Introduction [9a]

The numbers in [brackets] in this protocol refer to 2025 SPIRIT checklist item numbers. The order of the items has been modified to group similar items (see https://www.equator-network.org/reporting-guidelines/spirit-2013-statement-defining-standard-protocol-items-for-clinical-trials/).

Preterm birth affects more than 10% of all births globally, and adversely impacts long-term morbidity amongst survivors.1 Extremely preterm infants (born <29 weeks’ gestational age; GA) are at greatest risk if their immature lung cannot support adequate gas exchange because of respiratory distress syndrome (RDS).2 All forms of respiratory support can cause lung injury, and bronchopulmonary dysplasia (BPD).3 The risk of RDS-mediated lung injury begins with air-breathing from birth.2 Reducing the burden of preterm lung disease should therefore begin in the delivery room (DR).4 However, such lung protective ventilation strategies have not been optimised adequately.

Positive end-expiratory pressure (PEEP) is now universally used during all forms of invasive (intubated) mechanical ventilation and non-invasive ventilation.5 PEEP supports the surfactant-deficient lung during expiration when it is at greatest risk of collapse. When appropriately applied, PEEP improves lung mechanics, gas exchange, work of breathing and ventilation-perfusion matching. Although current recommendations for preterm infants stipulate that any type of respiratory support for RDS includes PEEP,6 this practice has arisen without specific trial evidence to guide application.

The respiratory transition to air-breathing at birth confers additional challenges.7,8 At birth, the lung is fluid-filled and needs rapid aeration to establish a functional residual capacity before tidal ventilation can be supported. Preclinical work has demonstrated that 1) the PEEP required to facilitate effective lung liquid clearance is higher than the PEEP needed to support later tidal ventilation; and 2) titrating PEEP to physiological need after birth (dynamic PEEP) reduces lung injury compared to a static and lower PEEP.6,8,9,10,11 Most infants born <29 weeks’ GA require respiratory support during delivery room (DR) stabilisation immediately after birth. PEEP is a simple, feasible and cost-effective therapy to support extremely preterm infants and is used globally in all delivery rooms. However, the most effective and safe level of PEEP to use after preterm birth lacks evidence-based guidance and remains an important unanswered question in neonatal medicine.

Observational DR studies have demonstrated that applying a dynamic PEEP strategy using levels between 5 and 15 cmH2O titrated to clinical need is feasible.12,13 These studies suggested that a dynamic PEEP strategy may reduce BPD, as well as short-term respiratory outcomes without increasing morbidity.12 The POLAR randomised controlled trial (RCT) is designed to determine whether this strategy is superior to the current practice of static PEEP.

Objectives [10]

The primary objective is to establish whether a high, dynamic 8–12 cmH2O PEEP level strategy to support the lung during stabilisation at birth, as compared to a static 5–6 cmH2O PEEP level (‘standard’) strategy, will decrease the rate of death or BPD in extremely preterm infants born <29 weeks’ GA. Secondary aims are to assess if the experimental strategy reduces rates of common neonatal morbidities.

We hypothesise that using PEEP that is 1) higher than commonly used in standard practice and 2) titrated to clinical need (dynamic) in preterm infants born <29 weeks’ GA during stabilisation at birth will: increase survival without BPD and reduce rates of common neonatal morbidities.

For brevity, and to align with common clinical nomenclature, the term ‘PEEP’ is used to define both the minimal pressure setting during non-invasive and invasive positive pressure ventilation (PPV) and the pressure level set during continuous positive applied pressure (CPAP).

Trial design [12]

This is a phase III/IV, two parallel group, 1:1 randomised controlled, multi-national, multi-centre, superiority trial comparing dynamic PEEP (dynamic group) with standard PEEP (static group) strategy.

Methods: participants, interventions and outcomes

Trial setting [13]

The trial will be performed in 28 tertiary perinatal centres across Australia, Europe the United Kingdom and North America (Supplementary Table S1).

Eligibility criteria [14a]

Infants must be:

  1. 1.

    Born between 23 weeks 0 days and 28 weeks 6 days GA (by best obstetric estimate)

  2. 2.

    Planned to receive respiratory intervention (resuscitation) at birth with CPAP and/or PPV in the DR

  3. 3.

    Consented by a parent or legal guardian who understands the informed consent form on the infant’s behalf.

Exclusion criteria:

  1. 1.

    Anticipated severe pulmonary hypoplasia due to rupture of membranes <22 weeks’ GA with anhydramnios or fetal hydrops

  2. 2.

    Major congenital anomaly or anticipated alternative cause for respiratory failure

  3. 3.

    Refusal of informed consent by their parent or guardian.

Who will take informed consent [32a]

Informed consent will be obtained in one of two methods, either prospective consent (antenatal) approach or consent to continue (‘deferred consent’) approach. For prospective consent, a trained study team member will approach parents of potentially eligible infants with threatened preterm birth between 230/7 and 286/7 GA to offer study participation and to obtain written informed consent. If antenatal prospective consent is not possible at sites where the Ethics Board permits deferred consent to be used, eligible participants will be randomised at birth, and intervention delivered as per allocated study group. A study team member will approach the infant’s parents/guardians at an appropriate time after birth to obtain informed consent for continued study participation and data collection. The consent pathways by participating site are detailed in Supplementary Table S1.

Parents(s)/Guardian(s) are free to withdraw their infant from the study at any time. No further data entry for events occurring after the date of withdrawal is required for withdrawn participants.

Interventions

Setting

The intervention will be performed in the participating site DR.

Intervention description [15a-b, d]

DR stabilisation is defined as supporting the transition to air breathing. The intervention period is defined as the first 20 min after a permitted interface (facemask, nasopharyngeal tube or nasal prong; “mask on face”) is first placed on the infant’s face after birth, by which time infants are expected to have achieved transition.

The study intervention can be ceased before 20 min if transition is achieved, and

  1. 1.

    The infant is stable for transport to another location or

  2. 2.

    Care is focusing on post-stabilisation interventions (for example line placement in the DR).

DR management common to all participants

Neonatal stabilisation in the DR is delivered using an algorithm and follows a series of decision-making time points based on clinical measures of cardiorespiratory status that will be assessed at least every 60 s for all infants (Table 1).

Table 1 Assessment of cardiorespiratory status during the POLAR intervention.
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Except for the assigned PEEP strategy, most other aspects of stabilisation (including umbilical cord management and exogenous surfactant administration) during the intervention period will follow local guidelines and practices unless detailed below. Local resuscitation practices and regional guidelines are assessed by the Trial Steering Committee (TSC) for consistency with current best practice during formal Site Feasibility assessment. Respiratory support must only be delivered via a T-piece device with manometer that allows manipulation of PEEP between 5 and 12 cmH2O, inflation pressure and rate, as well as adjustment of fraction of inspired oxygen (FiO2).

Several interventions are not permitted during the trial. (i) The use of any form of sustained inflation (SI; defined as an intentional positive inflation pressure provided for >5 s as an alternative method of facilitating lung aeration). (ii) The use of any other form of PEEP recruitment manoeuvre within the first 10 days of life, specifically any PEEP recruitment manoeuvre that is designed to reduce CPAP/non-invasive ventilation (NIV) failure. The only exception is the implementation of an ‘open lung’ strategy during high-frequency oscillatory ventilation in centres in which this is already established practice in intubated infants.14,15,16

Strategies to improve adherence to interventions [15c]

Team huddle

A brief clinical team huddle prior to the infant’s birth is recommended. During the team huddle, the clinical team should allocate responsibilities, tasks and study procedures to each participating team member.

Respiratory deterioration during the intervention period

The criteria for defining respiratory deterioration during DR stabilisation, and the responses, including addressing reversible causes, are detailed in Table 2.

Table 2 Definition of respiratory deterioration and escalation pathway for common interventions in the delivery room.
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Static PEEP group

Respiratory support will include delivery of PEEP being fixed at 5–6 cmH2O via a T-piece resuscitator, with all other aspects as per the current local resuscitation guidelines. Initial fraction of inspired oxygen (FiO2) of 0.30 will be administered through standard interfaces (facemask, nasopharyngeal tube or nasal prong). PEEP will not be altered during the intervention period beyond the 5–6 cmH2O range. Figure 1 provides an example of the Static PEEP stabilisation strategy. Resuscitation care is to be escalated if the infant meets criteria for respiratory deterioration. Intubation is only permitted if an infant meets the criteria detailed in Table 3. PEEP 5–6 cmH2O will be used after intubation.

Fig. 1: Static PEEP intervention arm strategy template.
Fig. 1: Static PEEP intervention arm strategy template.The alternative text for this image may have been generated using AI.
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Sites could select and adapt the Strategy from a template library. Each Site’s final template was then approved by the TSC before Site training began.

Table 3 Criteria to intubate during the POLAR Trial intervention period (delivery room stabilization).
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Dynamic PEEP group

Resuscitative care within the Dynamic PEEP Group (Fig. 2) will be as in the static PEEP group, but has three fundamental differences:

  1. 1.

    If the infant is stable, the applied PEEP level continues, unless.

  2. 2.

    If the criteria for respiratory deterioration are met, PEEP will also be increased as part of escalating support as detailed below.

  3. 3.

    If an infant meets the criteria of cardiorespiratory improvement detailed below, at a PEEP > 8 cmH2O, then the PEEP will be decreased.

Fig. 2: Dynamic PEEP intervention arm strategy template.
Fig. 2: Dynamic PEEP intervention arm strategy template.The alternative text for this image may have been generated using AI.
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Sites could select and adapt the Strategy from a template library. Each Site’s final template was then approved by the TSC before Site training began.

Infants in the Dynamic Group PEEP will commence at the lowest permissible level of 8 cmH2O. If the infant meets respiratory deterioration criteria at any time, then reversible causes should be addressed and the PEEP increased to 10 cmH2O (with or without PPV as per Static Group). PEEP will then be further increased to 12 cmH2O if there is continued respiratory deterioration after at least 60 s at 10 cmH2O. Intubation is only permitted at a PEEP of 12 cmH2O if there is further respiratory deterioration despite appropriate resuscitation and the infant meets intubation criteria. PEEP 8 cmH2O will be used after an infant is intubated.

If an infant displays evidence of respiratory improvement during resuscitative care (heart rate >100 bpm and FiO2 ≤0.30 for at least 60 s), the PEEP will be reduced to the previous PEEP level (i.e. reduced by 2 cmH2O). Further stepwise reductions in PEEP (no lower than 8 cmH2O) continue if respiratory improvement continues at least 60 s after a PEEP reduction.

Importantly, changes in PEEP levels are dynamic and PEEP levels can be increased or decreased throughout the intervention period if respiratory deterioration criteria or improvement criteria are met. For infants requiring PPV, the same PIP settings will be used in both Static and Dynamic groups (Table 2), resulting in a lower tidal change in pressure in the Dynamic PEEP group.

Post-intervention DR care

After 20 min, the period of Dynamic PEEP strategy ends, and further study intervention is not permitted in either group. After 20 min, PEEP levels can be applied as per sites’ standard practice in the DR or during transfer, but if the infant has clinically responded, it is recommended that the final PEEP level in use during the intervention period be continued. For ongoing management after the intervention period, the following are permissible if standard practice at site:

  1. 1.

    Static group: For non-intubated infants, an increase of PEEP up to 8–10 cmH2O to prevent intubation.

  2. 2.

    Dynamic group: For intubated and non-intubated infants, stepwise weaning of PEEP below 8 cmH2O (minimum 5–6 cmH2O) for stable infants with FiO2 ≤0.30.

NICU management

Data collection for the main trial outcomes ends either at discharge home from the primary hospital admission or death, whichever is first. NICU care during this period is provided as per local guidelines, including the use of caffeine, postnatal corticosteroid and type of NIV. PEEP levels during CPAP after admission to the NICU are not mandated. Sites will be encouraged to maintain the allocated PEEP level on admission, and consider:

  1. 1.

    Use of PEEP within a range of 5–8 cmH2O

  2. 2.

    Increase of PEEP up to 8 cmH2O to prevent intubation

  3. 3.

    Using a stepwise strategy of weaning PEEP from 8 cmH2O to a minimum 5–6 cmH2O during disease recovery (stable work of breathing, no apnoea and/or FiO2 ≤ 0.30).

If conventional ventilation is commenced, PEEP levels are not mandated but sites encouraged to use a PEEP between 5 and 8 cmH2O as per each site’s practice. Modes that synchronise all inflations and use volume-targeted ventilation are recommended.

Bundles of non-invasive respiratory care within each site, for example minimally invasive methods of administering surfactant (including in the DR), will be permitted and will not constitute treatment failure unless an endotracheal tube used to administer surfactant (such as INSURE) is in situ for >4 h. As receiving invasive mechanical ventilation is an independent predictor of long-term respiratory outcomes and other morbidities, the POLAR Trial will have criteria for intubation in the first 72 h (Supplementary Table S2) and extubation in the first 10 days post-birth (Supplementary Table S3) in the NICU.

Provisions for post-trial care [34]

There is no plan for ancillary or post-trial care or compensation for trial participants.

Outcomes [16]

Primary outcome

The primary outcome is the composite outcome of death or BPD as assessed using the Modified Walsh definition and standard oxygen reduction test (ORT) assessed between 360/7 and 366/7 weeks post-menstrual age (PMA).17 We report BPD as a dichotomous outcome.18,19 The TSC has approved an algorithm for determining a diagnosis of BPD in cases where an ORT was indicated but performed incorrectly or not performed. This algorithm used data collected at time of BPD assessment (or 36+0 weeks PMA). If an infant was receiving <2 L/min of gas flow, the effective FiO2 was calculated and BPD diagnosed if the effective FiO2 was >0.21. Infants discharged home before 36+0 weeks PMA without any oxygen therapy were deemed not to have BPD.20,21,22

Secondary outcomes

We have pre-defined 32 secondary outcome measures (Table 4). These include all initial DR resuscitation, short-term respiratory morbidity and potential harm secondary outcomes.19 Table 5 summarises the participation timeline.

Table 4 The POLAR trial secondary outcomes
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Table 5 Participation timeline and schedule of assessments [18].
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Sample size [19]

Using data from our neonatal networks23,24 we estimate the rate of death or BPD at 36 weeks corrected PMA (primary outcome) in the control group to be 52%. A decrease in death or BPD to 41% would represent a clinically important advance in care for individuals and NICUs, and is consistent with other recent large RCTs with similar populations.18,19,25 A sample size of 906 infants (453 per group) is required to detect a relative reduction in death or BPD of 21% (absolute reduction of 11% from control group) from the anticipated event rate (assuming 5% drop-out rate with 90% power with 2-tailed 0.05 significance level). Data from our neonatal networks allows us to estimate that 1/3 of infants recruited will be in the most vulnerable 23–25-week GA subgroup. A sample size of 155 infants from the 23–25-weeks’ GA stratum (310 total) will detect a difference between 59% and 74% death or BPD (RRR of 20%, absolute reduction 15%; 80% power and 2-tailed 0.05 significance level). The sample size for the primary outcome would detect a difference in the important secondary outcome of failure of non-invasive support (treatment failure) between 52% in the intervention group and 65% in the control group26 (2-tailed 0.05 significance level) with 97% power. These analyses will be conducted for exploratory purposes.

Recruitment [20]

As the intervention is applied at birth, screening will occur in the antenatal period. The Study Team will evaluate maternal admissions in Antenatal Wards and Delivery Unit at participating sites to assess eligibility based on estimated GA and maternal labour status. Study teams at each site will maintain an electronic screening log of all screened mothers-infants indicating eligibility, and eligible mothers who have consented to the study and who has refused study participation. Participating sites must ensure local procedures and mechanisms are in place to ensure prospective participants approached in the antenatal setting who subsequently decline study participation are not enrolled via the deferred consent (consent to continue pathway) should they present again precipitously.

Assignment of interventions: allocation

Sequence generation [21]

A statistician not directly involved in the analysis of the study results will prepare the randomisation schedule using permuted block randomisation of variable length, an allocation ratio of 1:1 and stratification by study centre and GA (that is 23–25 weeks and 26–28 weeks’ GA) to maintain balance between the two PEEP groups. Infants born as one of multiples (i.e. twins and above) will be randomised independently.

Concealment mechanism [22]

Paper Randomisation Envelopes will be used to allow the clinical team to immediately access randomisation allocation, as these can be taken to any site of imminent birth, and have been successfully used in previous DR studies.18,25,27 Immediately before the infant’s birth, the person responsible for opening the randomisation envelope should select the next envelope in the sequence based on the infant’s estimated GA. Randomisation envelopes are located nearby each DR within each participating site. Allocation will be unknown at the time of eligibility determination. Mechanisms for reporting and managing deviations related to randomisation, such as envelopes not being used, envelopes opened in error or the next sequential envelope opened, will be in place within the POLAR data management system (DMS).

Implementation [23]

The randomisation process will occur in the DR prior to the delivery of any PEEP, ideally before the infant is born and with sufficient time to allow a Team Huddle (Supplementary Fig. S1).

Assignment of interventions: blinding

Who will be blinded [24a-b]

The intervention allocation will be known to the clinical team within the DR following randomisation, as well as the Study Team at the participating site. The Data Manager, Database Programmer, members of the Data Safety Monitoring Committee (DSMC), the independent statistician in charge of the Data Safety Monitoring Board interim analyses, and the external independent DR Compliance Monitors will be unblinded members. All other members of the trial oversight and monitoring will be blinded to the allocated intervention.

Procedure for unblinding if needed [24c]

On completion of the main study, after database lock, the trial statistician will request the randomisation list from the independent statistician to break the blind and complete the final statistical analyses for the study.

Data collection and management

Plans for assessment and collection of outcomes [25a]

All participating Site Principal Investigators are responsible for ensuring the accuracy, completeness, legibility, and timeliness of the data reported. Data collection will include screening, baseline (including maternal history), DR intervention and physiological data, and outcomes (NICU inpatient stay and 2-year follow up) and adverse events previously described. A Data Dictionary and Statistical Analysis Plan (SAP) detailing data collected will be reported.

Plans to promote participant retention and complete follow-up [25b]

Inpatient data will be obtained directly from the medical record. All attempts to follow up, especially for 2-year follow up will be made without unduly imposing on parents.

Data management [26]

Data collection and data capture

All Site Principal Investigators are responsible for ensuring the accuracy, completeness and timeliness of the data reported. The Principal Investigators will maintain adequate case histories of study participants, including accurate case report forms (CRFs) and source documentation. The Data Coordinating Centre (DCCe; Melbourne Children’s Trials Centre (MCTC) provides a REDCap (Research Data Capture, Vanderbuilt University) DMS for the secure entry and storage of POLAR Trial data.28 Participating site clinical teams/research teams will enter trial data directly into the secure POLAR trial DMS, with the exception of the DR data which will initially be captured on the paper CRF or local electronic medical record and subsequently transcribed into the database.

Source documents

Source data will be the electronic or paper-based medical record (hospital records, observation/respiratory charts) for each participant, plus the physiological findings made in the DR, NICU and/or at BPD assessment, as appropriate.

Data verification and validation

Source documents pertaining to the trial must be maintained by participating sites and redacted copies provided to the DDCe in accordance with the POLAR Data Validation Plan (DVP) and enable remote Source Data Verification. Remote Source Data Verification will be undertaken in accordance with the POLAR Clinical Monitoring Plan and observing the European Medicines Agency Guidance on the Management of Clinical Trials during the COVID-19 Pandemic (v5.0, 10/02/2022), ensuring that 100% (where possible) of all primary and secondary endpoint data is checked, cleaned and verified in readiness for final analysis.

Confidentiality [33]

Due to the international scope of the trial, the study will comply with all applicable local, national and international data protection and privacy laws. To maintain confidentiality, all data will be de-identified upon collection and entered and stored within a password-protected, 2-Factor Authentication-enabled REDCap DMS hosted in Australia. The anonymity of participants will be preserved in all scientific publications and presentations. Prior to the sharing of any data with future research projects, the POLAR Trial dataset will be anonymised, so that individuals cannot be identified, either directly or indirectly.

Statistical methods

Statistical methods for primary and secondary outcomes [27a]

A detailed SAP will be finalised and submitted for publication prior to database lock. The most current version of the SAP is available at https://doi.org/10.25374/MCRI.30153775.v2. Statistical analysis will follow standard methods for randomised trials, and reporting of findings will be performed in accordance with CONSORT guidelines.

The primary intention to treat analysis of all outcome data will include all randomised participants analysed according to the group they were originally assigned, regardless of the intervention received, participants’ compliance, crossover to other interventions, or withdrawal from the study. In line with the ICH E9 (R1) addendum on estimands and sensitivity analysis, we will implement the estimand framework to ensure clarity in defining the treatment effect of interest and how intercurrent events will be handled. The estimands to be used will be specified in detail in the SAP. For dichotomous outcomes, including the primary outcome, proportions will be compared using the risk ratio and risk difference with 95% confidence interval obtained using the standardisation approach (a logistic regression model fitting main effects of covariates to produce predictions, then standardisation will be implemented using in Stata’s margins command) with adjustment for geographical location and GA category (used in the randomisation).

Interim analyses [28b]

An independent DSMC conducted pre-defined interim analyses for safety (including number of deaths), data completeness, and general study conduct at 50, 100, 302 (33% planned recruitment) and 604 (67%) infants. The DSMC requested an additional safety analysis at 450 (50%) after the 33% analysis. Recruitment was not halted and the DSMC recommended to continue unchanged for any of these analyses

Methods for additional analyses (e.g. subgroup analyses) [27 d]

We will explore evidence for heterogeneity of effects between the two GA strata and between different geographical locations (which may include factors such as consent pathway) using interaction tests and subgroup analyses, if deemed appropriate.

Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data [27c]

The proportion of infants who received the correctly assigned intervention will be reported overall and by group. The number, type, and severity (minor vs major) of deviations will be tabulated and described by group. Infants who did not receive any intervention at all will be explicitly identified and handled as part of the trial’s estimand framework. Missing data are expected to be minimal, as infant death is always recorded and BPD assessment at 36 weeks’ PMA will almost always occur in hospital and be entered directly into the trial database. We therefore anticipate little missing data for primary or secondary outcomes. If ≤10% of primary outcomes are missing, handling of missing data will be described within each outcome section. If more than 10% of primary outcome data is missing, multiple imputation by chained equations (fully conditional specification) will be used for the primary and secondary outcomes. Ordinal, continuous, and binary outcomes will be imputed using appropriate regression models (ordinal, linear/predictive mean matching, logistic). Baseline variables will be included as auxiliaries, and imputations will be performed separately by treatment group to preserve treatment effects, generating 50 imputed datasets.

Plans to give access to the full protocol, participant level-data and statistical code [26]

The POLAR Trial is registered with clinicaltrials.gov (NCT04372953) and ANZCTR (ACTRN12618001686291). Further information is available at the trial website (www.polartrial.org.au). The trial recognises the value of open data sharing and adherence to data sharing principles that align with applicable laws, regulations, and ethical guidelines, therefore, anonymised data from this trial will be made available via a controlled access data sharing mechanism. Interested researchers may request access to the data by submitting a formal data sharing request to the Sponsor, the Murdoch Children’s Research Institute (MCRI). The request will be reviewed by the Sponsor and the Chief-Investigator, and any relevant MCRI data sharing committee, considering factors such as scientific merit, data security, and adherence to the approved research objectives.

The anonymised data set collected for the analysis of the POLAR trial will be made available 6 months after publication of the primary outcome. Trial documentation, including the study protocol, SAP, informed consent forms and statistical analysis code, will also be made available after completion of data access or material transfer agreement approval by the MCRI.

Oversight and monitoring [21]

Composition of the coordinating centre and trial steering committee [3 d]

The organisational and governance structure is summarised in Supplementary Fig. S2. The POLAR Trial Research Network will form a TSC consisting of a parent representative (person with lived experience) along with 17 representatives with leadership roles from the participating sites within Australia, the United Kingdom, North America and Europe. The TSC, in collaboration with the trial statistician, will provide overall scientific leadership for the study. Within the TSC, there will be an appointed Trial Executive Committee. The TSC will meet at least quarterly.

As detailed in the Supplement, clinical leadership, research operations, overall clinical trial management and data management, statistical analysis and database programming and maintenance will be managed by the Trial Coordinating Centre (TCC), DCCe and Clinical Epidemiology and Biostatistics Unit (CEBU; Statistical Analysis), MCRI). The TCC will meet at least fortnightly.

A team of external independent Medical Monitors will provide overall intervention-vigilance for the study and are tasked with reviewing all reported serious adverse events (SAE) in real-time, determining the expectedness and relatedness of the safety event and the appropriate course of action. If deemed necessary, the Medical Monitors will report any significant safety issues (SSIs) identified to the DSMC via the TCC.

To ensure systematic issues with protocol compliance do not occur within the POLAR Trial, and to maintain blinding of the TCC, a protocol compliance committee will review the application of the assigned intervention for the first 20 infants recruited at each site and then at least 10% of ongoing participants. The protocol compliance committee will be unblinded to the assigned intervention, only have access to the DR CRFs and consist of neonatologists from non-participating sites. The compliance committee is led by a senior academic neonatologist with expertise in clinical trials and respiratory physiology.

Composition of the data monitoring committee, its role and reporting structure [28a]

The DSMC will consist of 4 independent members comprising a chair, 2 neonatal clinicians (one a neonatal ethicist) and an independent statistician. The DSMC will be established to review emerging external evidence and monitor protocol compliance, adverse events, safety, progress of recruitment, and data completeness in accordance with the DSMC Charter provided by the TSC. The DSMC will be blinded to the study intervention.

In addition, a sub-committee of the DSMC termed the Study Endpoint Adjudication Committee (SEAC) will provide overall mortality monitoring for the study, identifying any mortality safety signals of concern. The SEAC will be independent of the TSC and TCC and report any SSIs to the Chair of the DSMC.

Adverse event reporting and harms [17]

Safety and adverse events will be monitored during the study to ensure timely detection of events that may affect safety or continued participation in accordance with the standards of the National Health and Medical Research Council (NHMRC).29 The POLAR Trial population involves critically ill preterm infants and high numbers of adverse events (AEs) and SAEs anticipated. Therefore, the protocol has pre-designated study-specific AEs and SAEs (Supplementary Table S4).

The Site Principal Investigator is responsible for recording all AEs/SAEs within the POLAR DMS and reporting all pre-defined SAEs to the Sponsor within 24 h of first knowledge of the event. In addition, the Site Principal Investigator is responsible for reporting any SSIs or Urgent Safety Measures (USMs) to their Ethics Board and/or Regulatory Authorities, as per local country-specific laws and regulations. ‘Death’ is a component of the composite primary outcome of the POLAR Trial and an outcome of an SAE. Reporting death in the first 72 h as an SAE allows causality and expectedness to be fully investigated. This is explored further in the Discussion.

All AEs/SAEs must have their relationship to the trial intervention assessed by the investigator who evaluates the AE based on temporal relationship and their clinical judgement. In a clinical trial, the intervention should always be suspected.

Frequency and plans for auditing trial conduct [29]

The Sponsor’s monitoring frequency has been determined by an initial risk assessment performed prior to the start of the trial. A detailed Clinical Monitoring Plan has been developed detailing the frequency, scope and risk-based approach taken to the monitoring of the trial. Throughout the conduct of the trial, the risk assessment will be reviewed, and the monitoring frequency adjusted, as necessary. Remote and central monitoring will be conducted for all participating sites. Where remote source data verification is not permitted by participating sites, virtual or onsite monitoring visits will be conducted. The DVP will serve as a reference document that describes the procedures used to verify the validity of the clinical trial data according to the protocol specifications. The DVP includes the conditions that clinical data must meet to be considered valid for analysis.

Plans for communicating important protocol amendments to relevant parties [31]

This study will be conducted in compliance with the current version of the approved protocol. There have not been any major changes to the trial protocol since the trial began. Minor changes and additions have been submitted for approval to the Royal Children’s Hospital Human Research Ethics Committee and to all other relevant ethics committees and then distributed and communicated to all sites.

Dissemination plans [8]

The TCC and/or DDCe will distribute trial information to participating sites and investigators via distribution lists, and to the public using direct email correspondence, newsletters, the POLAR Trial website and social media platforms.

Discussion

The POLAR Trial potentially represents a paradigm shift in neonatal lung protection trials. We are focused on optimising a critical component of lung protective support (PEEP). This trial’s design and research question present unique methodological challenges. Herein, we discuss some of the important considerations in developing our trial protocol.

Defining PEEP levels

There is wide variation in neonatal practice globally when it comes to the level of PEEP applied in the DR and in NICU. Levels of 5 to 8 cmH2O are most commonly used but levels between 3 and 15 cmH2O have been reported.30,31,32,33 It is generally accepted that a ‘high’ PEEP is required to establish at birth,7 but the interpretation of ‘high’ PEEP remains subject to debate. Additionally, the degree of respiratory failure differs in each infant, and can change rapidly during the respiratory transition at birth.9 Thus, a single PEEP value cannot be assumed to be appropriate, or safe, for all infants at all times. A more physiological approach is to define appropriate PEEP by the pressure needs at that time; high PEEP when aerated volume is low, then reduced to minimise harm once lung aeration has been established and, finally, accepting that these values may differ between infants. From these conclusions, the concept of dynamic PEEP arose.

Practically, the PEEP is step-wised increased if an infant shows signs of inadequate aeration and then reduced again once aeration is improved to avoid the hazards associated with over-distension. This requires physiological feedback to guide PEEP decisions. The choice of physiological feedback in the DR is limited due to inaccuracies during face mask support and lack of generalisability of sophisticated monitoring.34,35 Oxygenation is the best studied measure of aeration in infants,15,36 and SpO2 monitoring recommended in high-risk DR stabilisation.37,38,39 Using existing tools should also improve clinical compliance and accelerate the clinical translation of the POLAR Trial. Thus, we elected for a composite set of physiological measures utilising those currently applied by clinicians to determine if an infant is responding to treatment or not.37,38

PEEP levels of 5–6 cmH2O have been selected for the control (static) arm of this trial, as they represent two of the most commonly used levels in current international DR practice, are included in and represent the lower range of the Neonatal Resuscitation Program algorithm40 and consistent with previous DR trials.18,25,27 The Dynamic arm will see PEEP levels of 8–12 cmH2O applied and individualised to clinical need. These pressures have been chosen based on clinical and preclinical evidence demonstrating physiological demarcation between PEEP 6 cmH2O, including improved aeration and feasibility.10,11,41 These findings are supported by the results of two additional observational studies, where a high dynamic PEEP strategy (to 15 cmH2O and 35 cmH2O, respectively) was shown to be associated with lower oxygen requirements and reduced need for intubation and mechanical ventilation.12,13

It has been advocated that a PEEP at the high end of our range should be applied at birth and then weaned once the high resistance anticipated due to the fluid-filled state of the lung falls.7,19,42 The recent study of Kannan and colleagues reported that only 50% of infants required a PEEP above 8 cmH2O.12 Thus, if replicated in the POLAR Trial, a large number of infants would be exposed to unnecessarily high PEEP. As such, we proposed the safer approach is to start at the lower range of high PEEP and titrate up if clinically indicated. This will also provide valuable information on the range of PEEP levels needed by preterm infants and the ability of clinicians to determine them.

Pneumothorax risk

Historically, there has been hesitation from some neonatologists to use high PEEP levels, for fear it may result in air leak such as pneumothorax. In one of the largest studies, the COIN Trial, preterm infants managed with an initial NIV PEEP 8 cmH2O had a higher incidence of pneumothorax compared to those who were intubated.18 A higher air leak rate was also reported with an escalating high PEEP (12–35 cmH2O) at birth compared to 5–8 cmH2O in a recent observational study.13 Both trials did not have a de-escalation strategy for the high PEEP levels being used, or a restriction on duration. At birth, the initial high PEEP should be transient and allow weaning when the infant shows clinical improvement following respiratory transition.7,10 POLAR is the first large clinical study of the dynamic PEEP approach. In smaller clinical12,41 and preclinical studies10 of dynamic PEEP, where both an increasing and weaning PEEP strategy is included, there have been no differences in rates of pneumothorax.

Death as a primary outcome

Death is the outcome of greatest concern to clinicians and parents,43 and failure to consider death may impact interpretation of other outcomes (‘healthy survivor effect’). High mortality rates are anticipated in studies involving extremely preterm infants. A criticism of past neonatal trials has been the lack of clarity around reporting the timing of death relative to the intervention, as well as cause of death.43 This has led to difficulties in the interpretation of differences in reported mortality rates.19 The POLAR Trial is collecting extensive clinical data on all reported deaths within the trial. The SEAC will review and evaluate cause of death and stratify each mortality event using the previously described stratification criteria along with assessing whether the death was related to the trial intervention.44

Consent pathways

Ideally, all participants in a clinical trial should consent to participation prior to receipt of the randomly allocated study treatment. For trials involving emergency interventions, this can be challenging. Participation in DR neonatal trials limited to prospective antenatal consent risks may introduce bias, restricting representation and limiting generalisability.45 Infants enrolled when the time between presentation and birth is long enough to allow proper informed consent have been shown to be at lower risk of poor outcome than those excluded from participation due to lack of opportunity to seek prospective consent. Consent-to-continue pathways have been adopted in neonatal DR trials,19 and the Australian NHMRC allows consent-to-continue pathways if a trial meets pre-defined criteria.46 The POLAR Trial was deemed to meet these criteria and a mixed model of consent, mandating prospective consent where possible, but allowing consent-to-continue when not, was agreed by the TSC with additional DSMC safety reviews. Subsequently, the consent-to-continue approach is only adopted at participating sites where local regulations permit its use and ethical board approval has been obtained.

Trial status [2]

The current protocol is version number 5.0, dated 20th December 2023. Recruitment opened in Australia in May 2021 at the Royal Women’s Hospital, Melbourne, and internationally in October 2021 at Hospital of the University of Pennsylvania, Philadelphia. The last participating site opened to recruitment in August 2024. Recruitment is expected to be completed in late 2025 with primary endpoint results expected in early 2026. Follow-up is expected to continue until mid-2028.