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Angiotensin 2 for AKI After OLT

Primary Purpose

Cirrhosis, Liver, End Stage Liver DIsease, Acute Kidney Injury

Status
Enrolling by invitation
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Angiotensin II
Norepinephrine
Sponsored by
University of California, Los Angeles
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Cirrhosis, Liver

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

A. End stage liver disease (ESLD) with acceptance of organ allocation offer. B. Stable renal function in the 48 hours prior to transplant (defined as < 30% change in serum creatinine) C. Adult patients > 18 years old

Exclusion Criteria:

A. Active use of renal replacement therapies B. Recent (within last 3 months) history of CVA or MI C. Patients with hypercoagulable state as evidenced by pre-existing venous thromboembolism or known thrombophilia (Antiphospholipid syndrome, Factor V- Leiden etc.) D. Combined liver transplant and intrathoracic surgery cases (not including chest tube placement) E. Multiple organ transplantation F. Congestive heart failure defined as left ventricular ejection fraction <45% G. Inability to obtain consent from the patient or surrogate H. Known allergy or sensitivity to any study medication I. Hepatocellular Carcinoma

Sites / Locations

  • Michael Y Lin

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Intervention

Control

Arm Description

Patients assigned to the study group will receive Ang 2 infusion in addition to standard vasopressor regimen. Ang 2 is currently approved at UCLA as a second line vasopressor and will be used as such for the purposes of our study. Hemodynamic goals will be established at the beginning of the case by the anesthesiology and surgical teams. Ang 2 will be started as a second vasopressor once the norepinephrine dose has reached 0.05mcg/kg/min. Ang 2 will be initiated at a starting dose of 5ng/kg/min. That dose will be up titrated one time to 10ng/kg/min as vasopressor requirements escalate. Once a patient is on the 10ng/kg/min dose of ang 2, no additional up titration will be performed. Hemodynamic management will continue throughout the case with titration of other vasopressors as needed. Ang 2 will be continued throughout the intraoperative period but will be weaned off prior to leaving the operating room.

Patients assigned to the control group will undergo intraoperative management with a standard vasopressor regimen composed of norepinephrine, vasopressin and epinephrine based on hemodynamic goals established by the surgical and anesthesia teams prior to surgery.

Outcomes

Primary Outcome Measures

Incidence of Acute kidney Injury
Measured by change in serum creatinine from baseline based on KDIGO criteria.

Secondary Outcome Measures

Need for Renal Replacement therapies
In hospital mortalituy
Urine output
Urine output measured in ml
Vasopressor doses
Vasopressor doses evaluated as norepinephrine equivalents
Adverse events
deep vein thrombosis, pulmonary embolus, intracardiac thrombus, stroke, myocardial infarction, peripheral ischemia, hepatic artery thrombosis, mesenteric ischemia, infusion site reaction, new infection, intraoperative tachycardia, intraoperative acidosis, lactatemia

Full Information

First Posted
October 14, 2020
Last Updated
April 17, 2023
Sponsor
University of California, Los Angeles
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1. Study Identification

Unique Protocol Identification Number
NCT04592744
Brief Title
Angiotensin 2 for AKI After OLT
Official Title
Intraoperative Angiotensin 2 for the Prevention of Kidney Injury After Liver Transplant
Study Type
Interventional

2. Study Status

Record Verification Date
April 2023
Overall Recruitment Status
Enrolling by invitation
Study Start Date
April 8, 2022 (Actual)
Primary Completion Date
September 2023 (Anticipated)
Study Completion Date
December 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of California, Los Angeles

4. Oversight

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
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Kidney injury is a common complication following liver transplantation and is associated with a higher complication rate and increased risk of death. While there are many factors that likely contribute to kidney injury in the perioperative period, a relative low serum level of angiotensin 2 (Ang 2) (a protein hormone that causes blood vessels to narrow) found in patients with liver cirrhosis (late stage of liver damage) may increase their risk of developing acute kidney injury (sudden episode of kidney failure or damage). We propose to investigate how early administration of Ang 2, a new vasopressor drug approved by the FDA in December 2017 for patients with low blood pressure, during the intra-operative period of liver transplant surgery affects the rate of kidney injury after transplantation. Patients who are deemed appropriate candidates for the study will be randomized 1:1 to the treatment and control groups. The intervention period of the study will occur in the operating room during transplant surgery and will be performed by their anesthesiologists. In the Treatment group, patients will receive Ang 2 infusions in addition to other standard vasopressors while patients in the control group will receive standard vasopressors alone. The infusion of Ang 2 in the treatment group will continue through the duration of the surgery and will be stopped prior to leaving the operating room. Both the treatment group and the control group will then be followed for 14 days to evaluate rates of kidney injury and to look for any complications. The follow up period will be extended to 28 days to look at in-hospital mortality rates in both groups. The daily follow up analysis will occur while the enrolled patients are inpatient following their transplantation surgery and will be done by looking at lab values and other data that is routinely gathered by their managing teams. This study will serve as a pilot study to evaluate feasibility of our protocol and to collect some preliminary data on the use of Ang 2 in this patient population. As such we plan to enroll approximately 30 patients who have accepted an offer to receive a donor liver. We hope to reach our goal enrollment within 5 months of starting the study.
Detailed Description
Acute kidney injury is a common perioperative complication following liver transplantation with an incidence of approximately 55%. Due to the complex physiologic derangements present in cirrhotic patients, multiple etiologies and processes may contribute, including chronic and acute hepatorenal syndrome, ATN, renal toxic medication administration, microvascular circulatory dysfunction from vasopressors, and hypoperfusion from the vasodilatory and hypovolemic forms of shock that are common during liver transplantation. While some of the risk factors for these causes of AKI can be mitigated, our current area of investigation revolves around the modulation of the renin-angiotensin system in the prevention of perioperative AKI. In cirrhosis, poor renal blood flow causes an increase in circulating levels plasma renin. However, recent studies suggest low levels of angiotensinogen and angiotensin 2, which are associated with AKI in cirrhotic patients5 and may contribute to the risk of perioperative AKI in liver transplant patients. Angiotensin 2 was approved for clinical use as a vasopressor in 2017. The efficacy of angiotensin 2 at increasing systemic blood pressure in patients with vasodilatory shock was demonstrated by the ATHOS 3 trial. This study found that the addition of angiotensin 2 increased MAP by close to 10mmHg compared to placebo (12.5 vs 2.9 mmHg p< 0.001) and allowed for a decrease in other vasopressor utilization. Post-hoc analysis of the ATHOS-3 trial by Tumlin et al demonstrated that patients in vasodilatory shock with AKI had higher rates of recovery from AKI and fewer days requiring dialysis than those who did not receive angiotensin 2. As vasodilatory shock is common among patients undergoing LT, this finding is relevant to our patient population. We hypothesize that angiotensin 2 will reduce AKI in patients undergoing LT, where vasodilatory shock is also very common. Hypothesis: We propose that a relative deficiency of angiotensin 2 predisposes cirrhotic patients to develop acute kidney injury following liver transplantation. We hypothesize that initiating angiotensin 2 infusion as a short duration infusion during the intra-operative period of liver transplant surgery will decrease the incidence of postoperative acute kidney injury. Aim1: Evaluate the efficacy of Angiotensin 2 to reduce incidence of acute kidney injury (AKI) following liver transplantation. Rates of recovery from AKI in patients with septic shock have been established in post-hoc analysis of the ATHOS-3 study. With high rates of AKI following transplant surgery as well as a patient population with predisposition for AKI in part due to a relative angiotensin 2 deficiency, we hope to demonstrate that the addition of angiotensin 2 to standard vasopressor regimens during transplant surgery decreases the incidence of postoperative AKI. Aim 2: Evaluate the safety of angiotensin 2 in cirrhotic patients. While cirrhotic patients were included in the two largest studies of synthetic angiotensin 2 (ATHOS-1 and ATHOS-3), those with MELD > 40 were excluded, and no specific subgroup analysis was done. While several case reports of safe administration of angiotensin 2 in patients with cirrhosis have been published, we hope to further investigate its safety during liver transplant surgery. We hypothesize that angiotensin 2 can safely be administered in cirrhotic patients

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cirrhosis, Liver, End Stage Liver DIsease, Acute Kidney Injury, Liver Transplant; Complications

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Model Description
Patients will be randomized to the intervention group receiving angiotensin 2 in addition to standard vasopressors or to the control group in which patients will receive standard vasopressors alone.
Masking
None (Open Label)
Allocation
Randomized
Enrollment
30 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Intervention
Arm Type
Experimental
Arm Description
Patients assigned to the study group will receive Ang 2 infusion in addition to standard vasopressor regimen. Ang 2 is currently approved at UCLA as a second line vasopressor and will be used as such for the purposes of our study. Hemodynamic goals will be established at the beginning of the case by the anesthesiology and surgical teams. Ang 2 will be started as a second vasopressor once the norepinephrine dose has reached 0.05mcg/kg/min. Ang 2 will be initiated at a starting dose of 5ng/kg/min. That dose will be up titrated one time to 10ng/kg/min as vasopressor requirements escalate. Once a patient is on the 10ng/kg/min dose of ang 2, no additional up titration will be performed. Hemodynamic management will continue throughout the case with titration of other vasopressors as needed. Ang 2 will be continued throughout the intraoperative period but will be weaned off prior to leaving the operating room.
Arm Title
Control
Arm Type
Active Comparator
Arm Description
Patients assigned to the control group will undergo intraoperative management with a standard vasopressor regimen composed of norepinephrine, vasopressin and epinephrine based on hemodynamic goals established by the surgical and anesthesia teams prior to surgery.
Intervention Type
Drug
Intervention Name(s)
Angiotensin II
Intervention Description
Angiotensin II infusion for Intraoperative management during liver transplantation
Intervention Type
Drug
Intervention Name(s)
Norepinephrine
Other Intervention Name(s)
Vasopressin, Epinephrine
Intervention Description
Vasopressor infusion for management of Intraoperative hypotension in liver transplantation.
Primary Outcome Measure Information:
Title
Incidence of Acute kidney Injury
Description
Measured by change in serum creatinine from baseline based on KDIGO criteria.
Time Frame
Every day for 14 days following intervention
Secondary Outcome Measure Information:
Title
Need for Renal Replacement therapies
Time Frame
Every day for 14 days following intervention
Title
In hospital mortalituy
Time Frame
28 days
Title
Urine output
Description
Urine output measured in ml
Time Frame
14 days
Title
Vasopressor doses
Description
Vasopressor doses evaluated as norepinephrine equivalents
Time Frame
14 days
Title
Adverse events
Description
deep vein thrombosis, pulmonary embolus, intracardiac thrombus, stroke, myocardial infarction, peripheral ischemia, hepatic artery thrombosis, mesenteric ischemia, infusion site reaction, new infection, intraoperative tachycardia, intraoperative acidosis, lactatemia
Time Frame
14 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: A. End stage liver disease (ESLD) with acceptance of organ allocation offer. B. Stable renal function in the 48 hours prior to transplant (defined as < 30% change in serum creatinine) C. Adult patients > 18 years old Exclusion Criteria: A. Active use of renal replacement therapies B. Recent (within last 3 months) history of CVA or MI C. Patients with hypercoagulable state as evidenced by pre-existing venous thromboembolism or known thrombophilia (Antiphospholipid syndrome, Factor V- Leiden etc.) D. Combined liver transplant and intrathoracic surgery cases (not including chest tube placement) E. Multiple organ transplantation F. Congestive heart failure defined as left ventricular ejection fraction <45% G. Inability to obtain consent from the patient or surrogate H. Known allergy or sensitivity to any study medication I. Hepatocellular Carcinoma
Facility Information:
Facility Name
Michael Y Lin
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
28528561
Citation
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.
Results Reference
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PubMed Identifier
29509568
Citation
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.
Results Reference
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Angiotensin 2 for AKI After OLT

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