Effect of Azithromycin on Lung Function in 6-18 Year-olds With Cystic Fibrosis (CF) Not Infected With P. Aeruginosa

Azithromycin is an antibiotic that has been shown to improve lung function in patients with
cystic fibrosis (CF) whose lungs are infected with a bacterium called Pseudomonas
aeruginosa. Scientists are not sure how azithromycin works in cystic fibrosis. It does not
appear to work by killing the bacteria Pseudomonas aeruginosa, but it may make these
bacteria and other bacteria less damaging to the lungs by reducing their ability to attach
to the lining of the lung, or by reducing the bacteria's ability to make substances that
damage the lungs of patients with cystic fibrosis. Azithromycin may also work directly on
the cells in the lungs to improve lung function. This could occur by reducing inflammation
(swelling) in the lungs, and/or making the mucus less sticky, or by affecting the salt
channel that doesn't function correctly in CF. If azithromycin works in one or more of these
ways; it may also be effective in improving lung function in cystic fibrosis patients who
are not infected with Pseudomonas aeruginosa.

We are conducting this research study to examine the safety, effect on lung function and
frequency of symptoms relating to cystic fibrosis during 24 weeks of treatment with the
antibiotic azithromycin. This study is designed to determine if patients with cystic
fibrosis whose lungs are not infected with the bacteria Pseudomonas aeruginosa will benefit
from 24 weeks of treatment with the antibiotic azithromycin. Benefit will be determined as
having better pulmonary function tests and getting sick less often compared to a placebo
(sugar pill). This study is also designed to determine if azithromycin is safe when
administered for 24 weeks to cystic fibrosis patients not infected with Pseudomonas
aeruginosa. By doing this study, we hope to learn more about CF and improve the way in which
we treat it.

Comparison: Three times weekly azithromycin tablets added to standard care, compared to
three times weekly placebo tablets added to standard care.

Inclusion Criteria:

- Male or female, 6-18 years of age at enrollment

- Confirmed diagnosis of CF

- Written informed consent (and assent when applicable)

- Clinically stable at enrollment as assessed by the site investigator

- FEV1 % predicted > 50%

- Ability to comply with medication use, study visits, and study procedures

- Ability to swallow a 250 mg tablet

Exclusion Criteria:

- Weight less than 18.0 kg

- Respiratory culture positive for P. aeruginosa, NTM, or B. cepacia complex within 1
year or at screening, or AFB positive at screening

- Allergy to macrolide antibiotics

- Use of macrolide antibiotics (e.g., azithromycin, clarithromycin) within 60 days of
screening

- Use of systemic corticosteroids or intravenous or oral antibiotics within 14 days of
screening

- Initiation of high dose ibuprofen, Pulmozyme®, hypertonic saline or aerosolized
antibiotics within 30 days of screening

- Chronic therapy with drugs known to have rare but serious interactions with
azithromycin: amiodarone, digoxin, disopyramide, lovastatin, pimozide, rifabutin, and
nelfinavir

- Investigational drug use within 30 days of screening

- Laboratory abnormalities (creatinine, liver function or neutropenia) at screening and
confirmed at follow-up testing prior to randomization

- History of biliary cirrhosis, portal hypertension, or splenomegaly, or splenomegaly
on physical exam

- History of ventricular arrhythmia

- Other major organ dysfunction, excluding pancreatic dysfunction

- History of lung transplantation or currently on lung transplant list

- Relative decrease in FEV1 % predicted ≥ 20% between the screening and enrollment
visit

- Positive serum pregnancy test at screening

- Pregnant, breastfeeding, or if post-menarche female, unwilling to practice birth
control during participation in the study

- History of alcohol, illicit drug or medication abuse within 1 year of screening in
the judgment of the site investigator

- Presence of a condition or abnormality that in the opinion of the site investigator
would compromise the safety of the subject or the quality of the data