A Placebo-Controlled, Double-Blind Study to Confirm the Reversal of Hepatorenal Syndrome Type 1 With Terlipressin

A Multi-Center, Randomized, Placebo-controlled, Double-Blind Study to Confirm the Reversal of Hepatorenal Syndrome Type 1 With Lucassin® (Terlipressin) (The REVERSE Study)

This study is designed to evaluate the efficacy and safety of intravenous terlipressin versus placebo for the treatment of type 1 hepatorenal syndrome (HRS) in participants receiving standard of care albumin therapy.

Study Overview

• Status: Completed
• Conditions: Hepatorenal Syndrome
• Intervention / Treatment: Drug: Terlipressin; Drug: Placebo

Detailed Description

Hepatorenal syndrome is a rare syndrome of marked renal dysfunction in patients with cirrhosis, decompensated liver disease, and portal hypertension. Hepatorenal syndrome type 1 is characterized by a rapid progressive renal impairment and has a very poor prognosis with > 80% mortality within 3 months. At present, there are no approved drug therapies for HRS type 1 in the US, Australia, or Canada. The only curative treatment for HRS type 1 and the underlying end-stage cirrhosis is liver transplantation. However, many patients will not survive long enough to receive a liver transplant and therapy, which may provide a bridge to transplantation, is badly needed. Increased understanding of the pathophysiology of HRS type 1 has demonstrated that vasoconstrictive drug therapy may reverse HRS type 1. Substantial data available from many published clinical investigations in the literature provide compelling evidence suggesting that administration of terlipressin improves renal function in patients with HRS.

• Study Type: Interventional
• Enrollment (Actual): 196
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2C4
      • Toronto General Hospital
  • Quebec
    • Montreal, Quebec, Canada, H2X 3J4
      • CHUM, Hopital St-Luc
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic Arizona
    • Phoenix, Arizona, United States, 85006
      • Banner Good Samaritan Medical Center/Liver Disease Center
    • Tucson, Arizona, United States, 85713
      • University of Arizona Medical Center South Campus
    • Tucson, Arizona, United States, 85724
      • University Of Arizona Liver Research Institute
  • California
    • Colton, California, United States, 92324
      • Arrowhead Regional Medical Center
    • Coronado, California, United States, 92118
      • Scti Research Foundation
    • La Jolla, California, United States, 92037
      • Scripps Clinic
    • Los Angeles, California, United States, 90033
      • USC University Hospital
    • Sacramento, California, United States, 95817
      • UC Davis Medical Center
    • San Diego, California, United States, 92161
      • Veteran's Administration Medical Center
    • San Francisco, California, United States, 94115
      • California Pacific Medical Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Denver
  • Connecticut
    • Hartford, Connecticut, United States, 06102
      • Hartford Hospital
    • New Haven, Connecticut, United States, 06520
      • Yale University School of Medicine
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Georgetown University Hospital
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic
    • Miami, Florida, United States, 33136
      • University of Miami
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University Hospital
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
    • Chicago, Illinois, United States, 60637
      • University of Chicago
    • Maywood, Illinois, United States, 60153
      • Loyola University Medical Center
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Health - University Hospital
  • Iowa
    • Iowa City, Iowa, United States, 52246
      • Iowa City VA Health Care System
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky Chandler Medical Center
    • Louisville, Kentucky, United States, 40202
      • University of Louisville
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Tulane Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Lsrael Deaconess Medical Center
    • Burlington, Massachusetts, United States, 01805
      • Lahey Clinic Medical Center
    • Worcester, Massachusetts, United States, 01655
      • University of Massachusetts Medical Center
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55414
      • University of Minnesota
  • Missouri
    • Kansas City, Missouri, United States, 64111
      • Saint Luke's Hospital
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
    • Saint Louis, Missouri, United States, 63110
      • Saint Louis University
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska Medical Center
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • New York, New York, United States, 10016
      • Bellevue Hospital
    • New York, New York, United States, 10029
      • Mount Sinai Medical Center
    • New York, New York, United States, 10016
      • NYU Langhorn Medical Center
    • Valhalla, New York, United States, 10595
      • New York Medical College/Westchester Medical Center
  • North Carolina
    • Charlotte, North Carolina, United States, 28203
      • Carolinas Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati, Internal Medicine-Digestive Diseases
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73112
      • Integris Baptist Medical Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Orgeon Health & Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19141
      • Albert Einstein Medical Center
    • Philadelphia, Pennsylvania, United States, 19102
      • Drexel University College of Medicine
    • Philadelphia, Pennsylvania, United States, 19140
      • Temple University Hospital
    • Pittsburgh, Pennsylvania, United States, 15240
      • VA Pittsburgh Healthcare System
  • South Carolina
    • Columbia, South Carolina, United States, 29209
      • WJB Dorn VA Medical Center
  • Tennessee
    • Nashville, Tennessee, United States, 37212
      • Vanderbilt Medical Center
  • Texas
    • Dallas, Texas, United States, 75390
      • UT Southwestern Medical Center
    • Dallas, Texas, United States, 75246
      • Baylor University Medical Center
    • Dallas, Texas, United States, 75216
      • Dallas VA Medical Center
    • Fort Worth, Texas, United States, 76104
      • Baylor All Saints Medical Center
    • Galveston, Texas, United States, 77555
      • The University of Texas Medical Branch at Galveston
    • Houston, Texas, United States, 77030
      • The Methodist Hospital
    • Houston, Texas, United States, 77030
      • St. Luke's Advanced Liver Therapies
    • Houston, Texas, United States, 77030
      • University of Texas Health Science Center at Houston - Memorial Hermann Hospital
    • San Antonio, Texas, United States, 78229
      • The University of Texas Health Science Center at San Antonio
    • San Antonio, Texas, United States, 78229
      • University of Texas Health Science Center
    • San Antonio, Texas, United States, 78229
      • Methodist Specialty Transplant Hospital Lab
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah
  • Virginia
    • Richmond, Virginia, United States, 23249
      • McGuire DVAMC
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University Health System
  • Washington
    • Seattle, Washington, United States, 98101
      • Virginia Mason Medical Center
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Written informed consent by subject or legally authorized representative
2. At least 18 years of age
3. Cirrhosis and ascites

4. Rapidly progressive reduction in renal function characterized by:

   • Serum creatinine (SCr) ≥ 2.5 mg/dL
   • Doubling of SCr within 2 weeks (or for observations of shorter duration, SCr values over time meeting slope-based criteria for proportional increases likely to be representative of at least a doubling within 2 weeks
5. No sustained improvement in renal function (< 20% decrease in SCr and SCr ≥ 2.25 mg/dL) 48 hours after both diuretic withdrawal and the beginning of plasma volume expansion with albumin:

Note: Albumin doses recommended by the International Ascites Club (IAC) are 1 g/kg on the first day (Maximum 100 g) and 20 - 40 g/day thereafter as clinically indicated. It is recommended (if clinically appropriate) that the albumin dose is kept constant during the study drug administration period.

Note: The qualifying SCr value is the SCr value at least 48 hrs after both diuretic withdrawal (if applicable) and the beginning of albumin fluid challenge. The qualifying SCr value must be ≥ 2.25 mg/dL AND at least 80% of the diagnostic (pre-fluid challenge) SCr value.

Exclusion Criteria:

1. SCr > 7 mg/dL
2. Shock Note: Hypotension (Mean Arterial Pressure < 70 mm Hg or a decrease > 40 mm Hg in systolic blood pressure from baseline) with evidence of hypoperfusion abnormalities despite adequate fluid resuscitation.

3. Sepsis or systemic inflammatory response syndrome (SIRS)

   Note: SIRS: Presence of 2 or more of the following findings:

   Temperature > 38°C or < 36°C; heart rate > 90/min; respiratory rate of > 20/min or a PaCO2 of < 32 mm Hg; white blood cell count of > 12,000 cells/µL or < 4,000/ µL.

   Note: Sepsis: Documented infection and systemic inflammatory response syndrome.

4. < 2 days anti-infective therapy for documented or suspected infection
5. Proteinuria > 500 mg/day
6. Hematuria or microhematuria (> 50 red blood cells per high power field)
7. Clinically significant casts on urinalysis, including granular casts Note: Urine sediment examination is required to exclude presence of granular casts and other clinically significant casts [e.g., red blood cell (RBC) casts].
8. Evidence of intrinsic or parenchymal renal disease (including acute tubular necrosis)
9. Obstructive uropathy or other renal pathology on ultrasound or other medical imaging
10. Current or recent treatment (within 4 weeks) with nephrotoxic drugs, e.g., aminoglycosides, nonsteroidal anti-inflammatory drugs (NSAID) Note: Up to 3 doses of an NSAID within the prior month (prescription or over the counter) is acceptable Note: Use of short-term (< 2 weeks) oral neomycin for acute encephalopathy is acceptable.
11. Current or recent (within 4 weeks) renal replacement therapy
12. Superimposed acute liver failure/injury due to factors other than alcoholic hepatitis, including acute viral hepatitis, drugs, medications (e.g., acetaminophen), or other toxins (e.g., mushroom [Amanita] poisoning)
13. Current or recent treatment (within 48 hours) with octreotide, midodrine, vasopressin, dopamine or other vasopressors
14. Severe cardiovascular disease as judged by investigator
15. Estimated life expectancy of less than 3 days
16. Confirmed pregnancy
17. Known allergy or sensitivity to terlipressin or another component of the study treatment
18. Participation in other clinical research studies involving the evaluation of other investigational drugs or devices within 30 days of randomization

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Terlipressin; Participants receive terlipressin intravenously as a bolus injection, followed by a saline flush. Dose, duration, retreatment and/or discontinuation may be modified by the investigator, per protocol.	Drug: Terlipressin; Each 6 mL vial contains 1 mg lyophilized terlipressin acetate and 10 mg mannitol in sterile 0.9% sodium chloride solution.; Other Names: Lucassin®
PLACEBO_COMPARATOR: Placebo; Participants receive matching placebo intravenously as a bolus injection, followed by a saline flush. Dose, duration, retreatment and/or discontinuation may be modified by the investigator, per protocol.	Drug: Placebo; 11 mg mannitol reconstituted with 5 ml of sterile 0.9% sodium chloride solution.; Other Names: Saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Confirmed Hepatorenal Syndrome (HRS) Reversal	Confirmed HRS Reversal: The percentage of participants with two serum creatinine (SCr) values of ≤ 1.5 mg/dL at least 48 hours apart, on treatment, and without intervening renal replacement therapy or liver transplant.	within 14 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With HRS Reversal	HRS reversal is defined as at least one SCr value of ≤ 1.5 mg/dL on treatment (up to 24 hours after the last dose of study medication).	within 14 days
Percentage of Participants With Transplant-free Survival	Transplant-Free Survival up to 90 days, defined as the time (in days) that each participant survives without liver transplantation from the day of randomization.	Up to 90 days
Percentage of Participants With Overall Survival	Overall Survival up to 90 days, defined as the time (in days) that each participant survives from the day of randomization.	Up to 90 days
Percentage of Participants With Serious Adverse Events	Clinically significant changes in vital signs, height, weight, immunogenicity and laboratory assessments which qualified for the definition of serious adverse event are reported.	Up to 30 days post treatment (within 44 days)

Collaborators and Investigators

• Sponsor: Mallinckrodt

Publications and helpful links

General Publications

• Sanyal AJ, Boyer TD, Frederick RT, Wong F, Rossaro L, Araya V, Vargas HE, Reddy KR, Pappas SC, Teuber P, Escalante S, Jamil K. Reversal of hepatorenal syndrome type 1 with terlipressin plus albumin vs. placebo plus albumin in a pooled analysis of the OT-0401 and REVERSE randomised clinical studies. Aliment Pharmacol Ther. 2017 Jun;45(11):1390-1402. doi: 10.1111/apt.14052. Epub 2017 Mar 29.
• Wong F, Pappas SC, Boyer TD, Sanyal AJ, Bajaj JS, Escalante S, Jamil K; REVERSE Investigators. Terlipressin Improves Renal Function and Reverses Hepatorenal Syndrome in Patients With Systemic Inflammatory Response Syndrome. Clin Gastroenterol Hepatol. 2017 Feb;15(2):266-272.e1. doi: 10.1016/j.cgh.2016.07.016. Epub 2016 Jul 25.
• Boyer TD, Sanyal AJ, Wong F, Frederick RT, Lake JR, O'Leary JG, Ganger D, Jamil K, Pappas SC; REVERSE Study Investigators. Terlipressin Plus Albumin Is More Effective Than Albumin Alone in Improving Renal Function in Patients With Cirrhosis and Hepatorenal Syndrome Type 1. Gastroenterology. 2016 Jun;150(7):1579-1589.e2. doi: 10.1053/j.gastro.2016.02.026. Epub 2016 Feb 16.

Study record dates

Study Major Dates

• Study Start (ACTUAL): October 11, 2010
• Primary Completion (ACTUAL): February 1, 2013
• Study Completion (ACTUAL): May 10, 2013

Study Registration Dates

• First Submitted: June 11, 2010
• First Submitted That Met QC Criteria: June 11, 2010
• First Posted (ESTIMATE): June 14, 2010

Study Record Updates

• Last Update Posted (ACTUAL): November 29, 2022
• Last Update Submitted That Met QC Criteria: November 4, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: Cirrhosis; Ascites; Renal failure; Hepatorenal syndrome; Alcoholic hepatitis
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Kidney Diseases; Urologic Diseases; Disease; Liver Diseases; Syndrome; Hepatorenal Syndrome; Antihypertensive Agents; Vasoconstrictor Agents; Terlipressin
• Other Study ID Numbers: IK-4001-HRS-301

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Discussion of statistical endpoints and analysis are included in manuscripts. Summary aggregate (basic) results (including adverse events information) and the study protocol are made available on clinicaltrials.gov (NCT02770716) when required by regulation. Individual de-identified patient data will not be disclosed. Requests for additional information should be directed to the company at medinfo@mnk.com.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No