Clinical trial NCT01143246: A Placebo-Controlled, Double-Blind Study to Confirm the Reversal of Hepatorenal Syndrome Type 1 With Terlipressin
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hepatorenal Syndrome
Keywords: Hepatorenal syndrome
Renal failure
Cirrhosis
Alcoholic hepatitis
Ascites
Lead sponsor: Mallinckrodt
Sponsor class: INDUSTRY
First posted: 2010-06-14
Enrollment: 196
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Percentage of Participants With Confirmed Hepatorenal Syndrome (HRS) Reversal
timeFrame: within 14 days
Secondary outcomes:
measure: Percentage of Participants With HRS Reversal
timeFrame: within 14 days
measure: Percentage of Participants With Transplant-free Survival
timeFrame: Up to 90 days
measure: Percentage of Participants With Overall Survival
timeFrame: Up to 90 days
measure: Percentage of Participants With Serious Adverse Events
timeFrame: Up to 30 days post treatment (within 44 days)
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Phoenix
country: United States
facility: Banner Good Samaritan Medical Center/Liver Disease Center
state: Arizona
city: Phoenix
country: United States
facility: Mayo Clinic Arizona
state: Arizona
city: Tucson
country: United States
facility: University of Arizona Medical Center South Campus
state: Arizona
city: Tucson
country: United States
facility: University of Arizona Liver Research Institute
state: Arizona
city: Colton
country: United States
facility: Arrowhead Regional Medical Center
state: California
city: Coronado
country: United States
facility: SCTI Research Foundation
state: California
city: La Jolla
country: United States
facility: Scripps Clinic
state: California
city: Los Angeles
country: United States
facility: USC University Hospital
state: California
city: Sacramento
country: United States
facility: UC Davis Medical Center
state: California
city: San Diego
country: United States
facility: Veteran's Administration Medical Center
state: California
city: San Francisco
country: United States
facility: California Pacific Medical Center
state: California
city: Aurora
country: United States
facility: University of Colorado Denver
state: Colorado
city: Hartford
country: United States
facility: Hartford Hospital
state: Connecticut
city: New Haven
country: United States
facility: Yale University School of Medicine
state: Connecticut
city: Washington
country: United States
facility: Georgetown University Hospital
state: District of Columbia
city: Jacksonville
country: United States
facility: Mayo Clinic
state: Florida
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Atlanta
country: United States
facility: Emory University Hospital
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Maywood
country: United States
facility: Loyola University Medical Center
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University Health - University Hospital
state: Indiana
city: Iowa City
country: United States
facility: Iowa City VA Health Care System
state: Iowa
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Lexington
country: United States
facility: University of Kentucky Chandler Medical Center
state: Kentucky
city: Louisville
country: United States
facility: University of Louisville
state: Kentucky
city: New Orleans
country: United States
facility: Tulane Medical Center
state: Louisiana
city: Baltimore
country: United States
facility: University of Maryland
state: Maryland
city: Boston
country: United States
facility: Beth Lsrael Deaconess Medical Center
state: Massachusetts
city: Burlington
country: United States
facility: Lahey Clinic Medical Center
state: Massachusetts
city: Worcester
country: United States
facility: University of Massachusetts Medical Center
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Kansas City
country: United States
facility: Saint Luke's Hospital
state: Missouri
city: Saint Louis
country: United States
facility: Saint Louis University
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: New York
country: United States
facility: Bellevue Hospital
state: New York
city: New York
country: United States
facility: NYU Langhorn Medical Center
state: New York
city: New York
country: United States
facility: Mount Sinai Medical Center
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Valhalla
country: United States
facility: New York Medical College/Westchester Medical Center
state: New York
city: Charlotte
country: United States
facility: Carolinas Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati, Internal Medicine-Digestive Diseases
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Oklahoma City
country: United States
facility: INTEGRIS Baptist Medical Center
state: Oklahoma
city: Portland
country: United States
facility: Orgeon Health & Science University
state: Oregon
city: Philadelphia
country: United States
facility: Drexel University College of Medicine
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Philadelphia
country: United States
facility: Temple University Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: Albert Einstein Medical Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: VA Pittsburgh Healthcare System
state: Pennsylvania
city: Columbia
country: United States
facility: WJB Dorn VA Medical Center
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt Medical Center
state: Tennessee
city: Dallas
country: United States
facility: Dallas VA Medical Center
state: Texas
city: Dallas
country: United States
facility: Baylor University Medical Center
state: Texas
city: Dallas
country: United States
facility: UT Southwestern Medical Center
state: Texas
city: Fort Worth
country: United States
facility: Baylor All Saints Medical Center
state: Texas
city: Galveston
country: United States
facility: The University of Texas Medical Branch at Galveston
state: Texas
city: Houston
country: United States
facility: St. Luke's Advanced Liver Therapies
state: Texas
city: Houston
country: United States
facility: The Methodist Hospital
state: Texas
city: Houston
country: United States
facility: University of Texas Health Science Center at Houston - Memorial Hermann Hospital
state: Texas
city: San Antonio
country: United States
facility: Methodist Specialty Transplant Hospital Lab
state: Texas
city: San Antonio
country: United States
facility: The University of Texas Health Science Center at San Antonio
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Science Center
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Richmond
country: United States
facility: McGuire DVAMC
state: Virginia
city: Richmond
country: United States
facility: Virginia Commonwealth University Health System
state: Virginia
city: Seattle
country: United States
facility: Virginia Mason Medical Center
state: Washington
city: Madison
country: United States
facility: University of Wisconsin
state: Wisconsin
city: Toronto
country: Canada
facility: Toronto General Hospital
state: Ontario
city: Montreal
country: Canada
facility: CHUM, Hopital St-Luc
state: Quebec
Study officials:
affiliation: Mallinckrodt
name: Clinical Team Leader
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.