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Safety and Pharmacokinetics of Ifetroban in Hepatorenal Syndrome Patients

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2014 by Cumberland Pharmaceuticals
Sponsor:
Information provided by (Responsible Party):
Cumberland Pharmaceuticals
ClinicalTrials.gov Identifier:
NCT01436500
First received: August 31, 2011
Last updated: September 23, 2014
Last verified: September 2014
  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


Estimated Enrollment: 64
Study Start Date: October 2011
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: December 2014 (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 renal dysfunction defined as follows:

    • Type 1:

      i. At least a doubling of the initial serum creatinine to > 220 µmol/L (2.5 mg/dL), occurring over a period of less than 2 week, OR ii. A 50% or greater reduction in the initial 24-hour creatinine clearance to < 20 mL/min occurring over a period of less than 2 weeks.

    • 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 1st administration CTM. Oliguria is defined as either of the following:

    • An average urine output of < 35 mL/hr measured for at least 4 hours, occurring with a measured central venous pressure (CVP) > 12 mmHg, OR
    • In the absence of CVP monitoring, oliguria that is not corrected by a fluid challenge of at least 20mL/kg isotonic crystalloid or comparable volume of colloid.

Exclusion Criteria:

  1. History of allergy or hypersensitivity to ifetroban
  2. Pregnant or nursing
  3. Less than 18 years of age
  4. Serum creatinine (SCr) > 5.0 mg/dL
  5. Platelet count at screening of < 30,000/ µL
  6. Active gastrointestinal hemorrhage
  7. Evidence of obstructive or parenchymal renal disease (e.g., acute tubular necrosis, glomerular diseases, interstitial nephritis, and urinary obstruction, or lab results indicating proteinuria > 500 mg/day, microhematuria [> 50 RBCs/high power field], and/or abnormal renal ultrasound scanning).
  8. Current or recent (within the preceding 5 days) treatment with any of the following drugs: aminoglycosides, acyclovir, cisplatin, methotrexate, cyclosporine, amphotericin B.
  9. Presence of shock defined as hypotension, with a mean arterial pressure less than 50 mmHG.
  10. New York Heart Association class 3 or 4 heart failure.
  11. Presence of hepatocellular carcinoma not transplantable by Milan criteria
  12. Cardiopulmonary arrest without full recovery of mental status
  13. Moribund and death expected within five days
  14. Uncontrolled bacterial or fungal infections, defined as receiving appropriate antimicrobial therapy for > 24 hours
  15. Burns > 30% body surface area
  16. Exposed to investigational drugs within 30 days before 1st CTM administration.
  17. 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).
  18. Refusal to provide written authorization for use and disclosure of protected health information.
  19. Be otherwise unsuitable for the study, in the opinion of the Investigator.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01436500

  Show 26 Study Locations
Sponsors and Collaborators
Cumberland Pharmaceuticals
Investigators
Principal Investigator: Brendan McGuire, MD University of Alabama at Birmingham
  More Information

No publications provided

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: September 23, 2014
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
Hematologic Agents
Pharmacologic Actions
Platelet Aggregation Inhibitors
Therapeutic Uses

ClinicalTrials.gov processed this record on November 20, 2014