Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12619000163101
Ethics application status
Approved
Date submitted
21/01/2019
Date registered
5/02/2019
Date last updated
28/08/2023
Date data sharing statement initially provided
5/02/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
HAbIT Part 3: Human Leukocyte Antigen (HLA) antibodies after red cell transfusion- a randomised controlled trial
Scientific title
HAbIT Part 3: Incidence of De novo HLA Antibody formation after Transfusion with blood products in patients requiring transfusion: A prospective, double-blinded, randomised controlled trial of red cell transfusion from donors selected to maximise HLA compatibility.
Secondary ID [1] 296970 0
Nil
Universal Trial Number (UTN)
U1111-1226-2330
Trial acronym
HAbIT3
Linked study record

Health condition
Health condition(s) or problem(s) studied:
anaemia 310941 0
Condition category
Condition code
Blood 309607 309607 0 0
Anaemia
Inflammatory and Immune System 310000 310000 0 0
Other inflammatory or immune system disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
HLA compatible red cell transfusion. This will be a personalised form of standard of care blood transfusion (as per Australian Patient Blood Management Guidelines), in which the blood donor will be selected to maximise HLA compatibility with the recipient. Selection will involve comparing the donor and recipient HLA types and choosing a donor who is matched as closely as possible with the recipient by HLA antigens and/or by epitope based methods. The red cells will also be irradiated, as is standard of care for red cell transfusions in some settings, but otherwise will not differ from standard of care red cell transfusion. The number of red cell units given to correct the participant's anaemia to the satisfaction of the treating clinical team will comprise a single "transfusion event". In the absence of a satisfactory response, the "transfusion event" will end when 7 days have elapsed after the first unit was transfused.
Intervention code [1] 313251 0
Treatment: Other
Comparator / control treatment
Standard of care red cell transfusion. There will be 2 control arms: irradiated and non-irradiated standard of care red cell transfusion (as per Australian Patient Blood Management Guidelines). Adult participants in the control group receive non-irradiated transfusions and paediatric participants (<1 year old) in the control group will receive irradiated red cell transfusions. Participants will be randomised to either control group or the interventional group in equal proportions (1:1).
Control group
Active

Outcomes
Primary outcome [1] 318567 0

The primary outcome is the incidence proportion of patients with de novo blood donor-specific HLA antibodies following transfusion. Antibody positivity will be defined according to standard Australian Red Cross Blood Service Transplantation and Immunogenetics Services practice, and specificity determined with reference to blood donor HLA typing. An antibody positive in the post-transfusion sample but not the pre-transfusion sample will be considered de novo for the purposes of the study. Where participants are transfused with additional compatible red cells, unselected blood cells, or other blood products within 6 weeks of the study transfusion the data will be analysed separately, and an analysis performed that excludes these patients. Additional patients may be recruited if the number of patients in these groups is sufficient to affect the power of an analysis excluding them. Further samples will be collected 4-8 weeks after the second transfusion event as per standard of care, and these will be part of the separate analysis. The primary endpoint analysis will compare treatment and control groups in both arms (ie adults and infants) separately. The study will be considered to have met its primary endpoint if the proportion of patients with de novo blood donor-specific HLA antibodies following transfusion is significantly lower in the HLA compatible group than in the control group, for either or both arms.
Timepoint [1] 318567 0
The timepoint for the primary outcome is visit 3, which can occur at any time between 4 and 8 weeks after the transfusion visit (visit 2).
Secondary outcome [1] 365394 0
Incidence of de novo non-DSA in participants receiving the intervention. De novo non-DSA will be defined as per de novo DSA, but where antibodies are not directed at donor epitopes. Antibody test results will be assessed by laboratory staff with expertise in HLA antibody test interpretation, who will be blinded to the status of participants.
Timepoint [1] 365394 0
The timepoint for this secondary outcome is visit 3, which can occur at any time between 4 and 8 weeks after the transfusion visit (visit 2).
Secondary outcome [2] 365395 0
Compatibility assessment- median HLA compatibility of supplied product by antigen (number of antigens mismatched) and eplet score.
Timepoint [2] 365395 0
Time of supply.
Secondary outcome [3] 407149 0
Factors associated with de novo antibody formation and incidence of bDSA, as well as de novo non-bDSA, in patients with and without transfusion associated de novo HLA antibodies. This will comprise an exploratory multivariate analysis incorporating clinical and laboratory measures, as well as a comparison of the compatibility of the transfusions between the treatment and control groups.
Timepoint [3] 407149 0
4-8 weeks post transfusion.

Eligibility
Key inclusion criteria
a) Eligible for blood transfusion according to local site clinical guidelines and anticipated to require a red cell transfusion on clinical grounds by participating unit
b) Patient assessed as competent to consent and participate or has a competent parent or guardian for paediatric participants
c) Transfusion must occur in a hospital setting (including satellite dialysis units)
d) Anticipated to be able to provide a further blood sample 4-8 weeks post-transfusion
e Patients younger than 18 years of age may be recruited from paediatric hospital sites only
f) Not pregnant
Minimum age
0 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
a) Blood transfusion in 4 weeks prior to enrolment or anticipated need for further transfusion in less than 4 weeks after the study transfusion event.
b) Immunoglobulin therapy within 6 months prior to enrolment or scheduled within 6 weeks after enrolment (for treatments scheduled 4-8 weeks after enrolment the post-transfusion sample can be taken immediately prior to the treatment)
c) Severe illness that, in the opinion of the investigator, would compromise the ability of the subject to undergo further blood tests 4-8 weeks after transfusion
d) Pre-existing requirement for specific red cell product (e.g. directed donation) or non red cell blood product (e.g. platelets, fresh frozen plasma)). For paediatric patients only, patients requiring plasma products in addition to the red cell transfusion may be enrolled at the discretion of the investigator.
e) Urgent transfusion (such that, in the opinion of the site investigator, delay in the transfusion for enrolment and provision of the intervention product would compromise patient care)
f) Use of relevant (in the opinion of the investigator) biologic medications targeting immune cells, that in the opinion of the investigator would affect the outcome of the trial, in 12 months prior to the trial (e.g. rituximab, bortezomib), or anticipated use of these medications in the 4 weeks post-transfusion.
g) Hyperkalaemia prior to transfusion (i.e. serum potassium elevated sufficiently above the local site laboratory reference range to increase the risk associated with an irradiated transfusion, according to the investigator) or anticipated need for >4 units
h) Pregnant patient
i) Previous bone marrow allograft or haematological malignancy that could affect the primary outcome, in the opinion of the investigator
j) Patient at risk of Transfusion-associated Graft-Versus-Host Disease (TA-GVHD) under Australian and New Zealand Society of Blood Transfusion guidelines, and/or deemed by treating clinical team to require irradiated red cells only (for adult patients only)

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Randomisation will be central, at the Australian Red Cross Blood Service. The red cell units supplied will be labelled (as per standard of care) and designated for the participant, but will have no indication as to the participant's group within the trial, apart from mandatory labelling of irradiated units.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Minimisation- The allocation of participants to the respective HLA compatible, irradiated unselected (paediatric group) and non-irradiated unselected (adult group) groups will be in a 1:1 ratio. After providing signed consent, participants will be randomized according to a randomization/minimization algorithm including age, sex, transfusion history and immunosuppressive treatment as factors. The algorithm has been developed by a statistician and will be applied by the sponsor at the time of enrolment. Due to the nature of the study, a proportion of participants is likely to be randomised but not transfused. There is the capacity to adjust the algorithm according to a pre-specified plan if this results in an imbalance between groups.
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
Participants may be enrolled for more than one transfusion, in which case they will be randomised separately for each transfusion.
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Statistical methods
The proportion (95% confidence interval) of the primary outcome will be calculated and compared between the groups using appropriate non-parametric test(s). Adjustment for pre-existing sensitisation will not form part of the formal primary endpoint statistics, but will be performed and discussed. The same calculations will be performed for the non-bDSA analysis. An exploratory multivariate analysis will be performed aiming to identify possible predictors of de novo bDSA and non-bDSA.

Sample size and power
The primary outcome is to evaluate the difference in the proportion of de novo antibody formation after transfusion between study groups. Few studies provide relevant information regarding our primary outcome. Scornik and colleagues (2011) reported the incidence proportion of HLA sensitisation by solid phase assay (the type of assay to be used in this study) following a red cell transfusion varies from 10% (in unselected transfusion recipients) to 50% in parous women and 70% in patients with a previous solid organ transplant. Mackie (2010), in a review of the now-discontinued practice of (organ) donor specific transfusion prior to transplant, describes a rate of de novo bDSA of up to 30%. Although post-transplantation patients are not formally excluded, this is a small population and unlikely to affect the study endpoints. There are no published data specific to the target population on which we could evaluate the power assessment for this study, and in particular a paucity of data relating to HLA antibodies in the paediatric group. We have therefore based power considerations on the adult group.

We are assuming that among adults within the non-irradiated group, 50% of female participants have had at least one previous pregnancy, and that the proportion of females to males recruited will be 50%. Assuming 40 – 50% population in the control group having incidence of de novo bDSA, and a clinically plausible difference of 25% in the intervention group, 47 – 55 individuals in each group are needed to observe a 25% absolute difference with 80% power and 5% type 1 error.

We are proposing an exploratory study, and with the recruitment constraints, we anticipate a realistic recruitment of about 40 – 45 individuals in each group. The paediatric group will have the same target.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
26/10/2020
Actual
26/10/2020
Date of last participant enrolment
Anticipated
1/05/2023
Actual
11/04/2023
Date of last data collection
Anticipated
1/07/2023
Actual
21/06/2023
Sample size
Target
150
Accrual to date
Final
142
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 12961 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [2] 21880 0
The Royal Childrens Hospital - Parkville
Recruitment hospital [3] 21881 0
Austin Health - Austin Hospital - Heidelberg
Recruitment postcode(s) [1] 25439 0
3050 - Parkville
Recruitment postcode(s) [2] 36964 0
3052 - Parkville
Recruitment postcode(s) [3] 36965 0
3084 - Heidelberg

Funding & Sponsors
Funding source category [1] 301539 0
Charities/Societies/Foundations
Name [1] 301539 0
Australian Red Cross Lifeblood
Country [1] 301539 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
Australian Red Cross Blood Service
Address
100-154 Batman Street
West Melbourne 3003
VICTORIA
Country
Australia
Secondary sponsor category [1] 301241 0
None
Name [1] 301241 0
Address [1] 301241 0
Country [1] 301241 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302278 0
Australian Red Cross Blood Service HREC
Ethics committee address [1] 302278 0
Ethics committee country [1] 302278 0
Australia
Date submitted for ethics approval [1] 302278 0
05/02/2019
Approval date [1] 302278 0
25/03/2019
Ethics approval number [1] 302278 0
2019#03
Ethics committee name [2] 310498 0
Austin Health
Ethics committee address [2] 310498 0
Ethics committee country [2] 310498 0
Australia
Date submitted for ethics approval [2] 310498 0
27/05/2019
Approval date [2] 310498 0
09/10/2019
Ethics approval number [2] 310498 0
HREC/56995/Austin-2019

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

Contacts
Principal investigator
Name 89666 0
Dr Jeremy McComish
Address 89666 0
Australian Red Cross Blood Service
100-154 Batman Street
West Melbourne
VIC 3003
Country 89666 0
Australia
Phone 89666 0
+61 412 504 506
Fax 89666 0
Email 89666 0
[email protected]
Contact person for public queries
Name 89667 0
Jeremy McComish
Address 89667 0
Australian Red Cross Blood Service
100-154 Batman Street
West Melbourne
VIC 3003
Country 89667 0
Australia
Phone 89667 0
+61 412 504 506
Fax 89667 0
Email 89667 0
[email protected]
Contact person for scientific queries
Name 89668 0
Jeremy McComish
Address 89668 0
Australian Red Cross Blood Service
100-154 Batman Street
West Melbourne
VIC 3003
Country 89668 0
Australia
Phone 89668 0
+61 412 504 506
Fax 89668 0
Email 89668 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
Information can be provided but subject to local privacy legislation.


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.