Angiotensin II in Liver Transplantation (AngLT-1)

December 20, 2023 updated by: University of California, San Francisco

Angiotensin II in Liver Transplantation (AngLT-1): A Pilot Randomized Controlled Trial

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Estimated)

50

Phase

  • Phase 2
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • United States
    • California
      • San Francisco, California, United States, 94143
        • Recruiting
        • University of California, San Francisco
        • Contact:
        • Contact:
        • Principal Investigator:
          • Michael P Bokoch, MD, PhD
        • Sub-Investigator:
          • Matthieu M Legrand, MD, PhD
        • Sub-Investigator:
          • Garrett R Roll, MD
        • Principal Investigator:
          • Dieter Adelmann, MD, PhD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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 Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Angiotensin II (Giapreza)
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.
Drug: Angiotensin II
Infusion of Angiotensin II initiated if participants require norepinephrine at a rate of > 0.05 mcg/kg/min. The infusion will be titrated no more frequently than every 10 minutes during liver transplantation as a second line vasopressor and discontinued prior to leaving the operating room when the surgery is complete.
Other Names:
  • Giapreza (synthetic human angiotensin II)
Placebo Comparator: Saline
Sterile 0.9% saline, initiated and titrated at an equivalent volume infusion rate to the study drug, administered by continuous intravenous infusion.
Drug: Saline
Infusion of 0.9% saline initiated if participants require norepinephrine at a rate of > 0.05 mcg/kg/min. The infusion will be titrated no more frequently than every 10 minutes during liver transplantation as a second line vasopressor and discontinued prior to leaving the operating room when the surgery is complete.
Other Names:
  • 0.9% normal saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
Time Frame: 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.
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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
Proportion of patients requiring 3rd and 4th line vasopressor infusions (epinephrine or vasopressin) during LT
Time Frame: 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
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.
Time spent below target MAP (65 mmHg)
Time Frame: 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 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.
Dose of vasopressin administered during LT, averaged over case duration and TBW.
Time Frame: 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.
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.
Dose of epinephrine administered during LT, excluding boluses within the 5 min immediately following portal reperfusion, averaged over case duration and TBW.
Time Frame: 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.
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.
Change in direct renin
Time Frame: 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
Time of surgical incision and 2 hours after reperfusion of the portal vein, approximately 4 hours.
Incidence of severe (stage 2 or 3) acute kidney injury (AKI) within 48 hours after LT.
Time Frame: 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.
48 hours
Change in intraoperative urine output in mL/kg/hr before and after initiation of study drug
Time Frame: 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.
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.
Major adverse kidney events (MAKE) at 30 days (MAKE-30) after LT
Time Frame: 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.
30 days
Incidence of early allograft dysfunction (EAD) by Olthoff criteria
Time Frame: 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
7 days
Model for Early Allograft Function (MEAF) score
Time Frame: 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.
3 days
Duration of renal replacement therapy (RRT) after LT
Time Frame: Up to 1 year
Total duration of RRT following LT, limited to the stratum of subjects on RRT immediately prior to surgery.
Up to 1 year
Duration of ICU stay after LT
Time Frame: Up to 1 year
Total duration of intensive care unit stay following LT.
Up to 1 year
Duration of hospital stay after LT
Time Frame: Up to 1 year
Total duration of hospital stay after LT
Up to 1 year
Patient and graft survival at 30 days after LT
Time Frame: 30 days
Defined as patient death or need for re-transplant within 30 days following LT.
30 days
Patient and graft survival at 1 year after LT
Time Frame: 1 year
Defined as patient death or need for re-transplant within 1 year following LT.
1 year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of California, San Francisco

Collaborators

La Jolla Pharmaceutical Company

Investigators

  • Principal Investigator: Michael P Bokoch, M.D., Ph.D., Department of Anesthesia and Perioperative Care, University of California, San Francisco

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

June 28, 2022

Primary Completion (Estimated)

September 1, 2025

Study Completion (Estimated)

September 1, 2026

Study Registration Dates

First Submitted

May 20, 2021

First Submitted That Met QC Criteria

May 20, 2021

First Posted (Actual)

May 25, 2021

Study Record Updates

Last Update Posted (Actual)

December 21, 2023

Last Update Submitted That Met QC Criteria

December 20, 2023

Last Verified

December 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 20-30948

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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