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Hepatorenal SyndromePhase 3NCT01143246

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

A Phase 3 study testing Terlipressin in people with Hepatorenal Syndrome, run by Mallinckrodt at 73 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Hepatorenal Syndrome
What is being tested?
Terlipressin
Type of treatment
Injection or infusion
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
196 participants
Where
73 sitesin 2 countries
Study dates
11 Oct 2010to 10 May 2013
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
Show all 9Show fewer
  • 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.

Who cannot join

  • 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.
Show all 21Show fewer
  • < 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)
  • Current or recent treatment (within 48 hours) with octreotide, midodrine, vasopressin, dopamine or other vasopressors
  • Severe cardiovascular disease as judged by investigator
  • Estimated life expectancy of less than 3 days
  • Confirmed pregnancy
  • Known allergy or sensitivity to terlipressin or another component of the study treatment
  • Participation in other clinical research studies involving the evaluation of other investigational drugs or devices within 30 days of randomization

Trial locations and contacts

73 sites in 2 countries.

73 sites in 2 countries

United States71 sites

  • Emory University Hospital

    Atlanta, Georgia, 30322

  • University of Colorado Denver

    Aurora, Colorado, 80045

  • University of Maryland

    Baltimore, Maryland, 21201

  • University of Alabama at Birmingham

    Birmingham, Alabama, 35294

  • Beth Lsrael Deaconess Medical Center

    Boston, Massachusetts, 02215

  • Lahey Clinic Medical Center

    Burlington, Massachusetts, 01805

  • Carolinas Medical Center

    Charlotte, North Carolina, 28203

  • Northwestern University

    Chicago, Illinois, 60611

  • University of Chicago

    Chicago, Illinois, 60637

  • University of Cincinnati, Internal Medicine-Digestive Diseases

    Cincinnati, Ohio, 45267

  • Cleveland Clinic

    Cleveland, Ohio, 44195

  • Arrowhead Regional Medical Center

    Colton, California, 92324

  • WJB Dorn VA Medical Center

    Columbia, South Carolina, 29209

  • SCTI Research Foundation

    Coronado, California, 92118

  • Dallas VA Medical Center

    Dallas, Texas, 75216

  • Baylor University Medical Center

    Dallas, Texas, 75246

  • UT Southwestern Medical Center

    Dallas, Texas, 75390

  • Henry Ford Hospital

    Detroit, Michigan, 48202

  • Baylor All Saints Medical Center

    Fort Worth, Texas, 76104

  • The University of Texas Medical Branch at Galveston

    Galveston, Texas, 77555

  • Hartford Hospital

    Hartford, Connecticut, 06102

  • St. Luke's Advanced Liver Therapies

    Houston, Texas, 77030

  • The Methodist Hospital

    Houston, Texas, 77030

  • University of Texas Health Science Center at Houston - Memorial Hermann Hospital

    Houston, Texas, 77030

  • Indiana University Health - University Hospital

    Indianapolis, Indiana, 46202

  • Iowa City VA Health Care System

    Iowa City, Iowa, 52246

  • Mayo Clinic

    Jacksonville, Florida, 32224

  • University of Kansas Medical Center

    Kansas City, Kansas, 66160

  • Saint Luke's Hospital

    Kansas City, Missouri, 64111

  • Scripps Clinic

    La Jolla, California, 92037

  • University of Kentucky Chandler Medical Center

    Lexington, Kentucky, 40536

  • USC University Hospital

    Los Angeles, California, 90033

  • University of Louisville

    Louisville, Kentucky, 40202

  • University of Wisconsin

    Madison, Wisconsin, 53792

  • Loyola University Medical Center

    Maywood, Illinois, 60153

  • University of Miami

    Miami, Florida, 33136

  • University of Minnesota

    Minneapolis, Minnesota, 55414

  • Vanderbilt Medical Center

    Nashville, Tennessee, 37212

  • Yale University School of Medicine

    New Haven, Connecticut, 06520

  • Tulane Medical Center

    New Orleans, Louisiana, 70112

  • Bellevue Hospital

    New York, New York, 10016

  • NYU Langhorn Medical Center

    New York, New York, 10016

  • Mount Sinai Medical Center

    New York, New York, 10029

  • Columbia University Medical Center

    New York, New York, 10032

  • INTEGRIS Baptist Medical Center

    Oklahoma City, Oklahoma, 73112

  • University of Nebraska Medical Center

    Omaha, Nebraska, 68198

  • Drexel University College of Medicine

    Philadelphia, Pennsylvania, 19102

  • University of Pennsylvania

    Philadelphia, Pennsylvania, 19104

  • Temple University Hospital

    Philadelphia, Pennsylvania, 19140

  • Albert Einstein Medical Center

    Philadelphia, Pennsylvania, 19141

  • Banner Good Samaritan Medical Center/Liver Disease Center

    Phoenix, Arizona, 85006

  • Mayo Clinic Arizona

    Phoenix, Arizona, 85054

  • VA Pittsburgh Healthcare System

    Pittsburgh, Pennsylvania, 15240

  • Orgeon Health & Science University

    Portland, Oregon, 97239

  • McGuire DVAMC

    Richmond, Virginia, 23249

  • Virginia Commonwealth University Health System

    Richmond, Virginia, 23298

  • UC Davis Medical Center

    Sacramento, California, 95817

  • University of Utah

    Salt Lake City, Utah, 84132

  • Methodist Specialty Transplant Hospital Lab

    San Antonio, Texas, 78229

  • The University of Texas Health Science Center at San Antonio

    San Antonio, Texas, 78229

  • University of Texas Health Science Center

    San Antonio, Texas, 78229

  • Veteran's Administration Medical Center

    San Diego, California, 92161

  • California Pacific Medical Center

    San Francisco, California, 94115

  • Virginia Mason Medical Center

    Seattle, Washington, 98101

  • Saint Louis University

    St Louis, Missouri, 63110

  • Washington University School of Medicine

    St Louis, Missouri, 63110

  • University of Arizona Medical Center South Campus

    Tucson, Arizona, 85713

  • University of Arizona Liver Research Institute

    Tucson, Arizona, 85724

  • New York Medical College/Westchester Medical Center

    Valhalla, New York, 10595

  • Georgetown University Hospital

    Washington D.C., District of Columbia, 20007

  • University of Massachusetts Medical Center

    Worcester, Massachusetts, 01655

Other trials in United States

Canada2 sites

  • CHUM, Hopital St-Luc

    Montreal, Quebec, H2X 3J4

  • Toronto General Hospital

    Toronto, Ontario, M5G 2C4

Other trials in Canada

About this study

Official title: 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.

Read the 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.

Being tested
Terlipressin, Placebo
Keywords
Hepatorenal syndrome, Renal failure, Cirrhosis, Alcoholic hepatitis, Ascites
Medical subject headings
Hepatorenal Syndrome, Renal Insufficiency, Fibrosis, Hepatitis, Alcoholic, Ascites

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • TerlipressinDrug

    Also called Lucassin®

    Each 6 mL vial contains 1 mg lyophilized terlipressin acetate and 10 mg mannitol in sterile 0.9% sodium chloride solution.

  • PlaceboDrug

    Also called Saline

    11 mg mannitol reconstituted with 5 ml of sterile 0.9% sodium chloride solution.

Study groups in NCT01143246
Study groupRoleWhat they receive
TerlipressinExperimentalParticipants 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.
Receives: Drug: Terlipressin
PlaceboPlacebo 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.
Receives: Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: within 14 days

Secondary outcomes (4)

  1. 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).

    Measured: within 14 days

  2. 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.

    Measured: Up to 90 days

  3. 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.

    Measured: Up to 90 days

  4. 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.

    Measured: Up to 30 days post treatment (within 44 days)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted14 Jun 2010 (estimated)
  2. Study start11 Oct 2010
  3. Primary completionFeb 2013
  4. Study completion10 May 2013

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Double blind
Who is masked
Participant, Investigator
Enrolment
196 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01143246
Sponsor's protocol ID
IK-4001-HRS-301
Status last verified
Nov 2022
First submitted
11 Jun 2010
Last updated
29 Nov 2022
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No: 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.

Publications

  • 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.

    PubMed 40704461

  • Mujtaba 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.

    PubMed 37302573

  • Velez 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.

    PubMed 37143199

  • Curry 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.

    PubMed 36633470

  • 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.

    PubMed 28370090

  • 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.

    PubMed 27464593

  • 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.

    PubMed 26896734

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Terlipressin in people with Hepatorenal Syndrome, run by Mallinckrodt at 73 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 9 inclusion and 21 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 29 Nov 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 73 sites in United States, Canada. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 29 Nov 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Percentage of Participants With Confirmed Hepatorenal Syndrome (HRS) Reversal (time frame: within 14 days). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01143246, which also lists 7 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Nov 2022.

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