Improving Treatment of Nontuberculous Mycobacterial Infection in Cystic Fibrosis

• Register: ClinicalTrials.gov
• Last refreshed on: 8 August 2016
• Main ID: NCT02372383
• Date of registration: 20/06/2014
• Prospective Registration: Yes
• Primary sponsor: University of Colorado, Denver
• Public title: Improving Treatment of Nontuberculous Mycobacterial Infection in Cystic Fibrosis
• Scientific title: Pharmacokinetic Evaluation of Nontuberculous Mycobacterial Antibiotics in Cystic Fibrosis Versus Controls
• Date of first enrolment: October 2014
• Target sample size: 32
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/show/NCT02372383
• Study type: Interventional
• Study design: Allocation: Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment
• Phase: N/A

Countries of recruitment

United States

Contacts

• Name: Stacey Martiniano, MD
• Affiliation: University of Colorado, Denver

Key inclusion & exclusion 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.



Age minimum: 16 Years
Age maximum: 45 Years
Gender: Both

Health Condition(s) or Problem(s) studied

Cystic Fibrosis

Intervention(s)

Drug: Azithromycin

Drug: Rifampin

Drug: Ethambutol

Drug: Pancrelipase

Primary Outcome(s)

Mean maximal drug concentration (Cmax) [Time Frame: 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose]

Secondary Outcome(s)

Covariates of PK measures: BUN [Time Frame: baseline]

Covariates of PK measures: drug metabolite Cmax [Time Frame: baseline]

Covariates of PK measures: creatinine [Time Frame: baseline]

Other PK measures: drug clearance [Time Frame: 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose]

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]

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]

Covariates of PK measures: age [Time Frame: baseline]

Covariates of PK measures: body mass index [Time Frame: baseline]

Covariates of PK measures: C-reactive protein (CRP) [Time Frame: baseline]

Covariates of PK measures: circulating neutrophils [Time Frame: baseline]

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]

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]

Covariates of PK measures: CF genotype [Time Frame: baseline]

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]

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]

Covariates of PK measures: drug metabolite AUC [Time Frame: baseline]

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]

Secondary ID(s)

14-1043

UL1TR001082

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Secondary Sponsor(s)

Colorado Clinical & Translational Sciences Institute

Cystic Fibrosis Foundation Therapeutics