Clinical trial NCT02003911
Conditions: Asthma
Keywords: Asthma Acute asthma exacerbation Pediatric Azithromycin Macrolide Length of Stay Hospital Medicine
Sponsor: Montefiore Medical Center
Start date: 2013-10-01; Completion date: 2018-06-01
Enrollment: 159 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Asthma is a chronic lung condition in children, and often requires hospitalization for acute exacerbations. Azithromycin has been used successfully in other chronic lung diseases, including cystic fibrosis. Despite limited clinical evidence, some pediatricians use azithromycin in children hospitalized with asthma, citing either treatment of atypical pathogens or its proposed anti-inflammatory properties. This study proposes a clinical trial to determine if azithromycin will shorten length of stay in children hospitalized with acute asthma exacerbations.

Detailed description:
Asthma is a chronic lung condition that accounts for over 130,000 pediatric hospitalizations nationally at a cost of almost 1.4 billion dollars. Atypical pathogens have been implicated both in initiating asthma and triggering acute asthma exacerbations. Azithromycin, a macrolide antibiotic, is known to have antibacterial activity against atypical pathogens and gram positive bacteria. More recently, macrolides have been increasingly used and effective against gram negative bacteria and inflammation in the lungs of patients with chronic respiratory illnesses. This effect may be secondary to the immunomodulatory effects macrolides possess, in addition to their anti-bacterial effects. In long-term therapy with macrolides, patients with asthma have shown improved bronchiolar hyperreactivity, spirometry, symptoms, and quality of life. However, studies of short-term treatment in the acute setting and in children are limited. Some practitioners use azithromycin in the treatment of acute asthma, despite limited data.

The investigators propose a double-blind, randomized, placebo-controlled trial of azithromycin in children aged 4-12 years with persistent asthma hospitalized with acute asthma exacerbations. Children will be enrolled within 12 hours of admission and will be randomized to receive three days of either azithromycin or placebo suspension (10mg/kg/dose, max of 500mg). The primary outcome measure will be length of stay (LOS). Secondary outcome measures will include: days of school/work missed, readmission rates, return to medical care rates, recurrence of symptoms, and steroid courses. In the future, patients may also be approached to enroll in the "Mechanism Subset Study" a separate pilot and feasibility study which will require two blood samples and two nasal aspirate samples and will test for atypical pathogens, interleukin-8 levels, and neutrophil/eosinophil counts. The average length of stay for patients in this age range with asthma in 2011 at our institution was 3.0 days. The investigators will enroll to achieve a power of 80%, with an alpha of 0.05, which will require 107 patients in each group to detect a 16 hour (0.67 day) difference in the primary outcome, LOS. This study hypothesizes that azithromycin treatment in children hospitalized with acute asthma will decrease LOS.

Arms: arm 1: Azithromycin suspension at 10mg/kg/dose (max 500mg)

Once daily for 3 days arm 2: Same volume as active drug

Once daily for 3 days
Interventions: intervention 1: Azithromycin intervention 2: Placebo
Intervention descriptions: intervention 1: Azithromycin suspension (200mg/5mL) intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
Principal Investigator (Last, First, Middle):    Douglas, Lindsey, Caroline 
 
 
 
 
 
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A Double-Blind, Randomized, Placebo-Controlled Trial of Azithromycin  
in Children Hospitalized with Acute Asthma Exacerbations 
 
 
AIMS 
1. To determine the clinical efficacy of azithromycin in the treatment of children with 
persistent asthma hospitalized with acute asthma exacerbations. 
2. To obtain preliminary data regarding the mechanisms of action of azithromycin in 
children with acute asthma exacerbations. 
BACKGROUND 
Asthma is a chronic lung condition in children and adults, characterized by 
bronchospasm and inflammation with clinical wheezing and dyspnea.  Atypical pathogens, 
including Mycoplasma pneumoniae and Chlamydia pneumoniae, have been implicated both in 
predisposing to asthma diagnosis and triggering acute asthma exacerbations.  Small, but 
promising, studies have shown improvement in lung inflammation and asthma symptoms in 
patients treated with macrolide antibiotics.  This effect may be secondary to treatment of 
atypical pathogens or due to the anti-inflammatory effects of macrolides. 
 
Macrolides and Atypical Pathogens 
Macrolides have primary anti-bacterial activity against atypical pathogens, including 
Mycoplasma pneumoniae and Chlamydia pneumoniae.  Multiple studies have shown higher 
prevalence of these organisms in patients with stable and acute asthma, implying that these 
organisms may play a role in the pathogenesis of the disease.  Mycoplasma pneumoniae 
infection has been associated with recurrent wheezing and lower forced vital capacity even in 
asymptomatic patients.1  Prevalence rates range from 18-56% for Mycoplasma pneumoniae 
and/or Chlamydia pneumoniae in serologic titers, serum polymerase chain reaction (PCR), 
nasopharyngeal aspirates, or sputum of patients with asthma, and tend to be higher during 
acute exacerbations.2-8  In children with asthma and Chlamydia pneumonia, IL-8 levels and 
neutrophils numbers are increased in bronchoalveolar lavage (BAL) specimens.9 In children with 
asthma and Mycoplasma pneumoniae infection, IgE levels are lower.10  In addition, Chlamydia 
pneumoniae infection induces MUC5AC production and gene expression needed for mucous 
production, which is reduced after treatment with clarithromycin.11   
 
Immunomodulatory Effects of Macrolides 
In addition to direct inhibition of microbial growth, macrolides have a number of anti-
microbial properties including inhibition of biofilm formation, bacterial adherence, and flagella 
mobility, especially in Pseudomonas aeruginosa. In addition, they suppress both bacterial 
quorum sensing and production of cytotoxic enzymes, and promote phagocytosis12. 
There have been a variety of anti-inflammatory properties associated with macrolides.  This 
class of drugs consistently decreases interleukin-8 (IL-8), a pro-inflammatory chemokine that 
attracts neutrophils, in nasopharyngeal aspirates8, sputum13, and serum14 of asthma patients.  
Other inflammatory markers have been shown to be modulated by macrolides including, TNF-
α8,15 IL-1β8, IL-108, IL-5, IL-1215, MUC5AC needed for mucin production11, neutrophil elastase, 
MMP-913, superoxide production by neutrophils16, and VEGF14.  A decreased number of 
neutrophils has also been shown in patients with asthma treated with macrolides.13,16,17   
Macrolides decrease serum and sputum eosinophil counts.18,19  Asthma models in mice have 
corroborated many of these findings, in addition to finding other anti-inflammatory cytokine and 
chemokine effects. 20-23  The clinical immunomodulatory effects of macrolides have been 


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postulated by some studies to be secondary to a reduction in steroid metabolism which results 
increased levels of circulating steroids – a “steroid-sparing” effect.24 
 
Clinical Use of Macrolides in Lung Disease 
Recognizing the above effects in lung tissue, many investigators have used macrolides 
in the treatment of various chronic respiratory illnesses including diffuse panbronchiolitis, cystic 
fibrosis, non-cystic-fibrosis bronchiectasis, chronic obstructive pulmonary disease, chronic 
rhinosinusitis, cryptogenic organized pneumonia, bronchopulmonary dysplasia, and asthma.  
The most impressive results have been seen in diffuse panbronchiolitis and cystic fibrosis.  After 
erythromycin began being used widely three decades ago for diffuse panbronchiolitis, a chronic 
respiratory illness found almost exclusively in Japan, the five year survival rates improved from 
30% to 90%.25  A large trial in children with cystic fibrosis infected with Pseudomonas and 
treated for 24 weeks with azithromycin, found improvement in FEV1, fewer pulmonary 
exacerbations, and improved weight gain.26   
 
Clinical Use of Macrolides in Asthma 
In long-term therapy with macrolides, adult patients with asthma have shown improved 
bronchiolar hyperreactivity (measured by PC20, defined as a 20% fall in FEV1).19,27,28  In 
addition, spirometry has improved in many patients with asthma treated with long-term 
macrolides,15,29 while others have seen no change in spirometry28.  Multiple studies found 
improvement in reported asthma symptoms13,30,31 or improvement in quality of life scoring.13,31  
Reduced steroid use was also reported in some studies.32,33  In pediatric patients, macrolides 
have been shown to improve cough, bronchoconstriction34, PC2034, FEV117, and steroid use.35    
There is less data on the potential role of macrolides in the treatment of acute asthma 
exacerbations.  The only clinical study in short-term use of macrolide was in adults receiving 
telithromycin; it showed a reduction in asthma scores, but no change in spirometry.7  There has 
only been one study in short-term macrolide treatment in children, however, only chemokine 
concentrations were reported and clinical effects were not followed.8   
A Cochrane review in 2005 concluded that considering the small number of patients, there 
was “insufficient evidence to support or to refute the use of macrolides in patients with chronic 
asthma”.36 
 
Azithromycin and Asthma at CHAM 
At the Children’s Hospital at Montefiore (CHAM), the macrolide azithromycin is currently 
being used by some practitioners for its presumed anti-inflammatory effects in patients with 
acute asthma exacerbations.  In 2010, 14% of 895 pediatric patients with a primary diagnosis of 
asthma received azithromycin during their inpatient stay.  (Data obtained from a Clinical Looking 
Glass preliminary search).  The length of stay of patients who received azithromycin was longer 
(mean: 4.5 days, median 3.8 days) than those who did not receive azithromycin (mean: 3.2 
days, median 2 days) which may suggest that the current practice includes administering 
azithromycin to more severe asthma patients or patients refractory to standard treatments.  A 
similar search of patients admitted with a primary diagnosis of asthma from 2008-2010 and 
transferred at any time to a pediatric intensive care bed, revealed that even more received 
azithromycin – over 30%.  However, the length of stay for the critical care patients was 
unchanged whether they received azithromycin or not (both groups had a mean: 5.0 days, and 
median: 4.0 days).   Although currently 14-30% of children admitted with acute asthma to CHAM 
receive azithromycin, there is currently no evidence on the efficacy of this treatment practice.   
We propose to conduct the first double-blind, randomized, placebo-controlled trial to 
determine whether azithromycin will effect inpatient length of stay in children with acute asthma 
exacerbations. 
 


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OBJECTIVES  
 
Primary Objective:   
To conduct a double-blind, randomized, placebo-controlled trial to determine the clinical efficacy 
of azithromycin treatment in hospitalized children with acute asthma exacerbations, as 
measured by length of stay. 
 
Secondary Objectives in a Subset of Patients – “Mechanism Subset Study”: 
1. To quantify the relative prevalence of atypical infection in the inpatient pediatric asthma 
population. 
2. To determine if atypical infection with Mycoplasma pneumoniae or Chlamydia pneumoniae 
is associated with treatment effect, if found.   
3. To determine immunomodulatory effects of azithromycin in children hospitalized with acute 
asthma exacerbations, as measured by neutrophil counts, eosinophil counts, and 
interleukin-8. 
Hypothesis: 
Azithromycin treatment will decrease length of stay in children with persistent asthma 
hospitalized with acute asthma exacerbation.   
 
 
OUTCOME MEASURES 
 
Primary Outcome:   
Length of Stay 
 
Secondary Outcomes: 
Telephone follow-up at one week and one month: 
1. Hospital readmission rate 
2. Days missed of school for patient 
3. Days missed of work for parent/guardian 
4. Number of emergency room visits for asthma symptoms since discharge 
5. Number of physician office visits for asthma symptoms since discharge 
6. Number of recurrences of asthma symptoms since discharge 
7. Number of courses of oral steroids since discharge (only at 1 month follow-up) 
 
Also monitored: Respiratory viral panel or rapid viral testing results (if obtained as part of 
medical care), chest x-ray results (if obtained as part of medical care), medication side effects 
(diarrhea, abdominal pain, vomiting, flatulence), transfer to intensive care unit, time of wean of 
beta-agonists (q3h and q4h), and asthma severity (PASS score) at time of enrollment 
 
 
“Mechanism Subset Study”: A Pilot and Feasibility Study in the subset of patients who consent 
to sample retrieval: 
 
Nasopharyngeal aspirate samples on enrollment and at 48 hours – measure a set of 
select biomarkers associated with inflammation (including IL-8) via Bioluminex or ELISA 
technology, eosinophil and neutrophil count per high power field, Mycoplasma and 
Chlamydia PCR 


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Serum on enrollment and at 48 hours – measure same biomarkers of inflammation as in 
above aspirate, Mycoplasma and Chlamydia IgM and IgG, Mycoplasma and Chlamydia 
PCR, absolute neutrophil and eosinophil count  
 
METHODS 
 
Population  
The study will include patients between the ages of 4-12 years of age admitted to the pediatric 
inpatient unit or pediatric intensive care unit at the Children’s Hospital at Montefiore (CHAM). 
 
Inclusion Criteria:  Patients will be considered for enrollment if 4-12 years of age with an 
admission diagnosis of asthma and a history of persistent asthma (as defined by National Heart, 
Lung, and Blood Institute; see below and Eligibility Questionnaire).    
 
 


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Exclusion Criteria:  Receiving albuterol every 4 hours (q4h) at the time of enrollment, concurrent 
bacterial infection requiring antibiotics, antibiotics received within previous 2 weeks, 
contraindication to azithromycin (including allergy to macrolides), chronic lung disease other 
than asthma (including bronchopulmonary dysplasia, cystic fibrosis, bronchiectasis), 
immunodeficiency (primary or acquired), chronic systemic steroid use, invasive or non-invasive 
mechanical ventilation required acutely as result of current asthma admission, significant 
cardiac co-morbidity (including hemodynamically significant cardiac disease or arrhythmia), liver 
disease (hepatitis), pregnancy, seizure disorder, currently on medication contraindication for use 
with azithromycin, and/or previous enrollment in study. 
 
Withdrawal from study will occur for:  
1. Parent/guardian preference  
2. Primary attending preference 
3. Worsening of clinical status requiring invasive or non-invasive ventilatory support 
4. Diagnosis of infection requiring antibiotics during the 3-day course of azithromycin/ 
placeboso.  (However, if the diagnosis of infection and initiation of antibiotics is after the 


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completion of the 3-day course of azithromycin/placebo, the antibiotic will be recorded 
and reported.  Patients given antibiotics after the completion of the 3-day course of study 
drug will not be withdrawn from the study and their outcomes will be included in 
analysis.) 
 
Safety Exit Criteria: Worsening of clinical status requiring invasive or non-invasive ventilatory 
support 
 
Study Design 
This is a double-blind, randomized, placebo-controlled trial.  Patients between the ages 
of 4-12 years of age admitted to the Children’s Hospital at Montefiore (CHAM) with an 
admission diagnosis of asthma exacerbation, as determined by the admitting physician, will be 
assessed for eligibility within 12 hours of admission by study personnel.  Patients may be 
enrolled in the pediatric emergency room, pediatric inpatient units, or pediatric intensive care 
unit.   
Potential study patients will be identified by the pediatric emergency room staff, pediatric 
housestaff who will page the research pager upon admission.  In addition, attending physicians 
in the emergency room, pediatric units, and pediatric intensive care unit can refer patients by 
paging the research paper.  Study personnel will review with primary care team any studies 
(including chest x-ray) that may alter the decision to start antibiotics prior to enrollment in the 
study.  A member of the medical team caring for the patient will approach the parent/guardian 
and inquire if study personnel can discuss the study with him/her.  If a parent/guardian is not 
available, the research personnel will return when one is available.  If the parent/guardian 
agrees, study personnel will approach him/her and complete a standardized interview to 
determine if the patient meets eligibility requirements (see Eligibility Questionnaire).  If eligibility 
requirements are met, the research personnel will obtain informed consent from the 
parent/guardian and assent from the child (if applicable) for participation in the study.  If a 
female patient has achieved menarche, a pregnancy test will be administered with the consent 
of the parent/guardian and assent of the patient.  Pregnant patients will be excluded from the 
study. 
The research personnel will then conduct a standardized interview to obtain baseline 
demographic, clinical, and contact information from the parent/guardian (see Enrollment 
Questionnaire).    
The enrolled patient will then be randomized by the Pharmacy Investigational Drug 
Services.  Patients will either receive azithromycin suspension or indistinguishable placebo 
suspension once daily for three days at a dose of 10 mg/kg/dose with a maximum dose of 500 
mg/dose.  All research personnel, medical staff, patients, and parents/guardians will be blinded 
to the composition of suspension prepared in the research pharmacy.  If the patient is 
discharged before the third dose of medication is administered, the pharmacy will provide any 
remaining suspension doses to be completed by patient as an outpatient. 
The selection of the intervention dose of azithromycin (once daily dosing of 10 mg/kg/dose 
with a maximum dose of 500 mg) was made for several reasons.  This dosing is shorter and 
more convenient to administer than the more commonly used 5 day course with 10 mg/kg/day 
for one day and 5 mg/kg/day for subsequent days.  Since the average length of stay for patients 
4-12 years old with asthma is 3 days, it is more likely that patients will complete this dosing 
during hospitalization.  This dosing is currently recommended for other infectious indications 
including otitis media in penicillin allergic patients.  In addition, this dosing is consistent with an 
open trial registered at clinicaltrials.gov in Denmark studying azithromycin treatment in children 
1-3 years of age with recurrent asthma (planned enrollment November 2010 until November 
2014). 


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At the time of enrollment, the patient will have an asthma severity score performed by 
research personnel via the Pediatric Asthma Severity Score (PASS), which has been validated 
in children 1-18 years old.37,38  The score will be conducted within 30 minutes prior a scheduled 
beta-agonist treatment or at any time if patient is on continuous albuterol.  This score will be 
used to determine severity of the patient’s asthma exacerbation at the time of enrollment. 
 
Pediatric Asthma Severity Scoring (PASS) 
Signs 
0 
1 
2 
Wheezing (= expiratory sounds heard auscultation) 
None/mild 
Moderate 
Severe or absent due to poor 
air entry 
Respiratory work (= utilization of accessory muscles or 
retractions) 
None/mild 
Moderate 
Severe 
Prolongation of expiration (= ratio of the length of 
expiration over inspiration) 
Normal/mild 
prolongation 
Moderate 
prolongation 
Severe prolongation 
 
Other than the administration of azithromycin suspension or placebo, the medical 
treatment of the enrolled patients will be at the discretion of the medical team.  The current 
standard of care for treatment of acute asthma exacerbations in hospitalized children includes 
inhaled beta-agonists and systemic steroids.  The medical team often continues or initiates 
“controller” asthma medications during the inpatient stay (ie inhaled corticosteroids, leukotriene 
receptor antagonists).  In addition, patients with severe asthma might receive intravenous 
medications (ie magnesium sulfate, terbutaline, aminophylline).  No medical treatments will 
constitute exclusion from the study.  However, invasive or non-invasive mechanical ventilatory 
support will be part of safety exit criteria.  
At 7-10 days and again between 28 and 35 days after discharge, research personnel with 
contact the parent/guardian of enrolled patient for a follow-up interview.  This interview will 
include questions about recurrence of asthma symptoms, days of work/school missed, hospital 
readmissions, emergency room visits, pediatrician visits, subsequent steroid courses, and 
medication side effects. 
 
Mechanism Subset Study: A Pilot and Feasibility Study in a Subset of Patients 
After enrollment, and at the time of the PASS asthma severity scoring, research 
personnel will ask parents/guardians if they would also be willing to participate in a separate 
subset study involving blood and nasal aspirate samples.  If parents/guardians consent, they will 
be offered compensation for their time and inconvenience (if funding is available).  If the 
parent/guardian is interested, the research personnel will obtain a separate, additional informed 
consent from the parent/guardian and assent from the child for the “Mechanism Subset Study”.  
At that time, a nasal aspirate sample will be obtained by the research personnel (who will be 
trained on proper technique prior to the start of study).  A blood sample will be obtained as soon 
as possible.  A second sample of both blood and nasal aspirate will be obtained on the calendar 
day that is 48 hours from the first sample.  Two samples will allow for baseline and post-
treatment samples to be compared. 
The blood samples will be obtained by the unit phlebotomist.  As is unit policy, an effort 
will be made to apply a topical anesthetic before the blood sample is obtained.  A maximum of 
three (3) trials will be made to obtain the blood.  If unable to obtain first blood sample, the 
patient will still have attempt for blood sample in 48 hours. 
The nasal aspirate samples will be obtained using the same protocol as a previous study 
in children 4-17 years old8.  Study personnel will be trained on the technique of obtaining the 


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samples.  The study personnel will instill 1.5mL of saline into each nostril and then using low-
wall suction and an intransal catheter, will aspirate into a mucus trap. 
If the enrolled patient is discharged before 48 hours or research personnel are not 
available, the second set of samples will not be obtained for that patient. 
 
 
Laboratory 
If patients enrolled in the study have a rapid viral testing, respiratory viral panel, or 
complete blood count performed as part of medical care and at the discretion of the primary 
medical team, the results will be recorded.  A urine pregnancy test will be performed for all 
female patients that have achieved menarche; pregnant patients will be excluded. 
 
For the “Mechanism Subset Study”: 
Blood samples will be tested for absolute neutrophil count, absolute eosinophil count, 
Mycoplasma pneumoniae IgM/IgG, Chlamydia pneumoniae IgM/IgG, Mycoplasma pneumoniae 
PCR, Chlamydia pneumoniae PCR, and a set of select biomarkers associated with inflammation 
including cytokines, chemokines, and other immune mediators via Bioluminex or ELISA 
technology.   
Nasal aspirate samples will be tested for neutrophil count per high power field, 
eosinophil count per high power field, Mycoplasma pneumoniae PCR, Chlamydia pneumoniae 
PCR, and a set of select biomarkers associated with inflammation including cytokines, 
chemokines, and other immune mediators via Bioluminex or ELISA technology.   
Neutrophil and eosinophil counts will be performed at the Montefiore Medical Center 
Lab. Biomarkers associated with inflammation via Bioluminex or ELISA will be performed at 
Albert Einstein College of Medicine in Dr. Betsy Herold’s Laboratory.  PCR and serology will be 
performed at the Microbiology Laboratory at University of Massachusetts, Amherst, by outside 
collaborator, Dr. Wilmore Webley. 
 
 
STATISTICAL ANALYSIS 
The primary outcome measure is hospital length of stay (LOS).  Preliminary data 
obtained from a Clinical Looking Glass search reveals that in 2011, there were 410 children 
between the ages of 4-12 years admitted to CHAM with a primary diagnosis of asthma.  During 
their admission, 237 patients received inhaled steroids, a marker of a persistent asthma 
diagnosis.  Using this data, the mean length of stay was 3.0 days, median 2.5 days, and 
standard deviation 1.6.  The distribution approximated normal distribution in this group.  A 
clinically significant difference in length of stay would be 16 hours or 0.67 days (equivalent to 
0.4 standard deviations). 
Data analysis will be conducted with the assistance of a statistician.  LOS between the 
two groups will be compared using independent samples t-test, if the data is normally 
distributed.  If the data is not normally distributed, log transformation will be attempted and if the 
results of the transformation yield normal distribution for both groups, then t-test will be used for 
the logged values and reported as a geometric mean.   If log transformation is not successful in 
yielding normal distribution, non-parametric Mann-Whitney U test will be used to report median 
and interquartile ranges.  All tests will be two-tailed with an α= 0.05 to denote clinical 
significance.   
In order determine the number of patients needed to enroll to detect a 16 hour (0.67 day) 
difference in length of stay with a power of 80%, PASS software was utilized, with the 
assistance of a statistician, to model various types of adjustments for non-parametric distribution 
–normal distribution adjustment, uniform distribution adjustment, and logistic distribution 
adjustment.  For each of these adjustments, the number of patients required for enrollment per 


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group ranged from 83 to 96 patients.  Using the largest number, 96, and assuming a 10% 
attrition rate for parent/guardian preference, attending preference, or safety exit criteria, the 
sample size will need to be 107 patients in each group.  We anticipate it will take approximately 
15-18 months to enroll this number of patients. 
The data from the interview questionnaire will be coded and descriptive statistics will be 
used to analyze the baseline characteristics of the two groups.  If the parent characteristics are 
not balanced, multi-variable analysis will be utilized to adjust for variables not balanced by 
randomization.  Secondary outcome measures will be compared using chi-squared test for 
categorical data and t-test or Mann-Whitney U test for continuous data, with statistical 
significance considered a p value < 0.05. 
Due to the invasive nature of the sample collection in the “Mechansim Subset Study”, 
only 25% of patients are expected to agree to submit to this portion of the study.  These patients 
may not be representative of all patients in each arm of the study and will not be randomized.  
This subset study will be a pilot and feasibility study for future investigation into the potential 
mechanism of action of azithromycin in asthma.  Data will be analyzed to compare the 
proportion of positive lab findings in each group using chi-squared analysis.  There will not likely 
be sufficient power to find statistical significance, but the results will be used to estimate the 
effect size for subsequent study.   
 
ETHICAL CONSIDERATIONS 
 
Risks/Benefits 
The potential risks are considered minimal.  This study meets the category in the U.S. 
Department of Health and Human Services Code of Federal Regulations, Part 46, Subpart D 
(§46.405) for research involving greater than minimal risk but presenting the prospect of direct 
benefit to the individual subjects.  The risks are deemed by the investigators to be justified by 
the anticipated benefit to the subjects; and the anticipated benefit is at least as favorable to the 
subjects as that presented by available alternative approaches.   
The intervention medication, azithromycin, is a relatively commonly used antibiotic in the 
pediatric population for a variety of illnesses, including otitis media, atypical pneumonia, and 
pharyngitis.  It is relatively well tolerated.  The major side effects are gastrointestinal and 
temporary.  Other side effects, including elevation of hepatic enzymes and prolonged QT 
syndrome, are rarely reported (less than 1%) and considered unlikely by the investigators.  
Patients will be monitored by the primary medical team for symptoms of rare and common side 
effects and will inform the PI of any concerns.  Education will be conducted on pediatric units 
and in the critical care unit regarding side effects to ensure adequate monitoring by the primary 
medical teams.  There is little clinical evidence on the use of azithromycin in children 
hospitalized with acute asthma, therefore it is possible that azithromycin will worsen the 
condition of some patients and increase length of stay.    Previous studies in long-term 
macrolide use have shown either clinical improvement or no effect and none have reported any 
significant harm. 
The alternative treatment for children hospitalized with acute asthma is the current standard 
of care: inhaled beta-agonists and systemic steroids.  All patients enrolled, at the discretion of 
the attending physician and medical team, are expected to received these treatments in addition 
to the study medication. 
The potential benefit of this study to research participants is that azithromycin may decrease 
length of stay in the hospital and days of symptoms.  In addition, it may have longer-term effects 
and decrease rate of readmission to the hospital or subsequent medical visits or steroid courses 
in the month following administration. 
 
 


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Protections Against Risk 
All patients will be hospitalized at the Children’s Hospital at Montefiore (CHAM), a 120-bed 
tertiary level pediatric hospital well equipped for the management of children with acute 
respiratory illnesses, including severe asthma.  Clinical risks to patients will be protected by 
close clinical monitoring for patients who meet exit criteria of mechanical ventilation.  In the 
event of an adverse event to a patient enrolled in the study, the patient will be assessed by the 
attending physician, research investigator, and/or the Pediatric Rapid Response Team (PMET) 
or pediatric code team. 
Privacy risks will be protected by allowing only study personnel access to confidential 
information and by assigning a study number that will be kept separate from medical record 
number and identifiers.  Only research personnel will have access the individually identified 
private information.  After enrollment, patient will receive a study number.  A list of medical 
record numbers and study numbers will be kept by the PI separately.  All written and digital data 
will be identified by study number and kept in locked cabinet or password protected computer.   
For the “Mechanism Subset Study”, all patients will be approached, and the investigators 
anticipate only a subset of patients will consent, as invasive blood and nasal sampling will be 
obtained in this group.  This subset of patients will have blood and nasal aspirate samples 
obtained on two occasions during the inpatient stay.  Samples will be sent to another institution 
for testing, and the investigator at that institution will comply with the same privacy protection 
protocols.  Samples supplied to other institutions will be identified only by assigned study 
number, without other identifiers. IRB approval will be obtained by the collaborating institution 
(University of Massachsetts, Amherst, Dr. Wilmore Webley).   
Identifiers will be destroyed at earliest possible time. 
 
Importance of Knowledge Gained 
 
Although some practitioners currently use azithromycin in the routine management of 
hospitalized children with acute asthma exacerbation, there is little data to support this practice.  
This study will be the first double-blind, randomized, placebo-controlled trial to determine if 
azithromycin has a clinical effect on children hospitalized with acute asthma.  In addition, the 
“Mechanism Subset Study” will provide preliminary data to determine the mechanism of action 
of azithromycin in children with acute asthma exacerbations. 
 
 
Recruitment and Informed Consent 
Patients will be recruited after identification by pediatric emergency room staff, admitting 
physician, or pediatric residents of patient with admission diagnosis of acute asthma 
exacerbation in the age range of 4-12 years.  After the medical staff has determined if the 
parent/guardian is willing to meet with research personnel, the parent/guardian of the admitted 
child will be approached and undergo a standardized interview to determine if the patient meets 
eligibility requirements.  If eligibility requirements are met, the research personnel will obtain 
informed consent from the parent/guardian and assent from the child (if applicable) for 
participation in the study.   
The details of the study will be explained by research personnel and all questioned will be 
answered before consent and assent are obtained.  Potential risks and benefits will be 
discussed.  The parent/guardian will need to be physically present at the bedside of the child 
and written confirmation of consent will be obtained via signature on a consent form.  For 
children 7-12 years of age capable of assent, assent will be obtained after verbal confirmation 
via signature of the child on an assent form.   


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For the “Mechanism Subset Study”: After enrollment, and at the time of the PASS asthma 
severity scoring, research personnel will ask parents/guardians if they would also be willing to 
participate in a subset study involving blood and nasal aspirate samples.  If the parent/guardian 
is interested, the research personnel will obtain a second and separate informed consent from 
the parent/guardian and assent from the child (7-12 years) for the “Mechanism Subset Study”.   
 
 
 
Adverse Event Monitoring 
Adverse events that will be monitored include: bronchospasm or worsening clinical status 
(as determined by the primary medical team), transfer to the intensive care unit, medication side 
effects (abdominal pain, diarrhea, flatulence, vomiting), and readmission for asthma within 30 
days.  Additional unanticipated adverse events will also be monitored.  Adverse events will be 
standardly documented and reported to the IRB within 30 days.  All co-investigators and 
research personnel will immediately report any serious adverse events to the PI who will report 
them to the IRB within 48 hours.   
Withdrawal from the study will occur for parent/guardian preference, primary attending 
preference, or worsening of clinical status requiring invasive or non-invasive ventilatory support.   
Ventilatory support (invasive or non-invasive) will serve as the safety exit criteria. 
 
 
Data and Safety Monitoring Plan 
The PI will be continuously responsible for data and safety monitoring, including adverse 
events.  The IRB will also be responsible for data and safety monitoring. 
An internal Data and Safety Monitoring Board was created with three established clinical 
investigators with knowledge of clinical trials (Dr. Peter Belamarich, Dr. Tsoline Kogaoglanian, 
and Dr. H. Michael Ushay) and a biostatistician, Aileen McGinn, PhD.  The PI will provide data 
to the Board every 3 months during the enrollment process, and they will meet to assess the 
safety of enrolled patients.  The Board will report their findings to the PI and IRB every 3 
months, and will have the authority to recommend termination of the trial if the rates of adverse 
events are deemed unsafe to study participants. 
 
 
Inclusion of Women, Minorities, and Children 
Female children and children of all minorities will be screened for eligibility after hospital 
admission for asthma.  A urine pregnancy test will be performed for all female patients that have 
achieved menarche; pregnant patients will be excluded.  Asthma affects both genders and has 
been described in nearly all minority groups; there are no anticipated exclusions of females or 
minorities.  The population served by the Children’s Hospital at Montefiore (CHAM) in Bronx 
borough of New York City is primarily Hispanic, Black/African American, and White patients with 
limited numbers of American Indian, Alaskan Native, Native Hawaiian, and Pacific Islander 
patients.  However, if a patient from any of these underrepresented groups presents with acute 
asthma in the age range specified, the patient will be approached for eligibility and enrollment. 
Children are included in this trial as asthma is a chronic lung condition common in childhood 
and the investigators will determine whether azithromycin will change the length of hospital stay 
for children hospitalized with acute asthma.  Children between the ages of 4-12 years 
hospitalized for acute asthma will be included in the study.  National Heart, Lung, and Blood 
Institute (NHLBI) has clear guidelines for classifying asthma in specific age ranges.  We will use 
the guidelines for children aged 5-11 years in the eligibility questionnaire to determine and 
include only children with persistent asthma in the study.  We expanded the age range by one 
year on each side of NHLBI guidelines to better capture children in the “school age” range.   


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ClinicalTrials.gov Requirements 
 
The trial will be registered with clinicaltrials.gov within 21 days of the first enrolled 
patient. 
 
_____  IRB revisions - 8/20/12 
_____  IRB amendment – 12/4/13 
_____  IRB amendment – 1/2/14 
 
 
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