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

Hepatorenal Syndrome Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01143246
• Other study ID #: IK-4001-HRS-301
• Status: Completed
• Phase: Phase 3
• Start date: October 11, 2010
• Est. completion date: May 10, 2013

Study information

• Verified date: November 2022
• Source: Mallinckrodt
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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.

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 information / eligibility

• Status: Completed
• Enrollment: 196
• Est. completion date: May 10, 2013
• Est. primary completion date: February 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Hepatorenal Syndrome
• Syndrome

Intervention

Drug:
• Terlipressin
Each 6 mL vial contains 1 mg lyophilized terlipressin acetate and 10 mg mannitol in sterile 0.9% sodium chloride solution.
• Placebo
11 mg mannitol reconstituted with 5 ml of sterile 0.9% sodium chloride solution.

Locations

Country	Name	City	State
Canada	CHUM, Hopital St-Luc	Montreal	Quebec
Canada	Toronto General Hospital	Toronto	Ontario
United States	Emory University Hospital	Atlanta	Georgia
United States	University of Colorado Denver	Aurora	Colorado
United States	University of Maryland	Baltimore	Maryland
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Beth Lsrael Deaconess Medical Center	Boston	Massachusetts
United States	Lahey Clinic Medical Center	Burlington	Massachusetts
United States	Carolinas Medical Center	Charlotte	North Carolina
United States	Northwestern University	Chicago	Illinois
United States	University of Chicago	Chicago	Illinois
United States	University of Cincinnati, Internal Medicine-Digestive Diseases	Cincinnati	Ohio
United States	Cleveland Clinic	Cleveland	Ohio
United States	Arrowhead Regional Medical Center	Colton	California
United States	WJB Dorn VA Medical Center	Columbia	South Carolina
United States	SCTI Research Foundation	Coronado	California
United States	Baylor University Medical Center	Dallas	Texas
United States	Dallas VA Medical Center	Dallas	Texas
United States	UT Southwestern Medical Center	Dallas	Texas
United States	Henry Ford Hospital	Detroit	Michigan
United States	Baylor All Saints Medical Center	Fort Worth	Texas
United States	The University of Texas Medical Branch at Galveston	Galveston	Texas
United States	Hartford Hospital	Hartford	Connecticut
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	Indiana University Health - University Hospital	Indianapolis	Indiana
United States	Iowa City VA Health Care System	Iowa City	Iowa
United States	Mayo Clinic	Jacksonville	Florida
United States	Saint Luke's Hospital	Kansas City	Missouri
United States	University of Kansas Medical Center	Kansas City	Kansas
United States	Scripps Clinic	La Jolla	California
United States	University of Kentucky Chandler Medical Center	Lexington	Kentucky
United States	USC University Hospital	Los Angeles	California
United States	University of Louisville	Louisville	Kentucky
United States	University of Wisconsin	Madison	Wisconsin
United States	Loyola University Medical Center	Maywood	Illinois
United States	University of Miami	Miami	Florida
United States	University of Minnesota	Minneapolis	Minnesota
United States	Vanderbilt Medical Center	Nashville	Tennessee
United States	Yale University School of Medicine	New Haven	Connecticut
United States	Tulane Medical Center	New Orleans	Louisiana
United States	Bellevue Hospital	New York	New York
United States	Columbia University Medical Center	New York	New York
United States	Mount Sinai Medical Center	New York	New York
United States	NYU Langhorn Medical Center	New York	New York
United States	INTEGRIS Baptist Medical Center	Oklahoma City	Oklahoma
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Albert Einstein Medical Center	Philadelphia	Pennsylvania
United States	Drexel University College of Medicine	Philadelphia	Pennsylvania
United States	Temple University Hospital	Philadelphia	Pennsylvania
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	Banner Good Samaritan Medical Center/Liver Disease Center	Phoenix	Arizona
United States	Mayo Clinic Arizona	Phoenix	Arizona
United States	VA Pittsburgh Healthcare System	Pittsburgh	Pennsylvania
United States	Orgeon Health & Science University	Portland	Oregon
United States	McGuire DVAMC	Richmond	Virginia
United States	Virginia Commonwealth University Health System	Richmond	Virginia
United States	UC Davis Medical Center	Sacramento	California
United States	Saint Louis University	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	University of Utah	Salt Lake City	Utah
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	Veteran's Administration Medical Center	San Diego	California
United States	California Pacific Medical Center	San Francisco	California
United States	Virginia Mason Medical Center	Seattle	Washington
United States	University of Arizona Liver Research Institute	Tucson	Arizona
United States	University of Arizona Medical Center South Campus	Tucson	Arizona
United States	New York Medical College/Westchester Medical Center	Valhalla	New York
United States	Georgetown University Hospital	Washington	District of Columbia
United States	University of Massachusetts Medical Center	Worcester	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Mallinckrodt

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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).	within 14 days
Secondary	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.	Up to 90 days
Secondary	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.	Up to 90 days
Secondary	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.	Up to 30 days post treatment (within 44 days)