Angiotensin II in Liver Transplantation

NCT04901169 | Active Not Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: 20-30948
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

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.

Conditions

Liver Transplant; Complications; Vasoplegia

Keywords

Vasoplegia; Angiotensin II; Cirrhosis; Liver Transplant; Liver Transplantation; Hypotension; Acute Kidney Injury

Outcome Measures

Primary Outcomes (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.

  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 Outcomes (15)

• 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.

• 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.

• 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.

• 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.

• Change in direct renin

  Time of surgical incision and 2 hours after reperfusion of the portal vein, approximately 4 hours.

Study Arms (2)

Angiotensin II (Giapreza)

EXPERIMENTAL

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

Saline

PLACEBO COMPARATOR

Sterile 0.9% saline, initiated and titrated at an equivalent volume infusion rate to the study drug, administered by continuous intravenous infusion.

Drug: Saline

Interventions

Angiotensin II DRUG

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.

Also known as: Giapreza (synthetic human angiotensin II)

Angiotensin II (Giapreza)

Saline DRUG

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.

Also known as: 0.9% normal saline

Saline

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of California, San Francisco: lead
• La Jolla Pharmaceutical Company: collaborator

Study Sites (1)

University of California, San Francisco

San Francisco, California, 94143, United States

Location

Related Publications (16)

• Khanna A, English SW, Wang XS, Ham K, Tumlin J, Szerlip H, Busse LW, Altaweel L, Albertson TE, Mackey C, McCurdy MT, Boldt DW, Chock S, Young PJ, Krell K, Wunderink RG, Ostermann M, Murugan R, Gong MN, Panwar R, Hastbacka J, Favory R, Venkatesh B, Thompson BT, Bellomo R, Jensen J, Kroll S, Chawla LS, Tidmarsh GF, Deane AM; ATHOS-3 Investigators. Angiotensin II for the Treatment of Vasodilatory Shock. N Engl J Med. 2017 Aug 3;377(5):419-430. doi: 10.1056/NEJMoa1704154. Epub 2017 May 21.

  PMID: 28528561 BACKGROUND

• Tumlin JA, Murugan R, Deane AM, Ostermann M, Busse LW, Ham KR, Kashani K, Szerlip HM, Prowle JR, Bihorac A, Finkel KW, Zarbock A, Forni LG, Lynch SJ, Jensen J, Kroll S, Chawla LS, Tidmarsh GF, Bellomo R; Angiotensin II for the Treatment of High-Output Shock 3 (ATHOS-3) Investigators. Outcomes in Patients with Vasodilatory Shock and Renal Replacement Therapy Treated with Intravenous Angiotensin II. Crit Care Med. 2018 Jun;46(6):949-957. doi: 10.1097/CCM.0000000000003092.

  PMID: 29509568 BACKGROUND

• Shim KY, Eom YW, Kim MY, Kang SH, Baik SK. Role of the renin-angiotensin system in hepatic fibrosis and portal hypertension. Korean J Intern Med. 2018 May;33(3):453-461. doi: 10.3904/kjim.2017.317. Epub 2018 Feb 21.

  PMID: 29462546 BACKGROUND

• Casey S, Schierwagen R, Mak KY, Klein S, Uschner F, Jansen C, Praktiknjo M, Meyer C, Thomas D, Herath C, Jones R, Trebicka J, Angus P. Activation of the Alternate Renin-Angiotensin System Correlates with the Clinical Status in Human Cirrhosis and Corrects Post Liver Transplantation. J Clin Med. 2019 Mar 27;8(4):419. doi: 10.3390/jcm8040419.

  PMID: 30934723 BACKGROUND

• Coleman PJ, Nissen AP, Kim DE, Ainsworth CR, McCurdy MT, Mazzeffi MA, Chow JH. Angiotensin II in Decompensated Cirrhosis Complicated by Septic Shock. Semin Cardiothorac Vasc Anesth. 2020 Sep;24(3):266-272. doi: 10.1177/1089253219877876. Epub 2019 Sep 20.

  PMID: 31540560 BACKGROUND

• Busse LW, Wang XS, Chalikonda DM, Finkel KW, Khanna AK, Szerlip HM, Yoo D, Dana SL, Chawla LS. Clinical Experience With IV Angiotensin II Administration: A Systematic Review of Safety. Crit Care Med. 2017 Aug;45(8):1285-1294. doi: 10.1097/CCM.0000000000002441.

  PMID: 28489648 BACKGROUND

• Angeli P, Gines P, Wong F, Bernardi M, Boyer TD, Gerbes A, Moreau R, Jalan R, Sarin SK, Piano S, Moore K, Lee SS, Durand F, Salerno F, Caraceni P, Kim WR, Arroyo V, Garcia-Tsao G; International Club of Ascites. Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites. Gut. 2015 Apr;64(4):531-7. doi: 10.1136/gutjnl-2014-308874. Epub 2015 Jan 28. No abstract available.

  PMID: 25631669 BACKGROUND

• Olthoff KM, Kulik L, Samstein B, Kaminski M, Abecassis M, Emond J, Shaked A, Christie JD. Validation of a current definition of early allograft dysfunction in liver transplant recipients and analysis of risk factors. Liver Transpl. 2010 Aug;16(8):943-9. doi: 10.1002/lt.22091.

  PMID: 20677285 BACKGROUND

• Pareja E, Cortes M, Hervas D, Mir J, Valdivieso A, Castell JV, Lahoz A. A score model for the continuous grading of early allograft dysfunction severity. Liver Transpl. 2015 Jan;21(1):38-46. doi: 10.1002/lt.23990. Epub 2014 Nov 24.

  PMID: 25204890 BACKGROUND

• Kellum JA, Zarbock A, Nadim MK. What endpoints should be used for clinical studies in acute kidney injury? Intensive Care Med. 2017 Jun;43(6):901-903. doi: 10.1007/s00134-017-4732-1. Epub 2017 Mar 2. No abstract available.

  PMID: 28255614 BACKGROUND

• Bellomo R, Forni LG, Busse LW, McCurdy MT, Ham KR, Boldt DW, Hastbacka J, Khanna AK, Albertson TE, Tumlin J, Storey K, Handisides D, Tidmarsh GF, Chawla LS, Ostermann M. Renin and Survival in Patients Given Angiotensin II for Catecholamine-Resistant Vasodilatory Shock. A Clinical Trial. Am J Respir Crit Care Med. 2020 Nov 1;202(9):1253-1261. doi: 10.1164/rccm.201911-2172OC.

  PMID: 32609011 BACKGROUND

• Depret F, Amzallag J, Pollina A, Fayolle-Pivot L, Coutrot M, Chaussard M, Santos K, Hartmann O, Jully M, Fratani A, Oueslati H, Cupaciu A, Benyamina M, Guillemet L, Deniau B, Mebazaa A, Gayat E, Farny B, Textoris J, Legrand M; PRONOBURN group. Circulating dipeptidyl peptidase-3 at admission is associated with circulatory failure, acute kidney injury and death in severely ill burn patients. Crit Care. 2020 Apr 22;24(1):168. doi: 10.1186/s13054-020-02888-5.

  PMID: 32321571 BACKGROUND

• Hollinger A, Wittebole X, Francois B, Pickkers P, Antonelli M, Gayat E, Chousterman BG, Lascarrou JB, Dugernier T, Di Somma S, Struck J, Bergmann A, Beishuizen A, Constantin JM, Damoisel C, Deye N, Gaudry S, Huberlant V, Marx G, Mercier E, Oueslati H, Hartmann O, Sonneville R, Laterre PF, Mebazaa A, Legrand M. Proenkephalin A 119-159 (Penkid) Is an Early Biomarker of Septic Acute Kidney Injury: The Kidney in Sepsis and Septic Shock (Kid-SSS) Study. Kidney Int Rep. 2018 Aug 22;3(6):1424-1433. doi: 10.1016/j.ekir.2018.08.006. eCollection 2018 Nov.

  PMID: 30450469 BACKGROUND

• Albert C, Zapf A, Haase M, Rover C, Pickering JW, Albert A, Bellomo R, Breidthardt T, Camou F, Chen Z, Chocron S, Cruz D, de Geus HRH, Devarajan P, Di Somma S, Doi K, Endre ZH, Garcia-Alvarez M, Hjortrup PB, Hur M, Karaolanis G, Kavalci C, Kim H, Lentini P, Liebetrau C, Lipcsey M, Martensson J, Muller C, Nanas S, Nickolas TL, Pipili C, Ronco C, Rosa-Diez GJ, Ralib A, Soto K, Braun-Dullaeus RC, Heinz J, Haase-Fielitz A. Neutrophil Gelatinase-Associated Lipocalin Measured on Clinical Laboratory Platforms for the Prediction of Acute Kidney Injury and the Associated Need for Dialysis Therapy: A Systematic Review and Meta-analysis. Am J Kidney Dis. 2020 Dec;76(6):826-841.e1. doi: 10.1053/j.ajkd.2020.05.015. Epub 2020 Jul 15.

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• Nalesso F, Cattarin L, Gobbi L, Fragasso A, Garzotto F, Calo LA. Evaluating Nephrocheck(R) as a Predictive Tool for Acute Kidney Injury. Int J Nephrol Renovasc Dis. 2020 Apr 24;13:85-96. doi: 10.2147/IJNRD.S198222. eCollection 2020.

  PMID: 32425580 BACKGROUND

• Bokoch MP, Tran AT, Brinson EL, Marcus SG, Reddy M, Sun E, Roll GR, Pardo M, Fields S, Adelmann D, Kothari RP, Legrand M. Angiotensin II in liver transplantation (AngLT-1): protocol of a randomised, double-blind, placebo-controlled trial. BMJ Open. 2023 Nov 19;13(11):e078713. doi: 10.1136/bmjopen-2023-078713.

  PMID: 37984940 DERIVED

MeSH Terms

Conditions

Vasoplegia; Fibrosis; Hypotension; Acute Kidney Injury

Interventions

Angiotensin II; Giapreza; Sodium Chloride; Saline Solution

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases; Postoperative Complications; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Angiotensins; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Nerve Tissue Proteins; Proteins; Autacoids; Inflammation Mediators; Biological Factors; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Study Officials

• Michael P Bokoch, M.D., Ph.D.

  Department of Anesthesia and Perioperative Care, University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Identically-labeled infusion bags of either angiotensin II or saline placebo will be prepared by a research pharmacist.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Randomized, double-blind, placebo-controlled.

Study Record Dates

• First Submitted: May 20, 2021
• First Posted: May 25, 2021
• Study Start: June 28, 2022
• Primary Completion: March 18, 2026
• Study Completion (Estimated): March 18, 2027
• Last Updated: March 20, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)