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

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)

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.

Study Overview

• Status: Completed
• Conditions: Hepatorenal Syndrome
• Intervention / Treatment: Drug: Terlipressin; Other: Placebo

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 Type: Interventional
• Enrollment (Actual): 300
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Montréal, Canada, H4A3J1
    • McGill University Health Centre
  • Québec, Canada, H2X3J4
    • Centre Hospitalier de l'Université de Montréal
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z IM9
      • Vancouver General Hospital, Gordon and Leslie Diamond Health Care Centre
  • Ontario
    • Ottawa, Ontario, Canada, K1H 8L6
      • Ottawa Hospital
    • Toronto, Ontario, Canada, M5G2C4
      • University of Toronto 9N/983 Toronto General Hospital
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
  • Arizona
    • Phoenix, Arizona, United States, 85006
      • Banner Good Samaritan Medical Center
    • Phoenix, Arizona, United States, 85057
      • Mayo Clinic - AZ
    • Tucson, Arizona, United States, 85724
      • University of Arizona
  • California
    • Los Angeles, California, United States, 90033
      • USC Healthcare
    • Palo Alto, California, United States, 94305
      • Stanford Hospital and Clinics
    • San Diego, California, United States, 90095
      • UCLA Medical Center
    • San Diego, California, United States, 92118
      • Southern California Research Center
    • San Francisco, California, United States, 94115
      • California Pacific Medical Center
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • MedStar Georgetown University Hospital
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic - FL
    • Miami, Florida, United States, 33136
      • University of Miami
    • Miami, Florida, United States, 33136
      • Jackson Memorial Hospital
    • Tampa, Florida, United States, 33606
      • Tampa General Medical Group
  • Georgia
    • Atlanta, Georgia, United States, 30329
      • Emory University Hospital
    • Atlanta, Georgia, United States, 30309
      • Piedmont Hospital Transplant
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals & Clinics
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • Ochsner Clinic Foundation
  • Maryland
    • Baltimore, Maryland, United States, 21202
      • Mercy Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Medical Center
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
    • Rochester, Minnesota, United States, 55902
      • Mayo Clinic - MN
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University in St. Louis
    • Saint Louis, Missouri, United States, 63110
      • Saint Louis University
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska Medical Center
  • New Jersey
    • Newark, New Jersey, United States, 07102
      • Rutgers New Jersey Medical School
  • New York
    • Bronx, New York, United States, 10467
      • Montefiore Medical Center
    • New York, New York, United States, 10016
      • NYU Langone Health
    • New York, New York, United States, 10029
      • Mount Sinai Medical Center
    • New York, New York, United States, 10021
      • Weil Cornell Medical College
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Case Western Reserve Transplant
    • Columbus, Ohio, United States, 43210
      • The Ohio State University Wexner Medical Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73112
      • Integris Baptist Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Hospital of the University of Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19102
      • Drexel University
    • Philadelphia, Pennsylvania, United States, 19107
      • Jefferson University
    • Pittsburgh, Pennsylvania, United States, 15240
      • VA Pittsburgh Healthcare System
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Dallas, Texas, United States, 75390
      • UT Southwestern Medical Center
    • Dallas, Texas, United States, 75246
      • Baylor University Medical Center
    • Dallas, Texas, United States, 75235
      • Parkland Health and Hospital System
    • Fort Worth, Texas, United States, 76104
      • Baylor Scott and White All Saints Medical Center
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine (St. Luke's)
    • Houston, Texas, United States, 77030
      • Methodist Center for Liver Disease and Transplantation
    • San Antonio, Texas, United States, 78229
      • University of Texas Health Science Center at San Antonio
    • San Antonio, Texas, United States, 78229
      • Methodist Transplant Hospital
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Medical Center
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University
    • Richmond, Virginia, United States, 23245
      • McGuire VA Medical Center
  • Washington
    • Seattle, Washington, United States, 98105
      • University of Washington
    • Seattle, Washington, United States, 98104
      • Swedish Organ Transplant and Liver Center
    • Seattle, Washington, United States, 98104
      • Harborview Medical Center/Univ. of Washington

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: Terlipressin; Terlipressin solution for injection
Placebo Comparator: 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.	Other: Placebo; Matching placebo solution for injection; Other Names: Matching Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Verified HRS Reversal	Defined as the percentage of participants with 2 consecutive SCr values ≤ 1.5 mg/dL at least 2 hours apart, while on treatment by Day 14 or discharge (on treatment defined as up to 24 hours after the final dose of study drug), per protocol.	within 15 Days
Percentage of Participants Who Were Viable (Per Protocol) for Inclusion in the Primary End Point Analysis	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 endpoint analysis	within 25 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With HRS Reversal	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	within 14 days
Percentage of Participants With Durable HRS Reversal	Defined as the percentage of participants maintaining HRS reversal without RRT to Day 30	Day 30
Percentage pf Participants in the SIRS Subgroup With HRS Reversal	Defined as the percentage of participants in the SIRS subgroup with HRS reversal by Day 14 or discharge	within 14 days
Percentage of Participants With Verified HRS Reversal Without HRS Recurrence by 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	Day 30

Collaborators and Investigators

• Sponsor: Mallinckrodt
• Investigators: Study Director: Clinical Team Lead, Mallinckrodt

Publications and helpful links

General Publications

• Wong F, Pappas SC, Curry MP, Reddy KR, Rubin RA, Porayko MK, Gonzalez SA, Mumtaz K, Lim N, Simonetto DA, Sharma P, Sanyal AJ, Mayo MJ, Frederick RT, Escalante S, Jamil K; CONFIRM Study Investigators. Terlipressin plus Albumin for the Treatment of Type 1 Hepatorenal Syndrome. N Engl J Med. 2021 Mar 4;384(9):818-828. doi: 10.1056/NEJMoa2008290.

Study record dates

Study Major Dates

• Study Start (Actual): July 13, 2016
• Primary Completion (Actual): July 24, 2019
• Study Completion (Actual): July 24, 2019

Study Registration Dates

• First Submitted: May 10, 2016
• First Submitted That Met QC Criteria: May 11, 2016
• First Posted (Estimate): May 12, 2016

Study Record Updates

• Last Update Posted (Actual): November 29, 2022
• Last Update Submitted That Met QC Criteria: November 4, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: Type 1
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Kidney Diseases; Urologic Diseases; Disease; Liver Diseases; Syndrome; Hepatorenal Syndrome; Antihypertensive Agents; Vasoconstrictor Agents; Terlipressin
• Other Study ID Numbers: MNK19013058

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: Discussion of statistical endpoints and analysis are included in manuscripts. Summary aggregate (basic) results (including adverse events information) and the study protocol are made available on clinicaltrials.gov (NCT02770716) when required by regulation. Individual de-identified patient data will not be disclosed. Requests for additional information should be directed to the company at medinfo@mnk.com.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No