Clinical trial NCT01272635: Treatment of Preschool Children With Upper Respiratory Tract Illnesses Using Azythromycin and Lower Respiratory Tract Symptoms Using Oral Corticosteroids.
Official title: Azithromycin for Preventing the Development of Upper Respiratory Tract Illness Into Lower Respiratory Tract Symptoms in Children and Oral Corticosteroids for Treating Episodes of Significant Lower Respiratory Tract Symptoms in Children
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Asthma
Wheezing
Keywords: Asthma
Wheezing
Respiratory Tract Illness
Azythromycin
Prednisolone
Preschool-age
Lead sponsor: Milton S. Hershey Medical Center
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2011-01-10
Enrollment: 607
Sex: ALL
Minimum age (years): 12
Maximum age (years): 71
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This protocol is comprised of two separate, but linked, clinical trials for treating preschool-aged children with recurrent severe episodes of wheezing. The first study (APRIL) will try to prevent wheezing illness from developing using azithromycin. If a wheezing illness does occur, the second trial (OCELOT) will try to decrease the severity of symptoms using oral corticosteroids.

Detailed description: Preschool aged children often have severe bouts of coughing and/or wheezing that lead to visits to the doctor's office, urgent care, emergency room and often hospitalization. APRIL-OCELOT is a randomized, double-blind, placebo controlled study in 600 preschool children with a history of significant wheezing episodes in the year prior to enrollment. All children enter the APRIL portion of the study, which will compare azithromycin to placebo, given for 5 days during the early signs of an upper respiratory tract illness, for preventing the development of lower respiratory tract symptoms. APRIL is a 78 week study, but participation will end earlier if the child requires a fourth course of APRIL treatment or develops significant lower respiratory tract symptoms. Only those children who develop significant lower respiratory tract symptoms during APRIL will enter the OCELOT portion of the study, which will compare oral corticosteroid to placebo for treating lower respiratory tract symptoms as measured by the Pediatric Respiratory Assessment Measure (PRAM). OCELOT participation will be complete after 14 days. Children may not reenter APRIL after completing OCELOT.

Eligibility criteria: Inclusion Criteria:

* 12-71 months of age.
* Recurrent significant wheezing in the past year (any of the following):

  * \>3 episodes, ≥1 of which was clinically significant\*; OR
  * \>2 clinically significant\* episodes; OR
  * \>4 months of daily controller therapy AND \>1 clinically significant\* episode.
  * \* Clinically significant episode: requiring any of the following: (1) systemic corticosteroids (oral or injectable), (2) unscheduled physician office visit, (3) ED visit, (4) urgent care visit, or (5) hospitalization.
* Up to date with immunizations, including varicella (unless the subject has already had clinical varicella). If the subject needs varicella vaccine, this will be arranged with the primary care physician and must be received prior to randomization.
* Willingness to provide informed consent by the child's parent or guardian.

Exclusion Criteria:

Participants who meet any of the following criteria are NOT eligible for enrollment, but may be re-enrolled if these exclusion criteria are resolved:

* \>4 courses of systemic corticosteroids in past 12 months.
* More than 1 hospitalization for wheezing illnesses within the preceding 12 months.
* Use of long-term controller medications for asthma, including inhaled corticosteroids, leukotriene modifiers, cromolyn/nedocromil, or theophylline for more than 8 months (cumulative use) in the past 12 months.
* Current use of higher than step 2 NAEPP asthma guideline therapy (e.g. medium-high dose ICS alone or combination therapy of low-medium-high dose ICS + LABA, montelukast, theophylline or cromolyn). NOTE: children who have evidence of well-controlled symptoms immediately preceding study entry while receiving Step 2 controller therapy (presence of self-reported symptoms on average no more than 2 times per week and less than 2 nights per month of nocturnal awakenings, requiring albuterol, during the 4 weeks preceding visit 1) may be enrolled and will have their controller therapy discontinued upon study entry.
* Use of OCS in the past 2 weeks.
* Daily symptoms or \>2 nocturnal awakenings, requiring albuterol, on average in the last 2 weeks.
* Use of antibiotics in the past month.
* Current treatment with antibiotics for diagnosed sinus disease.
* Participation presently or in the past month in another investigational drug trial.
* Evidence that the family may be unreliable or nonadherent, or may move from the clinical center area before trial completion.
* Contraindication of use of systemic corticosteroids or azithromycin.
* Clinically relevant gastroesophageal reflux.
* Concurrent medical conditions other than asthma that are likely to require oral or injectable corticosteroids during the study.
* If receiving allergy shots, change in dose within the past 3 months.

Participants who meet any of the following criteria are NOT eligible for enrollment, and may not be re-enrolled:

* Gestation less than late preterm as defined as birth before 34 weeks gestational age.
* Presence of lung disease other than asthma, such as cystic fibrosis and BPD. Evaluation during the screening process will assure that an adequate evaluation of other lung diseases has been performed.
* Presence of other significant medical illnesses (cardiac, liver, gastrointestinal, endocrine) that would place the study subject at increased risk of participating in the study.
* Immunodeficiency disorders.
* History of respiratory failure requiring mechanical ventilation.
* History of hypoxic seizure.
* History of significant adverse reaction to any study medication ingredient.
* The child has significant developmental delay/failure to thrive, defined as crossing of two major percentile lines during the last year for age and gender. If a child plots less than the 10th percentile for age and gender, a growth chart for the previous year will be obtained from the child's primary care provider.

Primary outcomes:
measure: Progression to Clinically Significant Lower Respiratory Tract Symptoms
timeFrame: 14 days after initiation of APRIL therapy
measure: OCELOT: Pediatric Respiratory Assessment Measure
timeFrame: 36-72 hours after initiation of OCELOT therapy
Secondary outcomes:
measure: Asthma Related Symptoms Among RTI Progressing to Severe LRTI
timeFrame: 14 days after initiation of therapy
measure: Absence From School, Daycare, and/or Parental Work
timeFrame: 14 days after initiation of therapy
measure: Urgent Care Visits, ED Visits and Hospitalizations
timeFrame: 14 days after initiation of therapy
measure: Drug Related Side Effects
timeFrame: 14 days after initiation of therapy
Other outcomes:
Locations:
city: Tucson
country: United States
facility: University of Arizona College of Medicine
state: Arizona
city: Oakland
country: United States
facility: Children's Hospital & Research Center Oakland
state: California
city: San Francisco
country: United States
facility: UCSF Benioff Children's Hospital
state: California
city: Denver
country: United States
facility: National Jewish Health
state: Colorado
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Chicago
country: United States
facility: Children's Memorial Hospital
state: Illinois
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Boston
country: United States
facility: Children's Hospital Boston
state: Massachusetts
city: St. Louis
country: United States
facility: St. Louis Children's Hospital
state: Missouri
city: Albuquerque
country: United States
facility: University of New Mexico
state: New Mexico
city: Cleveland
country: United States
facility: University Hospitals Case Medical Center
state: Ohio
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh of UPMC
state: Pennsylvania
city: Charlottesville
country: United States
facility: University of Virginia Health System
state: Virginia
city: Madison
country: United States
facility: University of Wisconsin
state: Wisconsin
city: Milwaukee
country: United States
facility: Center for Urban Population Health
state: Wisconsin
Study officials:
affiliation: University of Wisconsin, Madison
name: William B Busse, MD
role: STUDY_CHAIR
affiliation: Washington University School of Medicine
name: Leonard B Bacharier, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Arizona
name: Fernando D Martinez, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Penn State University
name: David T Mauger, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Wisconsin, Madison
name: Robert F Lemanske, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Boston Children's Hospital
name: Wanda Phipatanakul, MD, MS
role: PRINCIPAL_INVESTIGATOR
affiliation: Ann & Robert H Lurie Children's Hospital of Chicago
name: Jacqueline Pongracic, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Comer Children's Hospital
name: David Gozal, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Rush University Medical Center
name: James Moy, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: National Jewish Health
name: Stanley Szefler, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of New Mexico
name: Hengameh Raissy, PharmD
role: PRINCIPAL_INVESTIGATOR
affiliation: Aurora Sinai Medical Center
name: Elizabeth Bade, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Pittsburgh
name: Fernando Holguin, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Case Western Reserve University School of Medicine
name: James Chmiel, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, San Francisco
name: Michael Cabana, MD, MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: UCSF Benioff Children's Hospital Oakland
name: Mindy Benson, PNP
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Virginia Health System
name: W. Gerald Teague, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Emory University
name: Anne Fitzpatrick, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bacharier LB, Guilbert TW, Mauger DT, Boehmer S, Beigelman A, Fitzpatrick AM, Jackson DJ, Baxi SN, Benson M, Burnham CD, Cabana M, Castro M, Chmiel JF, Covar R, Daines M, Gaffin JM, Gentile DA, Holguin F, Israel E, Kelly HW, Lazarus SC, Lemanske RF Jr, Ly N, Meade K, Morgan W, Moy J, Olin T, Peters SP, Phipatanakul W, Pongracic JA, Raissy HH, Ross K, Sheehan WJ, Sorkness C, Szefler SJ, Teague WG, Thyne S, Martinez FD. Early Administration of Azithromycin and Prevention of Severe Lower Respiratory Tract Illnesses in Preschool Children With a History of Such Illnesses: A Randomized Clinical Trial. JAMA. 2015 Nov 17;314(19):2034-2044. doi: 10.1001/jama.2015.13896.