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

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

AZ-SWED is a parallel group, double blind, placebo control efficacy clinical trial with two separate hypotheses. The trial compared 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 made separate comparisons in children in whom specific pathogenic bacteria isolated from nasopharyngeal swabs, and in those in whom they were not isolated. The primary outcome was the Asthma Flare-up Diary for Young Children (ADYC), a validated instrument that caregivers will transmit electronically daily after discharge from the ED. Families were contacted daily during the five-day treatment to collect the ADYC, and to assess compliance and complications. A randomly chosen subset of enrolled children participated 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.

Study Overview

• Status: Terminated
• Conditions: Asthma; Wheezing
• Intervention / Treatment: Drug: Azithromycin; Drug: Placebo

Detailed 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. The study recruited eligible patients from seven EDs. We tested 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.

This study had three visits. All enrolled patients participated on the Day 0 visit for screening, the informed consent process, enrollment, randomization, treatment initiation and dispensing drug. A sub-group of randomly selected patients participated in two follow-up visits on Day 5 - 8 and Day 14 - 21 where they were tested for antibiotic resistance.

The primary outcome was 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.

• Study Type: Interventional
• Enrollment (Actual): 840
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Children's Healthcare of Atlanta, Emory University
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
  • New York
    • New York, New York, United States, 10032
      • Children's Hospital of New York Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • The Children's Hospital of Philadelphia (CHOP)
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Medical Center
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • The Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 5 years (Child)
• Accepts Healthy Volunteers: No

Description

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 invasive 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 of the parent or guardian to speak English or Spanish.
• Positive PCR or antigen test for COVID-19 from hospital/doctor's office/testing center within the past 30 days.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Treatment - Active; Eligible participants were randomly assigned to the Azithromycin arm (1:1)	Drug: Azithromycin; oral azithromycin (12 mg/kg per day for 5 days) Local investigational drug pharmacies were provided with active study medication (azithromycin) from a central pharmacy. Azithromycin was reconstituted with water at the local pharmacy, and resembled placebo with regards to appearance, flavor, consistency and packaging.
Placebo Comparator: Treatment - Placebo; Eligible patients were randomly assigned to the placebo arm, per the randomization schedule (1:1).	Drug: Placebo; oral placebo (12 mg/kg per day for 5 days) Local investigational drug pharmacies were provided with placebo from a central pharmacy. Placebo was reconstituted with water at the local pharmacy, and resembled azithromycin with regards to appearance, flavor, consistency and packaging.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ADYC (Median, IQR)	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) filled 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 was 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. For each of the five follow-up days, the ADYC score was calculated as the average score per question and the trial primary outcome was the sum of these ADYC scores over the five days. The range of possible primary outcome values was a ADYC score of 5 to 35.	5 day course of azithromycin

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ED Length of Stay (Median, IQR)	The continuous secondary variable of length of stay was analyzed in the same manner as the primary outcome. The measurement is the duration from arrival to ED to discharge. Subjects are separated by treatment arm and by bacterial designation. Together, the rows equal the total number of participants analyzed.	From admission at ED to discharge from ED, up to 23 hours and 59 minutes
Hospital Length of Stay (Median, IQR)	The continuous secondary variable of length of stay was analyzed in the same manner as the primary outcome. The measurement is the duration of hospitalization from admission. Subjects are separated by treatment arm and by bacterial designation. Together, the rows equal the total number of participants analyzed.	From hospital admission to discharge from hospital
Return Visit	Visits to the ED or hospital within 72 hours of the initial visit (randomization time) are counted as a revisit outcome. This outcome was tabulated by treatment for each stratum (site and baseline severity of symptoms). The dichotomous outcome of the second ED visit or hospitalization is compared using a Mantel-Haenszel chi-square test, stratified by clinical center and baseline severity.	Within 72 hours after randomization

Collaborators and Investigators

• Sponsor: University of Arizona
• Collaborators: Children's Hospital of Philadelphia; University of Pittsburgh; Boston Children's Hospital; Emory University; University of Texas Southwestern Medical Center; Children's Hospital Medical Center, Cincinnati; University of Utah; Children's Hospital and Health System Foundation, Wisconsin; Morgan Stanley Children's Hospital
• Investigators: Principal Investigator: Kurt Denninghoff, MD, University of Arizona; Principal Investigator: Charlie Casper, PhD, University of Utah; Principal Investigator: Fernando D Martinez, MD, University of Arizona

Publications and helpful links

General Publications

• Denninghoff KR, Casper TC, Zorc JJ, Ruddy RM, Satola S, Wendt WJ, Morris CR, Tavarez MM, Lipshaw MJ, Kwok MY, Nesiama JO, Nelson KA, Webb M, Martinez FD; PECARN AZ-SWED Trial Study Group. Azithromycin for Preschoolers with Wheezing in the Emergency Department. N Engl J Med. 2026 May 18:10.1056/NEJMoa2516505. doi: 10.1056/NEJMoa2516505. Online ahead of print.

Study record dates

Study Major Dates

• Study Start (Actual): November 22, 2021
• Primary Completion (Actual): December 10, 2024
• Study Completion (Actual): January 8, 2025

Study Registration Dates

• First Submitted: December 2, 2020
• First Submitted That Met QC Criteria: December 11, 2020
• First Posted (Actual): December 16, 2020

Study Record Updates

• Last Update Posted (Actual): June 23, 2026
• Last Update Submitted That Met QC Criteria: May 26, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Wheezing Lower Respiratory Illness (WLRI)
• Additional Relevant MeSH Terms: Immune System Diseases; Respiratory Tract Diseases; Lung Diseases; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Signs and Symptoms, Respiratory; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Asthma; Respiratory Sounds; Organic Chemicals; Macrolides; Lactones; Erythromycin; Polyketides; Azithromycin
• Other Study ID Numbers: UG3HL147016 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: After subject enrollment and follow up have been completed, the DCC may prepare a final study database for analysis. A releasable database will be produced and completely de-identified in accordance with the definition provided in the Health insurance Portability and Accountability Act (HIPAA). HIPAA will be recoded in a manner that will make it impossible to deduce or impute the specific identity of any patient. The database will not contain any institutional identifiers. This releasable database will be forwarded to the Biologic Specimen and Data Repository Information Coordinating Center (BIOLINCC) or, in case AZ-SWED samples and data are not deposited in BIOLINCC, to users in electronic form, in accordance with policies determined by the investigators and funding sponsors.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes