A Study To Confirm Efficacy and Safety of Terlipressin in 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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT02770716
Recruitment Status : Recruiting
First Posted : May 12, 2016
Last Update Posted : December 21, 2018
Information provided by (Responsible Party):

Brief Summary:
This study is to confirm the efficacy and safety of intravenous terlipressin versus placebo in the treatment of adult subjects with hepatorenal syndrome (HRS) Type 1.

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

Detailed Description:
This is a Phase 3, randomized, double-blind, placebo-controlled, multicenter pivotal trial of terlipressin in subjects with HRS type 1. HRS is a rare syndrome of marked renal dysfunction in patients with cirrhosis, decompensated liver disease, and portal hypertension. HRS type 1 is characterized by a rapid progressive renal impairment and has a very poor prognosis with >80% mortality within 3 months. At present, there are no approved drug therapies for HRS type 1 in the US or Canada. The only curative treatment for HRS type 1 and the underlying end-stage cirrhosis is liver transplantation. However, many patients will not survive long enough to receive a liver transplant. Increased understanding of the pathophysiology of HRS type 1 has demonstrated that vasoconstrictive drug therapy may reverse HRS type 1. Substantial data available from many published clinical investigations in the literature provide compelling evidence suggesting that administration of terlipressin improves renal function in patients with HRS. A total of 300 subjects are planned to be enrolled at approximately 70 sites in the US and Canada. An interim analysis is scheduled after 150 subjects are enrolled. The study will be stopped if the pre-specified threshold for efficacy criteria is met at interim analysis.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 300 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
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)
Study Start Date : July 13, 2016
Estimated Primary Completion Date : November 2019
Estimated Study Completion Date : November 2019

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Terlipressin
Lyophilized terlipressin acetate, IV, 1 mg by bolus injection q 6 hours
Drug: Terlipressin acetate
Lyophilized terlipressin acetate, IV, 1 mg by bolus injection q 6 hours

Placebo Comparator: Placebo Comparator
Placebo, IV, 1 mg by bolus injection q 6 hours
Other: Placebo Comparator
11 mg mannitol reconstituted with 5 ml of sterile 0.9% sodium chloride solution

Primary Outcome Measures :
  1. Verified HRS Reversal [ Time Frame: Up to 14 Days ]
    Defined as the percentage of participants with 2 consecutive SCr values ≤1.5 mg/dL at least 2 hours apart.

Secondary Outcome Measures :
  1. Incidence of participants with HRS reversal [ Time Frame: Up to 14 Days ]
    Incidence of participants with HRS reversal, defined as the percentage of participants with a SCr value ≤1.5 mg/dL by Day 14 or discharge.

  2. Durability of HRS reversal [ Time Frame: Day 30 ]
    Percentage of participants with HRS reversal without RRT to Day 30.

  3. Incidence of HRS Reversal in the systemic inflammatory response syndrome (SIRS) [ Time Frame: Day 14 ]
    Defined as the percentage of SIRS participants with HRS reversal.

  4. Incidence of verified HRS reversal without HRS recurrence by Day 30 [ Time Frame: Day 30 ]
    Incidence of verified HRS reversal, defined as the percentage of participants with 2 consecutive SCr values no more than 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).

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

Inclusion Criteria:

  • Written informed consent by subject or legally authorized representative.
  • At least 18 years of age.
  • 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.

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 (eg, persisting bacteremia, persisting ascitic fluid leucocytosis, fever, increasing leucocytosis with vasomotor instability).
  • Less than 2 days anti-infective therapy for documented or suspected infection.
  • Shock.
  • Current or recent (within 4 weeks) treatment with or exposure to nephrotoxic agents: eg, aminoglycosides, amphotericin, cyclosporine A, cisplatin, nonsteroidal anti-inflammatory drugs (NSAIDs: eg, ibuprofen, naproxen, diclofenac), significant exposure to radiographic contrast agents (large doses or multiple injections of iodinated contrast media; eg, during coronary or abdominal angiogram).
  • Estimated life expectancy of less than 3 days.
  • Superimposed acute liver injury due to drugs (eg, acetaminophen), dietary supplements, herbal preparations, viral hepatitis, or toxins (eg, Amanita toxin with mushroom poisoning carbon tetrachloride), 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.

Note: Urine sediment examination is required to exclude presence of heme granular casts and other clinically significant casts.

  • Subjects known to be pregnant; all women of child-bearing age and potential must have a negative pregnancy test.
  • Severe cardiovascular disease, including, but not limited to, unstable angina, pulmonary edema, congestive heart failure requiring increasing doses of drug therapy, or persisting symptomatic peripheral vascular disease, myocardial infarction or stable chronic angina within the past 12 months, or any other cardiovascular disease judged by the investigator to be severe.
  • Current or recent (within 4 weeks) renal replacement therapy (RRT).
  • 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 (eg, norepinephrine, epinephrine or vasopressin dopamine or other vasopressors ) of at least 3 consecutive days within the prior 14-day screening period. Patients receiving a vasopressor other than midodrine within 24 hours of qualifying SCr are excluded, ie, a 24-h washout is required prior to enrollment.

Note: Patients receiving midodrine and octreotide may be enrolled. Midodrine and octreotide treatment must be stopped prior to randomization.

* Known allergy or sensitivity to terlipressin or another component of the study treatment.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02770716

Contact: Lisa Fitzgerald 800-556-3314

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Sponsors and Collaborators
Study Director: Khurram Jamil, MD Mallinckrodt

Responsible Party: Mallinckrodt Identifier: NCT02770716     History of Changes
Other Study ID Numbers: MNK19013058
First Posted: May 12, 2016    Key Record Dates
Last Update Posted: December 21, 2018
Last Verified: December 2018

Additional relevant MeSH terms:
Hepatorenal Syndrome
Pathologic Processes
Liver Diseases
Digestive System Diseases
Kidney Diseases
Urologic Diseases
Antihypertensive Agents
Vasoconstrictor Agents
Antidiuretic Agents
Natriuretic Agents
Physiological Effects of Drugs