Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12618001686291
Ethics application status
Approved
Date submitted
26/09/2018
Date registered
12/10/2018
Date last updated
9/02/2023
Date data sharing statement initially provided
10/05/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Positive End-Expiratory Pressure (PEEP) Levels during Resuscitation of Preterm Infants at Birth (The POLAR Trial).
Scientific title
Does the use of a high, dynamic, positive end-expiratory pressure strategy to support the lung during stabilisation at birth, compared with a standard, static PEEP, reduce the rate of death or bronchopulmonary dysplasia (BPD); and/or the rate of failure of non-invasive respiratory support in the first 72 hours after birth?
Secondary ID [1] 296181 0
NCT04372953
Universal Trial Number (UTN)
U1111-1221-1430
Trial acronym
The POLAR Trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Preterm Birth 309808 0
Respiratory Distress Syndrome 309809 0
Condition category
Condition code
Respiratory 308605 308605 0 0
Other respiratory disorders / diseases
Reproductive Health and Childbirth 308606 308606 0 0
Complications of newborn
Reproductive Health and Childbirth 308607 308607 0 0
Childbirth and postnatal care

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
High dynamic Positive End-expiratory Pressure (PEEP): Initial PEEP delivered at 8 cmH2O via a T-Piece resuscitator in an initial fraction of inspired oxygen (FiO2) of 0.30 via local standard interface (facemask, nasopharyngeal tube or nasal prong). Increase in PEEP to 10 cmH2O (2 cmH2O increment) at 60s if infant meets pre-defined criteria for respiratory deterioration (see below). Ongoing resuscitative care at PEEP 10 cmH2O unless the infant has a heart rate >120 bpm and oxygen needs <0.30 for more than 60s in which case PEEP will be reduced to 8 cmH2O.

Respiratory Deterioration is defined as a heart rate <100 beats per minute (bpm), apnoea, and/or increasing oxygen required to maintain heart rate and SpO2 targets, these criteria indicating that additional resuscitation measures need to be implemented.
Intervention code [1] 312509 0
Treatment: Other
Intervention code [2] 312510 0
Treatment: Devices
Comparator / control treatment
Standard Static PEEP (current practice): PEEP of 5 to 6 cmH2O (depending on local practice) delivered via a T-Piece resuscitator in an initial fraction of inspired oxygen (FiO2) of 0.30 via local standard interface (facemask, nasopharyngeal tube or nasal prong).
Control group
Active

Outcomes
Primary outcome [1] 307572 0
The primary outcome is death or Bronchopulmonary Dysplasia (BPD) at 36 weeks PMA, as assessed using the Modified Walsh definition and standard oxygen reduction test.
Timepoint [1] 307572 0
36 weeks Post Menstrual Age (PMA).
Secondary outcome [1] 352316 0
Oxygen Requirement as determined from data-linkage to medical records
Timepoint [1] 352316 0
First 72 hours life
Secondary outcome [2] 352317 0
Need for surfactant replacement therapy as determined from data-linkage to medical records
Timepoint [2] 352317 0
First 72 hours life
Secondary outcome [3] 352318 0
Airleak requiring drainage as determined from data-linkage to medical records
Timepoint [3] 352318 0
First 72 hours life
Secondary outcome [4] 352319 0
Heart Rate (neonate) in the Delivery Room as determined from data-linkage to medical records of oximetry or ecg monitoring
Timepoint [4] 352319 0
Time in the Delivery Room
Secondary outcome [5] 352320 0
Duration of chest drain insitu as determined from data-linkage to medical records
Timepoint [5] 352320 0
Duration of NICU care
Secondary outcome [6] 352321 0
Oxygen profile as determined from data-linkage to medical records of oximetry monitoring
Timepoint [6] 352321 0
Over first 24 hours of life
Secondary outcome [7] 352322 0
Highest applicable FiO2 as determined from data-linkage to medical records
Timepoint [7] 352322 0
First 72 hours life
Secondary outcome [8] 352323 0
Area under curve FiO2 as determined from data-linkage to medical records
Timepoint [8] 352323 0
First 72 hours life
Secondary outcome [9] 352324 0
Death as determined from data-linkage to medical records and searching National Death Index and/or national births and deaths registry
Timepoint [9] 352324 0
First 72 hours life
Secondary outcome [10] 352325 0
Grade 3 or 4 Intraventricular Haemorrhage as determined from data-linkage to medical records
Timepoint [10] 352325 0
First 72 hours life and day 7-10 if clinically available
Secondary outcome [11] 352326 0
Death as determined from data-linkage to medical records
Timepoint [11] 352326 0
36 weeks post-menstrual age
Secondary outcome [12] 352327 0
Survival to discharge home without BPD, retinopathy of prematurity (grades 3 & 4), or significant brain abnormalities on head ultrasound as determined from data-linkage to medical records
Timepoint [12] 352327 0
Hospital Discharge
Secondary outcome [13] 352328 0
Pneumothorax as determined from data-linkage to medical records
Timepoint [13] 352328 0
Hospital Discharge
Secondary outcome [14] 352329 0
Duration of respiratory support (ventilation, CPAP, supplemental oxygen) as determined from data-linkage to medical records
Timepoint [14] 352329 0
Hospital discharge
Secondary outcome [15] 352330 0
Retinopathy of prematurity (ROP) stage 3 or greater requiring treatment as determined from data-linkage to medical records
Timepoint [15] 352330 0
Hospital discharge
Secondary outcome [16] 352331 0
Use of postnatal steroids for treatment of BPD as determined from data-linkage to medical records
Timepoint [16] 352331 0
Hospital discharge
Secondary outcome [17] 352332 0
Death before discharge as determined from data-linkage to medical records
Timepoint [17] 352332 0
Hospital discharge
Secondary outcome [18] 352333 0
Length of hospital stay as determined from data-linkage to medical records
Timepoint [18] 352333 0
Hospital discharge
Secondary outcome [19] 352747 0
BPD as determined from data-linkage to medical records
Timepoint [19] 352747 0
36 weeks post menstrual age
Secondary outcome [20] 352748 0
Pulmonary interstitial emphysema (PIE) as determined from data-linkage to medical records
Timepoint [20] 352748 0
Hospital discharge

Eligibility
Key inclusion criteria
Each infant must meet all of the following criteria to be enrolled in this study:
1. Born between 23 weeks 0 days and 28 weeks 6 days PMA (by best obstetric estimate)
2. Receives respiratory intervention (resuscitation) at birth with CPAP and/or positive pressure ventilation in the DR to support transition and/or respiratory failure related to prematurity
3. 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).
Minimum age
0 Hours
Maximum age
0 Hours
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Infants meeting any of the following criteria will be excluded from the study:
1. Not for active care based on assessment of the attending clinician or family decision
2. Anticipated severe pulmonary hypoplasia due to rupture of membranes <22 weeks’ with anhydramnios or fetal hydrops
3. Major congenital anomaly or anticipated alternative cause for respiratory failure
4. Refusal of informed consent by their legally acceptable representative
5. Does not have a guardian who can provide informed consent.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Sealed opaque allocation envelopes provided by the Data Coordinating Centre. Each envelope will have the site ID and the randomisation code on a sticker on the outside, and will be colour coded by stratum and kept in close proximity to the Delivery Room. The envelopes in each stratum will be sequentially assigned to infants in that stratum. The randomisation envelope will be opened and treatment allocation announced to the neonatal clinical team prior to the infant being born.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A permuted block randomisation of variable length, an allocation ratio of 1:1 and stratification by study centre and by gestational age (23-25 weeks and 26-28 weeks) will be employed (provided by the Data Management Centre). Multiple parity infants will be randomised independently.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3 / Phase 4
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Sample Size: Sample size is based on an estimated the rate of death/BPD at 36 weeks corrected PMA (primary outcome 1) in the control arm to be 49%, and failure of non-invasive respiratory support in the first 72 hours (primary outcome 2) to be 65%. A 20% relative reduction (RRR) in each co-primary outcome would represent a major advance in care for individuals and NICUs, and is consistent with similar trials. For primary outcome 1, death/BPD a sample size of 430 per arm (860 total) will provide 80% power with 2-tailed 0.04 significance level (80% of the global significance level), to detect the difference between 39% death/BPD in the intervention arm and 49% in the control arm (which corresponds to a RRR of 20% and absolute reduction of 10% from the control arm). For primary outcome 2, failure of non-invasive respiratory support, a sample size of 335 per arm (670 total) will provide 80% power with 2-tailed 0.01 significance level (20% of the global significance level) to detect the difference between 52% failure rate in the intervention group and 65% in the control arm (corresponding to a RRR of 20% and absolute reduction of 13% from the control arm). Allowing for 5% drop-out rate, we will recruit 453 babies per arm (906 in total).

It is anticipated that 1/3 of infants recruited will be in the most vulnerable 23-25 week PMA subgroup. A sample of 151 23-25 week PMA infants per arm (302 total) will provide 80% power with 2-tailed 0.05 significance level to detect the difference between 59% death/BPD rate in the intervention group and 74% in the control group (which corresponds to a RRR of 20% and absolute reduction of 15% from the control group). This analysis will be conducted for exploratory purposes.

Statistical Analysis: Statistical analysis will follow standard methods for randomised trials and the primary analysis will be by intention to treat. For dichotomous outcomes, including the primary outcomes, proportions will be compared using the risk ratio with 95% confidence interval (CI) (96% CI for primary outcome 1, 99% CI for primary outcome 2) obtained from generalized linear models for the binomial family with adjustment for the strata (defined by centre and gestational age category) used in the randomisation. Alternatively, should these models not reach convergence, odds ratio with 95% CI (or 96% CI for primary outcome 1, 99% CI for primary outcome 2), will be obtained from a logistic regression analysis with adjustment for the strata used in the randomisation. Continuous outcomes will be compared using differences between mean values and 95% (or 96% CI for primary outcome 1, 99% CI for primary outcome 2), estimated from normal linear regression models with the same stratification adjustments. Secondary analyses will use expanded regression models to explore potential confounding effects of chance imbalances between arms in birth weight, gender, antenatal steroids, or mode of delivery. In further secondary analysis, we will explore evidence for heterogeneity of effects between the two gestational age strata, using interaction tests and subgroup analyses.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
12/05/2021
Actual
19/05/2021
Date of last participant enrolment
Anticipated
30/05/2026
Actual
Date of last data collection
Anticipated
30/05/2028
Actual
Sample size
Target
906
Accrual to date
132
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 12012 0
The Royal Women's Hospital - Parkville
Recruitment hospital [2] 12013 0
King Edward Memorial Hospital - Subiaco
Recruitment hospital [3] 19385 0
Mater Mother's Hospital - South Brisbane
Recruitment hospital [4] 21879 0
Womens and Childrens Hospital - North Adelaide
Recruitment postcode(s) [1] 24169 0
3052 - Parkville
Recruitment postcode(s) [2] 24170 0
6008 - Subiaco
Recruitment postcode(s) [3] 33964 0
4101 - South Brisbane
Recruitment postcode(s) [4] 36963 0
5006 - North Adelaide
Recruitment outside Australia
Country [1] 20871 0
Netherlands
State/province [1] 20871 0
Amsterdam
Country [2] 20872 0
United States of America
State/province [2] 20872 0
PH, AK, CA
Country [3] 23687 0
Austria
State/province [3] 23687 0
Feldkirch
Country [4] 24641 0
United Kingdom
State/province [4] 24641 0
England and Scotland
Country [5] 24642 0
France
State/province [5] 24642 0
Paris
Country [6] 24643 0
Italy
State/province [6] 24643 0
Milan, Florence and Rome
Country [7] 24644 0
Poland
State/province [7] 24644 0
Poznan

Funding & Sponsors
Funding source category [1] 300771 0
Government body
Name [1] 300771 0
Medical Research Future Fund (MRFF) c/o NHMRC
Country [1] 300771 0
Australia
Primary sponsor type
Other
Name
Murdoch Children's Research Institute
Address
50 Flemington Rd
Parkville, Victoria 3052
Country
Australia
Secondary sponsor category [1] 300315 0
None
Name [1] 300315 0
Address [1] 300315 0
Country [1] 300315 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301554 0
Royal Children's Hospital Human Research and Ethics Committee
Ethics committee address [1] 301554 0
Ethics committee country [1] 301554 0
Australia
Date submitted for ethics approval [1] 301554 0
10/01/2020
Approval date [1] 301554 0
02/06/2020
Ethics approval number [1] 301554 0
HREC/60303/RCHM-2020

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 87366 0
Prof David Tingay
Address 87366 0
Neonatal Research
Murdoch Children's Research Institute
50 Flemington Rd
Parkville, Victoria 3052
Country 87366 0
Australia
Phone 87366 0
+61 3 93454023
Fax 87366 0
Email 87366 0
[email protected]
Contact person for public queries
Name 87367 0
Laura Galletta
Address 87367 0
Neonatal Research
Murdoch Children's Research Institute
50 Flemington Rd
Parkville, Victoria 3052
Country 87367 0
Australia
Phone 87367 0
+61 3 93454023
Fax 87367 0
Email 87367 0
[email protected]
Contact person for scientific queries
Name 87368 0
David Tingay
Address 87368 0
Neonatal Research
Murdoch Children's Research Institute
50 Flemington Rd
Parkville, Victoria 3052
Country 87368 0
Australia
Phone 87368 0
+61 3 93454023
Fax 87368 0
Email 87368 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
All of the available individual participant data collected during the trial,
after deidentification.
When will data be available (start and end dates)?
The de-identified data set collected for this analysis of the POLAR trial will be available six months after publication of the primary outcome.
Available to whom?
Investigators whose proposed use of the data has been approved by an independent review committee (learned intermediary) identified for this purpose.
Available for what types of analyses?
To achieve aims in approved Data Access Applications.
How or where can data be obtained?
Data requests should be directed to [email protected]. To gain access, data requestors will need to sign a Data Transfer Agreement.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
11629Study protocol  [email protected]
11630Statistical analysis plan  [email protected]
11631Informed consent form  [email protected]
11632Ethical approval  [email protected]
11633Analytic code  [email protected]



Results publications and other study-related documents

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