Safety and Pharmacokinetics of Ifetroban in Hepatorenal Syndrome Patients

Overview

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.

Full Title of Study: “A Multi-Center, Double-Blind, Randomized, Controlled Study to Determine the Safety and Pharmacokinetics of Ifetroban Injection in Hepatorenal Syndrome”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Triple (Participant, Care Provider, Investigator)
  • Study Primary Completion Date: June 2015

Interventions

  • Drug: Ifetroban Injection
    • Ifetroban sodium injectable, diluted in sterile water with 5% dextrose
  • Drug: Placebo
    • Sterile water with 5% Dextrose

Arms, Groups and Cohorts

  • Experimental: 5 mg ifetroban, Type 1
    • 60-minute intravenous infusion of 5 mg ifetroban given once daily for 3 days to subjects with Type 1 HRS.
  • Placebo Comparator: Placebo, Type 1
    • 60-minute intravenous infusion of 5% dextrose in sterile water given once daily for 3 days to subjects with Type 1 HRS.
  • Experimental: 5 mg ifetroban, Type 2
    • 60-minute intravenous infusion of 5 mg ifetroban given once daily for 3 days to subjects with Type 1 HRS.
  • Experimental: 15 mg ifetroban, Type 1
    • 60-minute intravenous infusion of 15 mg ifetroban given once daily for 3 days to subjects with Type 1 HRS.
  • Experimental: 15 mg ifetroban, Type 2
    • 60-minute intravenous infusion of 15 mg ifetroban given once daily for 3 days to subjects with Type 2 HRS.
  • Experimental: 50 mg ifetroban, Type 1
    • 60-minute intravenous infusion of 50 mg ifetroban given once daily for 3 days to subjects with Type 1 HRS.
  • Experimental: 50 mg ifetroban, Type 2
    • 60-minute intravenous infusion of 50 mg ifetroban given once daily for 3 days to subjects with Type 2 HRS.
  • Experimental: 150 mg ifetroban, Type 2
    • 60-minute intravenous infusion of 150 mg ifetroban given once daily for 3 days to subjects with Type 2 HRS.
  • Placebo Comparator: Placebo, Type 2
    • 60-minute intravenous infusion of 5% dextrose in sterile water given once daily for 3 days to subjects with Type 2 HRS.

Clinical Trial Outcome Measures

Primary Measures

  • Half-life (T-1/2) of Ifetroban and Ifetroban Acylglucuronide
    • Time Frame: 3 days
    • Plasma concentrations of ifetroban and its major active metabolite were measured at Baseline and Study Hours 1, 2, 4, 8, 12, 24, 48, 49, 50, 52, 56, 60, and 72 to determine the Pharmacokinetic parameters.
  • Pharmacokinetic Parameters (Exposure) of Ifetroban and Ifetroban Acylglucuronide After Three Days of Treatment
    • Time Frame: 3 days
    • Plasma concentrations of ifetroban and its primary active metabolite were measured at Baseline and Study Hours 1, 2, 4, 8, 12, 24, 48, 49, 50, 52, 56, 60, and 72 to determine the Pharmacokinetic parameters.
  • Pharmacokinetic Parameters (Concentration) of Ifetroban and Ifetroban Acylglucuronide After Three Days of Treatment
    • Time Frame: 3 days
    • Plasma concentrations of ifetroban and it’s major active metabolite were measured at Baseline and Study Hours 1, 2, 4, 8, 12, 24, 48, 49, 50, 52, 56, 60, and 72 to determine the Pharmacokinetic parameters.

Secondary Measures

  • Safety: Day 28 Mortality
    • Time Frame: 28 days
  • Percentage of Patients Achieving a Treatment-period Serum Creatinine Reduction Below 1.5 mg/dL
    • Time Frame: Day 0 through Day 5
  • The Percentage of Patients Achieving a Reduction of Creatinine Clearance to Below Baseline on Two Consecutive Daily Measurements
    • Time Frame: Day 0 to Day 5
  • Change in 24-hour Urine Volume
    • Time Frame: Baseline to Hour 96
    • The volume of urine collected in a 24-hour post-treatment period minus the volume collected in a 24-hour pre-treatment period.

Participating in This Clinical Trial

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.

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Cumberland Pharmaceuticals
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Brendan McGuire, MD, Principal Investigator, University of Alabama at Birmingham

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