Study To Confirm Efficacy and Safety of Terlipressin in Hepatorenal Syndrome (HRS) Type 1

• ClinicalTrials.gov Identifier: NCT02770716
• Recruitment Status: Completed
• First Posted: May 12, 2016
• Last Update Posted: May 27, 2020
• Sponsor: Mallinckrodt
• Information provided by (Responsible Party): Mallinckrodt

Study Description

Brief Summary:

This study is to treat adult patients with hepatorenal syndrome (HRS) Type 1.

Out of every three participants, two will receive terlipressin and one will receive placebo.

Assignments will be made randomly.

Condition or disease	Intervention/treatment	Phase
Hepatorenal Syndrome	Drug: Terlipressin; Other: Placebo Comparator	Phase 3

Detailed Description:

The primary objective of this trial is to confirm the efficacy and safety of intravenous terlipressin versus placebo in the treatment of adult subjects with hepatorenal syndrome (HRS) Type 1.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 300 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Multi-Center, Randomized, Placebo Controlled, Double-Blind Study to Confirm Efficacy and Safety of Terlipressin in Subjects With Hepatorenal Syndrome Type 1 (The CONFIRM Study)
• Actual Study Start Date: July 13, 2016
• Actual Primary Completion Date: July 24, 2019
• Actual Study Completion Date: July 24, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: Terlipressin; Participants will receive terlipressin intravenously as a bolus injection over 2 minutes at a dose of 1 mg (1 vial) every 6 hours (+/- 30 minutes), followed by a saline flush. Dose, duration, retreatment and/or discontinuation may be modified by the investigator, per protocol.	Drug: Terlipressin; Each 6 mL vial contains 1 mg lyophilized terlipressin acetate and 10 mg mannitol in sterile 0.9% sodium chloride solution
Placebo Comparator: Placebo; Participants will receive 1 vial of matching placebo intravenously as a bolus injection of 1 vial over 2 minutes every 6 hours (+/- 30 minutes), followed by a saline flush. Dose, duration, retreatment and/or discontinuation may be modified by the investigator, per protocol.	Other: Placebo Comparator; 11 mg mannitol reconstituted with 5 ml of sterile 0.9% sodium chloride solution

Outcome Measures

Primary Outcome Measures :

1. Verified HRS Reversal [ Time Frame: within 15 Days ]
   Defined as the percentage of participants with 2 consecutive qualified SCr values ≤1.5 mg/dL at least 2 hours apart.
2. Percentage of participants who were viable (per protocol) for inclusion in the primary end point analysis [ Time Frame: within 25 days ]
   Defined as the percentage of participants with verified HRS reversal who lived at least 10 days without RRT, and were otherwise viable (per protocol) for inclusion in the primary end point analysis

Secondary Outcome Measures :

1. Incidence of participants with HRS reversal [ Time Frame: within 14 days ]
   Defined as the percentage of participants with a SCr value no more than 1.5 mg/dL by Day 14 or discharge, and were viable (per protocol) for inclusion in the secondary endpoint analysis
2. Durability of HRS reversal [ Time Frame: Day 30 ]
   Defined as the percentage of participants maintaining HRS reversal without RRT to Day 30
3. Incidence of HRS reversal in the systemic inflammatory response syndrome (SIRS) subgroup [ Time Frame: within 14 days ]
   Defined as the percentage of participants in the SIRS subgroup with HRS reversal by Day 14 or discharge
4. Incidence of verified HRS reversal without HRS recurrence by Day 30 [ Time Frame: Day 30 ]
   Defined as the percentage of participants who had achieved verified HRS reversal by Day 15 or discharge and did not revert to baseline measures by day 30

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Written informed consent by participant or legally authorized representative
• Cirrhosis and ascites
• Rapidly progressive worsening in renal function to a serum creatinine (SCr) at least 2.25 mg/dL and meeting a trajectory for SCr to double over 2 weeks
• No sustained improvement in renal function (less than 20% decrease in SCr and SCr at least 2.25 mg/dL) at least 48 hours after diuretic withdrawal and the beginning of plasma volume expansion with albumin
• Discontinues midodrine and octreotide before randomization if applicable

Exclusion Criteria:

• Serum creatinine level greater than 7.0 mg/dL
• At least 1 event of large volume paracentesis (LVP) at least 4 L within 2 days of randomization
• Sepsis and/or uncontrolled bacterial infection
• Less than 2 days anti-infective therapy for documented or suspected infection
• Shock
• Being treatment with or exposure to nephrotoxic agents, nonsteroidal anti-inflammatory drugs, or significant radiographic contrast agents (within the last 4 weeks)
• Estimated life expectancy of less than 3 days
• Superimposed acute liver injury due to drugs, dietary supplements, herbal preparations, viral hepatitis, or toxins, with the exception of acute alcoholic hepatitis
• Proteinuria greater than 500 mg/day
• Evidence of obstructive uropathy or parenchymal renal disease on ultrasound or other imaging
• Tubular epithelial casts, heme granular casts, hematuria or microhematuria (greater than 50 red blood cells per high power field in the absence of recent catheterization) on urinalysis
• Pregnancy; all women of child-bearing age and potential must have a negative pregnancy test
• Cardiovascular disease judged by the investigator to be severe
• Current or recent renal replacement therapy (RRT) within the past 4 weeks
• Participation in other clinical research involving investigational medicinal products within 30 days of randomization
• Transjugular intrahepatic portosystemic shunt (TIPS) within 30 days of randomization
• Use of vasopressors for at least 3 consecutive days within the 14-day screening period - patients receiving any vasopressor other than midodrine and octreotide within 24 hours of qualifying SCr are also excluded, ie, a 24-hour washout is required prior to enrollment
• Known allergy or sensitivity to terlipressin or another component of the study treatment

Contacts and Locations

Locations

United States, Alabama

University of Alabama at Birmingham

Birmingham, Alabama, United States, 35294

United States, Arizona

Banner Good Samaritan Medical Center

Phoenix, Arizona, United States, 85006

Mayo Clinic - AZ

Phoenix, Arizona, United States, 85057

University of Arizona

Tucson, Arizona, United States, 85724

United States, California

USC Healthcare

Los Angeles, California, United States, 90033

Stanford Hospital and Clinics

Palo Alto, California, United States, 94305

UCLA Medical Center

San Diego, California, United States, 90095

Southern California Research Center

San Diego, California, United States, 92118

California Pacific Medical Center

San Francisco, California, United States, 94115

United States, District of Columbia

MedStar Georgetown University Hospital

Washington, District of Columbia, United States, 20007

United States, Florida

University of Florida

Gainesville, Florida, United States, 32610

Mayo Clinic - FL

Jacksonville, Florida, United States, 32224

Jackson Memorial Hospital

Miami, Florida, United States, 33136

University of Miami

Miami, Florida, United States, 33136

Tampa General Medical Group

Tampa, Florida, United States, 33606

United States, Georgia

Piedmont Hospital Transplant

Atlanta, Georgia, United States, 30309

Emory University Hospital

Atlanta, Georgia, United States, 30329

United States, Illinois

Northwestern University

Chicago, Illinois, United States, 60611

Rush University Medical Center

Chicago, Illinois, United States, 60612

United States, Iowa

University of Iowa Hospitals & Clinics

Iowa City, Iowa, United States, 52242

United States, Kansas

University of Kansas Medical Center

Kansas City, Kansas, United States, 66160

United States, Louisiana

Ochsner Clinic Foundation

New Orleans, Louisiana, United States, 70121

United States, Maryland

Mercy Medical Center

Baltimore, Maryland, United States, 21202

United States, Massachusetts

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States, 02215

United States, Michigan

University of Michigan Medical Center

Ann Arbor, Michigan, United States, 48109

United States, Minnesota

University of Minnesota

Minneapolis, Minnesota, United States, 55455

Mayo Clinic - MN

Rochester, Minnesota, United States, 55902

United States, Missouri

Saint Louis University

Saint Louis, Missouri, United States, 63110

Washington University in St. Louis

Saint Louis, Missouri, United States, 63110

United States, Nebraska

University of Nebraska Medical Center

Omaha, Nebraska, United States, 68198

United States, New Jersey

Rutgers New Jersey Medical School

Newark, New Jersey, United States, 07102

United States, New York

Montefiore Medical Center

Bronx, New York, United States, 10467

NYU Langone Health

New York, New York, United States, 10016

Weil Cornell Medical College

New York, New York, United States, 10021

Mount Sinai Medical Center

New York, New York, United States, 10029

United States, Ohio

Case Western Reserve Transplant

Cleveland, Ohio, United States, 44106

The Ohio State University Wexner Medical Center

Columbus, Ohio, United States, 43210

United States, Oklahoma

INTEGRIS Baptist Medical Center

Oklahoma City, Oklahoma, United States, 73112

United States, Pennsylvania

Drexel University

Philadelphia, Pennsylvania, United States, 19102

Hospital of the University of Pennsylvania

Philadelphia, Pennsylvania, United States, 19104

Jefferson University

Philadelphia, Pennsylvania, United States, 19107

VA Pittsburgh Healthcare System

Pittsburgh, Pennsylvania, United States, 15240

United States, South Carolina

Medical University of South Carolina

Charleston, South Carolina, United States, 29425

United States, Tennessee

Vanderbilt University Medical Center

Nashville, Tennessee, United States, 37232

United States, Texas

Parkland Health and Hospital System

Dallas, Texas, United States, 75235

Baylor University Medical Center

Dallas, Texas, United States, 75246

UT Southwestern Medical Center

Dallas, Texas, United States, 75390

Baylor Scott and White All Saints Medical Center

Fort Worth, Texas, United States, 76104

Baylor College of Medicine (St. Luke's)

Houston, Texas, United States, 77030

Methodist Center for Liver Disease and Transplantation

Houston, Texas, United States, 77030

Methodist Transplant Hospital

San Antonio, Texas, United States, 78229

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

University of Virginia Medical Center

Charlottesville, Virginia, United States, 22908

McGuire VA Medical Center

Richmond, Virginia, United States, 23245

Virginia Commonwealth University

Richmond, Virginia, United States, 23298

United States, Washington

Harborview Medical Center/Univ. of Washington

Seattle, Washington, United States, 98104

Swedish Organ Transplant and Liver Center

Seattle, Washington, United States, 98104

University of Washington

Seattle, Washington, United States, 98105

Canada, British Columbia

Vancouver General Hospital, Gordon and Leslie Diamond Health Care Centre

Vancouver, British Columbia, Canada, V5Z IM9

Canada, Ontario

Ottawa Hospital

Ottawa, Ontario, Canada, K1H 8L6

University of Toronto 9N/983 Toronto General Hospital

Toronto, Ontario, Canada, M5G2C4

Canada

McGill University Health Centre

Montréal, Canada, H4A3J1

Centre Hospitalier de l'Université de Montréal

Québec, Canada, H2X3J4

Sponsors and Collaborators

Mallinckrodt

Investigators

• Study Director: Clinical Team Lead; Mallinckrodt

More Information

• Responsible Party: Mallinckrodt
• ClinicalTrials.gov Identifier: NCT02770716
• Other Study ID Numbers: MNK19013058
• First Posted: May 12, 2016
• Last Update Posted: May 27, 2020
• Last Verified: May 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Mallinckrodt:

Type 1

Additional relevant MeSH terms:

Hepatorenal Syndrome; Syndrome; Disease; Pathologic Processes; Liver Diseases; Digestive System Diseases; Kidney Diseases; Urologic Diseases; Terlipressin; Antihypertensive Agents; Vasoconstrictor Agents