Safety and Pharmacokinetics of Ifetroban in Hepatorenal Syndrome Patients

Study Overview
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Brief Summary
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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.

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

Conditions
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Hepatorenal Syndrome

Intervention / Treatment
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* Drug: Ifetroban Injection
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Chronic liver disease, defined as cirrhosis with ascites based on clinical findings (biopsy not necessary). 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). 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: History of allergy or hypersensitivity to ifetroban Pregnant or nursing Less than 18 years of age Serum creatinine at the time of enrollment greater than or equal to 5.0 mg/dL Platelet count at screening less than 30 x 10^3 platelets/µL Anticipated of planned need for dialysis within 5 days of first CTM dose. Active gastrointestinal hemorrhage (where active is defined as evidence of bleeding within 48 hours of the first dose of CTM) 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. 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. Presence of shock defined as hypotension, with a mean arterial pressure less than 50 mmHG. New York Heart Association class 3 or 4 heart failure. Presence of hepatocellular carcinoma not transplantable by Milan criteria Cardiopulmonary arrest without full recovery of mental status Moribund and death expected within five days Bacterial or fungal infections which have been unresponsive to at least 24 hours of appropriate antimicrobial therapy Burns > 30% body surface area Exposed to investigational drugs within 30 days before 1st CTM administration. 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). Refusal to provide written authorization for use and disclosure of protected health information. Be otherwise unsuitable for the study, in the opinion of the Investigator.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 5 mg ifetroban, Type 1<br>60-minute intravenous infusion of 5 mg ifetroban given once daily for 3 days to subjects with Type 1 HRS. | Drug: Ifetroban Injection<br>* Ifetroban sodium injectable, diluted in sterile water with 5% dextrose<br>|
| Placebo Comparator: Placebo, Type 1<br>60-minute intravenous infusion of 5% dextrose in sterile water given once daily for 3 days to subjects with Type 1 HRS. | Drug: Placebo<br>* Sterile water with 5% Dextrose<br>* Other names: D5W;|
| Experimental: 5 mg ifetroban, Type 2<br>60-minute intravenous infusion of 5 mg ifetroban given once daily for 3 days to subjects with Type 1 HRS. | Drug: Ifetroban Injection<br>* Ifetroban sodium injectable, diluted in sterile water with 5% dextrose<br>|
| Experimental: 15 mg ifetroban, Type 1<br>60-minute intravenous infusion of 15 mg ifetroban given once daily for 3 days to subjects with Type 1 HRS. | Drug: Ifetroban Injection<br>* Ifetroban sodium injectable, diluted in sterile water with 5% dextrose<br>|
| Experimental: 15 mg ifetroban, Type 2<br>60-minute intravenous infusion of 15 mg ifetroban given once daily for 3 days to subjects with Type 2 HRS. | Drug: Ifetroban Injection<br>* Ifetroban sodium injectable, diluted in sterile water with 5% dextrose<br>|
| Experimental: 50 mg ifetroban, Type 1<br>60-minute intravenous infusion of 50 mg ifetroban given once daily for 3 days to subjects with Type 1 HRS. | Drug: Ifetroban Injection<br>* Ifetroban sodium injectable, diluted in sterile water with 5% dextrose<br>|
| Experimental: 50 mg ifetroban, Type 2<br>60-minute intravenous infusion of 50 mg ifetroban given once daily for 3 days to subjects with Type 2 HRS. | Drug: Ifetroban Injection<br>* Ifetroban sodium injectable, diluted in sterile water with 5% dextrose<br>|
| Experimental: 150 mg ifetroban, Type 2<br>60-minute intravenous infusion of 150 mg ifetroban given once daily for 3 days to subjects with Type 2 HRS. | Drug: Ifetroban Injection<br>* Ifetroban sodium injectable, diluted in sterile water with 5% dextrose<br>|
| Placebo Comparator: Placebo, Type 2<br>60-minute intravenous infusion of 5% dextrose in sterile water given once daily for 3 days to subjects with Type 2 HRS. | Drug: Placebo<br>* Sterile water with 5% Dextrose<br>* Other names: D5W;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Half-life (T-1/2) of Ifetroban and Ifetroban Acylglucuronide | 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. | 3 days | 
| Pharmacokinetic Parameters (Exposure) of Ifetroban and Ifetroban Acylglucuronide After Three Days of Treatment | 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. | 3 days | 
| Pharmacokinetic Parameters (Concentration) of Ifetroban and Ifetroban Acylglucuronide After Three Days of Treatment | 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. | 3 days | 

Secondary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatorenal Syndrome, HRS, ifetroban