title: Bronchiectasis exacerbation study on azithromycin and amoxycillin-clavulanate for respiratory exacerbations in children (BEST-2): study protocol for a randomized controlled trial.
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.
  
  
  CONCLUSIONS
  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 (bronchiectasis exacerbation study; 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.
  
  
  BACKGROUND
  Australia and New Zealand Clinical Trials Register (ANZCTR) number http://ACTRN12612000010897. http://www.anzctr.org.au/trial_view.aspx?id=347879.
authors: Child Health Division, Menzies School of Health Research, Charles Darwin University, Darwin, NT, Australia. annechang@ausdoctors.net
authors: Anne B
authors: AB
authors: Chang
authors: Keith
authors: K
authors: Grimwood
authors: Andrew C
authors: AC
authors: Wilson
authors: Peter P
authors: PP
authors: van Asperen
authors: Catherine A
authors: CA
authors: Byrnes
authors: Kerry-Ann F
authors: KA
authors: O'Grady
authors: Theo P
authors: TP
authors: Sloots
authors: Colin F
authors: CF
authors: Robertson
authors: Paul J
authors: PJ
authors: Torzillo
authors: Gabrielle B
authors: GB
authors: McCallum
authors: Ian B
authors: IB
authors: Masters
authors: Helen M
authors: HM
authors: Buntain
authors: Ian M
authors: IM
authors: Mackay
authors: Jacobus
authors: J
authors: Ungerer
authors: Joanne
authors: J
authors: Tuppin
authors: Peter S
authors: PS
authors: Morris
mesh_terms: D019980:Amoxicillin-Potassium Clavulanate Combination / Q000627:therapeutic use*; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D017963:Azithromycin / Q000627:therapeutic use*; D001987:Bronchiectasis / Q000188:drug therapy*; D002985:Clinical Protocols; D004311:Double-Blind Method; D006801:Humans; D017063:Outcome Assessment, Health Care; D018401:Sample Size
chemical_list: D000900:Anti-Bacterial Agents; D019980:Amoxicillin-Potassium Clavulanate Combination; D017963:Azithromycin