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

NCT ID: NCT01143246

Last Updated: 2022-11-29

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 196 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-10-11
• Study Completion Date: 2013-05-10

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.

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.

Conditions

Hepatorenal Syndrome

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

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.

Group Type: EXPERIMENTAL

Terlipressin

Intervention Type: DRUG

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

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.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

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

Interventions

Terlipressin

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

Intervention Type: DRUG

Placebo

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

Intervention Type: DRUG

Other Intervention Names

Lucassin®; Saline

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Mallinckrodt

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Clinical Team Leader

Role: STUDY_DIRECTOR

Mallinckrodt

Locations

University of Alabama at Birmingham

Birmingham, Alabama, United States

Banner Good Samaritan Medical Center/Liver Disease Center

Phoenix, Arizona, United States

Mayo Clinic Arizona

Phoenix, Arizona, United States

University of Arizona Medical Center South Campus

Tucson, Arizona, United States

University of Arizona Liver Research Institute

Tucson, Arizona, United States

Arrowhead Regional Medical Center

Colton, California, United States

SCTI Research Foundation

Coronado, California, United States

Scripps Clinic

La Jolla, California, United States

USC University Hospital

Los Angeles, California, United States

UC Davis Medical Center

Sacramento, California, United States

Veteran's Administration Medical Center

San Diego, California, United States

California Pacific Medical Center

San Francisco, California, United States

University of Colorado Denver

Aurora, Colorado, United States

Hartford Hospital

Hartford, Connecticut, United States

Yale University School of Medicine

New Haven, Connecticut, United States

Georgetown University Hospital

Washington D.C., District of Columbia, United States

Mayo Clinic

Jacksonville, Florida, United States

University of Miami

Miami, Florida, United States

Emory University Hospital

Atlanta, Georgia, United States

Northwestern University

Chicago, Illinois, United States

University of Chicago

Chicago, Illinois, United States

Loyola University Medical Center

Maywood, Illinois, United States

Indiana University Health - University Hospital

Indianapolis, Indiana, United States

Iowa City VA Health Care System

Iowa City, Iowa, United States

University of Kansas Medical Center

Kansas City, Kansas, United States

University of Kentucky Chandler Medical Center

Lexington, Kentucky, United States

University of Louisville

Louisville, Kentucky, United States

Tulane Medical Center

New Orleans, Louisiana, United States

University of Maryland

Baltimore, Maryland, United States

Beth Lsrael Deaconess Medical Center

Boston, Massachusetts, United States

Lahey Clinic Medical Center

Burlington, Massachusetts, United States

University of Massachusetts Medical Center

Worcester, Massachusetts, United States

Henry Ford Hospital

Detroit, Michigan, United States

University of Minnesota

Minneapolis, Minnesota, United States

Saint Luke's Hospital

Kansas City, Missouri, United States

Saint Louis University

St Louis, Missouri, United States

Washington University School of Medicine

St Louis, Missouri, United States

University of Nebraska Medical Center

Omaha, Nebraska, United States

Bellevue Hospital

New York, New York, United States

NYU Langhorn Medical Center

New York, New York, United States

Mount Sinai Medical Center

New York, New York, United States

Columbia University Medical Center

New York, New York, United States

New York Medical College/Westchester Medical Center

Valhalla, New York, United States

Carolinas Medical Center

Charlotte, North Carolina, United States

University of Cincinnati, Internal Medicine-Digestive Diseases

Cincinnati, Ohio, United States

Cleveland Clinic

Cleveland, Ohio, United States

INTEGRIS Baptist Medical Center

Oklahoma City, Oklahoma, United States

Orgeon Health & Science University

Portland, Oregon, United States

Drexel University College of Medicine

Philadelphia, Pennsylvania, United States

University of Pennsylvania

Philadelphia, Pennsylvania, United States

Temple University Hospital

Philadelphia, Pennsylvania, United States

Albert Einstein Medical Center

Philadelphia, Pennsylvania, United States

VA Pittsburgh Healthcare System

Pittsburgh, Pennsylvania, United States

WJB Dorn VA Medical Center

Columbia, South Carolina, United States

Vanderbilt Medical Center

Nashville, Tennessee, United States

Dallas VA Medical Center

Dallas, Texas, United States

Baylor University Medical Center

Dallas, Texas, United States

UT Southwestern Medical Center

Dallas, Texas, United States

Baylor All Saints Medical Center

Fort Worth, Texas, United States

The University of Texas Medical Branch at Galveston

Galveston, Texas, United States

St. Luke's Advanced Liver Therapies

Houston, Texas, United States

The Methodist Hospital

Houston, Texas, United States

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

Houston, Texas, United States

Methodist Specialty Transplant Hospital Lab

San Antonio, Texas, United States

The University of Texas Health Science Center at San Antonio

San Antonio, Texas, United States

University of Texas Health Science Center

San Antonio, Texas, United States

University of Utah

Salt Lake City, Utah, United States

McGuire DVAMC

Richmond, Virginia, United States

Virginia Commonwealth University Health System

Richmond, Virginia, United States

Virginia Mason Medical Center

Seattle, Washington, United States

University of Wisconsin

Madison, Wisconsin, United States

Toronto General Hospital

Toronto, Ontario, Canada

CHUM, Hopital St-Luc

Montreal, Quebec, Canada

Countries

United States; Canada

References

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 Jul 24. doi: 10.1111/apt.70297. Online ahead of print.

Reference Type: DERIVED

PMID: 40704461 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 37302573 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 37143199 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 36633470 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 28370090 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 27464593 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 26896734 (View on PubMed)

Other Identifiers

IK-4001-HRS-301

Identifier Type: -

Identifier Source: org_study_id