This trial will be conducted in compliance with the guidelines of Tthe Declaration of Helsinki in its latest form, the International Conference on Harmonization Good Clinical Practice guidelines (20), and applicable national regulations and directives. No clinical site will start randomiszation before their eligibility has been confirmed and the protocol has been approved by the relevant ethics committee. Any amendments to the protocol will need approval by the Steering Committee and ethical review before being implemented. Written informed consent will be obtained by a qualified physician or nurse connected to the trial, prior to randomiszation of any participant, unless the Neonatal Intensive Care Unit (NICU) uses deferred informed consent or prior assent as consent methods (see below). These consent procedures will be approved by local ethics committees or institutional review boards.
The objective of this trial is to examine the benefits and harms of treatment based on NIRS monitoring compared with treatment as usual (standard monitoring and treatment) to reduce cerebral hypoxia during the first 72 hours of life in extremely preterm infants. The hypothesis is that the application of treatment based on NIRS monitoring will decrease a composite outcome of severe brain injury or death at 36 weeks postmenstrual age.
Roles and responsibilities for committees
SafeBoosC -III is led by a Steering Committee comprising the coordinating investigator (GG), the national coordinators, and two representatives from the Copenhagen Trial Unit (CG and JCJ). Decisions will be by a simple majority. The executive committee will be responsible for the day-to-day management and will comprise the coordinating investigator, the trial manager (MLH), co-investigators (AP, GD, JM, SHS), and the two representatives from the Copenhagen Trial Unit (CG and JCJ).
There will be one principal investigator in each department, responsible for obtaining ethical approval, organisze local Good Clinical Practice Monitoring, inform clinical staff members on the web-based training and certification program, recruitment of patients, and data entry into the patientCase rReport fForms. Copenhagen Trial Unit will be responsible for randomiszation, development of the patientCase rReport fForms and central monitoring.
This is an investigator-initiated multinational randomiszed, pragmatic phase III clinical trial with a two-parallel group design that will enrol 1,600 extremely preterm infants from 20 countries (Austria, Belgium, China, Czech Republic, Denmark, England, France, Germany, Greece, India, Ireland, Italy, Netherlands, Norway, Poland, Portugal, Switzerland, Scotland, Spain, Turkey, USA). A list of all study sites will be available at www.safeboosc.eu before enrolment. It is an open label trial, but parts will be conducted blinded to intervention (see 'Blinding’).).
The trial has been designed according to the SPIRIT guidelines (see figure 1 and appendix 1) (21).
The inclusion criteria will beconsist of infants born before 28 weeks postmenstrual age and signed parental informed consent, unless the NICU has chosen to use ‘opt-out’ or deferred consent as their consent method.
The exclusion criteria will be noconsist of missing signed parental informed consent (or if the ‘opt-out’ method is used, lack of a record that the clinical staff have explained the trial and the ‘opt-out’ consent process to parents, and/or a record in the infant’s clinical file of 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 monitoring within six hours after birth.
Participation in other trials
Participants included in the SafeBoosC-III trial can participate in any other study or intervention on the condition, that itthe trial does not 1) allow clinical staff access to cerebral oximetry in the control group, from inclusion in SafeBoosC III, to the end of intervention period 72 hours after birth, andor 2) exclude a treatment that would be clearly indicated by the SafeBoosC-III evidence-based treatment guideline during the intervention period. All partners are encouraged to design ancillary studies and draw on data collected by SafeBoosC -III, if not compromising the blinding of assessors or the equipoise of the trial. Ancillary studies must seek approval by the SafeBoosC Steering Committee.
Participant discontinuation and withdrawal
The participants’ parents are free to withdraw their infant’s participation from the intervention or from the SafeBoosC-III trial entirely at any time, and this will not have any consequences for the infant’s further treatment. Reasons for discontinuation, if providedoffered by the parents, will be documented. When possible, the parents will be asked if they will allow their child’s data to be used in the analysis.
The attending clinician can withdraw the any participant from the trial intervention at any time in case there are safety concerns. Reasons for withdrawal will be documented. There are no pre-specified criteria for discontinuation of participants from the trial. Discontinuation of participants from the trial will not result in replacement with new participants.
In this phase III trial, we have prolonged the enrolment period from three hours, as used in SafeBoosC II, to six hours after birth, although we recommend that monitoring isbe started as early as possible to help decision-making when cardio-respiratory support is established. This six-hour window is similar to what is currently used for another neonatal intervention—therapeutic hypothermia for hypoxic-ischaemic encephalopathy after birth asphyxia (22). We believe this will make the trial relevant in settings where antenatal transfer to a perinatal centreer is used less often, and thereby increase recruitment feasibility without compromising the effect of NIRS monitoring.
Extremely preterm infants are expected to be included at about 50 NICUs in about 20 countries. The 93 units that took part in a previous funding application for the SafeBoosC- III trial had, have rates of admission of between 15 and 90 extremely preterm infants per year. The total admissions were estimated to be 3,000 infants per year. We The trial should therefore, have a good chance of recruiting 1,600 participants within two years.Sites that expect to enroll at least 15 participants per year within the two-year recruitment period will take part. Inclusion of new NICUs after the common start date will be done ad hoc, considering expected contributions and time remaining.
Infants will be centrally randomiszed to either the experimental or control group with a 1:1 allocation ratio at the Copenhagen Trial Unit using a web-based randomiszation application. The allocation sequence will be computer-generated with varying block sizes. It will be concealed for all investigators, as the web-based program will not release the randomisation until the patient has been included in the trial and stratified by NICU and gestational age group (lower gestational age (<26 weeks) compared to higher gestational age (≥26 weeks)). Twin couples will be randomiszed to the same group, either intervention or control. In centres, where only one or two NIRS devices are available, it may not be possible to include all infants from twin births. Thus, only one of a pair of twins may be included. The sibling enrolled will be the one born last.
Due to the nature of the experimental intervention, it is not possible to blind the clinical staff, the infant, orand the parents to study group allocation. Outcome assessment of mortality will not primarily be blinded but the mortality data will be checked by Good Clinical Practice via source data verification in all patients. The diagnosis and classification of brain injury along with the entry of these data into the patient repord fonline Case Report Form will be conducted by an assessor blinded to study group allocation. Data entry procedures will depend on local factors and will be agreed on between the principal investigator at each NICU and the coordinating investigator. The data managers, statisticians, and those drawing conclusions will be blinded to study grouptreatment allocation. Details on this iswill be described in a report on the statistical analysis plan (23) (see ‘statistical analysis plan’).
Experimental group participants will undergo cerebral NIRS monitoring applied as soon as possible after arrival in the NICU and always within six hours after delivery and receive treatment based on NIRS monitoring during the first 72 hours of life. These treatments will be based on the same evidence-based guideline as used in the SafeBoosC- II trial (see below) (24).
The control group participants will not receive any cerebral NIRS monitoring and will be monitored and treated according to local guidelines and clinical practices.
Treatment guideline based on NIRS monitoring
An evidence-basedtreatment guideline recommending modification of cardio-respiratory support or interventions aiming at increasing blood oxygen transport capacity, will be followed in order to maintain cerebral oxygenation above 55% (see Appendix 2) (24). As the SafeBoosC- II trial showed a low burden of hyperoxia unaffected by monitoring-based interventions, the SafeBoosC- III trial will not target cerebral hyperoxia and therefore the interventions for hyperoxia have been removed from this trial’s treatment guidelines. The same SafeBoosC- III treatment guideline will be used in all participating centres.
All commercially available cerebral oximeters that are approved for clinical use in newborns may be used. The aim is to use several different devices to generate results of generic value. There are now sevensix commercially available devices that are approved for clinical use in different countries:; INVOS (Medtronics, Minneapolis, MN, USA);, NIRO (Hamamatsu, Hamamatsu City, Japan);, Fore-Sight (CAS Medical, Branford, CT, USA); Sensmart (Nonin Medical, Plymouth, MN, USA); O3 (Masimo, Irvine, CA, USA);, Egos (Enginmed, Suzhou, China); and Oxyprem 1.4 (Oxyprem, Zürich, Switzerland). The normal range of rStO2 was determined with the INVOS adult sensor (17) and defined the rStO2 thresholds for intervention used in the SafeBoosC- II trial. Each eligible device in SafeBoosC III will be compared with the INVOS adult sensor in a blood lipid phantom and device-specific thresholds will be determined (25), before being used in the SafeBoosC- III trial.
Training and certification
Clinical staff will be offered a web-based training and certification program consisting of short modules covering the trial rationale; NIRS and monitoring of cerebral oxygenation; the treatment guideline; cerebral ultrasound and classification of brain injury; and Good Clinical Practice (www.safeboosc.eu). The use of these modules and the completion rate will be monitored and reported with the results of the trial. Sites with low compliance may be selected for subgroup analyses.
NIRS monitoring will start within six postnatal hours and the intervention will last until 72 hours of life. Each participant will be followed up at 36 weeks postmenstrual age.
To allow comparisons between intervention groups, additional baseline clinical data will be obtained, including birth weight, gestational age, mechanical ventilation, and use of cardiovascular support. Data will be drawn from clinical records at 72 hours of age, and 36 weeks postmenstrual age, the same time as the primary and exploratorysecondary outcomes are assessed and documented. The majority of these selectedchosen variables are usually reported to neonatal network databases such as the Vermont Oxford Network (26).
Primary and exploratory outcomes will be assessed at 36 weeks postmenstrual age as documented in the infants’ clinical files. If the infant in question has been discharged to a step-down unit, data will be sought from that unit, and if this is not possible, data will be used until the date of discharge to the step-down unit. In case in which the last entry in an infant’s clinical file is prior to 36+0 weeks postmenstrual age, for example due to discharge home, the date of discharge will be reported in the online patient Case rReport fForm.
The primary outcome is a composite of either death or severe brain injury detected on any one of a series of cranial ultrasound scans that are routinely performed in extremely premature infants. Severe brain injury is defined as grade III or IV intraventricular haemorrhage (IVH), cystic periventricular leukomalacia (cPVL), cerebellar haemorrhage, post-haemorrhagic ventricular dilatation, or cerebral atrophy. The exploratory outcomes will be bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP) stage 3+, necrotiz
sing enterocolitis (NEC) stage 2 or higher using the modified Bell’s staging system and/or focal intestinal perforation, and late-onset sepsis (>72 hours after birth) defined as being treated with antibiotics for a minimum of five days, and a count of the presence of three major neonatal morbidities (BPD, ROP and severe brain injury). All diagnoses, except severe brain injury, are made as per routine in each NICU.
Statistical plan and data analysis
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.
We have calculated our sample size based on the composite primary outcome, with an alpha of 5%, a power of 90%, and a ratio of experimental trial participants to control trial participants of 1:1.
In the 2009 EuroNeoNet report, the mortality among extremely preterm infants was 33% and severe intracranial haemorrhage was observed in 15%. In the SafeBoosC-II trial, the proportion of participants with the composite primary outcome was approximately 34% in the control group and 26% in the experimental group (27).
Based on the above, a total of 1600 infants would be required to demonstrate a similar relative risk reduction of 22%, with an alpha of 5%, and a power of 90%.
In SafeBoosC II, the intra-class correlation coefficient (ICC) of the burden of hypoxia within pairs of twins was negligible. The ICC for death before discharge and for intraventricular haemorrhage grade 3 or 4 have previously been estimated to 0.00 (95% confidence interval (CI) –0.04 to 0.02) and –0.01 (95% CI –0.05 to 0.01) (28). These values correlate to a design effect very close to one (28). Based on this, we have not included twin ICC in the sample size estimation.
Analysis of the primary outcome
The primary outcome analysis will be made on the intention-to-treat population, and we will use mixed-effect logistic regression. ‘Site’ will be included as a random effect (intercept) and the remaining stratification variables, age and intervention groups, will be included as fixed effects. In addition, we will perform a range of pre-defined sensitivity analyses to inform the interpretation of the results of the primary analysis (23)
Predefined serious adverse reactions (SAR) will be reported at 72-hours after birth and serious adverse events (SAE) will be reported at 36 weeks’ postmenstrual age. Expedited reporting will not be used. An independent data monitoring and safety committee is established to monitor mortality, neonatal morbidity, and SARs with ‘certain’ or ‘probably/likely’ relationships with the cerebral NIRS oximeter and/or the application of the evidence-basedtreatment guideline or any of its interventions. They include two neonatologists and a biostatistician. The charter for the data monitoring and safety committee will be written prior to the enrolment of trial participants. The trial will not be stopped early because of futility, and Lan-DeMets sequential monitoring boundaries will be used at each interim analysis to assess if thresholds for statistical significance of benefits or harms have been crossed (29). 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. The recommendations will be guided by the statistical monitoring guidelines, which is defined in the data monitoring and safety committee charter (available from www.safeboosc.eu).
The preterm population is at high risk for serious adverse events and most adverse events may be of a serious nature with or without relevance to the SafeBoosC-III trial interventions. Both groups of the trial are expected to have a high proportion of serious adverse events. It is therefore neitherot feasible, nor meaningful, to record and report all adverse events. Therefore, we have decided only to record and report predefined SAEs and SARs. The SAEs include any event of death, severe brain injury, necrotiszing enterocolitis, bronchopulmonary dysplasia, retinopathy of prematurity, or sepsis as defined under primary and exploratory outcomes. These predefined SAEs have been chosen since they cover the major neonatal morbidities seen in this study population. The SARs are defined as any adverse reaction related to the trial intervention that results in death, is life-threatening, requires prolongation of existing hospitaliszation, results in persistent or significant disability or incapacity, or requires intervention to prevent permanent impairment or damage. This includes physical mishaps associated with managing the oximeter and sensors, such as severe skin damage, critical displacement of endotracheal tubes or endovascular lines, and clinical mismanagement based on cerebral oximetry monitoring data, such as interventions aiming at improving cardiovascular status, respiratory status and/or oxygen transport.
All participants’ data are protected in accordance with the Danish Act on the processing of personal data and the Danish Health Act. The Copenhagen Trial Unit will provide central, web-based data entry through an online patient Case rReport fForm, in the open open-source clinical trials software OpenClinica®. This will handle the inclusion procedure, the documentation of the stratification and randomiszation process, the severe adverse reactions, and the relevant clinical data from enrolled subjects, including primary and exploratorysecondary outcomes and explanatory variables. The data will be entered into the online patientCase rReport fForm directly by the medical staff. FA forms for randomiszation/inclusion, end-of-monitoring at 72 hours of age, and the 36 weeks follow-up will be created. Data will be stored in accordance with guidelines issued by the Danish Data Protection Agency, with whom approval of the trial will be sought. Only NICU numbers and study numbers will be used to identify participants (i.e. the data kept at Copenhagen Trial Unit is pseudo-anonymiszed), while lists of study numbers and personal identifying information (e.g. to allow Good Clinical Practice, data cleansing, and later follow-up) will be kept at the NICUs. Six months after the acceptance of the publication that presents the primary outcome, the dataset will be transferred to the Danish data archive. Before transfer, subject study numbers will be removed, NICU numbers will be replaced, sexgender documentation removed, and birth weight and gestational age recoded into binary variables to minimisze the risk of re-identification. Use by other researchers will depend on the permission of the trial Steering Group.
The investigators permit trial-related monitoring, audits and regulatory inspections by providing direct access to the source data and other relevant documents. Trial data will be handled according to regulations of data protection agencies in the respective countries.
Internal monitoring will be conducted by the Copenhagen Trial Unit, who will monitor 1) patient recruitment, and 2) quality, completeness, and timeliness of data entry. In case of problems, the principal investigator will be contacted.
External monitoring will be conducted by a Good Clinical Practice person assigned by the principal investigator at each site. The Good Clinical Practice person will perform monitoring according to the monitoring plan, which will is be developed and available at www.safeboosc.eu. before inclusion of trial participants.
To obtain evidence-based knowledge on the potential benefit and harms of NIRS-based cerebral monitoring in the clinical management of premature infants, a large-scale randomiszed clinical trials are is required. The SafeBoosC-II trial served as a feasibility trial for the present large-scale SafeBoosC-III trial.
In most NICUs, there is still clinical equipoise regarding the use of NIRS monitoring, meaning there is genuine uncertainty over whether cerebral oximetry monitoring and subsequent monitoring-based treatments are clinically beneficial or harmful. Nevertheless, some NICUs have started to use cerebral oxygenation monitoring as part of routine clinical management. Thus, there might be a limited time-window for this trial, since it may be more difficult to test an intervention that is already in clinical use (30). Therefore, we aim at a pragmatic trial, rather than doing a proof-of-concept trial first.
Extremely preterm infants demonstrate stress reactions during routine manipulation. Positioning and re-positioning of cerebral NIRS sensors can result in such reactions. There are, however, no data to support substantially more risk or discomfort as compared with no intervention or compared with current routine care. All interventions proposed in the evidence-based treatment guideline are commonly used in this patient group (21).
‘Treatment as usual’ defined as treatment according to participating hospital’s standard procedures, will be provided to the control group. Also, this will be the care provided to any participant that withdraws consent, in addition to infants who are not included in the trial. Multiple births will be randomised together and undergo allocation to the same study group. This is to avoid parents ascribing differences in their infants’ clinical courses and outcomes based on group allocation resulting from participation in this trial.
The trial protocol is registered at clinicaltrials.gov (NCT03770741) and all versions are available at www.safeboosc.eu. Following trial completion, summary trial data will additionally be entered at www.clinicaltrials.gov. Further summary data of main outcomes will be entered after statistical analyses are conducted. Attempts will be made to publish all results, positive, neutral, as well as negative, in a peer-reviewed international journals. Authorship will be determined according to the International Committee of Medical Journal Editors. An additional requirement is one author per NICU completing at least 30 participants. Ancillary studies with results potentially affecting equipoise regard to the value of NIRS, shall not be published before the main publication of the SafeBoosC-III trial. After the publication of trial results, depersonalised individual patient data will be uploaded at Zenodo.