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Trial record 1 of 3 for:    Denver AND cystic Fibrosis AND martiniano
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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

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.

Condition or disease Intervention/treatment Phase
Cystic Fibrosis Drug: Ethambutol Drug: Rifampin Drug: Azithromycin Drug: Pancrelipase Not Applicable

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 32 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Pharmacokinetic Evaluation of Nontuberculous Mycobacterial Antibiotics in Cystic Fibrosis Versus Controls
Study Start Date : October 2014
Actual Primary Completion Date : July 2016
Actual Study Completion Date : July 2016

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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

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

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

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

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

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




Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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.

  16. 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.

  17. 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   16 Years to 45 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02372383


Locations
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United States, Colorado
Children's Hospital Colroado
Aurora, Colorado, United States, 80045
Sponsors and Collaborators
University of Colorado, Denver
Cystic Fibrosis Foundation
Colorado Clinical & Translational Sciences Institute
Investigators
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Principal Investigator: Stacey Martiniano, MD University of Colorado, Denver
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Responsible Party: University of Colorado, Denver
ClinicalTrials.gov Identifier: NCT02372383    
Other Study ID Numbers: 14-1043
UL1TR001082 ( U.S. NIH Grant/Contract )
First Posted: February 26, 2015    Key Record Dates
Last Update Posted: July 26, 2016
Last Verified: July 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Keywords provided by University of Colorado, Denver:
Cystic Fibrosis
Pharmacokinetics
Pharmacodynamics
Nontuberculous Mycobacteria
Treatment
Additional relevant MeSH terms:
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Cystic Fibrosis
Fibrosis
Pathologic Processes
Pancreatic Diseases
Digestive System Diseases
Lung Diseases
Respiratory Tract Diseases
Genetic Diseases, Inborn
Infant, Newborn, Diseases
Azithromycin
Rifampin
Ethambutol
Pancrelipase
Pancreatin
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antitubercular
Antitubercular Agents
Leprostatic Agents
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Cytochrome P-450 CYP2B6 Inducers
Cytochrome P-450 Enzyme Inducers
Cytochrome P-450 CYP2C8 Inducers
Cytochrome P-450 CYP2C19 Inducers
Cytochrome P-450 CYP2C9 Inducers
Cytochrome P-450 CYP3A Inducers
Gastrointestinal Agents