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

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.

Inclusion Criteria:

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.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:

1. Serum creatinine > 7 mg/dL

2. 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.

3. 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.

4. < 2 days anti-infective therapy for documented or suspected infection

5. Proteinuria > 500 mg/day

6. Hematuria or microhematuria (> 50 red blood cells per high power field)

7. 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).

8. Evidence of intrinsic or parenchymal renal disease (including acute tubular necrosis)

9. Obstructive uropathy or other renal pathology on ultrasound or other medical imaging

10. 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.

11. Current or recent (within 4 weeks) renal replacement therapy

12. 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)

13. Current or recent treatment (within 48 hours) with octreotide, midodrine,
vasopressin, dopamine or other vasopressors

14. Severe cardiovascular disease as judged by investigator

15. Estimated life expectancy of less than 3 days

16. Confirmed pregnancy

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

18. Participation in other clinical research studies involving the evaluation of other
investigational drugs or devices within 30 days of randomization.