A MULTI-CENTER, DOUBLE-BLIND, RANDOMIZED, CONTROLLED STUDY TO DETERMINE THE SAFETY AND PHARMACOKINETICS OF IFETROBAN INJECTION IN HEPATORENAL SYNDROME
This Phase 2a double-blind, multi-center, randomized, controlled study will evaluate the
pharmacokinetics, safety and tolerability of ifetroban administered as daily IV doses in
recently diagnosed HRS patients. Patients will be stratified based upon Type 1 or Type II
HRS diagnosis. Cohorts of eight HRS patients (per HRS type) will be assigned
sequentially to escalating daily dose levels of ifetroban or vehicle (3:1) for assessment of
pharmacokinetics. Escalation to the next dose level will be contingent upon the safety and
tolerability of the preceding dose level as determined by a DSMB. If all regimens are
studied, a total of 64 patients will be enrolled.
The study duration will be 28 days. One of four dose regimens of ifetroban will be
administered to cohorts of 6 patients with either HRS I or HRS II, once every 24 hours,
over one hour, for three days during the Treatment Period. An additional 2 patients per
cohort will receive placebo. During the Post-Treatment Period, assessments of vital signs,
laboratory measurements and safety monitoring will continue to be performed through
Hour 168. In addition, illness severity (mortality; requirements for continued
hospitalization, intensive care) will be evaluated at Day 28.
The 28 day study period will be preceded by a 48-hour screening period. During this
period, patients will be consented for participation, and then screened for eligibility.
Inclusion into the study will require that the patient meets one of the protocol specified
criteria for oliguria (see Section 5.2.1). Thus patients must either be observed to have a
protocol specified reduction in urine output for a required amount of time, or have
reduced urine output in the presence of a fluid challenge. A patient will then be
randomized for CTM treatment provided no significant improvement in renal function
occurs and he/she meets all other eligibility criteria.
To be considered eligible to participate in this study, a subject must meet the following
1. Chronic liver disease, defined as cirrhosis with ascites based on clinical findings
(biopsy not necessary).
2. Subjects with either Type 1 or Type 2 renal dysfunction defined as follows:
a. Type 1:
i. At least a doubling of the initial serum creatinine to >220 [MICRO-SYMBOL]mol/L
(2.5 mg/dL), occurring over a period of less than 2 weeks.
ii. A 50% or greater reduction in the initial 24-hour creatinine
clearance to <20 mL/min occurring over a period of less than
b. Type 2: defined as at least a 33% reduction in creatinine clearance
occurring over a period of greater than 2 weeks, with a serum creatinine
>133[MICRO-SYMBOL]mol/L (1.5 mg/dL).
3. Oliguria occurring within 48 hours prior to 1st administration CTM. Oliguria is
defined as either of the following:
a. An average urine output of <35 mL/hr measured for at least 4 hours,
occurring with a measured central venous pressure (CVP) >12 mmHg.
b. In the absence of CVP monitoring, oliguria that is not corrected by a fluid
challenge of at least 20mL/kg isotonic crystalloid or comparable volume