A Feasibility Study of Octreotide Infusion During Liver Transplant. (Octreotide)

A Double-blind Randomised Placebo-controlled Feasibility Study to Assess the Impact of Octreotide Infusion During Liver Transplantation on Post-operative Renal Failure.

The purpose of the study is to determine whether an octreotide infusion during liver transplantation improves renal outcomes, intraoperative blood pressure and reduces haemorrhage and transfusion requirement.

Common and serious complications of liver transplantation surgery include renal failure, haemorrhage and blood transfusion. These complications prolong post-operative recovery, increase the risk of liver graft failure, mortality and the need for long-term renal dialysis. The drug octreotide is a synthetic analogue of somatostatin with comparable physiological effects and a good side-effect profile. Existing evidence in liver transplantation supports octreotide efficacy in improving renal function, reducing bleeding and enhancing blood pressure. However, there is no robust randomised controlled trial evidence for octreotide in liver transplantation and limited safety data regarding its use in this setting. This is a multi centre, prospective double-blind, randomised, placebo-controlled trial of octreotide infusion during liver transplantation. The patients will be randomised in a 2:1 ratio to either octreotide or placebo groups. Stratified randomisation of patients is by donation type (DCD vs. DBD). Patients will be randomised in the anaesthetic room and study medication given as an initial bolus of 5ml (100mcg octreotide or saline) prior to surgical incision and then continued throughout surgery at 5ml/hr (100mcg/hour octreotide or saline).

Patients will be randomised in a 2:1 ratio to either octreotide or placebo groups. Stratified randomisation of patients by source of liver graft (brain death or cardiac death) will be performed.

Blinding (masking) will be achieved through the use of identical active drug product and control study drug syringes that are allocated by centrally-controlled and administered randomisation such that no clinical, research or statistical support staff are aware of allocation.

Octreotide intravenous infusion, 100mcg bolus with a subsequent infusion of 100mcg per hour during surgery.

Octreotide syringes will contain 50ml of octreotide acetate at 20mcg/ml in 0.9% w/v sodium chloride in water.

This will be assessed by: • Ability to recruit patients (target: ≥ 30% consent rate of eligible patients admitted for transplant)

This will be assessed by: • The percentage of patients successfully completing the study intervention. Defined as eligible patients who receive the entire study drug infusion in a blinded manner.

This will be defined by Acute Kidney Injury Network stage 1 criteria (a 50% increase in serum creatinine from baseline or less than 0.5 ml/kg/hr urine output for 6-12 hours post-transplant).

This is defined as a new persistent estimated glomerular filtration rate below 60 ml/min/1.73m2 or a decline in pre-existing glomular function to a more severe KDIGO chronic kidney disease. status.

Early allograft dysfunction defined by the presence of one or more of the following: total bilirubin ≥ 10 mg/dL (171 μmol/L) or, INR ≥ 1.6 on day 7, and ALT/AST > 2,000 IU/L within the first 7 days post-operatively.

Total volume of intra-operative red blood cell salvage available for reinfusion following washing and centrifugation.

Volume of packed red blood cell transfusion administered intra-operatively and at 24, 72 and 168 hours post-operatively.

Recorded adverse events are: abnormal QTc interval (460ms in men, 470ms in women) or associated ventricular arrhythmia or Torsades de Pointes, unexpected or resistant hypoglycaemia (blood sugar < 4mM) and clinical suspicion of allergic or anaphylactic reaction.

PROMs (Patient Recorded Outcome Measures) of quality of life . The questionnaires to be used to quantify quality of life is EuroQoL-5D-5L.

PROMs (Patient Recorded Outcome Measures) of quality of life . The questionnaires to be used to quantify quality of life is LDQOL.

Inclusion Criteria: Adults aged 18 years and over undergoing primary liver transplantation of a whole or partial liver graft from a cardiac or brain dead donor. Provision of written informed consent. Exclusion Criteria: Previous solid organ transplant. Acute liver failure. Fulminant hepatic failure. Patients receiving a living donor liver graft. Patients currently admitted to ICU prior to transplantation. Requirement of haemodialysis or CVVHF pre-operatively. Known allergy or adverse reaction to octreotide. Pre-operative decision to use intra-operative CVVHF. A positive pregnancy test.

We would only provide IPD on specific application for that data as part of meta-analysis or other comparable research, rather than providing an 'open book' approach. Eligible requests will come from genuine non-commercial research institutes with a plan to publish meta-analytical or systematic review outcomes. Requests will be reviewed by the TMG with discussion with the TSC as needed. Data will be provided in a basic spreadsheet database via institutional email, ensuring no PID is contained.

Fabes J, Ambler G, Shah B, Williams NR, Martin D, Davidson BR, Spiro M. Protocol for a prospective double-blind, randomised, placebo-controlled feasibility trial of octreotide infusion during liver transplantation. BMJ Open. 2021 Dec 2;11(12):e055864. doi: 10.1136/bmjopen-2021-055864.