Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12620000530921
Ethics application status
Approved
Date submitted
18/12/2019
Date registered
30/04/2020
Date last updated
11/03/2022
Date data sharing statement initially provided
30/04/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Does washing blood for transfusion make a difference to preterm babies?
Scientific title
Transfusion with washed versus unwashed red blood cells to reduce morbidity and mortality in infants born less than 28 weeks gestation: a multi-centre, blinded, parallel group, randomised controlled trial. The WashT trial.
Secondary ID [1] 300134 0
ID1183561
Universal Trial Number (UTN)
U1111-1245-6677
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Bronchopulmonary dysplasia 315662 0
Intraventricular Haemorrhage 315663 0
Retinopathy of Prematurity 315664 0
Necrotizing Enterocolitis 315665 0
Neonatal Mortality 315666 0
Condition category
Condition code
Inflammatory and Immune System 313954 313954 0 0
Other inflammatory or immune system disorders
Reproductive Health and Childbirth 315069 315069 0 0
Complications of newborn
Respiratory 315070 315070 0 0
Other respiratory disorders / diseases
Oral and Gastrointestinal 315071 315071 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
Eye 315072 315072 0 0
Diseases / disorders of the eye
Infection 315073 315073 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Group O Rhesus negative, washed leukodepleted red blood cells will be provided by Australian Red Cross Lifeblood. Washing of red blood cells will occur as per current established protocols. The washed leukodepleted red blood cells will be divided into four packs (quad-packs) using closed techniques. Washed leukodepleted red blood cell quad-packs will be supplied to the participating centres on a weekly basis. Washed, leukodepleted red cells split into quad packs using this process have a mean volume of 65 ± 6 mL/unit, a mean haematocrit of 54.8 ± 3.48.
Each infant will receive their allocated red blood cell pack type for the first red blood cell transfusion and any subsequent red blood cell transfusions to first discharge home.
The approach to transfusion will be standardised within each study centre, using a pre-defined restrictive haemoglobin threshold used in the Transfusion of Prematures (TOP) study. The haemoglobin threshold will be derived from a capillary, arterial or venous blood haemoglobin concentration ([Hb]) and adjusted for whether or not the infant is receiving respiratory support (invasive ventilation via endotracheal tube (ETT), nasal continuous positive airway pressure (CPAP), nasal non-invasive ventilation, nasal high flow, or supplemental oxygen) and by postnatal age. The protocol does not dictate sampling mode or how often [Hb] will be determined; this will be conducted according to local policies/clinician discretion. All [Hb] values derived from a complete blood examination (CBE) will be recorded to determine compliance with the transfusion threshold algorithm. Transfusion will be indicated whenever the [Hb] equals or falls below the threshold value and requires an active decision to transfuse to be made as soon as possible (at least within six hours of [Hb] determination) after the attainment of a threshold value. A fixed transfusion volume of 15 mL/kg will be given.
Weekly reviews of the database and on-site audits using medical and online records will be conducted at each site to determine adherence to the transfusion protocol.
1. Adherence to transfusion protocol – each screened infants’ [Hb] from a CBE and respiratory support requirements at time of [Hb] will be entered into REDcap by a research nurse, or nominee, on a daily basis for the first three weeks of life. Following this, weekly [Hb] results will be recorded.
An in-built alert system will alert clinicians and study personnel if a transfusion event has been triggered.
2. Dispensing and product accountability – compliance with the randomised intervention will be managed by the transfusion laboratory with each study participant and allocated product identified electronically through REDCap. This process will be audited routinely to ensure individual units and transfusions laboratories are maintaining randomisation compliance. This information will be communicated, blinded, to the Trial Management Committee.
Intervention code [1] 316407 0
Treatment: Other
Comparator / control treatment
Group O Rhesus negative, unwashed, leukodepleted red blood cells will be provided by Australian Red Cross Lifeblood as per current standard practice. Red cells, paediatric, leukocyte depleted (quad packs) have a mean volume of 60 ± 4 mL/unit and a mean haematocrit of 61 ± 4. 48.
Each infant will receive their allocated red blood cell pack type for the first red blood cell transfusion and any subsequent red blood cell transfusions to first discharge home.
The number of transfusions received will be determined by the number of times each newborn reaches the standardised haemoglobin threshold which will be derived from a capillary, arterial or venous blood haemoglobin concentration ([Hb]) and adjusted for whether or not the infant is receiving respiratory support (invasive ventilation via endotracheal tube (ETT), nasal continuous positive airway pressure (CPAP), nasal non-invasive ventilation, nasal high flow, or supplemental oxygen) and by postnatal age. The protocol does not dictate sampling mode or how often [Hb] will be determined; this will be conducted according to local policies/clinician discretion. All [Hb] values derived from a complete blood examination (CBE) will be recorded to determine compliance with the transfusion threshold algorithm. Transfusion will be indicated whenever the [Hb] equals or falls below the threshold value and requires an active decision to transfuse to be made as soon as possible (at least within six hours of [Hb] determination) after the attainment of a threshold value. A fixed transfusion volume of 15 mL/kg will be given.
Control group
Active

Outcomes
Primary outcome [1] 322355 0
A composite of mortality and/or major neonatal morbidities prior to first discharge home:
1. Death – defined as death from any cause.
2. BPD – defined as a continued need for any form of respiratory support (supplemental oxygen and/or assisted ventilation) at 36 weeks post menstrual age (±2 days), or discharge home whichever occurs first. Based on a standardised diagnostic approach, a modified Walsh air reduction test, routinely performed in each of the participating centres.
3. ROP - greater than grade 2 (uni- or bilateral)
4. NEC - equal or greater then Bell’s stage =2

Timepoint [1] 322355 0
Death or until primary hospital discharge
Secondary outcome [1] 378192 0
all-cause mortality after enrolment
Timepoint [1] 378192 0
time of death following enrolment
Secondary outcome [2] 378193 0
Bronchopulmonary dysplasia – defined as a continued need for any form of respiratory support (supplemental oxygen and/or assisted ventilation) at 36 weeks post menstrual age (±2 days), or discharge home whichever occurs first. Based on a standardised diagnostic approach, a modified Walsh air reduction test, routinely performed in each of the participating centres. Results will be collected from the subjects medical record
Timepoint [2] 378193 0
At death or at primary hospital discharge
Secondary outcome [3] 378194 0
Intraventricular haemorrhage greater than Grade 2 diagnosed by cranial ultrasound with results obtained from the subjects medical record.
Timepoint [3] 378194 0
At death or at primary hospital discharge
Secondary outcome [4] 378195 0
Retinopathy of Prematurity greater than grade 2 - diagnosed by formal ophthalmology examination and result obtained from subjects medical record
Timepoint [4] 378195 0
At death of at to primary hospital discharge
Secondary outcome [5] 378196 0
necrotising enterocolitis greater to or equal to Bells Stage 2 - data obtained from subjects medical record
Timepoint [5] 378196 0
At death or at primary hospital discharge
Secondary outcome [6] 381733 0
Severity of BPD (Grade 1, 2 or 3) recorded from the subjects medical record
Timepoint [6] 381733 0
AT death or at primary hospital discharge
Secondary outcome [7] 381734 0
Postnatal steroids for broncho-pulmonary dysplasia recorded from subjects medical record
Timepoint [7] 381734 0
At death or at primary hospital discharge
Secondary outcome [8] 381735 0
Total hours of invasive ventilatory support (via endotracheal tube), nasal continuous positive pressure ventilation, nasal/non-invasive ventilation, nasal high flow, and any respiratory support recorded from the subjects medical record.
Timepoint [8] 381735 0
At death or at primary hospital discharge
Secondary outcome [9] 381736 0
Total hours of high frequency oscillatory ventilation recorded from the subjects medical record
Timepoint [9] 381736 0
At death or at primary hospital discharge
Secondary outcome [10] 381737 0
Home oxygen therapy recorded from the subjects medical record
Timepoint [10] 381737 0
At primary hospital discharge
Secondary outcome [11] 381738 0
Patent ductus arteriosus requiring treatment (pharmacological and/or surgical) recorded from the subjects medical record
Timepoint [11] 381738 0
At death or at primary hospital discharge
Secondary outcome [12] 381739 0
Bacterial, fungal or viral at greater than 48 hours of age (blood or cerebrospinal fluid culture or polymerase chain reaction positive and treatment with antibiotics with therapeutic intent) recorded from the subjects medical record
Timepoint [12] 381739 0
At death or at primary hospital discharge
Secondary outcome [13] 381740 0
Spontaneous intestinal perforation (not necrotising enterocolitis associated) recorded from the subjects medical record
Timepoint [13] 381740 0
At death or primary hospital discharge
Secondary outcome [14] 381741 0
Porencephalic cysts, periventricular leukomalacia and any intracranial haemorrhage diagnosed by cranial ultrasound and record from the subjects medical record
Timepoint [14] 381741 0
At death or at primary hospital discharge
Secondary outcome [15] 381742 0
Maximal grade ROP to 3 months’ corrected age recorded from subjects medical record
Timepoint [15] 381742 0
At three months corrected age
Secondary outcome [16] 381743 0
Retinal ablation or medical treatment (anti-VEGF) to 3 months’ corrected age recorded from the subjects medical record
Timepoint [16] 381743 0
at 3 months corrected age
Secondary outcome [17] 381744 0
Total hours of parenteral nutrition recorded from the subjects medical record
Timepoint [17] 381744 0
At death or at primary hospital discharge
Secondary outcome [18] 381745 0
Weight, length and head circumference z-score at first discharge home recorded from the subjects medical record
Timepoint [18] 381745 0
At primary hospital discharge
Secondary outcome [19] 381748 0
Length of hospital stay from birth to first discharge home recorded from subjects medical record
Timepoint [19] 381748 0
At primary discharge home
Secondary outcome [20] 381750 0
Within trial cost-effectiveness - The outcome for the analysis will be the additional cost per case of major neonatal morbidity/death avoided (i.e. primary end point) at hospital discharge. The total volume of major categories of resource use (e.g. red blood cell packs, days in each level of care and total length of hospitalisation) will be collected. Resource use will be valued using the most relevant unit pricing. For example, by multiplying the National Weighted Activity Unit (NWAU) for the infant’s diagnosis related group (DRG) relating to their initial hospitalisation, by the Net Efficient Price for the given reference year. Red blood cell packs from the Red Cross will be valued at market prices where available. Volumes of resource use and costs will be tabulated by allocated group. Cost data are likely to be right skewed meaning logarithm transformation of cost data will be considered for analysis. Mean costs with standard deviations and total costs for each group will be reported in Australian dollars for the most recent reference year. Linear mixed models will be used to compare resource use and costs between the two groups.
An incremental cost effectiveness ratio (ICER) will be reported for the cost per neonatal morbidity/death avoided of the washed red blood cell group compared with the unwashed red blood cell group. Results will be plotted on a cost-effectiveness plane. Bootstrapping will be used to estimate a distribution around costs and outcomes and to calculate confidence intervals around the ICER. A cost-effectiveness acceptability curve will be plotted providing the probability of the intervention being cost-effective given a decision maker’s willingness to pay for preterm infant morbidity/death avoided. One-way sensitivity analyses will be conducted on key variables, for example, cost of washed red blood cells, gestational age, plurality, and study centre.
Timepoint [20] 381750 0
At primary hospital discharge
Secondary outcome [21] 381751 0
Modelled cost-effectiveness analysis - Given the morbidity from ROP, NEC, BPD, IVH has a longer-term impact on visual impairment, gastro-intestinal dysfunction, and asthma; a modelled cost-effectiveness analysis is necessary. Resource use and long-term outcomes beyond the first hospital discharge will be obtained from a number of administrative datasets including the 2-3-year neurodevelopmental follow-up of the ANZNN, National Perinatal Data Collection, MBS and PBS. Linkage will be through AIHW or Services Australia (formerly Department of Human Services). Data linkage of state-based admission data for consenting individuals will enable the per participant calculation of health system resource use and costs up to 2 years after the primary hospital discharge.
A Markov-model will be built to estimate the long-term costs (in Australian dollars) and health outcomes associated with RBC transfusion, using all data collected by ANZNN at 2-3 years and then extrapolated over the subsequent 10 years to capture long term effects of common morbidities including asthma and neuro-cognitive delay. Previous neonatal interventions have reported a sustained effect up to middle school age. 5% discounting per year will be applied to costs and outcomes, as per Australian government recommendations. The analysis will be performed using TreeAge Pro 2018 and R software. The model structure and analysis will follow best practice modelling guidelines from ISPOR.
Timepoint [21] 381751 0
At three years of age

Eligibility
Key inclusion criteria
Infants born born less than 28 weeks’ gestation.
Require one or more red blood cell transfusion
Minimum age
23 Weeks
Maximum age
28 Weeks
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Infants who have received a fetal transfusion.
Infants with major congenital or chromosomal abnormalities.
Infants whose parents have opted out of trial participation.
Infants who have previously received a red blood cell transfusion

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)
Many very preterm newborns require emergency transfusion in the first hours of life as part of their initial resuscitation and stabilisation. While unwashed RBCs are the standard product currently utilised in Australia for newborn transfusion, both unwashed and washed RBCs are approved for use in the newborn. With all outcome data routinely collected as part of the Australia and New Zealand Neonatal Network audit process, a waiver of consent will be employed allowing all eligible newborns to be randomised to either washed or unwashed red blood cells. Randomisation, by a customised web-based randomisation service, will occur when the infant reaches the pre-defined transfusion threshold. A unique study ID will be generated, assigned and held by each institution’s transfusion laboratory. Due to statutory regulations transfusion laboratory staff alone will be unblinded to treatment arm allocation.
Study investigators, attending clinicians and nursing staff and parents will be blinded to product allocation through the use of an opaque sticker applied to the transfusion pack by the transfusion laboratory. This alteration in normal practice has been approved by the Australian Red Cross Ethics Committee (ID2013#6). Transfusion pack issue and administration complies with all other current ordering and safety protocols. Compliance with the randomised intervention will be managed by the transfusion laboratory with each study participant and allocated product identified electronically.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A computer-generated randomisation schedule using balanced variable block design with an allocation ratio of 1:1 will be generated by an independent statistician not involved with trial participants or data analysis. Stratification will occur for study centre, sex and gestational age <25 and 25+0 to 27+6 weeks gestation. The randomisation schedule will be accessed via a web-based randomisation system (REDCap) housed on South Australian Health and Medical Research Institute (SAHMRI) secure servers. Infants from multiple births will be randomised individually.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Consent: This study has Human Research Ethics Committee (HREC) approval for waiver of consent, given that:
1. At least one third of eligible infants require a RBC transfusion within the first 4 hours of life,
2. Both washed and unwashed RBCs are standard products available for use in the newborn (although unwashed is the current standard of care), and
3. Outcome data are routinely collected as part of the ANZNN core data set.
Screening: All infants born <28 weeks gestation will be screened for randomisation by the study research nurse, lead investigator or nominee. Infants in receipt of a fetal transfusion, who have congenital or chromosomal abnormalities, whose parents opt out of the study, or who have received a RBC transfusion prior to randomisation will be excluded. Screening for the remainder of infants for requirement for RBC transfusion will continue until first discharge home, with all [Hb] recorded. Baseline data (gestational age, sex, date and time of birth, birth weight, head circumference and length) for all screened infants will be entered into REDCap by the study research nurses, lead investigator or nominee/s and infants allocated a screening identifier. Outcomes of the screening process will be recorded (i.e. randomised or not transfused) with sufficient data for CONSORT reporting.51
Trial entry: Infants meeting the inclusion criteria will be randomised at the point they first reach the predefined transfusion threshold, or clinician decision to transfuse. Infants will be randomised to receive washed leukodepleted or unwashed leukodepleted RBCs for all RBC transfusions required up to the time of their first discharge home.
Information for parents: All parents admitted to the NICU will receive an information leaflet about the study as part of their admission material.
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Using control group data from CI Collins N3RO trial, the expected incidence of mortality and/or significant neonatal morbidity prior to first discharge home in preterm infants <28 weeks gestation who required a RBC transfusion is 69%. To detect a 10% absolute reduction in the incidence of this composite outcome from 69% to 59% with 90% power and overall two-sided alpha 0.05 (0.049 at the final analysis), a sample size of 1010 infants (505 per group) is required. A 10% absolute reduction in the incidence in the primary outcome is likely to be clinically relevant and result in rapid adoption of a change in transfusion practice within neonatal intensive care. No adjustment for clustering due to multiple births is required in these calculations, since infants will be randomised individually and the design effect for binary outcomes is approximately one in this case.53 To account for 10% missing outcome data due to missed oxygen reduction test or study withdrawal, a total of 1124 infants will be randomised.
We will conduct an interim analysis of the primary outcome once 50% of participants have outcome data available, with unblinded results reviewed by an independent DSMC. O’Brien-Fleming stopping criteria will be used to maintain the overall alpha for the primary outcome at 0.05.
Analyses will be performed on an intention-to-treat basis according to a pre-specified statistical analysis plan, written to conform with recent recommendations on the content of clinical trial analysis plans.55 The incidence of mortality and/or major morbidities prior to first discharge from NICU will be compared between groups using log binomial regression. Generalised estimating equations with an independence working correlation structure will be used to account for clustering due to multiple births. Adjustment will be made for randomisation strata (study centre, sex and gestational age <26 weeks and 26+1 to 27+6 weeks gestation), with the difference between groups expressed as a relative risk with a confidence interval and two-sided p-value. Statistical significance will account for a single pre-specified interim analysis using the O’Brien Fleming approach.
Secondary outcomes will be analysed using linear, log-binomial and negative binomial regression models for continuous, binary and count outcomes, respectively, with generalized estimating equations used to account for dependence due to multiple births. In a planned sub-group analyses of the primary outcome we will examine the effect of transfusion with washed RBCs on infants with gestational age <26 weeks and 26+1 to 27+6 weeks gestation. Relative risks and confidence intervals will be reported for each gestational age group, along with a p-value for the interaction between gestational age and randomised group.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
4/01/2021
Actual
1/03/2021
Date of last participant enrolment
Anticipated
1/07/2026
Actual
Date of last data collection
Anticipated
1/07/2028
Actual
Sample size
Target
1214
Accrual to date
51
Final
Recruitment in Australia
Recruitment state(s)
QLD,SA,VIC
Recruitment hospital [1] 15536 0
Womens and Childrens Hospital - North Adelaide
Recruitment hospital [2] 15537 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [3] 15538 0
The Royal Women's Hospital - Parkville
Recruitment hospital [4] 15540 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [5] 18159 0
The Royal Childrens Hospital - Parkville
Recruitment hospital [6] 21955 0
Mater Mother's Hospital - South Brisbane
Recruitment postcode(s) [1] 28905 0
5006 - North Adelaide
Recruitment postcode(s) [2] 28906 0
5042 - Bedford Park
Recruitment postcode(s) [3] 28907 0
3052 - Parkville
Recruitment postcode(s) [4] 28909 0
3168 - Clayton
Recruitment postcode(s) [5] 32156 0
3052 - Melbourne University
Recruitment postcode(s) [6] 37048 0
4101 - South Brisbane

Funding & Sponsors
Funding source category [1] 304571 0
Government body
Name [1] 304571 0
National Health and Medical Research Council
Country [1] 304571 0
Australia
Primary sponsor type
Other
Name
South Australian Health and Medical Reseach Institute
Address
North Terrace, Adelaide SA 5000
Country
Australia
Secondary sponsor category [1] 304856 0
None
Name [1] 304856 0
Address [1] 304856 0
Country [1] 304856 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304997 0
WCHN Human Research Ethics Committee
Ethics committee address [1] 304997 0
Ethics committee country [1] 304997 0
Australia
Date submitted for ethics approval [1] 304997 0
04/12/2019
Approval date [1] 304997 0
19/12/2019
Ethics approval number [1] 304997 0
HREC/19/WCHN/182

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 98910 0
A/Prof Michael Stark
Address 98910 0
The Robinson Research Institute
Level 3, The Norwich Centre
55 King William Road
North Adelaide
South Australia
5006
Country 98910 0
Australia
Phone 98910 0
+61 8 8313 1325
Fax 98910 0
Email 98910 0
[email protected]
Contact person for public queries
Name 98911 0
Michael Stark
Address 98911 0
The Robinson Research Institute
Level 3, The Norwich Centre
55 King William Road
North Adelaide
South Australia
5006
Country 98911 0
Australia
Phone 98911 0
+61 8 8313 1325
Fax 98911 0
Email 98911 0
[email protected]
Contact person for scientific queries
Name 98912 0
Michael Stark
Address 98912 0
The Robinson Research Institute
Level 3, The Norwich Centre
55 King William Road
North Adelaide
South Australia
5006
Country 98912 0
Australia
Phone 98912 0
+61 8 8313 1325
Fax 98912 0
Email 98912 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Clinical characteristics, transfusion exposure, clinical outcomes
When will data be available (start and end dates)?
Completion of the primary outcome - projected 2025. There will be no end date for data availability
Available to whom?
Only researchers who provide a methodologically sound proposal, case-by-case basis at the discretion of study chief investigators
Available for what types of analyses?
IPD meta-analyses, systematic review
How or where can data be obtained?
Access will subject to approvals by Principal Investigator and study chief investigators following formal application. Initial contact with the principle investigator will be by email ([email protected]) with formal submission of request reviewed by the trial steering committee.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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