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

Trials

Peter S Morris⁸  Joanne Tuppin⁶  Jacobus Ungerer⁹  Ian M Mackay^1,10  Helen M Buntain⁶  Ian B Masters⁶  Gabrielle B McCallum⁴  Paul J Torzillo¹  Colin F Robertson⁷  Theo P Sloots^1,10  Kerry-Ann F O’Grady⁶  Catherine A Byrnes³  Peter P van Asperen⁵  Andrew C Wilson²  Keith Grimwood^1,10  Anne B Chang⁶ 

[1] Royal Prince Alfred Hospital, Sydney, Australia;Department of Respiratory Medicine, Princess Margaret Hospital, Perth, Australia;Department of Paediatrics, University of Auckland and Starship Children’s Hospital, Auckland, New Zealand;Child Health Division, Menzies School of Health Research, Charles Darwin University, Darwin, NT, Australia;Department of Respiratory Medicine, The Children’s Hospital at Westmead and Sydney Medical School, University of Sydney, Sydney, NSW, Australia;Queensland Children’s Medical Research Institute, Brisbane, QLD, Australia;Department of Respiratory Medicine, Royal Children’s Hospital, Murdoch Children’s Research Institute, University of Melbourne, Melbourne, VIC, Australia;Department of Paediatrics, Royal Darwin Hospital, Darwin, NT, Australia;Department Chemical Pathology, Queensland Pathology, Royal Brisbane Hospital, Brisbane, Australia;Queensland Paediatric Infectious Diseases Laboratory, Royal Children’s Hospital, Brisbane, QLD, Australia

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

Others  :  1094705
DOI  :  10.1186/1745-6215-14-53

 received in 2012-10-04, accepted in 2013-01-22,  发布年份 2013

【 摘 要 】

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

【 授权许可】

   
2013 Chang et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Dogru D, Nik-Ain A, Kiper N, Gocmen A, Ozcelik U, Yalcin E, Aslan AT: Bronchiectasis: the consequence of late diagnosis in chronic respiratory symptoms. J Trop Pediatr 2005, 51:362-365.
• [2]Chang AB, Grimwood K, Macguire G, King PT, Morris PS, Torzillo PJ: Management of bronchiectasis and chronic suppurative lung disease (CSLD) in Indigenous children and adults from rural and remote Australian communities. Med J Aust 2008, 189:386-393.
• [3]Donnelly DE, Critchlow A, Everard ML: Outcomes in children treated for persistent bacterial bronchitis. Thorax 2007, 62:80-84.
• [4]Gupta S, Siddiqui S, Haldar P, Raj JV, Entwisle JJ, Wardlaw AJ, Bradding P, Pavord ID, Green RH, Brightling CE: Qualitative analysis of high resolution computed tomography scans in severe asthma. Chest 2009, 136:1521-1528.
• [5]O’Brien C, Guest PJ, Hill SL, Stockley RA: Physiological and radiological characterisation of patients diagnosed with chronic obstructive pulmonary disease in primary care. Thorax 2000, 55:635-642.
• [6]O’Grady KA, Torzillo PJ, Chang AB: Hospitalisation of Indigenous children in the Northern Territory for lower respiratory illness in the first year of life. Med J Aust 2010, 192:586-590.
• [7]Simons L, Simons J, Friedlander Y, McCallum J: Chronic bronchitis and risk of coronary heart disease. Lancet 1996, 348:1388-1389.
• [8]Kiechl S, Egger G, Mayr M, Wiedermann CJ, Bonora E, Oberhollenzer F, Muggeo M, Xu Q, Wick G, Poewe W, Willeit J: Chronic infections and the risk of carotid atherosclerosis: prospective results from a large population study. Circulation 2001, 103:1064-1070.
• [9]Seitz AE, Olivier KN, Steiner CA, De Oca RM, Holland SM, Prevots DR: Trends and burden of bronchiectasis-associated hospitalizations: USA, 1993–2006. Chest 2010, 138:944-949.
• [10]Santamaria F, Montella S, Pifferi M, Ragazzo V, De SS, De PN, Maglione M, Boner AL: A descriptive study of non-cystic fibrosis bronchiectasis in a pediatric population from central and southern Italy. Respiration 2009, 77:160-165.
• [11]Roberts HJ, Hubbard R: Trends in bronchiectasis mortality in England and Wales. Respir Med 2010, 104:981-985.
• [12]Steinfort DP, Brady S, Weisinger HS, Einsiedel L: Bronchiectasis in Central Australia: a young face to an old disease. Respir Med 2008, 102:574-578.
• [13]Weycker D, Edelsberg J, Oster G, Tino G: Prevalence and economic burden of bronchiectasis. Clin Pulm Med 2005, 12:205-209.
• [14]Chang AB, Robertson CF, van Asperen PP, Glasgow NJ, Masters IB, Mellis CM, Landau LI, Teoh L, Morris PS: Can a management pathway for chronic cough in children improve clinical outcomes: protocol for a multicentre evaluation. Trials 2010, 11:103. BioMed Central Full Text
• [15]Chang AB, Robertson CF, van Asperen PP, Glasgow NJ, Mellis CM, Masters IB, Teoh L, Tjhung I, Morris PS, Petsky HL, Willis C, Landau LI: A multi-centre study on chronic cough in children: burden and etiologies based on a standardized management pathway. Chest 2012. epub ahead Mar 29
• [16]Chang AB, Masel JP, Boyce NC, Wheaton G, Torzillo PJ: Non-CF bronchiectasis-clinical and HRCT evaluation. Pediatr Pulmonol 2003, 35:477-483.
• [17]Twiss J, Metcalfe R, Edwards EA, Byrnes C: New Zealand national incidence of bronchiectasis “too high” for a developed country. Arch Dis Child 2005, 90:737-740.
• [18]Farrell PM: The prevalence of cystic fibrosis in the European Union. J Cyst Fibros 2008, 7:450-453.
• [19]Chang AB: Editorial. Bronchiectasis: so much yet to learn and to do. Paediatr Respir Rev 2011, 12:89-90.
• [20]Cystic Fibrosis Foundation, Frequently Asked Questions[http://www.cff.org/AboutCF/Faqs webcite] Accessed 24 December 2010
• [21]Haidopoulou K, Calder A, Jones A, Jaffe A, Sonnappa S: Bronchiectasis secondary to primary immunodeficiency in children: longitudinal changes in structure and function. Pediatr Pulmonol 2009, 44:669-675.
• [22]Bastardo CM, Sonnappa S, Stanojevic S, Navarro A, Lopez PM, Jaffe A, Bush A: Non-cystic fibrosis bronchiectasis in childhood: longitudinal growth and lung function. Thorax 2009, 64:246-251.
• [23]Kapur N, Masters IB, Chang AB: Longitudinal growth and lung function in pediatric non-CF bronchiectasis - what influences lung function stability? Chest 2010, 138:158-164.
• [24]Chang AB, Bell SC, Byrnes CA, Grimwood K, Holmes PW, King PT, Kolbe J, Landau LI, Maguire GP, McDonald MI, Reid DW, Thien FC, Torzillo PJ: Bronchiectasis and chronic suppurative lung disease (CSLD) in children and adults in Australian and New Zealand: thoracic society of Australia and New Zealand and Australian lung foundation position statement. Med J Aust 2010, 193:356-365.
• [25]King PT, Holdsworth SR, Farmer M, Freezer N, Villanueva E, Holmes PW: Phenotypes of adult bronchiectasis: onset of productive cough in childhood and adulthood. COPD 2009, 6:130-136.
• [26]Chang AB, Byrnes CA, Everard ML: Diagnosing and preventing chronic suppurative lung disease (CSLD) and bronchiectasis. Paediatr Respir Rev 2011, 12:97-103.
• [27]Kapur N, Masters IB, Newcombe P, Chang AB: The burden of disease in pediatric non-cystic fibrosis bronchiectasis. Chest 2012, 141:1018-1024.
• [28]Chang AB: Pediatric cough: children are not miniature adults. Lung 2010, 188:S33-S40.
• [29]Chang AB, Redding GJ, Everard ML: State of the Art - Chronic wet cough: protracted bronchitis, chronic suppurative lung disease and bronchiectasis. Pediatr Pulmonol 2008, 43:519-531.
• [30]Pasteur MC, Bilton D, Hill AT: British thoracic society guideline for non-CF bronchiectasis. Thorax 2010, 65:i1-i58.
• [31]Cole PJ: Inflammation: a two edged sword. The model of bronchiectasis. Eur J Respir Dis Suppl 1986, 147:6-15.
• [32]Chang AB, Grimwood K, Wilson A, van Asperen PP, O’Grady KA, Robertson CF, Sloots TP, Torzillo PJ, Bailey EJ, McCallum GB, Masters IB, Byrnes CA, Chatfield MD, Buntain H, Mackay IM, Morris PS: Randomised placebo-controlled trial on antibiotics for bronchiectasis exacerbations in children: rationale and protocol. Trials 2012, 13:156. BioMed Central Full Text
• [33]Grimwood K: Airway microbiology and host defenses in paediatric non-CF bronchiectasis. Paediatr Respir Rev 2011, 12:111-118.
• [34]Morris PS, Gadil G, McCallum GB, Wilson CA, Smith-Vaughan HC, Torzillo P, Leach AJ: Single-dose azithromycin versus seven days of amoxycillin in the treatment of acute otitis media in Aboriginal children (AATAAC): a double blind, randomised controlled trial. Med J Aust 2010, 192:24-29.
• [35]Saiman L, Anstead M, Mayer-Hamblett N, Lands LC, Kloster M, Hocevar-Trnka J, Goss CH, Rose LM, Burns JL, Marshall BC, Ratjen F: Effect of azithromycin on pulmonary function in patients with cystic fibrosis uninfected with Pseudomonas aeruginosa: a randomized controlled trial. JAMA 2010, 303:1707-1715.
• [36]Steinkamp G, Schmitt-Grohe S, Doring G, Staab D, Pfrunder D, Beck G, Schubert R, Zielen S: Once-weekly azithromycin in cystic fibrosis with chronic Pseudomonas aeruginosa infection. Respir Med 2008, 102:1643-1653.
• [37]Kapur N, Grimwood K, Masters IB, Morris PS, Chang AB: Lower airway microbiology and cellularity in children with newly diagnosed non-CF bronchiectasis. Pediatr Pulmonol 2012, 47:300-307.
• [38]Hotomi M, Arai J, Billal DS, Takei S, Ikeda Y, Ogami M, Kono M, Beder LB, Toya K, Kimura M, Yamanaka N: Nontypeable Haemophilus influenzae isolated from intractable acute otitis media internalized into cultured human epithelial cells. Auris Nasus Larynx 2010, 37:137-144.
• [39]Starner TD, Shrout JD, Parsek MR, Appelbaum PC, Kim GH: Subinhibitory concentrations of azithromycin decrease nontypeable haemophilus influenzae biofilm formation and diminish established biofilms. Antimicrob Agents Chemother 2008, 52:137-145.
• [40]Gielen V, Johnston SL, Edwards MR: Azithromycin induces anti-viral responses in bronchial epithelial cells. Eur Respir J 2010, 36:646-654.
• [41]Giamarellos-Bourboulis EJ: Macrolides beyond the conventional antimicrobials: a class of potent immunomodulators. Int J Antimicrob Agents 2008, 31:12-20.
• [42]Kramer BW, Kallapur S, Newnham J, Jobe AH: Prenatal inflammation and lung development. Semin Fetal Neonatal Med 2009, 14:2-7.
• [43]Milstone AP: Use of azithromycin in the treatment of acute exacerbations of COPD. Int J Chron Obstruct Pulmon Dis 2008, 3:515-520.
• [44]Cymbala AA, Edmonds LC, Bauer MA, Jederlinic PJ, May JJ, Victory JM, Amsden GW: The disease-modifying effects of twice-weekly oral azithromycin in patients with bronchiectasis. Treat Respir Med 2005, 4:117-122.
• [45]Wong C, Jayaram L, Karalus N, Eaton T, Tong C, Hockey H, Milne D, Fergusson W, Tuffery C, Sexton P, Storey L, Ashton T: Azithromycin for prevention of exacerbations in non-cystic fibrosis bronchiectasis (EMBRACE): a randomised, double-blind, placebo-controlled trial. Lancet 2012, 380:660-667.
• [46]Chang AB, Newman RG, Carlin J, Phelan PD, Robertson CF: Subjective scoring of cough in children: parent-completed vs child-completed diary cards vs an objective method. Eur Respir J 1998, 11:462-466.
• [47]Chang AB, Eastburn MM, Gaffney J, Faoagali J, Cox NC, Masters IB: Cough quality in children: a comparison of subjective vs. bronchoscopic findings. Respir Res 2005, 6:3. BioMed Central Full Text
• [48]Kapur N, Masters IB, Morris PS, Galligan J, Ware R, Chang AB: Defining pulmonary exacerbation in children with non-cystic fibrosis bronchiectasis. Pediatr Pulmonol 2012, 47:68-75.
• [49]Leach AJ, Boswell JB, Asche V, Nienhuys TG, Mathews JD: Bacterial colonization of the nasopharynx predicts very early onset and persistence of otitis media in Australian aboriginal infants. Pediatr Infect Dis J 1994, 13:983-989.
• [50]Chang AB, Grimwood K, White AV, Maclennan C, Sloots TP, Sive A, McCallum GB, Mackay IM, Morris PS: Randomized placebo-controlled trial on azithromycin to reduce the morbidity of bronchiolitis in Indigenous Australian infants: rationale and protocol. Trials 2011, 12:94. BioMed Central Full Text
• [51]Hare KM, Grimwood K, Leach AJ, Smith-Vaughan HC, Torzillo PJ, Morris P, Chang AB: Respiratory bacterial pathogens in the nasopharynx and lower airways of Australian Indigenous children with bronchiectasis. J Pediatr 2010, 157:1001-1005.
• [52]Wood LG, Scott HA, Garg ML, Gibson PG: Innate immune mechanisms linking non-esterified fatty acids and respiratory disease. Prog Lipid Res 2009, 48:27-43.
• [53]Wood LG, Simpson JL, Wark PA, Powell H, Gibson PG: Characterization of innate immune signalling receptors in virus-induced acute asthma. Clin Exp Allergy 2011, 41:640-648.
• [54]Chang AB, Phelan PD, Robertson CF, Roberts RDG, Sawyer SM: Relationship between measurements of cough severity. Arch Dis Child 2003, 88:57-60.
• [55]Newcombe PA, Sheffield JK, Juniper EF, Halstead RA, Masters IB, Chang AB: Development of a parent-proxy quality-of-life chronic cough-specific questionnaire: clinical impact vs psychometric evaluations. Chest 2008, 133:386-395.
• [56]Newcombe PA, Sheffield JK, Juniper EF, Petsky HL, Willis C, Chang AB: Validation of a parent-proxy quality-of-life questionnaire (PC-QOL) for paediatric chronic cough. Thorax 2010, 65:819-823.
• [57]Newcombe PA, Sheffield JK, Chang AB: Minimally important change in a parent-proxy quality of life questionnaire for pediatric chronic cough (PC-QOL). Chest 2010, 139:576-580.
• [58]Watt JP, O’Brien KL, Katz S, Bronsdon MA, Elliott J, Dallas J, Perilla MJ, Reid R, Murrow L, Facklam R, Santosham M, Whitney CG: Nasopharyngeal versus oropharyngeal sampling for detection of pneumococcal carriage in adults. J Clin Microbiol 2004, 42:4974-4976.
• [59]Stubbs E, Hare K, Wilson C, Morris P, Leach AJ: Streptococcus pneumoniae and noncapsular Haemophilus influenzae nasal carriage and hand contamination in children: a comparison of two populations at risk of otitis media. Pediatr Infect Dis J 2005, 24:423-428.
• [60]Hare KM, Morris P, Smith-Vaughan H, Leach AJ: Random colony selection versus colony morphology for detection of multiple pneumococcal serotypes in nasopharyngeal swabs. Pediatr Infect Dis J 2008, 27:178-180.
• [61]Arden KE, Chang AB, Lambert SB, Nissen M, Sloots TP, Mackay IM: Newly identified respiratory viruses in children with asthma exacerbation not requiring admission into hospital. J Med Virology 2010, 82:1458-1461.
• [62]Syrmis MW, Whiley DM, Thomas M, Mackay IM, Williamson J, Siebert DJ, Nissen MD, Sloots TP: A sensitive, specific, and cost-effective multiplex reverse transcriptase-PCR assay for the detection of seven common respiratory viruses in respiratory samples. J Mol Diagn 2004, 6:125-131.
• [63]McErlean P, Shackelton LA, Andrews E, Webster DR, Lambert SB, Nissen MD, Sloots TP, Mackay IM: Distinguishing molecular features and clinical characteristics of a putative new rhinovirus species, human rhinovirus C (HRV C). PLoS One 2008, 3:e1847.
• [64]Wisdom A, Leitch EC, Gaunt E, Harvala H, Simmonds P: Screening respiratory samples for detection of human rhinoviruses (HRVs) and enteroviruses: comprehensive VP4-VP2 typing reveals high incidence and genetic diversity of HRV species C. J Clin Microbiol 2009, 47:3958-3967.
• [65]Altman DG: Relation between several variables. In Practical Statistics for Medical Research. Chapman & Hall, London; 1991:326-364.
• [66]Schulz KF, Altman DG, Moher D: CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. Trials 2010, 11:32. BioMed Central Full Text
• [67]Chang AB, Torzillo PJ, Boyce NC, White AV, Stewart PA, Wheaton GR, Purdie DM, Wakerman J, Valery PC: Zinc and vitamin-A supplementation in Indigenous children hospitalised with episodes of lower respiratory tract infection: a randomised controlled trial. Med J Aust 2006, 184:107-112.
• [68]Chang AB, Marsh RL, Smith-Vaughan HC, Hoffman LR: Emerging drugs for bronchiectasis. Expert Opin Emerg Drugs 2012, 17:361-78.
• [69]Wurzel D, Marchant JM, Yerkovich ST, Upham JW, Masters IB, Chang AB: Short courses of antibiotics for children and adults with bronchiectasis. Cochrane Database Syst Rev 2011, 6:CD008695.
• [70]Kolbe J, Wells AU: Bronchiectasis: a neglected cause of respiratory morbidity and mortality. Respirology 1996, 1:221-225.
• [71]Tsang KW, Bilton D: Clinical challenges in managing bronchiectasis. Respirology 2009, 14:637-650.
• [72]O’Donnell AE, Barker AF, Ilowite JS, Fick RB: Treatment of idiopathic bronchiectasis with aerosolized recombinant human DNase I. rhDNase Study Group. Chest 1998, 113:1329-1334.
• [73]Desai M, Weller PH, Spencer DA: Clinical benefit from nebulized human recombinant DNase in Kartagener’s syndrome. Pediatr Pulmonol 1995, 20:307-308.
• [74]Wark PAB, Tooze M, Cheese L: Viral infections trigger exacerbations of cystic fibrosis in adults and children. Eur Respir J 2012, 40:510-512.
• [75]Proud D, Chow CW: Role of viral infections in asthma and chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol 2006, 35:513-518.
• [76]Hutchinson AF, Black J, Thompson MA, Bozinovski S, Brand CA, Smallwood DM, Irving LB, Anderson GP: Identifying viral infections in vaccinated chronic obstructive pulmonary disease (COPD) patients using clinical features and inflammatory markers. Influenza Other Respir Viruses 2010, 4:33-39.
• [77]Kapur N, Masters IB, Chang AB: Exacerbations in non cystic fibrosis bronchiectasis: clinical features and investigations. Respir Med 2009, 103:1681-1687.
• [78]Valery PC, Morris PS, Grimwood K, Torzillo PJ, Byrnes CA, Masters IB, Bauert P, McCallum GB, Mobberly C, Chang AB: Azithromycin for Indigenous children with bronchiectasis: study protocol for a multi-centre randomized controlled trial. BMC Pediatr 2012, 12:122. BioMed Central Full Text
• [79]Courtney JM, Kelly MG, Watt A, Garske L, Bradley J, Ennis M, Elborn JS: Quality of life and inflammation in exacerbations of bronchiectasis. Chron Respir Dis 2008, 5:161-168.
• [80]Murray MP, Turnbull K, Macquarrie S, Hill AT: Assessing response to treatment of exacerbations of bronchiectasis in adults. Eur Respir J 2009, 33:312-318.