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Angiotensin II in Liver Transplantation (AngLT-1)

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ClinicalTrials.gov Identifier: NCT04901169
Recruitment Status : Not yet recruiting
First Posted : May 25, 2021
Last Update Posted : October 6, 2021
Sponsor:
Collaborator:
La Jolla Pharmaceutical Company
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Liver Transplant; Complications Vasoplegia Drug: Angiotensin II Drug: Saline Phase 2 Phase 3

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 the need for renal replacement therapy preoperatively.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Randomized, double-blind, placebo-controlled.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Identically-labeled infusion bags of either angiotensin II or saline placebo will be prepared by a research pharmacist.
Primary Purpose: Treatment
Official Title: Angiotensin II in Liver Transplantation (AngLT-1): A Pilot Randomized Controlled Trial
Estimated Study Start Date : January 1, 2022
Estimated Primary Completion Date : September 1, 2023
Estimated Study Completion Date : September 1, 2024

Resource links provided by the National Library of Medicine


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 Name: 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 Name: 0.9% normal saline




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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

  2. 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.

  3. 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.

  4. 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.

  5. 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

  6. 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.

  7. 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.

  8. 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.

  9. 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

  10. 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.

  11. 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.

  12. Duration of ICU stay after LT [ Time Frame: Up to 1 year ]
    Total duration of intensive care unit stay following LT.

  13. Duration of hospital stay after LT [ Time Frame: Up to 1 year ]
    Total duration of hospital stay after LT

  14. 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.

  15. 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age > or = 18 years
  • Liver transplantation from a deceased donor after brain death (DBD)
  • 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)
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04901169


Contacts
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Contact: Erika L Brinson, M.D. (415) 502-2341 erika.brinson@ucsf.edu
Contact: Michael P Bokoch, M.D., Ph.D. (415) 476-8389 michael.bokoch@ucsf.edu

Locations
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United States, California
University of California, San Francisco
San Francisco, California, United States, 94143
Contact: Erika L Brinson, MD    415-502-2341    erika.brinson@ucsf.edu   
Contact: Michael P Bokoch, MD, PhD    (415) 476-8389    Michael.Bokoch@ucsf.edu   
Principal Investigator: Erika L Brinson, MD         
Principal Investigator: Michael P Bokoch, MD, PhD         
Sub-Investigator: Claus U Niemann, MD         
Sub-Investigator: Matthieu M Legrand, MD, PhD         
Sub-Investigator: Garrett R Roll, MD         
Sub-Investigator: Dieter Adelmann, MD, PhD         
Sponsors and Collaborators
University of California, San Francisco
La Jolla Pharmaceutical Company
Investigators
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Principal Investigator: Erika L Brinson, M.D. Department of Anesthesia and Perioperative Care, University of California, San Francisco
Principal Investigator: Michael P Bokoch, M.D., Ph.D. Department of Anesthesia and Perioperative Care, University of California, San Francisco
Publications:

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Responsible Party: University of California, San Francisco
ClinicalTrials.gov Identifier: NCT04901169    
Other Study ID Numbers: 20-30948
First Posted: May 25, 2021    Key Record Dates
Last Update Posted: October 6, 2021
Last Verified: October 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Keywords provided by University of California, San Francisco:
Vasoplegia
Angiotensin II
Cirrhosis
Liver Transplant
Liver Transplantation
Hypotension
Acute Kidney Injury
Additional relevant MeSH terms:
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Vasoplegia
Vascular Diseases
Cardiovascular Diseases
Postoperative Complications
Pathologic Processes
Angiotensin II
Giapreza
Angiotensinogen
Vasoconstrictor Agents
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action