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Trial registered on ANZCTR


Registration number
ACTRN12619000711112
Ethics application status
Approved
Date submitted
28/03/2019
Date registered
13/05/2019
Date last updated
19/08/2021
Date data sharing statement initially provided
13/05/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
WithHolding or continuing Enteral feeds Around blood Transfusion (WHEAT) to prevent necrotising enterocolitis (NEC) in preterm infants
Scientific title
WithHolding or continuing Enteral feeds Around blood Transfusion (WHEAT) to prevent necrotising enterocolitis (NEC) in preterm infants: The Australian arm of the multinational WHEAT International collaboration
Secondary ID [1] 297811 0
None
Universal Trial Number (UTN)
U1111-1230-6981
Trial acronym
WHEAT Australia
Linked study record
WHEAT International is a collaboration between WHEAT UK (ISRCTN62501859), WHEAT Australia and similar studies planned in New Zealand, Canada and Europe. Studies contributing to WHEAT International will use identical protocols and be monitored by a single Data and Safety Monitoring Committee (DSMC).

Health condition
Health condition(s) or problem(s) studied:
Necrotising Enterocolitis 312175 0
Condition category
Condition code
Oral and Gastrointestinal 310725 310725 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
Reproductive Health and Childbirth 311302 311302 0 0
Complications of newborn

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Comparative effectiveness superiority trial of two clinical care pathways. As both comparator pathways of care are in standard use in Australia, there is no experimental arm.
PATHWAY 1 – WITHHOLDING FEEDS AROUND TRANSFUSION
Within the withholding feeds around transfusion pathway of care, all enteral feeds will be discontinued (the infant will be placed nil by mouth) for a period of 4 hours prior to packed red cell transfusion, during the packed red cell transfusion and until 4 hours post packed red cell transfusion. The bedside nurse will be responsible for adhering to the pathway and assessment of fidelity to the intervention will be by audit of bedside nursing notes.
Intervention code [1] 314053 0
Treatment: Other
Comparator / control treatment
PATHWAY 2 – CONTINUING FEEDS AROUND TRANSFUSION
Within the continuing feeds around transfusion pathway of care, enteral feeds will continue to be given prior, during and after the packed red cell transfusion, as per local guidelines in the manner in which they were being given prior to the decision to transfuse. The bedside nurse will be responsible for adhering to the pathway and assessment of fidelity to the intervention will be by audit of bedside nursing notes.
Control group
Active

Outcomes
Primary outcome [1] 319571 0
Stage II Bells or higher NEC after the first transfusion
Timepoint [1] 319571 0
Up to and including 40 weeks postmenstrual age or neonatal unit discharge (if earlier)
Secondary outcome [1] 368722 0
Severe NEC (death or surgery associated with NEC): histologically or surgically confirmed, or recorded as the cause of death on the death certificate
Timepoint [1] 368722 0
Up to and including 40 weeks postmenstrual age or neonatal unit discharge (if earlier)
Secondary outcome [2] 368723 0
All-cause mortality
Timepoint [2] 368723 0
Up to and including 40 weeks postmenstrual age or neonatal unit discharge (if earlier)
Secondary outcome [3] 368725 0
Duration of hospital stay: including all levels of care in days (according to network database records)
Timepoint [3] 368725 0
Up to and including 40 weeks postmenstrual age or neonatal unit discharge (if earlier)
Secondary outcome [4] 368726 0
Late onset sepsis (according to network database records)
Timepoint [4] 368726 0
Up to and including 40 weeks postmenstrual age or neonatal unit discharge (if earlier)
Secondary outcome [5] 368727 0
Weight z-score (according to network database records)
Timepoint [5] 368727 0
Up to and including 40 weeks postmenstrual age or neonatal unit discharge (if earlier)

Eligibility
Key inclusion criteria
1. Preterm birth at less than 30 weeks gestation
2. Parents do not opt out of trial participation
Minimum age
No limit
Maximum age
3 Months
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Infants with major congenital malformation of the gastrointestinal tract
2. Parents have chosen to opt out from participation
3. Given packed red cell transfusion with concurrent enteral feeds before enrolment (infants who have received a packed red cell transfusion while nil by mouth ARE still eligible)
4. Previous episode of NEC

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Central randomisation by computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Among infants born <30 weeks gestation in Australia and New Zealand, we assume an annual rate of 111/ 2,138 (5.2%) infants with Stage II or higher Bells NEC, the primary outcome of WHEAT Australia. We also assume that (i) 82% were treated in Australian neonatal units; (ii) 75% (3.9%) of these infants developed NEC after their first blood transfusion, which represents the population who may benefit from withholding feeds during transfusion; and (iii) 75% are enrolled in WHEAT Australia. These assumptions yield an annual enrolment of 2,138 x 0.82 x 0.75 x 0.75 = 986 infants, equating to a planned sample of 4,437 in 4.5 years. The estimated relative risk reduction (RRR) is 40%. Assuming a non-compliance/ crossover rate of 2%, a sample isze of 4,226 infants yields >80% power to show a 40% RRR in the primary outcome.
The primary analysis will be a comparison between care pathways on the incidence of the primary outcome using a chi-squared statistic that accommodates possible correlation of data between siblings from multiple births. Other binary secondary outcomes will be analysed using the same method, whilst comparable approaches applicable to continuous data will be applied as required. Estimates of the treatment effect adjusted for baseline characteristics will be calculated in sensitivity analyses using the relevant linear modelling approach. These modelling techniques will also be used to identify clinically important prognostic factors and to perform tests of heterogeneity in any subgroup analyses. Hypothesis tests will be undertaken at the two-sided 5% level of significance. P-values from secondary analyses that are unadjusted for multiple comparisons will be interpreted in proper context.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
2/09/2019
Actual
10/01/2020
Date of last participant enrolment
Anticipated
1/03/2025
Actual
Date of last data collection
Anticipated
3/07/2025
Actual
Sample size
Target
4437
Accrual to date
63
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 13490 0
Royal Hospital for Women - Randwick
Recruitment hospital [2] 13491 0
John Hunter Children's Hospital - New Lambton
Recruitment hospital [3] 13492 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [4] 20301 0
Liverpool Hospital - Liverpool
Recruitment hospital [5] 20302 0
Mercy Hospital for Women - Heidelberg
Recruitment hospital [6] 20303 0
Monash Children’s Hospital - Clayton
Recruitment postcode(s) [1] 26109 0
2031 - Randwick
Recruitment postcode(s) [2] 26110 0
2305 - New Lambton
Recruitment postcode(s) [3] 26111 0
2050 - Camperdown
Recruitment postcode(s) [4] 35043 0
2170 - Liverpool
Recruitment postcode(s) [5] 35044 0
3084 - Heidelberg
Recruitment postcode(s) [6] 35045 0
3168 - Clayton

Funding & Sponsors
Funding source category [1] 302336 0
Government body
Name [1] 302336 0
NHMRC
Country [1] 302336 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australian and New Zealand Neonatal Network
Address
National Perinatal Epidemiology and Statistics Unit
Centre for Big Data Research in Health
Level 4, Lowy Cancer Research Centre (C25)
UNSW Sydney
NSW 2052, Australia
Country
Australia
Secondary sponsor category [1] 302215 0
Other
Name [1] 302215 0
NHMRC Clinical Trials Centre
Address [1] 302215 0
NHMRC Clinical Trials Centre
Locked Bag 77
Camperdown NSW 1450
Country [1] 302215 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 303011 0
Hunter New England Human Research Ethics Committee
Ethics committee address [1] 303011 0
Research Ethics and Governance Office
Hunter New England Local Health District
Locked Bag 1
New Lambton NSW 2305
Ethics committee country [1] 303011 0
Australia
Date submitted for ethics approval [1] 303011 0
29/03/2019
Approval date [1] 303011 0
11/07/2020
Ethics approval number [1] 303011 0

Summary
Brief summary
Necrotising Enterocolitis (NEC) is a devastating neonatal disease associated with high risks of death and disability. The pathogenesis of NEC is incompletely understood but we know there is a temporal association between red cell transfusion and NEC. There is uncertainty about the impact of feeding during red cell transfusions and how this affects the chance of developing NEC.
WHEAT aims to answer:
In infants born <30 weeks (Patient), does withholding enteral feeds around the time of blood transfusion (Intervention), versus continued feeding around the time of blood transfusion (Comparator), reduce the rate of NEC after the first transfusion (Outcome)?
Design/methods:
Randomised, controlled, unblinded, multi-centre, comparative effectiveness superiority trial of two clinical care pathways. The two care pathways are: (1) Withholding feeds around transfusion; (2) Continuing feeds around transfusion.
Expected outcomes:
If withholding or continuing feeds during transfusion reduces the incidence of NEC, adopting this practice will help to improve preterm outcomes.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 92154 0
Prof Kei Lui
Address 92154 0
Department of Newborn Care
Royal Hospital for Women
Barker St
Randwick NSW 2031
Country 92154 0
Australia
Phone 92154 0
+61 (2) 93826190
Fax 92154 0
+61 (2) 93826191
Email 92154 0
[email protected]
Contact person for public queries
Name 92155 0
Prof Kei Lui
Address 92155 0
Department of Newborn Care
Royal Hospital for Women
Barker St
Randwick NSW 2031
Country 92155 0
Australia
Phone 92155 0
+61 (2) 93826190
Fax 92155 0
+61 (2) 93826191
Email 92155 0
[email protected]
Contact person for scientific queries
Name 92156 0
Prof Kei Lui
Address 92156 0
Department of Newborn Care
Royal Hospital for Women
Barker St
Randwick NSW 2031
Country 92156 0
Australia
Phone 92156 0
+61 (2) 93826190
Fax 92156 0
+61 (2) 93826191
Email 92156 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
Not available


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.