Angiotensin 2 for Hepatorenal Syndrome

Cirrhosis Clinical Trial

— ANTHEM  

Official title:

Angiotensin 2 as a Novel Treatment for Hepatorenal Syndrome

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT04048707
• Other study ID #: #19-005718
• Status: Withdrawn
• Phase: Phase 2
• Start date: July 1, 2021
• Est. completion date: July 1, 2023

Study information

• Verified date: March 2024
• Source: University of California, Los Angeles
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Hepatorenal syndrome (HRS) is a disease in which patients with cirrhosis (end stage liver failure) develop secondary kidney injury and failure. The current treatment available in the United States is a combination of octreotide and midodrine, which are meant to decrease the release of those hormones and raise the blood pressure, respectively, which would increase blood flow to the kidneys. Angiotensin 2 (Ang2) is a new vasopressor drug that was approved by the FDA in December 2017 for patients with low blood pressure and has been shown to have similar effects to octreotide and midodrine. This study will investigate whether Ang2 reverses HRS among patients admitted to the intensive care unit (ICU) at Ronald Reagan Medical Center. Our study population will be patients with HRS who are already or will be admitted to the ICU. HRS will be defined by new internationally accepted guidelines published by the International Club of Ascites. All patients who are consented will undergo an Ang2 response trial, where low-dose Ang2 will be administered for 4 hours to see how the patients respond. This will help us characterize the nature of the patients' kidney failure for later analysis. Patients will then be randomized into the control group or the study group. Patients in the control group will receive octreotide (a subcutaneous injection) and midodrine (an oral drug). Patients in the study group will continue receiving intravenous infusion of Ang2. Patients in both groups will also receive albumin, a protein found commonly in human blood. Treatment will continue in both groups for four days, until complete reversal of HRS, dialysis, or death. Our primary outcome will be rate of reversal of HRS, defined as improvement in kidney function.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: July 1, 2023
• Est. primary completion date: June 30, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria: Patients in the ICU with HRS-AKI defined as

• Acute kidney injury defined as an increase in serum creatinine (sCr) >=0.3 mg/dl or >=50% from baseline within 7 days
• Presence of cirrhosis and ascites
• Absence of other causes such as shock, nephrotoxic drugs, or other suspected causes of kidney injury.
• Lack of response to diuretic withdrawal and albumin challenge of 1 g/kg of body weight

Exclusion Criteria:

• Age <18 years
• Current or anticipated (within 24 hours) need for renal replacement therapy (RRT)
• Cr > 6 mg/dl
• Renal transplantation status
• Fractional Excretion of Sodium (FeNa) > 2%
• Pregnancy
• Recent Cerebrovascular Accident (CVA), Myocardial Infarction (MI), venous or arterial thrombosis (within last 3 months)
• Known hypercoagulable state other than cirrhosis
• Uncontrolled hypertension (SBP > 160)
• Anticipated mortality within 72 hours
• Inability to obtain consent.

Related Conditions & MeSH terms

• Acute Kidney Injury
• Cirrhosis
• Hepatorenal Syndrome
• Kidney Failure, Acute
• Renal Insufficiency
• Syndrome

Intervention

Drug:
• Angiotensin II
Intravenous
• Midodrine
Pill
• Octreotide
Subcutaneous
• Albumin solution
Intravenous suspension

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
University of California, Los Angeles

References & Publications (2)

Khanna A, Ostermann M, Bellomo R. Angiotensin II for the Treatment of Vasodilatory Shock. N Engl J Med. 2017 Dec 28;377(26):2604. doi: 10.1056/NEJMc1714511. No abstract available. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Reversal of hepatorenal syndrome	Partial or complete reversal of HRS. Serum creatinine will be measured daily and compared against the patient's baseline creatinine.; Partial reversal is defined defined as improvement of at least one AKI stage as defined by International Club of Ascites Acute Kidney Injury (ICA-AKI) criteria Complete defined as improvement of serum creatinine to within 0.3 mg/dl of baseline value).; ICA-AKI criteria: Stage 1: increase in sCr =0.3 mg/dl (26.5 µmol/L) or an increase in sCr =1.5-fold to 2-fold from baseline; Stage 2: increase in sCr >2-fold to 3-fold from baseline; Stage 3: increase of sCr >3-fold from baseline or sCr =4.0 mg/dl (353.6 µmol/L) with an acute increase =0.3 mg/dl (26.5 µmol/L) or initiation of renal replacement therapy Angeli P et al. J Hepatology 2015:62(968-974)	4 days
Secondary	Need for renal replacement therapy	The treating team with the assistance of nephrology will assess the acute need for dialysis on a daily basis. If the patient does require urgent hemodialysis at their determination, this will be noted. The proportion of each group who required hemodialysis will be compared.	4 days
Secondary	Mortality	In-hospital mortality	28 days
Secondary	Serum sodium	Change in serum sodium from the beginning of the study to the end of the study.	4 days
Secondary	Relapse of hepatorenal syndrome	Recurrence of HRS-AKI after withdrawal of study drug, defined as a worsening of AKI by at least one stage according to ICA-AKI criteria AKI grade as defined by ICA-AKI criteria (J Hepatology 2015:62[968-974])	14 days