Improving Treatment of Nontuberculous Mycobacterial Infection in Cystic Fibrosis

• ClinicalTrials.gov Identifier: NCT02372383
• Recruitment Status: Completed
• First Posted: February 26, 2015
• Results First Posted: February 11, 2021
• Last Update Posted: February 11, 2021
• Sponsor: University of Colorado, Denver
• Collaborators: Cystic Fibrosis Foundation; Colorado Clinical & Translational Sciences Institute
• Information provided by (Responsible Party): University of Colorado, Denver

Tracking Information

• First Submitted Date: June 20, 2014
• First Posted Date: February 26, 2015
• Results First Submitted Date: November 26, 2019
• Results First Posted Date: February 11, 2021
• Last Update Posted Date: February 11, 2021
• Actual Study Start Date: October 2014
• Actual Primary Completion Date: June 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 20, 2021)

Median 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 (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

Current Secondary Outcome Measures (submitted: January 20, 2021)

• Other PK Measures: Median 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: 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 Reported here are the Median (range) CL in the CF fasting state compared to HC for Rifampin.
• 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 ]
  Median Concentration of C-reactive Protein. Begin to investigate the influence of inflammation, host characteristics, and drug metabolism on the PK of the antimycobacterial drugs.
• Covariates of PK Measures: Circulating Neutrophil Count [ Time Frame: baseline ]
  Circulating neutrophil count. 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 ]
  Body mass index (BMI). 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 ]
  Creatinine. Begin to investigate the influence of inflammation, host characteristics, and drug metabolism on the PK of the antimycobacterial drugs
• Area Under the 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.

Original Secondary Outcome Measures (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.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Improving Treatment of Nontuberculous Mycobacterial Infection in Cystic Fibrosis
• Official Title: 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: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Cystic Fibrosis

Intervention

• 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

• 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 *: Martiniano SL, Wagner BD, Brennan L, Wempe MF, Anderson PL, Daley CL, Anthony M, Nick JA, Sagel SD. Pharmacokinetics of oral antimycobacterials and dosing guidance for Mycobacterium avium complex treatment in cystic fibrosis. J Cyst Fibros. 2021 Sep;20(5):772-778. doi: 10.1016/j.jcf.2021.04.011. Epub 2021 May 21.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 20, 2021): 31
• Original Estimated Enrollment (submitted: February 20, 2015): 30
• Actual Study Completion Date: June 2016
• Actual Primary Completion Date: June 2016 (Final data collection date for primary outcome measure)

Eligibility 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 16 Years to 45 Years (Child, Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02372383
• Other Study ID Numbers: 14-1043; UL1TR001082 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: University of Colorado, Denver
• Original Responsible Party: Same as current
• Current Study Sponsor: University of Colorado, Denver
• Original Study Sponsor: Same as current

Collaborators

• Cystic Fibrosis Foundation
• Colorado Clinical & Translational Sciences Institute

Investigators

• Principal Investigator: Stacey Martiniano, MD; University of Colorado, Denver

• PRS Account: University of Colorado, Denver
• Verification Date: January 2021