Cerebral Near-infrared Spectroscopy Monitoring Versus Treatment as Usual for Extremely Preterm Infants: a Protocol for the Follow-up Study for the SafeBoosC-III Trial
Conditions: Deficits, Neurologic, Extreme Prematurity, Brain Damage
Sponsor: Gorm Greisen

 
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SafeBoosC III two-year follow-up 
Safeguarding the Brain of our smallest Children 
 
 
Cerebral near-infrared spectroscopy monitoring 
versus treatment as usual for extremely preterm 
infants: a protocol for the follow-up study for the 
SafeBoosC-III trial 
 
 
Sponsor: 
 
Region Hovedstaden 
Department of Neonatology 5024, Rigshospitalet 
Blegdamsvej 9, 2100 Copenhagen Ø, Denmark 
Phone: +45 3545 1326 
Email: gorm.greisen@regionh.dk 
 
 
 
 
 
 
 

 
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Revision history 
Version Author 
Date 
Major changes 
1.0 
draft 
The SafeBoosC-III 
Trial Group 
17.05.2021 
Initial version 
2.0 
draft 
The SafeBoosC-III 
Trial Group 
27.05.2021 
• Condensing of exploratory 
outcomes 
• Addition of Bayley IV to the co-
primary outcomes and handling 
of scores 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Summary 
 
Background 
In the SafeBoosC-III trial, the objective is to investigate the effect of treatment based on cerebral 
near-infrared spectroscopy (NIRS) monitoring of brain oxygenation compared with treatment as 
usual in extremely preterm infants. The primary outcome of the trial is death or survival with severe 
brain injury at 36 weeks’ postmenstrual age. Despite an association between severe brain injury 
diagnosed in the neonatal period and later neurodevelopmental disability, this relationship is not 
always strong. Therefore, if treatment based on cerebral NIRS monitoring decreases the risks of 
death or survival with severe brain injury, it is important to document if the beneficial effect persists 
into early childhood, in the form of better neurodevelopmental outcome. Furthermore, it is also 
important to identify evidence of unexpected harms. It would be unfortunate if cerebral NIRS 
monitoring became standard practice without good evidence that long-term patient-relevant benefits 
outweigh possible harms. In the SafeBoosC phase-II trial, 115/135 alive infants were followed-up at 
24 months’ corrected age to test if the intervention was beneficial in terms of improving 
neurodevelopment. No significant differences were found between the experimental versus control 
group. However, the trial was not powered to detect differences in long-term clinical outcomes. As 
the SafeBoosC-III trial intends to randomise 1600 infants, there is potential to achieve sufficient 
power for a meaningful assessment of the experimental intervention’s effect on long-term 
neurodevelopment, as well as an evaluation of unexpected harms. 
 
Methods 
In total, 1600 infants will be randomised in the SafeBoosC-III trial. We expect approximately 1250 
infants to survive and potentially be available for follow-up.  
 
Inclusion criteria: Participation in the SafeBoosC-III trial and enrollment in a neonatal intensive 
care unit (NICU) taking part in the follow-up study, with parental consent according to local 
regulations.  
Exclusion criteria: Parental objection to the use of their child’s data in the follow-up study. 
Participation criteria for NICUs: All NICUs participating in the SafeBoosC-III trial will be invited.  
Assessments: We aim to collect follow-up data on as many children as possible by including data 
from routine neurodevelopmental follow-up programmes, utilizing all other health care records 
from the age of at least 12 months and by parental questionnaires including the PARCA-R. 

 
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Blinding: Due to the nature of the trial intervention, children and their parents will not be blinded to 
treatment allocation. A local co-investigator who is blinded to group allocation will conduct 
outcome assessments. To ensure that outcome assessment from health care records is blinded, the 
principal investigator and the co-investigator from each NICU will develop a local blinding 
procedure describing their individual workflow. Each local NICU blinding process will be approved 
by the central trial unit. Data managers, statisticians and those writing the abstracts as well as 
drawing conclusions will also be blinded. 
 
Outcomes 
There will be two co-primary outcomes: 
Dichotomous effect measure: death or moderate-or-severe neurodevelopmental disability 
A child will be classified with moderate-or-severe neurodevelopmental disability if any of the 
following conditions are present: cerebral palsy with a Gross Motor Function Classification Score ≥ 
2; a cognitive function score below -2 standard deviations from the norm (or Bayley-III/IV < 85); 
hearing impairment; or vision impairment. Available data from at least 12 months’ corrected age 
from health care records, including standardised neurodevelopmental assessments, as well as 
parental questionnaires completed between 18-30 months’ corrected age will be used to assess 
mortality and neurodevelopment. 
Power calculation: Based on answers from the questionnaire on systematic routine follow-up, as 
well as implementing parental questionnaires and informal assessments to classify 
neurodevelopment, we estimate the total sample size for the outcome death or moderate-or-severe 
NDD to 1600 children. Based on results from two randomised controlled clinical trials investigating 
neuroprotection in extremely preterm infants, it is estimated that the proportion of children with the 
outcome of death or moderate-or-severe NDD will be 50% in the control group. 
An indicative power calculation shows that if we want to test a risk difference of eight percent 
between the experimental and control group, at an alfa of 2.5% and a sample size of 800 infants in 
each group, i.e. a total of 1600, we will reach a power of 80%.   
 
Continuous effect measure: mean Bayley III/IV cognitive score  
The cognitive scores from the Bayley III/IV assessment will constitute a single continuous outcome 
measure.  

 
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Power calculation: Based on answers to an investigator questionnaire, we expect to have access to 
data from Bayley III/IV assessments of 850 children. An indicative power estimation shows that if 
we want to test a mean difference of five points on the Bayley cognitive score, with a standard 
deviation of 20 (Cohens d’ 0.25) between the experimental and the control group, at an alfa of 
2.5%, and a sample size of 425 infants from each group i.e. a total of 850, we will reach a power of 
90%.  
 
The exploratory outcomes will be daily medication the last two months (yes/no), any other chronic 
illness (defined as any problem which has been diagnosed by a doctor and which 1) is expected to 
last more than a few months, 2) causes problems in everyday life, or 3) is a risk of early death or 
disability), mean head circumference, mean height and mean body weight. 
All components of the co-primary outcomes will be reported for the two groups separately as well 
as effect estimates with confidence intervals and will be taken into consideration when interpreting 
the main results  
 
Time plan 
The first randomised infant in SafeBoosC III will reach two years of corrected age in September 
2021, while the last follow-up assessment is expected to be completed before the end of 2024, 
which is an estimate of when the last infant randomised will reach two years of corrected age plus 
six months of reserve. 
 
Organisation and funding 
The SafeBoosC-III trial Steering Committee will be responsible for principal decisions. Professor 
Gorm Greisen will be the Coordinating Investigator. Local expenses must be covered by each 
NICU. The central expenses will be covered by the Sponsor (The Capital Region of Denmark, 
Copenhagen University Hospital).   
 
 
 
 
 

 
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1. Background and introduction 
 
1.1 The population and condition 
Worldwide, approximately 15 million infants are born preterm (below 37 weeks’ gestational age) 
each year. Hereof, around 50,000 are born extremely preterm (below 28 weeks’ gestational age) in 
countries where neonatal intensive care is offered routinely (1). The advances in neonatal intensive 
care over the past decades have resulted in a significant increase in the survival of extremely 
preterm infants (2-5). Currently, mortality is around 20%, but those surviving have a high risk of 
neonatal brain injury and subsequently long-term neurodevelopment disability (6). The risk of brain 
injury is especially high during the first days of life, as the infant transitions from intra- to 
extrauterine life. The combination of immature organs and impaired cerebral autoregulation may 
cause large fluctuations in cerebral blood flow (7), detectable by cerebral oximetry using near-
infrared spectroscopy (NIRS). Brain injury acquired in the neonatal period may result in 
neurodevelopmental disability later in life. It is estimated that as many as 40% of surviving 
extremely preterm infants suffer from long-term neurodevelopmental disability such as cerebral 
palsy, cognitive and neurosensory deficits, attention deficit disorder, and major psychiatric disorder 
(8). These disabilities result in life-long consequences for the children and their families, such as 
reduced quality of life as well as increased health care and educational costs (9, 10). Evidence 
suggests that cerebral hypoxia is associated with the risk of brain injury as well as death in 
extremely preterm infants. Thus, it is plausible that a reduction of cerebral hypoxia during the first 
days of life may reduce the risk of severe brain injuries (11) and thus the risk of later 
neurodevelopmental disability (12). 
 
1.2 The SafeBoosC consortium 
1.2.1 The SafeBoosC II trial 
The SafeBoosC phase-II trial demonstrated that NIRS monitoring in combination with an evidence-
based treatment guideline reduced the burden of cerebral hypoxia and hyperoxia by more than 50%, 
compared with treatment as usual, during the first 72 hours of life (13). Furthermore, there were 
trends towards reduced mortality and occurrence of severe brain injury assessed at 36 weeks’ 
postmenstrual age (PMA). In total, 115/135 (85%) infants that were alive at 24 months’ corrected 
age were followed-up to test if the intervention was beneficial in terms of improving 
neurodevelopment later in life. No differences were found between the experimental and control 

 
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group in regards to the mean mental developmental index assessed by the Bayley II (89.6±19.5 
versus 88.4±14.7, p=0.77) or the total Ages and Stages Questionnaire score (215±58 versus 213±58, 
p=0.88). The number of infants with moderate-or-severe neurodevelopmental disability were also 
similar, with ten (15%) in the experimental group and six (12%) in the control group (p = 0.58) 
(12). However, the SafeBoosC II trial was not powered to detect a relevant difference on any of the 
long-term clinical outcomes and thus there is a possibility that the neutral results were due to type II 
errors (14). Based on the above, the larger SafeBoosC-III trial is now being conducted, to test the 
effect of the intervention on clinical outcomes. 
 
1.2.2 The SafeBoosC III trial 
SafeBoosC III is a multi-centre, international, pragmatic phase III clinical trial investigating the 
effects of treatment guided by cerebral NIRS monitoring in extremely preterm infants (15). The 
hypothesis is that treatment based on cerebral NIRS monitoring of cerebral oxygenation in 
extremely preterm infants will result in a reduction of death or severe brain injury at 36 weeks’ 
PMA. Infants randomised to the experimental group are monitored during the first 72 hours of life 
and receive cardio-respiratory support guided by cerebral NIRS monitoring (11). The NIRS sensor 
must be placed within six hours from birth. The control group does not receive any cerebral NIRS 
monitoring and is treated according to local guidelines and clinical practices. The SafeBoosC III 
trial will randomise 1600 infants, having started in June 2019 with recruitment expected to be 
completed by the end of 2021. Nearly 90 neonatal intensive care units (NICUs) from Europe, USA, 
China and India have signed up to take part in the trial (15). As of May 1st 2021, over 1000 infants 
have been randomised. The trial is registered at clinicaltrials.gov (NCT03770741).  
 
The original sample size of the SafeBoosC III trial is calculated based on the primary outcome, 
which is a composite of death or severe brain injury at 36 weeks’ PMA (16). Severe brain injury is 
defined as cerebral haemorrhage grade III or IV, cystic periventricular leukomalacia, cerebellar 
haemorrhage, post-haemorrhagic ventricular dilatation or cerebral atrophy detected on any of the 
cerebral ultrasound scans that are routinely performed in these infants up until 36 weeks’ PMA or 
discharge to home, whichever comes first.  
 
1.3 Assessment of brain injury and neurodevelopment 
 
1.3.1 Ultrasound 

 
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Cerebral ultrasound is used to diagnose neonatal brain injury in the SafeBoosC III trial at 36 weeks’ 
PMA. Severe (grade III or IV) periventricular-intraventricular haemorrhage is associated with an 
increased risk of adverse neurodevelopmental outcomes, including cerebral palsy and lower 
cognitive scores, but odds ratios are only 2 to 3 (18). Cystic periventricular leukomalacia is less 
common, but a stronger predictor of cerebral palsy and developmental delays for extremely preterm 
infants (19).  
 
Cerebral ultrasound is less sensitive in the detection of mild to moderate types of brain injury as 
compared to magnetic resonance imaging (20, 21). This can potentially result in an underestimation 
of infants at risk of long-term neurodevelopmental disabilities. For example, in one study, among 
extremely preterm infants with no ultrasound abnormalities in the neonatal period, 23% had delayed 
mental development and 26% had delayed psychomotor development at two years of age (19). 
Thus, despite neonatal brain injury diagnosed by ultrasound being a clinically relevant outcome, it 
is not a definitive surrogate for long-term neurodevelopment, a more patient-relevant outcome. 
Therefore, assessment later in life is also important.  
 
1.3.2 Neurodevelopmental assessment  
While neuropsychological abilities can only fully be assessed in adulthood, very young childrens’ 
abilities to walk, talk, see, hear, and develop at approximately the same pace as peers, is relevant in 
itself for the full life of a child, as well as being relevant milestones in the overall 
neurodevelopmental trajectory. Therefore, assessment in early childhood is relevant, optimally by a 
standardised neurodevelopmental assessment, which measures the child’s skills compared to a 
norm. Assessment at two years of corrected age is commonly used clinically as well as for research 
purposes (22). The predictive value of such assessments for later function is relatively poor for the 
individual child, except for the most severe disabilities with score values below minus 3 SD (23, 
24). This is likely partly due to the difficulties of assessing young, intermittently cooperating 
children, but also due to the irregular pace of development in individual infants, as well as the fact 
that some elements of cognition only develop later, and that childhood and upbringing also 
influence development. As an example, while measures of intelligence quotient (IQ) track well 
from the age of five years and onwards through adult life, measures of cognition at two years do not 
correlate well with measures of IQ at 5 years  (8). However, on a group level, these assessments 
fairly consistently quantify differences between extremely preterm born children and children born 

 
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at term (nearly one SD). Therefore, these assessments are likely to be valuable as outcome measures 
in randomised clinical trials, since assessments will be compared on a group level (25).  
 
Multiple validated methods exist to assess neurodevelopment in early childhood, with the most 
frequently used being the Bayley Scales of Infant Development (Bayley) and the Griffiths Scale of 
Childhood Development (Griffiths) (32,33). However, these assessments are lengthy for both the 
children, parents and clinicians and reliability is compromised if a child is unable to cooperate well. 
Parental questionnaires, drawing on the knowledge of the child’s abilities in daily life, may be a 
good, pragmatic and cost-effective substitute for a face-to-face neurodevelopmental assessment by a 
qualified examiner (26). The Parent Report of Children’s Abilities-Revised (PARCA-R) is a 
parental questionnaire, evaluating cognitive and language development at two years of age (27). It 
has high sensitivity and specificity for identifying neurodevelopmental disability among very 
preterm infants, supporting its use as an outcome measure in randomised trials (28, 29). For further 
elaboration please see section 2.6 ‘Outcome assessment tools’ in the Methods section.  
 
 
1.4 Potential harms 
It would be unfortunate if cerebral NIRS monitoring became standard practice without good 
evidence that patient-relevant benefits outweigh harms. As an example, studies investigating the use 
of early systemic postnatal corticosteroids for preventing bronchopulmonary dysplasia (BPD) (30) 
in preterm infants, at first showed significantly improved short-term outcomes, such as earlier 
extubation and less prevalence of BPD. However, when two-year follow-up assessments were 
conducted, several adverse neurological effects were reported, in particular cerebral palsy (31). 
Based on this, the clinical use of corticosteroids was restricted to those infants at very high risk of 
BPD or death. Studies like these demonstrate the importance of long-term follow-up for randomised 
clinical trials.  
 
The SafeBoosC-II trial did indeed show a trend towards higher prevalence of BPD and retinopathy 
of prematurity in the experimental group. Therefore, it is possible that cerebral NIRS monitoring 
may cause harm. Such harms could theoretically be caused by inappropriate modifications in 
cardio-respiratory support based on hypoxic values and/or unnecessary infant disturbance. 
 

 
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1.5 Recruitment and loss to follow-up 
Loss to follow-up in studies with long-term outcomes is common and data are rarely missing 
completely at random. Studies have shown that children lost to follow-up often have a lower 
socioeconomic status and tend to have more neurodevelopmental impairment than children 
participating in follow-up programmes (41). Factors affecting loss to follow-up include maternal 
education, age, substance abuse, poverty level, and marital status, among others (42). As this is a 
pragmatic study, we do not expect that all eligible children will participate. However, we aim to 
ascertain follow-up data on as many children as possible by collecting data from all health care 
records from 12 months’ corrected age onward as well as by parental questionnaires (see Methods 
section 2.6 ‘outcome assessment tools’).  
 
In the Summer of 2020, when recruitment was well-established, a questionnaire was sent out to all 
active NICUs asking if they were interested in participating in the follow-up study and how their 
local follow-up programmes were structured. Sixty-two NICUs completed the questionnaire and all 
expressed interest in taking part in the two-year follow-up study. All NICUs reported having a 
systematic follow-up programme of extremely preterm infants. Eighty percent reported a routine 
follow-up rate of 75% or more, and 65% routinely perform a Bayley III/IV assessment between 18 
and 30 months’ corrected age. Furthermore, several other standardised developmental assessments 
and screening methods were reported to be utilized from 18 to 30 months’ corrected age, including 
Griffiths, Denver Developmental Screening Test II, Peabody II, Gessell, Ages and Stages 
Questionnaire, PARCA-R, Alberta Infant Motor Scales, etc. Almost all NICUs conduct a 
standardised neurodevelopmental assessment around two years’ corrected age. Based on these 
investigator questionnaire responses, we have planned the SafeBoosC-III two-year follow-up study.  
 
Since the summer of 2020, more NICUs have joined the SafeBoosC-III consortium, thus 
strengthening the chances of obtaining sufficient statistical power for a meaningful test of the 
intervention’s effect on neurodevelopment.  
 
 
 
 

 
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2 Methods 
2.1 Objective and hypothesis 
The objective of the SafeBoosC III follow-up study is to investigate the benefits and harms of 
treatment guided by cerebral NIRS monitoring of brain oxygenation in extremely preterm infants 
during the first 72 hours of life, assessed at two years’ corrected age.  
The hypothesis is that the intervention will decrease a composite of death or moderate-or-severe 
neurodevelopmental disability at two years’ corrected age, and/or increase cognitive function in 
survivors assessed by the Bayley III/IV test, with insignificant harms. 
 
2.2 Inclusion criteria  
Participation in the SafeBoosC III trial, enrollment in a NICU taking part in the follow-up study, 
and parental consent according to local regulations. 
 
2.3 Exclusion criteria 
Parental objection to use of their child’s data in the study. 
 
2.5 Outcomes  
2.4.1 Primary outcomes 
The two co-primary outcomes are: 
1) Death or moderate-or-severe neurodevelopmental disability (NDD).  
A child will be classified with moderate-or-severe NDD if any of the four following conditions are 
present:  
- 
cerebral palsy with functional impairment corresponding to Gross Motor Function 
Classification Score (GMFCS) ≥ 2;  
- 
a score below -2 standard deviations from the norm of a standardised developmental assessment 
(if using the Bayley III/IV test, the cognitive score cut-off will be < 85), or an informal 
classification of moderate-or-severe NDD;  
- 
vision impairment defined as moderately reduced vision, or only being able to perceive light or 
light reflecting objects; or blind in one eye with good vision in the contralateral eye. 
- 
hearing impairment defined as hearing loss corrected with aids (usually moderate 40-70dBHL) 
or some hearing but loss not corrected by aids (usually severe 70-90dBHL). 

 
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2) Bayley III/IV mean cognitive score  
 
2.4.2 Exploratory outcomes 
The exploratory outcomes are as follows: 
• Daily medication the last two months (yes/no)  
• Any other chronic illness (defined as any problem which has been diagnosed by a doctor 
and which 1) is expected to last more than a few months, 2) causes problems in everyday 
life, or 3) is a risk of early death or disability) 
• Mean head circumference  
• Mean height  
• Mean body weight, with one decimal 
 
All components of the co-primary outcomes will be reported for the two groups separately as well 
as effect estimates with confidence intervals and will be taken into consideration when interpreting 
the main results  
 
All outcomes will be assessed from health care records by a blinded assessor at a minimum of 12 
months of corrected age. 
 
2.6 Outcome assessment tools 
The following outcome assessments tools may be used to collect data on children in the SafeBoosC 
III follow-up study. We aim to collect data on as many children as possible and will do this by 
collecting clinical data from health care records as well as answers from parental questionnaires. 
 
2.6.1 The Bayley assessment 
The Bayley Scales of Infant Development (Bayley) is a commonly used neurodevelopmental 
assessment tool for children from 1 to 42 months of age (32). There now exists a second (Bayley 
II), third (Bayley III) and fourth (Bayley-IV) version. The Bayley II measures a Mental 
Developmental Index (MDI), which is based on a composite of early cognitive and language 
development, as well as a Psychomotor Development Index (PDI), which assesses motor abilities 
(33). In the revised Bayley III (2008), the two indexes, MDI and PDI, were replaced by five 
individual subcategories: cognitive, language, motor, social-emotional and adaptive behaviour (34).. 

 
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The correspondence between the Bayley II and III has been examined in previous studies (12, 34, 
35). Bayley III scores are approximately 10 points higher than the Bayley II, thus resulting in less 
infants being diagnosed with neurodevelopment impairment using conventional cut-offs (-2SD). 
This has implications for both clinical practice as well as research, where the underestimation of 
neurodevelopmental impairment may lead to reduced statistical power in randomised trials.  
Some NICUs may switch to the Bayley-IV during the SafeBoosC-IIIfu study. In published data 
from Pearson (52) it is argued that there is evidence to support the accuracy and validity of the 
Bayley-IV scores. Furthermore, as the Bayley-IV (2019) retains the same subcategories and 
assessment methods as Bayley III, it predicted yield similar  scores to the Bayley III. No 
randomised clinical trials have used and published results using the Bayley IV as an outcome 
measure yet, and therefore the scores will be treated equal to the Bayley-III scores in the co-primary 
outcome Bayley III mean cognitive score. In the event of a possible difference between the Bayley 
III and IV scores, the nature of a randomised trial and block randomisation will equally distribute 
the differences between the experimental and control group. Furthermore we will conduct a 
sensitivity analysis investigating a possible influence on treatment effect caused by differences in 
Bayley III and IV scores.  
For the purpose of the co-primary outcome Bayley III/IV mean cognitive score, the unadjusted 
mean scores from the experimental and control group will be compared. If the Bayley III/IV 
cognitive score is used to evaluate cognitive function in co-primary outcome death or moderate-or-
severe NDD, the cognitive function cut-off will be <85, as done in previous trials and recommended 
by experts (35). 
 
2.6.2 Medical examination 
A medical examination will ideally include measurement of head circumference, height and weight, 
and the child’s vision and hearing will be tested, either formally or informally. Signs of cerebral 
palsy is usually be documented as well as motor abilities (40). Furthermore, the presence of chronic 
illnesses and/or medication usage will be obtained from medical records. 
 
2.6.3 Parental questionnaires 
The parental questionnaires will be comprised of the PARCA-R and a health and development 
questionnaire. 
 

 
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2.6.3.1 PARCA-R 
The Parent Report of Children’s Abilities – Revised (PARCA-R) is a parental questionnaire that can 
be used to assess children’s non-verbal cognitive and language development at 24 months’ 
corrected age. The PARCA-R provides a high test-retest reliability and correlates well with the 
Mental Development Index (MDI) of the Bayley II, and with the cognitive score of the Bayley III 
(28, 36, 37). The questionnaire has been used as a two-year outcome measure in multiple clinical 
trials (29) and has furthermore been translated into several languages. For this follow-up study, an 
online platform will be developed, where parents of the participating children will be invited to 
complete the non-verbal cognitive (NVC) part of the PARCA-R questionnaire, in their respective 
languages. This typically takes less than 15 minutes to complete (38). The full PARCA-R will not 
be used, since a validated language component is not available in all countries; PARCA-R has only 
been standardised for use in the UK. The PARCA-R must be assessed on children between 23.5 and 
27.5 months of corrected age. Children will be classified as having moderate-or-severe NDI when 
scores correspond to a scale score of -2SD from the norm (39). 
 
The NVC scale consists of 34 forced-choice items, scored zero or one, from which a total NVC 
score is derived, which is adjusted for the child’s corrected age. In cases where no physical 
standardised assessment (i.e. Bayley, Griffiths etc) of the child is available, NVC cut-off scores will 
be used as the measure of cognitive function for the co-primary outcome death or moderate-or-
severe NDD. When more than four items are missing, the NVCs will not be calculated, but will be 
categorised as ”unknown.”  
 
2.6.3.2 Health and development questionnaire 
The PARCA-R questionnaire will be supplemented with a number of health and developmental 
questions to be answered by the parents as well. The questions focus mainly on the individual 
components of the moderate-or-severe NDD outcome definition, as well as quality of life questions. 
It will be available on the online platform as well. The coding of the health and development 
questionnaire for the co-primary outcome moderate-or-severe NDD can be found in Appendix B.  
 
2.7 Data extraction  
All data extraction from health care records and data entry into the e-CRF will be done by an 
assessor who is blinded to group allocation (see section ‘2.8 Blinding’). The co-primary outcome 

 
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Bayley III/IV mean cognitive score will be extracted from the records of the Bayley III/IV test. The 
co-primary outcome death or moderate-or-severe NDD will primarily be based on an assessment of 
available health care records, from when the child was between 18 and 30 months’ corrected age. If 
more than one formal neurodevelopmental assessment has been conducted, the score of the latest 
should be used. If formal assessment of all four components is not available, the central trial unit 
will substitute the missing components with answers from parental questionnaires (PARCA-R and 
health and development questionnaire). The answers from the questionnaires will be reported 
directly by the parents to the central trial unit. If answers from parental questionnaires are not 
available, either the PI will be contacted by the central trial unit and requested to provide an 
informal assessment of the presence or absence of moderate-or-severe NDD. The assessment should 
be based on all available information from the child from at least 12 months’ corrected age. For 
additional details on this approach, see appendix A.  
 
2.8 Blinding 
Due to the nature of the trial intervention, children and their parents will not be blinded to treatment 
allocation. A co-investigator who is blinded to group allocation will conduct outcome assessments. 
To ensure that outcome assessment is blinded, the principal investigator and co-investigator from 
each NICU must develop a local blinding procedure describing the workflow. This process will be 
approved by the central trial unit before study commencement. Data managers, statisticians and 
those writing the abstracts as well as drawing conclusions will also be blinded.  
 
2.9 Participation criteria 
All NICUs participating in the SafeBoosC-III trial will be invited to participate in the follow-up 
study. In the spring of 2021, NICUs will receive an official invitation to participate, along with this 
protocol, which has been approved by the Steering Committee. NICUs will be asked to state 
explicitly what data they will provide in the follow-up and as well as their expected follow-up 
percentage. NICUs will be encouraged to provide as much data as possible since this will strengthen 
the quality of the study.  
 
The tasks for NICUs are as follows: 
1. Obtain addendum ethical approval to conduct the follow-up study in their NICU, if 
necessary. 

 
Page 16 of 31 
 
2. Obtain addendum contract and legal approval, if necessary 
3. Delegate the review of health care records and outcome assessment to a co-investigator, who 
can be blinded to the group allocation in the SafeBoosC-III trial. 
4. Develop local work flow and blinding procedure  
5. Ensure that the contact information, ideally e-mail addresses of the parents, is maintained 
and that links to the web-based platform with the PARCA-R questionnaire and the health 
and development questionnaire are forwarded to the parents as necessary 
Parents of all infants included in the SafeBoosC III trial, and alive at the time point where routine 
follow-up assessments are initiated, should be invited to participate in the follow-up study.  
 
Since the first randomised infant in SafeBoosC III will reach two years of corrected age in 
September 2021, we expect that follow-up assessments will begin around this time point. The last 
follow-up assessment is expected to be completed before the end of 2024 since this is the time 
where we expect the last randomised infant to reach two years of corrected age plus six months of 
reserve.  
 
2.10 Ethical considerations 
2.10.1 Ethical review 
The need for supplementary approval of the follow-up study by a Research Ethics Committee 
(REC) may differ among countries. In some countries, an REC approval may be an addition to the 
approval of the randomised clinical trial. 
 
As the SafeBoosC-III follow-up study does not include exposures to any additional interventions, 
there is no safety risk for children. Thus, an interim analysis is not necessary. 
 
2.10.2 Consent  
When infants were randomised in the SafeBoosC-III trial, the parents were made aware of the 
possibility of a potential follow-up study and permission to contact families as foreseen in the 
information sheet the parents were given at inclusion. The study-related interventions consist of 
extracting data from health care records, and parental questionnaires. The need for explicit consent 
for using clinical data from health care records for the SafeBoosC-III follow-up study may differ 

 
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between countries. In some countries, turning up for examination or answering questionnaires will 
be considered sufficient, implicit consent.  
 
2.10.3 Transfer of data 
Permissions for data collection and transfer to the centrial trial unit in Copenhagen must be obtained 
according to local/national regulations. If necessary, the contract between the partners must be 
extended. 
 
2.11 Resources 
The cost of the central trial unit is covered by the sponsor, while the costs of the NICUs is covered 
locally or nationally.  
 
2.12 Data management plan 
All the participating children’s data are protected in accordance with the Danish Act on the 
processing of personal data and the Danish Health Act. Data entry will be managed through a web-
based clinical trial software, OpenClinica, provided by Copenhagen Trial Unit. The electronic case 
report form has already been used as the platform for data entries in the SafeBoosC-III trial, using 
end-to-end encryption. For this follow-up study, an additional data entry module will be added to 
the SafeBoosC-III OpenClinica setup. Data will be stored in accordance with guidelines issued by 
the Danish Data Protection Agency, where the follow-up study will also seek approval from. Data 
are pseudonymised, only NICU numbers and study numbers are used to identify children. Personal 
identifying information linking to study numbers will be kept in the trial master file at the local 
NICU.  
 
Six months after the acceptance of the main publication presenting the primary outcome, the dataset 
will be transferred to the Danish data archive, after re-coding of variables (birth weight, gestational 
age, sex, NICU, study number) that may be used for reidentification. This data set can be made 
available for others as decided by the trial steering committee. Due to the residual risk of re-
identification, the dataset will not be placed in public space. 
 
 
 

 
Page 18 of 31 
 
3 Statistical analysis plan 
Full details regarding statistical considerations and data analysis will be outlined in a separate 
report, which will be published before the analysis of the SafeBoosC-III trial data, expected late 
spring 2022.  
 
Power estimations for the co-primary outcomes 
The sample size of 1600 infants for the SafeBoosC-III trial is based on mortality and the prevalence 
of survivors with severe brain injury in the SafeBoosC II trial, i.e. a 22% relative risk reduction in 
the composite primary outcome from 34% to 26.5% (absolute risk reduction of 7,5%), at an alpha 
level of 5%, and a power of 90%. The latest Data Monitoring Report from March 2021 revealed a 
tentative mortality rate of 21% in the SafeBoosC-III trial, based on first 580 randomised infants. 
Assuming the mortality rate will stay constant, there will be 1264 infants alive at two years of 
corrected age, and thus, be available for follow-up assessment.  
 
Death or moderate-or-severe neurodevelopmental disability power calculation  
Based on answers from the questionnaire on systematic routine follow-up, as well as implementing 
parental questionnaires and informal assessments to classify neurodevelopment, we estimate the 
total sample size for the outcome death or moderate-or-severe NDD to 1600 children. 
Based on results from two randomised controlled clinical trials (49,50) investigating 
neuroprotection in preterm infants, it is estimated that the proportion of children with the outcome 
death or moderate-or-severe NDD will be 50% in the control group. An indicative power 
calculation shows that if we want to test an absolute risk difference of eight percentage, between the 
experimental and control group, at an alfa of 2.5% and a sample size of 800 infants in each group, 
i.e. a total of 1600, we will reach a power of 80%.   
 
Bayley III/IV mean cognitive score power calculation  
Based on answers to a questionnaire on systematic routine follow-up from participating NICUs in 
the SafeBoosC-III consortium (see section 1.5 ‘recruitment and loss to follow up), it is expected 
that 65% of the NICUs will be able to provide data from a Bayley III/IV assessment around two 
years of corrected age for each child. Assuming that these NICUs enrol their proportion of the 1600 
infants to the SafeBoosC-III trial, and a mortality rate of 21% (12), approximately 850 infants will 
be available for Bayley III/IV assessments at two years of age.  

 
Page 19 of 31 
 
An indicative power estimation shows, that if we want to test a mean difference of five points on 
the Bayley cognitive score, with a standard deviation of 20 (Cohens d’ 0.25) between the 
experimental and the control group, at a 2.5% alfa-level, with a sample size of 425 infants from 
each group in the follow-up study i.e. a total of 850, we will reach a power of 90%.  
 
3.1 Primary analyses  
The primary analysis of all outcomes will be based on the intention-to-treat population. Mixed-
effect linear regression and mixed-effect logistic regression will be used to analyse the dichotomous 
and continuous co-primary outcomes, respectively. Data from all participating sites will be used in 
the primary analysis of both co-primary outcomes. In the regression models, ‘site’ will be included 
as a random effect, while ‘gestational age below or above 26 weeks of postmenstrual age’ and 
‘group allocation’ will be included as fixed effects. To correct for multiple testing, the threshold for 
statistical significance will undergo Bonferroni adjustment, and thus a p-value of 0.025 for each 
primary outcome is chosen. Superiority of the intervention will only be claimed if at least one of the 
two co-primary outcomes is statistically significant. All other outcome results will be considered 
hypothesis-generating only. In addition, we will perform a range of pre-defined sensitivity analyses 
to inform the interpretation of the results of the primary analysis. A full statistical analysis plan will 
be developed and submitted for publication before the analysis of the SafeBoosC-III trial data. 
 
3.2 Blinding of statisticians 
All data managers, statisticians, and those drawing conclusions will be blinded to group allocation. 
Two blinded statisticians connected to The Copenhagen Trial Unit, will independently perform all 
statistical analyses and the two statistical reports will be published as supplemental material.  
 
3.3 Publication plan 
Once all data from follow-up assessments has been analysed, the results will be published in a peer-
reviewed international journal. Members of the steering group will be offered authorship. 
Furthermore, one investigator per participating NICU can obtain co-authorship. All authors must 
fulfil the Vancouver Criteria. The blinded assessor completing the data entries will obtain non-
byline co-authorship (51). Ancillary studies with results potentially affecting the main study or 
compromise its publication, shall not be published before the main results of the follow-up study 
have been published, as decided by the trial steering committee. 

 
Page 20 of 31 
 
Appendix A: Prioritisation of data for the co-primary outcome moderate-or-severe NDD  
 
NDD = moderate-or-severe neurodevelopmental disability = positive findings for at least one of the four components or NDD based 
on an informal blinded assessment of all available information 
No NDD = no moderate-or-severe neurodevelopmental disability = no positive findings in any of the four components and no NDD 
based on an informal blinded assessment of all available information 
Unclassifiable = if one or more components are unknown and none are positive and there is no informal assessment. 

 
Page 21 of 31 
 
Moderate-or-severe neurodevelopmental disability defined as: 
 
Diagnosis of motor impairment: cerebral palsy with functional impairment corresponding to a 
GMFCS >=2, but it is not necessary that a GMFCS grading is available from the health care 
records) 
 
Diagnosis of visual impairment: defined as moderate reduced vision or worse (blind in one eye 
with good vision in the contralateral eye or blind or can only perceive light or light reflecting 
objects).   
 
Diagnosis of hearing impairment: defined as hearing loss corrected with aids or some hearing but 
loss not corrected by aids or no useful hearing even with aids. 
 
Cognitive impairment:  
- 
Bayley-III/IV cognitive score < 85 (1st priority) 
- 
Any developmental assessment < -2SD (including the PARCA-R) (2nd priority)  
- 
If none of the above are available, blinded assessment of health care records from 12 months 
of corrected age and onwards concluding that the child has a cognitive impairment 
equivalent to moderate or-severe nerudevelopmental disability (3rd priority). 
 
Informal assessment of moderate-or-severe NDD 
When there are no relevant health care records from corrected age 18-30 months the records will be 
accessed by a the blinded assessor and all health care records from corrected age 12 months and 
onwards will be informally assessed to conclude whether or not the child has moderate-or-severe 
neurodevelopmental disability. 
 
 
Prioritisation and possible substitution of data will be done centrally. 
 
 
 
 
 
 
 
 
 
 
 
 

 
Page 22 of 31 
 
Appendix B: Classification of NDD based on parental questionnaire (in cases where 
components of the co-primary outcomes are unknown or if it is not possible for the blinded assessor 
to assess NDD based on the health care records):  
 
YES to cerebral palsy:   
A doctor has said the child has cerebral palsy 
 
 
The child CANNOT walk independently at two years of age 
 
NO to cerebral palsy:  
A doctor has said the child has cerebral palsy 
 
 
The child CAN walk independently at two years of age 
 
NO to cerebral palsy:  
A doctor has NOT said the child has cerebral palsy 
 
 
The child CANNOT walk independently at two years of age 
 
NO to cerebral palsy:  
A doctor has NOT said the child has cerebral palsy 
 
 
The child CAN walk independently at two years of age 
 
YES to visual impairment: The child is blind in one or two eyes OR has poor vision even with 
glasses 
 
NO to visual impairment:  The child has visual problems 
 
 
The child wears glasses 
The child has a squint (the eyes look in different directions) 
 
YES to hearing impairment: The child wears aids or cochlear implants 
 
The child will be categorised as no moderate-or-severe NDD if all components are ”no”.  
The child will be categorised as “not able to classify”, if one or more components are unknown and 
none are positive. Thereby all four components of the primary outcome must be “no”, to be 
classified as no moderate-or-severe NDD. 
Example:  
From health care records: no to cerebral palsy 
From parental questionnaire: no vision impairment,  

 
Page 23 of 31 
 
No clinical record or parental information of hearing impairment or standardised developmental 
assessment or PARCA-R score.  
The child will be  “not able to classify” 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Page 24 of 31 
 
Appendix C: ancillary studies 
The SafeBoosC-III two-year follow-up study will provide important data on the long-term 
consequences of extreme prematurity. Therefore, we are therefore drafting multiple secondary 
analyses on data from the SafeBoosC-III trial and follow-up study.  
 
Predictive value of neonatal cerebral ultrasound at 36 weeks postmenstrual age in relation to 
neurodevelopmental impairment at 24 months of corrected age in extremely preterm infants  
In the SafeBoosC-III trial, the primary outcome is a composite of death or severe brain injury. One 
of the co-primary outcomes of the SafeBoosC-III follow-up study is death or moderate-to-severe 
neurodevelopmental disability at two years of corrected age. For the purpose of this secondary 
analysis, the correlation between the brain injury diagnoses included in the ‘severe brain injury’ 
criteria at 36 weeks PMA and the diagnosis of moderate-to-severe neurodevelopmental impairment 
at two years of age will be investigated. For the brain injuries cerebral haemorrhage grade III or IV, 
cystic periventricular leukomalacia, cerebellar haemorrhage, post-haemorrhagic ventricular 
dilatation or cerebral atrophy, each injury will be computed for the proportion of children with 1) 
CP (GMFCS ≥ 2)  a Bayley III/IV cognitive score below 85, and 3) moderate-or-severe 
neurodevelopmental disability. To describe the correlation between brain injury diagnosed during 
the neonatal period and the outcomes, risk ratios will be calculated adjusted for gestational age as 
well as 95% confidence intervals. 
 
Two-year outcomes of extremely preterm infants: mechanically ventilated vs non-ventilated 
In neonates with respiratory failure, mechanical ventilation is a life-saving intervention. It is often 
the sickest neonates that are requiring mechanical ventilation, whom are frequently suffering from 
circulatory failure as well. The combination of circulatory and respiratory failure, on top of an 
increased risk of in advert hyperventilation due to the mechanical ventilation, puts this group of 
neonates in increased risk of cerebral hypoxia (49). Thus, we hypothesise that these neonates would 
have the largest effect of clinical care with access to cerebral NIRS monitoring. In order to test this 
hypothesis, we plan to conduct a secondary analysis, comparing children in the experimental group 
that underwent mechanical ventilation, to children in the experimental group that did not undergo 
mechanical ventilation and children in the control group, in regard to the two co-primary outcomes 
of the SafeBoosC-III trial follow-up, as well as the interactions with the group allocation. The 

 
Page 25 of 31 
 
hypothesis is that the effect of the SafeBoosC-III intervention would greater in ventilated compared 
to non-ventilated infants. 
 
Correlation between Bayley III/IV and PARCA-R 
The PARCA-R questionnaire has previously shown a good correlation to Bayley II and Bayley III 
scores in national studies (36). However, the literature is sparse when investigating the correlation 
in an international trial setting using results from routine Bayley tests. The SafeBoosC-III follow-up 
study plans to make PARCA-R available to the parents of all infants included in the SafeBoosC-III 
trial. Furthermore, at least 36 NICU will use the Bayley III/IV assessment as an outcome measure. 
We therefore plan to compare and calculate the correlation between Bayley III/IV scores and 
PARCA-R scores. The Bayley III/IV cognitive score will be used as a gold standard to assess 
concurrent validity of the NVC of the PARCA-R. The Pearson correlation coefficient (Pearson’s r) 
will be calculated to assess the relationship between the two continuous measures. Two receiver 
operating characteristic curves (ROC) will be plotted to investigate the diagnostic accuracy of NVC 
scores to predict Bayley III/IV cognitive scores below 85, which will be defined as moderate-to-
severe neurodevelopmental impairment. The accuracy of the NVC in detecting values below 85 and 
70 on the Bayley cognitive scale will be computed by the area under curve measurements.  
 
Standardised mean differences of all assessments used in the SafeBoosC-III follow-up 
Since the SafeBoosC-III follow-up study utilises many different assessments, a comparison may be 
complex. The Bayley III/IV measures differently from the Griffiths, however, the standardised 
mean difference (SMD) allows for outcomes of similar nature but measured on different scales, to 
be combined. The SMD will express the possible intervention effect relative to the variability 
between the developmental tests. This is a commonly used method in meta-analyses. The SMD is 
used interchangeable with the term “effect size”, and is furthermore often used in relation to 
Cohen’s d. The standardisation is obtained by dividing the difference in mean outcome between two 
groups, with the pooled standard deviation of the measurements. We believe this will provide a 
valuable point estimate of the effect of the intervention. For the purpose of this analysis, all 
quantitative scores derived from standardised developmental assessments at two years of corrected 
age, will be pooled for the statistical analyses and test values will be converted to SMD and will 
thus allow for comparison between the control and experimental group. All analyses will be 
intention to treat analyses.  

 
Page 26 of 31 
 
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