Clinical trial NCT03168516: Effects of Closed-loop Automatic Control of FiO2 in Extremely Preterm Infants
Official title: Effects of Closed-loop Automatic Control of the Inspiratory Fraction of Oxygen (FiO2-C) on Outcome of Extremely Preterm Infants - a Randomized Controlled Parallel Group Multicenter Trial for Safety and Efficacy
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Infant,Premature
Keywords: Oxygen
closed-loop automatic control
Oxygen saturation
preterm infants
Lead sponsor: University Hospital Tuebingen
Sponsor class: OTHER
First posted: 2017-05-30
Enrollment: 1065
Sex: ALL
Maximum age (years): 48
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Extremely low gestational age neonates (ELGANs), i.e. those born at \<28 weeks, frequently experience intermittent hypoxemic/hyperoxemic episodes. Observational data indicate that severe and prolonged hypoxemic episodes are associated with retinopathy of prematurity (ROP), impaired long-term development and death. Closed-loop automated control of the inspiratory fraction of oxygen (FiO2-C) reduces time outside the oxygen target range, decreases number and duration of hypo- and hyperoxemic episodes, and reduces caregivers' workload. The proposed observer-blinded randomized controlled trial was designed and will be powered to compare the effect of FiO2-C in addition to manual adjustments, in comparison with manual adjustments of FiO2 only, on death and severe complications of prematurity thought to be related to hypoxia/hyperoxia and neurodevelopmental impairment in ELGANs. The results of this trial may help to improve the quality of life of ELGANs and reduce the burden of significant morbidity as well as costs for health care and society

Detailed description: Approximately 0.5% of all neonates (i.e., about 25,000 infants per year in Europe) are extremely low gestational age neonates (ELGANs), i.e. have a gestational age (GA) of \<28 completed weeks at birth. ELGANs have higher incidences of mortality, retinopathy of prematurity (ROP), chronic lung disease and other risks of prematurity as well as severe neurodevelopmental impairment.

The vast majority of ELGANs require supplemental oxygen in addition to mechanical respiratory support (including CPAP). Irrespective of the SpO2 target, the vast majority of ELGANs suffers from recurrent intermittent hypoxemic and (as a consequence of inappropriate adjustments of FiO2) hyperoxemic episodes. Recurrent intermittent hypoxic episodes - i.e. wide fluctuations in oxygen levels - are associated with an increased risk of ROP and there are data that suggest that late deaths and neurodevelopmental impairment are also linked to them.

Continuous positive airway pressure (CPAP) has been shown to reduce extubation failure in preterm infants, which may in part be due to a reduced frequency and severity of apnea of prematurity and stabilized functional residual capacity during apnea. Keeping oxygen levels (i.e., SpO2) stable despite irregular breathing patterns in ELGANs, requires frequent adjustments of the FiO2 which is both challenging, time consuming, and often impossible due to limited personnel resources.

FiO2-Controllers have been developed by several manufacturers of infant ventilators. They reduce the burden of hyper-/hypoxemia in infants while being safe and accurate in very short-term studies. The effects of FiO2-C on clinically relevant outcome measures and the safety of long-term continuous application, however, have yet to be elucidated. Hence there is now a window of opportunity to assess this new technology for benefits and harms, before it is implemented into neonatal care without appropriate evaluation of its safety and efficacy.

Eligibility criteria: Inclusion Criteria:

* Preterm infants with a gestational age (GA) at birth of 23+0/7 - 27+6/7 weeks

Exclusion Criteria:

* Decision for palliative care
* congenital anomalies
* postnatal age \> 48h
* missing parental consent
* lack of device enabling closed-loop automatic control of FiO2

Primary outcomes:
measure: Primary outcome I: composite outcome of death, severe retinopathy of prematurity (ROP), chronic lung disease of prematurity (BPD), necrotizing enterocolitis (NEC)
timeFrame: until/at post-menstrual age (PMA) 36 weeks (death, BPD and NEC) and at latest at PMA 44 weeks for severity of ROP
measure: Primary outcome II: composite of death or neurodevelopmental impairment (NDI)
timeFrame: at 24 months of age corrected for prematurity
Secondary outcomes:
measure: Death
timeFrame: 24 months of age corrected for prematurity
measure: ROP Severity Score
timeFrame: at latest at PMA 44 weeks
measure: Severe ROP
timeFrame: at latest at PMA 44 weeks
measure: bronchopulmonary Dysplasia (BPD)
timeFrame: until 36 weeks PMA
measure: Necrotizing enterocolitis (NEC)
timeFrame: until 36 weeks PMA
measure: Neurodevelopmental impairment (NDI)
timeFrame: at 24 months of age corrected for prematurity
measure: Bayley III. Language composite score - dichotomized
timeFrame: at 24 months of age corrected for prematurity
measure: Bayley III: Language composite score - numerical
timeFrame: at 24 months corrected age
measure: Bayley III: Cognitive composite score - dichotomized
timeFrame: at 24 months of age corrected for prematurity
measure: Bayley III: Cognitive composite score - numerical
timeFrame: at 24 months of age corrected for prematurity
measure: Cerebral palsy
timeFrame: at 24 months of age corrected for prematurity
measure: Motor disability
timeFrame: at 24 months of age corrected for prematurity
measure: Score data of modified Gross Motor Function Classification Scale (GMFCS)
timeFrame: at 24 months of age corrected for prematurity
measure: Bayley III: Motor composite score - numerical
timeFrame: at 24 months of age corrected for prematurity
measure: Severe visual impairment
timeFrame: at 24 months of age corrected for prematurity
measure: Severe hearing impairment
timeFrame: at 24 months of age corrected for prematurity
Other outcomes:
Locations:
city: Xi'an
country: China
facility: Northwest Women's and Children's Hospital
city: Amberg
country: Germany
facility: Klinikum St. Marien - Klinik für Kinder und Jugendliche
city: Augsburg
country: Germany
facility: Josefinum - Klinik für Kinder und Jugendliche
city: Bad Kreuznach
country: Germany
facility: Diakonie Krankenhaus der Kreuznacher Diakonie
city: Bremen
country: Germany
facility: Klinikum Links der Weser
city: Dresden
country: Germany
facility: Universitätsklinikum Dresden
city: Düsseldorf
country: Germany
facility: Universitätsklinikum Düsseldorf
city: Erfurt
country: Germany
facility: HELIOS Klinikum Erfurt
city: Esslingen
country: Germany
facility: Klinikum Esslingen GmbH - Klinik für Kinder und Jugendliche
city: Freiburg
country: Germany
facility: Zentrum für Kinder- und Jugendmedizin
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg
city: Karlsruhe
country: Germany
facility: Städtisches Klinikum Karlsruhe
city: Leipzig
country: Germany
facility: University Hospital Leipzig
city: München - Großhadern
country: Germany
facility: Universitätsklinikum München
city: München
country: Germany
facility: Städtisches Klinikum - Klinik für Neonatologie
city: München
country: Germany
facility: München Klinik Harlaching
city: Münster
country: Germany
facility: Klinik für Kinder- und Jugendmedizin
city: Nürnberg
country: Germany
facility: Klinik Hallerwiese - Cnopf'sche Kinderklinik
city: Regensburg
country: Germany
facility: Krankenhaus Barmherzige Brüder
city: Reutlingen
country: Germany
facility: Klinikum am Steinenberg
city: Schweinfurt
country: Germany
facility: Leopoldina Krankenhaus der Stadt Schweinfurt GmbH
city: Speyer
country: Germany
facility: Diakonissen-Stiftungs-Krankenhaus Speyer
city: Stuttgart
country: Germany
facility: Klinikum Stuttgart, Olgahospital
city: Tübingen
country: Germany
facility: University Hospital Tübingen
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
city: Villingen-Schwenningen
country: Germany
facility: Schwarzwald-Baar-Klinik
city: Winnenden
country: Germany
facility: Rems-Murr-Kliniken gGmbH
city: Maastricht
country: Netherlands
facility: Kindergeneeskunde Maastricht Universitair Medisch Centrum
city: Veldhoven
country: Netherlands
facility: Máxima Medical Center
city: Zwolle
country: Netherlands
facility: Isala Kliniek Zwolle - Location Sophia
city: Middlesbrough
country: United Kingdom
facility: The James Cook University Hospital
Study officials:
affiliation: University Children's Hospital Tuebingen
name: Axel Franz, Prof. Dr.
role: STUDY_DIRECTOR
References:
citation: Maiwald CA, Niemarkt HJ, Poets CF, Urschitz MS, Konig J, Hummler H, Bassler D, Engel C, Franz AR; FiO2-C Study Group. Effects of closed-loop automatic control of the inspiratory fraction of oxygen (FiO2-C) on outcome of extremely preterm infants - study protocol of a randomized controlled parallel group multicenter trial for safety and efficacy. BMC Pediatr. 2019 Oct 21;19(1):363. doi: 10.1186/s12887-019-1735-9.