Angiotensin II in Liver Transplantation

Phase 2

Recruiting

• Conditions: Liver Transplant; Complications; Vasoplegia
• Interventions: Drug: Saline; Drug: Angiotensin II

• Registration Number: NCT04901169
• Lead Sponsor: University of California, San Francisco

Brief Summary

The purpose of this study is to determine the efficacy and safety of Angiotensin II as a second-line vasopressor (drug that raises the blood pressure) during liver transplantation.

Detailed Description

This is a single center, randomized, double-blind, placebo-controlled trial. Subjects will receive an infusion of either Angiotensin II (AngII) or a saline control (placebo) in addition to usual care with traditional vasopressors (catecholamines and vasopressin) during liver transplantation (LT). AngII is a vasopressor approved by the FDA for the treatment of vasodilatory shock. It targets the renin-angiotensin system (RAS) and has been shown to effectively raise the mean arterial blood pressure (MAP) in patients with septic shock. It also allows for lower doses of traditional vasopressors and may improve microcirculatory flow to the kidneys. The study drug will only be administered if the participants require \> 0.05 mcg/kg/min of norepinephrine while undergoing liver transplantation. The study drug will be titrated throughout the case and discontinued at the end of surgery. Randomization will be stratified based on (a) the need for renal replacement therapy preoperatively and (b) the use of normothermic machine perfusion of the liver graft.

Study Timeline

• Study First Submitted: 2021-05-20
• Study First Submitted QC: 2021-05-20
• Study First Posted: 2021-05-25
• Study Start: 2022-06-28
• Status Verified: 2025-05
• Last Update Submitted: 2025-05-15
• Last Update Posted: 2025-05-21
• Primary Completion: 2025-09-01
• Study Completion: 2026-09-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 50

Inclusion Criteria

• Age > or = 18 years
• Liver transplantation from a deceased donor
• Model for End-stage Liver Disease Sodium (MELD-Na) score > or = 25 at the time of transplant (not counting MELD exception points)
• Patient requiring > 0.05 mcg/kg/min of norepinephrine (NE) during LT

Exclusion Criteria

• Living-donor liver transplantation (LDLT)
• Split liver transplantation (isolated right or left lobe)
• Donation after cardiac death (DCD) without normothermic machine perfusion (NMP)
• Acute liver failure (ALF)
• Listed for or receiving simultaneous liver-kidney transplantation (SLKT)
• Liver re-transplantation (patient who has previously received a liver transplant)
• Preoperative treatment with angiotensin II receptor blocker or angiotensin converting enzyme inhibitor (within 48 h)
• Portopulmonary hypertension
• Left ventricular systolic dysfunction (defined as ejection fraction < 45%)
• Active bronchospasm at time of LT
• History of thrombotic or embolic disease, inherited hypercoagulable disorder, or therapeutic anticoagulation
• Portal vein thrombosis
• Celiac stenosis
• End-stage renal disease (chronic eGFR < 15 mL/min/1.73 m2 or chronic RRT - not including AKI requiring RRT)
• History of Raynaud's disease
• Known history of allergy to synthetic human angiotensin II
• Subject intubated and/or mechanically ventilated prior to entering OR for LT
• Presence of other condition or abnormality that would compromise the safety of the patient or quality of the data

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Saline	Saline	Sterile 0.9% saline, initiated and titrated at an equivalent volume infusion rate to the study drug, administered by continuous intravenous infusion.
Angiotensin II (Giapreza)	Angiotensin II	Giapreza (synthetic human angiotensin II), initiated at 5 ng/kg/min and titrated to between 1.25 ng/kg/min and 40 ng/kg/min, administered by continuous intravenous infusion.

Primary Outcome Measures

Name	Time	Method
Total dose of norepinephrine (NE), averaged over case duration and total body weight, utilized during liver transplantation (LT) to maintain mean arterial pressure (MAP) greater than or equal to 65 mmHg.	Duration of surgery - defined as the time period starting with skin incision by the surgeon, and ending at the time of skin closure, an average of 8 hours.	Calculated as the sum of all NE doses (in mcg) administered by either infusion or bolus during LT surgery, divided by the subjects total body weight (TBW, in kg), divided by the duration of surgery (in min). The Primary Outcome will be expressed in mcg/kg/min.

Secondary Outcome Measures

Name	Time	Method
Time spent below target MAP (65 mmHg)	Duration of surgery - defined as the time period starting with skin incision by the surgeon, and ending at the time of skin closure, an average of 8 hours.	Total time in minutes that the patient has a MAP \<65 mmHg during LT.
Duration of ICU stay after LT	Up to 1 year	Total duration of intensive care unit stay following LT.
Proportion of patients requiring 3rd and 4th line vasopressor infusions (epinephrine or vasopressin) during LT	Duration of surgery - defined as the time period starting with skin incision by the surgeon, and ending at the time of skin closure, an average of 8 hours.	The proportion of patients requiring 3rd and 4th line vasopressors (epinephrine or vasopressin, at the anesthesiologists discretion) in addition to NE and Study Drug to be administered by infusion for greater than or equal to 5 min during each of the following phases of LT will be tabulated: * Dissection phase - begins at the time of skin incision and ends with clamping of the inferior vena cava (IVC); * Anhepatic phase - begins at the time of IVC clamping and ends with unclamping of the portal vein; * Neohepatic phase - begins at the time of portal vein unclamping and ends at the time of skin closure
Incidence of severe (stage 2 or 3) acute kidney injury (AKI) within 48 hours after LT.	48 hours	The incidence of severe AKI (stage 2 or 3) is defined according to the International Club for Ascites (ICA) 2015 criteria, a revision of the Kidney Disease Improving Global Outcomes (KDIGO) criteria for patients with cirrhosis. Severe AKI is defined as an increase in sCr \> 2-fold from baseline, or sCr ≥ 4.0 with an acute increase of ≥ 0.3 mg/dL from baseline, or initiation of RRT. The baseline sCr is defined as the most recent value prior to LT. Limited to the stratum of patients not on RRT immediately prior to surgery.
Dose of vasopressin administered during LT, averaged over case duration and TBW.	Duration of surgery - defined as the time period starting with skin incision by the surgeon, and ending at the time of skin closure, an average of 8 hours.	Calculated as the sum of all vasopressin doses (in units) administered by either infusion or bolus during LT surgery, divided by the subject's TBW (in kg), divided by the duration of surgery (in hr). Expressed in units/kg/hr.
Incidence of early allograft dysfunction (EAD) by Olthoff criteria	7 days	Defined by one or more of the following: * Total bilirubin ≥ 10 mg/dL on postoperative day (POD) 7; * International normalized ratio (INR) ≥ 1.6 on POD 7; * Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \> 2000 units/L within the first 7 days after LT
Duration of renal replacement therapy (RRT) after LT	Up to 1 year	Total duration of RRT following LT, limited to the stratum of subjects on RRT immediately prior to surgery.
Patient and graft survival at 30 days after LT	30 days	Defined as patient death or need for re-transplant within 30 days following LT.
Dose of epinephrine administered during LT, excluding boluses within the 5 min immediately following portal reperfusion, averaged over case duration and TBW.	Duration of surgery - defined as the time period starting with skin incision by the surgeon, and ending at the time of skin closure, an average of 8 hours.	Calculated as the sum of all epinephrine doses (in mcg) administered by either infusion or bolus during LT surgery, divided by the subject's TBW (in kg), divided by the duration of surgery (in min). Expressed in mcg/kg/min. Boluses of epinephrine given from 0 to 5 min after portal vein reperfusion will be excluded.
Change in direct renin	Time of surgical incision and 2 hours after reperfusion of the portal vein, approximately 4 hours.	Change in plasma direct renin level from the time of surgical incision to 2 hours after reperfusion of the portal vein
Model for Early Allograft Function (MEAF) score	3 days	Calculated from the maximum ALT and INR within the first 3 PODs and the total bilirubin on POD 3. The MEAF score ranges from 0-10 with higher scores indicating worse liver function (i.e., more severe early allograft dysfunction) in the early postoperative period.
Change in intraoperative urine output in mL/kg/hr before and after initiation of study drug	Duration of surgery - defined as the time period starting with skin incision by the surgeon, and ending at the time of skin closure, an average of 8 hours.	Intraoperative urine output will be continuously monitored using an automated meter (Accuryn Monitoring System, Potrero Medical). The change in the rate of urine output will be compared before and after initiation of the study drug.
Major adverse kidney events (MAKE) at 30 days (MAKE-30) after LT	30 days	Defined as the composite of death, RRT, or a 25% reduction in estimated glomerular filtration rate (eGFR) by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation at 30 days after LT.
Patient and graft survival at 1 year after LT	1 year	Defined as patient death or need for re-transplant within 1 year following LT.
Duration of hospital stay after LT	Up to 1 year	Total duration of hospital stay after LT

Trial Locations

Locations (1)

University of California, San Francisco; 🇺🇸 San Francisco, California, United States