Clinical trial NCT04901169: Angiotensin II in Liver Transplantation
Official title: Angiotensin II in Liver Transplantation (AngLT-1): A Pilot Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Liver Transplant; Complications
Vasoplegia
Keywords: Vasoplegia
Angiotensin II
Cirrhosis
Liver Transplant
Liver Transplantation
Hypotension
Acute Kidney Injury
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
Collaborators: name: La Jolla Pharmaceutical Company
First posted: 2021-05-25
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized, double-blind, placebo-controlled.
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: 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.
timeFrame: 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.
Secondary outcomes:
measure: Proportion of patients requiring 3rd and 4th line vasopressor infusions (epinephrine or vasopressin) during LT
timeFrame: 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.
measure: Time spent below target MAP (65 mmHg)
timeFrame: 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.
measure: Dose of vasopressin administered during LT, averaged over case duration and TBW.
timeFrame: 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.
measure: Dose of epinephrine administered during LT, excluding boluses within the 5 min immediately following portal reperfusion, averaged over case duration and TBW.
timeFrame: 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.
measure: Change in direct renin
timeFrame: Time of surgical incision and 2 hours after reperfusion of the portal vein, approximately 4 hours.
measure: Incidence of severe (stage 2 or 3) acute kidney injury (AKI) within 48 hours after LT.
timeFrame: 48 hours
measure: Change in intraoperative urine output in mL/kg/hr before and after initiation of study drug
timeFrame: 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.
measure: Major adverse kidney events (MAKE) at 30 days (MAKE-30) after LT
timeFrame: 30 days
measure: Incidence of early allograft dysfunction (EAD) by Olthoff criteria
timeFrame: 7 days
measure: Model for Early Allograft Function (MEAF) score
timeFrame: 3 days
measure: Duration of renal replacement therapy (RRT) after LT
timeFrame: Up to 1 year
measure: Duration of ICU stay after LT
timeFrame: Up to 1 year
measure: Duration of hospital stay after LT
timeFrame: Up to 1 year
measure: Patient and graft survival at 30 days after LT
timeFrame: 30 days
measure: Patient and graft survival at 1 year after LT
timeFrame: 1 year
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
Study officials:
affiliation: Department of Anesthesia and Perioperative Care, University of California, San Francisco
name: Michael P Bokoch, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
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