Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12613000237785
Ethics application status
Approved
Date submitted
26/02/2013
Date registered
27/02/2013
Date last updated
29/01/2021
Date data sharing statement initially provided
29/01/2021
Date results information initially provided
29/01/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Effect of Transfusion of Washed Reed Blood Cells on Neonatal Outcome: A Pilot Randomised Controlled Trial
Scientific title
The Effect of Washed versus Unwashed Packed Red Blood Cell Transfusion on Immune Responses in the Extremely Preterm Newborn: A Pilot Randomised Trial
Secondary ID [1] 281860 0
None
Universal Trial Number (UTN)
Trial acronym
WashT
Linked study record

Health condition
Health condition(s) or problem(s) studied:
neonatal morbidity and mortality
 288227 0
Bronchopulmonary dysplasia 288228 0
Retinopathy of prematurity 288229 0
Necrotising enterocolitis 288230 0
Peri/ Intraventricular haemorrhage 288231 0
Nosocomial infection 288232 0
Condition category
Condition code
Inflammatory and Immune System 288591 288591 0 0
Other inflammatory or immune system disorders
Respiratory 288592 288592 0 0
Other respiratory disorders / diseases
Infection 288593 288593 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Standard (red cell leukodeplete) packed red blood cells will be supplied from Australian Red Cross Blood Service to the study centres. Two 3-day old Group O Rh- cross-match compatible standard packed red blood cell packs will be washed at the Blood Service following standard methodology and subsequently divided into 4 paediatric packs using closed techniques. The prepared washed packed red blood cells, with a shelf life of 28 days will be supplied on a weekly basis for use in study subjects. Only washed packs aged less than 14 days will be allocated to enrolled subjects, controlling for red cell lesion, and residual unused packs will be discarded weekly. Infants randomised to this group will receive standard packed red blood cells washed pre-transfusion. Infants who require more than one transfusion will continue to receive washed packed red blood cells for any subsequent transfusion that is required. If an infant requires an emergency transfusion and no washed packed red blood cells are available for issue from blood bank, O-negative, cross-match compatible, unwashed packed red blood cells will be administered in accordance with current neonatal practice guidelines. Enrolled infants will receive either washed or standard packed red blood cell transfusion from 24 hours of age until discharge from their primary hospital admission.
Intervention code [1] 286421 0
Treatment: Other
Comparator / control treatment
Standard red cell leukodeplete red blood cells. Infants who require more than one transfusion will continue to receive standard PRBCs for any subsequent transfusion that is required.
Control group
Active

Outcomes
Primary outcome [1] 326354 0

Post-transfusion markers of endothelial activation (Composite of plasminogen activation inhibitor (PAI)-1, macrophage migration inhibitory factor (MIF), soluble intracellular adhesion molecule (sICAM), soluble vascular cellular adhesion molecule (sVCAM) in the transfusion recipient.
Timepoint [1] 326354 0
6 hours post-transfusion
Primary outcome [2] 326355 0
Post-transfusion levels of circulating plasma cytokines (Composite of Interleukin (IL)-1ß, IL-6, IL-8, IL-10, IL-12, IL17A and tumour necrosis factor (TNF)-a) in the transfusion recipient.
Timepoint [2] 326355 0
6 hours post-transfusion
Secondary outcome [1] 391135 0
heart rate measured using continuous ECG monitoring
Timepoint [1] 391135 0
1-4 hours post transfusion
Secondary outcome [2] 391136 0
cardiac output measured by echocardiography
Timepoint [2] 391136 0
1-4 hours post-transfusion
Secondary outcome [3] 391137 0
systemic vascular resistance calculated using the equation Systemic vascular resistance = mean arterial blood pressure / cardiac output. Mean arterial blood pressure was measured by invasive arterial blood pressure monitoring and cardiac output by echocardiography
Timepoint [3] 391137 0
1-4 hours post-transfusion
Secondary outcome [4] 391138 0
blood pressure measured continuously by invasive arterial catheter
Timepoint [4] 391138 0
1-4 hours post-transfusion
Secondary outcome [5] 391139 0
mean airway pressure recorded from the mode invasive or non-invasive respiratory support
Timepoint [5] 391139 0
1-4 hours post-transfusion
Secondary outcome [6] 391140 0
Fractional inspired oxygen measured from the mode of invasive or non-invasive respiratory support
Timepoint [6] 391140 0
1-4 hours post-transfusion
Secondary outcome [7] 391141 0
respiratory severity score is a validated proxy measure of oxygenation index calculated from the mean airway pressure delivered by invasive or non-invasive respiratory support and the fractional inspired oxygen
Timepoint [7] 391141 0
1-4 hours post-transfusion

Eligibility
Key inclusion criteria
Infant’s born with a gestational age up to 28 weeks 6 days clinically requiring a packed red blood cell transfusion transfusion.
Minimum age
23 Weeks
Maximum age
28 Weeks
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Infants with major congenital or chromosomal abnormalities

Infants who have received a packed red blood cell transfusion in the first 24 hours of life.

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)
Infants will be identified from the neonatal intensive care units of participating study sites within 24 hours of birth. Women who present in the antenatal period and who are considered to be at risk of preterm birth or a low birth weight infant will also be provided with information about the study and counseled where appropriate. Parents will be provided with an information sheet and counseled about participation by a researcher, and informed written consent obtained.
Once consent has been obtained enrolled infants will be randomised into “washed PRBC” and “standard PRBC” groups, with an allocation ratio of 1:1. A web-based randomisation procedure that requires confirmation of eligibility criteria and consent will be employed. The Australian Research Centre for Health of Women and Babies (ARCH), Discipline of Obstetrics and Gynaecology, The University of Adelaide will provide the randomisation schedule and web-based server.

Each infant will be given a unique trial identification number. The randomisation schedule will be prepared by a statistician not involved in clinical care and will be sent to the institutions transfusion laboratory for PRBC pack allocation and dispatch. The attending clinicians, caregivers and the project investigators determining the study outcomes will be blinded to treatment allocation. PRBC packs will be identifiable only to blood bank personnel through the use of Australian Red Cross Blood Service “luggage tags” to conform to statutory requirements.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The randomisation will be in randomly permuted blocks of variable length, stratified by centre and gestational age (less than or equal to 25 weeks +6 days and =26 weeks). Twins and higher order multiples will be randomised independently.The randomisation schedule will be prepared by a statistician not involved in clinical care and will be sent to the institutions transfusion laboratory for PRBC pack allocation and dispatch.
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
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
A range of pro-inflammatory cytokines have previously been demonstrated to increase following exposure to leukodepleted unwashed packed red blood cells. However, there is inconsistency in the timing of post-transfusion measurement in the literature. IL-17A has been shown to be increased at multiple time-points post-transfusion therefore the current studies sample size was based on the delta change (the difference between post- and pre-concentrations) in IL-17A from pilot data in 40 extremely preterm newborns exposed to unwashed packed red blood cells. The mean delta change was 15.3 pg/ml with a standard deviation of 13.1 pg/ml. It was calculated that a sample size of 77 newborns per group would provide 90% power to detect a group difference of 66 pg/ml (on-half of a SD) of the mean IL-17A with an alpha =0.05. Since it could not be determined prospectively which newborns would be transfused, enrollment exceeded that necessary for the sample size calculation to ensure adequate power for the primary aim in transfused subjects.

Very preterm newborns will have a median number of 3-5 transfusion exposures during their primary hospital admission. Therefore, transfusion associated changes in circulating cytokines and markers of endothelial activation for the first 4 transfusions . Analysis will be conducted blinded to study allocation.

As the plasma cytokine concentrations are not normally distributed the Friedman test will be used to assess differences between baseline cytokine concentrations prior to each transfusion exposure with the alpha level set at 0.01 to adjust for multiple comparisons. Differences in pre- and post-transfusion levels of plasma cytokines will be assessed using the Wilcoxon signed rank test with the p value <0.05 considered significant. Where the pre- post-transfusion change is significant for both unwashed and washed groups, the magnitude of the difference (delta change) between the groups will be compared by Mann-Whitney U test. Delta changes in plasma cytokines and markers of endothelial activation, in each group across the transfusion exposures will be analysed using a Linear Mixed Model. Heterogenous compound symmetry will be used as the repeated covariance type and LSD as the confidence interval adjustment, to compare changes within treatment groups. To investigate whether transfusion related changes in cytokines and markers of endothelial activation were influenced by gestational age, sex, age at first transfusion, and pre-transfusion haemoglobin, these variables will be included as co-variates.
Temporal changes in the cardiovascular and respiratory parameters which comprise the secondary outcomes will be analysed using Linear Mixed Models with transfusion pack type (unwashed or washed) used as a fixed factor and post-hoc paired t-tests with a Bonferroni correction.
The health economic analysis will not be conducted due to lack of funding. The study will therefore only have the existing primary and secondary clinical outcomes

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/04/2013
Actual
1/07/2015
Date of last participant enrolment
Anticipated
Actual
21/10/2019
Date of last data collection
Anticipated
Actual
6/01/2020
Sample size
Target
222
Accrual to date
Final
223
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 681 0
Womens and Childrens Hospital - North Adelaide
Recruitment hospital [2] 682 0
Flinders Medical Centre - Bedford Park
Recruitment postcode(s) [1] 6429 0
5006 - North Adelaide
Recruitment postcode(s) [2] 6430 0
5024 - Fulham Gardens

Funding & Sponsors
Funding source category [1] 286805 0
University
Name [1] 286805 0
Robinson Institute, University of Adelaide
Country [1] 286805 0
Australia
Funding source category [2] 307716 0
Charities/Societies/Foundations
Name [2] 307716 0
Channel 7 Research Foundation
Country [2] 307716 0
Australia
Funding source category [3] 307717 0
Government body
Name [3] 307717 0
National Blood Authority
Country [3] 307717 0
Australia
Primary sponsor type
University
Name
Robinson Institute
Address
University of Adelaide
55 Norwich
King William Road
North Adelaide
SA 5006
Country
Australia
Secondary sponsor category [1] 285596 0
Commercial sector/Industry
Name [1] 285596 0
Australian Red Cross Blood Service
Address [1] 285596 0
Research and Development,
Australian Red Cross Blood Service
17 O'Riordan St, Alexandria, NSW, 2015
Country [1] 285596 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 288871 0
WCHN Human Research Ethics Committee
Ethics committee address [1] 288871 0
Level 2
Samuel Way Building
72 King William Road
North Adelaide
SA 5006
Ethics committee country [1] 288871 0
Australia
Date submitted for ethics approval [1] 288871 0
Approval date [1] 288871 0
11/12/2012
Ethics approval number [1] 288871 0
HREC/12/WCHN/55

Summary
Brief summary
Extremely low gestational age newborns represent the smallest and most immature newborns and are at greatest risk of dying or surviving with significant morbidity particularly neurodevelopmental disability. Over 90% of these newborns receive at least one packed red blood cell (PRBC) transfusion whilst in neonatal intensive care with the majority receiving between 3 and 5 transfusions during their primary hospital admission. There is increasing evidence that PRBC transfusions are independently associated with more frequent and severe cardiopulmonary, gastrointestinal and neurodevelopmental morbidities. Indeed, in comparison to other populations, these transfusion associated adverse events are more common in the preterm newborn.

Packed red blood cells are biologically active. We have shown that PRBC transfusion results in endothelial activation, inflammation and oxidative stress in preterm neonates. This transfusion related immunomodulation (TRIM) might contribute to the recognised association between allogeneic PRBC transfusion and adverse clinical outcomes. It is unclear if TRIM is a response to red blood cells themselves, the time-dependent accumulation of bioactive substances in the supernatant (storage lesion), or both. However, in adult and childhood populations significant benefit is gained from modifications in blood product processing such as PRBC washing, though this has never been studied in the preterm neonate. Any reduction in PRBC transfusion related harm would be of substantial clinical benefit in this at risk population. This pragmatic clinical trial aims to identify if transfusion with washed PRBCs reduces harm from transfusion in high-risk newborns.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 37434 0
A/Prof Michael Stark
Address 37434 0
Department of Neonatal Medicine
Women's and Children's Hospital Adelaide
72 King William Road
North Adelaide
SA 5006
Country 37434 0
Australia
Phone 37434 0
+61 08 83131325
Fax 37434 0
+61 08 83131325
Email 37434 0
michael.stark@adelaide.edu.au
Contact person for public queries
Name 37435 0
Michael Stark
Address 37435 0
Department of Neonatal Medicine
Women's and Children's Hospital Adelaide
72 King William Road
North Adelaide
SA 5006
Country 37435 0
Australia
Phone 37435 0
+61 83131325
Fax 37435 0
Email 37435 0
michael.stark@adelaide.edu.au
Contact person for scientific queries
Name 37436 0
Michael Stark
Address 37436 0
Department of Neonatal Medicine
Women's and Children's Hospital Adelaide
72 King William Road
North Adelaide
SA 5006
Country 37436 0
Australia
Phone 37436 0
+61 08 83131325
Fax 37436 0
Email 37436 0
michael.stark@adelaide.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?
clinical characteristics, transfusion exposure, post-transfusion changes in circulating cytokines and markers of endothelial activation as per the revised primary outcome.
When will data be available (start and end dates)?
Available now with no end date for availability.
Available to whom?
Only researchers who provide a methodologically sound proposal, case-by-case basis at the discretion of the study investigators
Available for what types of analyses?
IPD meta-analyses, systematic review
How or where can data be obtained?
Access will be subject to approvals by the principle and study chief investigators following formal application. Initial contact with the principle investigator will be by email (michael.stark@adelaide.edu.au) with formal submission of any request reviewed by all co-investigators


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
TypeIs Peer Reviewed?DOICitations or Other DetailsAttachment
Basic resultsNo 363594-(Uploaded-22-04-2020-16-43-33)-Basic results summary.docx
Plain language summaryNo A growing body of observational data has recognise... [More Details]

Documents added automatically
SourceTitleYear of PublicationDOI
Dimensions AIEffect of washed versus unwashed red blood cells on transfusion-related immune responses in preterm newborns2022https://doi.org/10.1002/cti2.1377
EmbaseDoes donor sex influence the potential for transfusion with washed packed red blood cells to limit transfusion-related immune responses in preterm newborns?.2023https://dx.doi.org/10.1136/archdischild-2022-324531
EmbaseStudy protocol of the WashT Trial: Transfusion with washed versus unwashed red blood cells to reduce morbidity and mortality in infants born less than 28 weeks' gestation-A multicentre, blinded, parallel group, randomised controlled trial.2023https://dx.doi.org/10.1136/bmjopen-2022-070272
N.B. These documents automatically identified may not have been verified by the study sponsor.