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

Tracking Information

• First Submitted Date: May 10, 2016
• First Posted Date: May 12, 2016
• Last Update Posted Date: May 27, 2020
• Actual Study Start Date: July 13, 2016
• Actual Primary Completion Date: July 24, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (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 (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.

Current Secondary Outcome Measures (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 (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: 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)

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: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Hepatorenal Syndrome

Intervention

• 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

• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 11, 2016): 300
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: July 24, 2019
• Actual Primary Completion Date: July 24, 2019 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, United States

Administrative Information

• NCT Number: NCT02770716
• Other Study ID Numbers: 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

• Plan to Share IPD: No

• Responsible Party: Mallinckrodt
• Study Sponsor: Mallinckrodt
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Team Lead; Mallinckrodt

• PRS Account: Mallinckrodt
• Verification Date: May 2020