Safety and Pharmacokinetics of Ifetroban in Hepatorenal Syndrome Patients

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Cumberland Pharmaceuticals
ClinicalTrials.gov Identifier:
NCT01436500
First received: August 31, 2011
Last updated: December 1, 2015
Last verified: December 2015
  Purpose
Cumberland Pharmaceuticals Inc. (CPI) is developing ifetroban for treatment of hepatorenal syndrome (HRS) and proposes to conduct a study in hospitalized adult patients with HRS to assess the safety and pharmacokinetics of escalating doses of ifetroban.

Condition Intervention Phase
Hepatorenal Syndrome
Drug: 5mg Ifetroban Injection
Drug: 15mg Ifetroban Injection
Drug: 50mg Ifetroban Injection
Drug: 150mg Ifetroban Injection
Other: 5% Dextrose in Water
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Basic Science
Official Title: A Multi-Center, Double-Blind, Randomized, Controlled Study to Determine the Safety and Pharmacokinetics of Ifetroban Injection in Hepatorenal Syndrome

Resource links provided by NLM:


Further study details as provided by Cumberland Pharmaceuticals:

Primary Outcome Measures:
  • Pharmacokinetic profile (Cmax, Cmin, Vdss, T1/2, AUC 0-24, and AUC 0-inf) of ifetroban and ifetroban acylglucuronide [ Time Frame: 5 days ] [ Designated as safety issue: No ]

    To evaluate the primary objective of determining the pharmacokinetic profile of multiple daily intravenous doses of ifetroban, the following endpoints will be measured:

    • Pharmacokinetic parameters, including serum concentration versus time profile of ifetroban and its major metabolite ifetroban acylglucuronide for the 24-hour period after the first dose, Cmax, Cmin, Vdss, T1/2, AUC 0-24 (area under the curve during 24 hours), and AUC 0-inf (area under the curve extrapolated to infinity), will be determined from analysis of collected blood samples.


  • Vital signs, clinical chemistry, urine electrolytes, coagulation/hematology assessments, treatment emergent adverse events, and Day 28 mortality of ifetroban injection in patients with HRS. [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]

    To evaluate the primary objective of determining the tolerability and safety of ifetroban injection in patients with HRS, the following endpoints will be measured:

    • Vital signs (heart rate, respiratory rate, blood pressure, temperature, pulse oximetry saturation)
    • Clinical chemistry, urine electrolytes, coagulation and hematology assessments
    • Treatment emergent adverse events
    • Day 28 mortality


Secondary Outcome Measures:
  • Serum creatinine, Creatinine clearance, BUN, urine output, estimated GFR, Urinary TxB2-M, and plasma F2-isoprostane levels of ifetroban injection in patients with HRS. [ Time Frame: Baseline and 5 days ] [ Designated as safety issue: No ]

    To evaluate the secondary objective of evaluating the incidence and magnitude of renal function change relative to criteria for HRS reversal, the following endpoint will be measured:

    • Serum creatinine reduction below 1.5 mg/dL
    • Creatinine clearance improvement over baseline confirmed in two sequential measurements
    • BUN, urine output, estimated GFR, and dialysis requirement
    • Urinary TxB2-M and plasma F2-isoprostane levels


Enrollment: 55
Study Start Date: October 2011
Study Completion Date: July 2015
Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Ifetroban Injection Drug: 5mg Ifetroban Injection
Cohort 1: 5 mg Ifetroban Injection administered IV over 60 minutes once daily; During 72-hr treatment period. Total of 3 doses of CTM will be administered.
Drug: 15mg Ifetroban Injection
Cohort 2: 15 mg Ifetroban Injection administered IV over 60 minutes once daily During 72-hr treatment period. Total of 3 doses of CTM will be administered.
Drug: 50mg Ifetroban Injection
Cohort 3: 50 mg Ifetroban Injection administered IV over 60 minutes once daily During 72-hr treatment period. Total of 3 doses of CTM will be administered.
Drug: 150mg Ifetroban Injection
Cohort 4: 150 mg Ifetroban Injection administered IV over 60 minutes once daily During 72-hr treatment period. Total of 3 doses of CTM will be administered.
Placebo Comparator: Placebo Other: 5% Dextrose in Water
5% Dextrose in Water
Other Name: D5W

Detailed Description:

Ifetroban sodium (ifetroban) is an investigational drug that has been studied previously in healthy volunteers and patients with cardiovascular diseases. Cumberland Pharmaceuticals Inc. (CPI) is developing ifetroban for treatment of type 1 and type 2 hepatorenal syndrome (HRS) and proposed to conduct a study in hospitalized adult patients with HRS to assess the safety and pharmacokinetics of escalating doses of ifetroban. The primary objective of this study is as follows:

  • To determine the pharmacokinetic profile of multiple daily intravenous doses of ifetroban and its major metabolite ifetroban acylglucuronide.
  • To determine the tolerability and safety of ifetroban injection in patients with HRS.

The secondary objective of this study is as follows:

• To determine if ifetroban changes renal function, showing evidence of HRS reversal.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01436500

Locations
United States, Arizona
Mayo Clinic - Arizona
Phoenix, Arizona, United States, 85054
United States, California
UCSD, Hillcrest Medical Center Hospital
La Jolla, California, United States, 92093
UCSF (University of California-San Francisco)
San Francisco, California, United States, 94143
United States, Georgia
Emory University Hospital
Atlanta, Georgia, United States, 30322
United States, Indiana
Indiana University (Division of Gastroenterology/Hepatology)
Indianapolis, Indiana, United States, 46202
United States, Michigan
University of Michigan Hospital
Ann Arbor, Michigan, United States, 48109
United States, New York
NYU Langone Medical Center
New York, New York, United States, 10016
United States, Ohio
The Ohio State University
Columbus, Ohio, United States, 43210
United States, Texas
Baylor All Saints Medical Center
Fort Worth, Texas, United States, 76104
United States, Utah
University of Utah Health Sciences Center
Salt Lake City, Utah, United States, 84132
United States, Virginia
Virginia Commonwealth University
Richmond, Virginia, United States, 23298
India
MIDAS Multispeciality Hospital PVT LTD
Nagpur, Maharashtra, India, 440010
Sponsors and Collaborators
Cumberland Pharmaceuticals
Investigators
Principal Investigator: Brendan McGuire, MD University of Alabama at Birmingham
  More Information

Responsible Party: Cumberland Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01436500     History of Changes
Other Study ID Numbers: CPI-IFE-001 
Study First Received: August 31, 2011
Last Updated: December 1, 2015
Health Authority: United States: Food and Drug Administration

Keywords provided by Cumberland Pharmaceuticals:
Type 1 Hepatorenal Syndrome
Type 2 Hepatorenal Syndrome
Hepatorenal Syndrome
Type 1 HRS
Type 2 HRS
HRS

Additional relevant MeSH terms:
Hepatorenal Syndrome
Syndrome
Digestive System Diseases
Disease
Kidney Diseases
Liver Diseases
Pathologic Processes
Urologic Diseases
Ifetroban
Platelet Aggregation Inhibitors

ClinicalTrials.gov processed this record on May 22, 2016