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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]

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

Cerebral Palsy

Nature/mechanism of brain injury very early in the fetal or neonatal period

Condition category

Condition code

Neurological

Other neurological disorders

Reproductive Health and Childbirth

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]

Early Detection / Screening

Intervention code [2]

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]

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]

24 Months Corrected Age

Primary outcome [2]

Diagnosis of Cerebral Palsy made by a paediatrician/neonatologist using MRI and clinical assessments

Timepoint [2]

24 Months Corrected Age

Primary outcome [3]

Evaluation of spontaneous movement using the General Movements Assessment in combination with General Movements Motor Optimality Scoring.

Timepoint [3]

40 weeks gestational age (TEA) and 3 months corrected age.

Secondary outcome [1]

Detection of anatomical landmarks for risk of CP in MRI

Timepoint [1]

32 weeks gestational age and 40 weeks gestational age (TEA)

Secondary outcome [2]

Location of brain injury assessed using EEG measurements of the electrical activity of the brain.

Timepoint [2]

32 weeks gestational age and 40 weeks gestational age (TEA)

Secondary outcome [3]

Identification of CP biomarkers from cord and infant blood samples, specifically genomic markers from circulating cell free DNA (ccfDNA)

Timepoint [3]

32 weeks gestational age and 40 weeks gestational age (TEA)

Secondary outcome [4]

Neurological evaluations using Hammersmith Neonatal Neurological Evaluation (HNNE) and/or Hammersmith Infant Neurological Evaluation (HINE)

Timepoint [4]

32 weeks gestational age, 40 weeks gestational age (TEA), 3 months CA and 24 months CA

Secondary outcome [5]

Evaluation of vision utilising the Neonatal Visual Assessment

Timepoint [5]

32 weeks gestational age, 40 weeks gestational age (TEA) and 3 months CA

Secondary outcome [6]

Emotional Availability - Self Report (Parent)

Timepoint [6]

3 months CA and 24 months CA

Secondary outcome [7]

Depression Anxiety Stress Scales (DASS-21)

Timepoint [7]

32 weeks gestational age, 3 months CA and 24 months CA

Secondary outcome [8]

Life Events List Questionnaire

Timepoint [8]

3 months CA and 24 months CA

Secondary outcome [9]

CYW Adverse Childhood Experiences Questionnaire for Children

Timepoint [9]

3 months CA and 24 months CA

Secondary outcome [10]

EQ-5D-5L Parent Questionnaire for identifying parent self-rated health.

Timepoint [10]

24 months CA

Secondary outcome [11]

Neurosensory Motor Development Assessment (NSMDA)

Timepoint [11]

24 months CA

Secondary outcome [12]

Peabody Developmental Motor Scales (PDMS)

Timepoint [12]

24 months CA

Secondary outcome [13]

Paediatric Evaluation of Disability Inventory - compute adaptive test (PEDI-CAT)

Timepoint [13]

24 months CA

Secondary outcome [14]

Infant Toddler Social and Emotional Assessment

Timepoint [14]

24 months CA

Secondary outcome [15]

Behaviour Assessment System for Children (BASC-3)

Timepoint [15]

24 months CA

Secondary outcome [16]

Infant Toddler Quality of Life Questionnaire (ITQoL)

Timepoint [16]

24 months CA

Secondary outcome [17]

Social Attention and Communication Surveillance - Revised (SACS-R)

Timepoint [17]

24 months CA

Secondary outcome [18]

Behavior Rating Inventory of Executive Function®–Preschool Version

Timepoint [18]

24 months CA

Secondary outcome [19]

Health Resource Use form

Timepoint [19]

24 months CA

Secondary outcome [20]

Preverbal Visual Assessment (PreViAs)

Timepoint [20]

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?

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

Final

Recruitment in Australia

Recruitment state(s)

NSW,QLD,VIC

Recruitment hospital [1]

Royal Brisbane & Womens Hospital - Herston

Recruitment hospital [2]

Monash Children’s Hospital - Clayton

Recruitment hospital [3]

The Children's Hospital at Westmead - Westmead

Recruitment hospital [4]

Queensland Children's Hospital - South Brisbane

Recruitment postcode(s) [1]

4029 - Herston

Recruitment postcode(s) [2]

3168 - Clayton

Recruitment postcode(s) [3]

2145 - Westmead

Recruitment postcode(s) [4]

4101 - South Brisbane

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

NHMRC Synergy Grants

Address [1]

National Health and Medical Research Council
GPO Box 1421
Canberra ACT 2601

Country [1]

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]

University

Name [1]

Griffith University

Address [1]

176 Messines Ridge Rd
Mount Gravatt QLD
4122

Country [1]

Australia

Other collaborator category [1]

University

Name [1]

Monash University

Address [1]

900 Dandenong Road
Caulfield East
Victoria 3145

Country [1]

Australia

Other collaborator category [2]

University

Name [2]

University of Adelaide

Address [2]

10 Pulteney Street
The University of Adelaide
Adelaide SA 5005

Country [2]

Australia

Other collaborator category [3]

Other

Name [3]

CSIRO

Address [3]

70-72 Bowen Street,
Spring Hill
Queensland 4000

Country [3]

Australia

Other collaborator category [4]

University

Name [4]

University of Sydney

Address [4]

The University of Sydney
NSW 2006
Australia

Country [4]

Australia

Other collaborator category [5]

Government body

Name [5]

Queensland Institute of Medical Research Berghofer Medical Research

Address [5]

QIMR Berghofer
Locked Bag 2000
Royal Brisbane Hospital QLD 4029
Australia

Country [5]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Children's Health Queensland Hospital and Health Service HREC

Ethics committee address [1]

Centre for Children’s Health Research
Queensland Children’s Hospital Precinct
Level 7, 62 Graham Street
South Brisbane QLD 4101

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

30/03/2022

Approval date [1]

01/06/2022

Ethics approval number [1]

HREC/22/QCHQ/85661

Ethics committee name [2]

The University of Queensland Medical Research Ethics Committee

Ethics committee address [2]

The University of Queensland
Brisbane QLD 4072 Australia

Ethics committee country [2]

Australia

Date submitted for ethics approval [2]

30/03/2022

Approval date [2]

Ethics approval number [2]

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

Prof Roslyn Boyd

Address

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

Australia

Phone

+61 7 3069 7372

Fax

[email protected]

Contact person for public queries

Name

Roslyn Boyd

Address

Country

Australia

Phone

+61 7 3069 7372

Fax

[email protected]

Contact person for scientific queries

Name

Roslyn Boyd

Address

Country

Australia

Phone

+61 7 3069 7372

Fax

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

What supporting documents are/will be available?

Doc. No.	Type	Email	Attachment
15358	Study protocol	[email protected]
15359	Informed consent form	[email protected]	383725-(Uploaded-07-06-2023-14-47-01)-Study-related document.pdf
15360	Ethical 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.

Trial Review

Documents added manually

Documents added automatically