Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12625000506493
Ethics application status
Approved
Date submitted
21/04/2025
Date registered
22/05/2025
Date last updated
22/05/2025
Date data sharing statement initially provided
22/05/2025
Type of registration
Prospectively registered

Titles & IDs
Public title
A direct comparison of angiotensin vs. noradrenaline therapy for the management of liver transplantation-associated hypotension: an open-label, randomised feasibility trial (The D’ARTAGNAN Trial)
Scientific title
A direct comparison of angiotensin vs. noradrenaline therapy for the management of liver transplantation-associated hypotension: an open-label, randomised feasibility trial (The D’ARTAGNAN Trial)
Secondary ID [1] 314235 0
Nil known
Universal Trial Number (UTN)
U1111-1321-7928
Trial acronym
D’ARTAGNAN
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Hypotension 337143 0
Liver transplantation 337147 0
Condition category
Condition code
Anaesthesiology 333565 333565 0 0
Anaesthetics
Cardiovascular 333566 333566 0 0
Diseases of the vasculature and circulation including the lymphatic system
Oral and Gastrointestinal 333567 333567 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is an open-label, parallel-group, randomised controlled feasibility trial comparing angiotensin-II to noradrenaline as a primary vasopressor in liver transplant recipients. Eligible patients undergoing liver transplantation will be randomised to either the intervention arm (Angiotensin-II) or the control arm (Noradrenaline) in a 1:1 ratio.

Angiotensin-II will be prepared at a concentration of 5000ng/ml (2.5 mg angiotensin-II in 500ml of normal saline). The rate of intravenous administration will be titrated to achieve a target MAP between 60-90 mmHg, with a dose range equivalent to 0 to 40 ng/kg/min.

The allocated study drug (either Angiotensin-II or Noradrenaline) will be administered as needed (titrated based on MAP) from the time that central venous access is established (in the operating theatre) until the early post-operative period (for a maximum of 48 hours in ICU). The drug will be administered by the treating anaesthetist within the operating theatre, and subsequently by the intensive care unit nursing staff, under the guidance of the treating intensivist within the ICU.
Intervention code [1] 330848 0
Treatment: Drugs
Comparator / control treatment
Noradrenaline will be prepared as 60mcg/ml (6 mg noradrenaline in 100ml of 5 % glucose). The rate of intravenous administration will be titrated to achieve a target MAP between 60-90 mmHg, with a dose range equivalent to 0 to 0.4 mcg/kg/min.

The allocated study drug (either Angiotensin-II or Noradrenaline) will be administered as needed (titrated based on MAP) from the time that central venous access is established (in the operating theatre) until the early post-operative period (for a maximum of 48 hours in ICU). The drug will be administered by the treating anaesthetist within the operating theatre, and subsequently by the intensive care unit nursing staff, under the guidance of the treating intensivist within the ICU.
Control group
Active

Outcomes
Primary outcome [1] 341142 0
Consent rate (percentage of eligible participants who consented)
Timepoint [1] 341142 0
At study conclusion
Primary outcome [2] 341158 0
Proportional duration of study drug as a percentage of intra-operative time
Timepoint [2] 341158 0
Intra-operatively
Primary outcome [3] 341159 0
Proportion of intra-operative time below mean arterial pressure (MAP) target range (< 60 mmHg)
Timepoint [3] 341159 0
Intra-operatively
Secondary outcome [1] 446496 0
Eligibility rate (percentage of screened participants fulfilling eligibility criteria)
Timepoint [1] 446496 0
At study conclusion
Secondary outcome [2] 446529 0
Recruitment rate (average number of participants recruited per month)
Timepoint [2] 446529 0
At study conclusion
Secondary outcome [3] 446530 0
Proportion of intra-operative time within mean arterial pressure (MAP) target range (60-90 mmHg)
Timepoint [3] 446530 0
Intra-operatively
Secondary outcome [4] 446552 0
Time-weighted average mean arterial pressure (MAP) (mmHg)
Timepoint [4] 446552 0
Intra-operatively
Secondary outcome [5] 446553 0
Total study drug administered
Timepoint [5] 446553 0
Intra-operatively, Post-operatively in ICU (limited by first 48 hours, or until ICU discharge)
Secondary outcome [6] 446554 0
Maximal study drug rate
Timepoint [6] 446554 0
Intra-operatively, Post-operatively in ICU (limited by first 48 hours, or until ICU discharge)
Secondary outcome [7] 446555 0
Vasopressin infusion use
Timepoint [7] 446555 0
Intra-operatively, Post-operatively in ICU (limited by first 48 hours, or until ICU discharge)
Secondary outcome [8] 446556 0
Vasopressin maximal rate
Timepoint [8] 446556 0
Intra-operatively, Post-operatively in ICU (limited by first 48 hours, or until ICU discharge)
Secondary outcome [9] 446557 0
Adrenaline infusion use
Timepoint [9] 446557 0
Intra-operatively, Post-operatively in ICU (limited by first 48 hours, or until ICU discharge)
Secondary outcome [10] 446558 0
Adrenaline maximal rate
Timepoint [10] 446558 0
Intra-operatively, Post-operatively in ICU (limited by first 48 hours, or until ICU discharge)
Secondary outcome [11] 446559 0
Use of alternate (non-allocated) study drug (crossover)
Timepoint [11] 446559 0
Intra-operatively, Post-operatively in ICU (limited by first 48 hours, or until ICU discharge)
Secondary outcome [12] 446560 0
Use of methylene blue
Timepoint [12] 446560 0
Intra-operatively, Post-operatively in ICU (limited by first 48 hours, or until ICU discharge)
Secondary outcome [13] 446561 0
Peak post-operative serum creatinine
Timepoint [13] 446561 0
Within 7 days post-transplant
Secondary outcome [14] 446562 0
Acute kidney injury (AKI), as defined by KDIGO criteria
Timepoint [14] 446562 0
Within 7 days post-transplant
Secondary outcome [15] 446563 0
Requirement for renal replacement therapy (RRT)
Timepoint [15] 446563 0
Within 7 days post-transplant
Secondary outcome [16] 446564 0
Hepatic artery thrombosis
Timepoint [16] 446564 0
Within 7 days post-transplant
Secondary outcome [17] 446565 0
Portal vein thrombosis
Timepoint [17] 446565 0
Within 7 days post-transplant
Secondary outcome [18] 446566 0
Hepatic vein thrombosis
Timepoint [18] 446566 0
Within 7 days post-transplant
Secondary outcome [19] 446567 0
Deep vein thrombosis
Timepoint [19] 446567 0
Within 7 days post-transplant
Secondary outcome [20] 446568 0
Pulmonary embolism
Timepoint [20] 446568 0
Within 7 days post-transplant
Secondary outcome [21] 446569 0
Continuous renal replacement therapy (CRRT) circuit thrombosis
Timepoint [21] 446569 0
Within 7 days post-transplant
Secondary outcome [22] 446570 0
Myocardial infarction, as defined by the 4th Universal Definition of Myocardial Infarction
Timepoint [22] 446570 0
Within 7 days post-transplant
Secondary outcome [23] 446571 0
Ischaemic stroke
Timepoint [23] 446571 0
Within 7 days post-transplant
Secondary outcome [24] 446572 0
Mesenteric ischaemia
Timepoint [24] 446572 0
Within 7 days post-transplant
Secondary outcome [25] 446573 0
Limb ischaemia
Timepoint [25] 446573 0
Within 7 days post-transplant
Secondary outcome [26] 446574 0
Severe hypertension, defined as systolic blood pressure (SBP) > 180 mmHg, diastolic blood pressure (DBP) > 110 mmHg or mean arterial pressure (MAP) > 130 mmHg for more than 5 minutes
Timepoint [26] 446574 0
During study drug administration
Secondary outcome [27] 446575 0
New-onset atrial fibrillation
Timepoint [27] 446575 0
Within 7 days post-transplant
Secondary outcome [28] 446576 0
Early allograft dysfunction, as defined by the Olthoff Criteria
Timepoint [28] 446576 0
Within 7 days post-transplant
Secondary outcome [29] 446577 0
ICU length of stay
Timepoint [29] 446577 0
Assessed at ICU discharge
Secondary outcome [30] 446578 0
30-day mortality
Timepoint [30] 446578 0
Assessed at day 30 post-operatively
Secondary outcome [31] 446579 0
Renin
Timepoint [31] 446579 0
Baseline intra-operative (t1), Post-reperfusion (t2), Post-operative day 1 (t3)
Secondary outcome [32] 446580 0
Aldosterone
Timepoint [32] 446580 0
Baseline intra-operative (t1), Post-reperfusion (t2), Post-operative day 1 (t3)
Secondary outcome [33] 446581 0
Angiotensin Converting Enzyme (ACE) Level
Timepoint [33] 446581 0
Baseline intra-operative (t1), Post-reperfusion (t2), Post-operative day 1 (t3)
Secondary outcome [34] 446582 0
Serum ACE2 Activity
Timepoint [34] 446582 0
Baseline intra-operative (t1), Post-reperfusion (t2), Post-operative day 1 (t3)
Secondary outcome [35] 446583 0
Urinary ACE2 Activity (normalised to urinary creatinine)
Timepoint [35] 446583 0
Baseline intra-operative (t1), Post-reperfusion (t2), Post-operative day 1 (t3)
Secondary outcome [36] 447685 0
Hospital length of stay
Timepoint [36] 447685 0
Assessed at hospital discharge
Secondary outcome [37] 447686 0
In-hospital mortality
Timepoint [37] 447686 0
Assessed at hospital discharge

Eligibility
Key inclusion criteria
* Adult patients (greater than or equal to 18 years)
* Listed for isolated liver transplantation
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Surgical Factors:
* Concurrent multi-visceral transplantation
* Planned use of intra-operative veno-venous bypass

Patient Factors:
* Known allergy to angiotensin-II, noradrenaline or any excipients used in their formulation (e.g., mannitol or sodium metabisulphite respectively)
* Extremes of body weight (TBW less than 50 kg OR TBW greater than or equal to 140 kg)
* Fulminant liver failure
* Pre-operative vasopressor requirement (including terlipressin)
* Pre-existing end-stage kidney disease, defined as baseline estimated glomerular filtration rate (eGFR) < 15ml/min/1.73m2 OR pre-operative requirement for renal replacement therapy (peritoneal or haemodialysis within previous month)
* History of splanchnic venous thrombosis (e.g., Budd-Chiari syndrome, portal venous thrombosis, mesenteric vein thrombosis) ever
* History of other venous thrombosis (deep vein thrombosis, pulmonary embolism) or arterial thrombosis (myocardial infarction, ischaemic stroke, mesenteric ischaemia) within the preceding 6 months
* Therapeutic anticoagulation (e.g., DOACs) for any medical indication not otherwise outlined above
* Inherited hypercoagulability disorders (e.g., Factor V Leiden)
* Vasospastic diseases (e.g., Raynaud’s disease or acrocyanosis)
* Severe left ventricle (LV) systolic impairment (LVEF < 30%)
* Unrepaired aortic aneurysm or dissection
* Pregnant or breast-feeding women
* Patients lacking capacity, or inadequate language comprehension for informed consent
* Patients previously included in the study (i.e., previous LTx during recruitment period)

Logistic Factors:
* Non-availability of raw haemodynamic data (i.e., surgical case proceeding outside of the usual liver transplant theatre)

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)
Allocation will be concealed at the time of eligibility assessment. An independent researcher (not involved in participant enrolment) will be designated to upload a computer-generated randomisation sequence table to REDCap. No other researchers will have user permission rights to view the randomisation sequence. Subsequent randomisation will then occur via the REDCap randomisation module.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computer-generated sequence, permuted block randomisation
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis
Summary statistics will be used to describe the clinical data and presented as mean ± SD, median with interquartile range or percentages as appropriate. A Bayesian analysis will be considered and all Bayesian models will be fitted with the integrated nested Laplace approximation (INLA), allowing the calculation of posterior effect estimates with their 95% credible intervals (CrI). Prior distributions for individual treatment effects for all analyses will be neutral (weakly informative).

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
2/06/2025
Actual
Date of last participant enrolment
Anticipated
2/06/2027
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
40
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 27788 0
Austin Health - Austin Hospital - Heidelberg
Recruitment postcode(s) [1] 43977 0
3084 - Heidelberg

Funding & Sponsors
Funding source category [1] 318752 0
Charities/Societies/Foundations
Name [1] 318752 0
Austin Intensive Care Trust Fund
Country [1] 318752 0
Australia
Primary sponsor type
Hospital
Name
Austin Health
Address
Country
Australia
Secondary sponsor category [1] 321192 0
None
Name [1] 321192 0
Address [1] 321192 0
Country [1] 321192 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 317366 0
Austin Health Human Research Ethics Committee
Ethics committee address [1] 317366 0
Ethics committee country [1] 317366 0
Australia
Date submitted for ethics approval [1] 317366 0
Approval date [1] 317366 0
18/02/2025
Ethics approval number [1] 317366 0
HREC/112563/Austin/2024

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

Contacts
Principal investigator
Name 140822 0
Dr Rebecca Caragata
Address 140822 0
Austin Health, 145 Studley Rd, Heidelberg VIC 3084
Country 140822 0
Australia
Phone 140822 0
+61 3 9496 5704
Fax 140822 0
Email 140822 0
[email protected]
Contact person for public queries
Name 140823 0
Rebecca Caragata
Address 140823 0
Austin Health, 145 Studley Rd, Heidelberg VIC 3084
Country 140823 0
Australia
Phone 140823 0
+61 3 9496 5704
Fax 140823 0
Email 140823 0
[email protected]
Contact person for scientific queries
Name 140824 0
Rebecca Caragata
Address 140824 0
Austin Health, 145 Studley Rd, Heidelberg VIC 3084
Country 140824 0
Australia
Phone 140824 0
+61 3 9496 5704
Fax 140824 0
Email 140824 0
[email protected]

Data sharing statement
Will the study consider sharing 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.