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Improving Treatment of Nontuberculous Mycobacterial Infection in Cystic Fibrosis

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: NCT02372383
Recruitment Status : Completed
First Posted : February 26, 2015
Last Update Posted : July 26, 2016
Sponsor:
Collaborators:
Cystic Fibrosis Foundation
Colorado Clinical & Translational Sciences Institute
Information provided by (Responsible Party):
University of Colorado, Denver

Tracking Information
First Submitted Date  ICMJE June 20, 2014
First Posted Date  ICMJE February 26, 2015
Last Update Posted Date July 26, 2016
Study Start Date  ICMJE October 2014
Actual Primary Completion Date July 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 20, 2015)
Mean maximal drug concentration (Cmax) [ Time Frame: 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose ]
Cmax of the oral antimycobacterial drugs (azithromycin, rifampin and ethambutol) under both fasting conditions and when taken with food plus supplemental pancreatic enzymes in subjects with pancreatic insufficient CF, compared to healthy controls
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 20, 2015)
  • Other PK measures: mean time to maximal drug concentration (Tmax) [ Time Frame: 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose ]
    Tmax of the oral antimycobacterial drugs (azithromycin, rifampin and ethambutol) under both fasting conditions and when taken with food plus supplemental pancreatic enzymes in subjects with pancreatic insufficient CF, compared to healthy controls
  • Other PK measures: area under the plasma drug concentration vs. time curve (AUC) [ Time Frame: 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose ]
    AUC of the oral antimycobacterial drugs (azithromycin, rifampin and ethambutol) under both fasting conditions and when taken with food plus supplemental pancreatic enzymes in subjects with pancreatic insufficient CF, compared to healthy controls
  • Other PK measures: half-life (t1/2) [ Time Frame: 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose ]
    t1/2 of the oral antimycobacterial drugs (azithromycin, rifampin and ethambutol) under both fasting conditions and when taken with food plus supplemental pancreatic enzymes in subjects with pancreatic insufficient CF, compared to healthy controls
  • Other PK measures: drug clearance [ Time Frame: 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose ]
    drug clearance of the oral antimycobacterial drugs (azithromycin, rifampin and ethambutol) under both fasting conditions and when taken with food plus supplemental pancreatic enzymes in subjects with pancreatic insufficient CF, compared to healthy controls
  • Other PK measures: volume of distribution (Vd) [ Time Frame: 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose ]
    Vd of the oral antimycobacterial drugs (azithromycin, rifampin and ethambutol) under both fasting conditions and when taken with food plus supplemental pancreatic enzymes in subjects with pancreatic insufficient CF, compared to healthy controls
  • Covariates of PK measures: C-reactive protein (CRP) [ Time Frame: baseline ]
    Begin to investigate the influence of inflammation, host characteristics, and drug metabolism on the PK of the antimycobacterial drugs
  • Covariates of PK measures: circulating neutrophils [ Time Frame: baseline ]
    Begin to investigate the influence of inflammation, host characteristics, and drug metabolism on the PK of the antimycobacterial drugs
  • Covariates of PK measures: age [ Time Frame: baseline ]
    Begin to investigate the influence of inflammation, host characteristics, and drug metabolism on the PK of the antimycobacterial drugs
  • Covariates of PK measures: body mass index [ Time Frame: baseline ]
    Begin to investigate the influence of inflammation, host characteristics, and drug metabolism on the PK of the antimycobacterial drugs
  • Covariates of PK measures: CF genotype [ Time Frame: baseline ]
    Begin to investigate the influence of inflammation, host characteristics, and drug metabolism on the PK of the antimycobacterial drugs
  • Covariates of PK measures: creatinine [ Time Frame: baseline ]
    Begin to investigate the influence of inflammation, host characteristics, and drug metabolism on the PK of the antimycobacterial drugs
  • Covariates of PK measures: BUN [ Time Frame: baseline ]
    Begin to investigate the influence of inflammation, host characteristics, and drug metabolism on the PK of the antimycobacterial drugs
  • Covariates of PK measures: drug metabolite Cmax [ Time Frame: baseline ]
    Begin to investigate the influence of inflammation, host characteristics, and drug metabolism on the PK of the antimycobacterial drugs
  • Covariates of PK measures: drug metabolite AUC [ Time Frame: baseline ]
    Begin to investigate the influence of inflammation, host characteristics, and drug metabolism on the PK of the antimycobacterial drugs
  • PD measures: AUC vs. minimum inhibitory concentration (MIC) for azithromycin [ Time Frame: 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose ]
    Estimate an optimized dosing regimen for the antimycobacterial drugs against Mycobacterium avium complex (MAC) using historic minimum inhibitory concentration (MIC) data and models of Mycobacterium tuberculosis or MAC infection.
  • PD measures: AUC vs. minimum inhibitory concentration (MIC) for rifampin [ Time Frame: 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose ]
    Estimate an optimized dosing regimen for the antimycobacterial drugs against Mycobacterium avium complex (MAC) using historic minimum inhibitory concentration (MIC) data and models of Mycobacterium tuberculosis or MAC infection.
  • PD measures: Cmax/MIC for ethambutol [ Time Frame: 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose ]
    Estimate an optimized dosing regimen for the antimycobacterial drugs against Mycobacterium avium complex (MAC) using historic minimum inhibitory concentration (MIC) data and models of Mycobacterium tuberculosis or MAC infection.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Improving Treatment of Nontuberculous Mycobacterial Infection in Cystic Fibrosis
Official Title  ICMJE Pharmacokinetic Evaluation of Nontuberculous Mycobacterial Antibiotics in Cystic Fibrosis Versus Controls
Brief Summary The purpose of this study is to determine antimycobacterial drug pharmacokinetics (PK) and pharmacodynamics (PD) in patients with cystic fibrosis (CF) to improve treatment of nontuberculous mycobacterial (NTM) lung disease.
Detailed Description

The purpose of this study is to determine antimycobacterial drug pharmacokinetics (PK) and pharmacodynamics (PD) in patients with cystic fibrosis (CF) to improve treatment of nontuberculous mycobacterial (NTM) lung disease.

Aim 1: Determine the PK profile of oral antimycobacterial drugs (azithromycin, rifampin and ethambutol) under both fasting conditions and when taken with food plus supplemental pancreatic enzymes in subjects with pancreatic insufficient, compared to healthy controls.

Aim 2: Begin to investigate the influence of inflammation, host characteristics, and drug metabolism on the PK of the antimycobacterial drugs.

Aim 3: Estimate an optimized dosing regimen for the antimycobacterial drugs against Mycobacterium avium complex (MAC) using historic minimum inhibitory concentration (MIC) data and models of Mycobacterium tuberculosis or MAC infection.

The central goal of this study is to improve treatment of NTM infection in CF. Upon completion of this study the investigators will determine if and why PK of the antimycobacterial drugs are altered in CF. More importantly, the investigators will develop CF-specific guidelines to achieve therapeutic goals with recommendations for drug dosing (including dose, dose frequency and timing in relation to meals and supplemental pancreatic enzymes) and timing of therapeutic monitoring to be used for future treatment of NTM lung disease in CF.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Cystic Fibrosis
Intervention  ICMJE
  • Drug: Ethambutol
    Anti-mycobacterial oral drug
    Other Name: Myambutol
  • Drug: Rifampin
    Anti-mycobacterial oral drug
    Other Name: Rifadin
  • Drug: Azithromycin
    Anti-mycobacterial oral drug
    Other Name: Zithromax
  • Drug: Pancrelipase
    Pancreatic enzyme replacement therapy
    Other Names:
    • Creon
    • Zenpep
    • Pertzye
Study Arms  ICMJE
  • Experimental: Fasting

    Subjects with CF will be given the antimycobacterial drugs in the fasting state, without supplemental pancreatic enzymes

    • Rifampin 10mg/kg oral once daily (max 600mg, round to closest 150mg)
    • Ethambutol 15mg/kg oral once daily (max 2500mg, round to nearest 100mg)
    • Azithromycin 10mg/kg oral once daily (max 500mg, rounded to the nearest 250mg)

    Blood will be drawn at time points 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose

    Interventions:
    • Drug: Ethambutol
    • Drug: Rifampin
    • Drug: Azithromycin
  • Experimental: Food/Enzymes

    Subjects with CF will be given the antimycobacterial drugs with a standardized meal plus a typical meal-dose of pancreatic enzymes (Pancrelipase).

    • Rifampin 10mg/kg oral once daily (max 600mg, round to closest 150mg)
    • Ethambutol 15mg/kg oral once daily (max 2500mg, round to nearest 100mg)
    • Azithromycin 10mg/kg oral once daily (max 500mg, rounded to the nearest 250mg)

    Blood will be drawn at time points 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose

    Interventions:
    • Drug: Ethambutol
    • Drug: Rifampin
    • Drug: Azithromycin
    • Drug: Pancrelipase
  • Active Comparator: Healthy Controls

    Healthy subjects without CF will be given the antimycobacterial drugs in the fasting state, without supplemental pancreatic enzymes

    • Rifampin 10mg/kg oral once daily (max 600mg, round to closest 150mg)
    • Ethambutol 15mg/kg oral once daily (max 2500mg, round to nearest 100mg)
    • Azithromycin 10mg/kg oral once daily (max 500mg, rounded to the nearest 250mg)

    Blood will be drawn at time points 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose

    Interventions:
    • Drug: Ethambutol
    • Drug: Rifampin
    • Drug: Azithromycin
Publications * Not Provided

*   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: July 25, 2016)
32
Original Estimated Enrollment  ICMJE
 (submitted: February 20, 2015)
30
Actual Study Completion Date  ICMJE July 2016
Actual Primary Completion Date July 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

CF Subject Inclusion Criteria:

  • CF diagnosis defined as a sweat chloride >60mEq/L and/or the presence of two disease-causing CFTR mutations.
  • Ages 16 years and above.
  • Pancreatic insufficient status defined as previous fecal pancreatic elastase <100mcg/g stool and/or having 2 disease-causing CFTR mutations known to be associated with pancreatic insufficiency, and taking supplemental pancreatic enzymes between 1000-2500 lipase units/kg/meal.
  • No positive NTM cultures in the last 2 years.
  • Pulmonary function: Most recent FEV1 > 40% predicted.
  • Willing to participate in and comply with the study procedures, and willingness of a parent or legally authorized representative to provide written informed consent for those subjects less than 18 years of age.

Healthy Control Inclusion Criteria:

  • Ages 18 years and above.
  • BMI below 30 to best match CF body type.
  • Willing to participate in and comply with the study procedures, and willingness of a parent or legally authorized representative to provide written informed consent for those subjects less than 18 years of age.

CF Subject Exclusion Criteria:

  • Allergy or intolerance to rifampin, ethambutol, or azithromycin.
  • Hepatic insufficiency defined as having an AST or ALT greater than three times the upper limit of normal at the screening appointment.
  • Previous surgical bowel resection.
  • Previous lung transplant.
  • Use of medications known to interact with the antimycobacterial drug levels; of note, the most common interactions in CF patients are the use of itraconazole, voriconazole, and ivacaftor. We will have subjects hold H2 blockers and proton pump inhibitors for 3 days prior to each PK study day.
  • Inability to hold azithromycin: Subjects will not be excluded if they are on chronic azithromycin for immunomodulatory purposes; however, we will ask that the subjects hold the azithromycin starting at the screening visit, through a 2 week wash-out period prior to Visit 2, and remain off through the end of Visit 3 (about 4 weeks total).
  • Acute exacerbations: exclusion if any addition of oral, IV, or inhaled antibiotics, or an acute gastrointestinal illness with vomiting or diarrhea in the 2 weeks prior to each visit. No exclusion for previously prescribed alternating chronic inhaled or oral antibiotics.
  • We will also exclude pregnant women (urine pregnancy test will be performed for females on the day of each PK study) and decisionally challenged subjects.

Healthy Control Exclusion Criteria:

  • Allergy or intolerance to rifampin, ethambutol, or azithromycin.
  • Hepatic insufficiency defined as having an AST or ALT greater than three times the upper limit of normal at the screening appointment.
  • Previous chronic GI disease or surgical bowel resection.
  • Use of medications known to interact with the antimycobacterial drug levels. We will have subjects hold H2 blockers and proton pump inhibitors for 3 days prior to the PK study day.
  • Acute illness: exclusion if respiratory illness requiring antibiotics or gastrointestinal illness with vomiting or diarrhea in the 2 weeks prior to the PK visit.
  • We will also exclude pregnant women (urine pregnancy test will be performed on the day of PK study) and decisionally challenged subjects.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 16 Years to 45 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE Yes
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 NCT02372383
Other Study ID Numbers  ICMJE 14-1043
UL1TR001082 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party University of Colorado, Denver
Study Sponsor  ICMJE University of Colorado, Denver
Collaborators  ICMJE
  • Cystic Fibrosis Foundation
  • Colorado Clinical & Translational Sciences Institute
Investigators  ICMJE
Principal Investigator: Stacey Martiniano, MD University of Colorado, Denver
PRS Account University of Colorado, Denver
Verification Date July 2016

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