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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02770716
Recruitment Status : Completed
First Posted : May 12, 2016
Last Update Posted : May 27, 2020
Sponsor:
Information provided by (Responsible Party):
Mallinckrodt

Tracking Information
First Submitted Date  ICMJE May 10, 2016
First Posted Date  ICMJE May 12, 2016
Last Update Posted Date May 27, 2020
Actual Study Start Date  ICMJE July 13, 2016
Actual Primary Completion Date July 24, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 6, 2019)
  • 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.
  • 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
Original Primary Outcome Measures  ICMJE
 (submitted: May 11, 2016)
Verified HRS Reversal [ Time Frame: Up to 14 Days ]
Defined as the percentage of subjects with 2 consecutive SCr values ≤1.5 mg/dL at least 2 hours apart.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 6, 2019)
  • 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
  • Durability of HRS reversal [ Time Frame: Day 30 ]
    Defined as the percentage of participants maintaining HRS reversal without RRT to Day 30
  • 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
  • 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
Original Secondary Outcome Measures  ICMJE
 (submitted: May 11, 2016)
  • Incidence of subjects with HRS reversal [ Time Frame: Up to 14 Days ]
    Incidence of subjects with HRS reversal, defined as the percentage of subjects with a SCr value ≤1.5 mg/dL by Day 14 or discharge.
  • Durability of HRS reversal [ Time Frame: Day 30 ]
    Percentage of subjects with HRS reversal without RRT to Day 30.
  • Incidence of HRS Reversal in the systemic inflammatory response syndrome (SIRS) [ Time Frame: Day 14 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study To Confirm Efficacy and Safety of Terlipressin in Hepatorenal Syndrome (HRS) Type 1
Official Title  ICMJE 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)
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Hepatorenal Syndrome
Intervention  ICMJE
  • Drug: Terlipressin
    Each 6 mL vial contains 1 mg lyophilized terlipressin acetate and 10 mg mannitol in sterile 0.9% sodium chloride solution
  • Other: Placebo Comparator
    11 mg mannitol reconstituted with 5 ml of sterile 0.9% sodium chloride solution
Study Arms  ICMJE
  • 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.

    Intervention: Drug: Terlipressin
  • 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.

    Intervention: Other: Placebo Comparator
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 11, 2016)
300
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE July 24, 2019
Actual Primary Completion Date July 24, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02770716
Other Study ID Numbers  ICMJE MNK19013058
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Mallinckrodt
Study Sponsor  ICMJE Mallinckrodt
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Clinical Team Lead Mallinckrodt
PRS Account Mallinckrodt
Verification Date May 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP