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Trial registered on ANZCTR


Registration number
ACTRN12623000672651
Ethics application status
Approved
Date submitted
9/03/2022
Date registered
21/06/2023
Date last updated
16/06/2024
Date data sharing statement initially provided
21/06/2023
Type of registration
Retrospectively registered

Titles & IDs
Public title
e-PINO: early Prediction of Infant Neurodevelopmental Outcomes using novel biomarkers
Scientific title
e-PINO: early Prediction of Infant Neurodevelopmental Outcomes using novel biomarkers
Secondary ID [1] 306642 0
Synergy Grants 2021 2010736
Universal Trial Number (UTN)
U1111-1279-4156
Trial acronym
SYNERGY- e-PINO
Linked study record
ePino is a follow-on of PREBO- ACTRN12619000155190 building on the already collected data

Health condition
Health condition(s) or problem(s) studied:
Brain development in preterm infants 325565 0
Cerebral Palsy 325566 0
Nature/mechanism of brain injury very early in the fetal or neonatal period 325567 0
Condition category
Condition code
Neurological 322939 322939 0 0
Other neurological disorders
Reproductive Health and Childbirth 322940 322940 0 0
Complications of newborn

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
We will recruit 480 infants born very preterm (VPT), moderate-to-late preterm (MLPT), term but small for gestational age (SGA) or with hypoxic ischaemic encephalopathy (HIE) and 60 healthy term born infants (HT) (total n=540 infants), and collect advanced MRI (structural and multi-shell diffusion), EEG, blood, and a suite of motor/neurological assessment data, including Hammersmith Neonatal Neurological Examination (HNNE)/ Hammersmith Infant Neurological Assessment (HINE), General Movements Assessment (GMA), General Movements Optimality Score (GMOS), Motor Optimality Score (MOS) and visual assessment. These assessments will be conducted between birth, term equivalent age (TEA) and 3 months corrected age (CA). All assessments conducted are carried out at a hospital (Royal Brisbane Women’s Hospital, Monash Medical Centre or Westmead Hospital). Assessments at birth and TEA will be conducted across 2 sessions, while the 3-month assessments will be conducted in 1 session. Each session is estimated to take around 2 hours to complete. Assessments will be carried out by the appropriate health professionals, including radiologists (MRI), research nurses (MRI, EEG, sample collection, motor/neurological assessments), neonatologists (MRI, medical evaluation, primary outcomes) and physiotherapists (motor/neurological assessments).
Primary outcomes will be Bayley-4 cognitive, motor, language and behaviour and executive function in addition to medical diagnosis of cerebral palsy (CP), developmental disability (DD), and symptomology of autism spectrum disorder (ASD), foetal alcohol spectrum disorder (FASD) at 2 years CA. We will use machine learning (ML) to predict Bayley-4 scores from neonatal MRI, EEG and motor/neurological/behavioural assessments to determine the strongest biomarkers for accurate prediction of neurodevelopment (i.e., assessment and time points). ML models will be trained using our previously recruited VPT infant cohort (PREBO; n=272), with transfer learning to improve predictions.
Secondly, we will collect cord blood, infant blood and meconium at birth in participants enrolled in the study prior to birth, as well as infant blood, faecal samples and breast milk samples soon after birth in all participants. and at the same time points as neonatal assessments described above. This sample will be bio banked to provide a comprehensive resource for the characterisation of infants born preterm, small for gestational age (SGA), with Hypoxic-ischemic encephalopathy (HIE) or Stroke. In addition, we will collect and bank the birthing mother/both parent’s blood or saliva for this project’s analysis and for future analysis of HREC approved projects.
Intervention code [1] 323082 0
Early Detection / Screening
Intervention code [2] 323084 0
Diagnosis / Prognosis
Comparator / control treatment
Active Control 1 - A subset of infants identified with HIE, Stroke or born SGA and healthy controls in the e-PINO Study will undergo blood analysis to determine diagnostic and prognostic biomarkers.
Historical -Control 2- A subset of infants' data from the already-completed PREBO study will be used to train the machine learning algorithm to determine predictions of cerebral palsy.
Control group
Active

Outcomes
Primary outcome [1] 330706 0
Developmental evaluation using the Bayley Scales of Infant and Toddler Development, 4th Edition: Australian and New Zealand Standardised Edition (Bayley-4 A&NZ)
Timepoint [1] 330706 0
24 Months Corrected Age
Primary outcome [2] 330707 0
Diagnosis of Cerebral Palsy made by a paediatrician/neonatologist using MRI and clinical assessments
Timepoint [2] 330707 0
24 Months Corrected Age
Primary outcome [3] 330982 0
Evaluation of spontaneous movement using the General Movements Assessment in combination with General Movements Motor Optimality Scoring.
Timepoint [3] 330982 0
40 weeks gestational age (TEA) and 3 months corrected age.
Secondary outcome [1] 407270 0
Detection of anatomical landmarks for risk of CP in MRI
Timepoint [1] 407270 0
32 weeks gestational age and 40 weeks gestational age (TEA)
Secondary outcome [2] 408340 0
Location of brain injury assessed using EEG measurements of the electrical activity of the brain.
Timepoint [2] 408340 0
32 weeks gestational age and 40 weeks gestational age (TEA)
Secondary outcome [3] 422790 0
Identification of CP biomarkers from cord and infant blood samples, specifically genomic markers from circulating cell free DNA (ccfDNA)
Timepoint [3] 422790 0
32 weeks gestational age and 40 weeks gestational age (TEA)
Secondary outcome [4] 422791 0
Neurological evaluations using Hammersmith Neonatal Neurological Evaluation (HNNE) and/or Hammersmith Infant Neurological Evaluation (HINE)
Timepoint [4] 422791 0
32 weeks gestational age, 40 weeks gestational age (TEA), 3 months CA and 24 months CA
Secondary outcome [5] 422792 0
Evaluation of vision utilising the Neonatal Visual Assessment
Timepoint [5] 422792 0
32 weeks gestational age, 40 weeks gestational age (TEA) and 3 months CA
Secondary outcome [6] 422793 0
Emotional Availability - Self Report (Parent)
Timepoint [6] 422793 0
3 months CA and 24 months CA
Secondary outcome [7] 422794 0
Depression Anxiety Stress Scales (DASS-21)
Timepoint [7] 422794 0
32 weeks gestational age, 3 months CA and 24 months CA
Secondary outcome [8] 422795 0
Life Events List Questionnaire
Timepoint [8] 422795 0
3 months CA and 24 months CA
Secondary outcome [9] 422796 0
CYW Adverse Childhood Experiences Questionnaire for Children
Timepoint [9] 422796 0
3 months CA and 24 months CA
Secondary outcome [10] 422797 0
EQ-5D-5L Parent Questionnaire for identifying parent self-rated health.
Timepoint [10] 422797 0
24 months CA
Secondary outcome [11] 422798 0
Neurosensory Motor Development Assessment (NSMDA)
Timepoint [11] 422798 0
24 months CA
Secondary outcome [12] 422799 0
Peabody Developmental Motor Scales (PDMS)
Timepoint [12] 422799 0
24 months CA
Secondary outcome [13] 422800 0
Paediatric Evaluation of Disability Inventory - compute adaptive test (PEDI-CAT)
Timepoint [13] 422800 0
24 months CA
Secondary outcome [14] 422801 0
Infant Toddler Social and Emotional Assessment
Timepoint [14] 422801 0
24 months CA
Secondary outcome [15] 422802 0
Behaviour Assessment System for Children (BASC-3)
Timepoint [15] 422802 0
24 months CA
Secondary outcome [16] 422803 0
Infant Toddler Quality of Life Questionnaire (ITQoL)
Timepoint [16] 422803 0
24 months CA
Secondary outcome [17] 422809 0
Social Attention and Communication Surveillance - Revised (SACS-R)
Timepoint [17] 422809 0
24 months CA
Secondary outcome [18] 422810 0
Behavior Rating Inventory of Executive Function®–Preschool Version
Timepoint [18] 422810 0
24 months CA
Secondary outcome [19] 422811 0
Health Resource Use form
Timepoint [19] 422811 0
24 months CA
Secondary outcome [20] 422812 0
Preverbal Visual Assessment (PreViAs)
Timepoint [20] 422812 0
3 months CA and 24 months CA

Eligibility
Key inclusion criteria
Infant’s admitted to the Neonatal Intensive Care Units at the (i) Royal Brisbane and Women’s Hospital (ii) Monash Children’s Hospital (iii) Westmead Hospital and Westmead Children’s Hospital will be invited to participate if they meet the following inclusion criteria (1) six groups neonates (n=540) Preterm-born with any birth weight (BW), very preterm (VPT) less than 32 weeks,
(ii) Moderate to Late Preterm MLPT (Born 32-37 weeks)
(iii) near-term small for gestational age (SGA) (BW less than 10th percentile) or with Fetal Growth Restriction (FGR);
(iv) Term born with Hypoxic ischemic encephalopathy (HIE) and/or stroke;
(v) Healthy Term (HT); (2) no known chromosomal abnormalities; (3) inborn at Royal Brisbane/Monash/Westmead Hospitals; (4) live within 200 km; (5) English spoken.
Minimum age
No limit
Maximum age
24 Months
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Have a congenital or chromosomal abnormality that would impact their development

Study design
Purpose
Screening
Duration
Cross-sectional
Selection
Defined population
Timing
Both
Statistical methods / analysis
Developing a standardised risk rating and decision framework for genetic testing: Statistical Analyses: Samples will be analysed to correlate genetic variation with outcomes. We will identify risk factors and comorbidities to compare pre-and perinatal risk factor profiles of CP cases with/without genetic aetiology. We will compare CP motor type/distribution/severity, neuroimaging findings, congenital abnormalities and Bayley-IV scores to identify clinical predictors of genetic aetiology. We will consider “genetic/no genetic diagnosis” to derive a prevalence ratio for each risk factor. Risk factors and clinical features associated with a genetic diagnosis will generate a decision framework for genetic testing. A forward and backward stepwise feature selection will identify predictive markers for genetic aetiology. Sample size (SS): Our SS is informed by >85% retention at 2-years as in PREBO. Assuming similar retention, we anticipate 561 (of 627) infants will return for a 2-year follow-up. With this SS, we will identify associations between early assessments and 2-year outcomes at r-values 0.15-0.30 for each outcome (a=0.05, power=80%).

Epigenetics to identify underlying environmental or genetic aetiology - Statistical Analyses: we will correlate variations in methylation with neurodevelopmental outcomes to identify risk factors and comorbidities, particularly those with pre-and perinatal risk factor profiles of CP. We will test existing and develop new predictive models for CP based on AI/ML approaches trained on epigenetic data.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
7/06/2023
Date of last participant enrolment
Anticipated
30/04/2027
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
660
Accrual to date
18
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,VIC
Recruitment hospital [1] 21939 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [2] 21940 0
Monash Children’s Hospital - Clayton
Recruitment hospital [3] 21942 0
The Children's Hospital at Westmead - Westmead
Recruitment hospital [4] 21943 0
Queensland Children's Hospital - South Brisbane
Recruitment postcode(s) [1] 37027 0
4029 - Herston
Recruitment postcode(s) [2] 37028 0
3168 - Clayton
Recruitment postcode(s) [3] 37030 0
2145 - Westmead
Recruitment postcode(s) [4] 37031 0
4101 - South Brisbane

Funding & Sponsors
Funding source category [1] 310967 0
Government body
Name [1] 310967 0
NHMRC Synergy Grants
Country [1] 310967 0
Australia
Primary sponsor type
University
Name
University of Queensland
Address
Queensland Cerebral Palsy and Rehabilitation Research Centre.
School of Medicine, The University of Queensland,
Rm 722A, Level 7, Block 6,
Royal Brisbane and Women's Hospital
Herston
QLD
4029
Country
Australia
Secondary sponsor category [1] 312279 0
University
Name [1] 312279 0
Griffith University
Address [1] 312279 0
176 Messines Ridge Rd
Mount Gravatt QLD
4122
Country [1] 312279 0
Australia
Other collaborator category [1] 282198 0
University
Name [1] 282198 0
Monash University
Address [1] 282198 0
900 Dandenong Road
Caulfield East
Victoria 3145
Country [1] 282198 0
Australia
Other collaborator category [2] 282199 0
University
Name [2] 282199 0
University of Adelaide
Address [2] 282199 0
10 Pulteney Street
The University of Adelaide
Adelaide SA 5005
Country [2] 282199 0
Australia
Other collaborator category [3] 282200 0
Other
Name [3] 282200 0
CSIRO
Address [3] 282200 0
70-72 Bowen Street,
Spring Hill
Queensland 4000
Country [3] 282200 0
Australia
Other collaborator category [4] 282201 0
University
Name [4] 282201 0
University of Sydney
Address [4] 282201 0
The University of Sydney
NSW 2006
Australia
Country [4] 282201 0
Australia
Other collaborator category [5] 282330 0
Government body
Name [5] 282330 0
Queensland Institute of Medical Research Berghofer Medical Research
Address [5] 282330 0
QIMR Berghofer
Locked Bag 2000
Royal Brisbane Hospital QLD 4029
Australia
Country [5] 282330 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310525 0
Children's Health Queensland Hospital and Health Service HREC
Ethics committee address [1] 310525 0
Centre for Children’s Health Research
Queensland Children’s Hospital Precinct
Level 7, 62 Graham Street
South Brisbane QLD 4101
Ethics committee country [1] 310525 0
Australia
Date submitted for ethics approval [1] 310525 0
30/03/2022
Approval date [1] 310525 0
01/06/2022
Ethics approval number [1] 310525 0
HREC/22/QCHQ/85661
Ethics committee name [2] 310530 0
The University of Queensland Medical Research Ethics Committee
Ethics committee address [2] 310530 0
The University of Queensland
Brisbane QLD 4072 Australia
Ethics committee country [2] 310530 0
Australia
Date submitted for ethics approval [2] 310530 0
30/03/2022
Approval date [2] 310530 0
Ethics approval number [2] 310530 0

Summary
Brief summary
SYNERGY -A synergistic research program, incorporating advanced neuroimaging, genetics and liquid biopsy, enabling fetal and newborn diagnosis, prognosis and prediction of treatment responses to prevent, treat and cure CP using precision-medicine interventions. Prevention in this context means a 40% reduction in the rate of CP, and treatment response means a reduction in the size and severity of brain injury, enabling increased function, participation in education, independent living and employment long-term. We propose to do this by bringing together this unique team to:
• Accurately identifying the nature/mechanism of the brain injury very early in the fetal or neonatal period, to quantify the location, extent, mechanism and genomics of injury to determine the best prognosis and pathway to precision medicine interventions;
• Integrating currently disparate measures of neural injury using cross-cutting research methods across 3 themes involving (1) neuroimaging and EEG, (2) genomics, and (3) liquid biopsy;
• Synthesising and converging outputs from themes 1-3 using machine learning (ML) methods to inform theme 4: Translation to precision-medicine trials to prevent, treat and cure CP.
• Developing systems to comprehensively monitor how these biomarkers, genomics and precision-medicine interventions impact both the incidence and severity of CP at a population level using our national CP population register (Australian Cerebral Palsy Register, largest country-wide register).
Trial website
Trial related presentations / publications
nil
Public notes
nil

Contacts
Principal investigator
Name 117958 0
Prof Roslyn Boyd
Address 117958 0
Queensland Paediatric Rehabilitation Service, Queensland Children's Hospital.
Scientific Director, Queensland Cerebral Palsy and Rehabilitation Research,
Faculty of Medicine, The University of Queensland.

Mail Address: Rm 611, level 6,
Children's Health Research Centre,
Faculty of Medicine, The University of Queensland.
62 Graham Street, South Brisbane, 4030.
Queensland. Australia.
.
Country 117958 0
Australia
Phone 117958 0
+61 7 3069 7372
Fax 117958 0
Email 117958 0
[email protected]
Contact person for public queries
Name 117959 0
Roslyn Boyd
Address 117959 0
Queensland Paediatric Rehabilitation Service, Queensland Children's Hospital.
Scientific Director, Queensland Cerebral Palsy and Rehabilitation Research,
Faculty of Medicine, The University of Queensland.

Mail Address: Rm 611, level 6,
Children's Health Research Centre,
Faculty of Medicine, The University of Queensland.
62 Graham Street, South Brisbane, 4030.
Queensland. Australia.
.
Country 117959 0
Australia
Phone 117959 0
+61 7 3069 7372
Fax 117959 0
Email 117959 0
[email protected]
Contact person for scientific queries
Name 117960 0
Roslyn Boyd
Address 117960 0
Queensland Paediatric Rehabilitation Service, Queensland Children's Hospital.
Scientific Director, Queensland Cerebral Palsy and Rehabilitation Research,
Faculty of Medicine, The University of Queensland.

Mail Address: Rm 611, level 6,
Children's Health Research Centre,
Faculty of Medicine, The University of Queensland.
62 Graham Street, South Brisbane, 4030.
Queensland. Australia.
.
Country 117960 0
Australia
Phone 117960 0
+61 7 3069 7372
Fax 117960 0
Email 117960 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
15358Study protocol  [email protected]
15359Informed consent form  [email protected] 383725-(Uploaded-07-06-2023-14-47-01)-Study-related document.pdf
15360Ethical approval  [email protected] 383725-(Uploaded-15-06-2022-08-56-49)-Study-related document.pdf



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.