Azithromycin to Prevent Wheezing Following Severe Respiratory Syncytial Virus (RSV) Bronchiolitis

Study Overview
=================
Brief Summary
-----------------
This trial is a proof-of-concept pilot study aim to investigate the biologic and clinical effects of early azithromycin treatment in children hospitalized with Respiratory Syncytial Virus (RSV) bronchiolitis. HYPOTHESES In infants hospitalized with RSV bronchiolitis, azithromycin therapy (compared to placebo) will result in: Decreased concentrations of inflammatory mediators (IL-8 as primary outcome) in serum and nasal wash measured on day 8 after randomization. A smaller proportion of participants with recurrent (≥2) wheezing episodes during weeks 3-52 following randomization.

Official Title
-----------------
Pilot Study: Azithromycin to Prevent Wheezing Following Severe RSV Bronchiolitis

Conditions
-----------------
RSV Bronchiolitis

Intervention / Treatment
-----------------
* Drug: Azithromycin
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age: 1-18 months. Hospitalization for the first episode of RSV bronchiolitis: Confirmed RSV infection by positive nasal swab results (viral culture and/or direct antigen detection) from the SLCH virology lab; AND At least two of the following symptoms/signs of bronchiolitis: respiratory rate greater than 40 breaths/minute; cough; wheezing; audible rales, crackles, and/or rhonchi; paradoxical chest movements (retractions). Duration of respiratory symptoms from initiation of symptoms to admission is 5 days or less. Time of admission will define by the time the child was seen in the ED for the visit that led to hospitalization. Randomization can be performed within 48 hours from time of admission (defined by time of first set of vital signs obtained on the floor). Willingness to provide informed consent by the child's parent or guardian - Exclusion Criteria: Prematurity (gestational age < 36 weeks). Presence or history of other significant disease (CNS, lung, cardiac, renal, GI, hepatic disease, hematologic, endocrine or immune disease). Children with atopic dermatitis will not be excluded from the study. Clinically significant gastroesophageal reflux currently treated with a daily anti-reflux medication (anti- H2 or PPI). The child has significant developmental delay/failure to thrive, defined as weight < 3% for age and gender. History of previous (before the current episode) wheeze or previous treatment with albuterol. Treatment (past of present) with corticosteroid (systemic or inhaled) and/or montelukast. Treatment with any antibiotics in the past 2 weeks. Treatment with Macrolide antibiotic (Azithromycin, clarithromycin or erythromycin) with the past 4 weeks. Current treatment with any daily medication (other then albuterol, vitamins or nutritional supplements). Participation in another clinical 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 azithromycin or any other macrolide antibiotics.

Ages Eligible for Study
-----------------
Minimum Age: 1 Month
Maximum Age: 18 Months

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Azithromycin<br>Oral azithromycin | Drug: Azithromycin<br>* Oral azithromycin 10 mg/kg once daily for 7 days followed by 5mg/kg once daily for additional 7 days.<br>|
| Placebo Comparator: Placebo<br>Oral Placebo | Drug: Placebo<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| IL-8 Concentrations | Biological outcome: The difference in IL-8 concentrations, measured in serum on day 8 after randomization, among infants treated with azithromycin and those treated with placebo. | Day 8 | 
| Proportion of Participants Who Experience Subsequent Recurrent (≥2) Wheezing Episodes | Clinical outcome: The difference in the proportion of participants who experience subsequent recurrent (≥2) wheezing episodes among infants treated with azithromycin and those treated with placebo. | 3-52 weeks following randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concentrations of IL-8 in Nasal Lavage on Day 15 |  | Day 15 | 
| Rates of Drug Related GI Side Effects. |  | One month from randomization | 
| Likelihood to Develop 3 or More Wheezing Episodes | Likelihood to develop 3 or more wheezing episodes measured by a Kaplan-Meier survival analysis | Week 3-52 | 
| Respiratory Symptoms Following RSV Bronchiolitis | Number of days with respiratory symptoms (cough, wheeze, or shortness of breath) | 3-52 weeks following randomization | 
| Number of Children Who Were Prescribed Inhaled Corticosteroids |  | 3-52 weeks following randomization | 
| Proportion of Participants With a Physician Diagnosis of Asthma | The proportion of participants with a physician diagnosis of asthma | Week 3-52 |