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)
1 other identifier
interventional
196
2 countries
73
Brief Summary
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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P25-P50 for phase_3
Started Oct 2010
Typical duration for phase_3
73 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
June 11, 2010
CompletedFirst Posted
Study publicly available on registry
June 14, 2010
CompletedStudy Start
First participant enrolled
October 11, 2010
CompletedPrimary Completion
Last participant's last visit for primary outcome
February 1, 2013
CompletedStudy Completion
Last participant's last visit for all outcomes
May 10, 2013
CompletedResults Posted
Study results publicly available
November 29, 2022
CompletedNovember 29, 2022
November 1, 2022
2.3 years
June 11, 2010
July 22, 2022
November 4, 2022
Conditions
Keywords
Outcome Measures
Primary Outcomes (1)
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 Outcomes (4)
Percentage of Participants With HRS Reversal
within 14 days
Percentage of Participants With Transplant-free Survival
Up to 90 days
Percentage of Participants With Overall Survival
Up to 90 days
Percentage of Participants With Serious Adverse Events
Up to 30 days post treatment (within 44 days)
Study Arms (2)
Terlipressin
EXPERIMENTALParticipants 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.
Placebo
PLACEBO COMPARATORParticipants 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.
Interventions
Each 6 mL vial contains 1 mg lyophilized terlipressin acetate and 10 mg mannitol in sterile 0.9% sodium chloride solution.
11 mg mannitol reconstituted with 5 ml of sterile 0.9% sodium chloride solution.
Eligibility Criteria
You may qualify if:
- Written informed consent by subject or legally authorized representative
- At least 18 years of age
- Cirrhosis and ascites
- 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
- 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.
You may not qualify if:
- SCr \> 7 mg/dL
- 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.
- 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.
- \< 2 days anti-infective therapy for documented or suspected infection
- Proteinuria \> 500 mg/day
- Hematuria or microhematuria (\> 50 red blood cells per high power field)
- 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 \[e.g., red blood cell (RBC) casts\].
- Evidence of intrinsic or parenchymal renal disease (including acute tubular necrosis)
- Obstructive uropathy or other renal pathology on ultrasound or other medical imaging
- 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.
- Current or recent (within 4 weeks) renal replacement therapy
- 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)
- +6 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- Mallinckrodtlead
Study Sites (73)
University of Alabama at Birmingham
Birmingham, Alabama, 35294, United States
Banner Good Samaritan Medical Center/Liver Disease Center
Phoenix, Arizona, 85006, United States
Mayo Clinic Arizona
Phoenix, Arizona, 85054, United States
University of Arizona Medical Center South Campus
Tucson, Arizona, 85713, United States
University of Arizona Liver Research Institute
Tucson, Arizona, 85724, United States
Arrowhead Regional Medical Center
Colton, California, 92324, United States
SCTI Research Foundation
Coronado, California, 92118, United States
Scripps Clinic
La Jolla, California, 92037, United States
USC University Hospital
Los Angeles, California, 90033, United States
UC Davis Medical Center
Sacramento, California, 95817, United States
Veteran's Administration Medical Center
San Diego, California, 92161, United States
California Pacific Medical Center
San Francisco, California, 94115, United States
University of Colorado Denver
Aurora, Colorado, 80045, United States
Hartford Hospital
Hartford, Connecticut, 06102, United States
Yale University School of Medicine
New Haven, Connecticut, 06520, United States
Georgetown University Hospital
Washington D.C., District of Columbia, 20007, United States
Mayo Clinic
Jacksonville, Florida, 32224, United States
University of Miami
Miami, Florida, 33136, United States
Emory University Hospital
Atlanta, Georgia, 30322, United States
Northwestern University
Chicago, Illinois, 60611, United States
University of Chicago
Chicago, Illinois, 60637, United States
Loyola University Medical Center
Maywood, Illinois, 60153, United States
Indiana University Health - University Hospital
Indianapolis, Indiana, 46202, United States
Iowa City VA Health Care System
Iowa City, Iowa, 52246, United States
University of Kansas Medical Center
Kansas City, Kansas, 66160, United States
University of Kentucky Chandler Medical Center
Lexington, Kentucky, 40536, United States
University of Louisville
Louisville, Kentucky, 40202, United States
Tulane Medical Center
New Orleans, Louisiana, 70112, United States
University of Maryland
Baltimore, Maryland, 21201, United States
Beth Lsrael Deaconess Medical Center
Boston, Massachusetts, 02215, United States
Lahey Clinic Medical Center
Burlington, Massachusetts, 01805, United States
University of Massachusetts Medical Center
Worcester, Massachusetts, 01655, United States
Henry Ford Hospital
Detroit, Michigan, 48202, United States
University of Minnesota
Minneapolis, Minnesota, 55414, United States
Saint Luke's Hospital
Kansas City, Missouri, 64111, United States
Saint Louis University
St Louis, Missouri, 63110, United States
Washington University School of Medicine
St Louis, Missouri, 63110, United States
University of Nebraska Medical Center
Omaha, Nebraska, 68198, United States
Bellevue Hospital
New York, New York, 10016, United States
NYU Langhorn Medical Center
New York, New York, 10016, United States
Mount Sinai Medical Center
New York, New York, 10029, United States
Columbia University Medical Center
New York, New York, 10032, United States
New York Medical College/Westchester Medical Center
Valhalla, New York, 10595, United States
Carolinas Medical Center
Charlotte, North Carolina, 28203, United States
University of Cincinnati, Internal Medicine-Digestive Diseases
Cincinnati, Ohio, 45267, United States
Cleveland Clinic
Cleveland, Ohio, 44195, United States
INTEGRIS Baptist Medical Center
Oklahoma City, Oklahoma, 73112, United States
Orgeon Health & Science University
Portland, Oregon, 97239, United States
Drexel University College of Medicine
Philadelphia, Pennsylvania, 19102, United States
University of Pennsylvania
Philadelphia, Pennsylvania, 19104, United States
Temple University Hospital
Philadelphia, Pennsylvania, 19140, United States
Albert Einstein Medical Center
Philadelphia, Pennsylvania, 19141, United States
VA Pittsburgh Healthcare System
Pittsburgh, Pennsylvania, 15240, United States
WJB Dorn VA Medical Center
Columbia, South Carolina, 29209, United States
Vanderbilt Medical Center
Nashville, Tennessee, 37212, United States
Dallas VA Medical Center
Dallas, Texas, 75216, United States
Baylor University Medical Center
Dallas, Texas, 75246, United States
UT Southwestern Medical Center
Dallas, Texas, 75390, United States
Baylor All Saints Medical Center
Fort Worth, Texas, 76104, United States
The University of Texas Medical Branch at Galveston
Galveston, Texas, 77555, United States
St. Luke's Advanced Liver Therapies
Houston, Texas, 77030, United States
The Methodist Hospital
Houston, Texas, 77030, United States
University of Texas Health Science Center at Houston - Memorial Hermann Hospital
Houston, Texas, 77030, United States
Methodist Specialty Transplant Hospital Lab
San Antonio, Texas, 78229, United States
The University of Texas Health Science Center at San Antonio
San Antonio, Texas, 78229, United States
University of Texas Health Science Center
San Antonio, Texas, 78229, United States
University of Utah
Salt Lake City, Utah, 84132, United States
McGuire DVAMC
Richmond, Virginia, 23249, United States
Virginia Commonwealth University Health System
Richmond, Virginia, 23298, United States
Virginia Mason Medical Center
Seattle, Washington, 98101, United States
University of Wisconsin
Madison, Wisconsin, 53792, United States
Toronto General Hospital
Toronto, Ontario, M5G 2C4, Canada
CHUM, Hopital St-Luc
Montreal, Quebec, H2X 3J4, Canada
Related Publications (7)
Bajaj JS, Kwo P, Pappas SC, O'Leary JG, Jamil K, Cardoza S, Wong F. Bradycardia and Other Arrhythmias in Patients With Hepatorenal Syndrome-Acute Kidney Injury Following Terlipressin Treatment: A Pooled Analysis of Three North American Phase III Clinical Studies. Aliment Pharmacol Ther. 2025 Dec;62(11-12):1192-1201. doi: 10.1111/apt.70297. Epub 2025 Jul 24.
PMID: 40704461DERIVEDMujtaba MA, Gamilla-Crudo AK, Merwat SN, Hussain SA, Kueht M, Karim A, Khattak MW, Rooney PJ, Jamil K. Terlipressin in combination with albumin as a therapy for hepatorenal syndrome in patients aged 65 years or older. Ann Hepatol. 2023 Sep-Oct;28(5):101126. doi: 10.1016/j.aohep.2023.101126. Epub 2023 Jun 10.
PMID: 37302573DERIVEDVelez JCQ, Wong F, Reddy KR, Sanyal AJ, Vargas HE, Curry MP, Gonzalez SA, Pappas SC, Jamil K. The Effect of Terlipressin on Renal Replacement Therapy in Patients with Hepatorenal Syndrome. Kidney360. 2023 Aug 1;4(8):1030-1038. doi: 10.34067/KID.0000000000000132. Epub 2023 May 5.
PMID: 37143199DERIVEDCurry MP, Vargas HE, Befeler AS, Pyrsopoulos NT, Patwardhan VR, Jamil K. Early treatment with terlipressin in patients with hepatorenal syndrome yields improved clinical outcomes in North American studies. Hepatol Commun. 2023 Jan 3;7(1):e1307. doi: 10.1097/01.HC9.0000897228.91307.0c. eCollection 2023 Jan 1.
PMID: 36633470DERIVEDSanyal 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.
PMID: 28370090DERIVEDWong 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.
PMID: 27464593DERIVEDBoyer 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.
PMID: 26896734DERIVED
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Results Point of Contact
- Title
- Medical Information Call Center
- Organization
- Mallinckrodt
Study Officials
- STUDY DIRECTOR
Clinical Team Leader
Mallinckrodt
Publication Agreements
- PI is Sponsor Employee
- No
- Restriction Type
- OTHER
- Restrictive Agreement
- Yes
Study Design
- Study Type
- interventional
- Phase
- phase 3
- Allocation
- RANDOMIZED
- Masking
- DOUBLE
- Who Masked
- PARTICIPANT, INVESTIGATOR
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- INDUSTRY
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
June 11, 2010
First Posted
June 14, 2010
Study Start
October 11, 2010
Primary Completion
February 1, 2013
Study Completion
May 10, 2013
Last Updated
November 29, 2022
Results First Posted
November 29, 2022
Record last verified: 2022-11
Data Sharing
- IPD Sharing
- Will not share
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.