The proposed trial was designed and is powered to compare the effect of FiO2-C in addition to manual adjustments, in comparison with RMC of FiO2 only, on death, NDI and severe complications of prematurity thought to be related to hypoxia/hyperoxia in ELGANs.
This is an outcome-assessor-blinded, randomized-controlled, multicenter parallel group comparison of phase III for superiority (evaluating FiO2-C in addition to RMC of FiO2 in comparison to RMC of FiO2 only) in ELGANs.
In Germany, this study is also considered as a phase IV pharmaceutical trial on safety of the investigational medication ‘oxygen’ using different modes of administration (decision of the German authority BfArM according to §4 para. 23,1 of the German Pharmaceutical Act). This may not apply to other countries.
Patients will be recruited in approximately 75 European tertiary care neonatal centers. Recruitment has started in Germany and is intended to expand to additional sites in other European countries, after appropriate approvals will have been obtained.
Decision not to provide full life support / decision for palliative care only before study entry
Severe congenital abnormalities (particularly those affecting respiratory, cardiovascular or gastrointestinal function or long-term neuro-cognitive development, whereas patent ductus arteriosus, patent foramen ovale (PFO), and atrial septal defects type II (ASDII) are not considered a congenital anomaly in preterm infants)
Postnatal age > 48 h
Lack of parental consent
Lack of device enabling closed-loop automatic control of FiO2 before randomization
Randomization and allocation concealment
Study participants are randomly assigned in a 1:1 ratio to FiO2-C in addition to RMC of FiO2 (test intervention) or RMC of FiO2 only (control intervention).
A web-based randomization tool provided by the Interdisciplinary Center of Clinical Studies at the University Medical Center of the Johannes Gutenberg University Mainz is being used in this study. This program enables bound (into the same treatment group) or free (into different treatment groups) randomization of multiples based on parental choice and the number of available devices enabling FiO2-C.
A minimization algorithm is applied to preferentially aim for an even distribution of treatment assignment in both GA strata (i.e. < 26 weeks and ≥ 26 weeks; 1st priority) and both gender strata (2nd priority) within each center.
This study is outcome-assessor-blinded, meaning that the personnel performing the ophthalmological examinations throughout the initial hospitalization as well as the personnel performing the neurocognitive evaluation at 24 months corrected age will be blinded to the infants’ treatment group assignment. Blinding of doctors, nurses, and parents is not possible with this type of study interventions.
FiO2-C is provided by commercially available and CE marked infant ventilators with a FiO2-C algorithm intended for use in preterm infants. The FiO2-C algorithm must have been tested in human infants and shown to increase the %-time spent in the assigned SpO2 target range or to reduce the time in hypoxemia or hyperoxemia or to reduce the incidence/duration of hypoxemic or hyperoxemic episodes.
Each FiO2-C algorithm should be applied in its “optimal mode” (with respect to potentially variable settings provided by the manufacturer such as: averaging time of SpO2-input, response/wait-time, etc.) based on either evidence in the literature or consensus of the users.
Manual adjustments are encouraged whenever automatic FiO2 settings seem sub-optimal. In case of FiO2/SpO2-oscillations brought about by FiO2-C, settings need to be adapted or FiO2-C has to be temporarily interrupted.
Whenever possible, every study center will use only one type of FiO2-C algorithm.
Infants in the control group are treated (whenever possible) with the same type of infant ventilator for respiratory support (FiO2-C turned off) and RMC of FiO2 is applied by bedside nurse and medical staff throughout the initial hospitalization.
Care is taken in both groups that all staff are informed about the relevance of intermittent hypoxemia and hyperoxemia and trained to execute prudent and careful RMC of FiO2. This training may include a standard operating procedure for RMC, where the speed of increase/decrease in FiO2 depends on the magnitude of deviation from the SpO2 target range as previously described [23, 24].
The intervention should start as soon as possible after randomization and within 48 h after birth. The scheduled end of the study intervention is any of the following (whichever comes first):
discharge home from hospital
transfer to another hospital where FiO2-C is not available (whereas such transfer is discouraged)
a PMA of 36 + 0/7 weeks
final discontinuation of positive pressure respiratory support, which does not include limited periods without positive pressure support for weaning.
If the infant requires positive pressure respiratory support again for any reason, the infant should again be supported by FiO
-C (provided a device supporting FiO
-C is available) until (other) criteria for scheduled end of study intervention are met.
a PMA of > 32 + 0/7 weeks provided the following two additional criteria of respiratory stability are both met:
◦ A) FiO2 = 0.21 for ≥48 h (for this criterion limited time periods with higher FiO2 for rescue or for recovery of intermittent hypoxemia will not be considered)
If criteria A) or B) are no longer met, the infant should again be supported by the FiO
-C device until (other) criteria for scheduled end of study intervention are met.
If the infant is re-admitted to intensive care, the infant should again be supported by FiO
-C (provided a device supporting FiO
-C is available) until (other) criteria for scheduled end of study intervention are met.
After the end of the study intervention, all study participants will be treated according to the state of the art care and local standards without further requirements or restrictions.
Concomitant interventions and medication
Any concomitant medication that is clinically considered necessary for the patient will be allowed within the study, except for the control group, where closed-loop automatic control of FiO2 or any other automatic control of airway pressure/respiratory support etc. based on SpO2 or other vital signals are not allowed.
SpO2 measurements to guide FiO2-C
All FiO2-Controllers should be based on SpO2-data generated by the same pulse oximeter technology (Masimo). In general, pre-ductal SpO2-sensor placement is preferred to guide FiO2-C as long as echocardiography demonstrates a patent ductus arteriosus.
SpO2-targets and alarm settings
The SpO2-target range selected by a center for clinical routine has to fulfill the following criteria:
Study centers need to have a written guideline on SpO2-target range to ensure that the same SpO2-target range is applied in both study groups
The SpO2-target has to be within the range of 87–95% (may include 87% and/or 95%),
Care has to be taken that the same SpO2-target ranges are applied in clinical routine and in both study groups
Documentation of the study intervention
In both study groups, the type of respiratory support, the type of ventilator and the application of FiO2-C have to be documented daily during the intervention period on a treatment log.
The primary outcome measure is a composite of death, BPD or NEC assessed at 36 weeks PMA and severe ROP assessed when full vascularization of the retina is documented.
Definitions of components of the primary outcome
Defined as any ROP stage 3 or higher, or acute posterior ROP, or any ROP in Zone 1, or any treatment for ROP. ROP will be diagnosed at routine ophthalmological examinations, beginning at a PMA of 32 weeks according to international recommendations and local standards until complete vascularization of the retina . The severity of ROP will be graded according to the international classification .
Defined as requiring positive pressure support or supplemental oxygen at 36 weeks ±2 days PMA, including an oxygen reduction test for infants requiring less than 0.3 FiO2, representing ‘moderate’ or ‘severe’ BPD according to the National Institute of Child Health and Development consensus definition .
Defined as modified Bell stage ≥IIa  until 36 weeks PMA.
The co-primary outcome (tested in a hierarchical design) is the composite outcome of death, language or cognitive delay, motor impairment, severe visual impairment or hearing impairment, all assessed at 24 ± 1 months corrected age.
Definitions of components of the co-primary outcome
Language or Cognitive delay: Defined as a language or cognitive composite score at the Bayley Scales of Infant Development 3rd edition  of < 85.
Motor impairment: Defined as a Gross Motor Function Classification System (GMFCS) score of 2–5 .
Severe visual impairment: Defined as best corrected vision in the better eye yields a visual acuity less than 6/60 m (20/200 ft) according to the relevant doctor’s reports / discharge summary.
Severe hearing impairment: need for a hearing aid or cochlear implant.
Any clinical suspicion of previously undiagnosed visual or hearing problems during the FiO2-C follow-up visit requires a referral to an eye specialist or an pedaudiologist.
If the parents refuse the assessment at the study center or if Bayley test cannot be performed:
Other assessments of neurocognitive and motor development will betaken into account, if parents refuse to attend the follow-up.
Cognitive- and language-composite-scores will then be imputed as follows:
A score “> 85” will be imputed if
a different cognitive test has been performed elsewhere and scored higher than 1SD below the mean
the family pediatrician/doctor/health professional caring for the child or the parents rate the infant as “normal”
A score “< 85” will be imputed if
a different cognitive test has been performed elsewhere and scored lower than 1SD below the mean
the family pediatrician/doctor/health professional caring for the child or the parents rate the infant as “delayed” or “impaired”.
Any such imputation will be described in the final report and the scientific publication.
Key secondary outcome variables are the individual components of the primary (death, severe ROP, BPD, NEC) and co-primary outcome variables (death, cognitive delay or language delay, motor impairment (GMFCS score of 2–5 ), as well as severe visual or hearing impairment,, the composite scores of the Bayley Scales (3rd edition), the rate of cerebral palsy (CP) according to the criteria defined by the European network ‘Surveillance of CP in Europe’, and the GMFCS score.
In addition to ‘severe ROP’ as component of the primary outcome, the ‘ROP Severity Score’ (also entitled ‘ROP activity and structure score’)  is assessed as secondary outcome, enabling better differentiation and likely being more relevant for functional outcome.
The Helsinki Declaration shall be applied to the clinical trial, as well as Good Clinical Practice (GCP). The protocol was submitted and approved by the Ethics Committee of the University Hospital Tübingen as the lead ethics committee. Furthermore, the relevant ethics committees responsible for any of the participating study sites will have to approve participation of the site.
A freely accessible web page for FiO2-C has been set up (www.fioc-study.eu), providing an overview of aims, partners, study outline, progress and milestones, meetings, findings and news.
Form of consent
Written informed consent from parents or legal guardians is required for participation in the study.
Where required by national law, insurance will be obtained for all study patients.
Sample size, power and study duration
The required sample size was calculated for the primary research hypothesis that the implementation of FiO2-C reduces the cumulative incidence of the composite primary outcome (death, severe ROP, BPD, or NEC).
The co-primary research hypothesis is that FiO2-C also reduces death or severe NDI (see outcome measures for details). These hypotheses are assessed as a-priori ordered hypotheses, where the co-primary hypothesis will only be tested in a confirmatory manner if the primary hypothesis has been confirmed. Consequently, no correction for multiple testing will be performed.
We assume that,
the cumulative incidence of the primary composite outcome of this study is 50% in the control group
FiO2-C reduces the burden of severe hypoxemia/hyperoxemia by 25–50% and (based on the assumption that (again) 25–50% of the outcome is associated with recurrent hypo−/hyperoxemia) effects a relative risk reduction in this outcome by at least 12.5%.
In summary, we assume a reduction in the primary outcome from 50% (in the control group) to 44% in the intervention group (FiO2-C).
Sample size calculations were based on a Χ2-test, assuming a power of 80% and a significance level of 5%. Based on these assumptions, 1110 infants are required in each treatment group (total 2220 infants). Because all components of this primary outcome will be determined during the initial hospitalization (i.e. until first discharge from neonatal care), the rate of drop-out before ascertainment of the primary outcome will be low as < 5%. Hence, a total of 2340 infants need to be enrolled and randomized (see Fig. 1).
Assuming an incidence of 50% for the co-primary outcome in the control group and a relative risk reduction (RRR) of 25% for the co-primary outcome in the FiO2-C group, the proposed sample size will have a power > 80% to prove this difference even if up to 20% of randomized infants will be lost to follow-up until 24 months corrected age.
It is estimated that about 90% of all ELGANs will qualify for inclusion into this study without any exclusion criteria. Estimating a participation rate of 80%, approximately 3350 infants have to be screened.
We estimate a recruitment of about 65 patients per month and therefore the recruitment phase of the study will last for approximately 36 months. The individual participation in the study will be about 27 months (between 56 and 91 days of treatment – depending on GA at birth - with an additional follow up to 24 months corrected age).
Analysis of the primary outcome will be based on the intention to treat analysis set, which comprises all randomized patients. Portions of infants with primary endpoint will be compared in a statistical model that accounts for the factors considered by the randomization procedure and the randomization of twins and other multiples. The treatment effect will be reported as a risk ratio and as a risk difference with 95% confidence interval. The co-primary outcome will be assessed only if superiority of FiO2-C with respect to the primary outcome is confirmed at the 2-sided level of 0.05. This hierarchical testing procedure maintains a multiple type I error of 0.05. All statistical analyses will be described in detail in a statistical analysis plan completed before closure of the database. An interim analysis for efficacy is not intended.
An independent Data Monitoring Committee (DMC) is instituted and monitors recruitment, compliance, and safety parameters after 50, 100, 200 and 300 patients have completed 44 + 0/7 weeks PMA, and after every 200 patients have reached this age thereafter.
Safety parameters monitored by the DMC include:
Early deaths (for the DMC defined as < 44 weeks PMA), late deaths (for the DMC defined as ≥44 weeks PMA), all deaths, BPD, discharge on home oxygen or home positive pressure respiratory support, severe ROP, NEC, (focal) intestinal perforation requiring laparotomy, PDA requiring treatment, intraventricular hemorrhage >grade 2, cystic periventricular leukomalacia. Because the safety parameters include components of the primary outcome, the incidence rates and 95% confidence intervals, these parameters will be ‘coded’ as “safety parameter A-I”.
Furthermore, safety analyses include occurrence and rates of reported adverse events and incidents by treatment group.
Sponsor of the FiO2-C-trial is the University Hospital Tübingen, Geissweg 3, 72,076 Tübingen, Germany. Contact is available at firstname.lastname@example.org.
Medical ethics committees
At the time of submission, the relevant ethics committee in Germany approved the study. Applications for approvals are currently underway in additional countries (e.g., the Netherlands and Switzerland).
National Regulatory/competent authorities
At the time of submission, the National Regulatory/Competent Authority of Germany (BfArM) approved the study. Authority approval may not be necessary elsewhere – but this will be determined in collaboration with the relevant ethics committees.