OPTIMIZing Treatment for Early Pseudomonas Aeruginosa Infection in Cystic Fibrosis

Cystic fibrosis (CF) lung disease begins in the first few months of life and follows a course
of recurrent lower airway bacterial infection and inflammation and progression of disease
over years and decades at a variable pace. With the development of chronic lung infection,
obstructive disease progressively worsens, ultimately leading to respiratory failure.
Pseudomonas aeruginosa (Pa) is the most important pathogen infecting the CF lower airways,
and its acquisition early in life is associated with a pro-inflammatory effect, lower lung
function, poor nutritional outcomes, and decreased survival.

Pseudomonas aeruginosa (Pa) infection of the cystic fibrosis (CF) airway typically proceeds
from early infection to chronic infection. Although some studies have shown that a minority
of individuals with CF spontaneously clear early Pseudomonas aeruginosa (Pa) infection, data
from multiple studies suggest that antibiotics are superior to no treatment in clearing
Pseudomonas aeruginosa (Pa) from respiratory cultures. Understanding the transition period
from early to chronic Pseudomonas aeruginosa (Pa) infection is thus of critical importance in
identifying strategies to prevent this progression.

The study will assess the clinical and microbiologic efficacy and safety of azithromycin
given three times weekly in combination with standardized tobramycin solution for inhalation
(TIS) therapy among children with early Pseudomonas aeruginosa (Pa). TIS therapy is defined
as an initial eradication treatment with 1-2 courses of 28 days TIS and subsequent 28 day
treatments only at times a quarterly respiratory culture is positive for Pseudomonas
aeruginosa (Pa). Eligible participants will be randomized within one month of their
Pseudomonas aeruginosa (Pa) positive culture to receive one of the following two treatment
strategies for 18 months: (1) oral placebo in addition to standardized TIS therapy, or (2)
oral azithromycin in addition to standardized TIS therapy.

At the first study visit, participants will undergo a physical examination and a review of
their medical history. Lung function will be measured via spirometry (in children greater
than four years of age who are able to perform spirometry), electrocardiogram (ECG) testing
will be conducted, and hearing ability will be measured via audiometry. Blood will be drawn
for laboratory tests and a specimen will be obtained for a respiratory culture before
randomization and study drug dispensing occurs. Subsequent study visits will take place at
Day 21, Weeks 13, 26, 39, 52, 65, and 78. At each visit, participants will undergo a physical
examination, a spirometry test (as appropriate), a respiratory specimen for Pseudomonas
aeruginosa (Pa) culture will be collected and study drug will be dispensed (except at Week
78). Participants will complete self-report or parent-completed respiratory symptom
questionnaires and signs and symptoms evaluations will be performed at all visits. Repeat
hearing and laboratory tests will be performed at Weeks 39 and 78 and ECG testing will be
repeated at Day 21 and Week 78. Participants will be required to maintain a medication diary
throughout the study.

Inclusion Criteria:

- Age ≥ 6 months to ≤ 18 years

- Documentation of a CF diagnosis as evidenced by one or more clinical features
consistent with the CF phenotype or positive CF Newborn Screening result for
immunoreactive trypsinogen (IRT) IRT/DNA or IRT/IRT and one or more of the following
criteria:

- sweat chloride ≥ 60 milliequivalent (mEq)/liter by quantitative by pilocarpine
iontophoresis test (QPIT)

- two well-characterized mutations in the cystic fibrosis transmembrane conductive
regulator (CFTR) gene

- Abnormal nasal potential difference (NPD) (change in NPD in response to a low chloride
solution and isoproteronol of less than - 5 mV)

- Documented new positive oropharyngeal, sputum or lower respiratory tract culture for
Pa within 30 days of the Baseline Visit (Visit 1), defined as: a) first lifetime
documented Pa positive culture; or b) Pa recovered after at least a two-year history
of Pa negative respiratory cultures (≥ 1 culture/ year)

- Clinically stable with no evidence of any significant respiratory symptoms at the
Baseline Visit that would require administration of intravenous anti- pseudomonal
antibiotics, oxygen supplementation, and/or hospitalization as determined by the study
physician

- Written informed consent obtained from participant or participant's legal
representative (and assent when applicable) and ability for participant to comply with
the requirements of the study

Exclusion Criteria:

- Macrolide antibiotic use within 30 days of the Baseline Visit

- Initiation of current course of treatment with TIS >14 days prior to Baseline Visit

- Weight <6.0 kg at the Baseline Visit

- History of aminoglycoside hypersensitivity or adverse reaction to inhaled
aminoglycoside

- History of azithromycin hypersensitivity or adverse reaction to azithromycin or
allergy to macrolide antibiotics

- History of positive respiratory culture for Non-tuberculous mycobacteria (NTM) or
Burkholderia cepacia complex within 2 years of the Baseline Visit

- History of unresolved, abnormal renal function (defined as serum creatinine greater
than 1.5 times the upper limit of normal for age).

- History of unresolved, abnormal liver function tests (defined as alanine
aminotransferase (ALT) and/or aspartate aminotransferase (AST) greater than 4 times
the upper limit of normal range) or history of portal hypertension

- History of unresolved, abnormal neutropenia (ANC ≤ 1000)

- Abnormal ECG test at the Baseline Visit defined as a QT interval corrected (QTc) (B)
of ≥460 msec or history of ventricular arrhythmia

- History of abnormal hearing sensitivity defined as hearing threshold levels >25 dB HL
(decibels Hearing Level) for visual reinforcement audiometry (VRA) at any frequency
(500-4000Hz) or >20 Decibels Hearing Level (dBHL) for play or standard audiometry at
any two frequencies (500-8000Hz) in either ear, not associated with middle ear disease
(including infection) or a flat (Type B) tympanogram

- New initiation of chronic therapy (greater than 21 days) with drugs known to prolong
QT interval (refer to Appendix III) within 30 days prior to the Baseline Visit or
coadministration of nelfinavir or oral anticoagulants

- Positive serum or urine pregnancy test at the Baseline Visit (to be performed on all
females of child-bearing potential) or for females of child bearing potential:
pregnant, breastfeeding, or unwilling to use barrier contraception during
participation in the study

- Administration of any investigational drug within 30 days prior to the Baseline Visit

- Presence of a condition or abnormality (e.g., pre-existing heart disease) that in the
opinion of the site investigator would compromise the safety of the participant or the
quality of the data