Angiotensin II in liver transplantation (AngLT-1): protocol of a randomised, double-blind, placebo-controlled trial

For the primary endpoint, all eligible subjects who are randomised and receive the study drug are included in the intention-to-treat analysis. Subjects that complete the study without protocol violation are included in the per-protocol analysis.

Doses of NE administered by bolus or infusion are summed and the total NE dose is divided by total body weight and case duration, expressed as µg kg-1 min-1. The case duration is defined as the start of surgery (skin incision) until the end of surgery (abdominal closure) and does not include time for anaesthesia induction, line placement or patient transport. Norepinephrine dose in each arm is summarised as median and IQR. The total dose of NE is compared between the two arms by a Mann-Whitney U test and significance declared if p<0.05 (one-tailed). A one-tailed test is justified given that assignment to AngII (a vasopressor drug) cannot plausibly increase the required NE dose.

The secondary endpoints for the trial are summarised in box 2.22–26 Vasopressors are reported as raw doses or norepinephrine equivalent dosage.13 Categorical variables are summarised by frequency and percentage and continuous variables as median and IQR by arm. Categorical variables are compared between the two arms by either chi-square or Fisher’s exact test as appropriate. Continuous variables are compared between the two arms by two-sample t-tests or Mann-Whitney U tests if the normality assumption does not hold. Time-to-event data is described by the Kaplan-Meier method and compared between the arms by log-rank tests. All statistical analyses are performed in Stata, GraphPad Prism and R software.

Adverse events within 28 days of LT are tabulated by treatment group and include the number of subjects that experienced the event, the rate of occurrence, severity and relationship to study drug (box 3). Serious adverse events are reviewed by an independent Data and Safety Monitoring Board that may make recommendations to adjust the trial protocol. Predefined safety outcomes are also collected for descriptive purposes (box 3). Given the incidence of early thromboembolism after LT is less than 10%,27 this trial lacks the power to detect a true difference in this complication and data will be purely descriptive.

Box 3

Safety assessments and predefined adverse events.

Safety assessments

Methylene blue or hydroxocobalamin administered during LT for vasoplegia

Vasopressor infusion required at the time of leaving the operating room (after study drug discontinuation)

Name and dose (in native units and norepinephrine equivalents) of vasopressor required at the time of leaving the operating room (after study drug discontinuation)

Adverse events during administration of study drug

Severe hypertension (systolic blood pressure >180 mm Hg for >5 min)

Cardiac arrhythmias, requiring treatment (excludes bradycardia typically seen with portal vein reperfusion)

Bronchospasm, requiring treatment

Congestive heart failure, cardiogenic shock or cardiogenic pulmonary oedema

Adverse events within 48 hours of the end of liver transplantation

Thromboembolism (venous or arterial)

  • Includes venous thromboembolism, portal vein thrombosis, inferior vena cava thrombosis, catheter-associated thrombosis or superficial thrombophlebitis

  • Includes myocardial infarction, ischaemic stroke, transient ischaemic attack, peripheral arterial thrombosis or hepatic artery thrombosis

  • Excludes disseminated intravascular coagulation because features of this condition (thrombocytopenia, low fibrinogen and elevated prothrombin time) are highly prevalent during and after LT (liver transplantation)

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