Angiotensin 2 for Hepatorenal Syndrome

NCT04048707 | Withdrawn Phase 2 FDA Drug

• 1 other identifier: #19-005718
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

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.

Conditions

Hepatorenal Syndrome; Cirrhosis; Kidney Failure, Acute

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (4)

• Need for renal replacement therapy

  4 days

• Mortality

  28 days

• Serum sodium

  4 days

• Relapse of hepatorenal syndrome

  14 days

Study Arms (2)

Midodrine/Octreotide

ACTIVE COMPARATOR

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

Drug: Midodrine; Drug: Octreotide; Drug: Albumin solution

Angiotensin 2

EXPERIMENTAL

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

Drug: Angiotensin II; Drug: Albumin solution

Interventions

Angiotensin II DRUG

Intravenous

Also known as: Giapreza

Angiotensin 2

Midodrine DRUG

Pill

Midodrine/Octreotide

Octreotide DRUG

Subcutaneous

Midodrine/Octreotide

Albumin solution DRUG

Intravenous suspension

Angiotensin 2; Midodrine/Octreotide

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of California, Los Angeles: lead

Related Publications (2)

• 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.

  PMID: 29509568 BACKGROUND

• 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.

  PMID: 29281568 BACKGROUND

MeSH Terms

Conditions

Hepatorenal Syndrome; Fibrosis; Acute Kidney Injury

Interventions

Angiotensin II; Giapreza; Midodrine; Octreotide

Condition Hierarchy (Ancestors)

Liver Diseases; Digestive System Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Renal Insufficiency

Intervention Hierarchy (Ancestors)

Angiotensins; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Nerve Tissue Proteins; Proteins; Autacoids; Inflammation Mediators; Biological Factors; Ethanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Amines; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 29, 2019
• First Posted: August 7, 2019
• Study Start: July 1, 2021
• Primary Completion: June 30, 2023
• Study Completion: July 1, 2023
• Last Updated: March 6, 2024

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will not share