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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
Scientific title
Cytokine Haemadsorption to Enhance Allograft Recovery and Treatments in adult patients undergoing orthotopic heart transplantation
Secondary ID [1] 313800 0
None
Universal Trial Number (UTN)
U1111-1318-0600
Trial acronym
CytoHEART
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Post-operative vasoplegia in adult patients undergoing orthotopic heart transplantation 336436 0
Condition category
Condition code
Cardiovascular 332957 332957 0 0
Diseases of the vasculature and circulation including the lymphatic system
Surgery 333034 333034 0 0
Other surgery

Intervention/exposure
Study type
Interventional
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.
Intervention code [1] 330389 0
Treatment: Devices
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.
Control group
Active

Outcomes
Primary outcome [1] 340495 0
Assessing the severity of post-operative vasoplegia using the Vasopressor-inotrope score (VIS)
Timepoint [1] 340495 0
At 24 hours and 48 hours post operatively
Secondary outcome [1] 444254 0
Presence of vasoplegia
Timepoint [1] 444254 0
Measured at any point during first 72 hours of ICU admission, or duration of ICU admission (if ICU admission is <72 hours)
Secondary outcome [2] 444255 0
Mortality
Timepoint [2] 444255 0
At ICU discharge or death (whichever is earlier)
Secondary outcome [3] 444256 0
ICU-free days
Timepoint [3] 444256 0
90 days post operatively
Secondary outcome [4] 444257 0
Ventilator-free days
Timepoint [4] 444257 0
90 days post-operatively
Secondary outcome [5] 444258 0
Hospital-free days
Timepoint [5] 444258 0
90 days post operatively
Secondary outcome [6] 444259 0
Incidence of acute kidney injury (AKI)
Timepoint [6] 444259 0
Day 30 and Day 90 post-transplant (early assessment will be confounded by use of the Oxiris filter in the intervention group)
Secondary outcome [7] 444260 0
Immunological analysis
Timepoint [7] 444260 0
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
Secondary outcome [8] 444265 0
Safety outcomes and adverse events related to intervention
Timepoint [8] 444265 0
Incidence of events up to 1 week post-operatively
Secondary outcome [9] 444266 0
Allograft outcomes
Timepoint [9] 444266 0
Day 7, Day 30 and Day 90 post-operatively
Secondary outcome [10] 444267 0
Pharmacokinetic analysis for calcineurin inhibitors to assess impact of cytokine haemadsorption on immunosuppression kinetics
Timepoint [10] 444267 0
Daily measurement for first 7 days post-operatively
Secondary outcome [11] 444491 0
Hospital mortality
Timepoint [11] 444491 0
At time of hospital discharge or death (whichever is earlier)
Secondary outcome [12] 444492 0
90 day mortality (90 days post-transplant)
Timepoint [12] 444492 0
90 days post-transplant

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).
Minimum age
16 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
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

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)
Yes - central randomisation by computer algorithm using UNSW RedCAP server
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
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
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.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/04/2025
Actual
Date of last participant enrolment
Anticipated
1/04/2027
Actual
Date of last data collection
Anticipated
1/07/2027
Actual
Sample size
Target
50
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 27569 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment postcode(s) [1] 43682 0
2010 - Darlinghurst

Funding & Sponsors
Funding source category [1] 318267 0
Hospital
Name [1] 318267 0
St Vincent's Clinic Foundation
Country [1] 318267 0
Australia
Primary sponsor type
Hospital
Name
St Vincent's Hospital, Sydney
Address
Country
Australia
Secondary sponsor category [1] 320656 0
None
Name [1] 320656 0
Address [1] 320656 0
Country [1] 320656 0
Other collaborator category [1] 283376 0
University
Name [1] 283376 0
The Kirby Institute, University of New South Wales
Address [1] 283376 0
Country [1] 283376 0
Australia
Other collaborator category [2] 283400 0
Other Collaborative groups
Name [2] 283400 0
The George Institute for Global Health, NSW
Address [2] 283400 0
Country [2] 283400 0
Australia

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 316907 0
St Vincent’s Hospital Human Research Ethics Committee
Ethics committee address [1] 316907 0
https://svhs.org.au/home/research-education/research-office
Ethics committee country [1] 316907 0
Australia
Date submitted for ethics approval [1] 316907 0
28/01/2025
Approval date [1] 316907 0
Ethics approval number [1] 316907 0

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.
Trial website
Trial related presentations / publications
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.

Contacts
Principal investigator
Name 139394 0
A/Prof Priya Nair
Address 139394 0
Department of Intensive Care, St Vincent's Hospital, 390 Victoria Street Darlinghurst NSW 2010
Country 139394 0
Australia
Phone 139394 0
+61 412122692
Fax 139394 0
Email 139394 0
[email protected]
Contact person for public queries
Name 139395 0
Ms Sally Newman
Address 139395 0
Department of Intensive Care, St Vincent's Hospital, 390 Victoria Street Darlinghurst NSW 2010
Country 139395 0
Australia
Phone 139395 0
+61 8382 1111
Fax 139395 0
Email 139395 0
[email protected]
Contact person for scientific queries
Name 139396 0
Priya Nair
Address 139396 0
Department of Intensive Care, St Vincent's Hospital, 390 Victoria Street Darlinghurst NSW 2010
Country 139396 0
Australia
Phone 139396 0
+61 412122692
Fax 139396 0
Email 139396 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
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.
When will data be available (start and end dates)?
From study completion with no end date determined.
Available to whom?
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.
Available for what types of analyses?
Pooled IPD meta-analyses (eg with similar trials of cytokine haemadsorption in adult patients undergoing orthotopic heart transplant)
How or where can data be obtained?
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.


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.