Open Access Study protocol

Bronchiectasis exacerbation study on azithromycin and amoxycillin-clavulanate for respiratory exacerbations in children (BEST-2): study protocol for a randomized controlled trial

Anne B Chang123*, Keith Grimwood34, Andrew C Wilson5, Peter P van Asperen6, Catherine A Byrnes7, Kerry-Ann F O’Grady3, Theo P Sloots34, Colin F Robertson8, Paul J Torzillo9, Gabrielle B McCallum1, Ian B Masters23, Helen M Buntain23, Ian M Mackay34, Jacobus Ungerer10, Joanne Tuppin23 and Peter S Morris111

Author Affiliations

1 Child Health Division, Menzies School of Health Research, Charles Darwin University, Darwin, NT, Australia

2 Queensland Children’s Respiratory Centre, Royal Children’s Hospital, Brisbane, QLD, Australia

3 Queensland Children’s Medical Research Institute, Brisbane, QLD, Australia

4 Queensland Paediatric Infectious Diseases Laboratory, Royal Children’s Hospital, Brisbane, QLD, Australia

5 Department of Respiratory Medicine, Princess Margaret Hospital, Perth, Australia

6 Department of Respiratory Medicine, The Children’s Hospital at Westmead and Sydney Medical School, University of Sydney, Sydney, NSW, Australia

7 Department of Paediatrics, University of Auckland and Starship Children’s Hospital, Auckland, New Zealand

8 Department of Respiratory Medicine, Royal Children’s Hospital, Murdoch Children’s Research Institute, University of Melbourne, Melbourne, VIC, Australia

9 Royal Prince Alfred Hospital, Sydney, Australia

10 Department Chemical Pathology, Queensland Pathology, Royal Brisbane Hospital, Brisbane, Australia

11 Department of Paediatrics, Royal Darwin Hospital, Darwin, NT, Australia

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Trials 2013, 14:53  doi:10.1186/1745-6215-14-53

Published: 20 February 2013

Abstract

Background

Bronchiectasis unrelated to cystic fibrosis (CF) is being increasingly recognized in children and adults globally, both in resource-poor and in affluent countries. However, high-quality evidence to inform management is scarce. Oral amoxycillin-clavulanate is often the first antibiotic chosen for non-severe respiratory exacerbations, because of the antibiotic-susceptibility patterns detected in the respiratory pathogens commonly associated with bronchiectasis. Azithromycin has a prolonged half-life, and with its unique anti-bacterial, immunomodulatory, and anti-inflammatory properties, presents an attractive alternative. Our proposed study will test the hypothesis that oral azithromycin is non-inferior (within a 20% margin) to amoxycillin-clavulanate at achieving resolution of non-severe respiratory exacerbations by day 21 of treatment in children with non-CF bronchiectasis.

Methods

This will be a multicenter, randomized, double-blind, double-dummy, placebo-controlled, parallel group trial involving six Australian and New Zealand centers. In total, 170 eligible children will be stratified by site and bronchiectasis etiology, and randomized (allocation concealed) to receive: 1) azithromycin (5 mg/kg daily) with placebo amoxycillin-clavulanate or 2) amoxycillin-clavulanate (22.5 mg/kg twice daily) with placebo azithromycin for 21 days as treatment for non-severe respiratory exacerbations. Clinical data and a parent-proxy cough-specific quality of life (PC-QOL) score will be obtained at baseline, at the start and resolution of exacerbations, and on day 21. In most children, blood and deep-nasal swabs will also be collected at the same time points. The primary outcome is the proportion of children whose exacerbations have resolved at day 21. The main secondary outcome is the PC-QOL score. Other outcomes are: time to next exacerbation; requirement for hospitalization; duration of exacerbation, and spirometry data. Descriptive viral and bacteriological data from nasal samples and blood inflammatory markers will be reported where available.

Discussion

Currently, there are no published randomized controlled trials (RCT) to underpin effective, evidence-based management of acute respiratory exacerbations in children with non-CF bronchiectasis. To help address this information gap, we are conducting two RCTs. The first (

    b
ronchiectasis
    e
xacerbation
    st
udy; BEST-1) evaluates the efficacy of azithromycin and amoxycillin-clavulanate compared with placebo, and the second RCT (BEST-2), described here, is designed to determine if azithromycin is non-inferior to amoxycillin-clavulanate in achieving symptom resolution by day 21 of treatment in children with acute respiratory exacerbations.

Trial registration

Australia and New Zealand Clinical Trials Register (ANZCTR) number http://ACTRN12612000010897 webcite. http://www.anzctr.org.au/trial_view.aspx?id=347879 webcite

Keywords:
Amoxycillin-clavulanate; Azithromycin; Bronchiectasis; Placebo; Pulmonary exacerbations; Randomized controlled trial