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Angiotensin 2 for Hepatorenal Syndrome (ANTHEM)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04048707
Recruitment Status : Not yet recruiting
First Posted : August 7, 2019
Last Update Posted : September 11, 2020
Sponsor:
Information provided by (Responsible Party):
Michael Lin, University of California, Los Angeles

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

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Study Type : Interventional  (Clinical Trial)
Estimated 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
Estimated Study Start Date : July 1, 2021
Estimated Primary Completion Date : June 30, 2023
Estimated Study Completion Date : July 1, 2023


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 Name: Giapreza

Drug: Albumin solution
Intravenous suspension




Primary Outcome Measures :
  1. Reversal of hepatorenal syndrome [ Time Frame: 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 :
  1. Need for renal replacement therapy [ Time Frame: 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.

  2. Mortality [ Time Frame: 28 days ]
    In-hospital mortality

  3. Serum sodium [ Time Frame: 4 days ]
    Change in serum sodium from the beginning of the study to the end of the study.

  4. Relapse of hepatorenal syndrome [ Time Frame: 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])



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04048707


Contacts
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Contact: Michael Y Lin, MD 3102678678 mylin@mednet.ucla.edu

Sponsors and Collaborators
University of California, Los Angeles
Publications:
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Responsible Party: Michael Lin, Principal Investigator, University of California, Los Angeles
ClinicalTrials.gov Identifier: NCT04048707    
Other Study ID Numbers: #19-005718
First Posted: August 7, 2019    Key Record Dates
Last Update Posted: September 11, 2020
Last Verified: September 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Additional relevant MeSH terms:
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Hepatorenal Syndrome
Renal Insufficiency
Acute Kidney Injury
Syndrome
Disease
Pathologic Processes
Kidney Diseases
Urologic Diseases
Liver Diseases
Digestive System Diseases
Octreotide
Midodrine
Angiotensin II
Giapreza
Angiotensinogen
Gastrointestinal Agents
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Sympathomimetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Vasoconstrictor Agents
Adrenergic alpha-1 Receptor Agonists
Adrenergic alpha-Agonists
Adrenergic Agonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Serine Proteinase Inhibitors