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

Primary Purpose

Asthma, Wheezing

Status
Recruiting
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
Azithromycin
Placebo
Sponsored by
University of Arizona
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Asthma focused on measuring Wheezing Lower Respiratory Illness (WLRI)

Eligibility Criteria

18 Months - 60 Months (Child)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Children's Healthcare of Atlanta, Emory UniversityRecruiting
  • Boston Children's HospitalRecruiting
  • Children's Hospital of New York Medical CenterRecruiting
  • Cincinnati Children's Hospital Medical CenterRecruiting
  • University of Pittsburgh Medical CenterRecruiting
  • The Medical College of WisconsinRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Treatment - Active

Treatment - Placebo

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Length of Stay
Secondary outcomes will include (1) ED length of stay (2) hospital length of stay, and (3) return ED visits or hospitalizations.
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.

Full Information

First Posted
December 2, 2020
Last Updated
November 30, 2022
Sponsor
University of Arizona
Collaborators
University of Utah, Emory University, Morgan Stanley Children's Hospital, University of Pittsburgh, Children's Hospital and Health System Foundation, Wisconsin, Children's Hospital of Philadelphia, Children's Hospital Medical Center, Cincinnati, Boston Children's Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT04669288
Brief Title
AZithromycin Therapy in Preschoolers With a Severe Wheezing Episode Diagnosed at the Emergency Department
Acronym
AZ-SWED
Official Title
AZithromycin Therapy in Preschoolers With a Severe Wheezing Episode Diagnosed at the Emergency Department (AZ-SWED)
Study Type
Interventional

2. Study Status

Record Verification Date
November 2022
Overall Recruitment Status
Recruiting
Study Start Date
September 22, 2021 (Actual)
Primary Completion Date
February 2025 (Anticipated)
Study Completion Date
August 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Arizona
Collaborators
University of Utah, Emory University, Morgan Stanley Children's Hospital, University of Pittsburgh, Children's Hospital and Health System Foundation, Wisconsin, Children's Hospital of Philadelphia, Children's Hospital Medical Center, Cincinnati, Boston Children's Hospital

4. Oversight

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
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Asthma, Wheezing
Keywords
Wheezing Lower Respiratory Illness (WLRI)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
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
ParticipantCare ProviderInvestigator
Masking Description
Equal allocation randomization tables will be provided by the Data Coordinating Center (DCC) to the central research pharmacy. The central research pharmacy will prepare consecutively numbered study kits according to the randomization schedule. Study kits will be sent to the clinical sites. Study products will be labeled with numerical codes that will maintain allocation concealment. Blinding/labeling of study medication bottles will be completed at the site pharmacy prior to dispensing to the patient. Randomization tables will be 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 will be used. The randomization number will be recorded in the database.
Allocation
Randomized
Enrollment
1476 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Treatment - Active
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Treatment - Placebo
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Azithromycin
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
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.
Primary Outcome Measure Information:
Title
Asthma Flare-up Diary for Young Children
Description
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.
Time Frame
5 day course of azithromycin
Secondary Outcome Measure Information:
Title
Length of Stay
Description
Secondary outcomes will include (1) ED length of stay (2) hospital length of stay, and (3) return ED visits or hospitalizations.
Time Frame
72 hours after randomization
Title
Number of participants that develop Azithromycin resistant organisms
Description
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.
Time Frame
21 days after randomization

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Months
Maximum Age & Unit of Time
60 Months
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Fernando D Martinez, MD
Phone
520-626-6387
Email
fdmartin@arizona.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Liz Firmage
Phone
520-626-7441
Email
beckette@arizona.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Fernando D Martinez, MD
Organizational Affiliation
University of Arizona
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Kurt Denninghoff, MD
Organizational Affiliation
University of Arizona
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Charlie Casper, PhD
Organizational Affiliation
University of Utah
Official's Role
Principal Investigator
Facility Information:
Facility Name
Children's Healthcare of Atlanta, Emory University
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Claudia R Morris, MD
Phone
404-727-5500
Email
claudia.r.morris@emory.edu
First Name & Middle Initial & Last Name & Degree
Claudia R Morris, MD
First Name & Middle Initial & Last Name & Degree
Anne Fitzpatrick, PhD,RN,CPNP
Facility Name
Boston Children's Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Kyle Nelson, MD,MPH
Phone
617-919-4223
Email
kyle.nelson@childrens.harvard.edu
First Name & Middle Initial & Last Name & Degree
Kyle Nelson, MD,MPH
First Name & Middle Initial & Last Name & Degree
Lise Nigrovic, MD,MPH
Facility Name
Children's Hospital of New York Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Maria Kwok, MD,MPH
Phone
212-305-6628
Email
myk2102@cumc.columbia.edu
First Name & Middle Initial & Last Name & Degree
Maria Kwok, MD,MPH
Facility Name
Cincinnati Children's Hospital Medical Center
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45229
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Matthew Lipshaw, MD
Email
matthew.lipshaw@cchmc.org
First Name & Middle Initial & Last Name & Degree
Matthew Lipshaw, MD
Facility Name
University of Pittsburgh Medical Center
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15213
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Melissa M Tavarez, MD,MS
Phone
412-692-7980
Email
melissa.tavarez2@chp.edu
First Name & Middle Initial & Last Name & Degree
Melissa M Tavarez, MD,MS
First Name & Middle Initial & Last Name & Degree
Robert Hickey, MD,FAAP,FAHA
Facility Name
The Medical College of Wisconsin
City
Milwaukee
State/Province
Wisconsin
ZIP/Postal Code
53226
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Wendi-Jo Wendt, MD
Email
wwendt@mcw.edu
First Name & Middle Initial & Last Name & Degree
Wendi-Jo Wendt, MD

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing 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.
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AZithromycin Therapy in Preschoolers With a Severe Wheezing Episode Diagnosed at the Emergency Department

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