Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621000904875
Ethics application status
Approved
Date submitted
17/05/2021
Date registered
12/07/2021
Date last updated
8/07/2022
Date data sharing statement initially provided
12/07/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
The NITric oxide during cardiopulmonary bypass to improve Recovery in Infants with Congenital heart defects (NITRIC) Follow-up Study
Scientific title
Gene Expression to Predict Long-Term Neurodevelopmental Outcome in Infants from the NITric oxide during cardiopulmonary bypass to improve Recovery in Infants with Congenital heart defects (NITRIC) Study – A Multicentre Prospective Trial
Secondary ID [1] 304213 0
ARGCHDG000036
Universal Trial Number (UTN)
Trial acronym
Linked study record
This study is a follow-up study of the participants recruited in trial: ACTRN12617000821392

Health condition
Health condition(s) or problem(s) studied:
congenital heart disease 321904 0
Condition category
Condition code
Cardiovascular 319629 319629 0 0
Other cardiovascular diseases
Surgery 319630 319630 0 0
Other surgery

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
The clinical cohort will be derived from the existing randomised controlled and blinded study NITric oxide during cardiopulmonary bypass to improve Recovery in Infants with Congenital heart defects (NITRIC; ACTRN12617000821392), where children with congenital heart disease less than two years of age requiring cardiopulmonary bypass (CPB) were recruited to standard care or delivery of nitric oxide (NO) into the CPB circuit during open heart surgery. In this follow-up study, we are observing these children up to their fifth birthday.

Participants in this study will be required to perform online yearly questionnaire-based longitudinal assessments until age five years, when a full face-to-face gold standard neuropsychological assessment will be performed (school entry/readiness assessment for school entry). The following tools will be administered during the online yearly assessments:
* Ages and Stages Questionnaire (ASQ-3)
* Behavior Rating Inventory of Executive Function-Preschool version (BRIEF-P)
* Strengths and Difficulties Questionnaire
* PedsQL Inventory 4 Generic Core Scales
* PedsQL Multidimensional Fatigue Scale – General Fatigue Subscale (6 items)
* Kessler Psychological Distress Scale (K6)
* Parenting Stress Index (PSI-4) Short Form

The following tools will be administered during the face-to-face assessment at five years of age:
* Wechsler Preschool & Primary Scale of Intelligence Scale (WPPSI-IV), including working memory and processing speed indices
* Movement Assessment Battery for Children (MABC2)
* Day/Night Stroop Test
* Test of Everyday Attention for Children (TEA-Ch2) – Balloon Hunt, Balloons 5 subtests only
* Clinical Evaluation of Language Fundamentals – Australian and New Zealand 5th Edition Screening Test (CELF-5 ANZ Screening Test)
* Social Responsiveness Scale (Autism)
* ADHD Rating Scale
* Adaptive Behaviour Assessment System (ABAS) Social Scale, 3rd Edition
* Connors Kiddie Continuous Performance Test, 2nd Edition (CONNERS K-CPT 2)
* Wide Range Assessment of Memory and Learning, 3rd Edition (WRAML3) – Story Memory subtest only
* Working Memory Test Battery for Children (WMTB-C) – Digit Recall subtest only
* PedsQL Multidimensional Fatigue Scale – Full scale
* Attachment Relationship Inventory-Caregiver Perspective (ARI-CP 2-5)

The face-to-face assessment will take place at the hospital, or for participants who live rurally or remotely, the neuropsychologist may visit their home.

Participants are not required to provide any samples for the genomic analysis component of this study, as these samples were collected during the NITRIC trial. During this follow-up study, these biobanked samples will be analysed using RNA sequencing.

All Australian and New Zealand participants from the NITRIC trial will be invited to participate.
Intervention code [1] 320546 0
Diagnosis / Prognosis
Comparator / control treatment
All Australian and New Zealand participants from the NITric oxide during cardiopulmonary bypass to improve Recovery in Infants with Congenital heart defects (NITRIC; ACTRN12617000821392) trial will be invited to participate, regardless of whether they received the intervention (nitric oxide in their bypass machine) or standard care. The follow-up assessments for this study do not differ between the participant's randomised group from the NITRIC trial, nor is the participant's randomised group from the NITRIC trial the primary exposure of interest.
Control group
Active

Outcomes
Primary outcome [1] 327492 0
Neurodevelopmental impairment identified during face-to-face assessment on any of the tools used at the five-year face-to-face assessment (i.e. composite measure of all tools):
* Mild neurodevelopmental impairment will be defined as a scores between 1 and 2 SD below the mean, in at least one of the five year old face-to-face assessment domains.
* Moderate neurodevelopmental impairment will be defined as a scores between 2 and 3 SD below the mean, in at least one of the five year old face-to-face assessment domains.
* Severe neurodevelopmental impairment will be defined as a scores <3 SD below the mean, in at least one of the five year old face-to-face assessment domains.

The following tools will be used at the five year face-to-face assessment to assess neurodevelopmental impairment:
* Wechsler Preschool & Primary Scale of Intelligence Scale (WPPSI-IV), including working memory and processing speed indices
* Movement Assessment Battery for Children (MAB2)
* Test of Everyday attention for Children (TEACh2 J)
* Beery-Buktenica Developmental Test of Visual-Motor Integration (VMI6)
* Clinical Evaluation of Language Fundamentals – Australian and New Zealand 5th Edition Screening Test (CELF-5 ANZ Screening Test)
* Social Skills Improvement System (SSIS) Rating Scales
* Social Responsiveness Scale (Autism)
* ADHD Rating Scale
* Wide Range Achievement Test, Section A
* PedsQL Multidimensional Fatigue Scale – Full scale
* Early Childhood Parental Acceptance and Rejection Questionnaire (ECPARQ)
* Hospital Anxiety and Depression Scale (HADS)
* Parenting Stress Index (PSI-4)
Timepoint [1] 327492 0
Five years of age
Secondary outcome [1] 395357 0
Neurodevelopmental impairment identified on any of the online screening tools (i.e. composite measure), defined as a score in each online screening domain > 1 SD below the mean, or cut-off points defined by the test manuals, on any of the domains.

The following tools will be used at the yearly online assessments to assess neurodevelopmental impairment:
* Ages and Stages Questionnaire (ASQ-3)
* Behavior Rating Inventory of Executive Function-Preschool version (BRIEF-P)
* Vineland Adaptive Behavior Scale (VABS-3)
* Strengths and Difficulties Questionnaire
* PedsQL Inventory 4 Generic Core Scales
* PedsQL Multidimensional Fatigue Scale – General Fatigue Subscale (6 items)
Timepoint [1] 395357 0
Each birthday from two years to five years of age

Eligibility
Key inclusion criteria
* Enrolled in the NITric oxide during cardiopulmonary bypass to improve Recovery in Infants with Congenital heart defects (NITRIC; ACTRN12617000821392) randomised controlled trial
* Consent of parents/guardian for long-term follow-up
Minimum age
0 Years
Maximum age
5 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Children are enrolled in the original NITRIC RCT are eligible for this study, therefore the same exclusion criteria as for the NITRIC RCT will apply:
•Signs of persistently elevated pulmonary vascular resistance preoperatively requiring inhaled NO or preoperative intravenous use of drugs involved in the NO pathway such as glyceryl trinitrate, within 48 hours prior to CPB (oral sildenafil treatment alone is not an exclusion);
•Patient is on ECLS immediately prior to surgery;
•Chronic ventilator dependency;
•Concurrent known confirmed bacterial sepsis/septic shock, diagnosed within <48hours prior to surgery and being actively treated with antibiotics at time of surgery (suspected sepsis treated with antibiotics is not an exclusion criteria unless inotropes are required for treatment of septic shock at time of surgery);
•Preoperative acute respiratory distress syndrome requiring high frequency oscillatory ventilation <48 hours of surgery;
•Patient requires high doses of vasoactive drugs prior to surgery with an inotrope score >=15 met within 24 hours prior to surgery: Inotrope requirement will be calculated by means of the Vasoactive-Inotrope Score (VIS) (2): VIS = dopamine dose (mcg/kg/min) + dobutamine dose (mcg/kg/min) + 100 x adrenaline dose (mcg/kg/min) + 100 x noradrenaline dose (mcg/kg/min) + 10 x milrinone dose (mcg/kg/min) + 10,000 x vasopressin dose (U/kg/min);
•Cardiac arrest within one week (seven days) prior to surgery;
•Emergency cardiac surgery which may preclude obtaining informed consent (defined as acutely required life-saving procedure in a patient unlikely to survive the next hours without the surgery); and
•Pre-existing methaemoglobinemia (MetHb>3%).

Study design
Purpose
Psychosocial
Duration
Longitudinal
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
Neurodevelopmental impairment at five years of age will be analysed using logistic regression including the age-group and physiology stratification as fixed effects; odds ratio along with 95% confidence interval (CI) and p-value will be presented. Unadjusted difference and chi-squared p-value will also be presented.

Logistic regression will be used to investigate individual, PICU treatment and community factors associated with neurodevelopmental vulnerability at five years of age. Groups of factors will be individually investigated, and multicollinearity explored. Significant factors across all groups will then be entered into a stepwise selection procedure to identify a final set of independent variables.

Latent, group based trajectory models will be developed to investigate different post NITRIC intervention recovery profiles measured by the annual assessment questionnaire at two, three, four and five years of age. The data will be explored graphically to determine the most functional form, and a series of models developed and compared using the chi-squared difference tests (nested models) or other criterion (such as AIC; non-nested models).

Using the SDQ, SSIS, SRS and ADHD Rating Scale assessments, machine learning methods will be used to derive behavioural phenotypes. The following steps will be taken: 1) determine the most appropriate clustering strategy using an OPTICS plot; 2) determine the optimal number of phenotypes, utilising a k-fold cross-validation approach; 3) describe and visualise the relationship between assessment tool domains and phenotypes using graphical methods; 4) the association between the derived behavioural phenotypes and demographic, clinical, social, and cognitive and academic outcomes using standard approaches such as chi-square tests, ANOVA and Kruskal-Wallis.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/09/2021
Actual
10/05/2022
Date of last participant enrolment
Anticipated
31/12/2022
Actual
Date of last data collection
Anticipated
30/06/2026
Actual
Sample size
Target
868
Accrual to date
152
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,WA,VIC
Recruitment outside Australia
Country [1] 23701 0
New Zealand
State/province [1] 23701 0

Funding & Sponsors
Funding source category [1] 308584 0
Government body
Name [1] 308584 0
Department of Health, Australian Government
Country [1] 308584 0
Australia
Primary sponsor type
University
Name
The University of Queensland
Address
St Lucia, Qld 4072
Country
Australia
Secondary sponsor category [1] 309443 0
None
Name [1] 309443 0
Address [1] 309443 0
Country [1] 309443 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 308523 0
Children's Health Queensland Human Research Ethics Committee
Ethics committee address [1] 308523 0
Centre for Children's Health Research
62 Graham St
South Brisbane
Qld 4101
Ethics committee country [1] 308523 0
Australia
Date submitted for ethics approval [1] 308523 0
23/11/2020
Approval date [1] 308523 0
21/12/2020
Ethics approval number [1] 308523 0
HREC/20/QCHQ/70626
Ethics committee name [2] 311242 0
Health and Disability Ethics Committees
Ethics committee address [2] 311242 0
Ministry of Health
133 Molesworth St
PO Box 5103
Wellingon 6011
Ethics committee country [2] 311242 0
New Zealand
Date submitted for ethics approval [2] 311242 0
Approval date [2] 311242 0
06/09/2021
Ethics approval number [2] 311242 0
21/NTA/83

Summary
Brief summary
Each year, over 1000 children with congenital heart disease (CHD) in Australia require heart surgery. The short and long-term outcomes of these children are primarily determined by pre-existing comorbidities and genetic factors, direct impact of the surgical intervention, the response to cardiopulmonary bypass (CPB), and the consequences thereof during their intensive care stay. Neurodevelopmental disabilities remain amongst the most common, and the most damaging, outcomes in children undergoing surgery for CHD.

Large longitudinal population-based studies assessing long-term outcome are lacking. One out of four infants undergoing heart surgery develop a harmful response to CPB, which leads to low cardiac output syndrome (LCOS). LCOS results in prolonged (multi-) organ dysfunction related to hypotension, organ hypoperfusion, renal failure, and brain ischemia. LCOS translates into adverse short-term outcomes (LCOS, need for extracorporeal life support (ECLS), and death), and determines adverse long-term outcomes manifesting into school age and beyond.

Currently, there are no reliable, sensitive, and rapid predictors for LCOS or adverse early and long-term outcomes. In addition, the concept of LCOS remains poorly understood, and clinical evidence indicated highly variable presentations, suggestive of variability of host response. Preventive strategies to reduce LCOS remain of limited effectiveness. Thanks to rapid sequencing technology, discriminative patterns of the individual response to CPB can now be tested in real-time. Transcriptomics therefore has huge potential to unravel the mechanisms underlying adverse outcomes after CPB surgery, to reveal biological phenotypes, and to identify novel interventional strategies.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 111006 0
A/Prof Kristen Gibbons
Address 111006 0
Centre for Children's Health Research
62 Graham St
South Brisbane Qld 4101
Country 111006 0
Australia
Phone 111006 0
+61 407966708
Fax 111006 0
Email 111006 0
[email protected]
Contact person for public queries
Name 111007 0
A/Prof Kristen Gibbons
Address 111007 0
Centre for Children's Health Research
62 Graham St
South Brisbane Qld 4101
Country 111007 0
Australia
Phone 111007 0
+61 407966708
Fax 111007 0
Email 111007 0
[email protected]
Contact person for scientific queries
Name 111008 0
A/Prof Luregn Schlapbach
Address 111008 0
University Children's Hospital Zurich – Eleonore Foundation
Steinwiesstrasse 75
CH-8032 Zurich
Country 111008 0
Switzerland
Phone 111008 0
+41 44 266 37 90
Fax 111008 0
Email 111008 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
SourceTitleYear of PublicationDOI
EmbaseLongitudinal cohort study investigating neurodevelopmental and socioemotional outcomes in school-entry aged children after open heart surgery in Australia and New Zealand: the NITRIC follow-up study protocol.2023https://dx.doi.org/10.1136/bmjopen-2023-075429
N.B. These documents automatically identified may not have been verified by the study sponsor.