AZithromycin Therapy in Preschoolers With a Severe Wheezing Episode Diagnosed at the Emergency Department

Study Overview
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Brief Summary
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AZ-SWED is a parallel group, double blind, placebo control efficacy clinical trial with two separate hypotheses. The trial will compare the 5-day outcome of preschool children presenting to an Emergency Department (ED) with an acute, severe wheezing episode and treated with either once daily oral Azithromycin (12 mg/kg/day for 5 days) or placebo. The AZ-SWED researchers will make separate comparisons in children in whom specific pathogenic bacteria are isolated from nasopharyngeal swabs, and in those in whom they are not isolated. The primary outcome will be the Asthma Flare-up Diary for Young Children (ADYC), a validated instrument that caregivers will transmit electronically daily after discharge from the ED. Families will be contacted daily during the five-day treatment to collect the ADYC, and to assess compliance and complications. A randomly chosen subset of enrolled children will participate in two follow-up visits 5-8 days and 14-21 days after visit 1 to assess development of resistance to study drug and treatment response related changes in the airway microbiome.

Detailed Description
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This Phase III trial is designed as a parallel group, placebo-controlled, double-blind, randomized, multi-center evaluation of AZ for the treatment of acute wheezing episodes. The study will recruit eligible patients from an estimated six EDs and enroll up to 2,000 patients. We will test two primary hypotheses: 1) AZ (12 mg/Kg/day) given for 5 days to preschool children with severe acute wheezing and harboring any of three specific pathogenic bacteria (H influenzae, M catarrhalis, or S pneumonia) in their nasopharynx will decrease the severity of the acute episode; and 2) AZ given on an identical schedule and dose will decrease the severity of wheezing episodes in children who do not harbor any of these three pathogenic bacteria in their nasopharynx. We will also explore whether variants in the genes encoding for Cadherin Related Family Member 3 (CDHR3), Interleukin-8 (IL-8) and in the 17q asthma-related gene cluster predict response to AZ. This short-term study has three planned visits. All enrolled patients will participate on the Day 0 visit for screening, the informed consent process, enrollment, randomization, treatment initiation and dispensing drug. A sub-group of 370 randomly selected patients will participate in two follow-up visits on Day 5 - 8 and Day 14 - 21 where they will be tested for antibiotic resistance. The primary outcome will be the sum of the Asthma Flare-up Diary for Young Children (ADYC) score, a validated instrument completed by the parent or guardian of the enrolled children during the 5-day treatment period. Secondary outcomes will include (1) ED length of stay (2) hospital length of stay, and (3) return ED visits or hospitalizations within 72 hours after randomization.

Official Title
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AZithromycin Therapy in Preschoolers With a Severe Wheezing Episode Diagnosed at the Emergency Department (AZ-SWED)

Conditions
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Asthma, Wheezing

Intervention / Treatment
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* Drug: Azithromycin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 months to <60 months. The presence of expiratory wheezing as ascertained by a physician or nurse practitioner at admission to the ED. A Pediatric Respiratory Assessment Measurement (PRAM) score of greater than or equal to 4 at any time during the ED admission. Exclusion Criteria: Presence of acute infection that requires systemic antibiotics, as determined by the physician. Current or previous use of systemic antibiotics within the last 2 weeks. Current or previous use of a steroid for wheezing within the last 2 weeks. Suspected foreign body induced aspiration during the last 2 weeks. A known systemic illness (other than allergy) including but not limited to: Recurrent seizures Gastroesophageal reflux (GER) requiring medical treatment Major congenital anomalies Physical and intellectual delay Cerebral palsy A history of chest surgery Tuberculosis or other chronic infections Primary or secondary immunodeficiency Gastrointestinal malformation or disease Cardiac disorder (except for a hemodynamically insignificant atrial septal defect (ASD), ventricular septal defect (VSD) or benign heart murmur) Born at less than 36 weeks estimated gestational age. Received oxygen for more than 5 days in the neonatal period, or received mechanical ventilation. Significant developmental delay / failure to thrive, defined as a child plotting less than 3rd percentile. Any chronic lung disease. The study intervention poses undue risk to patient in the opinion of the treating physician Known sensitivity or allergy to AZ. Participation in the evaluation of a drug or medical device currently or within the last 30 days. Previous enrollment into this trial. Inability to speak English or Spanish.

Ages Eligible for Study
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Minimum Age: 18 Months
Maximum Age: 60 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This Phase III trial is designed as a parallel group, placebo-controlled, double-blind, randomized, multi-center evaluation of AZ for the treatment of acute wheezing episodes. This short-term study has three planned visits. All enrolled patients will participate on the Day 0 visit for screening, the informed consent process, enrollment, randomization and dispensing. A sub-group of 370 randomly selected patients will participate in two follow-up visits on Day 5 - 8 and Day 14 - 21 where they will be tested for antibiotic resistance.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Treatment - Active<br>Eligible patients will be randomly assigned to one of two treatment groups (1:1) and one arm will be administered the active drug per the randomization schedule. Study medication will be provided to parents/guardians, along with instructions, for home-based administration. The first dose of the study medication will be administered before discharge from the ED. | Drug: Azithromycin<br>* oral azithromycin (12 mg/kg per day for 5 days) Local investigational drug pharmacies will be provided with active study medication (azithromycin) from a central pharmacy. Azithromycin will be reconstituted with water at the local pharmacy, and will resemble placebo with regards to appearance, flavor, consistency and packaging.<br>|
| Placebo Comparator: Treatment - Placebo<br>Eligible patients will be randomly assigned to one of two treatment groups (1:1) and one arm will be administered placebo per the randomization schedule. Study medication will be provided to parents/guardians, along with instructions, for home-based administration. The first dose of the study medication will be administered before discharge from the ED. | Drug: Placebo<br>* oral placebo (12 mg/kg per day for 5 days) Local investigational drug pharmacies will be provided with placebo from a central pharmacy. Placebo will be reconstituted with water at the local pharmacy, and will resemble azithromycin with regards to appearance, flavor, consistency and packaging.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Asthma Flare-up Diary for Young Children | The Asthma Flare-up Diary for Young Children (ADYC) is a validated instrument that consists of a 17-item questionnaire scored from 1 (best) to 7 (worst). The parent or guardian of the enrolled child (up to 60 months of age) will fill out the diary daily for 5 days, starting from the first day following the first dose of Azithromycin (AZ). The cumulative score at the end of 5 days will be used to assess response to the intervention (e.g. time to exacerbation, acute-care visit, hospitalization and no wheeze), with a higher score indicating a worse outcome. | 5 day course of azithromycin | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Length of Stay | Secondary outcomes will include (1) ED length of stay (2) hospital length of stay, and (3) return ED visits or hospitalizations. | 72 hours after randomization | 
| Number of participants that develop Azithromycin resistant organisms | Presence of azithromycin-resistant organisms will be assessed at baseline, and again at two follow-up visits 5-8 days and 14-21 days after enrollment in a randomly selected subset of trial subjects. A total of 370 subjects will be selected for this follow-up. Subjects in whom resistance is detected at baseline will not be included in the analysis of development of bacterial resistance at follow-up. Among subjects that are negative for bacterial resistance at baseline, follow-up resistance will be tabulated by treatment. The absolute risk diﬀerence, together with a 95% one-sided conﬁdence interval, will be used to summarize treatment diﬀerence. Participants who harbor or do not harbor the three pathogenic bacteria will be included in these analyses. | 21 days after randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Wheezing Lower Respiratory Illness (WLRI)