High-Flow Nasal Cannula Versus Continuous Positive Airway Pressure for Initial Respiratory Support in Very Preterm Infants: Study Protocol for a Multicenter Randomized Controlled Trial (SIMPLSAFE3)

High-Flow Nasal Cannula Versus Continuous Positive Airway Pressure for Initial Respiratory Support in Very Preterm Infants: Study Protocol for a Multicenter Randomized Controlled Trial (SIMPLSAFE3) | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article High-Flow Nasal Cannula Versus Continuous Positive Airway Pressure for Initial Respiratory Support in Very Preterm Infants: Study Protocol for a Multicenter Randomized Controlled Trial (SIMPLSAFE3) Tereza Lamberská, Klára Jonáš, Martina Borčinová, Yotam Ophir, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7871909/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract Background Non-invasive continuous positive airway pressure (CPAP) is the standard initial respiratory support for preterm infants. However, requirements such as optimal pressure delivery and facemask repositioning, which trigger unwanted reflexes and bradycardia, often necessitate the use of positive pressure ventilation (PPV). Findings from a pilot study suggested that high-flow nasal cannula (HFNC) may be a promising alternative to CPAP, with lower PPV requirements. We hypothesize that HFNC is a safe, effective, and user-friendly alternative to CPAP for stabilizing very preterm infants (28 + 0–31 + 6 weeks of gestation), potentially reducing the need for PPV. We aim to compare HFNC and CPAP as initial respiratory support strategies at birth. Methods This is a multicenter, randomized, stepped-wedge cluster trial. Infants will receive either HFNC (8 L/min) or CPAP (6 cmH₂O) immediately after birth with tactile stimulation. The fraction of inspired oxygen (FiO₂) will start at 0.30. PPV will be initiated if bradycardia or persistently low oxygen saturation (SpO₂) occurs. The primary outcome is stabilization with the assigned support without PPV administration. Secondary outcomes include: (A) achievement of SpO₂ ≥80% at 5 min (with ≤ 2 brief PPV episodes) as a surrogate of safety; (B) achievement of SpO₂ >90% with FiO₂ ≤0.40 at 10 min as a surrogate of efficacy. Overall, 446 infants will be recruited in both arms, with an estimated study duration of 2 years. Discussion The findings may inform future respiratory support guidelines for very preterm infants at birth. Trial registration : ClinicalTrials.gov NCT06543589, registered August 9, 2024. respiratory stabilization very preterm infants continuous positive airway pressure CPAP high-flow nasal cannula HFNC preterm delivery Figures Figure 1 Figure 2 Figure 3 Administrative information Note: the numbers in curly brackets in this protocol refer to SPIRIT checklist item numbers. The order of the items has been modified to group similar items (see http://www.equator-network.org/reporting-guidelines/spirit-2013-statement-defining-standard-protocol-items-for-clinical-trials/). Title {1} High-Flow Nasal Cannula Versus Continuous Positive Airway Pressure for Initial Respiratory Support in Very Preterm Infants: Study Protocol for a Multicenter Randomized Controlled Trial (SIMPLSAFE 3) Trial registration {2a and 2b}. ClinicalTrials.gov NCT06543589, registered August 9, 2024. Protocol version {3} Version 1.0, dated November 2024. Funding {4} This trial is supported by the Charles University in Prague (UNCE/24/MED/018); by the Charles University Research program ”Cooperatio – Maternal and Childhood Care, Neonatology;” and by the institutional grant of the General University Hospital in Prague (CZ-DRO-VFN64165). Author details {5a} Department of Gynaecology, Obstetrics and Neonatology, First Faculty of Medicine Charles University and General University Hospital in Prague, Prague, Czech Republic; Department of Paediatric and Inherited Metabolic Disorders, General University Hospital, First Faculty of Medicine, Charles University, Prague, Czech Republic Name and contact information for the trial sponsor {5b} General University Hospital in Prague, U Nemocnice 499/2, 128 08 Prague 2, Czech Republic. +420 224 961 111 Role of sponsor {5c} The funders had no role in the study design, collection, analysis, or interpretation of data; writing of the manuscript; or the decision to publish the results. Background and rationale {6a} Noninvasive continuous positive airway pressure (CPAP) is the recommended initial respiratory support for preterm infants; however, the optimal pressure level remains uncertain [ 1 ]. Additionally, prolonged exposure to higher pressures is ineffective if spontaneous breathing is absent or repeatedly interrupted [ 2 , 3 ]. In such cases, positive pressure ventilation (PPV) is typically initiated. Unfortunately, non-invasive PPV is often inadequate and can damage immature lung tissue [ 4 ]. Additionally, frequent facemask adjustments to reduce air leakage can provoke trigeminal or vagal nerve reflexes, leading to bradycardia and disrupted breathing [ 5 , 6 ]. High-flow nasal cannula (HFNC) represents a less invasive alternative, reducing facial stimulation but providing less precise pressure delivery. Pilot studies suggest that HFNC is feasible for stabilizing infants born between 28 + 0 and 31 + 6 weeks of gestation, although concerns remain regarding lower airway pressures potentially increasing PPV requirements [ 7 – 9 ]. In our single-arm pilot study, HFNC safely stabilized more than 80% of very preterm infants (VPIs), with PPV required in only 11% and escalation to CPAP in just 3% [ 10 ]. Importantly, the PPV requirement was substantially lower than in our recent historical cohort of comparable infants supported with CPAP via facemask or nasal interface (11% vs. 43% and 32%, respectively), as well as in other published CPAP-managed cohorts. [ 11 , 12 ]. We hypothesize that HFNC reduces upper airway resistance and minimizes stimulation of sensitive facial and nasal regions compared with using CPAP, thereby decreasing the need for PPV during the initial stabilization of VPIs. HFNC may also offer practical advantages over non-invasive CPAP in cases requiring simple ventilatory support, such as during continuous early skin-to-skin care (Fig. 1) and transport from the delivery room to the neonatal intensive care unit (NICU). Objectives {7} In the SIMPLSAFE3 trial (ClinicalTrials.gov, NCT06543589), we evaluate the clinical effectiveness of HFNC compared with that of CPAP as the primary mode of respiratory support in VPIs. The primary outcome is the need for PPV within the first 10 min after birth. Secondary outcomes include (1) achieving peripheral oxygen saturation (SpO₂) > 80% within the first 5 min of life, regardless of fraction of inspired oxygen (FiO₂) and PPV use, and (2) achieving SpO₂ > 90% with FiO₂ ≤ 0.40 within the first 10 min of life without PPV. Trial design {8} This is a multicenter, stepped-wedge cluster randomized controlled trial conducted across 10 tertiary NICUs, nine in the Czech Republic and one in Slovakia. The allocation ratio follows a cluster-based cross from CPAP to HFNC. The framework is superior. Methods: participants, interventions, and outcomes Study setting {9} Recruitment will take place across nine tertiary centers in the Czech Republic and one in Slovakia [ 13 , 14 ]. The study follows SPIRIT guidelines (Fig. 2) and has multicenter ethics approval (General University Hospital Prague, No.127/24 S-IV) and was additionally approved by the ethics committee of each participating institution [ 15 ]. Eligibility criteria {10} The inclusion criteria include all preterm infants born between 28 + 0 and 31 + 6 weeks of gestation in the participating centers. Infants with major anomalies, birthweight < 800 g, umbilical cord pH < 7.1, or without signed parental informed consent will be excluded. Who will take informed consent? {26a} Parental informed consent will be obtained before recruitment. Additional consent provisions for collection and use of participant data and biological specimens {26b} Not applicable. Interventions Explanation for the choice of comparators {6b} Continuous positive airway pressure (CPAP) is the recommended standard of care for initial non-invasive respiratory support in very preterm infants and is therefore selected as the comparator. High-flow nasal cannula (HFNC), although increasingly used in clinical practice, lacks sufficient evidence for safety and efficacy in the delivery room context, warranting its evaluation against CPAP. Intervention description {11a} Delivery room stabilization Infants will be randomized into two groups, either ARM A (HFNC) or ARM B (CPAP). Arm A (HFNC): Heated, humidified air-oxygen blends will be delivered via a binasal cannula with a diameter of approximately 50–80% of the patient’s nares. The specific equipment and cannula models may vary depending on the preferences of individual centers. The initial flow rate will be set at 8 L/min, with FiO₂ starting at 0.3 and adjusted based on the heart rate and SpO₂ targets. Arm B (CPAP): CPAP will be administered using a T-piece resuscitator or comparable device that can be used to provide heated, humidified gas with controlled pressures via a facemask or nasal prongs. Interfaces will be sized per the manufacturer’s guidelines to fit nares without tissue compression. The initial CPAP pressure will be set at 6 cmH₂O, adjustable up to a maximum of 8 cmH₂O based on clinical assessment. FiO₂ will begin at 0.30 and will be titrated in accordance with heart rate and SpO₂ targets. All infants will receive standard stabilization measures routinely employed in the delivery room, such as thermal protection, delayed cord clamping (≥ 60 s), and tactile stimulation, as clinically indicated in line with international neonatal resuscitation guidelines. Any local protocol deviations will be documented accordingly. Umbilical cord milking will be permitted only in cases of unfeasible delayed clamping. A pulse oximeter sensor will be placed on the right wrist, and electrocardiogram leads will be applied only if resuscitative measures are required. Respiratory support will commence immediately after birth. Criteria for discontinuing or modifying allocated interventions {11b} Criteria for positive pressure ventilation The PPV initiation criteria will be based on the target heart rate (dominant early indicator) and SpO₂ levels. PPV will be indicated if the pulse is < 100 beats per minute (bpm) at 3 min of life or < 120 bpm at 4 min of life, or if SpO₂ target levels will remain uncorrected despite administration of 100% oxygen. The infant’s clinical response to FiO₂ escalation will guide the timing of initiation. PPV will begin with five initial breaths delivered via T-piece facemask at 25 cmH₂O. Infants randomized to HFNC who require more than two episodes or prolonged PPV within the first 10 min may be switched early to CPAP at the clinician‘s discretion. Persistent apnea or bradycardia (< 100 bpm) will prompt conventional management, including suction, PPV, endotracheal intubation, and other resuscitation measures, as clinically indicated. The administration of surfactant in the delivery room will be at the attending physician’s discretion. Following stabilization, infants will be placed in skin-to-skin contact with one of their parents before transfer to NICU. Neonatal intensive care unit care Infants receiving respiratory support before NICU admission will continue the same support upon transfer. Standardized criteria for crossover will be available to guide appropriate transitions between HFNC and CPAP. HFNC will be changed to CPAP if FiO₂ requirements exceed 0.35 for > 30 min within the first 3 h at a flow of 8 L/min, or if FiO₂ remains above 0.30 beyond 3 h. CPAP will be changed to HFNC if FiO₂ requirements fall below 0.30 within the first 3 h or below 0.25 thereafter, indicating respiratory stability. These criteria do not apply to centers that exclusively use nasal CPAP for managing respiratory distress syndrome. Respiratory support will be completely discontinued at the discretion of the neonatologist. Surfactant administration in the NICU will follow local protocols. Strategies to improve adherence to interventions {11c} Adherence to the assigned intervention will be promoted through detailed standard operating procedures, staff training at each site, and use of predefined criteria for crossover to alternative support. All deviations from the assigned intervention will be documented in the electronic information system and will be monitored by the coordinating center to ensure protocol compliance. Relevant concomitant care permitted or prohibited during the trial {11d} Surfactant administration will be permitted at the discretion of the attending physician and will follow local protocols. Centers that use nasal CPAP exclusively for the management of respiratory distress syndrome will be exempt from crossover to HFNC after stabilization. Provisions for post-trial care {30} No specific post-trial care is required, as all interventions under study (CPAP and HFNC) are established components of standard neonatal care. Participants will continue to receive routine clinical management at the discretion of the treating neonatologist, and no additional compensation for trial-related harm is foreseen beyond existing institutional and national regulations. Outcomes {12} The primary endpoint is the proportion of infants who receive PPV within the first 10 min after birth. Secondary endpoints include: Safety surrogate: achieving SpO₂ > 80% within 5 min with no more than two brief episodes of PPV. Effectiveness surrogate: achieving SpO₂ > 90% with FiO₂ ≤ 0.40 by 10 min. Continued use of the assigned respiratory support at 3 h. Endotracheal intubation performed within the first 3 h of life. Additional outcomes will cover delivery room interventions, the overall respiratory course (including surfactant administration, air leaks, mechanical ventilation duration), and major morbidities such as bronchopulmonary dysplasia, necrotizing enterocolitis, intraventricular hemorrhage, retinopathy of prematurity, death, or home oxygen requirement prior to discharge. All outcomes will be recorded until discharge. Participant timeline {13} Participants will be enrolled at birth, with follow-up assessments at 3 hours, 3 days, 7 days, and the final visit at 36 weeks maternal postmenstrual age or hospital discharge. Assessments will include respiratory support, oxygen requirements, safety outcomes, and secondary/tertiary endpoints. The overall study period will thus extend from birth until 36 weeks maternal postmenstrual age or discharge. Figure 3 presents the participant flowchart for the SIMPLSAFE3 trial. Sample size {14} The primary outcome is the difference in the proportion of neonates requiring PPV within 10 min of birth between the HFNC and CPAP groups. We aim to detect a relative reduction of 15% (from 30 to 15%). Based on a pilot study and published literature, and assuming an intracluster correlation coefficient of 0.01, an alpha of 0.05, a power of 80%, an average cluster size of 15, and five clusters in a stepped-wedge design, approximately 443 infants are required to detect this difference. Recruitment {15} Based on the birth rate and incidence of preterm labour at the participating institutions, recruitment is expected to take up to 24 month. Assignment of interventions: allocation Sequence generation {16a} Cluster-based stepped-wedge randomization is applied across 10 tertiary NICUs, with each center crossing over from CPAP to HFNC at predefined intervals; the allocation sequence is generated using a computer-based random number generator to ensure unbiased allocation and balance over time. Concealment mechanism {16b} Due to the nature of the stepped-wedge cluster randomized design, concealment at the center level is not feasible; however, the randomization schedule is generated centrally and communicated to sites only at the beginning of each time period, while data analysts remain blinded to group allocation, thereby minimizing selection bias despite the open-label design. Implementation {16c} The allocation sequence will be generated centrally by the study statistician using a computer-based random number generator. Eligible infants are identified and enrolled by site investigators or designated neonatologists after obtaining parental informed consent. Assignment to the allocated intervention (CPAP or HFNC) is performed by the attending clinical team at each participating center according to the current step of the randomization schedule. Assignment of interventions: Blinding Who will be blinded {17a} Owing to the study nature, it is not feasible to blind participating centers to their intervention status. However, the data analysts will remain blinded to the group assignments to minimize bias. Procedure for unblinding if needed {17b} Not applicable. Data collection and management Plans for assessment and collection of outcomes {18a} Maternal data Maternal age, multiplicity, clinical signs of chorioamnionitis, antenatal steroid administration, premature rupture of membranes (duration and evidence), fetal position, mode of delivery, and use of general anesthesia will be recorded. Gestational age will be determined primarily by first-trimester ultrasound or the last menstrual period. For pregnancies without prenatal care, gestational age will be estimated using ultrasound before delivery and postnatal clinical assessments, such as the Ballard score and cerebellar imaging. Neonatal data The date of birth, sex, gestational age, birth weight, and randomized group allocation will be documented. Delivery room data will include the placental transfusion method (including delayed cord clamping duration), tactile stimulation, type of noninvasive respiratory support, provision of PPV, and intubation. Vital signs (temperature, heart rate, and preductal SpO2) will be recorded. Medications recorded will include surfactants (dose and timing), postnatal corticosteroids, treatments for patent ductus arteriosus, and intravitreal injections for retinopathy of prematurity. Neonatal morbidities will be diagnosed using the following standard criteria: intraventricular hemorrhage (Papile classification), necrotizing enterocolitis (Bell’s criteria), bronchopulmonary dysplasia (Jensen criteria), and cystic periventricular leukomalacia. Plans to promote participant retention and complete follow-up {18b} Given the neonatal setting, follow-up is conducted entirely during the initial hospitalization, up to 36 weeks maternal postmenstrual age or discharge. Retention is promoted by integrating study assessments into routine clinical care, ensuring minimal additional burden for families and clinical teams. Site investigators will monitor adherence to scheduled assessments and document outcomes prospectively in the electronic information system to minimize loss to follow-up Data management {19} Data will be recorded in a secure, web-based electronic case report form hosted on REDCap, which is compliant with General Data Protection Regulations, the Health Insurance Portability and Accountability Act, and other relevant regulations. Patient data will be pseudonymized with unique study identifiers, and identifiable information will be kept separately and securely at each site for 15 years. Confidentiality {27} Participant information is pseudonymized in the secure REDCap system, with identifiers stored separately at each site. Access is limited to authorized staff, and all data are managed under GDPR and institutional policies to ensure confidentiality before, during, and after the trial. Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in this trial/future use {33} Not applicable. Statistical methods Statistical methods for primary and secondary outcomes {20a} The primary endpoint will be analyzed using mixed-effects logistic regression, accounting for clustering by center and time period. The model will be used to estimate the odds ratios for the PPV requirement, adjusted for the stepped-wedge design. Interim analyses/ Methods for additional analyses (e.g. subgroup analyses) {20b; 21b} Not applicable/ not planned. Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c} Principal investigators will be responsible for recruitment, data collection, completeness, and quality, as well as regular reporting of adverse events. Monitoring will be provided by an appointed independent data monitor, who is responsible for checking the accuracy, completeness, and plausibility of all data and its compliance with the protocol and GCP requirements. The monitor will clarify the discrepancies with the respective trial site electronically via CIS. Trial sites are responsible for answering the electronic queriers without delay. Plans to give access to the full protocol, participant level-data and statistical code {31c} De-identified individual participant data, supporting documentation, and the full trial protocol from this ongoing clinical trial will be made available upon reasonable request following study completion and publication of the main results. Oversight and monitoring Composition of the coordinating center and trial steering committee {5d} The trial steering committee is composed by the trial chair, clinicians, and experts from the relevant disciplines. The committee will be responsible for the overall supervision of the trial and will provide the principal investigators with regular updates (via the newsletter or at investigator meetings). The committee will periodically review recommendations of the Independent Data monitoring committee and, on consideration of this information, recommend any appropriate amendments/actions for the trial as necessary. The committee will be responsible for preparations of the amendments to the protocol prior to submission to the relevant regulatory authority. The committee acts on behalf of the funder and the sponsor. Composition of the data monitoring committee, its role, and reporting structure {21a} An Independent Data Monitoring Committee (IDMC) will regularly review safety data and AE rates, in order to safeguard the interests of the trial participants, assess safety of the interventions during the trial, and monitor overall conduct of the trial. IDMC will periodically review the number of relevant events in both trial ARMs to ensure the safety of each treatment modality. This measure will provide sufficient safety monitoring while not putting additional demands on the sample size, as would an interim analysis. The IDMC will receive and review the progress and accruing data of this trial and provide advice on the conduct of the trial to the trial chair and Trial steering committee. IDMC members are independent and will be constructively critical of the ongoing trial but will also support the aims and methods of the trial. Adverse event reporting and harms {22} AEs related to respiratory support may include air leaks, pulmonary hemorrhage, intraventricular hemorrhage, facial injury from interfaces, and acidosis (pH < 7.20). Serious AEs (SAEs) include death, life-threatening conditions, prolonged hospitalization, or permanent disability. Given the vulnerability of the study population, many anticipated complications will not be classified or reported individually as SAE. All events will be graded as mild, moderate, or severe, and monitored until resolution or stabilization. If safety concerns arise during the trial, the trial will be temporarily paused. Frequency and plans for auditing trial conduct {23} An Independent Data Monitoring Committee will regularly review safety data and adverse event (AE) rates. An interim safety analysis will be performed by the Safety Board following the enrolment of every 100 participants. Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25} Any important protocol amendments will be promptly communicated to the relevant ethics committees, regulatory authorities, investigators, and trial participants as appropriate. Dissemination plans {31a} The trial results will be disseminated through postings in public trial registries, presentations at scientific meetings, publication in peer-reviewed journals, communication to trial participants and relevant stakeholders, and will be used to inform appropriate clinical guidelines, regardless of whether results are positive, negative, or inconclusive. Discussion Respiratory support in the delivery room is a critical component of care for very preterm infants. Although CPAP is widely recommended as the first-line non-invasive modality, its practical use is often limited by mask leaks, unstable pressure delivery, and stimulation of trigeminal or vagal reflexes, which can provoke bradycardia and interrupt spontaneous breathing [ 1 – 3 , 5 ]. These limitations frequently necessitate positive pressure ventilation (PPV), which carries a risk of lung injury in immature infants [ 4 ]. HFNC has been proposed as a less invasive alternative that circumvents many of these challenges. Preliminary data of our pilot study are encouraging, showing that HFNC safely stabilized more than 80% of VPIs, with PPV required in only 11% and escalation to CPAP in just 3%. However, our pilot study was single arm, conducted at a single center with a limited sample size, which restricts generalizability. In addition, published observational and retrospective reports on HFNC use in the delivery room remain heterogeneous, and direct randomized comparisons with CPAP are scarce. The SIMPLSAFE3 trial addresses these gaps by implementing a multicenter, stepped-wedge cluster randomized design across 10 tertiary NICUs that compare HFNC and CPAP therapy in infants born between 28 + 0 and 31 + 6 weeks. This design enables balanced within-center comparisons while facilitating broad clinical implementation [ 13 , 16 , 17 ]. However, some limitations must be acknowledged. Variations in clinical practice and local protocols may influence the results, and the stepped-wedge design introduces potential temporal confounding factors [ 16 ]. Nevertheless, this pragmatic approach may enhance the generalizability of the findings and their implications, as well as ensure comprehensive enrolment. In conclusion, if HFNC proves non-inferior or superior to CPAP, the findings will have immediate clinical implications, supporting the use of a simpler, less invasive modality for the stabilization of very preterm infants in the delivery room and during transport to the NICU. Such a shift could reduce airway trauma, improve infant comfort, and streamline neonatal resuscitation practices. Conversely, if HFNC is associated with higher rates of PPV or treatment failure, this will strengthen the evidence base for maintaining CPAP as the standard of care. Ultimately, this trial is designed not only to generate high-quality evidence to inform clinical practice but also to guide future updates of international neonatal resuscitation guidelines and non-invasive support strategies in VPIs. Trial status Recruitment opened on 1 December 2024. The current protocol version is 1.0 (dated November 2024). Recruitment is expected to be completed by 31 December 2026. Abbreviations CPAP Continuous Positive Airway Pressure HFNC High-Flow Nasal Cannula NICU Neonatal Intensive Care Unit PPV Positive Pressure Ventilation FiO₂ Fraction of Inspired Oxygen VPIs Very Premature Infants SpO₂ Peripheral Oxygen Saturation BPM Beats Per Minute AE Adverse Event SAE Serious Adverse Event Declarations Acknowledgements Not applicable. Authors’ contributions {31b} TL and RP are the chief investigators; they conceived the study, led the proposal, and developed the protocol. KJ contributed to the study design and the development of the study proposal. MB contributed to data analysis and interpretation. TL, KJ, and MB were responsible for the clinical coordination and data acquisition. YO contributed to the medical and linguistic refinement of the proposal. All the authors have read and approved the final version of the manuscript. Funding {4} This trial was supported by the Charles University in Prague (UNCE/24/MED/018); the Charles University Research program “Cooperatio – Maternal and Childhood Care, Neonatology;” and the institutional grant of The General University Hospital in Prague (CZ-DRO-VFN64165). The funders had no role in the study design; collection, analysis, or interpretation of data; writing of the manuscript; or the decision to publish the results. Availability of data and materials {29} Data will be provided by reasonable request to corresponding author of this manuscript. Ethics approval and consent to participate {24} The study protocol was approved by the institutional review board of the leading institution, the General University Hospital in Prague, in August 2024 (Ethics No. 127/24 S-IV), and was subsequently approved by the institutional review boards of all participating institutions. Parents receive verbal information antenatally; written consent may also be obtained postnatally, according to institutional and federal guidelines, before enrolment. Pseudonymized data are stored securely under the International Council for Harmonization – Good Clinical Practice standards and the Declaration of Helsinki. Consent for publication {32} Not applicable. Competing interests {28} The authors declare that they have no competing interests. References Madar J, Roehr CC, Ainsworth S, Ersdal H, Morley C, Rüdiger M, et al. European Resuscitation Council Guidelines 2021: Newborn resuscitation and support of transition of infants at birth. 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Considerations before selecting a stepped-wedge cluster randomized trial design for a practice improvement study. Ann Fam Med. 2022;20:255–61. https://doi.org/10.1370/afm.2810 . Hemming K, Taljaard M, Grimshaw J. Introducing the new CONSORT extension for stepped-wedge cluster randomised trials. Trials. 2019;20:68. https://doi.org/10.1186/s13063-018-3116-3 . Chan AW, Tetzlaff JM, Gøtzsche PC, Altman DG, Mann H, Berlin JA, et al. SPIRIT 2013 explanation and elaboration: Guidance for protocols of clinical trials. BMJ. 2013;346:e7586. https://doi.org/10.1136/bmj.e7586 . Hemming K, Haines TP, Chilton PJ, Girling AJ, Lilford RJ. The stepped wedge cluster randomised trial: Rationale, design, analysis, and reporting. BMJ. 2015;350:h391. https://doi.org/10.1136/bmj.h391 . Hussey MA, Hughes JP. Design and analysis of stepped wedge cluster randomized trials. Contemp Clin Trials. 2007;28:182–91. https://doi.org/10.1016/j.cct.2006.05.007 . Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 23 Feb, 2026 Reviewers invited by journal 23 Feb, 2026 Editor assigned by journal 25 Nov, 2025 First submitted to journal 24 Nov, 2025 Editorial decision: Minor revision 08 Nov, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7871909","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":595706703,"identity":"5ab4c6ff-b00a-40d6-a360-12d6f6f85cf2","order_by":0,"name":"Tereza Lamberská","email":"","orcid":"https://orcid.org/0000-0001-6693-3143","institution":"Charles University First Faculty of Medicine: Univerzita Karlova 1 lekarska fakulta","correspondingAuthor":false,"prefix":"","firstName":"Tereza","middleName":"","lastName":"Lamberská","suffix":""},{"id":595706704,"identity":"c879d75f-6214-498c-8ac4-16dac5571909","order_by":1,"name":"Klára Jonáš","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/UlEQVRIiWNgGAWjYDCCA0AsAcLsIF4FEDMzNxCphRnEOwPSwkiEFgaYFsY2EJOAFr4buQc/WFQclpdsZn724ee82mj+dqCWHxXbcGqRvJGXLCFx5rDhbGY245m9247nzjjM2MDYc+Y2Ti0GN3IMJCTb0hjnMTMYM/BuO5bbANTCzNiGV4vxD6AW+3nM7J8Z/845ljufCC1mQFtsEmcz8xgz8zbU5G4gpEXyzBszC4kzNskzm3mKmWWOHcjdCNRyEJ9f+I7nGN+WqJCwnXG8fTPjm5q63HnnDx988KMCtxYQYJZAsA+DyQN41QMB4wcEu46Q4lEwCkbBKBiBAAApb1kTOlt2pwAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0009-0008-4073-4224","institution":"General University Hospital in Prague: Vseobecna Fakultni Nemocnice v Praze","correspondingAuthor":true,"prefix":"","firstName":"Klára","middleName":"","lastName":"Jonáš","suffix":""},{"id":595706705,"identity":"915cccfd-2f28-4973-89f6-06465e630fa8","order_by":2,"name":"Martina Borčinová","email":"","orcid":"","institution":"Charles University First Faculty of Medicine: Univerzita Karlova 1 lekarska fakulta","correspondingAuthor":false,"prefix":"","firstName":"Martina","middleName":"","lastName":"Borčinová","suffix":""},{"id":595706706,"identity":"a43e6036-4167-468b-86b8-6518dfacbfb4","order_by":3,"name":"Yotam Ophir","email":"","orcid":"","institution":"Charles University First Faculty of Medicine: Univerzita Karlova 1 lekarska fakulta","correspondingAuthor":false,"prefix":"","firstName":"Yotam","middleName":"","lastName":"Ophir","suffix":""},{"id":595706707,"identity":"f94cbbe3-a818-42bb-ac7c-cf8d13feb4c7","order_by":4,"name":"Richard Plavka","email":"","orcid":"","institution":"Charles University First Faculty of Medicine: Univerzita Karlova 1 lekarska fakulta","correspondingAuthor":false,"prefix":"","firstName":"Richard","middleName":"","lastName":"Plavka","suffix":""}],"badges":[],"createdAt":"2025-10-15 23:00:55","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7871909/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7871909/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":103837800,"identity":"32c64bb4-4872-41f2-93ad-8e27b0b8c242","added_by":"auto","created_at":"2026-03-03 14:20:40","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":319587,"visible":true,"origin":"","legend":"\u003cp\u003eHFNC may be used during continuous early skin-to-skin care. Copyright Satyan Lakshminrusimha, with permission.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7871909/v1/fa403b71a1a8de2ecad12fb9.jpg"},{"id":103837801,"identity":"13143853-a8fd-481a-949c-fa81a7283b63","added_by":"auto","created_at":"2026-03-03 14:20:40","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":78984,"visible":true,"origin":"","legend":"\u003cp\u003eParticipant timeline: Schedule of enrollment, interventions, and assessments – according to SPIRIT guidelines.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7871909/v1/763e79f10689108bcadbcd69.png"},{"id":103837803,"identity":"b53e8b59-2159-4317-b61a-031fa1b1e9a4","added_by":"auto","created_at":"2026-03-03 14:20:40","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":400497,"visible":true,"origin":"","legend":"\u003cp\u003eParticipant flowchart in the SIMPLSAFE3 trial.\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7871909/v1/9375042f8e18e5c9ad62d085.jpg"},{"id":104400782,"identity":"ac9a0a30-7d7d-4a74-905d-0c12d3143e27","added_by":"auto","created_at":"2026-03-11 12:11:02","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2228157,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7871909/v1/96f8f126-2bba-447f-a545-dfcadfdb2bf9.pdf"}],"financialInterests":"","formattedTitle":"High-Flow Nasal Cannula Versus Continuous Positive Airway Pressure for Initial Respiratory Support in Very Preterm Infants: Study Protocol for a Multicenter Randomized Controlled Trial (SIMPLSAFE3)","fulltext":[{"header":"Administrative information","content":"\u003cp\u003eNote: the numbers in curly brackets in this protocol refer to SPIRIT checklist item numbers. The order of the items has been modified to group similar items (see http://www.equator-network.org/reporting-guidelines/spirit-2013-statement-defining-standard-protocol-items-for-clinical-trials/).\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"639\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 218px;\"\u003e\n \u003cp\u003eTitle {1}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 421px;\"\u003e\n \u003cp\u003eHigh-Flow Nasal Cannula Versus Continuous Positive Airway Pressure for Initial Respiratory Support in Very Preterm Infants: Study Protocol for a Multicenter Randomized Controlled Trial (SIMPLSAFE 3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 218px;\"\u003e\n \u003cp\u003eTrial registration {2a and 2b}.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 421px;\"\u003e\n \u003cp\u003eClinicalTrials.gov NCT06543589, registered August 9, 2024.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 218px;\"\u003e\n \u003cp\u003eProtocol version {3}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 421px;\"\u003e\n \u003cp\u003eVersion 1.0, dated November 2024.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 218px;\"\u003e\n \u003cp\u003eFunding {4}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 421px;\"\u003e\n \u003cp\u003eThis trial is supported by the Charles University in Prague (UNCE/24/MED/018); by the Charles University Research program \u0026rdquo;Cooperatio \u0026ndash; Maternal and Childhood Care, Neonatology;\u0026rdquo; and by the institutional grant of the General University Hospital in Prague (CZ-DRO-VFN64165).\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 218px;\"\u003e\n \u003cp\u003eAuthor details {5a}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 421px;\"\u003e\n \u003cp\u003eDepartment of Gynaecology, Obstetrics and Neonatology, First Faculty of Medicine Charles University and General University Hospital in Prague, Prague, Czech Republic; Department of Paediatric and Inherited Metabolic Disorders, General University Hospital, First Faculty of Medicine, Charles University, Prague, Czech Republic\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 218px;\"\u003e\n \u003cp\u003eName and contact information for the trial sponsor {5b}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 421px;\"\u003e\n \u003cp\u003eGeneral University Hospital in Prague, U Nemocnice 499/2, 128 08 Prague 2, Czech Republic. +420 224 961 111\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 218px;\"\u003e\n \u003cp\u003eRole of sponsor {5c}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 421px;\"\u003e\n \u003cp\u003eThe funders had no role in the study design, collection, analysis, or interpretation of data; writing of the manuscript; or the decision to publish the results.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Background and rationale {6a}","content":"\u003cp\u003eNoninvasive continuous positive airway pressure (CPAP) is the recommended initial respiratory support for preterm infants; however, the optimal pressure level remains uncertain [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Additionally, prolonged exposure to higher pressures is ineffective if spontaneous breathing is absent or repeatedly interrupted [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In such cases, positive pressure ventilation (PPV) is typically initiated. Unfortunately, non-invasive PPV is often inadequate and can damage immature lung tissue [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Additionally, frequent facemask adjustments to reduce air leakage can provoke trigeminal or vagal nerve reflexes, leading to bradycardia and disrupted breathing [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHigh-flow nasal cannula (HFNC) represents a less invasive alternative, reducing facial stimulation but providing less precise pressure delivery. Pilot studies suggest that HFNC is feasible for stabilizing infants born between 28\u0026thinsp;+\u0026thinsp;0 and 31\u0026thinsp;+\u0026thinsp;6 weeks of gestation, although concerns remain regarding lower airway pressures potentially increasing PPV requirements [\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. In our single-arm pilot study, HFNC safely stabilized more than 80% of very preterm infants (VPIs), with PPV required in only 11% and escalation to CPAP in just 3% [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Importantly, the PPV requirement was substantially lower than in our recent historical cohort of comparable infants supported with CPAP via facemask or nasal interface (11% vs. 43% and 32%, respectively), as well as in other published CPAP-managed cohorts. [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. We hypothesize that HFNC reduces upper airway resistance and minimizes stimulation of sensitive facial and nasal regions compared with using CPAP, thereby decreasing the need for PPV during the initial stabilization of VPIs. HFNC may also offer practical advantages over non-invasive CPAP in cases requiring simple ventilatory support, such as during continuous early skin-to-skin care (Fig.\u0026nbsp;1) and transport from the delivery room to the neonatal intensive care unit (NICU).\u003c/p\u003e\n\u003ch3\u003eObjectives {7}\u003c/h3\u003e\n\u003cp\u003eIn the SIMPLSAFE3 trial (ClinicalTrials.gov, NCT06543589), we evaluate the clinical effectiveness of HFNC compared with that of CPAP as the primary mode of respiratory support in VPIs. The primary outcome is the need for PPV within the first 10 min after birth. Secondary outcomes include (1) achieving peripheral oxygen saturation (SpO₂)\u0026thinsp;\u0026gt;\u0026thinsp;80% within the first 5 min of life, regardless of fraction of inspired oxygen (FiO₂) and PPV use, and (2) achieving SpO₂ \u0026gt; 90% with FiO₂ \u0026le; 0.40 within the first 10 min of life without PPV.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eTrial design {8}\u003c/h2\u003e \u003cp\u003eThis is a multicenter, stepped-wedge cluster randomized controlled trial conducted across 10 tertiary NICUs, nine in the Czech Republic and one in Slovakia. The allocation ratio follows a cluster-based cross from CPAP to HFNC. The framework is superior.\u003c/p\u003e \u003c/div\u003e"},{"header":"Methods: participants, interventions, and outcomes","content":"\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStudy setting {9}\u003c/h2\u003e \u003cp\u003eRecruitment will take place across nine tertiary centers in the Czech Republic and one in Slovakia [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The study follows SPIRIT guidelines (Fig.\u0026nbsp;2) and has multicenter ethics approval (General University Hospital Prague, No.127/24 S-IV) and was additionally approved by the ethics committee of each participating institution [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eEligibility criteria {10}\u003c/h3\u003e\n\u003cp\u003eThe inclusion criteria include all preterm infants born between 28\u0026thinsp;+\u0026thinsp;0 and 31\u0026thinsp;+\u0026thinsp;6 weeks of gestation in the participating centers. Infants with major anomalies, birthweight\u0026thinsp;\u0026lt;\u0026thinsp;800 g, umbilical cord pH\u0026thinsp;\u0026lt;\u0026thinsp;7.1, or without signed parental informed consent will be excluded.\u003c/p\u003e\n\u003ch3\u003eWho will take informed consent? {26a}\u003c/h3\u003e\n\u003cp\u003e Parental informed consent will be obtained before recruitment.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eAdditional consent provisions for collection and use of participant data and biological specimens {26b}\u003c/h2\u003e \u003cp\u003eNot applicable.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eInterventions\u003c/h3\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eExplanation for the choice of comparators {6b}\u003c/h2\u003e \u003cp\u003eContinuous positive airway pressure (CPAP) is the recommended standard of care for initial non-invasive respiratory support in very preterm infants and is therefore selected as the comparator. High-flow nasal cannula (HFNC), although increasingly used in clinical practice, lacks sufficient evidence for safety and efficacy in the delivery room context, warranting its evaluation against CPAP.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eIntervention description {11a}\u003c/h2\u003e \u003cdiv id=\"Sec12\" class=\"Section3\"\u003e \u003ch2\u003eDelivery room stabilization\u003c/h2\u003e \u003cp\u003eInfants will be randomized into two groups, either ARM A (HFNC) or ARM B (CPAP).\u003c/p\u003e \u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eArm A (HFNC): Heated, humidified air-oxygen blends will be delivered via a binasal cannula with a diameter of approximately 50\u0026ndash;80% of the patient\u0026rsquo;s nares. The specific equipment and cannula models may vary depending on the preferences of individual centers. The initial flow rate will be set at 8 L/min, with FiO₂ starting at 0.3 and adjusted based on the heart rate and SpO₂ targets.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eArm B (CPAP): CPAP will be administered using a T-piece resuscitator or comparable device that can be used to provide heated, humidified gas with controlled pressures via a facemask or nasal prongs. Interfaces will be sized per the manufacturer\u0026rsquo;s guidelines to fit nares without tissue compression. The initial CPAP pressure will be set at 6 cmH₂O, adjustable up to a maximum of 8 cmH₂O based on clinical assessment. FiO₂ will begin at 0.30 and will be titrated in accordance with heart rate and SpO₂ targets.\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e \u003cp\u003e All infants will receive standard stabilization measures routinely employed in the delivery room, such as thermal protection, delayed cord clamping (\u0026ge;\u0026thinsp;60 s), and tactile stimulation, as clinically indicated in line with international neonatal resuscitation guidelines. Any local protocol deviations will be documented accordingly. Umbilical cord milking will be permitted only in cases of unfeasible delayed clamping. A pulse oximeter sensor will be placed on the right wrist, and electrocardiogram leads will be applied only if resuscitative measures are required. Respiratory support will commence immediately after birth.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eCriteria for discontinuing or modifying allocated interventions {11b}\u003c/h2\u003e \u003cdiv id=\"Sec14\" class=\"Section3\"\u003e \u003ch2\u003eCriteria for positive pressure ventilation\u003c/h2\u003e \u003cp\u003eThe PPV initiation criteria will be based on the target heart rate (dominant early indicator) and SpO₂ levels. PPV will be indicated if the pulse is \u0026lt;\u0026thinsp;100 beats per minute (bpm) at 3 min of life or \u0026lt;\u0026thinsp;120 bpm at 4 min of life, or if SpO₂ target levels will remain uncorrected despite administration of 100% oxygen. The infant\u0026rsquo;s clinical response to FiO₂ escalation will guide the timing of initiation. PPV will begin with five initial breaths delivered via T-piece facemask at 25 cmH₂O. Infants randomized to HFNC who require more than two episodes or prolonged PPV within the first 10 min may be switched early to CPAP at the clinician\u0026lsquo;s discretion. Persistent apnea or bradycardia (\u0026lt;\u0026thinsp;100 bpm) will prompt conventional management, including suction, PPV, endotracheal intubation, and other resuscitation measures, as clinically indicated. The administration of surfactant in the delivery room will be at the attending physician\u0026rsquo;s discretion. Following stabilization, infants will be placed in skin-to-skin contact with one of their parents before transfer to NICU.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eNeonatal intensive care unit care\u003c/h2\u003e \u003cp\u003eInfants receiving respiratory support before NICU admission will continue the same support upon transfer. Standardized criteria for crossover will be available to guide appropriate transitions between HFNC and CPAP. HFNC will be changed to CPAP if FiO₂ requirements exceed 0.35 for \u0026gt;\u0026thinsp;30 min within the first 3 h at a flow of 8 L/min, or if FiO₂ remains above 0.30 beyond 3 h. CPAP will be changed to HFNC if FiO₂ requirements fall below 0.30 within the first 3 h or below 0.25 thereafter, indicating respiratory stability. These criteria do not apply to centers that exclusively use nasal CPAP for managing respiratory distress syndrome. Respiratory support will be completely discontinued at the discretion of the neonatologist. Surfactant administration in the NICU will follow local protocols.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eStrategies to improve adherence to interventions {11c}\u003c/h2\u003e \u003cp\u003eAdherence to the assigned intervention will be promoted through detailed standard operating procedures, staff training at each site, and use of predefined criteria for crossover to alternative support. All deviations from the assigned intervention will be documented in the electronic information system and will be monitored by the coordinating center to ensure protocol compliance.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eRelevant concomitant care permitted or prohibited during the trial {11d}\u003c/h2\u003e \u003cp\u003eSurfactant administration will be permitted at the discretion of the attending physician and will follow local protocols. Centers that use nasal CPAP exclusively for the management of respiratory distress syndrome will be exempt from crossover to HFNC after stabilization.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eProvisions for post-trial care {30}\u003c/h2\u003e \u003cp\u003eNo specific post-trial care is required, as all interventions under study (CPAP and HFNC) are established components of standard neonatal care. Participants will continue to receive routine clinical management at the discretion of the treating neonatologist, and no additional compensation for trial-related harm is foreseen beyond existing institutional and national regulations.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eOutcomes {12}\u003c/h2\u003e \u003cp\u003eThe primary endpoint is the proportion of infants who receive PPV within the first 10 min after birth.\u003c/p\u003e \u003cp\u003eSecondary endpoints include:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eSafety surrogate: achieving SpO₂ \u0026gt; 80% within 5 min with no more than two brief episodes of PPV.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eEffectiveness surrogate: achieving SpO₂ \u0026gt; 90% with FiO₂ \u0026le; 0.40 by 10 min.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eContinued use of the assigned respiratory support at 3 h.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eEndotracheal intubation performed within the first 3 h of life.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eAdditional outcomes will cover delivery room interventions, the overall respiratory course (including surfactant administration, air leaks, mechanical ventilation duration), and major morbidities such as bronchopulmonary dysplasia, necrotizing enterocolitis, intraventricular hemorrhage, retinopathy of prematurity, death, or home oxygen requirement prior to discharge.\u003c/p\u003e \u003cp\u003eAll outcomes will be recorded until discharge.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003eParticipant timeline {13}\u003c/h2\u003e \u003cp\u003eParticipants will be enrolled at birth, with follow-up assessments at 3 hours, 3 days, 7 days, and the final visit at 36 weeks maternal postmenstrual age or hospital discharge. Assessments will include respiratory support, oxygen requirements, safety outcomes, and secondary/tertiary endpoints. The overall study period will thus extend from birth until 36 weeks maternal postmenstrual age or discharge. Figure\u0026nbsp;3 presents the participant flowchart for the SIMPLSAFE3 trial.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003eSample size {14}\u003c/h2\u003e \u003cp\u003eThe primary outcome is the difference in the proportion of neonates requiring PPV within 10 min of birth between the HFNC and CPAP groups. We aim to detect a relative reduction of 15% (from 30 to 15%). Based on a pilot study and published literature, and assuming an intracluster correlation coefficient of 0.01, an alpha of 0.05, a power of 80%, an average cluster size of 15, and five clusters in a stepped-wedge design, approximately 443 infants are required to detect this difference.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec22\" class=\"Section2\"\u003e \u003ch2\u003eRecruitment {15}\u003c/h2\u003e \u003cp\u003eBased on the birth rate and incidence of preterm labour at the participating institutions, recruitment is expected to take up to 24 month.\u003c/p\u003e \u003cdiv id=\"Sec23\" class=\"Section3\"\u003e \u003ch2\u003eAssignment of interventions: allocation\u003c/h2\u003e \u003cdiv id=\"Sec24\" class=\"Section4\"\u003e \u003ch2\u003eSequence generation {16a}\u003c/h2\u003e \u003cp\u003eCluster-based stepped-wedge randomization is applied across 10 tertiary NICUs, with each center crossing over from CPAP to HFNC at predefined intervals; the allocation sequence is generated using a computer-based random number generator to ensure unbiased allocation and balance over time.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec25\" class=\"Section3\"\u003e \u003ch2\u003eConcealment mechanism {16b}\u003c/h2\u003e \u003cp\u003eDue to the nature of the stepped-wedge cluster randomized design, concealment at the center level is not feasible; however, the randomization schedule is generated centrally and communicated to sites only at the beginning of each time period, while data analysts remain blinded to group allocation, thereby minimizing selection bias despite the open-label design.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec26\" class=\"Section3\"\u003e \u003ch2\u003eImplementation {16c}\u003c/h2\u003e \u003cp\u003eThe allocation sequence will be generated centrally by the study statistician using a computer-based random number generator. Eligible infants are identified and enrolled by site investigators or designated neonatologists after obtaining parental informed consent. Assignment to the allocated intervention (CPAP or HFNC) is performed by the attending clinical team at each participating center according to the current step of the randomization schedule.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec27\" class=\"Section3\"\u003e \u003ch2\u003eAssignment of interventions: Blinding\u003c/h2\u003e \u003cdiv id=\"Sec28\" class=\"Section4\"\u003e \u003ch2\u003eWho will be blinded {17a}\u003c/h2\u003e \u003cp\u003eOwing to the study nature, it is not feasible to blind participating centers to their intervention status. However, the data analysts will remain blinded to the group assignments to minimize bias.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec29\" class=\"Section2\"\u003e \u003ch2\u003eProcedure for unblinding if needed {17b}\u003c/h2\u003e \u003cp\u003eNot applicable.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eData collection and management\u003c/h3\u003e\n\u003cdiv id=\"Sec31\" class=\"Section2\"\u003e \u003ch2\u003ePlans for assessment and collection of outcomes {18a}\u003c/h2\u003e \u003cdiv id=\"Sec32\" class=\"Section3\"\u003e \u003ch2\u003eMaternal data\u003c/h2\u003e \u003cp\u003eMaternal age, multiplicity, clinical signs of chorioamnionitis, antenatal steroid administration, premature rupture of membranes (duration and evidence), fetal position, mode of delivery, and use of general anesthesia will be recorded. Gestational age will be determined primarily by first-trimester ultrasound or the last menstrual period. For pregnancies without prenatal care, gestational age will be estimated using ultrasound before delivery and postnatal clinical assessments, such as the Ballard score and cerebellar imaging.\u003c/p\u003e \u003cdiv id=\"Sec33\" class=\"Section4\"\u003e \u003ch2\u003eNeonatal data\u003c/h2\u003e \u003cp\u003eThe date of birth, sex, gestational age, birth weight, and randomized group allocation will be documented. Delivery room data will include the placental transfusion method (including delayed cord clamping duration), tactile stimulation, type of noninvasive respiratory support, provision of PPV, and intubation. Vital signs (temperature, heart rate, and preductal SpO2) will be recorded. Medications recorded will include surfactants (dose and timing), postnatal corticosteroids, treatments for patent ductus arteriosus, and intravitreal injections for retinopathy of prematurity.\u003c/p\u003e \u003cp\u003eNeonatal morbidities will be diagnosed using the following standard criteria: intraventricular hemorrhage (Papile classification), necrotizing enterocolitis (Bell\u0026rsquo;s criteria), bronchopulmonary dysplasia (Jensen criteria), and cystic periventricular leukomalacia.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec34\" class=\"Section3\"\u003e \u003ch2\u003ePlans to promote participant retention and complete follow-up {18b}\u003c/h2\u003e \u003cp\u003eGiven the neonatal setting, follow-up is conducted entirely during the initial hospitalization, up to 36 weeks maternal postmenstrual age or discharge. Retention is promoted by integrating study assessments into routine clinical care, ensuring minimal additional burden for families and clinical teams. Site investigators will monitor adherence to scheduled assessments and document outcomes prospectively in the electronic information system to minimize loss to follow-up\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e\n\u003ch3\u003eData management {19}\u003c/h3\u003e\n\u003cp\u003eData will be recorded in a secure, web-based electronic case report form hosted on REDCap, which is compliant with General Data Protection Regulations, the Health Insurance Portability and Accountability Act, and other relevant regulations. Patient data will be pseudonymized with unique study identifiers, and identifiable information will be kept separately and securely at each site for 15 years.\u003c/p\u003e\n\u003ch3\u003eConfidentiality {27}\u003c/h3\u003e\n\u003cp\u003eParticipant information is pseudonymized in the secure REDCap system, with identifiers stored separately at each site. Access is limited to authorized staff, and all data are managed under GDPR and institutional policies to ensure confidentiality before, during, and after the trial.\u003c/p\u003e \u003cp\u003e \u003cb\u003ePlans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}\u003c/b\u003e \u003c/p\u003e \u003cp\u003eNot applicable.\u003c/p\u003e \u003cdiv id=\"Sec37\" class=\"Section2\"\u003e \u003ch2\u003eStatistical methods\u003c/h2\u003e \u003cdiv id=\"Sec38\" class=\"Section3\"\u003e \u003ch2\u003eStatistical methods for primary and secondary outcomes {20a}\u003c/h2\u003e \u003cp\u003eThe primary endpoint will be analyzed using mixed-effects logistic regression, accounting for clustering by center and time period. The model will be used to estimate the odds ratios for the PPV requirement, adjusted for the stepped-wedge design.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec39\" class=\"Section2\"\u003e \u003ch2\u003eInterim analyses/ Methods for additional analyses (e.g. subgroup analyses) {20b; 21b}\u003c/h2\u003e \u003cp\u003eNot applicable/ not planned.\u003c/p\u003e \u003cp\u003e \u003cb\u003eMethods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}\u003c/b\u003e \u003c/p\u003e \u003cp\u003ePrincipal investigators will be responsible for recruitment, data collection, completeness, and quality, as well as regular reporting of adverse events. Monitoring will be provided by an appointed independent data monitor, who is responsible for checking the accuracy, completeness, and plausibility of all data and its compliance with the protocol and GCP requirements. The monitor will clarify the discrepancies with the respective trial site electronically via CIS. Trial sites are responsible for answering the electronic queriers without delay.\u003c/p\u003e \u003cdiv id=\"Sec40\" class=\"Section3\"\u003e \u003ch2\u003ePlans to give access to the full protocol, participant level-data and statistical code {31c}\u003c/h2\u003e \u003cp\u003eDe-identified individual participant data, supporting documentation, and the full trial protocol from this ongoing clinical trial will be made available upon reasonable request following study completion and publication of the main results.\u003c/p\u003e \u003cp\u003e \u003cb\u003eOversight and monitoring\u003c/b\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e\n\u003ch3\u003eComposition of the coordinating center and trial steering committee {5d}\u003c/h3\u003e\n\u003cp\u003eThe trial steering committee is composed by the trial chair, clinicians, and experts from the relevant disciplines. The committee will be responsible for the overall supervision of the trial and will provide the principal investigators with regular updates (via the newsletter or at investigator meetings).\u003c/p\u003e \u003cp\u003eThe committee will periodically review recommendations of the Independent Data monitoring committee and, on consideration of this information, recommend any appropriate amendments/actions for the trial as necessary. The committee will be responsible for preparations of the amendments to the protocol prior to submission to the relevant regulatory authority. The committee acts on behalf of the funder and the sponsor.\u003c/p\u003e\n\u003ch3\u003eComposition of the data monitoring committee, its role, and reporting structure {21a}\u003c/h3\u003e\n\u003cp\u003eAn Independent Data Monitoring Committee (IDMC) will regularly review safety data and AE rates, in order to safeguard the interests of the trial participants, assess safety of the interventions during the trial, and monitor overall conduct of the trial.\u003c/p\u003e \u003cp\u003eIDMC will periodically review the number of relevant events in both trial ARMs to ensure the safety of each treatment modality. This measure will provide sufficient safety monitoring while not putting additional demands on the sample size, as would an interim analysis.\u003c/p\u003e \u003cp\u003eThe IDMC will receive and review the progress and accruing data of this trial and provide advice on the conduct of the trial to the trial chair and Trial steering committee. IDMC members are independent and will be constructively critical of the ongoing trial but will also support the aims and methods of the trial.\u003c/p\u003e\n\u003ch3\u003eAdverse event reporting and harms {22}\u003c/h3\u003e\n\u003cp\u003eAEs related to respiratory support may include air leaks, pulmonary hemorrhage, intraventricular hemorrhage, facial injury from interfaces, and acidosis (pH\u0026thinsp;\u0026lt;\u0026thinsp;7.20). Serious AEs (SAEs) include death, life-threatening conditions, prolonged hospitalization, or permanent disability. Given the vulnerability of the study population, many anticipated complications will not be classified or reported individually as SAE. All events will be graded as mild, moderate, or severe, and monitored until resolution or stabilization. If safety concerns arise during the trial, the trial will be temporarily paused.\u003c/p\u003e\n\u003ch3\u003eFrequency and plans for auditing trial conduct {23}\u003c/h3\u003e\n\u003cp\u003eAn Independent Data Monitoring Committee will regularly review safety data and adverse event (AE) rates. An interim safety analysis will be performed by the Safety Board following the enrolment of every 100 participants.\u003c/p\u003e\n\u003ch3\u003ePlans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}\u003c/h3\u003e\n\u003cp\u003eAny important protocol amendments will be promptly communicated to the relevant ethics committees, regulatory authorities, investigators, and trial participants as appropriate.\u003c/p\u003e \u003cp\u003e \u003cb\u003eDissemination plans {31a}\u003c/b\u003e \u003c/p\u003e \u003cp\u003e The trial results will be disseminated through postings in public trial registries, presentations at scientific meetings, publication in peer-reviewed journals, communication to trial participants and relevant stakeholders, and will be used to inform appropriate clinical guidelines, regardless of whether results are positive, negative, or inconclusive.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eRespiratory support in the delivery room is a critical component of care for very preterm infants. Although CPAP is widely recommended as the first-line non-invasive modality, its practical use is often limited by mask leaks, unstable pressure delivery, and stimulation of trigeminal or vagal reflexes, which can provoke bradycardia and interrupt spontaneous breathing [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. These limitations frequently necessitate positive pressure ventilation (PPV), which carries a risk of lung injury in immature infants [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. HFNC has been proposed as a less invasive alternative that circumvents many of these challenges. Preliminary data of our pilot study are encouraging, showing that HFNC safely stabilized more than 80% of VPIs, with PPV required in only 11% and escalation to CPAP in just 3%. However, our pilot study was single arm, conducted at a single center with a limited sample size, which restricts generalizability. In addition, published observational and retrospective reports on HFNC use in the delivery room remain heterogeneous, and direct randomized comparisons with CPAP are scarce.\u003c/p\u003e \u003cp\u003eThe SIMPLSAFE3 trial addresses these gaps by implementing a multicenter, stepped-wedge cluster randomized design across 10 tertiary NICUs that compare HFNC and CPAP therapy in infants born between 28\u0026thinsp;+\u0026thinsp;0 and 31\u0026thinsp;+\u0026thinsp;6 weeks. This design enables balanced within-center comparisons while facilitating broad clinical implementation [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHowever, some limitations must be acknowledged. Variations in clinical practice and local protocols may influence the results, and the stepped-wedge design introduces potential temporal confounding factors [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Nevertheless, this pragmatic approach may enhance the generalizability of the findings and their implications, as well as ensure comprehensive enrolment.\u003c/p\u003e \u003cp\u003eIn conclusion, if HFNC proves non-inferior or superior to CPAP, the findings will have immediate clinical implications, supporting the use of a simpler, less invasive modality for the stabilization of very preterm infants in the delivery room and during transport to the NICU.\u003c/p\u003e \u003cp\u003eSuch a shift could reduce airway trauma, improve infant comfort, and streamline neonatal resuscitation practices. Conversely, if HFNC is associated with higher rates of PPV or treatment failure, this will strengthen the evidence base for maintaining CPAP as the standard of care. Ultimately, this trial is designed not only to generate high-quality evidence to inform clinical practice but also to guide future updates of international neonatal resuscitation guidelines and non-invasive support strategies in VPIs.\u003c/p\u003e \u003cp\u003e \u003cb\u003eTrial status\u003c/b\u003e \u003c/p\u003e \u003cp\u003eRecruitment opened on 1 December 2024. The current protocol version is 1.0 (dated November 2024). Recruitment is expected to be completed by 31 December 2026.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCPAP Continuous Positive Airway Pressure\u003c/p\u003e \u003cp\u003eHFNC High-Flow Nasal Cannula\u003c/p\u003e \u003cp\u003eNICU Neonatal Intensive Care Unit\u003c/p\u003e \u003cp\u003ePPV Positive Pressure Ventilation\u003c/p\u003e \u003cp\u003eFiO₂ Fraction of Inspired Oxygen\u003c/p\u003e \u003cp\u003eVPIs Very Premature Infants\u003c/p\u003e \u003cp\u003eSpO₂ Peripheral Oxygen Saturation\u003c/p\u003e \u003cp\u003eBPM Beats Per Minute\u003c/p\u003e \u003cp\u003eAE Adverse Event\u003c/p\u003e \u003cp\u003eSAE Serious Adverse Event\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ contributions {31b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTL and RP are the chief investigators; they conceived the study, led the proposal, and\u003c/p\u003e\n\u003cp\u003edeveloped the protocol. KJ contributed to the study design and the development of the study proposal. MB contributed to data analysis and interpretation. TL, KJ, and MB were responsible for the clinical coordination and data acquisition. YO contributed to the medical and linguistic refinement of the proposal. All the authors have read and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding {4}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis trial was supported by the Charles University in Prague (UNCE/24/MED/018); the Charles University Research program “Cooperatio – Maternal and Childhood Care, Neonatology;” and the institutional grant of The General University Hospital in Prague (CZ-DRO-VFN64165). The funders had no role in the study design; collection, analysis, or interpretation of data; writing of the manuscript; or the decision to publish the results.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials {29}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData will be provided by reasonable request to corresponding author of this manuscript.\u003cbr\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate {24}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study protocol was approved by the institutional review board of the leading institution, the General University Hospital in Prague, in\u0026nbsp;August 2024 (Ethics No. 127/24 S-IV), and was subsequently approved by the institutional review boards of all participating institutions.\u0026nbsp;Parents receive verbal information antenatally; written consent may also be obtained postnatally, according to institutional and federal guidelines, before enrolment. Pseudonymized data are stored securely under the International Council for Harmonization – Good Clinical Practice standards and the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication {32}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests {28}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMadar J, Roehr CC, Ainsworth S, Ersdal H, Morley C, R\u0026uuml;diger M, et al. European Resuscitation Council Guidelines 2021: Newborn resuscitation and support of transition of infants at birth. 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Contemp Clin Trials. 2007;28:182\u0026ndash;91. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.cct.2006.05.007\u003c/span\u003e\u003cspan address=\"10.1016/j.cct.2006.05.007\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"respiratory stabilization, very preterm infants, continuous positive airway pressure CPAP, high-flow nasal cannula HFNC, preterm delivery","lastPublishedDoi":"10.21203/rs.3.rs-7871909/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7871909/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eNon-invasive continuous positive airway pressure (CPAP) is the standard initial respiratory support for preterm infants. However, requirements such as optimal pressure delivery and facemask repositioning, which trigger unwanted reflexes and bradycardia, often necessitate the use of positive pressure ventilation (PPV). Findings from a pilot study suggested that high-flow nasal cannula (HFNC) may be a promising alternative to CPAP, with lower PPV requirements. We hypothesize that HFNC is a safe, effective, and user-friendly alternative to CPAP for stabilizing very preterm infants (28\u0026thinsp;+\u0026thinsp;0\u0026ndash;31\u0026thinsp;+\u0026thinsp;6 weeks of gestation), potentially reducing the need for PPV. We aim to compare HFNC and CPAP as initial respiratory support strategies at birth.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis is a multicenter, randomized, stepped-wedge cluster trial. Infants will receive either HFNC (8 L/min) or CPAP (6 cmH₂O) immediately after birth with tactile stimulation. The fraction of inspired oxygen (FiO₂) will start at 0.30. PPV will be initiated if bradycardia or persistently low oxygen saturation (SpO₂) occurs. The primary outcome is stabilization with the assigned support without PPV administration. Secondary outcomes include: (A) achievement of SpO₂ \u0026ge;80% at 5 min (with \u0026le;\u0026thinsp;2 brief PPV episodes) as a surrogate of safety; (B) achievement of SpO₂ \u0026gt;90% with FiO₂ \u0026le;0.40 at 10 min as a surrogate of efficacy. Overall, 446 infants will be recruited in both arms, with an estimated study duration of 2 years.\u003c/p\u003e\u003ch2\u003eDiscussion\u003c/h2\u003e \u003cp\u003e The findings may inform future respiratory support guidelines for very preterm infants at birth.\u003c/p\u003e\u003ch2\u003eTrial registration\u003c/h2\u003e \u003cp\u003e: ClinicalTrials.gov NCT06543589, registered August 9, 2024.\u003c/p\u003e","manuscriptTitle":"High-Flow Nasal Cannula Versus Continuous Positive Airway Pressure for Initial Respiratory Support in Very Preterm Infants: Study Protocol for a Multicenter Randomized Controlled Trial (SIMPLSAFE3)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-03 14:20:35","doi":"10.21203/rs.3.rs-7871909/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2026-02-23T14:55:11+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-23T14:09:55+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-11-25T09:20:30+00:00","index":"","fulltext":""},{"type":"submitted","content":"Trials","date":"2025-11-24T08:07:33+00:00","index":"","fulltext":""},{"type":"decision","content":"Minor revision","date":"2025-11-08T11:33:17+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"3f7523d3-9789-4bc3-bd38-ff1ac5308657","owner":[],"postedDate":"March 3rd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-13T20:13:33+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-03 14:20:35","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7871909","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7871909","identity":"rs-7871909","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}