Angiotensin 2 for Hepatorenal Syndrome

Study Overview
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Brief Summary
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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.

Official Title
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Angiotensin 2 as a Novel Treatment for Hepatorenal Syndrome

Conditions
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Hepatorenal Syndrome, Cirrhosis, Kidney Failure, Acute

Intervention / Treatment
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* Drug: Angiotensin II
* Drug: Midodrine
* Drug: Octreotide
* Drug: Albumin solution


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Midodrine/Octreotide<br>This arm will receive standard of care treatment of midodrine, octreotide, and albumin. | Drug: Midodrine<br>* Pill<br>Drug: Octreotide<br>* Subcutaneous<br>Drug: Albumin solution<br>* Intravenous suspension<br>|
| Experimental: Angiotensin 2<br>This arm will receive the experimental treatment of angiotensin 2 infusion and albumin. | Drug: Angiotensin II<br>* Intravenous<br>* Other names: Giapreza;Drug: Albumin solution<br>* Intravenous suspension<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| Mortality | In-hospital mortality | 28 days | 
| Serum sodium | Change in serum sodium from the beginning of the study to the end of the study. | 4 days | 
| 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 |