Treatment of Preschool Children With Upper Respiratory Tract Illnesses Using Azythromycin and Lower Respiratory Tract Symptoms Using Oral Corticosteroids.

Preschool aged children often have severe bouts of coughing and/or wheezing that lead to
visits to the doctor's office, urgent care, emergency room and often hospitalization.
APRIL-OCELOT is a randomized, double-blind, placebo controlled study in 600 preschool
children with a history of significant wheezing episodes in the year prior to enrollment.
All children enter the APRIL portion of the study, which will compare azithromycin to
placebo, given for 5 days during the early signs of an upper respiratory tract illness, for
preventing the development of lower respiratory tract symptoms. APRIL is a 78 week study,
but participation will end earlier if the child requires a fourth course of APRIL treatment
or develops significant lower respiratory tract symptoms. Only those children who develop
significant lower respiratory tract symptoms during APRIL will enter the OCELOT portion of
the study, which will compare oral corticosteroid to placebo for treating lower respiratory
tract symptoms as measured by the Pediatric Respiratory Assessment Measure (PRAM). OCELOT
participation will be complete after 14 days. Children may not reenter APRIL after
completing OCELOT.

Inclusion Criteria:

- 12-71 months of age.

- Recurrent significant wheezing in the past year (any of the following):

- >3 episodes, ≥1 of which was clinically significant*; OR

- >2 clinically significant* episodes; OR

- >4 months of daily controller therapy AND >1 clinically significant* episode.

- * Clinically significant episode: requiring any of the following: (1) systemic
corticosteroids (oral or injectable), (2) unscheduled physician office visit,
(3) ED visit, (4) urgent care visit, or (5) hospitalization.

- Up to date with immunizations, including varicella (unless the subject has already
had clinical varicella). If the subject needs varicella vaccine, this will be
arranged with the primary care physician and must be received prior to randomization.

- Willingness to provide informed consent by the child's parent or guardian.

Exclusion Criteria:

Participants who meet any of the following criteria are NOT eligible for enrollment, but
may be re-enrolled if these exclusion criteria are resolved:

- >4 courses of systemic corticosteroids in past 12 months.

- More than 1 hospitalization for wheezing illnesses within the preceding 12 months.

- Use of long-term controller medications for asthma, including inhaled
corticosteroids, leukotriene modifiers, cromolyn/nedocromil, or theophylline for more
than 8 months (cumulative use) in the past 12 months.

- Current use of higher than step 2 NAEPP asthma guideline therapy (e.g. medium-high
dose ICS alone or combination therapy of low-medium-high dose ICS + LABA,
montelukast, theophylline or cromolyn). NOTE: children who have evidence of
well-controlled symptoms immediately preceding study entry while receiving Step 2
controller therapy (presence of self-reported symptoms on average no more than 2
times per week and less than 2 nights per month of nocturnal awakenings, requiring
albuterol, during the 4 weeks preceding visit 1) may be enrolled and will have their
controller therapy discontinued upon study entry.

- Use of OCS in the past 2 weeks.

- Daily symptoms or >2 nocturnal awakenings, requiring albuterol, on average in the
last 2 weeks.

- Use of antibiotics in the past month.

- Current treatment with antibiotics for diagnosed sinus disease.

- Participation presently or in the past month in another investigational drug trial.

- Evidence that the family may be unreliable or nonadherent, or may move from the
clinical center area before trial completion.

- Contraindication of use of systemic corticosteroids or azithromycin.

- Clinically relevant gastroesophageal reflux.

- Concurrent medical conditions other than asthma that are likely to require oral or
injectable corticosteroids during the study.

- If receiving allergy shots, change in dose within the past 3 months.

Participants who meet any of the following criteria are NOT eligible for enrollment, and
may not be re-enrolled:

- Gestation less than late preterm as defined as birth before 34 weeks gestational age.

- Presence of lung disease other than asthma, such as cystic fibrosis and BPD.
Evaluation during the screening process will assure that an adequate evaluation of
other lung diseases has been performed.

- Presence of other significant medical illnesses (cardiac, liver, gastrointestinal,
endocrine) that would place the study subject at increased risk of participating in
the study.

- Immunodeficiency disorders.

- History of respiratory failure requiring mechanical ventilation.

- History of hypoxic seizure.

- History of significant adverse reaction to any study medication ingredient.

- The child has significant developmental delay/failure to thrive, defined as crossing
of two major percentile lines during the last year for age and gender. If a child
plots less than the 10th percentile for age and gender, a growth chart for the
previous year will be obtained from the child's primary care provider.