Improving Treatment of Nontuberculous Mycobacterial Infection in Cystic Fibrosis

NCT02372383 | Completed Results DMC

• 2 other identifiers: 14-1043UL1TR001082
• Study Type: interventional
• Target: 31
• Locations: 1 country
• Sites: 1

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.

Conditions

Cystic Fibrosis

Keywords

Cystic Fibrosis; Pharmacokinetics; Pharmacodynamics; Nontuberculous Mycobacteria; Treatment

Outcome Measures

Primary Outcomes (1)

• 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

Secondary Outcomes (9)

• Other PK Measures: Median Time to Maximal Drug Concentration (Tmax)

  0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose

• Other PK Measures: Half-life (t1/2)

  0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose

• Other PK Measures: Drug Clearance

  0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose

• Other PK Measures: Volume of Distribution (Vd)

  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)

  baseline

Study Arms (3)

Fasting

EXPERIMENTAL

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

Drug: Ethambutol; Drug: Rifampin; Drug: Azithromycin

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). * 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

Drug: Ethambutol; Drug: Rifampin; Drug: Azithromycin; Drug: Pancrelipase

Healthy Controls

ACTIVE COMPARATOR

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

Drug: Ethambutol; Drug: Rifampin; Drug: Azithromycin

Interventions

Ethambutol DRUG

Anti-mycobacterial oral drug

Also known as: Myambutol

Fasting; Food/Enzymes; Healthy Controls

Rifampin DRUG

Anti-mycobacterial oral drug

Also known as: Rifadin

Fasting; Food/Enzymes; Healthy Controls

Azithromycin DRUG

Anti-mycobacterial oral drug

Also known as: Zithromax

Fasting; Food/Enzymes; Healthy Controls

Pancrelipase DRUG

Pancreatic enzyme replacement therapy

Also known as: Creon, Zenpep, Pertzye

Food/Enzymes

Eligibility Criteria

• Age: 16 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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).
• 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.
• We will also exclude pregnant women (urine pregnancy test will be performed on the day of PK study) and decisionally challenged subjects.

Sponsors & Collaborators

• University of Colorado, Denver: lead
• Cystic Fibrosis Foundation: collaborator
• Colorado Clinical & Translational Sciences Institute: collaborator

Study Sites (1)

Children's Hospital Colroado

Aurora, Colorado, 80045, United States

Location

Related Publications (1)

• 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.

  PMID: 34030986 DERIVED

MeSH Terms

Conditions

Cystic Fibrosis

Interventions

Ethambutol; Rifampin; Azithromycin; Pancrelipase

Condition Hierarchy (Ancestors)

Pancreatic Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Infant, Newborn, Diseases

Intervention Hierarchy (Ancestors)

Ethylenediamines; Diamines; Polyamines; Amines; Organic Chemicals; Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds; Erythromycin; Macrolides; Polyketides; Lactones; Lipase; Carboxylic Ester Hydrolases; Esterases; Hydrolases; Enzymes; Enzymes and Coenzymes; Pancreatic Extracts; Tissue Extracts; Complex Mixtures

Results Point of Contact

• Title: Dr. Stacey Martiniano
• Organization: UColorado

stacey.martiniano@childrenscolorado.org

7207776181

Study Officials

• Stacey Martiniano, MD

  University of Colorado, Denver

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 20, 2014
• First Posted: February 26, 2015
• Study Start: October 1, 2014
• Primary Completion: June 1, 2016
• Study Completion: June 1, 2016
• Last Updated: February 11, 2021
• Results First Posted: February 11, 2021

Record last verified: 2021-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)