Study Summary
This trial will test whether Angiotensin II is effective and safe as a second-line vasopressor during liver transplantation.
Eligible Conditions
- Liver Transplant Complications
- Vasoplegic Syndrome
Treatment Effectiveness
Effectiveness Progress
Study Objectives
1 Primary · 15 Secondary · Reporting Duration: 1 year
1 year
Patient and graft survival at 1 year after LT
3 days
Model for Early Allograft Function (MEAF) score
30 days
Major adverse kidney events (MAKE) at 30 days (MAKE-30) after LT
Patient and graft survival at 30 days after LT
48 hours
Kidney Failure, Acute
7 days
Incidence of early allograft dysfunction (EAD) by Olthoff criteria
Hour 8
Change in intraoperative urine output in mL/kg/hr before and after initiation of study drug
Dose of epinephrine administered during LT, excluding boluses within the 5 min immediately following portal reperfusion, averaged over case duration and TBW.
Dose of vasopressin administered during LT, averaged over case duration and TBW.
Proportion of patients requiring 3rd and 4th line vasopressor infusions (epinephrine or vasopressin) during LT
Time spent below target MAP (65 mmHg)
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.
Hour 4
Body Weight Changes
Up to 1 year
Duration of ICU stay after LT
Duration of hospital stay after LT
Duration of renal replacement therapy (RRT) after LT
Trial Safety
Safety Progress
This is further along than 68% of similar trials
Trial Design
2 Treatment Groups
Angiotensin II (Giapreza)
1 of 2
Saline
1 of 2
Experimental Treatment
Non-Treatment Group
50 Total Participants · 2 Treatment Groups
Primary Treatment: Angiotensin II · Has Placebo Group · Phase 2 & 3
Angiotensin II (Giapreza)
Drug
Experimental Group · 1 Intervention: Angiotensin II · Intervention Types: DrugSaline
Drug
PlaceboComparator Group · 1 Intervention: Saline · Intervention Types: DrugTreatment
First Studied
Drug Approval Stage
How many patients have taken this drug
Angiotensin II
FDA approved
Trial Logistics
Trial Timeline
Screening: ~3 weeks
Treatment: Varies
Reporting: 1 year
Who is running the clinical trial?
La Jolla Pharmaceutical CompanyIndustry Sponsor
21 Previous Clinical Trials
2,616 Total Patients Enrolled
University of California, San FranciscoLead Sponsor
2,283 Previous Clinical Trials
11,577,605 Total Patients Enrolled
Michael P Bokoch, M.D., Ph.D.Principal InvestigatorDepartment of Anesthesia and Perioperative Care, University of California, San Francisco
Erika L Brinson, M.D.Principal InvestigatorDepartment of Anesthesia and Perioperative Care, University of California, San Francisco
Eligibility Criteria
Age 18+ · All Participants · 3 Total Inclusion Criteria
Mark “Yes” if the following statements are true for you:You are 18 years of age or older.
You have a MELD-Na score of 25 or higher at the time of transplant, not counting any special exception points.
You need a dosage of greater than 0.05 micrograms per kilogram of body weight in norepinephrine (NE) during your long-term treatment.
References
- Kellum, John A., Alexander Zarbock, and Mitra K. Nadim. 2017. “What Endpoints Should Be Used for Clinical Studies in Acute Kidney Injury?”. Intensive Care Medicine. Springer Science and Business Media LLC. doi:10.1007/s00134-017-4732-1.
- Albert, Christian, Antonia Zapf, Michael Haase, Christian Röver, John W. Pickering, Annemarie Albert, Rinaldo Bellomo, et al.. 2020. “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”. American Journal of Kidney Diseases. Elsevier BV. doi:10.1053/j.ajkd.2020.05.015.
- Khanna, Ashish, Shane W. English, Xueyuan S. Wang, Kealy Ham, James Tumlin, Harold Szerlip, Laurence W. Busse, et al.. 2017. “Angiotensin II for the Treatment of Vasodilatory Shock”. New England Journal of Medicine. Massachusetts Medical Society. doi:10.1056/nejmoa1704154.
- Casey, Stephen, Robert Schierwagen, Kai Mak, Sabine Klein, Frank Uschner, Christian Jansen, Michael Praktiknjo, et al.. 2019. “Activation of the Alternate Renin-angiotensin System Correlates with the Clinical Status in Human Cirrhosis and Corrects Post Liver Transplantation”. Journal of Clinical Medicine. MDPI AG. doi:10.3390/jcm8040419.
- Nalesso, Federico, Leda Cattarin, Laura Gobbi, Antonio Fragasso, Francesco Garzotto, and Lorenzo Arcangelo Calò. 2020. “evaluating Nephrocheck® as a Predictive Tool for Acute Kidney Injury”. International Journal of Nephrology and Renovascular Disease. Informa UK Limited. doi:10.2147/ijnrd.s198222.
- Tumlin, James A., Raghavan Murugan, Adam M. Deane, Marlies Ostermann, Laurence W. Busse, Kealy R. Ham, Kianoush Kashani, et al.. 2018. “Outcomes in Patients with Vasodilatory Shock and Renal Replacement Therapy Treated with Intravenous Angiotensin II”. Critical Care Medicine. Ovid Technologies (Wolters Kluwer Health). doi:10.1097/ccm.0000000000003092.
- Angeli, Paolo, Pere Gines, Florence Wong, Mauro Bernardi, Thomas D Boyer, Alexander Gerbes, Richard Moreau, et al.. 2015. “Diagnosis and Management of Acute Kidney Injury in Patients with Cirrhosis: Revised Consensus Recommendations of the International Club of Ascites”. Gut. BMJ. doi:10.1136/gutjnl-2014-308874.
- Olthoff, Kim M., Laura Kulik, Benjamin Samstein, Mary Kaminski, Michael Abecassis, Jean Emond, Abraham Shaked, and Jason D. Christie. 2010. “Validation of a Current Definition of Early Allograft Dysfunction in Liver Transplant Recipients and Analysis of Risk Factors”. Liver Transplantation. Wiley. doi:10.1002/lt.22091.
- Bellomo, Rinaldo, Lui G. Forni, Laurence W. Busse, Michael T. McCurdy, Kealy R. Ham, David W. Boldt, Johanna Hästbacka, et al.. 2020. “Renin and Survival in Patients Given Angiotensin II for Catecholamine-resistant Vasodilatory Shock. A Clinical Trial”. American Journal of Respiratory and Critical Care Medicine. American Thoracic Society. doi:10.1164/rccm.201911-2172oc.
- Dépret, François, for the PRONOBURN group, Juliette Amzallag, Adrien Pollina, Laure Fayolle-Pivot, Maxime Coutrot, Maïté Chaussard, et al.. 2020. “Circulating Dipeptidyl Peptidase-3 at Admission Is Associated with Circulatory Failure, Acute Kidney Injury and Death in Severely Ill Burn Patients”. Critical Care. Springer Science and Business Media LLC. doi:10.1186/s13054-020-02888-5.
- Shim, Kwang Yong, Young Woo Eom, Moon Young Kim, Seong Hee Kang, and Soon Koo Baik. 2018. “Role of the Renin-angiotensin System in Hepatic Fibrosis and Portal Hypertension”. The Korean Journal of Internal Medicine. Korean Association of Internal Medicine. doi:10.3904/kjim.2017.317.
- Busse, Laurence W., Xueyuan Shelly Wang, Divya M. Chalikonda, Kevin W. Finkel, Ashish K. Khanna, Harold M. Szerlip, David Yoo, Sharon L. Dana, and Lakhmir S. Chawla. 2017. “Clinical Experience with IV Angiotensin II Administration”. Critical Care Medicine. Ovid Technologies (Wolters Kluwer Health). doi:10.1097/ccm.0000000000002441.
- Hollinger, Alexa, Xavier Wittebole, Bruno François, Peter Pickkers, Massimo Antonelli, Etienne Gayat, Benjamin Glenn Chousterman, et al.. 2018. “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 International Reports. Elsevier BV. doi:10.1016/j.ekir.2018.08.006.
- Coleman, Patrick J., Alexander P. Nissen, Daniel E. Kim, Craig R. Ainsworth, Michael T. McCurdy, Michael A. Mazzeffi, and Jonathan H. Chow. 2019. “Angiotensin II in Decompensated Cirrhosis Complicated by Septic Shock”. Seminars in Cardiothoracic and Vascular Anesthesia. SAGE Publications. doi:10.1177/1089253219877876.
- Pareja, Eugenia, Miriam Cortes, David Hervás, José Mir, Andrés Valdivieso, José V. Castell, and Agustín Lahoz. 2014. “A Score Model for the Continuous Grading of Early Allograft Dysfunction Severity”. Liver Transplantation. Wiley. doi:10.1002/lt.23990.
- 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.
- 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. Erratum In: Kidney Int Rep. 2018 Nov 17;4(1):187.
- 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.
- 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.
- 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. Erratum In: Crit Care Med. 2018 Aug;46(8):e824.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 2022. "Angiotensin II in Liver Transplantation". ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04901169.
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