The Anti-inflammatory Effect of Prophylactic Macrolides on Children With Chronic Lung Disease

STUDY DESIGN AND METHODS

Overview:

This pilot randomized control trial (RCT) will enroll 92 children from 6 months to 6 years of age that have chronic lung disease (CLD) such as bronchopulmonary dysplasia during two pulmonary illness seasons. If the minimum number of patients (n=92) in Season 1 is achieved, we will then perform an interim analysis of the data. However, if recruitment does not reach 92patients during the first season we will continue to recruit in Season 2 (2016-2017). These children will all be patients who receive their primary medical care from either the High Risk Children Clinic or the similar High Risk Infant Clinic that cares for premature infants from discharge until age 2. Clinic records will be screened to determine eligibility. Patients that have parental consent will be given a baseline EKG, a nasal aspirate, an oscillometer reading (over 2 years of age only), and a six month supply of either the medication or the placebo at an initial study or office visit. The medication/placebo will be taken once a day for three days a week: Monday, Wednesday and Friday. The azithromycin medication will be dosed at 5 mg/kg/day. Adjustments in dosage amount will not be made during the 6 month trial. Any child that is eligible to receive Synagis will be given this every 28-30 days in clinic. Patients will be followed on a monthly basis and closely monitored for adverse reactions; this will occur by phone, in clinic during their regularly scheduled appointments, and/or during any necessary illness visits. Any children with adverse reactions will discontinue the medication, but will continue to be followed clinically. At any clinic visit in which a child presents with respiratory infections, including pneumonia, upper respiratory illness, bronchiolitis, etc., he/she will have an additional nasal aspirate and an oscillometer reading performed. At the completion of the six month treatment phase, each child will have a final EKG, final nasal aspirate and an oscillometer reading performed. Data will continue to be collected for the following twelve months, to monitor for respiratory illnesses.

Study Procedures:

Patients will be randomized by the REDCap statistical program in a double blind manner. Parents will then be provided with an entire 6 months of medication or placebo. Half of the patients will receive azithromycin at a dose of 5 mg/kg to be given once a day on Monday, Wednesday, and Friday. The dosage will not be adjusted during the trial period. The other half, the control group, will be provided with a placebo medication of similar taste, color, texture, and consistency, also to be taken once a day on Monday, Wednesday, and Friday. Both the study medication and the placebo will be dispensed from Corner Compounding Pharmacy, mixed with a fish-oil base to ensure a shelf life of more than six months, and flavored with citrus to improve palatability. Parents will be contacted monthly, either in clinic or by phone, to monitor for any adverse reactions, including rash, nausea, vomiting, diarrhea, or abdominal cramping. If a significant adverse reaction occurs, the medication will be discontinued. If an allergic reaction (such as rash or shortness of breath) is noted, the blind will be broken by Claudia Pedroza, the statistician, who is not involved with the project. This un-blinding will be done to note if it is an allergy to the medication.

After the initial appointment, at any face to face encounter (unscheduled sick visit or hospital admission/ER admission Monday through Friday) in which the patient presents with respiratory symptoms, the patient will be evaluated by the research coordinator or one of the co-investigators. Specifically, if a patient presents with the following symptoms: cough, wheeze, tachypnea, rhinorrhea, increased respiratory secretions, hypoxemia, and/or an increased oxygen requirement, an additional nasal aspirate sample and an oscillometry reading (for patients over 2 years of age) will be performed. These samples will also be stored in the office of Dr. Piedra. At the conclusion of the six month treatment phase, a final nasal aspirate sample, an oscillometer reading and EKG will be performed while the patients are in clinic for an office visit. There will be no expected study visits and no compensation will be provided for parents or patients.

Research Aims

Primary Aim: To determine if the prophylactic use of azithromycin will reduce the total number of days when one or more unscheduled medical encounters occur in a clinic, urgent care, emergency room (ER) or hospital setting during the 3-6 month study period and subsequent 2 months.

Secondary Aims:

1. To determine if the prophylactic use of azithromycin will reduce the total number of days when one or more unscheduled medical encounters occur for acute respiratory illness in a clinic, urgent care, ER or hospital setting during the 3-6 month study period and subsequent 2 months.
2. To determine if the administration of azithromycin will have a similar number of adverse side effects, or adverse events leading to unscheduled face-to-face clinic, urgent care, ER or hospital visit as compared to placebo during the 3-6 month study period and subsequent 2 months.
3. To determine if the prophylactic use of azithromycin will reduce healthcare costs during the 3-6 month study period and subsequent 2 months.

Exploratory Outcomes:

1. To determine if the prophylactic use of azithromycin will reduce the level of pro-inflammatory cytokines and additional biomarkers of disease including Lactate Dehydrogenase and Myeloid Peroxidase, by 10%.
2. To determine if the prophylactic use of azithromycin during the 3-6 months intervention will reduce the level of airway resistance of patients with CLD during respiratory illness from their baseline when compared to the placebo group as measured by an Airwave Oscillometry System
3. To determine if prophylactic use of azithromycin will reduce the total number of unscheduled face-to-face provider visits for respiratory related illness in a clinic, urgent care, emergency room or hospital setting in the 12 months after the intervention phase.

Data Analysis Plan:

Patients will be randomized to one of two different branches by the REDCap data base randomization program. This will be a double-blind placebo controlled study. Standard frequentist and Bayesian analyses will be performed using an intent-to-treat approach. Total hospital days, total ER visits (counting one day for each ER visit), and unscheduled clinic visits (counting one day for each visit) will be analyzed and related to treatment (Azithromycin vs Placebo), with logistic regression models and the treatment group as a covariate and random intercept to account for within patient correlation (due to multiple ED visits). To assess the probability of benefit, we will use Bayesian hierarchical models with interaction terms between treatment groups (Azithromycin vs Placebo) and predefined potential moderators. The groups will be stratified by synagis use and if they have a tracheostomy.

Sample size and power:

Based on data from our HRCC, we expect the control group to have 1.6 encounters per child-year (SD=1.66). Assuming a two-sided alpha = 0.05, a sample size of 92 (46/group) will have 80% power to detect a difference of 1 in the encounter rate between placebo and azithromycin groups (i.e., 1.6 vs 0.6 in encounter rate or 38% reduction). Power will be more limited for secondary outcomes but Bayesian analyses will provide an estimate of the probability of benefit in these outcomes.