Improving Treatment of Nontuberculous Mycobacterial Infection in Cystic Fibrosis
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| ClinicalTrials.gov Identifier: NCT02372383 |
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Recruitment Status :
Completed
First Posted : February 26, 2015
Results First Posted : February 11, 2021
Last Update Posted : February 11, 2021
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Cystic Fibrosis | Drug: Ethambutol Drug: Rifampin Drug: Azithromycin Drug: Pancrelipase | Not Applicable |
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 (Clinical Trial) |
| Actual Enrollment : | 31 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 |
| Actual Study Start Date : | October 2014 |
| Actual Primary Completion Date : | June 2016 |
| Actual Study Completion Date : | June 2016 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: Fasting
Subjects with CF will be given the antimycobacterial drugs in the fasting state, without supplemental pancreatic enzymes
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 |
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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).
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:
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Active Comparator: Healthy Controls
Healthy subjects without CF will be given the antimycobacterial drugs in the fasting state, without supplemental pancreatic enzymes
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 |
- 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.
- 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.
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| Ages Eligible for Study: | 16 Years to 45 Years (Child, Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | Yes |
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.
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
| United States, Colorado | |
| Children's Hospital Colroado | |
| Aurora, Colorado, United States, 80045 | |
| Principal Investigator: | Stacey Martiniano, MD | University of Colorado, Denver |
| 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 |
| Results First Posted: | February 11, 2021 |
| Last Update Posted: | February 11, 2021 |
| Last Verified: | January 2021 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | No |
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Cystic Fibrosis Pharmacokinetics Pharmacodynamics Nontuberculous Mycobacteria Treatment |
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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 |