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

Primary Purpose

Hepatorenal Syndrome

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Terlipressin
Placebo
Sponsored by
Mallinckrodt
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hepatorenal Syndrome focused on measuring Type 1

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University of Alabama at Birmingham
  • Banner Good Samaritan Medical Center
  • Mayo Clinic - AZ
  • University of Arizona
  • USC Healthcare
  • Stanford Hospital and Clinics
  • UCLA Medical Center
  • Southern California Research Center
  • California Pacific Medical Center
  • MedStar Georgetown University Hospital
  • University of Florida
  • Mayo Clinic - FL
  • Jackson Memorial Hospital
  • University of Miami
  • Tampa General Medical Group
  • Piedmont Hospital Transplant
  • Emory University Hospital
  • Northwestern University
  • Rush University Medical Center
  • University of Iowa Hospitals & Clinics
  • University of Kansas Medical Center
  • Ochsner Clinic Foundation
  • Mercy Medical Center
  • Beth Israel Deaconess Medical Center
  • University of Michigan Medical Center
  • University of Minnesota
  • Mayo Clinic - MN
  • Saint Louis University
  • Washington University in St. Louis
  • University of Nebraska Medical Center
  • Rutgers New Jersey Medical School
  • Montefiore Medical Center
  • NYU Langone Health
  • Weil Cornell Medical College
  • Mount Sinai Medical Center
  • Case Western Reserve Transplant
  • The Ohio State University Wexner Medical Center
  • INTEGRIS Baptist Medical Center
  • Drexel University
  • Hospital of the University of Pennsylvania
  • Jefferson University
  • VA Pittsburgh Healthcare System
  • Medical University of South Carolina
  • Vanderbilt University Medical Center
  • Parkland Health and Hospital System
  • Baylor University Medical Center
  • UT Southwestern Medical Center
  • Baylor Scott and White All Saints Medical Center
  • Baylor College of Medicine (St. Luke's)
  • Methodist Center for Liver Disease and Transplantation
  • Methodist Transplant Hospital
  • University of Texas Health Science Center at San Antonio
  • University of Utah
  • University of Virginia Medical Center
  • McGuire VA Medical Center
  • Virginia Commonwealth University
  • Harborview Medical Center/Univ. of Washington
  • Swedish Organ Transplant and Liver Center
  • University of Washington
  • Vancouver General Hospital, Gordon and Leslie Diamond Health Care Centre
  • Ottawa Hospital
  • University of Toronto 9N/983 Toronto General Hospital
  • McGill University Health Centre
  • Centre Hospitalier de l'Université de Montréal

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Terlipressin

Placebo

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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.
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

Secondary Outcome Measures

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
Percentage of Participants With Durable HRS Reversal
Defined as the percentage of participants maintaining HRS reversal without RRT to 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
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

Full Information

First Posted
May 10, 2016
Last Updated
November 4, 2022
Sponsor
Mallinckrodt
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1. Study Identification

Unique Protocol Identification Number
NCT02770716
Brief Title
Study To Confirm Efficacy and Safety of Terlipressin in Hepatorenal Syndrome (HRS) Type 1
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)
Study Type
Interventional

2. Study Status

Record Verification Date
November 2022
Overall Recruitment Status
Completed
Study Start Date
July 13, 2016 (Actual)
Primary Completion Date
July 24, 2019 (Actual)
Study Completion Date
July 24, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Mallinckrodt

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hepatorenal Syndrome
Keywords
Type 1

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
300 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Terlipressin
Arm Type
Experimental
Arm Description
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.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Terlipressin
Intervention Description
Terlipressin solution for injection
Intervention Type
Other
Intervention Name(s)
Placebo
Other Intervention Name(s)
Matching Placebo
Intervention Description
Matching placebo solution for injection
Primary Outcome Measure Information:
Title
Percentage of Participants With Verified HRS Reversal
Description
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.
Time Frame
within 15 Days
Title
Percentage of Participants Who Were Viable (Per Protocol) for Inclusion in the Primary End Point Analysis
Description
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
Time Frame
within 25 days
Secondary Outcome Measure Information:
Title
Percentage of Participants With HRS Reversal
Description
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
Time Frame
within 14 days
Title
Percentage of Participants With Durable HRS Reversal
Description
Defined as the percentage of participants maintaining HRS reversal without RRT to Day 30
Time Frame
Day 30
Title
Percentage pf Participants in the SIRS Subgroup With HRS Reversal
Description
Defined as the percentage of participants in the SIRS subgroup with HRS reversal by Day 14 or discharge
Time Frame
within 14 days
Title
Percentage of Participants With Verified HRS Reversal Without HRS Recurrence by Day 30
Description
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
Time Frame
Day 30

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Clinical Team Lead
Organizational Affiliation
Mallinckrodt
Official's Role
Study Director
Facility Information:
Facility Name
University of Alabama at Birmingham
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35294
Country
United States
Facility Name
Banner Good Samaritan Medical Center
City
Phoenix
State/Province
Arizona
ZIP/Postal Code
85006
Country
United States
Facility Name
Mayo Clinic - AZ
City
Phoenix
State/Province
Arizona
ZIP/Postal Code
85057
Country
United States
Facility Name
University of Arizona
City
Tucson
State/Province
Arizona
ZIP/Postal Code
85724
Country
United States
Facility Name
USC Healthcare
City
Los Angeles
State/Province
California
ZIP/Postal Code
90033
Country
United States
Facility Name
Stanford Hospital and Clinics
City
Palo Alto
State/Province
California
ZIP/Postal Code
94305
Country
United States
Facility Name
UCLA Medical Center
City
San Diego
State/Province
California
ZIP/Postal Code
90095
Country
United States
Facility Name
Southern California Research Center
City
San Diego
State/Province
California
ZIP/Postal Code
92118
Country
United States
Facility Name
California Pacific Medical Center
City
San Francisco
State/Province
California
ZIP/Postal Code
94115
Country
United States
Facility Name
MedStar Georgetown University Hospital
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20007
Country
United States
Facility Name
University of Florida
City
Gainesville
State/Province
Florida
ZIP/Postal Code
32610
Country
United States
Facility Name
Mayo Clinic - FL
City
Jacksonville
State/Province
Florida
ZIP/Postal Code
32224
Country
United States
Facility Name
Jackson Memorial Hospital
City
Miami
State/Province
Florida
ZIP/Postal Code
33136
Country
United States
Facility Name
University of Miami
City
Miami
State/Province
Florida
ZIP/Postal Code
33136
Country
United States
Facility Name
Tampa General Medical Group
City
Tampa
State/Province
Florida
ZIP/Postal Code
33606
Country
United States
Facility Name
Piedmont Hospital Transplant
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30309
Country
United States
Facility Name
Emory University Hospital
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30329
Country
United States
Facility Name
Northwestern University
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
Rush University Medical Center
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60612
Country
United States
Facility Name
University of Iowa Hospitals & Clinics
City
Iowa City
State/Province
Iowa
ZIP/Postal Code
52242
Country
United States
Facility Name
University of Kansas Medical Center
City
Kansas City
State/Province
Kansas
ZIP/Postal Code
66160
Country
United States
Facility Name
Ochsner Clinic Foundation
City
New Orleans
State/Province
Louisiana
ZIP/Postal Code
70121
Country
United States
Facility Name
Mercy Medical Center
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21202
Country
United States
Facility Name
Beth Israel Deaconess Medical Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
University of Michigan Medical Center
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
Facility Name
University of Minnesota
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55455
Country
United States
Facility Name
Mayo Clinic - MN
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55902
Country
United States
Facility Name
Saint Louis University
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Washington University in St. Louis
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
University of Nebraska Medical Center
City
Omaha
State/Province
Nebraska
ZIP/Postal Code
68198
Country
United States
Facility Name
Rutgers New Jersey Medical School
City
Newark
State/Province
New Jersey
ZIP/Postal Code
07102
Country
United States
Facility Name
Montefiore Medical Center
City
Bronx
State/Province
New York
ZIP/Postal Code
10467
Country
United States
Facility Name
NYU Langone Health
City
New York
State/Province
New York
ZIP/Postal Code
10016
Country
United States
Facility Name
Weil Cornell Medical College
City
New York
State/Province
New York
ZIP/Postal Code
10021
Country
United States
Facility Name
Mount Sinai Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10029
Country
United States
Facility Name
Case Western Reserve Transplant
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44106
Country
United States
Facility Name
The Ohio State University Wexner Medical Center
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States
Facility Name
INTEGRIS Baptist Medical Center
City
Oklahoma City
State/Province
Oklahoma
ZIP/Postal Code
73112
Country
United States
Facility Name
Drexel University
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19102
Country
United States
Facility Name
Hospital of the University of Pennsylvania
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
Jefferson University
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19107
Country
United States
Facility Name
VA Pittsburgh Healthcare System
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15240
Country
United States
Facility Name
Medical University of South Carolina
City
Charleston
State/Province
South Carolina
ZIP/Postal Code
29425
Country
United States
Facility Name
Vanderbilt University Medical Center
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232
Country
United States
Facility Name
Parkland Health and Hospital System
City
Dallas
State/Province
Texas
ZIP/Postal Code
75235
Country
United States
Facility Name
Baylor University Medical Center
City
Dallas
State/Province
Texas
ZIP/Postal Code
75246
Country
United States
Facility Name
UT Southwestern Medical Center
City
Dallas
State/Province
Texas
ZIP/Postal Code
75390
Country
United States
Facility Name
Baylor Scott and White All Saints Medical Center
City
Fort Worth
State/Province
Texas
ZIP/Postal Code
76104
Country
United States
Facility Name
Baylor College of Medicine (St. Luke's)
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Methodist Center for Liver Disease and Transplantation
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Methodist Transplant Hospital
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78229
Country
United States
Facility Name
University of Texas Health Science Center at San Antonio
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78229
Country
United States
Facility Name
University of Utah
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84132
Country
United States
Facility Name
University of Virginia Medical Center
City
Charlottesville
State/Province
Virginia
ZIP/Postal Code
22908
Country
United States
Facility Name
McGuire VA Medical Center
City
Richmond
State/Province
Virginia
ZIP/Postal Code
23245
Country
United States
Facility Name
Virginia Commonwealth University
City
Richmond
State/Province
Virginia
ZIP/Postal Code
23298
Country
United States
Facility Name
Harborview Medical Center/Univ. of Washington
City
Seattle
State/Province
Washington
ZIP/Postal Code
98104
Country
United States
Facility Name
Swedish Organ Transplant and Liver Center
City
Seattle
State/Province
Washington
ZIP/Postal Code
98104
Country
United States
Facility Name
University of Washington
City
Seattle
State/Province
Washington
ZIP/Postal Code
98105
Country
United States
Facility Name
Vancouver General Hospital, Gordon and Leslie Diamond Health Care Centre
City
Vancouver
State/Province
British Columbia
ZIP/Postal Code
V5Z IM9
Country
Canada
Facility Name
Ottawa Hospital
City
Ottawa
State/Province
Ontario
ZIP/Postal Code
K1H 8L6
Country
Canada
Facility Name
University of Toronto 9N/983 Toronto General Hospital
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G2C4
Country
Canada
Facility Name
McGill University Health Centre
City
Montréal
ZIP/Postal Code
H4A3J1
Country
Canada
Facility Name
Centre Hospitalier de l'Université de Montréal
City
Québec
ZIP/Postal Code
H2X3J4
Country
Canada

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing 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.
Citations:
PubMed Identifier
33657294
Citation
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.
Results Reference
derived

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

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