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Infant,PrematurePhase 3FiO2-CNCT03168516

Effects of Closed-loop Automatic Control of FiO2 in Extremely Preterm Infants

A Phase 3 study of Infant,Premature, run by University Hospital Tuebingen at 32 sites in 4 countries.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages Up to 48 hours
Conditions the study is for
Infant,Premature
Type of treatment
Medical device
Could I receive a placebo?
No, everyone receives an active treatment
How many people
1,065 participants
Where
32 sitesin 4 countries
Study dates
27 Jul 2018to Dec 2026
Phase
Phase 3
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages Up to 48 hours
  • All sexes
  • No healthy volunteers
  • Child

Who may be able to join

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

Who cannot join

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

Trial locations and contacts

32 sites in 4 countries.

32 sites in 4 countries

Germany27 sites

  • Klinikum St. Marien - Klinik für Kinder und Jugendliche

    Amberg, 92224

  • Josefinum - Klinik für Kinder und Jugendliche

    Augsburg, 86154

  • Diakonie Krankenhaus der Kreuznacher Diakonie

    Bad Kreuznach, 55543

  • Klinikum Links der Weser

    Bremen, 29277

  • Universitätsklinikum Dresden

    Dresden, 01307

  • Universitätsklinikum Düsseldorf

    Düsseldorf, 40225

  • HELIOS Klinikum Erfurt

    Erfurt, 99089

  • Klinikum Esslingen GmbH - Klinik für Kinder und Jugendliche

    Esslingen am Neckar, 73730

  • Zentrum für Kinder- und Jugendmedizin

    Freiburg im Breisgau, 79106

  • Medizinische Hochschule Hannover

    Hanover, 30625

  • Universitätsklinikum Heidelberg

    Heidelberg, 69120

  • Städtisches Klinikum Karlsruhe

    Karlsruhe, 76133

  • University Hospital Leipzig

    Leipzig, 04103

  • Städtisches Klinikum - Klinik für Neonatologie

    München, 80804

  • München Klinik Harlaching

    München, 81545

  • Universitätsklinikum München

    München - Großhadern, 81377

  • Klinik für Kinder- und Jugendmedizin

    Münster, 48149

  • Klinik Hallerwiese - Cnopf'sche Kinderklinik

    Nuremberg, 90419

  • Krankenhaus Barmherzige Brüder

    Regensburg, 93049

  • Klinikum am Steinenberg

    Reutlingen, 72764

  • Leopoldina Krankenhaus der Stadt Schweinfurt GmbH

    Schweinfurt, 97422

  • Diakonissen-Stiftungs-Krankenhaus Speyer

    Speyer, 67346

  • Klinikum Stuttgart, Olgahospital

    Stuttgart, 70174

  • University Hospital Tübingen

    Tübingen, 72076

  • Universitätsklinikum Ulm

    Ulm, 89075

  • Schwarzwald-Baar-Klinik

    Villingen-Schwenningen, 78052

  • Rems-Murr-Kliniken gGmbH

    Winnenden, 71364

Other trials in Germany

Netherlands3 sites

  • Kindergeneeskunde Maastricht Universitair Medisch Centrum

    Maastricht, 6229

  • Máxima Medical Center

    Veldhoven, 5504 DB

  • Isala Kliniek Zwolle - Location Sophia

    Zwolle, 8025

Other trials in Netherlands

China1 site

  • Northwest Women's and Children's Hospital

    Xi'an, 710061

Other trials in China

United Kingdom1 site

  • The James Cook University Hospital

    Middlesbrough

Other trials in United Kingdom

About this study

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

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

Read the 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.

Being tested
closed-loop automatic control of the inspiratory fraction of oxygen (FiO2-C)
Keywords
Oxygen, closed-loop automatic control, Oxygen saturation, preterm infants
Medical subject headings
Premature Birth

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • closed-loop automatic control of the inspiratory fraction of oxygen (FiO2-C)Device

    Application of FiO2-C (provided by standard infant ventilators) in addition to manual adjustments of the inspired oxygen fraction (FiO2) during mechanical ventilation and continuous positive airway pressure (CPAP) in ELGANs at least up to 32weeks PMA according to a standardized protocol

Study groups in NCT03168516
Study groupRoleWhat they receive
Experimental interventionExperimentalclosed-loop automatic control of the inspiratory fraction of oxygen (FiO2-C)
Receives: Device: closed-loop automatic control of the inspiratory fraction of oxygen (FiO2-C)
Control interventionNo interventionStandard care, i.e. manual adjustments of the FiO2 only

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Primary outcome I: composite outcome of death, severe retinopathy of prematurity (ROP), chronic lung disease of prematurity (BPD), necrotizing enterocolitis (NEC)

    The primary outcome I is a composite of any of the following:

    • Death
    • Severe retinopathy of prematurity (severe ROP, as defined in 7.3.1)
    • Chronic lung disease of prematurity (BPD, according to the physiological definition, which is described in detail in the study protocol)
    • Necrotizing enterocolitis (NEC, as defined in the study protocol) until discharge from hospital

    The primary endpoint I will be analysed between the two intervention groups using a stratified chi2-test and Cochrane Mantel-Haenszel statistics will be presented (risk ratios and 95%-confidence intervals). The factors considered for randomization (center, sex and gestational age at birth (<26 weeks and ≥26 weeks) will also be used for analysis.

    Measured: until/at post-menstrual age (PMA) 36 weeks (death, BPD and NEC) and at latest at PMA 44 weeks for severity of ROP

  2. Primary outcome II: composite of death or neurodevelopmental impairment (NDI)

    The primary outcome II is a composite of any of the following:

    • death or neurodevelopmental impairment (defined as at least one of the following components: motor disability (GMFCS 2-5), language or cognitive delay (language composite score < 85 or cognitive composite score < 85 on Bayley Scales of Infant Development, 3rd edition) or severe visual or hearing impairment (need for a hearing aid or cochlear implant)). In case of missing Bayley III test results, Bayley II results, other developmental test results or PARCA-R parent questionnaire results may substitute for the Bayley III test results in a hierarchical manner described in the study protocol.

    The primary outcome II will be analysed between the two intervention groups using chi2-test and Cochrane Mantel-Haenszel statistics will be presented (risk ratios and 95%-confidence intervals). The factors considered for randomization (center, sex and gestational age at birth (<26 weeks and ≥26 weeks) will also be used for analysis.

    Measured: at 24 months of age corrected for prematurity

Secondary outcomes (16)

  1. Death

    Death rates will be compared between the two treatment groups and analyzed by Cochrane-Mantel-Haenszel- X²-Test.

    Measured: 24 months of age corrected for prematurity

  2. ROP Severity Score

    The most severe grade of ROP according to 25 categories currently developed by the working group of the international neonatal consortium (may have to be adapted as the consensus process proceeds), documented in either eye (for at least 2 consecutive examinations) will be analysed using Wilcoxon-Mann-Whitney test.

    Measured: at latest at PMA 44 weeks

  3. Severe ROP

    defined as: ROP stage 0, 1 or 2 (in Zone 2 or 3) = no/non-severe ROP versus 3, 4 or 5, or AP-ROP, or any ROP in Zone 1, or any treatment for ROP = severe ROP.

    Rates of severe ROP will be compared between the two treatment groups and analyzed by Cochrane-Mantel-Haenszel- X²-Test.

    Measured: at latest at PMA 44 weeks

  4. bronchopulmonary Dysplasia (BPD)

    As part of routine care, the presence of BPD will be determined at 36 weeks postmenstrual age (PMA) according to the physiological definition of Walsh et al. [Walsh, J Perinatol 2003].

    BPD rates will be compared between the two treatment groups and analyzed by Cochrane-Mantel-Haenszel- X²-Test.

    Measured: until 36 weeks PMA

  5. Necrotizing enterocolitis (NEC)

    NEC (modified Bell stage ≥ IIA according to [Bell, Ann Surg 1978]) or intestinal perforation will be diagnosed at surgery, at autopsy, or by either the finding of pneumatosis intestinalis, hepatobiliary gas, or free intraperitoneal air on abdominal x-ray, or by demonstration of gas (bubbles) in the portal vein on abdominal ultrasound or abdominal x-ray.

    NEC rates will be compared between the two treatment groups and analyzed by Cochrane-Mantel-Haenszel- X²-Test.

    Measured: until 36 weeks PMA

  6. Neurodevelopmental impairment (NDI)

    NDI is defined as at least one of the following components: motor disability (modified GMFCS 2-5), language or cognitive delay (language composite score < 85 or cognitive composite score < 85 on Bayley Scales of Infant Development, 3rd edition) or severe visual or hearing impairment (need for a hearing aid or cochlear implant).

    In case of missing Bayley III test results, Bayley II results, other developmental test results or PARCA-R parent questionnaire results may substitute for the Bayley III test results in a hierarchical manner described in the study protocol.

    NDI rates will be compared between the two treatment groups and analyzed by Cochrane-Mantel-Haenszel- X²-Test.

    Measured: at 24 months of age corrected for prematurity

  7. Bayley III. Language composite score - dichotomized

    The results of the language composite score of the Bayley Scales of Infant Development, 3rd edition, will be dichotomized by <85 (abnormal) versus >=85 (normal) and compared between the two treatment groups by Cochrane-Mantel-Haenszel- X²-Test.

    Measured: at 24 months of age corrected for prematurity

  8. Bayley III: Language composite score - numerical

    The raw numerical data of the language-composite-score will be analysed using Wilcoxon-Mann-Whitney test. The use of this test accounts for the fact that data will be cut due to lack sensitivity below 50 points.

    Measured: at 24 months corrected age

  9. Bayley III: Cognitive composite score - dichotomized

    The results of the cognitive composite score of the Bayley Scales of Infant Development, 3rd edition, will be dichotomized by <85 (abnormal) versus >=85 (normal) and compared between the two treatment groups by Cochrane-Mantel-Haenszel- X²-Test.

    Measured: at 24 months of age corrected for prematurity

  10. Bayley III: Cognitive composite score - numerical

    The numerical data of the cognitive-composite-score will be analysed using Wilcoxon-Mann-Whitney test. The use of this test accounts for the fact that data will be cut due to lack sensitivity below 50 points.

    Measured: at 24 months of age corrected for prematurity

  11. Cerebral palsy

    Cerebral palsy will be diagnosed if the child has a non-progressive motor impairment characterized by abnormal muscle tone and impaired range or control of movements, according to the criteria defined by the European network 'Surveillance of CP in Europe'.

    Rates of cerebral palsy will be compared between the two treatment groups and analyzed by Cochrane-Mantel-Haenszel- X²-Test.

    Measured: at 24 months of age corrected for prematurity

  12. Motor disability

    Motor disability is defined as a modified GMFCS 2-5 versus a modified GMFCS 0-1, which is regarded as being normal. Rates of motor disability will be compared between the two treatment groups and analyzed by Cochrane-Mantel-Haenszel- X²-Test.

    Measured: at 24 months of age corrected for prematurity

  13. Score data of modified Gross Motor Function Classification Scale (GMFCS)

    GMFCS-Score for quantification of the effects of cerebral palsy and other motor impairments (adapted from Palisano et al. [Palisano Med Child Neurol 1997]) using the FiO2-C-GMFCS-score sheet (separate document not part of this protocol) will be analysed. GMFCS-score consists of six categories. Analysis will be done by using Wilcoxon-Mann-Whitney test.

    Measured: at 24 months of age corrected for prematurity

  14. Bayley III: Motor composite score - numerical

    The numerical data of the motor-composite-score will be analysed using Wilcoxon-Mann-Whitney test. The use of this test accounts for the fact that data will be cut due to lack of sensitivity below 50 points.

    Measured: at 24 months of age corrected for prematurity

  15. Severe visual impairment

    Severe visual impairment is defined as an ophthalmological assesment indicating "severe visual impairment", e.g. the best corrected vision in the better eye yields a visual acuity less than 6/60 m (20/200 ft).

    Rates will be compared between the two treatment groups and analyzed by Cochrane-Mantel-Haenszel- X²-Test.

    Measured: at 24 months of age corrected for prematurity

  16. Severe hearing impairment

    Severe hearing impairment is defined as need for a hearing aid or cochlear implant. Rates will be compared between the two treatment groups and analyzed by Cochrane-Mantel-Haenszel- X²-Test.

    Measured: at 24 months of age corrected for prematurity

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted30 May 2017
  2. Study start27 Jul 2018
  3. Primary completionDec 2026 (estimated)
  4. Study completionDec 2026 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
1,065 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03168516
Sponsor's protocol ID
FiO2-C
Other IDs
2018-000453-41, BMBF-Fz01KG1602, 2018
Acronym
FiO2-C
Status last verified
Jul 2023
First submitted
18 May 2017
Last updated
27 Dec 2023
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Undecided

Publications

  • 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.

    PubMed 31630690

  • Franz AR, Maiwald CA, Niemarkt HJ, Ehrhardt H, Mendler MR, Essers J, Mohns T, Flemmer AW, Kley A, Bittrich HJ, Bohnhorst B, Jacobi C, Bai R, Mulder EEM, Neuberger P, Hutten MC, Rauch R, Volkl TMK, Hohn T, Brenner B, Gebauer C, Holz S, Hammond ENL, Korner HT, Mense L, Lubking LK, Nair V, Bender C, Fiedler A, Schneider HC, Gausepohl HJ, Kruger M, Kittel J, Schroth M, Sandkotter J, Lode HM, Kuntz M, Konig J, Seyfang A, Engel C, Stauch A, Bassler D, Hummler HD, Poets CF, Urschitz MS; FiO2-C Study Group. Automatic versus manual control of oxygen and neonatal clinical outcomes in extremely preterm infants: a multicentre, parallel-group, randomised, controlled, superiority trial. Lancet Child Adolesc Health. 2026 Mar;10(3):179-188. doi: 10.1016/S2352-4642(25)00351-7.

    PubMed 41679888

  • Konig J, Stauch A, Engel C, Urschitz MS, Franz AR; FiO2-C study group. Statistical analysis plan for the FiO2-C trial: effects of closed-loop automatic control of the inspiratory fraction of oxygen (FiO2-C) on outcomes of extremely preterm infants-a randomized-controlled parallel group multicentre trial for safety and efficacy. Trials. 2024 Nov 12;25(1):756. doi: 10.1186/s13063-024-08615-7.

    PubMed 39533330

Questions about this trial

What is this clinical trial studying?

A Phase 3 study of Infant,Premature, run by University Hospital Tuebingen at 32 sites in 4 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 1 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: under way, not looking for participants, as of the sponsor's last update on 27 Dec 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 32 sites in Germany, Netherlands, China, United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Primary outcome I: composite outcome of death, severe retinopathy of prematurity (ROP), chronic lung disease of prematurity (BPD), necrotizing enterocolitis (NEC) (time frame: until/at post-menstrual age (PMA) 36 weeks (death, BPD and NEC) and at latest at PMA 44 weeks for severity of ROP). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03168516, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Dec 2023.

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