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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)
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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)
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Secondary ID [1]
314235
0
Nil known
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Universal Trial Number (UTN)
U1111-1321-7928
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Trial acronym
D’ARTAGNAN
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Hypotension
337143
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Liver transplantation
337147
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Condition category
Condition code
Anaesthesiology
333565
333565
0
0
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Anaesthetics
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Cardiovascular
333566
333566
0
0
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Diseases of the vasculature and circulation including the lymphatic system
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Oral and Gastrointestinal
333567
333567
0
0
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Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
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Intervention/exposure
Study type
Interventional
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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.
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Intervention code [1]
330848
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Treatment: Drugs
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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.
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Control group
Active
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Outcomes
Primary outcome [1]
341142
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Consent rate (percentage of eligible participants who consented)
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Assessment method [1]
341142
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Assessed by screening log
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Timepoint [1]
341142
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At study conclusion
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Primary outcome [2]
341158
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Proportional duration of study drug as a percentage of intra-operative time
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Assessment method [2]
341158
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Assessed by infusion pump review and patient medical record
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Timepoint [2]
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Intra-operatively
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Primary outcome [3]
341159
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Proportion of intra-operative time below mean arterial pressure (MAP) target range (< 60 mmHg)
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Assessment method [3]
341159
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Assessed by electronic record of invasive monitoring data (arterial line)
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Timepoint [3]
341159
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Intra-operatively
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Secondary outcome [1]
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Eligibility rate (percentage of screened participants fulfilling eligibility criteria)
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Assessment method [1]
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Assessed by screening log
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Timepoint [1]
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At study conclusion
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Secondary outcome [2]
446529
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Recruitment rate (average number of participants recruited per month)
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Assessment method [2]
446529
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Assessed by screening log
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Timepoint [2]
446529
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At study conclusion
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Secondary outcome [3]
446530
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Proportion of intra-operative time within mean arterial pressure (MAP) target range (60-90 mmHg)
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Assessment method [3]
446530
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Assessed by electronic record of invasive monitoring data (arterial line)
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Timepoint [3]
446530
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Intra-operatively
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Secondary outcome [4]
446552
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Time-weighted average mean arterial pressure (MAP) (mmHg)
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Assessment method [4]
446552
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Assessed by electronic record of invasive monitoring data (arterial line)
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Timepoint [4]
446552
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Intra-operatively
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Secondary outcome [5]
446553
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Total study drug administered
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Assessment method [5]
446553
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Assessed by infusion pump review and patient medical record
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Timepoint [5]
446553
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Intra-operatively, Post-operatively in ICU (limited by first 48 hours, or until ICU discharge)
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Secondary outcome [6]
446554
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Maximal study drug rate
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Assessment method [6]
446554
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Assessed by infusion pump review and patient medical record
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Timepoint [6]
446554
0
Intra-operatively, Post-operatively in ICU (limited by first 48 hours, or until ICU discharge)
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Secondary outcome [7]
446555
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Vasopressin infusion use
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Assessment method [7]
446555
0
Assessed by infusion pump review and patient medical record
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Timepoint [7]
446555
0
Intra-operatively, Post-operatively in ICU (limited by first 48 hours, or until ICU discharge)
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Secondary outcome [8]
446556
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Vasopressin maximal rate
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Assessment method [8]
446556
0
Assessed by infusion pump review and patient medical record
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Timepoint [8]
446556
0
Intra-operatively, Post-operatively in ICU (limited by first 48 hours, or until ICU discharge)
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Secondary outcome [9]
446557
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Adrenaline infusion use
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Assessment method [9]
446557
0
Assessed by infusion pump review and patient medical record
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Timepoint [9]
446557
0
Intra-operatively, Post-operatively in ICU (limited by first 48 hours, or until ICU discharge)
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Secondary outcome [10]
446558
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Adrenaline maximal rate
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Assessment method [10]
446558
0
Assessed by infusion pump review and patient medical record
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Timepoint [10]
446558
0
Intra-operatively, Post-operatively in ICU (limited by first 48 hours, or until ICU discharge)
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Secondary outcome [11]
446559
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Use of alternate (non-allocated) study drug (crossover)
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Assessment method [11]
446559
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Assessed by infusion pump review and patient medical record
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Timepoint [11]
446559
0
Intra-operatively, Post-operatively in ICU (limited by first 48 hours, or until ICU discharge)
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Secondary outcome [12]
446560
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Use of methylene blue
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Assessment method [12]
446560
0
Assessed by patient medical record
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Timepoint [12]
446560
0
Intra-operatively, Post-operatively in ICU (limited by first 48 hours, or until ICU discharge)
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Secondary outcome [13]
446561
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Peak post-operative serum creatinine
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Assessment method [13]
446561
0
Assessed by blood samples collected daily
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Timepoint [13]
446561
0
Within 7 days post-transplant
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Secondary outcome [14]
446562
0
Acute kidney injury (AKI), as defined by KDIGO criteria
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Assessment method [14]
446562
0
Assessed by change in serum creatinine, on blood samples collected daily
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Timepoint [14]
446562
0
Within 7 days post-transplant
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Secondary outcome [15]
446563
0
Requirement for renal replacement therapy (RRT)
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Assessment method [15]
446563
0
Assessed by patient medical record
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Timepoint [15]
446563
0
Within 7 days post-transplant
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Secondary outcome [16]
446564
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Hepatic artery thrombosis
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Assessment method [16]
446564
0
Assessed by patient medical record – sonographic, radiologic or operative finding
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Timepoint [16]
446564
0
Within 7 days post-transplant
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Secondary outcome [17]
446565
0
Portal vein thrombosis
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Assessment method [17]
446565
0
Assessed by patient medical record – sonographic, radiologic or operative finding
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Timepoint [17]
446565
0
Within 7 days post-transplant
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Secondary outcome [18]
446566
0
Hepatic vein thrombosis
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Assessment method [18]
446566
0
Assessed by patient medical record – sonographic, radiologic or operative finding
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Timepoint [18]
446566
0
Within 7 days post-transplant
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Secondary outcome [19]
446567
0
Deep vein thrombosis
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Assessment method [19]
446567
0
Assessed by patient medical record – sonographic or radiologic finding
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Timepoint [19]
446567
0
Within 7 days post-transplant
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Secondary outcome [20]
446568
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Pulmonary embolism
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Assessment method [20]
446568
0
Assessed by patient medical record – echocardiographic or radiologic finding
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Timepoint [20]
446568
0
Within 7 days post-transplant
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Secondary outcome [21]
446569
0
Continuous renal replacement therapy (CRRT) circuit thrombosis
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Assessment method [21]
446569
0
Assessed by patient medical record – documentation of circuit failure requiring replacement in the context of increased transmembrane pressure or reduced blood flow
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Timepoint [21]
446569
0
Within 7 days post-transplant
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Secondary outcome [22]
446570
0
Myocardial infarction, as defined by the 4th Universal Definition of Myocardial Infarction
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Assessment method [22]
446570
0
Assessed by patient medical record – elevated cardiac troponin with associated electrocardiographic, echocardiographic or angiographic finding
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Timepoint [22]
446570
0
Within 7 days post-transplant
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Secondary outcome [23]
446571
0
Ischaemic stroke
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Assessment method [23]
446571
0
Assessed by patient medical record – radiologic finding
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Timepoint [23]
446571
0
Within 7 days post-transplant
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Secondary outcome [24]
446572
0
Mesenteric ischaemia
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Assessment method [24]
446572
0
Assessed by patient medical record – sonographic, radiologic or operative finding
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Timepoint [24]
446572
0
Within 7 days post-transplant
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Secondary outcome [25]
446573
0
Limb ischaemia
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Assessment method [25]
446573
0
Assessed by patient medical record – sonographic, radiologic or operative finding
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Timepoint [25]
446573
0
Within 7 days post-transplant
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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
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Assessment method [26]
446574
0
Assessed by invasive monitoring (arterial line)
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Timepoint [26]
446574
0
During study drug administration
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Secondary outcome [27]
446575
0
New-onset atrial fibrillation
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Assessment method [27]
446575
0
Assessed by patient medical record
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Timepoint [27]
446575
0
Within 7 days post-transplant
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Secondary outcome [28]
446576
0
Early allograft dysfunction, as defined by the Olthoff Criteria
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Assessment method [28]
446576
0
Assessed by patient medical record – routine blood samples
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Timepoint [28]
446576
0
Within 7 days post-transplant
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Secondary outcome [29]
446577
0
ICU length of stay
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Assessment method [29]
446577
0
Assessed by patient medical record
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Timepoint [29]
446577
0
Assessed at ICU discharge
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Secondary outcome [30]
446578
0
30-day mortality
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Assessment method [30]
446578
0
Assessed by patient medical record
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Timepoint [30]
446578
0
Assessed at day 30 post-operatively
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Secondary outcome [31]
446579
0
Renin
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Assessment method [31]
446579
0
Assessed by blood sample
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Timepoint [31]
446579
0
Baseline intra-operative (t1), Post-reperfusion (t2), Post-operative day 1 (t3)
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Secondary outcome [32]
446580
0
Aldosterone
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Assessment method [32]
446580
0
Assessed by blood sample
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Timepoint [32]
446580
0
Baseline intra-operative (t1), Post-reperfusion (t2), Post-operative day 1 (t3)
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Secondary outcome [33]
446581
0
Angiotensin Converting Enzyme (ACE) Level
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Assessment method [33]
446581
0
Assessed by blood sample
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Timepoint [33]
446581
0
Baseline intra-operative (t1), Post-reperfusion (t2), Post-operative day 1 (t3)
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Secondary outcome [34]
446582
0
Serum ACE2 Activity
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Assessment method [34]
446582
0
Assessed by blood sample
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Timepoint [34]
446582
0
Baseline intra-operative (t1), Post-reperfusion (t2), Post-operative day 1 (t3)
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Secondary outcome [35]
446583
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Urinary ACE2 Activity (normalised to urinary creatinine)
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Assessment method [35]
446583
0
Assessed by urine sample
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Timepoint [35]
446583
0
Baseline intra-operative (t1), Post-reperfusion (t2), Post-operative day 1 (t3)
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Secondary outcome [36]
447685
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Hospital length of stay
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Assessment method [36]
447685
0
Assessed by patient medical record
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Timepoint [36]
447685
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Assessed at hospital discharge
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Secondary outcome [37]
447686
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In-hospital mortality
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Assessment method [37]
447686
0
Assessed by patient medical record
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Timepoint [37]
447686
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Assessed at hospital discharge
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Eligibility
Key inclusion criteria
* Adult patients (greater than or equal to 18 years)
* Listed for isolated liver transplantation
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Minimum age
18
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
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)
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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)
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.
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computer-generated sequence, permuted block randomisation
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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
Phase 2
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Type of endpoint/s
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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).
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Recruitment
Recruitment status
Not yet recruiting
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Date of first participant enrolment
Anticipated
2/06/2025
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Actual
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Date of last participant enrolment
Anticipated
2/06/2027
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Actual
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Date of last data collection
Anticipated
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Actual
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Sample size
Target
40
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Accrual to date
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Final
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Recruitment in Australia
Recruitment state(s)
VIC
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Recruitment hospital [1]
27788
0
Austin Health - Austin Hospital - Heidelberg
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Recruitment postcode(s) [1]
43977
0
3084 - Heidelberg
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Funding & Sponsors
Funding source category [1]
318752
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Charities/Societies/Foundations
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Name [1]
318752
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Austin Intensive Care Trust Fund
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Address [1]
318752
0
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Country [1]
318752
0
Australia
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Primary sponsor type
Hospital
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Name
Austin Health
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Address
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Country
Australia
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Secondary sponsor category [1]
321192
0
None
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Name [1]
321192
0
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Address [1]
321192
0
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Country [1]
321192
0
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Ethics approval
Ethics application status
Approved
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Ethics committee name [1]
317366
0
Austin Health Human Research Ethics Committee
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Ethics committee address [1]
317366
0
https://www.austin.org.au/Office-for-Research/
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Ethics committee country [1]
317366
0
Australia
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Date submitted for ethics approval [1]
317366
0
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Approval date [1]
317366
0
18/02/2025
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Ethics approval number [1]
317366
0
HREC/112563/Austin/2024
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Summary
Brief summary
Liver transplantation is the only curative treatment option for patients with advanced liver disease. It is a prolonged and highly complex operation, during which many patients require medication to maintain their blood pressure at a safe level. Complications following this invasive (but life-saving) surgery are common. For example, approximately four in ten patients experience reduced kidney function, which can impact quality of life and life-expectancy. Many previous studies have sought to identify the risk factors for impaired kidney function following liver transplantation. There is evidence that both low blood pressure as well as the medication commonly used to raise blood pressure (noradrenaline) may increase the risk of kidney problems. However, a relatively novel medication, known as ‘angiotensin-II’ may offer a more kidney-friendly alternative, improving blood pressure with less risk of harming the kidneys. Our study will compare angiotensin-II to noradrenaline as a blood pressure support medication during liver transplantation. It is a small ‘pilot’ or ‘test’ study, with the aim of assessing the feasibility of a future larger trial. Our primary goal is to explore different assessments of study practicality, which will inform the running of the future study. In addition, we will compare various side-effects and safety outcomes between the two drugs, including the occurrence of kidney impairment, among others.
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Trial website
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
140822
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Dr Rebecca Caragata
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Address
140822
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Austin Health, 145 Studley Rd, Heidelberg VIC 3084
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Country
140822
0
Australia
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Phone
140822
0
+61 3 9496 5704
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Fax
140822
0
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Email
140822
0
[email protected]
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Contact person for public queries
Name
140823
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Rebecca Caragata
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Address
140823
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Austin Health, 145 Studley Rd, Heidelberg VIC 3084
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Country
140823
0
Australia
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Phone
140823
0
+61 3 9496 5704
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Fax
140823
0
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Email
140823
0
[email protected]
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Contact person for scientific queries
Name
140824
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Rebecca Caragata
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Address
140824
0
Austin Health, 145 Studley Rd, Heidelberg VIC 3084
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Country
140824
0
Australia
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Phone
140824
0
+61 3 9496 5704
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Fax
140824
0
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Email
140824
0
[email protected]
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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.
Download to PDF