AsthmaNet Azithromycin for Preventing the Development of Upper Respiratory Tract Illness Into Lower Respiratory Tract Symptoms in Children (APRIL) and Oral Corticosteroids for Treating Episodes of Significant Lower Respiratory Tract Symptoms in Children (OCELOT)
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March 2011 – January 2015
March 2, 2020
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Additional Study Information
This protocol is comprised of two separate, but linked, clinical trials for treating preschool-aged children with recurrent severe episodes of wheezing.
The APRIL study evaluated if early administration of azithromycin, started prior to the onset of severe lower respiratory tract illness (LRTI) symptoms, in preschool children with recurrent severe LRTIs can prevent the progression of these episodes. The OCELOT study assessed the efficacy of oral corticosteroids in decreasing the severity of symptoms of preschool children whose episode progressed to acute severe wheezing.
Children up to six years of age may commonly experience acute episodes of severe lower respiratory tract illness, which are often associated with substantial morbidity that result in urgent or emergency care. Children experiencing episodes of severe wheezing are often treated with oral corticosteroids (OCSs) based on their efficacy in the management of asthma in older children.
At the time of the studies, the etiology of these acute episodes was not well understood. Investigations have shown presence of both respiratory viruses as well as bacteria in nasopharyngeal secretions of such patients. Identification of Streptococcus pneumoniae or Moraxella catarrhalis in nasal samples also containing rhinovirus was associated with increased likelihood of having an asthma exacerbation in children 4 to 12 years of age. Telithromycin is a ketolide antibiotic that has been found to significantly improve symptom scores and lung function when administered within the first 24 hours of acute asthma episodes, suggesting a mechanism unrelated to direct antimicrobial action. Based on these and other findings, the APRIL study was initiated to investigate the early administration of the macrolide azithromycin in preschool children with recurrent severe LRTIs to determine if this intervention can safely prevent the progression of such episodes. In addition, the benefit of OCS use in severe episodes remained unclear, with the possibility for adverse reactions. Therefore the OCELOT trial was also initiated to evaluate OCS treatment in cases where the episode does progress.
Eligible participants were children aged 12 through 71 months with recurrent severe wheezing in the context of clinically significant LRTIs that required systemic corticosteroids, an unscheduled physician office visit, an urgent or emergency department visit, or hospitalization. Exclusion criteria included more than 4 courses of systemic corticosteroids or more than 1 hospitalization in the past 12 months, or use of long-term controllers for asthma for more than 8 months in the past 12 months. These criteria excluded children with more severe disease who require daily controller medication. Children receiving monotherapy with asthma controllers at enrollment were eligible but had their controller discontinued upon study entry, consistent with recommendations for step-down therapy. Children with significant symptomatic asthma and those with inadequate adherence to diary card completion (<80% of days) during the 2 to 4 week run-in period were also excluded.
Of 780 participants enrolled, 607 underwent randomization into the APRIL study, with 307 participants randomized to the azithromycin group and 300 participants randomized to the placebo group. 149 of these patients also participated in the OCELOT trial. A total of 61 children received OCELOT treatment in a per-protocol fashion, whereas 88 received open-label OCS as part of clinical care outside of the trial (early terminators).
APRIL participants were randomized in a 1:1 ratio to receive either oral azithromycin (12 mg/kg once daily for 5 days) or matching placebo. Caretakers were instructed to start study therapy as soon as the participant showed the symptoms or signs preceding the development of a severe LRTI. The initial trial follow-up period was 52 weeks, with study treatment used during a maximum of 3 treated respiratory tract illness (RTIs) not progressing to severe LRTI. During RTIs, all participants received albuterol inhalation treatments 4 times daily while awake for the first 48 hours as well as whenever needed at any time during the RTI. In June 2012, based upon a pre-specified interval assessment that demonstrated a lower than expected RTI rate, the follow-up period was extended to 78 weeks for those participating in the study at that time (n = 164) or enrolled thereafter (n = 292) and allowed for use of study treatment during a maximum of 4 treated RTIs.
The primary outcome measure was the number of treated RTIs that did not progress to severe LRTI, as defined as the requirement to treat with oral corticosteroids based on reported symptom severity (see OCELOT design below). Presence of azithromycin-resistant organisms in oropharyngeal samples, along with adverse events, were among the secondary outcome measures.
The OCELOT trial was a randomized, double-blind, placebo-controlled trial in children enrolled in the APRIL trial, who were randomized to receive either an OCS (1 mg/kg prednisolone administered twice daily for 5 days; maximum dose, 60 mg/d) or placebo when an RTI had progressed to an LTRI.
Families were instructed to contact either the study staff during the day or a centralized telephone triage center after hours when the child had specific LRTI symptoms, including respiratory symptoms that had not improved after 3 albuterol treatments in 1 hour, symptoms that required 2 albuterol treatments within 4 hours, use of 7 or more albuterol treatments in 24 hours, or concerning cough or wheeze for several days. Nurses at the telephone triage center used an algorithm to determine the appropriateness of initiating OCELOT therapy, followed by a research physician's confirmation by telephone. Albuterol and blinded trial medications were available at home, and OCELOT therapy was started based on this telephone assessment. The primary outcome measure of the OCELOT trial was the Pediatric Respiratory Assessment Measure (PRAM) score which was determined 15 minutes after bronchodilator and measured in the AsthmaNet clinic by a physician 36 to 72 hours after the initiation of OCELOT medication. Trial participation was terminated after 1 course of OCELOT therapy, and then the discharge care plan was prescribed by the research physician. Parents received asthma education and customized action plans.
Given the high rate of off-protocol use of open-label OCSs combined with the small number of children managed per-protocol and the potential for selection bias of children with more severe episodes being managed with open-label OCSs by providers outside the trial, the OCELOT Data Safety and Monitoring Board recommended premature termination of the trial because of a lack of feasibility in April 2013.
Among young children with histories of recurrent severe LRTIs, the APRIL trial found that the use of azithromycin early during an apparent RTI compared with placebo reduced the likelihood of severe LRTI. More information is needed on the development of antibiotic-resistant pathogens with this strategy.
Bacharier LB, Guilbert TW, Mauger DT, et al. 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.
Due to early termination of the OCELOT trial, the primary outcome was not able to be evaluated.
Guilbert TW, Bacharier LB, Mauger DT, et al. Challenges in assessing the efficacy of systemic corticosteroids for severe wheezing episodes in preschool children. J Allergy Clin Immunol. 2019 May;143(5):1934-1937.e4. doi: 10.1016/j.jaci.2018.10.071. Epub 2019 Jan 17.
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Resources AvailableStudy Datasets Only
- Data Dictionary (PDF - 643.4 KB)
- APRIL OCELOT Case Report Forms (PDF - 1.4 MB)
- APRIL OCELOT Combined Protocol (PDF - 2.1 MB)
- APRIL OCELOT Manual of Procedures (PDF - 2.4 MB)
- APRIL OCELOT User Guide (PDF - 283.9 KB)
- APRIL Protocol After OCELOT Closed (PDF - 2.1 MB)
- AsthmaNet Standard Manual of Procedures (PDF - 863.8 KB)
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