A Placebo-Controlled, Double-Blind Study to Confirm the Reversal of Hepatorenal Syndrome Type 1 With Terlipressin

Study Overview
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Brief Summary
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This study is designed to evaluate the efficacy and safety of intravenous terlipressin versus placebo for the treatment of type 1 hepatorenal syndrome (HRS) in participants receiving standard of care albumin therapy.

Detailed Description
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Hepatorenal syndrome is a rare syndrome of marked renal dysfunction in patients with cirrhosis, decompensated liver disease, and portal hypertension. Hepatorenal syndrome 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, Australia, 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 and therapy, which may provide a bridge to transplantation, is badly needed. 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.

Official Title
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A Multi-Center, Randomized, Placebo-controlled, Double-Blind Study to Confirm the Reversal of Hepatorenal Syndrome Type 1 With Lucassin® (Terlipressin) (The REVERSE Study)

Conditions
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Hepatorenal Syndrome

Intervention / Treatment
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* Drug: Terlipressin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent by subject or legally authorized representative At least 18 years of age Cirrhosis and ascites Rapidly progressive reduction in renal function characterized by: Serum creatinine (SCr) ≥ 2.5 mg/dL Doubling of SCr within 2 weeks (or for observations of shorter duration, SCr values over time meeting slope-based criteria for proportional increases likely to be representative of at least a doubling within 2 weeks No sustained improvement in renal function (< 20% decrease in SCr and SCr ≥ 2.25 mg/dL) 48 hours after both diuretic withdrawal and the beginning of plasma volume expansion with albumin: Note: Albumin doses recommended by the International Ascites Club (IAC) are 1 g/kg on the first day (Maximum 100 g) and 20 - 40 g/day thereafter as clinically indicated. It is recommended (if clinically appropriate) that the albumin dose is kept constant during the study drug administration period. Note: The qualifying SCr value is the SCr value at least 48 hrs after both diuretic withdrawal (if applicable) and the beginning of albumin fluid challenge. The qualifying SCr value must be ≥ 2.25 mg/dL AND at least 80% of the diagnostic (pre-fluid challenge) SCr value. Exclusion Criteria: SCr > 7 mg/dL Shock Note: Hypotension (Mean Arterial Pressure < 70 mm Hg or a decrease > 40 mm Hg in systolic blood pressure from baseline) with evidence of hypoperfusion abnormalities despite adequate fluid resuscitation. Sepsis or systemic inflammatory response syndrome (SIRS) Note: SIRS: Presence of 2 or more of the following findings: Temperature > 38°C or < 36°C; heart rate > 90/min; respiratory rate of > 20/min or a PaCO2 of < 32 mm Hg; white blood cell count of > 12,000 cells/µL or < 4,000/ µL. Note: Sepsis: Documented infection and systemic inflammatory response syndrome. < 2 days anti-infective therapy for documented or suspected infection Proteinuria > 500 mg/day Hematuria or microhematuria (> 50 red blood cells per high power field) Clinically significant casts on urinalysis, including granular casts Note: Urine sediment examination is required to exclude presence of granular casts and other clinically significant casts [e.g., red blood cell (RBC) casts]. Evidence of intrinsic or parenchymal renal disease (including acute tubular necrosis) Obstructive uropathy or other renal pathology on ultrasound or other medical imaging Current or recent treatment (within 4 weeks) with nephrotoxic drugs, e.g., aminoglycosides, nonsteroidal anti-inflammatory drugs (NSAID) Note: Up to 3 doses of an NSAID within the prior month (prescription or over the counter) is acceptable Note: Use of short-term (< 2 weeks) oral neomycin for acute encephalopathy is acceptable. Current or recent (within 4 weeks) renal replacement therapy Superimposed acute liver failure/injury due to factors other than alcoholic hepatitis, including acute viral hepatitis, drugs, medications (e.g., acetaminophen), or other toxins (e.g., mushroom [Amanita] poisoning) Current or recent treatment (within 48 hours) with octreotide, midodrine, vasopressin, dopamine or other vasopressors Severe cardiovascular disease as judged by investigator Estimated life expectancy of less than 3 days Confirmed pregnancy Known allergy or sensitivity to terlipressin or another component of the study treatment Participation in other clinical research studies involving the evaluation of other investigational drugs or devices within 30 days of randomization

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Terlipressin<br>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<br>* Each 6 mL vial contains 1 mg lyophilized terlipressin acetate and 10 mg mannitol in sterile 0.9% sodium chloride solution.<br>* Other names: Lucassin®;|
| Placebo Comparator: Placebo<br>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. | Drug: Placebo<br>* 11 mg mannitol reconstituted with 5 ml of sterile 0.9% sodium chloride solution.<br>* Other names: Saline;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Confirmed Hepatorenal Syndrome (HRS) Reversal | Confirmed HRS Reversal: The percentage of participants with two serum creatinine (SCr) values of ≤ 1.5 mg/dL at least 48 hours apart, on treatment, and without intervening renal replacement therapy or liver transplant. | within 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With HRS Reversal | HRS reversal is defined as at least one SCr value of ≤ 1.5 mg/dL on treatment (up to 24 hours after the last dose of study medication). | within 14 days | 
| Percentage of Participants With Transplant-free Survival | Transplant-Free Survival up to 90 days, defined as the time (in days) that each participant survives without liver transplantation from the day of randomization. | Up to 90 days | 
| Percentage of Participants With Overall Survival | Overall Survival up to 90 days, defined as the time (in days) that each participant survives from the day of randomization. | Up to 90 days | 
| Percentage of Participants With Serious Adverse Events | Clinically significant changes in vital signs, height, weight, immunogenicity and laboratory assessments which qualified for the definition of serious adverse event are reported. | Up to 30 days post treatment (within 44 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatorenal syndrome, Renal failure, Cirrhosis, Alcoholic hepatitis, Ascites