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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
28/02/2013
Type of registration
Prospectively registered

Titles & IDs
Public title
Effect of Transfusion of Washed Red Blood Cells on Neonatal Outcome: A Randomised Controlled Trial
Scientific title
For extremely low gestational age newborns will transfusion of washed red blood cells as compared to standard non-washed red blood cells reduce the incidence of neonatal mortality and improve survival free of significant morbidity
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] 288744 0
A composite of composite mortality and/or major neonatal morbidities associated with organ dysfunction or failure following transfusion, until discharge from neonatal intensive care, defined as one or more of the following: neonatal death (defined as death of a live born infant greater than 48 hours of age and excluding infants with known lethal congenital abnormalities); bronchopulmonary dysplasia (defined according to the physiological definition as the receipt of more than 30% supplemental oxygen or positive pressure support at 36 weeks post menstrual age, or the need for any supplemental oxygen at 36 weeks post menstrual age after an attempt at withdrawal of oxygen in infants requiring less than 30% oxygen. The withdrawal of oxygen will be conducted under the continuous observation of an experienced neonatal nurse, continuous oxygen-saturation and cardio-respiratory monitoring and involves a timed step-wise reduction in oxygen according to a strict protocol with clearly defined stopping rules); peri/intraventricular haemorrhage (grade based on standard criteria developed by Papile. For the purposes of this trial only grade III and IV intraventricular haemorrhage will be included as an outcome); retinopathy of prematurity (> grade 2); and necrotising enterocolitis (based upon a grading of stage 2 or greater using the criteria of Bell). Morbidities occurring prior to transfusion will not be included in the primary outcome.
Timepoint [1] 288744 0
Discharge from neonatal intensive care
Secondary outcome [1] 300889 0
Nosocomial infection (blood culture positive sepsis diagnosed >48 hours after birth)
Timepoint [1] 300889 0
Discharge from neonatal intensive care
Secondary outcome [2] 300890 0
Length of mechanical ventilation - recorded from medical records
Timepoint [2] 300890 0
Discharge from neonatal intensive care - recorded from medical records
Secondary outcome [3] 301446 0
Length of NICU stay - (from admission to neonatal intensive care to primary hospital discharge) recorded from medical records
Timepoint [3] 301446 0
Discharge from neonatal intensive care
Secondary outcome [4] 301447 0
Health economic analysis: The incremental cost per additional child surviving without severe BPD, ROP, NEC or brain injury, as per the primary outcome of the study, will also be estimated. Additional costs associated with the provision of washed, leucodeplete standard PRBCs will be estimated in consultation with the Australian Red Cross Blood Service.In the absence of a dominant result (e.g. the intervention costing less, and resulting in better outcomes), the cost-effectiveness results will be interpreted in the light of external evidence on the long-term effects of severe BPD, ROP, NEC or brain injury.
Timepoint [4] 301447 0
Discharge form hospital

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
Gender
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
The initial analysis will examine baseline characteristics of all randomised infants, as an indication of comparable treatment groups, and include gestational age, sex, antenatal glucocorticoid administration, confirmed chorioamnionitis, and mode of delivery. Primary and secondary outcomes will be analysed on an “intention to treat” basis, according to treatment allocation at randomisation to either washed PRBC or standard care. The relative risks and 95% confidence intervals will be reported for the major outcomes. Regression techniques will be used to examine the influence of prognostic factors on the major outcomes.
The incremental cost per additional child surviving without severe BPD, ROP, NEC or brain injury, as per the primary outcome of the study, will also be estimated. Additional costs associated with the provision of washed, leucodeplete standard PRBCs will be estimated in consultation with the Australian Red Cross Blood Service. Detailed analyses of resource use, and costs, associated with participating childrens’ time from randomization (within the first 48 hours of life) to discharge from initial hospital NICU admission will be informed by the trial clinical report forms, and routine hospital costing data. Uncertainty around the mean cost-effectiveness results will be represented using bootstrapping (sampling with replacement), and represented as 95% CIs and cost-effectiveness acceptability curves. In the absence of a dominant result (e.g. the intervention costing less, and resulting in better outcomes), the cost-effectiveness results will be interpreted in the light of external evidence on the long-term effects of severe BPD, ROP, NEC or brain injury.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA,VIC
Recruitment hospital [1] 681 0
Womens and Childrens Hospital - North Adelaide
Recruitment hospital [2] 682 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [3] 683 0
Mercy Hospital for Women - Heidelberg
Recruitment hospital [4] 684 0
The Royal Women's Hospital - Parkville
Recruitment postcode(s) [1] 6429 0
5006 - North Adelaide
Recruitment postcode(s) [2] 6430 0
5024 - Fulham Gardens
Recruitment postcode(s) [3] 6431 0
3052 - Parkville
Recruitment postcode(s) [4] 6432 0
3084 - Heidelberg

Funding & Sponsors
Funding source category [1] 286805 0
University
Name [1] 286805 0
Robinson Institute, University of Adelaide
Address [1] 286805 0
55 Norwich Building
King William Road
North Adelaide
SA 5006
Country [1] 286805 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
A/Prof 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
A/Prof 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

No information has been provided regarding IPD availability
Summary results
No Results