Clinical trial NCT01436500: Safety and Pharmacokinetics of Ifetroban in Hepatorenal Syndrome Patients
Official title: A Multi-Center, Double-Blind, Randomized, Controlled Study to Determine the Safety and Pharmacokinetics of Ifetroban Injection in Hepatorenal Syndrome
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hepatorenal Syndrome
Keywords: Hepatorenal Syndrome
HRS
ifetroban
Lead sponsor: Cumberland Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2011-09-19
Enrollment: 55
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: A study of ifetroban in the treatment of hepatorenal syndrome (HRS) in hospitalized adult patients to assess the safety and pharmacokinetics of 3 days of intravenous ifetroban.


Eligibility criteria: Inclusion Criteria:

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 HRS defined in a and b below:

   a. Type 1: i. At least a doubling of the serum creatinine to a minimum of 220 µmol/L (2.5 mg/dL) at enrollment, occurring over a period of less than 14 days, OR ii. A 50% or greater reduction in the estimated glomerular filtration rate (GFR - calculated by the method of Cockcroft-Gault) to below 20 mL/min at enrollment occurring over a period of less than 14 days.

   iii. A projected doubling of serum creatinine to a minimum of 2.5 mg/dL, expected to occur in less than 14 days based on the rate of change observed.

   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 (SCr) \> 133µmol/L (1.5 mg/dL).
3. Oliguria occurring within 48 hours prior to the first administration CTM. Oliguria is defined as an average urine output of \< 35 mL/hr (measured for a minimum of 4 hours) under either of the following circumstances:

   a. When measured central venous pressure (CVP) \> 12 mmHg, OR b. following a fluid challenge consisting of either: i. at minimum 20 mL/kg isotonic fluid (e.g. any combination of 5% albumin, normal saline, blood or blood products) given over no more than 6 hours ii. at minimum 1 g/kg of hypertonic fluid (e.g. 25% albumin) given over no more than 24 hours iii. an equivalent combination of 3.b.i and 3.b.ii

Exclusion Criteria:

1. History of allergy or hypersensitivity to ifetroban
2. Pregnant or nursing
3. Less than 18 years of age
4. Serum creatinine at the time of enrollment greater than or equal to 5.0 mg/dL
5. Platelet count at screening less than 30 x 10\^3 platelets/µL
6. Anticipated of planned need for dialysis within 5 days of first CTM dose.
7. Active gastrointestinal hemorrhage (where active is defined as evidence of bleeding within 48 hours of the first dose of CTM)
8. Evidence of current (within past 30 days) obstructive (post-renal) or intrinsic renal disease \[including but not limited to: acute tubular necrosis (ATN), glomerular diseases/glomerulonephritis, acute interstitial nephritis (AIN), known urinary obstruction, proteinuria \> 500 mg/day, microhematuria (\> 50 RBCs/high power field), abnormal renal ultrasound, fractional excretion of sodium (FeNa) \> 2.0%, any urinary casts other than hyaline.
9. Current or recent (within the preceding 5 days) treatment with nephrotoxic drugs including but not limited to: NSAIDs (prior 48 hours), angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), calcineurin inhibitors (cyclosporine, tacrolimus), aminoglycosides, amphotericin B, antiretrovirals and antivirals (adefovir, cidofovir, tenofovir, acyclovir, indinavir), cisplatin, methotrexate, cyclosporine, amphotericin B contrast agents, foscarnet, zoledronate, etc.
10. Presence of shock defined as hypotension, with a mean arterial pressure less than 50 mmHG.
11. New York Heart Association class 3 or 4 heart failure.
12. Presence of hepatocellular carcinoma not transplantable by Milan criteria
13. Cardiopulmonary arrest without full recovery of mental status
14. Moribund and death expected within five days
15. Bacterial or fungal infections which have been unresponsive to at least 24 hours of appropriate antimicrobial therapy
16. Burns \> 30% body surface area
17. Exposed to investigational drugs within 30 days before 1st CTM administration.
18. Inability to understand the requirements of the study. (Subjects must be willing to provide written informed consent or consent of legally recognized representative, as evidenced by signature on an informed consent document approved by an Institutional Review Board \[IRB\], and agree to abide by the study restrictions. If the subject is incapacitated, informed consent will be sought from a legally recognized representative).
19. Refusal to provide written authorization for use and disclosure of protected health information.
20. Be otherwise unsuitable for the study, in the opinion of the Investigator.

Primary outcomes:
measure: Half-life (T-1/2) of Ifetroban and Ifetroban Acylglucuronide
timeFrame: 3 days
measure: Pharmacokinetic Parameters (Exposure) of Ifetroban and Ifetroban Acylglucuronide After Three Days of Treatment
timeFrame: 3 days
measure: Pharmacokinetic Parameters (Concentration) of Ifetroban and Ifetroban Acylglucuronide After Three Days of Treatment
timeFrame: 3 days
Secondary outcomes:
measure: Safety: Day 28 Mortality
timeFrame: 28 days
measure: Percentage of Patients Achieving a Treatment-period Serum Creatinine Reduction Below 1.5 mg/dL
timeFrame: Day 0 through Day 5
measure: The Percentage of Patients Achieving a Reduction of Creatinine Clearance to Below Baseline on Two Consecutive Daily Measurements
timeFrame: Day 0 to Day 5
measure: Change in 24-hour Urine Volume
timeFrame: Baseline to Hour 96
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic - Arizona
state: Arizona
city: La Jolla
country: United States
facility: UCSD, Hillcrest Medical Center Hospital
state: California
city: San Francisco
country: United States
facility: UCSF (University of California-San Francisco)
state: California
city: Atlanta
country: United States
facility: Emory University Hospital
state: Georgia
city: Indianapolis
country: United States
facility: Indiana University (Division of Gastroenterology/Hepatology)
state: Indiana
city: Ann Arbor
country: United States
facility: University of Michigan Hospital
state: Michigan
city: New York
country: United States
facility: NYU Langone Medical Center
state: New York
city: Columbus
country: United States
facility: The Ohio State University
state: Ohio
city: Fort Worth
country: United States
facility: Baylor All Saints Medical Center
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah Health Sciences Center
state: Utah
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: Nagpur
country: India
facility: MIDAS Multispeciality Hospital PVT LTD
state: Maharashtra
Study officials:
affiliation: University of Alabama at Birmingham
name: Brendan McGuire, MD
role: PRINCIPAL_INVESTIGATOR
References: