Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12624000851561
Ethics application status
Approved
Date submitted
27/04/2024
Date registered
9/07/2024
Date last updated
9/07/2024
Date data sharing statement initially provided
9/07/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
BLUEPRINT: Predicting Long-term Outcomes of Prematurity from Early Life Events
Scientific title
Predicting Long-term Outcomes of Prematurity from Early Life Events
Secondary ID [1] 305020 0
Nil Known
Universal Trial Number (UTN)
U1111-1268-5755
Trial acronym
The BLUEPRINT Study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Prematurity 323191 0
Respiratory Disease 323192 0
Chronic Lung Disease of Infancy 323193 0
Condition category
Condition code
Respiratory 320774 320774 0 0
Normal development and function of the respiratory system
Respiratory 320775 320775 0 0
Other respiratory disorders / diseases
Reproductive Health and Childbirth 330543 330543 0 0
Complications of newborn

Intervention/exposure
Study type
Observational
Patient registry
True
Target follow-up duration
2
Target follow-up type
Years
Description of intervention(s) / exposure
The BLUEPRINT Study is a prospective longitudinal observational cohort study using clinical, lung imaging and plasma protein data to define the early postnatal respiratory endotypes following preterm birth, and to determine the relationship with bronchopulmonary dysplasia (BPD) and 1- and 2-year respiratory outcomes.

The primary objective of the BLUEPRINT Study is to comprehensively define respiratory endotypes in the first 7 days after birth in preterm infants born between 22 and 32 weeks’ inclusive gestation. The secondary objectives include: 1) To develop the first functional classification of preterm respiratory disease using a combination of clinical, lung imaging and molecular biomarkers, 2) To delineate how specific early preterm phenotypes relate to a diagnosis of BPD and develop a predictive modelling tool for early diagnosis, and 3) To characterise the respiratory and general health of preterm infants in the first 2 years corrected age.

Infants born between 22+0 and 31+6 weeks’ gestation admitted to a participating centre from whom parental informed consent can be obtained will be considered eligible. Eligible and enrolled infants will have clinical data relating to their antenatal, maternal and postnatal respiratory and neonatal intensive care course collected at pre-defined time points between birth and neonatal intensive care unit (NICU) discharge. In addition, a maximum of 0.5 ml of blood will be collected at 72 hours and 7 days for analysis of lung-specific proteins in the plasma using proteomics, and a brief lung ultrasound (LUS) and electrical impedance tomography (EIT) image of the lung performed at 48 and 72 hours, 7, 14 and 28 days, and then at 36 weeks’ corrected gestational age (BPD diagnosis). LUS, EIT and plasma proteomic analysis are not considered standard of care in the NICU and will only be performed in infants participating in the BLUEPRINT study, however these measurements will not be altering clinical care or clinical course of the participating infant. Lung imaging and assessment of respiratory health using standardised parental questionnaires will be repeated at 1 and 2 years corrected age in preterm survivors.

The parental questionnaires include:
PARCA-R questionnaire of developmental status (approximately 30 min to complete)
General Infant Respiratory and Health questionnaire (approximately 10-15 min to complete)

550 infants will be studied from all Level 6 Neonatal Intensive Care Units in Victoria. Recruitment and follow up is anticipated to be finished in approximately 5 years.
Intervention code [1] 321417 0
Early Detection / Screening
Intervention code [2] 321418 0
Diagnosis / Prognosis
Comparator / control treatment
No control Group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 338035 0
The types of respiratory endotypes present in preterm infants born between 22+0 and 31+6 weeks’ gestation at 7 days after birth.

Functional respiratory endotypes are defined from clinical, plasma protein and lung imaging measures using latent class analysis followed by external validation via group-based trajectory modelling.
Timepoint [1] 338035 0
At 7 days after birth
Secondary outcome [1] 434244 0
Level of assisted respiratory support using observational data at 72 hours after birth in preterm infants born between 22+0 and 31+6 weeks’ gestation.
Timepoint [1] 434244 0
72 hours after birth
Secondary outcome [2] 434245 0
Functional models of the preterm respiratory disease phenotype using a combination of clinical markers collected from medical records, lung imaging collected from measures of aeration and ventilation using lung ultrasound and electrical impedance tomography and molecular biomarkers determined from blood samples.
Timepoint [2] 434245 0
At 7 days after birth
Secondary outcome [3] 434246 0
Diagnosis of bronchopulmonary dysplasia (defined Walsh Definition and Jensen Grade of Severity).
Timepoint [3] 434246 0
36 weeks’ corrected post menstrual age.
Secondary outcome [4] 434247 0
Duration of invasive mechanical ventilation during primary Neonatal Intensive Care Unit admission (from medical records).
Timepoint [4] 434247 0
Discharge from primary Neonatal Intensive Care Unit Admission
Secondary outcome [5] 434248 0
Duration of supplementary oxygen support during primary Neonatal Intensive Care Unit admission (from medical records).
Timepoint [5] 434248 0
Discharge from primary Neonatal Intensive Care Unit Admission
Secondary outcome [6] 434249 0
The need for supplementary oxygen at discharge home from primary Neonatal Intensive Care Unit admission (from medical records).
Timepoint [6] 434249 0
Discharge from primary Neonatal Intensive Care Unit Admission
Secondary outcome [7] 434250 0
Mortality during primary Neonatal Intensive Care Unit admission.
Timepoint [7] 434250 0
Discharge from primary Neonatal Intensive Care Unit Admission
Secondary outcome [8] 434251 0
Respiratory health of preterm infants in the first 2 years (corrected) after birth as defined by composite of Respiratory health status questionnaire, gravity-dependent and right-left lung centre of ventilation and homogeneity index (electrical impedance tomography) and lung ultrasound scores.
Timepoint [8] 434251 0
2 years corrected age
Secondary outcome [9] 434252 0
Overall childhood health of preterm infants in the first 2 years (corrected) after birth assessed from medical records and clinical assessment at 2 years of age.
Timepoint [9] 434252 0
2 years corrected age
Secondary outcome [10] 434253 0
Neurodevelopmental state of preterm infants in the first 2 years (corrected) after birth using the PARCA-R questionnaire
Timepoint [10] 434253 0
2 years corrected age
Secondary outcome [11] 434254 0
Early childhood respiratory health assessed from medical records and clinical assessment at 2 years corrected age.
Timepoint [11] 434254 0
2 years corrected age
Secondary outcome [12] 434255 0
Early childhood respiratory health assessed from medical records and clinical assessment at 1 years corrected age.
Timepoint [12] 434255 0
1 year corrected age
Secondary outcome [13] 434258 0
Lung ultrasound-derived measures of respiratory status using the standardised lung ultrasound score at 28 days after birth.
Timepoint [13] 434258 0
28 days after birth
Secondary outcome [14] 434259 0
Regional ventilation and aeration as measured using electrical impedance tomography at 14 days after birth.
Timepoint [14] 434259 0
14 days after birth
Secondary outcome [15] 434260 0
Regional ventilation and aeration as measured using electrical impedance tomography at 28 days after birth.
Timepoint [15] 434260 0
28 days after birth
Secondary outcome [16] 434262 0
Lung-specific plasma protein expression at 72 hours.
Timepoint [16] 434262 0
72 hours after birth
Secondary outcome [17] 434263 0
Lung-specific plasma protein expression at 7 days after birth.
Timepoint [17] 434263 0
7 days after birth
Secondary outcome [18] 436762 0
Regional ventilation and aeration as measured using electrical impedance tomography at 3 days after birth.
Timepoint [18] 436762 0
3 days after birth
Secondary outcome [19] 436763 0
Regional ventilation and aeration as measured using electrical impedance tomography at 7 days after birth.
Timepoint [19] 436763 0
7 days after birth
Secondary outcome [20] 436764 0
Lung ultrasound-derived measures of respiratory status using the standardised lung ultrasound score at 3 days after birth.
Timepoint [20] 436764 0
3 days after birth
Secondary outcome [21] 436767 0
Lung ultrasound-derived measures of respiratory status using the standardised lung ultrasound score at 14 days after birth.
Timepoint [21] 436767 0
14 days after birth
Secondary outcome [22] 437028 0
Supplementary oxygen levels using observational data at 72 hours after birth in preterm infants born between 22+0 and 31+6 weeks’ gestation.
Timepoint [22] 437028 0
72 hours after birth
Secondary outcome [23] 437029 0
Respiratory function using observational data at 72 hours after birth in preterm infants born between 22+0 and 31+6 weeks’ gestation.
Timepoint [23] 437029 0
72 hours after birth

Eligibility
Key inclusion criteria
Each infant must meet all inclusion criteria to be eligible for enrolment in the BLUEPRINT study:
1. Born between 22+0 and 31+6 weeks’ gestation.
2. Birth admission in a participating perinatal Victorian Neonatal Intensive Care Unit.
3. The infant has a parent/legal representative capable of understanding the informed consent document and providing consent on the infant’s behalf AND consent is obtained antenatally or within 72 hours from birth.
Minimum age
0 Hours
Maximum age
72 Hours
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
If any of the following exclusion criteria are met, the infant will be ineligible for enrolment in the BLUEPRINT study:
1. Infants with a known major congenital anomaly (such as oesophageal atresia and central nervous system anomalies), congenital cardiac disease, congenital diaphragmatic hernia, congenital lung abnormalities and/or pulmonary hypoplasia.
2. Pulmonary hypoplasia due to anhydramnios or oligohydramnios before 22 weeks in which the neonatal clinician anticipates that pulmonary hypoplasia related respiratory failure will be the major respiratory problem in early postnatal life.
3. Primary cause of admission unrelated to prematurity.
4. Refusal of informed consent by their legally acceptable representative.
5. The infant does not have a parent/legal representative who can provide informed consent or consent can not be obtained before 72 hours of age.
In addition, any infant identified by the treating medical team may be excluded from the study at the request of the treating clinician in consultation with the site lead investigator.

Study design
Purpose
Natural history
Duration
Longitudinal
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
The sample size for BLUEPRINT is designed to address the robustness of early respiratory phenotypes identified predicting BPD. The prevalence of survival with bronchopulmonary dysplasia within the Australia and New Zealand Neonatal Network (ANZNN) is 69%. Assuming this bronchopulmonary dysplasia prevalence and a moderate C-index of 0.75 is achievable with a binary logistic regression prediction model with BPD (yes/no) as the outcome, a minimum sample size of 500, 550 and 600 infants was estimated based on 10, 11 or 12 predictor variables respectively (from any domain of clinical, imaging and protein data). We estimate that the predictive model developed in BLUEPRINT may have up to 10-12 predictor variables including several basic clinical and lung imaging covariates and only one to two proteins. This sample size prediction assumes the distribution of births within the 22-25+6-, 26-28+6- and 29-31+6-week GA cohorts as reported in the ANZNN.

Defining the early life respiratory phenotypes: Proteome, lung imaging, clinical and demographic data will be combined to examine longitudinal alterations with ANOVA (multi-comparison), generalised additive models and post-hoc analysis using Perseus/R. Both supervised and unsupervised multivariate approaches including principal component analysis (PCA), Latent Class Analysis, hierarchical cluster analysis and partial least square discriminant analysis (PLS-DA) maybe used to assess i) which clinical/protein/imaging measures tend to cluster at each time-point, ii) how background changes in protein densities, functional imaging and cardiorespiratory measures relate to different clinical treatments.

Development of a biomarker-based BPD risk (and 1- and 2- year) prediction model: We will develop a risk prediction model for BPD diagnosed at 36 weeks, based on a combination of proteins, imaging and clinical measures (minimum 7 inputs) derived within the first 7 days after birth. Model development will include several steps starting with methods for variable selection and model fitting to testing the performance and validation of models. To test measures originally significantly associated with BPD, and identify other measures that are predictive of BPD, binary logistic regression, multiple forward stepwise logistic regression and other classification models will be evaluated with likely measures as covariates. Model performance and discrimination will then be evaluated. Internal validation with both cross-validation and bootstrapping methods to adjust for model over-optimism and bias towards inherent overestimated performance metrics will be applied.

Alternative models of BPD risk will be evaluated using logistic regression and machine learning algorithms.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
31/08/2024
Actual
Date of last participant enrolment
Anticipated
30/11/2027
Actual
Date of last data collection
Anticipated
30/11/2029
Actual
Sample size
Target
550
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 26444 0
The Royal Women's Hospital - Parkville
Recruitment hospital [2] 26445 0
Monash Children’s Hospital - Clayton
Recruitment hospital [3] 26446 0
The Royal Childrens Hospital - Parkville
Recruitment hospital [4] 26447 0
Joan Kirner Women’s and Children’s Hospital - St Albans
Recruitment hospital [5] 26448 0
Mercy Hospital for Women - Heidelberg
Recruitment postcode(s) [1] 42423 0
3052 - Parkville
Recruitment postcode(s) [2] 42424 0
3168 - Clayton
Recruitment postcode(s) [3] 42425 0
3021 - St Albans
Recruitment postcode(s) [4] 42426 0
3084 - Heidelberg

Funding & Sponsors
Funding source category [1] 309408 0
Government body
Name [1] 309408 0
National Health and Medical Research Council
Country [1] 309408 0
Australia
Primary sponsor type
Other
Name
Murdoch Children's Research Institute
Address
Country
Australia
Secondary sponsor category [1] 310378 0
None
Name [1] 310378 0
Address [1] 310378 0
Country [1] 310378 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309213 0
The Royal Children’s Hospital Human Research Ethics Committee
Ethics committee address [1] 309213 0
Ethics committee country [1] 309213 0
Australia
Date submitted for ethics approval [1] 309213 0
26/04/2024
Approval date [1] 309213 0
05/07/2024
Ethics approval number [1] 309213 0
HREC/107608/RCHM-2024

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

Contacts
Principal investigator
Name 113366 0
Prof David Tingay
Address 113366 0
Neonatal Research, Murdoch Children's Research Institute, 50 Flemington Road, Parkville Victoria 3052
Country 113366 0
Australia
Phone 113366 0
+61 393454023
Fax 113366 0
Email 113366 0
[email protected]
Contact person for public queries
Name 113367 0
Merrin Pang
Address 113367 0
Neonatal Research, Murdoch Children's Research Institute, 50 Flemington Road, Parkville Victoria 3052
Country 113367 0
Australia
Phone 113367 0
+61 393457043
Fax 113367 0
Email 113367 0
[email protected]
Contact person for scientific queries
Name 113368 0
David Tingay
Address 113368 0
Neonatal Research, Murdoch Children's Research Institute, 50 Flemington Road, Parkville Victoria 3052
Country 113368 0
Australia
Phone 113368 0
+61 393454023
Fax 113368 0
Email 113368 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 individual participant data collected during the trial, after de-identification and publication of primary results will be available including lung imaging and protein data.
When will data be available (start and end dates)?
3 months after publication of primary results and up to 25 years after publication.
Available to whom?
Researchers who provide a methodologically sound proposal, with approval by an independent review committee (“learned intermediary”). Others who wish to access the data will be assessed on a case-by-case basis at the discretion of the Study Steering Committee.
Available for what types of analyses?
For methodologically sound purposes to achieve the aims in the approved proposal.
How or where can data be obtained?
Proposals should be directed to [email protected] to gain access. Data requestors will need to sign a data access or material transfer agreement approved by the Murdoch Children’s Research Institute.


What supporting documents are/will be available?




Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.