Efficacy of oral amoxicillin–clavulanate or azithromycin for non-severe respiratory exacerbations in children with bronchiectasis (BEST-1)

a multicentre, three-arm, double-blind, randomised placebo-controlled trial

Vikas Goyal, Keith Grimwood, Robert S. Ware, Catherine A. Byrnes, Peter S. Morris, I. Brent Masters, Gabrielle B. McCallum, Michael J. Binks, Heidi Smith-Vaughan, Kerry Ann F. O'Grady, Anita Champion, Helen M. Buntain, André Schultz, Mark Chatfield, Paul J. Torzillo, Anne B. Chang

    Research output: Contribution to journalArticleResearchpeer-review

    Abstract

    Background: Bronchiectasis guidelines recommend antibiotics for the treatment of acute respiratory exacerbations, but randomised placebo-controlled trials in children are lacking. We hypothesised that oral amoxicillin–clavulanate and azithromycin would each be superior to placebo in achieving symptom resolution of non-severe exacerbations in children by day 14 of treatment.

    Methods: In this multicentre, three-arm, parallel, double-dummy, double-blind, randomised placebo-controlled trial at four paediatric centres in Australia and New Zealand, we enrolled children aged 1–18 years with CT-confirmed bronchiectasis unrelated to cystic fibrosis, who were under the care of a respiratory physician and who had had at least two respiratory exacerbations in the 18 months before study entry. Participants were allocated (1:1:1) at exacerbation onset to receive oral suspensions of amoxicillin–clavulanate (45 mg/kg per day) plus placebo azithromycin, azithromycin (5 mg/kg per day) plus placebo amoxicillin–clavulanate, or both placebos for 14 days. An independent statistician prepared a computer-generated, permuted-block (size 2–8) randomisation sequence, stratified by centre, age, and cause. Participants, caregivers, study coordinators, and investigators were masked to treatment assignment until data analysis was completed. The primary outcome was the proportion of children with exacerbation resolution by day 14 in the intention-to-treat population. Treatment groups were compared using generalised linear models. Statistical significance was set at p<0·0245 to account for multiple comparisons. This trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12612000011886) and is completed.

    Findings: Between April 17, 2012, and March 1, 2017, 604 children were screened and 252 were enrolled. Between July 31, 2012, and June 26, 2017, 197 children were allocated at the start of an exacerbation (63 to the amoxicillin–clavulanate group, 67 to the azithromycin group, and 67 to the placebo group). Respiratory viruses were identified in 82 (53%) of 154 children with available nasal swabs on day 1 of treatment. Primary outcome data were available for 196 (99%) children (one child with missing data [placebo group] was recorded as non-resolved according to criteria defined a priori). By day 14, exacerbations had resolved in 41 (65%) children in the amoxicillin–clavulanate group, 41 (61%) in the azithromycin group, and 29 (43%) in the placebo group. Compared with placebo, relative risk for resolution by day 14 was 1·50 (95% CI 1·08–2·09, p=0·015; number-needed-to-treat [NNT] 5 [95% CI 3–20]) in the amoxicillin–clavulanate group and 1·41 (1·01–1·97, p=0·042; NNT 6 [3–79]) in the azithromycin group. Adverse events were recorded in 19 (30%) children in the amoxicillin–clavulanate group, 20 (30%) in the azithromycin group, and 14 (21%) in the placebo group, but no events were severe or life-threatening.

    Interpretation: Amoxicillin–clavulanate treatment is beneficial in terms of resolution of non-severe exacerbations of bronchiectasis in children, and should remain the first-line oral antibiotic in this setting. Funding: National Health and Medical Research Council (Australia), Cure Kids (New Zealand).

    Original languageEnglish
    Pages (from-to)791-801
    Number of pages11
    JournalThe Lancet Respiratory Medicine
    Volume7
    Issue number9
    DOIs
    Publication statusPublished - 1 Sep 2019

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    Azithromycin
    Bronchiectasis
    Randomized Controlled Trials
    Placebos
    New Zealand
    Numbers Needed To Treat
    Therapeutics
    Anti-Bacterial Agents
    Random Allocation
    Nose
    Cystic Fibrosis
    Caregivers
    Registries
    Biomedical Research
    Linear Models
    Suspensions

    Cite this

    Goyal, Vikas ; Grimwood, Keith ; Ware, Robert S. ; Byrnes, Catherine A. ; Morris, Peter S. ; Masters, I. Brent ; McCallum, Gabrielle B. ; Binks, Michael J. ; Smith-Vaughan, Heidi ; O'Grady, Kerry Ann F. ; Champion, Anita ; Buntain, Helen M. ; Schultz, André ; Chatfield, Mark ; Torzillo, Paul J. ; Chang, Anne B. / Efficacy of oral amoxicillin–clavulanate or azithromycin for non-severe respiratory exacerbations in children with bronchiectasis (BEST-1) : a multicentre, three-arm, double-blind, randomised placebo-controlled trial. In: The Lancet Respiratory Medicine. 2019 ; Vol. 7, No. 9. pp. 791-801.
    @article{9dd89cc0cb064e74bc74cce68072162b,
    title = "Efficacy of oral amoxicillin–clavulanate or azithromycin for non-severe respiratory exacerbations in children with bronchiectasis (BEST-1): a multicentre, three-arm, double-blind, randomised placebo-controlled trial",
    abstract = "Background: Bronchiectasis guidelines recommend antibiotics for the treatment of acute respiratory exacerbations, but randomised placebo-controlled trials in children are lacking. We hypothesised that oral amoxicillin–clavulanate and azithromycin would each be superior to placebo in achieving symptom resolution of non-severe exacerbations in children by day 14 of treatment. Methods: In this multicentre, three-arm, parallel, double-dummy, double-blind, randomised placebo-controlled trial at four paediatric centres in Australia and New Zealand, we enrolled children aged 1–18 years with CT-confirmed bronchiectasis unrelated to cystic fibrosis, who were under the care of a respiratory physician and who had had at least two respiratory exacerbations in the 18 months before study entry. Participants were allocated (1:1:1) at exacerbation onset to receive oral suspensions of amoxicillin–clavulanate (45 mg/kg per day) plus placebo azithromycin, azithromycin (5 mg/kg per day) plus placebo amoxicillin–clavulanate, or both placebos for 14 days. An independent statistician prepared a computer-generated, permuted-block (size 2–8) randomisation sequence, stratified by centre, age, and cause. Participants, caregivers, study coordinators, and investigators were masked to treatment assignment until data analysis was completed. The primary outcome was the proportion of children with exacerbation resolution by day 14 in the intention-to-treat population. Treatment groups were compared using generalised linear models. Statistical significance was set at p<0·0245 to account for multiple comparisons. This trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12612000011886) and is completed. Findings: Between April 17, 2012, and March 1, 2017, 604 children were screened and 252 were enrolled. Between July 31, 2012, and June 26, 2017, 197 children were allocated at the start of an exacerbation (63 to the amoxicillin–clavulanate group, 67 to the azithromycin group, and 67 to the placebo group). Respiratory viruses were identified in 82 (53{\%}) of 154 children with available nasal swabs on day 1 of treatment. Primary outcome data were available for 196 (99{\%}) children (one child with missing data [placebo group] was recorded as non-resolved according to criteria defined a priori). By day 14, exacerbations had resolved in 41 (65{\%}) children in the amoxicillin–clavulanate group, 41 (61{\%}) in the azithromycin group, and 29 (43{\%}) in the placebo group. Compared with placebo, relative risk for resolution by day 14 was 1·50 (95{\%} CI 1·08–2·09, p=0·015; number-needed-to-treat [NNT] 5 [95{\%} CI 3–20]) in the amoxicillin–clavulanate group and 1·41 (1·01–1·97, p=0·042; NNT 6 [3–79]) in the azithromycin group. Adverse events were recorded in 19 (30{\%}) children in the amoxicillin–clavulanate group, 20 (30{\%}) in the azithromycin group, and 14 (21{\%}) in the placebo group, but no events were severe or life-threatening. Interpretation: Amoxicillin–clavulanate treatment is beneficial in terms of resolution of non-severe exacerbations of bronchiectasis in children, and should remain the first-line oral antibiotic in this setting. Funding: National Health and Medical Research Council (Australia), Cure Kids (New Zealand).",
    author = "Vikas Goyal and Keith Grimwood and Ware, {Robert S.} and Byrnes, {Catherine A.} and Morris, {Peter S.} and Masters, {I. Brent} and McCallum, {Gabrielle B.} and Binks, {Michael J.} and Heidi Smith-Vaughan and O'Grady, {Kerry Ann F.} and Anita Champion and Buntain, {Helen M.} and Andr{\'e} Schultz and Mark Chatfield and Torzillo, {Paul J.} and Chang, {Anne B.}",
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    Efficacy of oral amoxicillin–clavulanate or azithromycin for non-severe respiratory exacerbations in children with bronchiectasis (BEST-1) : a multicentre, three-arm, double-blind, randomised placebo-controlled trial. / Goyal, Vikas; Grimwood, Keith; Ware, Robert S.; Byrnes, Catherine A.; Morris, Peter S.; Masters, I. Brent; McCallum, Gabrielle B.; Binks, Michael J.; Smith-Vaughan, Heidi; O'Grady, Kerry Ann F.; Champion, Anita; Buntain, Helen M.; Schultz, André; Chatfield, Mark; Torzillo, Paul J.; Chang, Anne B.

    In: The Lancet Respiratory Medicine, Vol. 7, No. 9, 01.09.2019, p. 791-801.

    Research output: Contribution to journalArticleResearchpeer-review

    TY - JOUR

    T1 - Efficacy of oral amoxicillin–clavulanate or azithromycin for non-severe respiratory exacerbations in children with bronchiectasis (BEST-1)

    T2 - a multicentre, three-arm, double-blind, randomised placebo-controlled trial

    AU - Goyal, Vikas

    AU - Grimwood, Keith

    AU - Ware, Robert S.

    AU - Byrnes, Catherine A.

    AU - Morris, Peter S.

    AU - Masters, I. Brent

    AU - McCallum, Gabrielle B.

    AU - Binks, Michael J.

    AU - Smith-Vaughan, Heidi

    AU - O'Grady, Kerry Ann F.

    AU - Champion, Anita

    AU - Buntain, Helen M.

    AU - Schultz, André

    AU - Chatfield, Mark

    AU - Torzillo, Paul J.

    AU - Chang, Anne B.

    PY - 2019/9/1

    Y1 - 2019/9/1

    N2 - Background: Bronchiectasis guidelines recommend antibiotics for the treatment of acute respiratory exacerbations, but randomised placebo-controlled trials in children are lacking. We hypothesised that oral amoxicillin–clavulanate and azithromycin would each be superior to placebo in achieving symptom resolution of non-severe exacerbations in children by day 14 of treatment. Methods: In this multicentre, three-arm, parallel, double-dummy, double-blind, randomised placebo-controlled trial at four paediatric centres in Australia and New Zealand, we enrolled children aged 1–18 years with CT-confirmed bronchiectasis unrelated to cystic fibrosis, who were under the care of a respiratory physician and who had had at least two respiratory exacerbations in the 18 months before study entry. Participants were allocated (1:1:1) at exacerbation onset to receive oral suspensions of amoxicillin–clavulanate (45 mg/kg per day) plus placebo azithromycin, azithromycin (5 mg/kg per day) plus placebo amoxicillin–clavulanate, or both placebos for 14 days. An independent statistician prepared a computer-generated, permuted-block (size 2–8) randomisation sequence, stratified by centre, age, and cause. Participants, caregivers, study coordinators, and investigators were masked to treatment assignment until data analysis was completed. The primary outcome was the proportion of children with exacerbation resolution by day 14 in the intention-to-treat population. Treatment groups were compared using generalised linear models. Statistical significance was set at p<0·0245 to account for multiple comparisons. This trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12612000011886) and is completed. Findings: Between April 17, 2012, and March 1, 2017, 604 children were screened and 252 were enrolled. Between July 31, 2012, and June 26, 2017, 197 children were allocated at the start of an exacerbation (63 to the amoxicillin–clavulanate group, 67 to the azithromycin group, and 67 to the placebo group). Respiratory viruses were identified in 82 (53%) of 154 children with available nasal swabs on day 1 of treatment. Primary outcome data were available for 196 (99%) children (one child with missing data [placebo group] was recorded as non-resolved according to criteria defined a priori). By day 14, exacerbations had resolved in 41 (65%) children in the amoxicillin–clavulanate group, 41 (61%) in the azithromycin group, and 29 (43%) in the placebo group. Compared with placebo, relative risk for resolution by day 14 was 1·50 (95% CI 1·08–2·09, p=0·015; number-needed-to-treat [NNT] 5 [95% CI 3–20]) in the amoxicillin–clavulanate group and 1·41 (1·01–1·97, p=0·042; NNT 6 [3–79]) in the azithromycin group. Adverse events were recorded in 19 (30%) children in the amoxicillin–clavulanate group, 20 (30%) in the azithromycin group, and 14 (21%) in the placebo group, but no events were severe or life-threatening. Interpretation: Amoxicillin–clavulanate treatment is beneficial in terms of resolution of non-severe exacerbations of bronchiectasis in children, and should remain the first-line oral antibiotic in this setting. Funding: National Health and Medical Research Council (Australia), Cure Kids (New Zealand).

    AB - Background: Bronchiectasis guidelines recommend antibiotics for the treatment of acute respiratory exacerbations, but randomised placebo-controlled trials in children are lacking. We hypothesised that oral amoxicillin–clavulanate and azithromycin would each be superior to placebo in achieving symptom resolution of non-severe exacerbations in children by day 14 of treatment. Methods: In this multicentre, three-arm, parallel, double-dummy, double-blind, randomised placebo-controlled trial at four paediatric centres in Australia and New Zealand, we enrolled children aged 1–18 years with CT-confirmed bronchiectasis unrelated to cystic fibrosis, who were under the care of a respiratory physician and who had had at least two respiratory exacerbations in the 18 months before study entry. Participants were allocated (1:1:1) at exacerbation onset to receive oral suspensions of amoxicillin–clavulanate (45 mg/kg per day) plus placebo azithromycin, azithromycin (5 mg/kg per day) plus placebo amoxicillin–clavulanate, or both placebos for 14 days. An independent statistician prepared a computer-generated, permuted-block (size 2–8) randomisation sequence, stratified by centre, age, and cause. Participants, caregivers, study coordinators, and investigators were masked to treatment assignment until data analysis was completed. The primary outcome was the proportion of children with exacerbation resolution by day 14 in the intention-to-treat population. Treatment groups were compared using generalised linear models. Statistical significance was set at p<0·0245 to account for multiple comparisons. This trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12612000011886) and is completed. Findings: Between April 17, 2012, and March 1, 2017, 604 children were screened and 252 were enrolled. Between July 31, 2012, and June 26, 2017, 197 children were allocated at the start of an exacerbation (63 to the amoxicillin–clavulanate group, 67 to the azithromycin group, and 67 to the placebo group). Respiratory viruses were identified in 82 (53%) of 154 children with available nasal swabs on day 1 of treatment. Primary outcome data were available for 196 (99%) children (one child with missing data [placebo group] was recorded as non-resolved according to criteria defined a priori). By day 14, exacerbations had resolved in 41 (65%) children in the amoxicillin–clavulanate group, 41 (61%) in the azithromycin group, and 29 (43%) in the placebo group. Compared with placebo, relative risk for resolution by day 14 was 1·50 (95% CI 1·08–2·09, p=0·015; number-needed-to-treat [NNT] 5 [95% CI 3–20]) in the amoxicillin–clavulanate group and 1·41 (1·01–1·97, p=0·042; NNT 6 [3–79]) in the azithromycin group. Adverse events were recorded in 19 (30%) children in the amoxicillin–clavulanate group, 20 (30%) in the azithromycin group, and 14 (21%) in the placebo group, but no events were severe or life-threatening. Interpretation: Amoxicillin–clavulanate treatment is beneficial in terms of resolution of non-severe exacerbations of bronchiectasis in children, and should remain the first-line oral antibiotic in this setting. Funding: National Health and Medical Research Council (Australia), Cure Kids (New Zealand).

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    DO - 10.1016/S2213-2600(19)30254-1

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    EP - 801

    JO - The Lancet Respiratory Medicine

    JF - The Lancet Respiratory Medicine

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    ER -