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Trial registered on ANZCTR
Registration number
ACTRN12625000193471p
Ethics application status
Submitted, not yet approved
Date submitted
25/01/2025
Date registered
19/02/2025
Date last updated
19/02/2025
Date data sharing statement initially provided
19/02/2025
Type of registration
Prospectively registered
Titles & IDs
Public title
A study of cytokine haemadsorption to improve outcomes in adult patients undergoing orthotopic heart transplantation
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Scientific title
Cytokine Haemadsorption to Enhance Allograft Recovery and Treatments in adult patients undergoing orthotopic heart transplantation
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Secondary ID [1]
313800
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None
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Universal Trial Number (UTN)
U1111-1318-0600
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Trial acronym
CytoHEART
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Post-operative vasoplegia in adult patients undergoing orthotopic heart transplantation
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Condition category
Condition code
Surgery
333034
333034
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0
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Other surgery
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Cardiovascular
332957
332957
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0
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Diseases of the vasculature and circulation including the lymphatic system
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Intra-operative and post-operative use of cytokine haemadsorption to modulate the inflammatory response thought to be contributing to vasoplegia.
Cytokine haemadsorption is performed using an extracorporeal circuit with a specific filter in series in the circuit. Pathogenic cytokines are adsorbed from the blood by the filter.
Intra-operatively, a Cytosorb (Cytosorbents) filter will be used in series with the cardiopulmonary bypass circuit to facilitate cytokine haemadsorption. Heparin anticoagulation will be used intraoperatively, with the level of anticoagulation guided by the cardiothoracic surgeon, anesthetist and perfusionist. The duration of cytokine haemadsorption will be dependent on the duration of cardiopulmonary bypass. The duration of cardiopulmonary bypass can vary significantly, for example depending on whether the patient has previously had a sternotomy, which can significantly increase bypass duration. The anticipated duration of bypass would range between 90 and 240 minutes.
Post-operatively in the ICU, cytokine haemadsorption will be performed for 24 hours using an Oxiris (Baxter) filter on a Prismaflex platform. This will use citrate anticoagulation guided by institutional policy and the treating intensivist (therapeutic anticoagulation using heparin immediately postoperatively will not be feasible or safe). The default dose prescribed will be 25ml/kg/hr with no fluid removal or ultrafiltration unless an indication for fluid removal is present. If the circuit clots within the 24 hour time period, a new circuit will be created with a new Oxiris filter to ensure the full 24 hours of post-operative cytokine haemadsorption is completed.
The intervention will be given in addition to standard surgical, anaesthetic and post-operative care of adult heart transplant patients.
Adherence to the intervention will be checked by reviewing intraoperative and ICU medical records.
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Intervention code [1]
330389
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Treatment: Devices
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Comparator / control treatment
The control group will receive standard intra and post-operative heart transplant care as per our institutional practice. This includes a standardised immunosuppression protocol, post-operative allograft monitoring and intensive care management as guided by the treating intensive care specialist, cardiothoracic surgeon and heart failure cardiologist.
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Control group
Active
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Outcomes
Primary outcome [1]
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Assessing the severity of post-operative vasoplegia using the Vasopressor-inotrope score (VIS)
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Assessment method [1]
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The VIS will be measured by calculating the mean daily dose of each inotrope and vasopressor after 24 hours and 48 hours of ICU admission
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Timepoint [1]
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At 24 hours and 48 hours post operatively
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Secondary outcome [1]
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Immunological analysis
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Assessment method [1]
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Serial analysis of serum cytokines assessing pro and antiflammatory cytokine panel
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Timepoint [1]
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Four timepoints: 1. Prior to going onto cardiopulmonary bypass 2. On admission to ICU 3. 24 hours after ICU admission 4, 48 hours after ICU admission
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Secondary outcome [2]
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Presence of vasoplegia
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Assessment method [2]
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MAP <65mmHg requiring vasopressor support with cardiac index >2.2L/min/m2 and no evidence of hypovolaemia or alternative cause for shock eg. Sepsis
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Timepoint [2]
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Measured at any point during first 72 hours of ICU admission, or duration of ICU admission (if ICU admission is <72 hours)
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Secondary outcome [3]
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Ventilator-free days
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Assessment method [3]
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Medical record review
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Timepoint [3]
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90 days post-operatively
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Secondary outcome [4]
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Incidence of acute kidney injury (AKI)
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Assessment method [4]
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AKI measured via the KDIGO (Kidney Disease Improving Global Outcomes) criteria
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Timepoint [4]
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Day 30 and Day 90 post-transplant (early assessment will be confounded by use of the Oxiris filter in the intervention group)
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Secondary outcome [5]
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Allograft outcomes
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Assessment method [5]
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Assessment for presence of allograft rejection - Allograft rejection assessed on biopsy using ISHLT rejection grading criteria
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Timepoint [5]
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Day 7, Day 30 and Day 90 post-operatively
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Secondary outcome [6]
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Hospital-free days
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Assessment method [6]
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Medical record review
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Timepoint [6]
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90 days post operatively
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Secondary outcome [7]
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Mortality
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Assessment method [7]
444255
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Review of ICU medical records
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Timepoint [7]
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At ICU discharge or death (whichever is earlier)
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Secondary outcome [8]
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90 day mortality (90 days post-transplant)
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Assessment method [8]
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Medical records review
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Timepoint [8]
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90 days post-transplant
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Secondary outcome [9]
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Hospital mortality
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Assessment method [9]
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Review of hospital medical records
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Timepoint [9]
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At time of hospital discharge or death (whichever is earlier)
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Secondary outcome [10]
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ICU-free days
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Assessment method [10]
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Medical record review
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Timepoint [10]
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90 days post operatively
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Secondary outcome [11]
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Safety outcomes and adverse events related to intervention
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Assessment method [11]
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Chart review to assess for incidence and severity of potential adverse events related to cytokine haemadsorption: 1. Bleeding events (measured by need for return to surgery for bleeding OR packed cell transfusion requirement within first 72 hour) 2. Metabolic abnormalities (metabolic acidosis or alkalosis, hypernatraemia) related to use of citrate anticoagulation for Oxiris filter 3. Complications related to vascular access from Vascath (infection, vessel injury, pneumothorax)
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Timepoint [11]
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Incidence of events up to 1 week post-operatively
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Secondary outcome [12]
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Pharmacokinetic analysis for calcineurin inhibitors to assess impact of cytokine haemadsorption on immunosuppression kinetics
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Assessment method [12]
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Serum trough tacrolimus levels
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Timepoint [12]
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Daily measurement for first 7 days post-operatively
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Eligibility
Key inclusion criteria
Adult patients undergoing elective OR emergency orthoptic heart transplant, with or without ventricular assist device (VAD) explant, with or without other solid organ transplant (eg. Lung, liver or kidney).
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Minimum age
16
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
Age <16
End-stage renal failure requiring long-term renal replacement therapy
Contraindication or inability to secure vascular access for haemadsorption
Allergy, anaphylaxis or contraindication to heparin (CytosorbÔ circuit requires heparin, and the OxirisÔ has heparin-bonded membrane)
Contraindication to citrate anticoagulation
Patients who are suspected or confirmed to be pregnant
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Yes - central randomisation by computer algorithm using UNSW RedCAP server
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Stratified allocation based on the presence of a ventricular-assist device (VAD) pre-operatively
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Parallel
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Other design features
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Phase
Not Applicable
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Type of endpoint/s
Efficacy
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Statistical methods / analysis
SAMPLE SIZE CALCULATION
This is an exploratory analysis of a relatively novel technology in this field and therefore a number of efficacy, safety and mechanistic endpoints have been selected. The VIS, which is a validated score in various forms of shock was selected as the primary endpoint as it will provide an objective measure of vasoplegia and a continuous variable allowing meaningful statistical analysis.
While this is not a patient-centred outcome, there is evidence of it being a surrogate for outcomes such as AKI, requirement for dialysis, duration of mechanical ventilation and ICU/hospital stay. Although the Oxiris filter cannot be used without simultaneously haemofiltering the patient, using RRT–free days at 90 days as a renal outcome in our secondary outcomes will still provide relevant information on the renal consequences of this therapy.
To achieve 90% power to detect a reduction in the VIS score of 5 points (20 to 15 ± 5) at an alpha of 0.05, a sample size of 42 patients (21 in each arm) will be required. Allowing for loss to follow up and participant withdrawal, we plan to recruit an additional 8 patients to give a total of 50 patients in the study.
STATISTICAL ANALYSIS PLAN
Descriptive statistics of data will be reported as median [interquartile range], mean ± standard deviation, and number of patients and frequency where appropriate. Mann–Whitney U test, two-sample t-test, Chi-square test or Fisher’s exact test will be performed for the univariate analysis of group comparisons. The comparative analyses of within-subjects changes in the cohort will be undertaken using the Wilcoxon signed-rank test. Statistical significance will be defined as a P value of 0.05 in all tests.
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Recruitment
Recruitment status
Not yet recruiting
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Date of first participant enrolment
Anticipated
1/04/2025
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Actual
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Date of last participant enrolment
Anticipated
1/04/2027
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Actual
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Date of last data collection
Anticipated
1/07/2027
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Actual
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Sample size
Target
50
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Accrual to date
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Final
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Recruitment in Australia
Recruitment state(s)
NSW
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Recruitment hospital [1]
27569
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St Vincent's Hospital (Darlinghurst) - Darlinghurst
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Recruitment postcode(s) [1]
43682
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2010 - Darlinghurst
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Funding & Sponsors
Funding source category [1]
318267
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Hospital
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Name [1]
318267
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St Vincent's Clinic Foundation
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Address [1]
318267
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Country [1]
318267
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Australia
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Primary sponsor type
Hospital
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Name
St Vincent's Hospital, Sydney
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Address
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Country
Australia
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Secondary sponsor category [1]
320656
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None
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Name [1]
320656
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Address [1]
320656
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Country [1]
320656
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Other collaborator category [1]
283400
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Other Collaborative groups
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Name [1]
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The George Institute for Global Health, NSW
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Address [1]
283400
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Country [1]
283400
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Australia
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Other collaborator category [2]
283376
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University
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Name [2]
283376
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The Kirby Institute, University of New South Wales
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Address [2]
283376
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Country [2]
283376
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Australia
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Ethics approval
Ethics application status
Submitted, not yet approved
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Ethics committee name [1]
316907
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St Vincent’s Hospital Human Research Ethics Committee
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Ethics committee address [1]
316907
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https://svhs.org.au/home/research-education/research-office
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Ethics committee country [1]
316907
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Australia
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Date submitted for ethics approval [1]
316907
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28/01/2025
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Approval date [1]
316907
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Ethics approval number [1]
316907
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Summary
Brief summary
Vasoplegia is a state of circulatory shock that is a common complication after orthotopic heart transplantation, and increases the risk of prolonged ICU and hospital stay, increases the risk of acute kidney injury, and carries a higher risk of requiring dialysis long-term. It is thought to occur due to an abnormal immune response following the surgery. Currently, there are no licensed therapies to prevent or treat vasoplegia. Cytokine haemadsorption is a form of blood purification therapy, that is believed to reduce the incidence and severity of vasoplegia by removing the immune chemicals contributing to its development. Early evidence has shown improved patient outcomes from using cytokine haemadsorption intraoperatively during heart transplantation, but to date no study has evaluated whether cytokine haemadsorption used post-operatively (in addition to intraoperatively) has benefit. Given the proposed mechanisms of vasoplegia and our institutional experience indicating that it can persist for days after the surgery, we believe that using cytokine haemadsorption intraoperatively and postoperatively may further improve patient outcomes by reducing the incidence and severity of vasoplegia. We therefore propose a randomised trial of cytokine haemadsorption plus standard care vs. standard care alone in adult patients undergoing orthotopic heart transplantation.
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Trial website
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Trial related presentations / publications
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Public notes
Existing evidence for cytokine haemadsorption in heart transplantation: 1. Nemeth E, Kovacs E, Racz K, Soltesz A, Szigeti S, Kiss N, et al. Impact of intraoperative cytokine adsorption on outcome of patients undergoing orthotopic heart transplantation-an observational study. Clin Transplant. 2018;32(4):e13211. 2. Nemeth E, Soltesz A, Kovacs E, Szakal-Toth Z, Tamaska E, Katona H, et al. Use of intraoperative haemoadsorption in patients undergoing heart transplantation: a proof-of-concept randomized trial. ESC Heart Fail. 2024;11(2):772-82. Our institutional evidence of acute kidney injury as a complication of postoperative vasoplegia: Gale D, Al-Soufi S, MacDonald P, Nair P. Severe Acute Kidney Injury Postheart Transplantation: Analysis of Risk Factors. Transplant Direct. 2024;10(3):e1585.
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Contacts
Principal investigator
Name
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A/Prof Priya Nair
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Address
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Department of Intensive Care, St Vincent's Hospital, 390 Victoria Street Darlinghurst NSW 2010
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Country
139394
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Australia
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Phone
139394
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+61 412122692
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Fax
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Email
139394
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[email protected]
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Contact person for public queries
Name
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Ms Sally Newman
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Address
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Department of Intensive Care, St Vincent's Hospital, 390 Victoria Street Darlinghurst NSW 2010
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Country
139395
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Australia
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Phone
139395
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+61 8382 1111
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Fax
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Email
139395
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[email protected]
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Contact person for scientific queries
Name
139396
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Priya Nair
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Address
139396
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Department of Intensive Care, St Vincent's Hospital, 390 Victoria Street Darlinghurst NSW 2010
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Country
139396
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Australia
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Phone
139396
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+61 412122692
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Fax
139396
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Email
139396
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[email protected]
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Data sharing statement
Will the study consider sharing individual participant data?
Yes
Will there be any conditions when requesting access to individual participant data?
Persons/groups eligible to request access:
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Clinical researchers with a sound research proposal within the domain of heart/lung transplant, cardiothoracic surgery and medicine, perfusion, cardiac anaesthesia and critical care. Will also make data available to manufacturers of the haemadsorption cartridges for secondary safety and efficacy analyses.
Conditions for requesting access:
•
-
What individual participant data might be shared?
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Outcome data related to cytokine haemadsorption. Any sharing of data will be subject to data sharing policy of the University of NSW and St Vincent's Health Australia.
What types of analyses could be done with individual participant data?
•
Pooled IPD meta-analyses (eg with similar trials of cytokine haemadsorption in adult patients undergoing orthotopic heart transplant)
When can requests for individual participant data be made (start and end dates)?
From:
From study completion with no end date determined.
To:
-
Where can requests to access individual participant data be made, or data be obtained directly?
•
Subject to approval by Principal Investigator (A/Prof Priya Nair, St Vincent's Hospital ICU Sydney NSW Australia
[email protected]
). Any data sharing will be subject to policies of UNSW and St Vincent's Health.
Are there extra considerations when requesting access to individual participant data?
No
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.
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