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

NCT04669288 | Terminated Phase 3 Results DMC FDA Drug

• 1 other identifier: UG3HL147016
• Study Type: interventional
• Target: 840
• Locations: 1 country
• Sites: 8

Brief Summary

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.

Conditions

Asthma; Wheezing

Keywords

Wheezing Lower Respiratory Illness (WLRI)

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (3)

• ED Length of Stay (Median, IQR)

  From admission at ED to discharge from ED, up to 23 hours and 59 minutes

• Hospital Length of Stay (Median, IQR)

  From hospital admission to discharge from hospital

• Return Visit

  Within 72 hours after randomization

Study Arms (2)

Treatment - Active

ACTIVE COMPARATOR

Eligible participants were randomly assigned to the Azithromycin arm (1:1)

Drug: Azithromycin

Treatment - Placebo

PLACEBO COMPARATOR

Eligible patients were randomly assigned to the placebo arm, per the randomization schedule (1:1).

Drug: Placebo

Interventions

Azithromycin DRUG

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.

Treatment - Active

Placebo DRUG

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.

Treatment - Placebo

Eligibility Criteria

• Age: 18 Months - 60 Months
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.

You may not qualify if:

• 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)

Sponsors & Collaborators

• University of Arizona: lead
• University of Utah: collaborator
• Emory University: collaborator
• Morgan Stanley Children's Hospital: collaborator
• University of Pittsburgh: collaborator
• Children's Hospital and Health System Foundation, Wisconsin: collaborator
• Children's Hospital of Philadelphia: collaborator
• Children's Hospital Medical Center, Cincinnati: collaborator
• Boston Children's Hospital: collaborator
• University of Texas Southwestern Medical Center: collaborator

Study Sites (8)

Children's Healthcare of Atlanta, Emory University

Atlanta, Georgia, 30322, United States

Location

Boston Children's Hospital

Boston, Massachusetts, 02115, United States

Location

Children's Hospital of New York Medical Center

New York, New York, 10032, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

The Children's Hospital of Philadelphia (CHOP)

Philadelphia, Pennsylvania, 19104, United States

Location

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, 15213, United States

Location

University of Texas Southwestern Medical Center

Dallas, Texas, 75390, United States

Location

The Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

Related Publications (1)

• 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.

  PMID: 42149992 DERIVED

MeSH Terms

Conditions

Asthma; Respiratory Sounds

Interventions

Azithromycin

Condition Hierarchy (Ancestors)

Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases; Signs and Symptoms, Respiratory; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Erythromycin; Macrolides; Polyketides; Lactones; Organic Chemicals

Limitations and Caveats

The initial target sample size was 1476. From September 2021 to December 2024, 840 patients were enrolled. In December 2024, as specified in the protocol, the DSMB reviewed the results of a futility analysis, and found that the conditional power of the trial in both cohorts was less than 16%, even when using a true effect of azithromycin as high as 1.3 on the sum ADYC score (primary outcome). Based on this finding, the NHLBI stopped the trial for futility, on recommendation by the DSMB.

Results Point of Contact

• Title: Fernando D. Martinez, MD
• Organization: Arizona Board of Regents, University of Arizona

fdmartin@arizona.edu

5206266387

Study Officials

• Fernando D Martinez, MD

  University of Arizona

  PRINCIPAL INVESTIGATOR

• Kurt Denninghoff, MD

  University of Arizona

  PRINCIPAL INVESTIGATOR

• Charlie Casper, PhD

  University of Utah

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: Equal allocation randomization tables were provided by the Data Coordinating Center (DCC) to the central research pharmacy. The central research pharmacy prepared consecutively numbered study kits according to the randomization schedule. Study kits were sent to the clinical sites. Study products were labeled with numerical codes that maintained allocation concealment. Blinding/labeling of study medication bottles were completed at the site pharmacy prior to dispensing to the patient. Randomization tables were created at the Data Coordinating Center using permuted-block randomization stratified by clinical site and baseline severity of symptoms. Permuted blocks of random lengths 2, 4, and 6 were used. The randomization number was recorded in the database.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Regents' Professor

Model Details: 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.

Study Record Dates

• First Submitted: December 2, 2020
• First Posted: December 16, 2020
• Study Start: November 22, 2021
• Primary Completion: December 10, 2024
• Study Completion: January 8, 2025
• Last Updated: June 23, 2026
• Results First Posted: June 23, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (8)