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

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Cystic Fibrosis
• Interventions: Drug: Ethambutol; Drug: Rifampin; Drug: Azithromycin; Drug: Pancrelipase
• Enrollment: 31

Participant Flow

Recruitment Details	20 CF subjects and 10 Healthy controls will be studied
Pre-assignment Details

Arm/Group Title	Healthy Controls (Fasting Only)	CF Patients, Fasting, Then Food	CF Patients, Food Then Fasting
Arm/Group Description	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 Ethambutol: Anti-mycobacterial oral drug Rifampin: Anti-mycobacterial oral drug Azithromycin: Anti-mycobacterial oral drug	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	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
Period Title: First Intervention (1 Day)
Started	10	11	10
Completed	10	10	10
Not Completed	0	1	0
Reason Not Completed
Unable to collect blood	0	1	0
Period Title: Washout (14 Days)
Started	10	10	10
Completed	10	10	10
Not Completed	0	0	0
Period Title: Second Intervention (1 Day)
Started	10	10	10
Completed	10	10	10
Not Completed	0	0	0

Baseline Characteristics

Arm/Group Title		CF Subjects	Healthy Controls (Fasting Only)	Total
Arm/Group Description		Fasting State 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 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.	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 Ethambutol: Anti-mycobacterial oral drug Rifampin: Anti-mycobacterial oral drug Azithromycin: Anti-mycobacterial oral drug	Total of all reporting groups
Overall Number of Baseline Participants		20	10	30
Baseline Analysis Population Description		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.
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	20 participants	10 participants	30 participants
	<=18 years	1 5.0%	0 0.0%	1 3.3%
	Between 18 and 65 years	19 95.0%	10 100.0%	29 96.7%
	>=65 years	0 0.0%	0 0.0%	0 0.0%
Age, Continuous; Median (Full Range); Unit of measure: Years
	Number Analyzed	20 participants	10 participants	30 participants
		18.3; (16.1 to 24.8)	25.3; (18.2 to 30.7)	20.6; (16.1 to 30.7)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	20 participants	10 participants	30 participants
	Female	7 35.0%	6 60.0%	13 43.3%
	Male	13 65.0%	4 40.0%	17 56.7%
Race and Ethnicity Not Collected [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	0 participants	0 participants	0 participants
				0
		[1] Measure Analysis Population Description: Race and Ethnicity were not collected from any participant.
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	20 participants	10 participants	30 participants
		20	10	30

Outcome Measures

1. Primary Outcome

Title	Median Maximal Drug Concentration (Cmax)
Description	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.
Time Frame	0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Healthy Controls	CF Fasting	CF Food
Arm/Group Description:	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 Ethambutol: Anti-mycobacterial oral drug Rifampin: Anti-mycobacterial oral drug Azithromycin: Anti-mycobacterial oral drug	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 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).	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 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).
Overall Number of Participants Analyzed	10	20	20
Median (Full Range); Unit of Measure: mg/L
Rifampin	16.56; (10.2 to 27.0)	12.5; (6.6 to 21.9)	11.2; (4.7 to 14.5)
Ethambutol	3.0; (2.3 to 4.7)	4.2; (1.1 to 6.8)	4.3; (1.0 to 5.7)
Azithromycin	1.1; (0.6 to 2.1)	2.0; (0.1 to 5.3)	2.2; (0.1 to 4.1)

2. Secondary Outcome

Title	Other PK Measures: Median Time to Maximal Drug Concentration (Tmax)
Description	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
Time Frame	0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Healthy Controls	CF Patients, Fasting	CF Patients, Food
Arm/Group Description:	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 Ethambutol: Anti-mycobacterial oral drug Rifampin: Anti-mycobacterial oral drug Azithromycin: Anti-mycobacterial oral drug	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 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).	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 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).
Overall Number of Participants Analyzed	10	20	20
Median (Full Range); Unit of Measure: hours
Rifampin	1.5; (1 to 4)	1.5; (1 to 3)	2.5; (1 to 6)
Ethambutol	2.3; (1 to 4)	2.3; (1 to 4)	2.0; (1 to 4)
Azithromycin	2.0; (1 to 3)	2.0; (1 to 4)	2.0; (1 to 4)

3. Secondary Outcome

Title	Other PK Measures: Half-life (t1/2)
Description	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
Time Frame	0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Healthy Controls	CF Fasting	CF Food
Arm/Group Description:	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 Ethambutol: Anti-mycobacterial oral drug Rifampin: Anti-mycobacterial oral drug Azithromycin: Anti-mycobacterial oral drug	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 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).	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 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).
Overall Number of Participants Analyzed	10	20	20
Median (Full Range); Unit of Measure: hours
Rifampin	3.8; (2.6 to 7.0)	3.4; (2.2 to 5.9)	3.4; (2.3 to 8.0)
Ethambutol	5.3; (3.3 to 6.0)	4.3; (3.1 to 7.2)	4.7; (3.0 to 15.1)
Azithromycin	6.2; (3.3 to 7.0)	5.2; (2.5 to 14.0)	6.6; (2.5 to 14.4)

4. Secondary Outcome

Title	Other PK Measures: Drug Clearance
Description	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.
Time Frame	0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Healthy Controls	CF Fasting	CF Food
Arm/Group Description:	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 Ethambutol: Anti-mycobacterial oral drug Rifampin: Anti-mycobacterial oral drug Azithromycin: Anti-mycobacterial oral drug	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 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).	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 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).
Overall Number of Participants Analyzed	10	20	20
Median (Full Range); Unit of Measure: L/h
Rifampin	5.1; (3.8 to 8.5)	7.9; (3.6 to 15.7)	7.6; (4.4 to 19.5)
Ethambutol	45.3; (34.3 to 61.8)	42.4; (23.6 to 156.6)	37.3; (27.7 to 185.2)
Azithromycin	88.6; (40.3 to 190.9)	73.6; (31.9 to 978.8)	82.8; (41.7 to 567.5)

5. Secondary Outcome

Title	Other PK Measures: Volume of Distribution (Vd)
Description	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
Time Frame	0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Healthy Controls	CF Fasting	CF Food
Arm/Group Description:	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 Ethambutol: Anti-mycobacterial oral drug Rifampin: Anti-mycobacterial oral drug Azithromycin: Anti-mycobacterial oral drug	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 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).	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 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).
Overall Number of Participants Analyzed	10	20	20
Median (Full Range); Unit of Measure: L
Rifampin	31.3; (16.4 to 39.0)	39.7; (21.3 to 67.5)	37.4; (25.9 to 105.6)
Ethambutol	352.8; (162.0 to 453.0)	274.6; (139.7 to 1045.9)	354.3; (147.3 to 1866.4)
Azithromycin	717.0; (406.1 to 1083.4)	549.2; (201.5 to 9503.5)	621.3; (249.3 to 8608.7)

6. Secondary Outcome

Title	Covariates of PK Measures: C-reactive Protein (CRP)
Description	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.
Time Frame	baseline

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Healthy Controls	CF Fasting	CF Food
Arm/Group Description:	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 Ethambutol: Anti-mycobacterial oral drug Rifampin: Anti-mycobacterial oral drug Azithromycin: Anti-mycobacterial oral drug	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 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).	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 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).
Overall Number of Participants Analyzed	10	20	0
Median (Full Range); Unit of Measure: mg/dL
	0.2; (0.0 to 5.1)	0.8; (0.2 to 9)

7. Secondary Outcome

Title	Covariates of PK Measures: Circulating Neutrophil Count
Description	Circulating neutrophil count. Begin to investigate the influence of inflammation, host characteristics, and drug metabolism on the PK of the antimycobacterial drugs
Time Frame	baseline

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Healthy Controls	CF Fasting	CF Food
Arm/Group Description:	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 Ethambutol: Anti-mycobacterial oral drug Rifampin: Anti-mycobacterial oral drug Azithromycin: Anti-mycobacterial oral drug	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 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).	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 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).
Overall Number of Participants Analyzed	10	20	0
Median (Full Range); Unit of Measure: 10^3 cells/uL
	3.0; (1.4 to 7.2)	3.8; (2.5 to 7.7)

8. Secondary Outcome

Title	Covariates of PK Measures: Body Mass Index
Description	Body mass index (BMI). Begin to investigate the influence of inflammation, host characteristics, and drug metabolism on the PK of the antimycobacterial drugs
Time Frame	baseline

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Healthy Controls	CF Fasting	CF Food
Arm/Group Description:	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 Ethambutol: Anti-mycobacterial oral drug Rifampin: Anti-mycobacterial oral drug Azithromycin: Anti-mycobacterial oral drug	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 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).	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 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).
Overall Number of Participants Analyzed	10	20	0
Median (Full Range); Unit of Measure: kg/m^2
	23.0; (18.9 to 25.1)	21.9; (18.0 to 26.6)

9. Secondary Outcome

Title	Covariates of PK Measures: Creatinine
Description	Creatinine. Begin to investigate the influence of inflammation, host characteristics, and drug metabolism on the PK of the antimycobacterial drugs
Time Frame	baseline

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Healthy Controls	CF Fasting	CF Food
Arm/Group Description:	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 Ethambutol: Anti-mycobacterial oral drug Rifampin: Anti-mycobacterial oral drug Azithromycin: Anti-mycobacterial oral drug	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 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).	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 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).
Overall Number of Participants Analyzed	10	20	0
Median (Full Range); Unit of Measure: mg/dL
	1.0; (0.8 to 1.2)	0.9; (0.7 to 1.1)

10. Secondary Outcome

Title	Area Under the Curve (AUC)
Description	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.
Time Frame	0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Healthy Controls	CF Fasting	CF Food
Arm/Group Description:	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 Ethambutol: Anti-mycobacterial oral drug Rifampin: Anti-mycobacterial oral drug Azithromycin: Anti-mycobacterial oral drug	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 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).	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 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).
Overall Number of Participants Analyzed	10	20	20
Median (Full Range); Unit of Measure: mg*h/L
Rifampin	118.3; (70.5 to 156)	76; (38.1 to 167.5)	79.2; (30.8 to 136.7)
Ethambutol	21.4; (16.2 to 30.4)	21.8; (6.4 to 38.2)	23.6; (5 to 36)
Azithromycin	5.6; (2.6 to 12.4)	6.8; (0.5 to 15.7)	6; (0.9 to 12)

Adverse Events

Time Frame	During the time of participation in the study, about 6 weeks.
Adverse Event Reporting Description	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.
Arm/Group Title	Healthy Controls	CF Patients, Fasting	CF Patients, Food
Arm/Group Description	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 Ethambutol: Anti-mycobacterial oral drug Rifampin: Anti-mycobacterial oral drug Azithromycin: Anti-mycobacterial oral drug	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 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).	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 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).
All-Cause Mortality
	Healthy Controls	CF Patients, Fasting	CF Patients, Food
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/10 (0.00%)	0/21 (0.00%)	0/20 (0.00%)
Serious Adverse Events
	Healthy Controls	CF Patients, Fasting	CF Patients, Food
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/10 (0.00%)	0/21 (0.00%)	0/20 (0.00%)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Healthy Controls	CF Patients, Fasting	CF Patients, Food
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/10 (0.00%)	0/21 (0.00%)	0/20 (0.00%)

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

Results Point of Contact

• Name/Title: Dr. Stacey Martiniano
• Organization: UColorado
• Phone: 7207776181
• EMail: stacey.martiniano@childrenscolorado.org

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: University of Colorado, Denver
• ClinicalTrials.gov Identifier: NCT02372383
• Other Study ID Numbers: 14-1043; UL1TR001082 ( U.S. NIH Grant/Contract )
• First Submitted: June 20, 2014
• First Posted: February 26, 2015
• Results First Submitted: November 26, 2019
• Results First Posted: February 11, 2021
• Last Update Posted: February 11, 2021