Not provided
| ID | Type | Description | Link |
|---|---|---|---|
| UL1TR001082 | U.S. NIH Grant/Contract | View source |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Class |
|---|---|
| Cystic Fibrosis Foundation | OTHER |
| Colorado Clinical & Translational Sciences Institute | OTHER |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
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.
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.
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Fasting | Experimental | 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 |
|
| Food/Enzymes | Experimental | 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 |
|
| Healthy Controls | Active Comparator | 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 |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Ethambutol | Drug | Anti-mycobacterial oral drug |
|
| Measure | Description | Time Frame |
|---|---|---|
| Median Maximal Drug Concentration (Cmax) | 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. | 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose |
| Measure | Description | Time Frame |
|---|---|---|
| Other PK Measures: Median Time to Maximal Drug Concentration (Tmax) | 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 | 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose |
Not provided
CF Subject Inclusion Criteria:
Healthy Control Inclusion Criteria:
CF Subject Exclusion Criteria:
Healthy Control Exclusion Criteria:
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Affiliation | Role |
|---|---|---|
| Stacey Martiniano, MD | University of Colorado, Denver | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Children's Hospital Colroado | Aurora | Colorado | 80045 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 34030986 | Derived | 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. |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
20 CF subjects and 10 Healthy controls will be studied
Not provided
| ID | Title | Description |
|---|---|---|
| FG000 | Healthy Controls (Fasting Only) | 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 Ethambutol: Anti-mycobacterial oral drug Rifampin: Anti-mycobacterial oral drug Azithromycin: Anti-mycobacterial oral drug |
| FG001 | CF Patients, Fasting, Then Food | Fasting for 1 day, then washout for 2 weeks, then Food for 1 day. 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 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 |
| FG002 | CF Patients, Food Then Fasting | Food for 1 day, then washout for 2 weeks, then Fasting for 1 day. 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 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 |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| First Intervention (1 Day) |
|
| ||||||||||||||||||
| Washout (14 Days) |
| |||||||||||||||||||
| Second Intervention (1 Day) |
|
One patient was unable to participate at day 1 from the CF Subjects arm, and baseline data was not collected. Baseline demographics data was not stratified between the "Fasting, then Food" versus "Food, then Fasting" sequences. Baseline data was only collected for Healthy Controls versus CF subjects.
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | CF Subjects | Fasting State 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 Ethambutol: Anti-mycobacterial oral drug Rifampin: Anti-mycobacterial oral drug Azithromycin: Anti-mycobacterial oral drug Food/Enzymes State Subjects with CF will then cross-over and be given the same dose of the 3 antimycobacterial drugs with a standardized meal plus a typical meal-dose of pancreatic enzymes (Pancrelipase). CF subjects will be randomized to either receive the medications in the Fasting or Food/Enzymes state first. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Median Maximal Drug Concentration (Cmax) | 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. | Posted | Median | Full Range | mg/L | 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose |
|
During the time of participation in the study, about 6 weeks.
Any untoward or unfavorable medical occurrence in a participant, including any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the participant's participation in the research, whether or not considered related to the participant's participation in the research. One participant is included in the Fasting arm who dropped out immediately after, prior to the Food period.
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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 Ethambutol: Anti-mycobacterial oral drug Rifampin: Anti-mycobacterial oral drug Azithromycin: Anti-mycobacterial oral drug |
Not provided
Not provided
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Stacey Martiniano | UColorado | 7207776181 | stacey.martiniano@childrenscolorado.org |
Not provided
| ID | Term |
|---|---|
| D003550 | Cystic Fibrosis |
| ID | Term |
|---|---|
| D010182 | Pancreatic Diseases |
| D004066 | Digestive System Diseases |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
Not provided
Not provided
| ID | Term |
|---|---|
| D004977 | Ethambutol |
| D012293 | Rifampin |
| D017963 | Azithromycin |
| D020799 | Pancrelipase |
| ID | Term |
|---|---|
| D005029 | Ethylenediamines |
| D003959 | Diamines |
| D011073 | Polyamines |
| D000588 | Amines |
| D009930 |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Rifampin | Drug | Anti-mycobacterial oral drug |
|
|
| Azithromycin | Drug | Anti-mycobacterial oral drug |
|
|
| Pancrelipase | Drug | Pancreatic enzyme replacement therapy |
|
|
| Other PK Measures: Half-life (t1/2) | 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 | 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose |
| Other PK Measures: Drug Clearance | 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. | 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose |
| Other PK Measures: Volume of Distribution (Vd) | 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 | 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose |
| Covariates of PK Measures: C-reactive Protein (CRP) | 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. | baseline |
| Covariates of PK Measures: Circulating Neutrophil Count | Circulating neutrophil count. Begin to investigate the influence of inflammation, host characteristics, and drug metabolism on the PK of the antimycobacterial drugs | baseline |
| Covariates of PK Measures: Body Mass Index | Body mass index (BMI). Begin to investigate the influence of inflammation, host characteristics, and drug metabolism on the PK of the antimycobacterial drugs | baseline |
| Covariates of PK Measures: Creatinine | Creatinine. Begin to investigate the influence of inflammation, host characteristics, and drug metabolism on the PK of the antimycobacterial drugs | baseline |
| Area Under the Curve (AUC) | 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. | 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose |
| NOT COMPLETED |
|
| NOT COMPLETED |
|
| BG001 | Healthy Controls (Fasting Only) | 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 Ethambutol: Anti-mycobacterial oral drug Rifampin: Anti-mycobacterial oral drug Azithromycin: Anti-mycobacterial oral drug |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Median | Full Range | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 | CF 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 Ethambutol: Anti-mycobacterial oral drug Rifampin: Anti-mycobacterial oral drug Azithromycin: Anti-mycobacterial oral drug CF subjects will then cross-over following at least a 2 week washout time point and and be given the same dose of the 3 antimycobacterial drugs with a standardized meal plus a typical meal-dose of pancreatic enzymes (Pancrelipase). |
| OG002 | CF Food | 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 Ethambutol: Anti-mycobacterial oral drug Rifampin: Anti-mycobacterial oral drug Azithromycin: Anti-mycobacterial oral drug CF subjects will then cross-over following at least a 2 week washout time point and and be given the same dose of the 3 antimycobacterial drugs with a standardized meal plus a typical meal-dose of pancreatic enzymes (Pancrelipase). |
|
|
| Secondary | Other PK Measures: Median Time to Maximal Drug Concentration (Tmax) | 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 | Posted | Median | Full Range | hours | 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose |
|
|
|
| Secondary | Other PK Measures: Half-life (t1/2) | 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 | Posted | Median | Full Range | hours | 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose |
|
|
|
| Secondary | Other PK Measures: Drug Clearance | 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. | Posted | Median | Full Range | L/h | 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose |
|
|
|
| Secondary | Other PK Measures: Volume of Distribution (Vd) | 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 | Posted | Median | Full Range | L | 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose |
|
|
|
| Secondary | Covariates of PK Measures: C-reactive Protein (CRP) | 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. | This Outcome Measure was only analyzed at the Fasting period and was not collected during the Food period of the study. Therefore, 0 participants are analyzed for the "CF Food" arm for this Outcome Measure. | Posted | Median | Full Range | mg/dL | baseline |
|
|
|
| Secondary | Covariates of PK Measures: Circulating Neutrophil Count | Circulating neutrophil count. Begin to investigate the influence of inflammation, host characteristics, and drug metabolism on the PK of the antimycobacterial drugs | This Outcome Measure was only analyzed at the Fasting period and was not collected during the Food period of the study. Therefore, 0 participants are analyzed for the "CF Food" arm for this Outcome Measure. | Posted | Median | Full Range | 10^3 cells/uL | baseline |
|
|
|
| Secondary | Covariates of PK Measures: Body Mass Index | Body mass index (BMI). Begin to investigate the influence of inflammation, host characteristics, and drug metabolism on the PK of the antimycobacterial drugs | This Outcome Measure was only analyzed at the Fasting period and was not collected during the Food period of the study. Therefore, 0 participants are analyzed for the "CF Food" arm for this Outcome Measure. | Posted | Median | Full Range | kg/m^2 | baseline |
|
|
|
| Secondary | Covariates of PK Measures: Creatinine | Creatinine. Begin to investigate the influence of inflammation, host characteristics, and drug metabolism on the PK of the antimycobacterial drugs | This Outcome Measure was only analyzed at the Fasting period and was not collected during the Food period of the study. Therefore, 0 participants are analyzed for the "CF Food" arm for this Outcome Measure. | Posted | Median | Full Range | mg/dL | baseline |
|
|
|
| Secondary | Area Under the Curve (AUC) | 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. | Posted | Median | Full Range | mg*h/L | 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose |
|
|
|
| 0 |
| 10 |
| 0 |
| 10 |
| 0 |
| 10 |
| EG001 | CF Patients, 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 Ethambutol: Anti-mycobacterial oral drug Rifampin: Anti-mycobacterial oral drug Azithromycin: Anti-mycobacterial oral drug CF subjects will then cross-over following at least a 2 week washout time point and and be given the same dose of the 3 antimycobacterial drugs with a standardized meal plus a typical meal-dose of pancreatic enzymes (Pancrelipase). | 0 | 21 | 0 | 21 | 0 | 21 |
| EG002 | CF Patients, Food | 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 Ethambutol: Anti-mycobacterial oral drug Rifampin: Anti-mycobacterial oral drug Azithromycin: Anti-mycobacterial oral drug CF subjects will then cross-over following at least a 2 week washout time point and and be given the same dose of the 3 antimycobacterial drugs with a standardized meal plus a typical meal-dose of pancreatic enzymes (Pancrelipase). | 0 | 20 | 0 | 20 | 0 | 20 |
Not provided
Not provided
Not provided
| D030342 |
| Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D007232 | Infant, Newborn, Diseases |
| Organic Chemicals |
| D012294 | Rifamycins |
| D006576 | Heterocyclic Compounds, 4 or More Rings |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D047029 | Lactams, Macrocyclic |
| D047028 | Macrocyclic Compounds |
| D011083 | Polycyclic Compounds |
| D004917 | Erythromycin |
| D018942 | Macrolides |
| D061065 | Polyketides |
| D007783 | Lactones |
| D008049 | Lipase |
| D002265 | Carboxylic Ester Hydrolases |
| D004950 | Esterases |
| D006867 | Hydrolases |
| D004798 | Enzymes |
| D045762 | Enzymes and Coenzymes |
| D010184 | Pancreatic Extracts |
| D014020 | Tissue Extracts |
| D045424 | Complex Mixtures |
|
| Azithromycin |
|
|
| Azithromycin |
|
|
| Azithromycin |
|
|
| Azithromycin |
|
|
| Azithromycin |
|