Safety and Pharmacokinetics of Ifetroban in Hepatorenal Syndrome Patients

Hepatorenal Syndrome Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01436500
• Other study ID #: CPI-IFE-001
• Status: Completed
• Phase: Phase 2
• First received: August 31, 2011
• Last updated: February 27, 2017
• Start date: October 2011
• Est. completion date: July 2015

Study information

• Verified date: February 2017
• Source: Cumberland Pharmaceuticals
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 55
• Est. completion date: July 2015
• Est. primary completion date: June 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Hepatorenal Syndrome
• Syndrome

Intervention

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

Locations

Country	Name	City	State
India	MIDAS Multispeciality Hospital PVT LTD	Nagpur	Maharashtra
United States	University of Michigan Hospital	Ann Arbor	Michigan
United States	Emory University Hospital	Atlanta	Georgia
United States	The Ohio State University	Columbus	Ohio
United States	Baylor All Saints Medical Center	Fort Worth	Texas
United States	Indiana University (Division of Gastroenterology/Hepatology)	Indianapolis	Indiana
United States	UCSD, Hillcrest Medical Center Hospital	La Jolla	California
United States	NYU Langone Medical Center	New York	New York
United States	Mayo Clinic - Arizona	Phoenix	Arizona
United States	Virginia Commonwealth University	Richmond	Virginia
United States	University of Utah Health Sciences Center	Salt Lake City	Utah
United States	UCSF (University of California-San Francisco)	San Francisco	California

Sponsors (1)

Lead Sponsor	Collaborator
Cumberland Pharmaceuticals

Countries where clinical trial is conducted

United States,  India, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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	Safety: Day 28 Mortality		28 days
Secondary	Percentage of Patients Achieving a Treatment-period Serum Creatinine Reduction Below 1.5 mg/dL		Day 0 through Day 5
Secondary	The Percentage of Patients Achieving a Reduction of Creatinine Clearance to Below Baseline on Two Consecutive Daily Measurements		Day 0 to Day 5
Secondary	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