Treatment of Preschool Children With Upper Respiratory Tract Illnesses Using Azythromycin and Lower Respiratory Tract Symptoms Using Oral Corticosteroids. (APRIL - OCELOT)

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

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.

Study Overview

• Status: Completed
• Conditions: Asthma; Wheezing
• Intervention / Treatment: Drug: Azithromycin; Drug: Prednisolone; Drug: Placebo Prednisolone; Other: Placebo Azithromycin

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.

• Study Type: Interventional
• Enrollment (Actual): 607
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Tucson, Arizona, United States, 85724
      • University of Arizona College of Medicine
  • California
    • Oakland, California, United States, 94609
      • Children's Hospital & Research Center Oakland
    • San Francisco, California, United States, 94143
      • UCSF Benioff Children's Hospital
  • Colorado
    • Denver, Colorado, United States, 80206
      • National Jewish Health
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
    • Chicago, Illinois, United States, 60614
      • Children's Memorial Hospital
    • Chicago, Illinois, United States, 60637
      • University of Chicago
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Children's Hospital Boston
  • Missouri
    • St. Louis, Missouri, United States, 63110
      • St. Louis Children's Hospital
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131
      • University of New Mexico
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Case Medical Center
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15224
      • Children's Hospital of Pittsburgh of UPMC
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Health System
  • Wisconsin
    • Madison, Wisconsin, United States, 53972
      • University of Wisconsin
    • Milwaukee, Wisconsin, United States, 53223
      • Center for Urban Population Health

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 months to 4 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Azythromycin (APRIL) and Prednisolone (OCELOT)	Drug: Azithromycin; Suspension, 12 mg/kg once daily for 5 days, maximum dose 500mg/day; Drug: Prednisolone; Syrup, 1 mg/kg/dose twice daily for 5 days, maximum dose 60mg/day
Experimental: Azythromycin (APRIL) and Placebo (OCELOT)	Drug: Azithromycin; Suspension, 12 mg/kg once daily for 5 days, maximum dose 500mg/day; Drug: Placebo Prednisolone; Syrup, 1 mg/kg/dose twice daily for 5 days, maximum dose 60mg/day
Experimental: Placebo (APRIL) and Prednisolone (OCELOT)	Drug: Prednisolone; Syrup, 1 mg/kg/dose twice daily for 5 days, maximum dose 60mg/day; Other: Placebo Azithromycin; Suspension, 12 mg/kg once daily for 5 days, maximum dose 500mg/day
Placebo Comparator: Placebo (APRIL) and Placebo (OCELOT)	Drug: Placebo Prednisolone; Syrup, 1 mg/kg/dose twice daily for 5 days, maximum dose 60mg/day; Other: Placebo Azithromycin; Suspension, 12 mg/kg once daily for 5 days, maximum dose 500mg/day

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression to Clinically Significant Lower Respiratory Tract Symptoms	Progression to clinically significant lower respiratory tract symptoms defined by: (1) having symptoms that were more than mild after 3 albuterol administrations over 1 hour, or (2) requiring albuterol administrations more often than once every 4 hours, or (3) requiring more than 6 albuterol treatments over a 24-hour period, or (4) having moderate to severe cough or wheeze for 5 or more days since study medication was initiated.	14 days after initiation of APRIL therapy
OCELOT: Pediatric Respiratory Assessment Measure	The Pediatric Respiratory Assessment Measure (PRAM) is a composite outcome with scores ranging from 0-12 with higher numbers representing worse symptoms. The score is calculated as the sum total of the follow five elements: (1) scalene retractions, (2) suprasternal retractions, (3) wheezing, (4) air entry, (5) oxygen saturation. A complete description can be found in: Ducharme FM, Chalut D, Plotnick L, et al. The Pediatric Respiratory Assessment Measure: a valid clinical score for assessing acute asthma severity from toddlers to teenagers. J Pediatr 2008;152:476-80.	36-72 hours after initiation of OCELOT therapy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Asthma Related Symptoms Among RTI Progressing to Severe LRTI	Asthma related symptoms as measured by the parent-completed Pre-school Asthma Symptom Diary (PAD). The PAD was completed daily starting on the first day of an illness and continued until the participant was symptom-free for 2 days. It contains questions of frequency of respiratory symptoms, each scored on a scale of 1 through 7, with higher scores representing increasingly frequent symptoms, with daily scores ranging from 0 (asymptomatic) to a maximum of 102. The total PAD score is the sum of the daily individual symptom scores over the duration of the illness, with higher scores representing more frequent symptoms.	14 days after initiation of therapy
Absence From School, Daycare, and/or Parental Work		14 days after initiation of therapy
Urgent Care Visits, ED Visits and Hospitalizations	Number of participants who had urgent care visits, ED visits, and/or hospitalizations for respiratory symptoms.	14 days after initiation of therapy
Drug Related Side Effects	Parent-reported gastrointestinal symptoms during treated RTI.	14 days after initiation of therapy

Collaborators and Investigators

• Sponsor: Milton S. Hershey Medical Center
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Study Chair: William B Busse, MD, University of Wisconsin, Madison; Principal Investigator: Leonard B Bacharier, MD, Washington University School of Medicine; Principal Investigator: David T Mauger, PhD, Penn State University; Principal Investigator: Robert F Lemanske, MD, University of Wisconsin, Madison; Principal Investigator: Jacqueline Pongracic, MD, Ann & Robert H Lurie Children's Hospital of Chicago; Principal Investigator: David Gozal, MD, Comer Children's Hospital; Principal Investigator: James Moy, MD, Rush University Medical Center; Principal Investigator: Stanley Szefler, MD, National Jewish Health; Principal Investigator: Hengameh Raissy, PharmD, University of New Mexico; Principal Investigator: Elizabeth Bade, MD, Aurora Sinai Medical Center; Principal Investigator: Fernando Holguin, MD, University of Pittsburgh; Principal Investigator: James Chmiel, MD, Case Western Reserve University School of Medicine; Principal Investigator: Michael Cabana, MD, MPH, University of California, San Francisco; Principal Investigator: Mindy Benson, PNP, UCSF Benioff Children's Hospital Oakland; Principal Investigator: W. Gerald Teague, MD, University of Virginia Health System; Principal Investigator: Anne Fitzpatrick, MD, Emory University

Publications and helpful links

General Publications

• 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. Erratum In: JAMA. 2016 Jan 12;315(2):204. JAMA. 2016 Jan 26;315(4):419.

Study record dates

Study Major Dates

• Study Start: March 1, 2011
• Primary Completion (Actual): January 1, 2015
• Study Completion (Actual): January 1, 2015

Study Registration Dates

• First Submitted: January 7, 2011
• First Submitted That Met QC Criteria: January 7, 2011
• First Posted (Estimate): January 10, 2011

Study Record Updates

• Last Update Posted (Estimate): December 28, 2016
• Last Update Submitted That Met QC Criteria: November 1, 2016
• Last Verified: November 1, 2016

More Information

Terms related to this study

• Keywords: Asthma; Wheezing; Prednisolone; Preschool-age; Respiratory Tract Illness; Azythromycin
• Additional Relevant MeSH Terms: Signs and Symptoms, Respiratory; Respiratory Sounds; Physiological Effects of Drugs; Anti-Infective Agents; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Neuroprotective Agents; Protective Agents; Anti-Bacterial Agents; Prednisolone; Methylprednisolone Acetate; Methylprednisolone; Methylprednisolone Hemisuccinate; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate; Azithromycin
• Other Study ID Numbers: AsthmaNet 002; 1U10HL098115 (U.S. NIH Grant/Contract)