A Multi-center, randomized, Placebo-controlled, double-blind study to confirm the reversal of Hepatorenal syndrome type 1 with Lucassin (Terlipressin) (REVERSE)

Summary

This is a phase 3 study, randomized, double-blind, and placebo-controlled . This study is designed to evaluate the efficacy and safety of intravenous Lucassin(TM) (terlipressin) versus placebo for the treatment of type 1 hepatorenal syndrome (HRS) in subjects receiving standard of care albumin therapy.
The primary objective of this study is to confirm the efficacy and safety of intravenous terlipressin versus placebo in the treatment of adult subjects with HRS type 1 receiving standard of care albumin therapy. Efficacy will be demonstrated by confirmed HRS reversal (two SCr values ? 1.5 mg/dL at least 48 hrs apart while on treatment).
Secondary Objective: To demonstrate that terlipressin reverses HRS type 1 compared to placebo.
The primary efficacy evaluation will be based on :
Confirmed HRS Reversal: the percentage of subjects with two SCr values of ? 1.5 mg/dL, at least 48 hours apart, on treatment.

Secondary Efficacy Endpoints: HRS Reversal: the percentage of subjects with at least one SCr value ? 1.5 mg/dL on treatment Transplant-free Survival up to 90 days, defined as the time (in days) that each subject survives without liver transplantation from the day of randomization. Overall Survival up to 90 days, defined as the time (in days) that each subject survives from the day of randomization
Other Efficacy Endpoints: Renal function: change from baseline through end of treatment in SCr values Glomerular filtration rate (GFR): change from baseline through end of treatment in GFR using both MDRD and Cockcroft-Gault equations Fractional excretion of sodium (FENa): change from baseline through end of treatment in FENa HRS type 1 recurrence until transplantation, hospital discharge, or Day 14, whichever occurs first. Dialysis free survival up to 90 days: defined as the time (in days) that each subject survives without dialysis from the day of randomization

Participant Eligibility

1. Written informed consent by subject or legally authorized representative
2. At least 18 years of age
3. Cirrhosis and ascites
4. Rapidly progressive reduction in renal function characterized by:
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.
5. 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 IAC are 1 g/kg on the first day (maximum 100 g) and 20 - 40 g/day thereafter as clinically indicated.41 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.