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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Ikaria
ClinicalTrials.gov Identifier:
NCT01143246
First received: June 11, 2010
Last updated: March 12, 2014
Last verified: March 2014
  Purpose

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


Condition Intervention Phase
Hepatorenal Syndrome Type 1
Drug: Terlipressin
Drug: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: Phase 3, Multi-Center Randomized, Placebo-Controlled, Double-Blind Study to Confirm the Reversal of Hepatorenal Syndrome Type 1 With Lucassin® (Terlipressin) (REVERSE Trial)

Resource links provided by NLM:


Further study details as provided by Ikaria:

Primary Outcome Measures:
  • Confirmed Hepatorenal syndrome reversal [ Time Frame: Baseline and 14 days ] [ Designated as safety issue: No ]
    Confirmed HRS Reversal: The percentage of subjects with two serum creatinine (SCr) values of ≤ 1.5 mg/dL at least 48 hours apart, on treatment, and without intervening RRT or liver transplant.


Secondary Outcome Measures:
  • Hepatorenal syndrome reversal [ Time Frame: 14 days ] [ Designated as safety issue: No ]
    Incidence of 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).

  • Transplant-free survival [ Time Frame: Up to 90 days ] [ Designated as safety issue: No ]
    Transplant-Free Survival up to 90 days, defined as the time (in days) that each subject survives without liver transplantation from the day of randomization.

  • Overall Survival [ Time Frame: Up to 90 days ] [ Designated as safety issue: No ]
    Overall Survival up to 90 days, defined as the time (in days) that each subject survives from the day of randomization.

  • Serious Adverse Events [ Time Frame: Up to 30 days post treatment ] [ Designated as safety issue: Yes ]

Enrollment: 196
Study Start Date: September 2010
Study Completion Date: May 2013
Primary Completion Date: February 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Terlipressin Drug: Terlipressin
Blinded terlipressin reconstituted with 5 mL of sterile 0.9% sodium chloride solution for injection will be administered intravenously as a slow bolus injection over 2 minutes at a dose of 1 mg (1 vial) every 6 hours (4 mg/day).
Other Name: Lucassin®
Placebo Comparator: Placebo
lyophilized mannitol
Drug: Placebo
Lyophilized mannitol reconstituted with 5 mL of sterile 0.9% sodium chloride solution administered intravenously as a slow bolus injection over 2 minutes at a dose of 1 mg (1 vial) every 6 hours (4 mg/day).

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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:

    • 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 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. Serum creatinine > 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01143246

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

No publications provided

Responsible Party: Ikaria
ClinicalTrials.gov Identifier: NCT01143246     History of Changes
Other Study ID Numbers: IK-4001-HRS-301
Study First Received: June 11, 2010
Last Updated: March 12, 2014
Health Authority: United States: Food and Drug Administration
Canada: Health Canada

Keywords provided by Ikaria:
Hepatorenal syndrome
Renal failure
Cirrhosis
Alcoholic hepatitis
Ascites

Additional relevant MeSH terms:
Syndrome
Hepatorenal Syndrome
Disease
Pathologic Processes
Liver Diseases
Digestive System Diseases
Kidney Diseases
Urologic Diseases
Terlipressin
Lypressin
Antihypertensive Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
Vasoconstrictor Agents
Hemostatics
Coagulants
Hematologic Agents
Antidiuretic Agents
Natriuretic Agents
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on October 19, 2014