Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12619000155190
Ethics application status
Approved
Date submitted
15/01/2019
Date registered
4/02/2019
Date last updated
28/01/2020
Date data sharing statement initially provided
4/02/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
PREBO-6: Prediction of childhood Brain Outcomes in infants born preterm
Scientific title
PREBO-6: Prediction of childhood Brain Outcomes in infants born preterm using neonatal MRI and concurrent clinical biomarkers
Secondary ID [1] 297046 0
Nil known
Universal Trial Number (UTN)
U1111-1226-5731
Trial acronym
PREBO-6
Linked study record
This study is a follow-up of ACTRN12613000280707 and ACTRN12615000591550.

Health condition
Health condition(s) or problem(s) studied:
Brain development in preterm infants 311036 0
Prematurity 311037 0
Condition category
Condition code
Neurological 309680 309680 0 0
Other neurological disorders
Reproductive Health and Childbirth 309681 309681 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
The PREBO-6 study is a prospective follow-up study of a cohort of children born very preterm (<31 weeks gestation) with early neonatal brain imaging and concurrent clinical assessment of motor, neurological and neurobehavioural function (PREMO - Prediction of Preterm Motor Outcomes, ACTRN12613000280707; PREBO - Prediction of Preterm Brain Outcomes, ACTRN12615000591550). We will now perform longer-term follow-up to capture longitudinal data on motor function, cognition, language, educational achievement, mental health and brain structure at 6 years corrected age. This will be a one-off assessment conducted over 2 days.
Intervention code [1] 313323 0
Not applicable
Comparator / control treatment
A reference group of healthy, term-born (38-41 weeks gestation) children.
Control group
Active

Outcomes
Primary outcome [1] 318648 0
Motor Function
Children’s motor ability will be assessed using the standardised and norm-referenced Movement Assessment Battery for Children, 2nd Edition (MABC-2).
Timepoint [1] 318648 0
The assessment will be performed when children reach 6 years corrected age.
Primary outcome [2] 318649 0
Composite Outcome: General Cognition
Children’s general cognitive development will be assessed using the Full Scale IQ score derived from the seven subtests of the Wechsler Intelligence Scale for Children (Primary Cognitive Outcome), 5th Edition: Australian and New Zealand Standardised Edition (WISC-V A&NZ). These subtests span across five core domains of verbal comprehension, visual-spatial ability, fluid reasoning, working memory and processing speed. Subtests include Similarities, Vocabulary, Block Design, Matrix Reasoning, Figure Weights, Digit Span and Coding.
Timepoint [2] 318649 0
The assessment will be performed when children reach 6 years corrected age.
Secondary outcome [1] 365585 0
Composite Outcome: Executive Function
Manifestations of everyday executive functioning across the domains of behavioural, emotional and cognitive regulation in the home and school environments will be assessed using the parent- and teacher-rated Behaviour Rating Inventory of Executive Function, Second Edition (BRIEF).

Two components of working memory, verbal and visual memory, will be assessed using The Digit Span subtest of the WISC-V A&NZ and the Corsi Blocks task. Cognitive flexibility and inhibitory control will be assessed using the Wisconsin Card Sorting Test and a Negative Priming task.
Timepoint [1] 365585 0
The assessments will be performed when children reach 6 years corrected age.
Secondary outcome [2] 365586 0
Attention
Children’s attention will be assessed using the Test of Everyday Attention-Children, 2nd Ed (TEA-Ch 2J).
Timepoint [2] 365586 0
The assessment will be performed when children reach 6 years corrected age,
Secondary outcome [3] 365587 0
Educational Achievement
The Australian adaptation of the Woodcock-Johnson Test of Achievement, 4th Edition will assess children’s emerging abilities of educational and academic attainment across the domains of reading and math.
Timepoint [3] 365587 0
The assessment will be performed when children reach 6 years corrected age.
Secondary outcome [4] 365588 0
Language
All children will have their language abilities assessed using 6 subtests of the Clinical Evaluation of Language Fundamentals, 5th Edition (CELF 5).
Timepoint [4] 365588 0
The assessment will be performed when children reach 6 years corrected age.
Secondary outcome [5] 365598 0
Mental Health
The Development and Well-Being Assessment (DAWBA), a semi-structured child psychiatric interview will be used for a comprehensive evaluation of the risk of DSM-5 psychiatric disorders.
Timepoint [5] 365598 0
The assessment will be performed when children reach 6 years corrected age.
Secondary outcome [6] 365601 0
Quality of Life
Children will also be assessed for quality of life using the Child Health Utility-9D questionnaire (CHU-9D).
Timepoint [6] 365601 0
The assessment will be performed when children reach 6 years corrected age.
Secondary outcome [7] 366248 0
Autism
Children will be assessed for autism using the Autism Spectrum Quotient-Child (AQ10-child) screening measure,
Timepoint [7] 366248 0
The assessment will be performed when children reach 6 years corrected age.
Secondary outcome [8] 366249 0
Composite Outcome: Brain neuroimaging
Brain MRI will be performed using a 3T Siemens Prisma with 64-channel head coil. MRI will include structural MRI T1 (3D MPRAGE, 1mm isotropic) and T2 (3D FLAIR, 1mm isotropic); Multi-shell diffusion MRI (8x b=0, 20x b=1000s/mm2, 60x b=3000s/mm2; 2mm isotropic), and functional MRI. These sequences will allow the investigation of (i) brain structure (volumetry, cortical thickness), (ii) brain microstructure (fibre density and organisation), and (iii) connectivity (both structural and functional).
Timepoint [8] 366249 0
An MRI will be performed when children reach 6 years corrected age.
Secondary outcome [9] 366252 0
Electrophysiology
Dense array EEG recordings will be obtained from all children. Following acquisition, EEG datasets will be pre-processed to generate artefact-free EEG and analysed using standard methods by power spectral density (PSD) to quantify brain activity at distinct frequencies and whole-brain connectivity measures will be subsequently employed. Whole-brain connectivity complements PSD by further assessing the strength of communication arising from brain regions, which are connected either by anatomical tracts or specific functional associations (i.e. motor, language or visual areas of the brain). We will evaluate the ability of the early EEG data already acquired to predict 6 year neurodevelopmental outcomes. To determine the capability of EEG metrics acquired at 6 years CA to predict functional outcomes, we will correlate the EEG PSD and whole-brain connectivity metrics with the 6 year neurodevelopmental outcomes using the predictive regression models. The correlation between EEG PSD and whole-brain connectivity metrics with 6 year neurodevelopmental outcomes will inform on the prognostic value of EEG measurements in this cohort.
Timepoint [9] 366252 0
The EEG will be performed when children reach 6 years corrected age.

Eligibility
Key inclusion criteria
Children are eligible for this study if they participated in the PPREMO or PREBO prospective study, and turn 6 years corrected age within the study period.

Preterm participants: Children who were born at <31 weeks gestation

Term-born participants: Children who were born between 38 and 41 weeks gestation following an uncomplicated pregnancy and delivery, had a birth weight above the 10th percentile, and were not admitted to neonatal intensive or special care units following their birth.
Minimum age
6 Years
Maximum age
6 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1) Children diagnosed with any congenital or chromosomal abnormality that could adversely affect their neurodevelopmental outcome.
2) Non-English speaking families.

Study design
Purpose
Natural history
Duration
Cross-sectional
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
Predictive regression models will be constructed. When models involve data from one time point standard regression models will be constructed; when models use data from multiple time-points, mixed-effects models that take into account within-child correlation will be used. Variables modelling the interaction between brain structure and child’s age will be included to account for potential longitudinal changes in brain anatomy. Linear regression will be used for continuous outcomes; logistic regression for binary outcomes; and multinomial logistic regression for categorical outcomes with > 2 categories. Initially, univariable associations between candidate predictor variables and outcomes will be investigated. Variables likely to be relevant in predicting response and potentially included in the model based on a priori expectation include perinatal variables, patient age, gender and socio-economic status. Multivariable analysis will determine the most appropriate combination of predictors. Models will be constructed using a step-wise feature selection/elimination procedure based on common criterions (Akaike Information Criterion, AIC; Bayesian Information Criterion, BIC). Results will be presented as effect estimates and 95% confidence intervals. Model calibration will be tested graphically and using Hosmer-Lemeshow statistic. Internal validation will be performed using bootstrap resampling. Model bias due to overfitting will be estimated and the final model corrected accordingly

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/05/2019
Actual
18/07/2019
Date of last participant enrolment
Anticipated
31/12/2023
Actual
Date of last data collection
Anticipated
31/12/2023
Actual
Sample size
Target
196
Accrual to date
3
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 12867 0
Lady Cilento Children's Hospital - South Brisbane
Recruitment postcode(s) [1] 25342 0
4101 - South Brisbane

Funding & Sponsors
Funding source category [1] 301615 0
Government body
Name [1] 301615 0
National Health and Medical Research Council
Country [1] 301615 0
Australia
Primary sponsor type
Individual
Name
Dr Joanne George
Address
The University of Queensland
Queensland Cerebral Palsy and Rehabilitation Research Centre
Centre for Children’s Health Research
Level 6, 62 Graham Street
South Brisbane QLD 4101
Country
Australia
Secondary sponsor category [1] 301318 0
University
Name [1] 301318 0
The University of Queensland
Address [1] 301318 0
Centre for Children’s Health Research
Level 6, 62 Graham Street
South Brisbane QLD 4101
Country [1] 301318 0
Australia
Other collaborator category [1] 280487 0
Government body
Name [1] 280487 0
Australian E-Health Research Centre, CSIRO
Address [1] 280487 0
Level 5 - UQ Health Sciences
Building 901/16, Royal Brisbane and Women's Hospital
Herston QLD 4029
Country [1] 280487 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302341 0
Childrens Health Queensland Hospital and Health Service Human Research Ethics Committee
Ethics committee address [1] 302341 0
Level 7,
Child Health Research Centre,
62 Graham street.,
South Brisbane.
QLD 4101.
Ethics committee country [1] 302341 0
Australia
Date submitted for ethics approval [1] 302341 0
21/01/2019
Approval date [1] 302341 0
Ethics approval number [1] 302341 0
Ethics committee name [2] 302345 0
The University of Queensland Institutional Human Research Ethics Committee
Ethics committee address [2] 302345 0
UQ Research & Innovation
Cumbrae Stewart Building (72)
The University of Queensland
St Lucia QLD 4072
Ethics committee country [2] 302345 0
Australia
Date submitted for ethics approval [2] 302345 0
18/02/2019
Approval date [2] 302345 0
20/02/2019
Ethics approval number [2] 302345 0
HREC/19/QCHQ/49800

Summary
Brief summary
Infants born preterm are at risk of adverse long-term neurodevelopmental outcomes, including cognitive, behavioural and motor deficits (including cerebra palsy). These adverse outcomes can significantly impair social and educational functioning and quality of life. We have established a cohort of infants born very preterm (<31 weeks gestation) with early neonatal brain imaging and concurrent clinical assessment of motor, neurological and neurobehavioural function (PREMO - Prediction of Preterm Motor Outcomes, ACTRN12613000280707; PREBO - Prediction of Preterm Brain Outcomes, ACTRN12615000591550). This study now aims to examine whether early MRI scans or clinical assessments can predict a child’s motor, cognitive, language, educational achievement and mental health outcomes at 6 years corrected age. If this is found to be the case, then in future, families will be provided with information on their child’s likely development much earlier. This will enable families to receive support and their children to be offered earlier treatments to help them with their movement, learning or behavioural development.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 89886 0
Dr Joanne George
Address 89886 0
The University of Queensland
Queensland Cerebral Palsy and Rehabilitation Research Centre
Centre for Children’s Health Research
Level 6, 62 Graham Street
South Brisbane QLD 4101
Country 89886 0
Australia
Phone 89886 0
+61 7 3069 7371
Fax 89886 0
Email 89886 0
j.george2@uq.edu.au
Contact person for public queries
Name 89887 0
Dr Joanne George
Address 89887 0
The University of Queensland
Queensland Cerebral Palsy and Rehabilitation Research Centre
Centre for Children’s Health Research
Level 6, 62 Graham Street
South Brisbane QLD 4101
Country 89887 0
Australia
Phone 89887 0
+61 3069 7371
Fax 89887 0
Email 89887 0
j.george2@uq.edu.au
Contact person for scientific queries
Name 89888 0
Dr Joanne George
Address 89888 0
The University of Queensland
Queensland Cerebral Palsy and Rehabilitation Research Centre
Centre for Children’s Health Research
Level 6, 62 Graham Street
South Brisbane QLD 4101
Country 89888 0
Australia
Phone 89888 0
+61 7 3069 7371
Fax 89888 0
Email 89888 0
j.george2@uq.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
The study team are available to collaborate with other research teams upon receipt of a reasonable request to access study data. Expressions of interest to access study data, made out to the Principal Investigator, Dr Joanne George, will be considered and then group level or individual level deidentified data could be shared as appropriate.
When will data be available (start and end dates)?
Data will be available on completion of data collection - 31/12/2023
Available to whom?
The study team are available to collaborate with other research teams upon receipt of a reasonable request to access study data.
Available for what types of analyses?
Expressions of interest to access study data, made out to the Principal Investigator, Dr Joanne George, will be considered and then group level or individual level deidentified data could be shared as appropriate.
How or where can data be obtained?
Expressions of interest to access study data, made out to the Principal Investigator, Dr Joanne George, will be considered.
Postal address: The University of Queensland Queensland Cerebral Palsy and Rehabilitation Research Centre Centre for Children’s Health Research Level 6, 62 Graham Street, South Brisbane QLD 4101
Email: j.george2@uq.edu.au


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
SourceTitleYear of PublicationDOI
EmbasePrediction of childhood brain outcomes in infants born preterm using neonatal MRI and concurrent clinical biomarkers (PREBO-6): Study protocol for a prospective cohort study.2020https://dx.doi.org/10.1136/bmjopen-2019-036480
N.B. These documents automatically identified may not have been verified by the study sponsor.