Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12618000893202
Ethics application status
Approved
Date submitted
29/01/2018
Date registered
28/05/2018
Date last updated
5/11/2019
Date data sharing statement initially provided
5/11/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Neonatal Encephalopathy Brain Outcomes (NEBO): Biomarkers in term born infants to improve accurate and earlier prediction of Cerebral Palsy
Scientific title
'Neonatal Encephalopathy Brain Outcomes (NEBO): Biomarkers in term born infants to improve accurate and earlier prediction of Cerebral Palsy
Secondary ID [1] 293895 0
Nil
Universal Trial Number (UTN)
Trial acronym
NEBO
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Neonatal Hypoxic Ischaemic Encephalopathy 306370 0
Cerebral Palsy 306371 0
Condition category
Condition code
Neurological 305454 305454 0 0
Other neurological disorders
Reproductive Health and Childbirth 305862 305862 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
Infants greater than 35+ weeks GA will undergo either a clinical MRI at 1.5T or a research brain MRI at 3T (at Day 1-10 post-delivery; day 5-7 optimal) to develop our understanding of the brain structure and maturation at this time point. They will have a concurrent neurological assessment (Hammersmith Neonatal Neurological Examination), visual assessment and General Movements Assessment (GMA). At 3 months of age infants will have a neurological assessment (Hammersmith Infant Neurological Examination), visual assessment and General Movements Assessment (GMA). At 24 months corrected age infants will be assessed for Cerebral Palsy (CP) and Motor and Cognitive outcomes. The results from these assessments will be compared to the results from the Gross Motor Function Classification System for Cerebral Palsy (GMFCS).
Intervention code [1] 300166 0
Diagnosis / Prognosis
Intervention code [2] 300167 0
Early Detection / Screening
Comparator / control treatment
Healthy term reference group:
Infants
a) born between 35 and 42 weeks gestation following an uncomplicated pregnancy and delivery,
b) have a birth weight above the 10th percentile
c) not admitted to neonatal intensive or special care units following their birth.
Control group
Active

Outcomes
Primary outcome [1] 304595 0
Sensitivity of Structural Magnetic Resonance Imaging (sMRI) in identifying children at risk of cerebral palsy will be compared to the results from the Gross Motor Function Classification System for Cerebral Palsy (GMFCS).
Timepoint [1] 304595 0
24 months corrected age
Primary outcome [2] 304596 0
Specificity of Structural Magnetic Resonance Imaging (sMRI) in identifying children at risk of cerebral palsy will be compared to the results from the Gross Motor Function Classification System for Cerebral Palsy (GMFCS).
Timepoint [2] 304596 0
24 months corrected age
Secondary outcome [1] 342501 0
Sensitivity of Diffusion MRI (dMRI) in identifying children at risk of cerebral palsy will be compared to the results from the Gross Motor Function Classification System for Cerebral Palsy (GMFCS).
Timepoint [1] 342501 0
24 months corrected age
Secondary outcome [2] 342528 0
Specificity of Diffusion MRI (dMRI) in identifying children at risk of cerebral palsy will be compared to the results from the Gross Motor Function Classification System for Cerebral Palsy (GMFCS).
Timepoint [2] 342528 0
24 months corrected age
Secondary outcome [3] 347367 0
Sensitivity of General Movements assessment (GMA) in identifying children at risk of cerebral palsy will be compared to the results from the Gross Motor Function Classification System for Cerebral Palsy (GMFCS).
Timepoint [3] 347367 0
24 months corrected age
Secondary outcome [4] 347371 0
Specificity of General Movements assessment (GMA) in identifying children at risk of cerebral palsy will be compared to the results from the Gross Motor Function Classification System for Cerebral Palsy (GMFCS).
Timepoint [4] 347371 0
24 months corrected age
Secondary outcome [5] 347374 0
Motor function will be assessed using the Motor Scale from the Bayley III.
Timepoint [5] 347374 0
24 months corrected age
Secondary outcome [6] 347375 0
Cognitive function will be assessed using the Cognitive Scale from the Bayley III.
Timepoint [6] 347375 0
24 months corrected age
Secondary outcome [7] 347376 0
Gross and fine motor skills will be assessed using the Neurosensory Motor Developmental Assessment (NSMDA).
Timepoint [7] 347376 0
24 months corrected age

Eligibility
Key inclusion criteria
HIE Group:
(a) All babies who enter the Paean Trial, are eligible for the NEBO follow-up trial.
(b) Moderate to severe encephalopathy in the first 7 days after term delivery (greater than 35 plus weeks PMA) using the modified Sarnat classification;
(c) Male or female infants born at 35 plus 0 weeks gestation with HIE (perinatal depression).
(d) One or more of the following indications of perinatal depression:
• Apgar of 5 at 10 minutes after birth OR
• receiving ongoing resuscitation e.g. assisted ventilation (positive pressure ventilation or CPAP) or chest compressions at 10 minutes after birth OR
• on cord blood or arterial or venous blood obtained at less than 60 minutes after birth,
• pH less than 7.00 OR
• base deficit of 12.0 mmol/L.
e) Moderate to severe encephalopathy, defined between one and six hours after birth by one or both of the following:
• 3 out of 6 modified Sarnat criteria indicating moderate/severe encephalopathy;
• OR
• 2 out of 6 modified Sarnat criteria between one and six hours after birth, plus seizure(s) requiring anticonvulsant treatment (diagnosed either clinically or using EEG monitoring) at any time of study entry;
f) Hypothermia treatment initiated by 6 hours of age; i.e. controlled whole-body cooling planned to continue for 72 hours, to a target temperature (adjusted manually or with a device) and subsequent controlled re-warming
g) Informed consent;
h) Ability to receive 3T MRI at 1-10 days post-delivery (day 5-7 optimal) at 35+ weeks PMA (no metal inserts; i.e. no VP shunts)
In ADDITION the following babies not entered into the PAEAN intervention trial would be eligible for the NEBO observational trial:
i. Babies cooled too late
ii. Postnatal arrest with subsequent HIE
iii. Parents not approached (e.g. mother in ICU/too ill on 1st day)
iv. Babies whose parents declined PAEAN (not happy about an intervention trial but would agree to an observational study).
v. Babies who met all other criteria for PAEAN but had a contraindication to cooling – e.g. uncontrolled pulmonary hypertension or coagulopathy/bleeding – so didn’t get cooled.

Healthy term reference group:
Infants
a) born between 35 and 42 weeks gestation following an uncomplicated pregnancy and delivery,
b) have a birth weight above the 10th percentile
c) not admitted to neonatal intensive or special care units following their birth.
Minimum age
35 Weeks
Maximum age
42 Weeks
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
(a) Unable to return for follow-up;
(b) Children with major congenital anomalies
(c) Where cessation of life support is under active discussion

Study design
Purpose
Screening
Duration
Longitudinal
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
Sample size calculations are based on a study investigating the ability of MRI at TEA, and the GMs assessment, to predict motor outcomes and CP at 12 months CA. In a prospective cohort of infants and in a total sample size of n=86, MRI was classified as normal (n=22), or with mild (n=54), moderate (n=6) or severe (n=4) white matter abnormality (WMA). Infants with normal or mild WMA were grouped (n=76), and infants with moderate and severe WMA were grouped (n=10). We assume the same ratio (7.6 MRI normal or with mild/moderate WMA: 1 MRI with moderate/severe WMA) will be observed in this study. Of the n=10 infants in the prior study that had moderate/severe WMA, n=5 (50%) developed CP. If we assume that 5% of infants with MRI normal or with mild/moderate WMA develop CP, then the study requires 69 infants to be recruited (8 with MRI with moderate/severe WMA and 61 with MRI normal or with mild/moderate WMA) in order to be able to reject the null hypothesis that the proportion of infants with CP in the two groups are equal with power=90%. The Type I error probability associated with this test of this null hypothesis is 0.05. To account for attrition a further 15% - 20% will be recruited, n=80. Consequently, the aim is to recruit a total sample size of 80 infants with full data sets.
When models involve brain structure and function data from one time point (40-42 weeks), standard regression models will be constructed. Models will be constructed using standard principles; first univariable analyses will be used to identify variables significant at the p<0.15 level and these variables then entered into multivariable models one-by–one, in decreasing order of significance. At each step the current model will be compared to previous models using the likelihood ratio test. Linear regression will be used for continuous outcomes (e.g. diffusion MRI measures of FA and MD); logistic regression for binary outcomes (e.g. disability/no disability); and multinomial logistic regression for categorical outcomes with > 2 categories (e.g. NSMDA categories of normal/suspect/abnormal). Results will be presented as effect estimates and 95% confidence intervals. The sensitivity and specificity of the predictive assessment model will be determined based on diagnosis of disability using standard definitions. Perinatal, clinical, demographic and social characteristics will be included as covariables when appropriate.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/06/2018
Actual
22/05/2019
Date of last participant enrolment
Anticipated
31/12/2020
Actual
Date of last data collection
Anticipated
31/12/2022
Actual
Sample size
Target
100
Accrual to date
4
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 9893 0
Mater Mother's Hospital - South Brisbane
Recruitment hospital [2] 9894 0
Royal Brisbane & Womens Hospital - Herston
Recruitment postcode(s) [1] 18699 0
4101 - South Brisbane
Recruitment postcode(s) [2] 18700 0
4029 - Herston

Funding & Sponsors
Funding source category [1] 298518 0
Government body
Name [1] 298518 0
Advance Queensland Innovation Partnerships
Country [1] 298518 0
Australia
Primary sponsor type
Individual
Name
Prof Roslyn Boyd
Address
Queensland Cerebral Palsy and Rehabilitation Research Centre
The University of Queensland
Centre for Children’s Health Research
Level 6
62 Graham St
South Brisbane
Queensland 4010
Country
Australia
Secondary sponsor category [1] 297674 0
None
Name [1] 297674 0
Address [1] 297674 0
Country [1] 297674 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299496 0
Children’s Health Queensland Hospital and Health Service Human Research Ethics Committee
Ethics committee address [1] 299496 0
Level 7
Centre for Children’s Health Research
Lady Cilento Children’s Hospital Precinct
62 Graham Street
South Brisbane
Queensland 4010
Ethics committee country [1] 299496 0
Australia
Date submitted for ethics approval [1] 299496 0
20/12/2017
Approval date [1] 299496 0
16/01/2018
Ethics approval number [1] 299496 0
HREC/17/QRCH/284

Summary
Brief summary
Broad aim of this prospective Observational study is to learn which tests (clinical, MRI and EEG) can be used in the neonatal period, to accurately identify which babies may have problems later in life, so that those babies and their families can be provided with the help they need as early as possible.
We aim to determine the risk of adverse neurodevelopment earlier and more accurately than currently possible in a cohort of up to 80 term babies born with HIE and a healthy term reference group between Royal Brisbane and Women's Hospital and Mater Mothers Hospital..
To do this we will use:
i) advanced brain MRI to determine the structural wiring diagram of the brain ('brain connectome'),
ii) dense array EEG to establish the functional activity or electrical 'traffic' being carried on the main branch of the connectome and
iii) structured clinical neurodevelopmental assessments to provide a cutting edge view of the state of brain development.
We aim to achieve this in a prospective longitudinal cohort study of up to 80 term infants born >35 weeks GA with HIE, and a reference group of 20 healthy term born infants.
Infants greater than 35+ weeks GA will undergo either a clinical MRI at 1.5T or a research brain MRI at 3T at day 1-10 post-delivery (day 5-7 optimal) to develop our understanding of the brain structure and maturation at this time point. A combination of neurological and neuromotor assessments will be performed at less than 7 days post MRI to understand the relationship between brain structure and function. These data will be compared to clinical neurodevelopmental assessments at 3 and 24 months corrected age.
HYPOTHESIS 1
In a prospective cohort of infants born at term at risk of CP, we will assess the following aims:
Aim 1: Determine the sensitivity and specificity of (i) Structural MRI (sMRI) and Diffusion MRI (dMRI), and (ii) General Movements assessment (GMA) at 41 weeks and at 3 months for CP diagnosis at 24 months corrected age (CA).
Hypothesis 1: (i) Absent myelination of the posterior limb of the internal capsule (PLIC) on T1-weighted MRI, and (ii) absent fidgety movements at 3 months will be sensitive and specific for CP at 24 months.
SECONDARY HYPOTHESES
Aim 2: Determine whether Diffusion MRI (dMRI) and EEG, Functional Connectivity (FC) are associated with severity of CP at age 24 months.
Hypothesis 2: (i) Lower fractional anisotropy (FA) of the corticospinal tracts, and (ii) reduced connectivity in the neonatal Connectome will be associated with a higher Gross Motor Function Classification System (GMFCS) classification and poorer function on Neurosensory Motor Developmental Assessment (NSMDA) and Bayley III scales of cognitive and motor development.
Aim 3: Determine whether structural MRI can predict the pattern of CP at age 24 months. Hypothesis 3: Location, extent and symmetry of brain injury will be associated with pattern and severity of CP.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 80614 0
Prof Roslyn Boyd
Address 80614 0
Rm 611, level 6
Children's Health Research Centre
62 Graham Street
South Brisbane
Queensland 4010
Country 80614 0
Australia
Phone 80614 0
+61 7 3069 7372
Fax 80614 0
+61 7 3069 7109
Email 80614 0
[email protected]
Contact person for public queries
Name 80615 0
Prof Roslyn Boyd
Address 80615 0
Rm 611, level 6
Children's Health Research Centre
62 Graham Street
South Brisbane
Queensland 4010
Country 80615 0
Australia
Phone 80615 0
+61 7 3069 7372
Fax 80615 0
+61 7 3069 7109
Email 80615 0
[email protected]
Contact person for scientific queries
Name 80616 0
Prof Roslyn Boyd
Address 80616 0
Rm 611, level 6
Children's Health Research Centre
62 Graham Street
South Brisbane
Queensland 4010
Country 80616 0
Australia
Phone 80616 0
+61 7 3069 7372
Fax 80616 0
+61 7 3069 7109
Email 80616 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?

No Supporting Document Provided



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.