Improving Treatment of Nontuberculous Mycobacterial Infection in Cystic Fibrosis

NCT ID: NCT02372383

Last Updated: 2021-02-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 31 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-10-31
• Study Completion Date: 2016-06-30

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.

Conditions

Cystic Fibrosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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

Group Type: EXPERIMENTAL

Ethambutol

Intervention Type: DRUG

Anti-mycobacterial oral drug

Rifampin

Intervention Type: DRUG

Anti-mycobacterial oral drug

Azithromycin

Intervention Type: DRUG

Anti-mycobacterial oral drug

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

Group Type: EXPERIMENTAL

Ethambutol

Intervention Type: DRUG

Anti-mycobacterial oral drug

Rifampin

Intervention Type: DRUG

Anti-mycobacterial oral drug

Azithromycin

Intervention Type: DRUG

Anti-mycobacterial oral drug

Pancrelipase

Intervention Type: DRUG

Pancreatic enzyme replacement therapy

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

Group Type: ACTIVE_COMPARATOR

Ethambutol

Intervention Type: DRUG

Anti-mycobacterial oral drug

Rifampin

Intervention Type: DRUG

Anti-mycobacterial oral drug

Azithromycin

Intervention Type: DRUG

Anti-mycobacterial oral drug

Interventions

Ethambutol

Anti-mycobacterial oral drug

Intervention Type: DRUG

Rifampin

Anti-mycobacterial oral drug

Intervention Type: DRUG

Azithromycin

Anti-mycobacterial oral drug

Intervention Type: DRUG

Pancrelipase

Pancreatic enzyme replacement therapy

Intervention Type: DRUG

Other Intervention Names

Myambutol; Rifadin; Zithromax; Creon; Zenpep; Pertzye

Eligibility Criteria

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.

• 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.

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.

• 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.

• Minimum Eligible Age: 16 Years
• Maximum Eligible Age: 45 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Cystic Fibrosis Foundation

OTHER

Sponsor Role: collaborator

Colorado Clinical & Translational Sciences Institute

OTHER

Sponsor Role: collaborator

University of Colorado, Denver

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Stacey Martiniano, MD

Role: PRINCIPAL_INVESTIGATOR

University of Colorado, Denver

Locations

Children's Hospital Colroado

Aurora, Colorado, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 34030986 (View on PubMed)

Other Identifiers

UL1TR001082

Identifier Type: NIH

Identifier Source: secondary_id

View Link

14-1043

Identifier Type: -

Identifier Source: org_study_id