Clinical trial NCT04669288: AZithromycin Therapy in Preschoolers With a Severe Wheezing Episode Diagnosed at the Emergency Department
Official title: AZithromycin Therapy in Preschoolers With a Severe Wheezing Episode Diagnosed at the Emergency Department (AZ-SWED)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Asthma
Wheezing
Keywords: Wheezing Lower Respiratory Illness (WLRI)
Lead sponsor: University of Arizona
Sponsor class: OTHER
Collaborators: name: University of Utah
name: Emory University
name: Morgan Stanley Children's Hospital
name: University of Pittsburgh
name: Children's Hospital and Health System Foundation, Wisconsin
name: Children's Hospital of Philadelphia
name: Children's Hospital Medical Center, Cincinnati
name: Boston Children's Hospital
First posted: 2020-12-16
Enrollment: 840
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: TREATMENT

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.

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 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.

Primary outcomes:
measure: Asthma Flare-up Diary for Young Children
timeFrame: 5 day course of azithromycin
Secondary outcomes:
measure: Length of Stay
timeFrame: 72 hours after randomization
measure: Number of participants that develop Azithromycin resistant organisms
timeFrame: 21 days after randomization
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta, Emory University
state: Georgia
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: New York
country: United States
facility: Children's Hospital of New York Medical Center
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Philadelphia
country: United States
facility: The Children's Hospital of Philadelphia (CHOP)
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Milwaukee
country: United States
facility: The Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: University of Arizona
name: Fernando D Martinez, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Arizona
name: Kurt Denninghoff, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Utah
name: Charlie Casper, PhD
role: PRINCIPAL_INVESTIGATOR
References: