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Trial registered on ANZCTR


Registration number
ACTRN12619000163101p
Ethics application status
Not yet submitted
Date submitted
21/01/2019
Date registered
5/02/2019
Date last updated
5/02/2019
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 3 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). Participants will be randomised to either control group or the interventional group in equal proportions (1:1:1).
Control group
Active

Outcomes
Primary outcome [1] 318567 0
The primary outcome is the 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 6-8 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 all 3 groups with individual, paired comparisons. 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 either of the other 2 groups, or in the two groups combined.
Timepoint [1] 318567 0
The timepoint for the primary outcome is visit 3, which can occur at any time between 6 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 6 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] 365913 0
Incidence of de novo DSA in participants receiving the unselected irradiated red cell units, compared to those receiving unselected non-irradiated units. 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 6-8 weeks after the second transfusion event as per standard of care, and these will be part of the separate analysis.
Timepoint [3] 365913 0
The timepoint for this secondary outcome is visit 3, which can occur at any time between 6 and 8 weeks after the transfusion visit (visit 2).

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
c) Transfusion must occur in a hospital setting (including satellite dialysis units)
d) Anticipated to be able to provide a further blood sample 6-8 weeks post-transfusion
e) > 18 years of age
f) Not pregnant
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
a) Blood transfusion in 6 weeks prior to enrolment, or anticipated need for further transfusion in less than 6 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 6-8 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 6-8 weeks after transfusion
d) Pre-existing requirement for specific red cell product (eg directed donation) or non red cell blood product (eg platelets, fresh frozen plasma)
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 biologic medications targeting immune cells in 12 months prior to the trial (eg rituximab, bortezomib), or anticipated use of these medications in the 6 weeks post-transfusion (for treatments scheduled 6-8 weeks after enrolment the post-transfusion sample can be taken immediately prior to the treatment)
g) Hyperkalaemia prior to transfusion (ie serum potassium above the local site laboratory reference range) or anticipated need for >4 units
h) < 18 years of age
i) Pregnant patient

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 and non-irradiated unselected groups will be in a 1:1:1 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 will be developed by a statistician and applied by the sponsor at the time of enrolment
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
From Scornik 2011, 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. Although post-transplantation patients are not formally excluded, this is a small population. Assuming therefore a cohort of transplant-naïve hospital inpatients, equally divided between males and females, and among which 50% of female patients have previously been pregnant, the average risk would be 20% (3/4 x 10% + ¼ x 50%). For a power of 80%, the ability to detect a difference of 20% (0% vs 20%) between the treatment and non-treatment groups would require about 30-35 patients in each group. Allowing for a small incidence of positivity in the intervention group, a total sample size of 150 (ie 50 participants in each group) was selected. This would provide sufficient power for separate comparisons between each of the 3 groups.

95% confidence intervals for the primary outcome will be calculated using the binomial distribution (and normal approximation to the binomial distribution) for a range of “true” risks of de novo bDSA formation in the reference population. 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 non-bDSA as a secondary endpoint. An exploratory multivariate analysis will be performed aiming to identify possible predictors of de novo bDSA and non-bDSA.

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)
VIC
Recruitment hospital [1] 12961 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment postcode(s) [1] 25439 0
3050 - Parkville

Funding & Sponsors
Funding source category [1] 301539 0
Charities/Societies/Foundations
Name [1] 301539 0
Australian Red Cross Blood Service
Address [1] 301539 0
100-154 Batman Street
West Melbourne 3003
VICTORIA
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
Not yet submitted
Ethics committee name [1] 302278 0
Australian Red Cross Blood Service HREC
Ethics committee address [1] 302278 0
Australian Red Cross Blood Service
17 O’Riordan Street
Alexandria | NSW | 2015
Ethics committee country [1] 302278 0
Australia
Date submitted for ethics approval [1] 302278 0
05/02/2019
Approval date [1] 302278 0
Ethics approval number [1] 302278 0

Summary
Brief summary
To examine a prospective cohort of patients who are planned to undergo transfusion with red blood cells (including transfusions optimised for HLA compatibility between donor and recipient), and examine the incidence of de novo formation of antibodies to blood donor HLA molecules (bDSA).
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
jmccomish@redcrossblood.org.au
Contact person for public queries
Name 89667 0
Dr 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
jmccomish@redcrossblood.org.au
Contact person for scientific queries
Name 89668 0
Dr 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
jmccomish@redcrossblood.org.au

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 other documents available
Summary results
No Results