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Population Pharmacokinetics and Safety of Intravenous Ceftolozane/Tazobactam in Adult Cystic Fibrosis Patients

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02421120
Recruitment Status : Completed
First Posted : April 20, 2015
Results First Posted : April 13, 2017
Last Update Posted : March 19, 2018
Sponsor:
Collaborators:
Cubist Pharmaceuticals LLC
Indiana University Health
University of North Carolina
St. Christopher's Hospital for Children
Information provided by (Responsible Party):
Joseph Kuti, Hartford Hospital

Tracking Information
First Submitted Date  ICMJE April 13, 2015
First Posted Date  ICMJE April 20, 2015
Results First Submitted Date  ICMJE February 28, 2017
Results First Posted Date  ICMJE April 13, 2017
Last Update Posted Date March 19, 2018
Study Start Date  ICMJE September 2015
Actual Primary Completion Date March 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 2, 2017)
  • Ceftolozane Clearance [ Time Frame: 0, 1-1.08, 1.25-1.5, 2-3, 4-5, and 7-8 hours after start of final dose ]
    This outcome determines the clearance of ceftolozane over the 8 hour dosing interval.
  • Ceftolozane Volume of Distribution (Central Compartment) [ Time Frame: 0, 1-1.08, 1.25-1.5, 2-3, 4-5, and 7-8 hours after start of final dose ]
    This outcome determines the volume of distribution of ceftolozane over the 8 hour dosing interval.
  • Tazobactam Clearance [ Time Frame: 0, 1-1.08, 1.25-1.5, 2-3, 4-5, and 7-8 hours after start of final dose ]
    This outcome determines the clearance of tazobactam over the 8 hour dosing interval.
  • Tazobactam Volume of Distribution (Central Compartment) [ Time Frame: 0, 1-1.08, 1.25-1.5, 2-3, 4-5, and 7-8 hours after start of final dose ]
    This outcome determines the volume of distribution of tazobactam over the 8 hour dosing interval.
Original Primary Outcome Measures  ICMJE
 (submitted: April 17, 2015)
  • Ceftolozane Clearance [ Time Frame: 8 hours ]
    This outcome determines the clearance of ceftolozane over the 8 hour dosing interval.
  • Ceftolozane Volume of Distribution [ Time Frame: 8 hours ]
    This outcome determines the volume of distribution of ceftolozane over the 8 hour dosing interval.
  • Tazobactam Clearance [ Time Frame: 8 hours ]
    This outcome determines the clearance of tazobactam over the 8 hour dosing interval.
  • Tazobactam Volume of Distribution [ Time Frame: 8 hours ]
    This outcome determines the volume of distribution of tazobactam over the 8 hour dosing interval.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 2, 2017)
  • Ceftolozane Probability of Target Attainment at 8 mcg/ml [ Time Frame: 24 hours ]
    This simulated outcome indicates the likelihood that ceftolozane will retain drug concentrations above the MIC for >/= 60% of the dosing interval at an MIC of 8 mcg/ml when administered as a 3g (2g ceftolozane/1g tazobactam) every 8 hour dose infused over 1 hour. This analysis is conducted via a Monte Carlo simulation using the population pharmacokinetic parameter estimates and dispersion from the 20 participants who contributed pharmacokinetic data to the study.
  • Safety and Tolerability (Changes in Serum Chemistry, Hematology and Hepatic Lab Values, as Well as Reported Adverse Events) [ Time Frame: 3 days ]
    This outcome will assess the safety and tolerability of ceftolozane/tazobactam in adults with CF after 4-6 doses, as measured by changes in serum chemistry, hematology and hepatic lab values, as well as reported adverse events by patients and providers.
Original Secondary Outcome Measures  ICMJE
 (submitted: April 17, 2015)
  • Ceftolozane Probability of Target Attainment [ Time Frame: 24 hours ]
    This simulated outcome indicates the likelihood that ceftolozane will retain drug concentrations above the MIC for >/= 39% of the dosing interval.
  • Safety and Tolerability (Changes in Serum Chemistry, Hematology and Hepatic Lab Values, as Well as Reported Adverse Events) [ Time Frame: 3 days ]
    This outcome will assess the safety and tolerability of ceftolozane/tazobactam in adults with CF after 4-6 doses, as measured by changes in serum chemistry, hematology and hepatic lab values, as well as reported adverse events by patients and providers.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Population Pharmacokinetics and Safety of Intravenous Ceftolozane/Tazobactam in Adult Cystic Fibrosis Patients
Official Title  ICMJE A Prospective, Multicenter, Open-Label Study to Assess Population Pharmacokinetics and Safety of Intravenous Ceftolozane/Tazobactam in Adult Cystic Fibrosis Patients Admitted With Acute Pulmonary Exacerbation
Brief Summary There is established evidence that adult patients with Cystic Fibrosis (CF) may have altered antibiotic pharmacokinetics compared with non-CF patients. Ceftolozane/Tazobactam is a newly approved broad spectrum intravenous antibiotic, which has potent in vitro activity against multidrug resistant Pseudomonas aeruginosa, the most common pathogen implicated in CF pulmonary exacerbations. This study will determine the pharmacokinetics and tolerability of ceftolozane/tazobactam in 20 adult CF patients admitted for a pulmonary exacerbation at one of 4 participating hospitals in the US. Patients will remain on standard of care IV antibiotics and receive 4-6 doses of ceftolozane/tazobactam 3 grams every 8 hours. Blood will be sampled after the final dose to determine concentrations and pharmacokinetics of ceftolozane and tazobactam. Safety and tolerability will be assessed throughout the 3 day study.
Detailed Description Participants will receive 4-6 doses of ceftolozane/tazobactam 3 grams every 8 hours, in addition to standard intravenous antibiotic therapy selected by the site. Just prior and then after the final dose, a total of six blood samples will be collected to measure ceftolozane and tazobactam concentrations. Data will be fit to a population pharmacokinetic model. The final model will be utilized in a Monte Carlo simulation to determine the probability of several different dosing regimens retaining concentrations above the minimum inhibitory concentration (MIC) for at least 39% of the dosing interval. These data will be utilized to determine an optimized dosing regimen for adults with CF.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Other
Condition  ICMJE
  • Cystic Fibrosis
  • Cystic Fibrosis Pulmonary Exacerbation
  • Pseudomonas Aeruginosa Infection
Intervention  ICMJE Drug: Ceftolozane/Tazobactam
1 hour intravenous infusion
Other Names:
  • Zerbaxa
  • CXA-101
Study Arms  ICMJE Experimental: Ceftolozane/Tazobactam
Ceftolozane/Tazobactam 3 grams every 8 hours intravenously for 4-6 doses
Intervention: Drug: Ceftolozane/Tazobactam
Publications * Monogue ML, Pettit RS, Muhlebach M, Cies JJ, Nicolau DP, Kuti JL. Population Pharmacokinetics and Safety of Ceftolozane-Tazobactam in Adult Cystic Fibrosis Patients Admitted with Acute Pulmonary Exacerbation. Antimicrob Agents Chemother. 2016 Oct 21;60(11):6578-6584. doi: 10.1128/AAC.01566-16. Print 2016 Nov.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 2, 2017)
21
Original Estimated Enrollment  ICMJE
 (submitted: April 17, 2015)
20
Actual Study Completion Date  ICMJE October 2016
Actual Primary Completion Date March 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Age 18 years or older
  2. Documented diagnosis of CF
  3. Acute pulmonary exacerbation as the primary reason for admission to the hospital with requirement to receive systemic antibiotic treatment
  4. If female, subjects must be non-pregnant and non-lactating. Females can be either not of a child-bearing potential or if of a child-bearing potential, on acceptable modes of birth control such as abstinence from sexual intercourse, oral/parenteral contraceptives, or barrier method

Exclusion Criteria:

  1. History of any moderate or severe hypersensitivity or allergic reaction to any β-lactam antibiotic (a history of mild rash to a cephalosporin followed by uneventful re-exposure is not a contraindication)
  2. Prior (within 24 hours of first dose of study drug) or concomitant receipt of piperacillin/tazobactam or probenecid
  3. History of lung transplant
  4. Moderate to severe renal dysfunction defined as a creatinine clearance < 50 mL/min (as calculated by the Cockcroft-Gault equation using actual body weight) or requirement for continuous renal replacement therapy or hemodialysis
  5. A hemoglobin less than 8 gm/dl at baseline
  6. Any rapidly-progressing disease or immediately life-threatening illness (defined as imminent death within 48 hours in the opinion of the investigator)
  7. Any condition or circumstance that, in the opinion of the investigator, would compromise the safety of the patient or the quality of study data
  8. Planned or prior participation in any other interventional drug study within 30 days
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02421120
Other Study ID Numbers  ICMJE HHC-2015-0107
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Joseph Kuti, Hartford Hospital
Study Sponsor  ICMJE Joseph Kuti
Collaborators  ICMJE
  • Cubist Pharmaceuticals LLC
  • Indiana University Health
  • University of North Carolina
  • St. Christopher's Hospital for Children
Investigators  ICMJE
Principal Investigator: Joseph L Kuti, PharmD Hartford Hospital
PRS Account Hartford Hospital
Verification Date February 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP