ANTHEM: Angiotensin 2 for Hepatorenal Syndrome

Sponsor

University of California, Los Angeles (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT04048707

Collaborator

(none)

Enrollment

Arms

Anticipated Duration (Months)

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Hepatorenal Syndrome Cirrhosis Kidney Failure, Acute	Drug: Angiotensin II Drug: Midodrine Drug: Octreotide Drug: Albumin solution	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

48 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Angiotensin 2 as a Novel Treatment for Hepatorenal Syndrome

Anticipated Study Start Date :

Jul 1, 2021

Anticipated Primary Completion Date :

Jun 30, 2023

Anticipated Study Completion Date :

Jul 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Midodrine/Octreotide This arm will receive standard of care treatment of midodrine, octreotide, and albumin.	Drug: Midodrine Pill Drug: Octreotide Subcutaneous Drug: Albumin solution Intravenous suspension
Experimental: Angiotensin 2 This arm will receive the experimental treatment of angiotensin 2 infusion and albumin.	Drug: Angiotensin II Intravenous Other Names: Giapreza Drug: Albumin solution Intravenous suspension

Arm

Intervention/Treatment

Active Comparator: Midodrine/Octreotide

This arm will receive standard of care treatment of midodrine, octreotide, and albumin.

Drug: Midodrine

Pill

Drug: Octreotide

Subcutaneous

Drug: Albumin solution

Intravenous suspension

Experimental: Angiotensin 2

This arm will receive the experimental treatment of angiotensin 2 infusion and albumin.

Drug: Angiotensin II

Intravenous

Other Names:

Giapreza

Drug: Albumin solution

Intravenous suspension

Outcome Measures

Primary Outcome Measures

Reversal of hepatorenal syndrome [4 days]
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)

Secondary Outcome Measures

Need for renal replacement therapy [4 days]
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.
Mortality [28 days]
In-hospital mortality
Serum sodium [4 days]
Change in serum sodium from the beginning of the study to the end of the study.
Relapse of hepatorenal syndrome [14 days]
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])

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.