the local impact of the COVID-19 lockdown on the everyday life of a pregnant woman.Results: The number of EP infant admissions during the first wave of the COVID-19 pandemic was 428 compared to 457 in the corresponding 3 months in 2019 (−6.6%, 95% CI −18.2 to +7.1%, p = 0.33). There were no statistically significant differences within individual geographic regions and no significant association between the level of lockdown restrictions and difference in the number of EP infant admissions. A post-hoc analysis based on data from the 46 NICUs found a decrease of 10.3%in the total number of NICU admissions (n = 7,499 in 2020 vs. n = 8,362 in 2019).Conclusion: This ad hoc study did not confirm previous reports of a major reduction in the number of extremely pretermbirths during the first phase of the COVID-19 pandemic.Clinical Trial Registration:ClinicalTrial.gov, identifier: NCT04527601 (registered August 26, 2020), https://clinicaltrials.gov/ct2/show/NCT04527601.

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 (

Abstract Background Cerebral oxygenation monitoring may reduce the risk of death and neurologic complications in extremely preterm infants, but no such effects have yet been demonstrated in preterm infants in sufficiently powered randomised clinical trials. The objective of the SafeBoosC III trial is to investigate the benefits and harms of treatment based on near-infrared spectroscopy (NIRS) monitoring compared with treatment as usual for extremely preterm infants. Methods/design SafeBoosC III is an investigator-initiated, multinational, randomised, pragmatic phase III clinical trial. Inclusion criteria will be infants born below 28 weeks postmenstrual age and parental informed consent (unless the site is using ‘opt-out’ or deferred consent). Exclusion criteria will be no parental informed consent (or if ‘opt-out’ is used, lack of a record that clinical staff have explained the trial and the ‘opt-out’ consent process to parents and/or a record of the parents’ decision to opt-out in the infant’s clinical file); decision not to provide full life support; and no possibility to initiate cerebral NIRS oximetry within 6 h after birth. Participants will be randomised 1:1 into either the experimental or control group. Participants in the experimental group will be monitored during the first 72 h of life with a cerebral NIRS oximeter. Cerebral hypoxia will be treated according to an evidence-based treatment guideline. Participants in the control group will not undergo cerebral oxygenation monitoring and will receive treatment as usual. Each participant will be followed up at 36 weeks postmenstrual age. The primary outcome will be a composite of either death or severe brain injury detected on any of the serial cranial ultrasound scans that are routinely performed in these infants up to 36 weeks postmenstrual age. Severe brain injury will be assessed by a person blinded to group allocation. To detect a 22% relative risk difference between the experimental and control group, we intend to randomise a cohort of 1600 infants. Discussion Treatment guided by cerebral NIRS oximetry has the potential to decrease the risk of death or survival with severe brain injury in preterm infants. There is an urgent need to assess the clinical effects of NIRS monitoring among preterm neonates. Trial registration ClinicalTrial.gov, NCT03770741. Registered 10 December 2018.

AimThe aim of this study was to evaluate long-term behavioural and neurodevelopmental complications of neonatal necrotizing enterocolitis at school age.MethodThis was a historic cohort study comparing all surviving children born in Denmark between 1st of January 2002 and 31st of December 2011 with a diagnosis of necrotizing enterocolitis to a group of children without necrotizing enterocolitis, but same gestational age, birth weight and year of birth. Outcomes were investigated through a parental questionnaire. The primary outcome was the Strength and Difficulties Questionnaire score and secondary outcomes were cerebral palsy and impaired head growth.ResultsResponse rates were 50% (163 of 328) and 36% (237 of 652) among children with and without necrotizing enterocolitis, respectively. There was a higher rate of abnormal Strength and Difficulties score (23.9 versus 17.8%), moderate/severe cerebral palsy (3.1 versus 0.9%) and small head circumference for age (11.7 versus 7.2%) among children with necrotizing enterocolitis. However, these differences were all statistically insignificant and did not change significantly by adjustment for potential confounders.ConclusionTo our knowledge, this study includes the largest cohort of necrotizing enterocolitis children evaluated for possible long-term complications at school age. The increased risks of behavioural- and neurodevelopmental impairments were statistically insignificant, moderate in magnitude and may be of little clinical importance for management in the neonatal period or when planning follow-up.