Positive End-Expiratory Pressure (PEEP) Levels During Resuscitation of Preterm Infants at Birth (The POLAR Trial).

Preterm Birth Clinical Trial

— POLAR  

Official title:

Positive End-Expiratory Pressure (PEEP) Levels During Resuscitation of Preterm Infants at Birth (The POLAR Trial).

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04372953
• Other study ID #: POLAR #60303
• Status: Recruiting
• Phase: N/A
• Start date: May 4, 2021
• Est. completion date: May 30, 2028

Study information

• Verified date: March 2024
• Source: Murdoch Childrens Research Institute
• Contact: David Tingay, MBBS FRACP
• Phone: +61 3 9345 4023
• Email: david.tingay[@]rch.org.au
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 906
• Est. completion date: May 30, 2028
• Est. primary completion date: November 30, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 23 Weeks to 28 Weeks

Eligibility

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.

Related Conditions & MeSH terms

• Lung Injury
• Premature Birth
• Preterm Birth

Intervention

Procedure:
• Positive End-Expiratory Pressure (PEEP)
PEEP is the delivery of any level of positive pressure to the lungs during expiration, by any method of assisted respiratory support. As the intervention in the Delivery Room PEEP will be administered via any of: Continuous Positive Applied Pressure (CPAP; 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. 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).

Locations

Country	Name	City	State
Australia	Women & Childrens Hospital Adelaide	Adelaide	South Australia
Australia	Joan Kirner Women & Children's Hospital - VIC	Melbourne	Victoria
Australia	The Royal Women's Hospital, Melbourne Australia	Parkville	Victoria
Australia	Mater Misericordiae	South Brisbane	Queensland
Australia	King Edward Memorial Hospital	Subiaco	Western Australia
Austria	Academic Teaching Hospital	Feldkirch
France	Antoine Beclere Medical Center / South Paris University Hospitals	Paris
Italy	Careggi Hospital	Florence
Italy	Ospedale Maggiore Policlinico	Milan
Italy	Vittore Buzzi Children's Hospital / Ospedale dei Bambini	Milan
Italy	San Gerardo Hospital	Monza	Milan
Italy	Gemelli University Hospital	Rome
Italy	Filippo del Ponte Hospital	Varese	Milan
Netherlands	Amsterdam University Medical Centre	Amsterdam
Netherlands	Amalia Children's Hospital Radboudumc	Nijmegen
Netherlands	Maxima Medical Centre	Veldhoven
Poland	Poznan University of Medical Sciences	Poznan	Poznan
United Kingdom	Birmingham Heartlands Hospital	Birmingham	England
United Kingdom	Southmead Hospital	Bristol	England
United Kingdom	Royal Infirmary Edinburgh	Edinburgh	Scotland
United Kingdom	Royal Hospital for Children	Glasgow	Scotland
United Kingdom	University Hospitals Leicester	Leicester
United Kingdom	James Cook University Hospital	Middlesbrough	England
United Kingdom	University Hospital Wishaw	Wishaw	Scotland
United States	Indiana University / Riley Children Health at Indiana University Health	Indianapolis	Indiana
United States	University of Arkansas for Medical Sciences	Little Rock	Arkansas
United States	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania
United States	Rady Children's at Rancho Springs Medical Center/UCSD	San Diego	California
United States	Rady Children's at Scripps Memorial Hospital La Jolla/UCSD	San Diego	California
United States	Sharp Mary Birch Hospital for Women & Newborns	San Diego	California

Sponsors (4)

Lead Sponsor	Collaborator
Murdoch Childrens Research Institute	Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA), University of Oxford, University of Pennsylvania

Countries where clinical trial is conducted

United States,  Australia,  Austria,  France,  Italy,  Netherlands,  Poland,  United Kingdom, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The prevalence of the composite outcome of either death or bronchopulmonary dysplasia (BPD), as assessed by standard oxygen reduction test.	This is defined as the proportion of participants in the analysis set with a confirmed death date or a diagnosis of bronchopulmonary dysplasia (BPD), at 36 weeks post menstrual age.	At 36 weeks post menstrual age.
Secondary	The rate/incidence of failure of non-invasive ventilation in first 72 hours, as assessed by intubation status.	This is defined as the proportion of participants in the analysis set requiring invasive ventilation (i.e. insertion of a Endotracheal Tube (ETT) within the first 72 hours after birth.	From the time of birth until 72 hours post birth.
Secondary	The rate/incidence of death within the first 10 days of life, as assessed by date of death.	This is defined as the proportion of participants in the analysis set having dies within the first 10 days post birth.	From the time of birth until 10 days post birth.
Secondary	Oxygen requirement =50% for 3 or more consecutive hours in first 72 hours	This is defined as highest FiO2 applied for 3 or more consecutive hours in the first 72 hours of age.	From the time of birth until 72 hours post birth.
Secondary	Supplementary oxygen use	This is defined as highest FiO2 in the delivery room, and then at 24 hours, 72 hours, 7 days and 10 days of age.	From the time of birth until 10 days of age.
Secondary	The rate/incidence of surfactant therapy requirement within the first 72 hours of life, as assessed by surfactant therapy status.	This is defined as the proportion of participants in the analysis set requiring surfactant therapy within the first 72 hours post birth.	From the time of birth until 72 hours post birth.
Secondary	The rate/incidence of grade 3 and 4 intraventricular haemorrhage within the first 72 hours of life, as defined via imaging.	This is defined as the proportion of participants in the analysis set requiring experiencing a grade 3 or 4 intraventricular haemorrhage, within the first 72 hours post birth.	From the time of birth until 72 hours post birth.
Secondary	The rate/incidence of treatment failure within the delivery room, as assessed by intubation status.	This is defined as the proportion of participants in the analysis set requiring intubation (i.e. insertion of a Endotracheal Tube (ETT) within the delivery room, but prior to transfer to NICU.	From the time of birth through transfer to NICU (within two hours from birth)
Secondary	The grade of bronchopulmonary dysplasia (BPD), based on the results of an oxygen reduction test.	This is defined as the grade bronchopulmonary dysplasia (BPD) assigned according to the results of an oxygen reduction test and mode or respiratory support at 36 weeks PMA (see Jensen et al Am J Resp Crit Care Med 2019;200:751-759).	At 36 weeks post menstrual age.
Secondary	Incidence of Death at 36 week PMA	This is defined as death at 36 weeks PMA (individual component of primary outcome)	At 36 weeks post menstrual age.
Secondary	Incidence of Bronchopulmonary dysplasia (BPD) at 36 week PMA	This is defined as the incidence of BPD at 36 weeks PMA (individual component of primary outcome)	At 36 weeks post menstrual age.
Secondary	Incidence of air leak and/or pulmonary interstitial emphysema (defined on chest radiograph; CXR) in the first 10 days after birth	Any airleak, defined as Pneumothorax, pulmonary interstitial emphysema and/or pneumomediastimum, diagnosed by chest radiology within the first 10 days after birth.	Birth to 10 days of age.
Secondary	Airleak	Any airleak, defined as Pneumothorax, pulmonary interstitial emphysema and/or pneumomediastimum, diagnosed by chest radiology. Airleak will be coded as occurring in the delivery room, in first 10 days of life, during hospital stay and if requiring drainage (e.g. via a chest tube)	During hospital stay, on average until 36 weeks PMA.
Secondary	Retinopathy of prematurity (stage 3 or higher or requiring treatment)	Defined as retinopathy of prematurity (stage 3 or higher or requiring treatment) diagnosed by ophthalmological examination at or before 36-week corrected PMA	36-week corrected PMA.
Secondary	Significant brain injury (IVH grade 3 or 4, periventricular leukomalacia)	Significant brain injury (IVH grade 3 or 4, periventricular leukomalacia) at or before 36-week corrected PMA as assessed by ultrasound or MRI cranial imaging.	36-week corrected PMA.
Secondary	Invasive ventilation at day 10 of age	The rates of invasive ventilation (placement of an endotracheal tube for >4 hours) by day 7 and 10 of age	First 10 days after birth.
Secondary	Highest PEEP used during non-invasive ventilation	Defined as the highest PEEP used during non-invasive ventilation in the NICU (after delivery room management) at 24 hours, 72 hours, 7 and 10 days of age.	Birth to 10 days of age.
Secondary	Duration of respiratory support	Defined as the total number of days of all forms of respiratory support (supplementary oxygen therapy, non-invasive and invasive ventilation)	36 week PMA.
Secondary	Postnatal steroid use	Defined as the incidence of one or more course of postnatal steroids for the treatment of BPD	36 week PMA.
Secondary	Inotrope use	Defined as the incidence of the administration of one or more inotropic agent by continuous infusion (not as a resuscitative agent) for more than 1 hour.	36 week PMA.
Secondary	Length of stay in hospital	Defined as the total number of completed days in hospital related to the initial admission for management of preterm birth.	Up to 44 weeks PMA
Secondary	Oxygen requirement at discharge to home	Defined as the incidence of infants being discharged home on any form of oxygen therapy	Up to 44 weeks PMA
Secondary	Patent ductus arteriosus requiring medical or surgical therapy in first 72 hours	Defined as the incidence of patent ductus arteriosus requiring medical or surgical therapy in first 72 hours	72 hours of age.
Secondary	Meeting the protocol criteria for failure of non-invasive ventilation during the intervention period	This is defined as the proportion of participants in the analysis set who met the criteria for requiring invasive ventilation (i.e. insertion of a Endotracheal Tube (ETT) within the first 72 hours after birth.	Up to the first 20 minutes after commencing respiratory support following birth.