Safety and Pharmacokinetics of Ifetroban in Hepatorenal Syndrome Patients
Condition: Hepatorenal Syndrome
MeSH terms: Hepatorenal Syndrome; Syndrome
Intervention: Ifetroban Injection; Placebo
Intervention description: Ifetroban sodium injectable, diluted in sterile water with 5% dextrose; Sterile water with 5% Dextrose
Intervention MeSH terms: Ifetroban
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 55.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Hepatorenal Syndrome; HRS; ifetroban

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.