A Placebo-Controlled, Double-Blind Study to Confirm the Reversal of Hepatorenal Syndrome Type 1 With Terlipressin
- Registration Number
- NCT01143246
- Lead Sponsor
- Mallinckrodt
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 196
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Written informed consent by subject or legally authorized representative
-
At least 18 years of age
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Cirrhosis and ascites
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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.
-
SCr > 7 mg/dL
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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.
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< 2 days anti-infective therapy for documented or suspected infection
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Proteinuria > 500 mg/day
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Hematuria or microhematuria (> 50 red blood cells per high power field)
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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].
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Evidence of intrinsic or parenchymal renal disease (including acute tubular necrosis)
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Obstructive uropathy or other renal pathology on ultrasound or other medical imaging
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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.
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Current or recent (within 4 weeks) renal replacement therapy
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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)
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Current or recent treatment (within 48 hours) with octreotide, midodrine, vasopressin, dopamine or other vasopressors
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Severe cardiovascular disease as judged by investigator
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Estimated life expectancy of less than 3 days
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Confirmed pregnancy
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Known allergy or sensitivity to terlipressin or another component of the study treatment
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Participation in other clinical research studies involving the evaluation of other investigational drugs or devices within 30 days of randomization
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo 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. Terlipressin 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.
- Primary Outcome Measures
Name Time Method Percentage of Participants With Confirmed Hepatorenal Syndrome (HRS) Reversal within 14 days 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.
- Secondary Outcome Measures
Name Time Method Percentage of Participants With Transplant-free Survival Up to 90 days 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.
Percentage of Participants With HRS Reversal within 14 days 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).
Percentage of Participants With Serious Adverse Events Up to 30 days post treatment (within 44 days) Clinically significant changes in vital signs, height, weight, immunogenicity and laboratory assessments which qualified for the definition of serious adverse event are reported.
Percentage of Participants With Overall Survival Up to 90 days Overall Survival up to 90 days, defined as the time (in days) that each participant survives from the day of randomization.
Trial Locations
- Locations (73)
Scripps Clinic
🇺🇸La Jolla, California, United States
University of Kentucky Chandler Medical Center
🇺🇸Lexington, Kentucky, United States
Iowa City VA Health Care System
🇺🇸Iowa City, Iowa, United States
New York Medical College/Westchester Medical Center
🇺🇸Valhalla, New York, United States
UT Southwestern Medical Center
🇺🇸Dallas, Texas, United States
Tulane Medical Center
🇺🇸New Orleans, Louisiana, United States
University of Massachusetts Medical Center
🇺🇸Worcester, Massachusetts, United States
NYU Langhorn Medical Center
🇺🇸New York, New York, United States
Temple University Hospital
🇺🇸Philadelphia, Pennsylvania, United States
Mount Sinai Medical Center
🇺🇸New York, New York, United States
Carolinas Medical Center
🇺🇸Charlotte, North Carolina, United States
SCTI Research Foundation
🇺🇸Coronado, California, United States
University of Maryland
🇺🇸Baltimore, Maryland, United States
Saint Louis University
🇺🇸Saint Louis, Missouri, United States
Toronto General Hospital
🇨🇦Toronto, Ontario, Canada
Columbia University Medical Center
🇺🇸New York, New York, United States
Northwestern University
🇺🇸Chicago, Illinois, United States
Beth Lsrael Deaconess Medical Center
🇺🇸Boston, Massachusetts, United States
Cleveland Clinic
🇺🇸Cleveland, Ohio, United States
Indiana University Health - University Hospital
🇺🇸Indianapolis, Indiana, United States
Veteran's Administration Medical Center
🇺🇸San Diego, California, United States
University of Cincinnati, Internal Medicine-Digestive Diseases
🇺🇸Cincinnati, Ohio, United States
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
California Pacific Medical Center
🇺🇸San Francisco, California, United States
University of Minnesota
🇺🇸Minneapolis, Minnesota, United States
Vanderbilt Medical Center
🇺🇸Nashville, Tennessee, 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
University of Arizona Medical Center South Campus
🇺🇸Tucson, Arizona, United States
University of Arizona Liver Research Institute
🇺🇸Tucson, Arizona, United States
Mayo Clinic
🇺🇸Jacksonville, Florida, United States
Georgetown University Hospital
🇺🇸Washington, District of Columbia, United States
CHUM, Hopital St-Luc
🇨🇦Montreal, Quebec, Canada
University of Miami
🇺🇸Miami, Florida, United States
Hartford Hospital
🇺🇸Hartford, Connecticut, United States
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 Colorado Denver
🇺🇸Aurora, Colorado, United States
Henry Ford Hospital
🇺🇸Detroit, Michigan, United States
University of Nebraska Medical Center
🇺🇸Omaha, Nebraska, United States
INTEGRIS Baptist Medical Center
🇺🇸Oklahoma City, Oklahoma, United States
Orgeon Health & Science University
🇺🇸Portland, Oregon, United States
Emory University Hospital
🇺🇸Atlanta, Georgia, United States
VA Pittsburgh Healthcare System
🇺🇸Pittsburgh, Pennsylvania, United States
Baylor University Medical Center
🇺🇸Dallas, 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
Baylor All Saints Medical Center
🇺🇸Fort Worth, Texas, United States
The Methodist Hospital
🇺🇸Houston, Texas, United States
Methodist Specialty Transplant Hospital Lab
🇺🇸San Antonio, Texas, United States
Virginia Commonwealth University Health System
🇺🇸Richmond, Virginia, United States
UC Davis Medical Center
🇺🇸Sacramento, California, United States
University of Chicago
🇺🇸Chicago, Illinois, United States
University of Wisconsin
🇺🇸Madison, Wisconsin, United States
Virginia Mason Medical Center
🇺🇸Seattle, Washington, United States
USC University Hospital
🇺🇸Los Angeles, California, United States
Arrowhead Regional Medical Center
🇺🇸Colton, California, United States
Loyola University Medical Center
🇺🇸Maywood, Illinois, United States
Lahey Clinic Medical Center
🇺🇸Burlington, Massachusetts, United States
Bellevue Hospital
🇺🇸New York, New York, United States
Drexel University College of Medicine
🇺🇸Philadelphia, Pennsylvania, United States
University of Pennsylvania
🇺🇸Philadelphia, Pennsylvania, United States
Albert Einstein Medical Center
🇺🇸Philadelphia, Pennsylvania, United States
WJB Dorn VA Medical Center
🇺🇸Columbia, South Carolina, United States
Dallas VA Medical Center
🇺🇸Dallas, Texas, United States
University of Texas Health Science Center at Houston - Memorial Hermann Hospital
🇺🇸Houston, Texas, United States
McGuire DVAMC
🇺🇸Richmond, Virginia, United States
Yale University School of Medicine
🇺🇸New Haven, Connecticut, United States
University of Louisville
🇺🇸Louisville, Kentucky, United States
Saint Luke's Hospital
🇺🇸Kansas City, Missouri, United States
University of Kansas Medical Center
🇺🇸Kansas City, Kansas, United States