A Study To Confirm Efficacy and Safety of Terlipressin in HRS Type 1

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.

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.