Clinical trial NCT04372953: Positive End-Expiratory Pressure (PEEP) Levels During Resuscitation of Preterm Infants at Birth (The POLAR Trial).
Official title: Positive End-Expiratory Pressure (PEEP) Levels During Resuscitation of Preterm Infants at Birth (The POLAR Trial).
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Lung Injury
Preterm Birth
Keywords: Resuscitation
Positive End-Expiratory Pressure (PEEP)
Bronchopulmonary Dysplasia
Lead sponsor: Murdoch Childrens Research Institute
Sponsor class: OTHER
Collaborators: name: University of Pennsylvania
name: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
name: University of Oxford
First posted: 2020-05-04
Enrollment: 906
Sex: ALL
Minimum age (years): 23
Maximum age (years): 28
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Two parallel group, non-blinded, 1:1 randomised controlled, multi-national, multi-centre, trial comparing dynamic PEEP ( dynamic group) with standard PEEP strategy (static group).
Primary purpose: PREVENTION

Brief summary: Premature babies often need help immediately after birth to open their lungs to air, start breathing and keep their hearts beating. Opening their lungs can be difficult, and once open the under-developed lungs of premature babies will often collapse again between each breath. To prevent this nearly all premature babies receive some form of mechanical respiratory support to aid breathing. Common to all types of respiratory support is the delivery of a treatment called positive end-expiratory pressure, or PEEP. PEEP gives air, or a mixture of air and oxygen, to the lung between each breath to keep the lungs open and stop them collapsing.

Currently, clinicians do not have enough evidence on the right amount, or level, of PEEP to give at birth. As a result, doctors around the world give different amounts (or levels) of PEEP to premature babies at birth.

In this study, the Investigators will look at 2 different approaches to PEEP to help premature babies during their first breaths at birth. At the moment, the Investigators do not know if one is better than the other. One is to give the same PEEP level to the lungs. The others is to give a high PEEP level at birth when the lungs are hardest to open and then decrease the PEEP later once the lungs are opened and the baby is breathing.

Very premature babies have a risk of long-term lung disease (chronic lung disease). The more breathing support a premature baby needs, the more likely the risk of developing chronic lung disease. The Investigators want to find out whether one method of opening the baby's lungs at birth results in them needing less breathing support.

This research has been initiated by a group of doctors from Australia, the Netherlands and the USA, all who look after premature babies.

Detailed description: All infants born \<29 weeks' postmenstrual age (PMA) require positive end-expiratory pressure (PEEP) at birth. PEEP is a simple, feasible and cost-effective therapy to support extremely preterm infants that is used globally. The effective and safe level of PEEP to use after preterm birth remains the most important unanswered question in neonatal respiratory medicine.

The Investigators will undertake an international multi-centre randomised controlled trial to address in extremely preterm infants, whether the use of a high, dynamic PEEP level strategy to support the lung during stabilisation ('resuscitation') at birth, compared to the current practice of a static PEEP level, will reduce the rate of death or bronchopulmonary dysplasia (BPD).

This trial will address the following four key knowledge gaps:

1. Assessing whether individualising (dynamic) PEEP is superior to static PEEP
2. The uncertainty regarding applied pressure strategies to support the lung during stabilisation at birth arising from the lack of a properly powered, well-designed randomised trial specifically addressing important outcomes for respiratory support in the Delivery Room
3. The optimal PEEP strategy to use
4. Determining the differential effects of PEEP at different gestational ages.

For this study, the term PEEP refers to the delivery of positive pressure (via a bias flow of gas) to the lungs during expiration by any method of assisted respiratory support, this includes:

1. Continuous Positive Applied Pressure (CPAP; a method of non-invasive respiratory support). During CPAP no other type of positive pressure is delivered as the infant supports tidal ventilation using her/his own spontaneous breathing effort. PEEP during CPAP has also been called 'continuous distending pressure.
2. Positive Pressure Ventilation (PPV). During PPV PEEP is delivered between periods of an applied inflating pressure (PIP) delivered at a clinician-determined rate. PPV can be delivered via a mask or other non-invasive interface (also termed non-invasive positive pressure ventilation; NIPPV), or via an endotracheal tube (often termed continuous mechanical ventilation; CMV).
3. High-frequency oscillatory ventilation (HFOV) or high-frequency jet ventilation. These are modes of invasive PPV in which PIP is delivered at very fast rates (\>120 inflations per minute) and at very small tidal volumes. During HFOV a mean airway pressure is determined by the clinician which is equivalent to the PEEP during other modes. During high-frequency jet ventilation the clinician sets a PEEP similar to CMV.

As all of these modes of ventilation have a similar goal of applying a pressure to the lung during expiration (usually to prevent lung collapse) the term PEEP has the same physiological result despite different methods of application.

The specific aim of the trial is to establish whether the use of a high, dynamic 8-12 cmH2O PEEP level ('dynamic') strategy to support the lung during stabilisation at birth, compared with a static 5-6 cmH2O PEEP level ('static') strategy, increases the rate of survival without bronchopulmonary dysplasia (BPD) in extremely preterm infants born \<29 weeks' PMA, and reduces rates of common neonatal morbidities.

The Investigators hypothesise that in preterm infants born \<29 weeks PMA who receive respiratory support during stabilisation at birth, a high, dynamic PEEP strategy (i.e. PEEP 8-12 cmH2O individualised to clinical need) as compared to a standard, static PEEP of 5-6 cmH2O, will:

1. Increase survival without BPD (primary outcome); and
2. Reduce rates of common neonatal morbidities such as failure of non-invasive respiratory support in the first 72 hours of life (secondary outcome).

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

The intervention will take place in the Delivery Room. The intervention period will be from the time of birth until 20 minutes of life or transfer from Delivery Room to NICU (whatever comes first). The follow-up period will extend to 36 weeks PMA (primary endpoint), and 24 months corrected GA to determine important long-term neurodevelopmental and respiratory outcomes.

The clinical team within the Delivery Room managing enrolled and randomised infants will not be masked/blinded to the intervention. Clinicians need to be able to see the PEEP delivery device to assess efficacy of pressure delivery. The Research Coordinator/Study team at site will also not be masked/blinded to the intervention, as they will be entering trial data into the data management system.

Research staff based at the central Trial Coordinating Centre (TCC), the Data Coordinating Centre (DCCe) and the trial statistician will be blinded to assigned treatment.

There will be a total of 906 infants recruited (453 in the Dynamic group, 453 in the Static group), over 25 recruitment centres across Australia, Europe, the United Kingdom, the Middle East, Canada and North America.

The study will have Regional Coordinating Centres (RCCs) established in the following jurisdictions:

1. Australia - The Murdoch Children's Research Institute/Royal Women's Hospital, Melbourne, AUS
2. The Netherlands - Amsterdam University Medical Centre, Netherlands, EU
3. The United Kingdom - The University of Oxford / National Perinatal Epidemiology Unit (NPEU), Oxford, UK, and
4. North America - the Hospital of the University of Pennsylvania, Pennsylvania, USA.

Eligibility criteria: Inclusion Criteria:

* Infants born between 23 weeks 0 days and 28 weeks 6 days PMA (by best obstetric estimate).
* Receives respiratory intervention (resuscitation) at birth with CPAP and/or positive pressure ventilation in the Delivery Room, to support transition and/or respiratory failure related to prematurity.
* Has a parent or other legally acceptable representative capable of understanding the informed consent document and providing consent on the participant's behalf either prospectively or after birth and randomisation if prenatal consent was not possible (at sites where the Ethics Committee permits waiver of prospective consent).

Exclusion Criteria:

* Not for active care based on assessment of the attending clinician or family decision
* Anticipated severe pulmonary hypoplasia due to rupture of membranes \<22 weeks with anhydramnios or fetal hydrops
* Major congenital anomaly or anticipated alternative cause for respiratory failure
* Refusal of informed consent by their legally acceptable representative
* Does not have a guardian who can provide informed consent.

Primary outcomes:
measure: The prevalence of the composite outcome of either death or bronchopulmonary dysplasia (BPD), as assessed by standard oxygen reduction test.
timeFrame: At 36 weeks post menstrual age.
Secondary outcomes:
measure: The rate/incidence of failure of non-invasive ventilation in first 72 hours, as assessed by intubation status.
timeFrame: From the time of birth until 72 hours post birth.
measure: The rate/incidence of death within the first 10 days of life, as assessed by date of death.
timeFrame: From the time of birth until 10 days post birth.
measure: Oxygen requirement ≥50% for 3 or more consecutive hours in first 72 hours
timeFrame: From the time of birth until 72 hours post birth.
measure: Supplementary oxygen use
timeFrame: From the time of birth until 10 days of age.
measure: The rate/incidence of surfactant therapy requirement within the first 72 hours of life, as assessed by surfactant therapy status.
timeFrame: From the time of birth until 72 hours post birth.
measure: The rate/incidence of grade 3 and 4 intraventricular haemorrhage within the first 72 hours of life, as defined via imaging.
timeFrame: From the time of birth until 72 hours post birth.
measure: The rate/incidence of treatment failure within the delivery room, as assessed by intubation status.
timeFrame: From the time of birth through transfer to NICU (within two hours from birth)
measure: The grade of bronchopulmonary dysplasia (BPD), based on the results of an oxygen reduction test.
timeFrame: At 36 weeks post menstrual age.
measure: Incidence of Death at 36 week PMA
timeFrame: At 36 weeks post menstrual age.
measure: Incidence of Bronchopulmonary dysplasia (BPD) at 36 week PMA
timeFrame: At 36 weeks post menstrual age.
measure: Incidence of air leak and/or pulmonary interstitial emphysema (defined on chest radiograph; CXR) in the first 10 days after birth
timeFrame: Birth to 10 days of age.
measure: Airleak
timeFrame: During hospital stay, on average until 36 weeks PMA.
measure: Retinopathy of prematurity (stage 3 or higher or requiring treatment)
timeFrame: 36-week corrected PMA.
measure: Significant brain injury (IVH grade 3 or 4, periventricular leukomalacia)
timeFrame: 36-week corrected PMA.
measure: Invasive ventilation at day 10 of age
timeFrame: First 10 days after birth.
measure: Highest PEEP used during non-invasive ventilation
timeFrame: Birth to 10 days of age.
measure: Duration of respiratory support
timeFrame: 36 week PMA.
measure: Postnatal steroid use
timeFrame: 36 week PMA.
measure: Inotrope use
timeFrame: 36 week PMA.
measure: Length of stay in hospital
timeFrame: Up to 44 weeks PMA
measure: Oxygen requirement at discharge to home
timeFrame: Up to 44 weeks PMA
measure: Patent ductus arteriosus requiring medical or surgical therapy in first 72 hours
timeFrame: 72 hours of age.
measure: Meeting the protocol criteria for failure of non-invasive ventilation during the intervention period
timeFrame: Up to the first 20 minutes after commencing respiratory support following birth.
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: University of Arkansas for Medical Sciences
state: Arkansas
city: San Diego
country: United States
facility: Rady Children's at Scripps Memorial Hospital La Jolla/UCSD
state: California
city: San Diego
country: United States
facility: Sharp Mary Birch Hospital for Women & Newborns
state: California
city: San Diego
country: United States
facility: Rady Children's at Rancho Springs Medical Center/UCSD
state: California
city: Indianapolis
country: United States
facility: Indiana University / Riley Children Health at Indiana University Health
state: Indiana
city: Philadelphia
country: United States
facility: Hospital of the University of Pennsylvania
state: Pennsylvania
city: South Brisbane
country: Australia
facility: Mater Misericordiae
state: Queensland
city: Adelaide
country: Australia
facility: Women & Childrens Hospital Adelaide
state: South Australia
city: Melbourne
country: Australia
facility: Joan Kirner Women & Children's Hospital - VIC
state: Victoria
city: Parkville
country: Australia
facility: The Royal Women's Hospital, Melbourne Australia
state: Victoria
city: Subiaco
country: Australia
facility: King Edward Memorial Hospital
state: Western Australia
city: Feldkirch
country: Austria
facility: Academic Teaching Hospital
city: Paris
country: France
facility: Antoine Beclere Medical Center / South Paris University Hospitals
city: Monza
country: Italy
facility: San Gerardo Hospital
state: Milan
city: Varese
country: Italy
facility: Filippo del Ponte Hospital
state: Milan
city: Florence
country: Italy
facility: Careggi Hospital
city: Milan
country: Italy
facility: Ospedale Maggiore Policlinico
city: Milan
country: Italy
facility: Vittore Buzzi Children's Hospital / Ospedale dei Bambini
city: Rome
country: Italy
facility: Gemelli University Hospital
city: Amsterdam
country: Netherlands
facility: Amsterdam University Medical Centre
city: Nijmegen
country: Netherlands
facility: Amalia Children's Hospital Radboudumc
city: Veldhoven
country: Netherlands
facility: Maxima Medical Centre
city: Poznań
country: Poland
facility: Poznan University of Medical Sciences
state: Poznan
city: Birmingham
country: United Kingdom
facility: Birmingham Heartlands Hospital
state: England
city: Bristol
country: United Kingdom
facility: Southmead Hospital
state: England
city: Middlesbrough
country: United Kingdom
facility: James Cook University Hospital
state: England
city: Edinburgh
country: United Kingdom
facility: Royal Infirmary Edinburgh
state: Scotland
city: Glasgow
country: United Kingdom
facility: Royal Hospital for Children
state: Scotland
city: Wishaw
country: United Kingdom
facility: University Hospital Wishaw
state: Scotland
city: Leicester
country: United Kingdom
facility: University Hospitals Leicester
Study officials:
affiliation: Royal Children's Hospital
name: David Tingay, MBBS FRACP
role: PRINCIPAL_INVESTIGATOR
References:
citation: Jensen EA, Dysart K, Gantz MG, McDonald S, Bamat NA, Keszler M, Kirpalani H, Laughon MM, Poindexter BB, Duncan AF, Yoder BA, Eichenwald EC, DeMauro SB. The Diagnosis of Bronchopulmonary Dysplasia in Very Preterm Infants. An Evidence-based Approach. Am J Respir Crit Care Med. 2019 Sep 15;200(6):751-759. doi: 10.1164/rccm.201812-2348OC.