Amoxicillin–clavulanate versus azithromycin for respiratory exacerbations in children with bronchiectasis (BEST-2): a multicentre, double-blind, non-inferiority, randomised controlled trial

Goyal, Vikas; Grimwood, Keith; Byrnes, Catherine A.; Morris, Peter S.; Masters, Ian Brent; Ware, Robert S.; McCallum, Gabrielle B.; Binks, Michael J.; Marchant, Julie M.; Asperen, Peter Van; O'Grady, Kerry‐Ann F; Champion, Anita; Buntain, Helen; Petsky, Helen; Torzillo, Paul J.; Chang, Anne B.

doi:10.1016/s0140-6736(18)31723-9

Cited by 57 publications

(77 citation statements)

References 31 publications

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“…18 Exacerbations, including their resolution or failure to respond to the study medication, were predefined as per our previous study 19 and RCT. 11 The baseline state for each child was ascertained at enrolment with use of a validated cough diary card 18 and clinical examination. A nonsevere exacerbation was defined as an increase in cough frequency, a change in character of the cough (ie, from dry to wet, or an increase in sputum volume or purulence) for at least 3 consecutive days and without any accompanying dyspnoea, hypoxia (oxygen saturation <90% in air), or need for hospitalisation, according to the treating clinician.…”

Section: Methodsmentioning

confidence: 99%

“…A nonsevere exacerbation was defined as an increase in cough frequency, a change in character of the cough (ie, from dry to wet, or an increase in sputum volume or purulence) for at least 3 consecutive days and without any accompanying dyspnoea, hypoxia (oxygen saturation <90% in air), or need for hospitalisation, according to the treating clinician. 11 An exacerbation was considered resolved when a cough score had returned to baseline for at least 2 consecutive days after randomisation and commencement of study medications, and when any other new symptoms associated with the episode (such as fever, See Online for appendix lethargy, or general malaise) had resolved. An exacerbation was considered resolved even if the child exited the study protocol for any reason after resolution.…”

Section: Methodsmentioning

confidence: 99%

“…10 Our previous RCT showed that, after 21 days of treatment, oral azithromycin was noninferior (within a 20% margin) to amoxicillinclavulanate for managing nonsevere (nonhospitalised) exacerbations in children with bronchiectasis. 11 However, those receiving azithromycin took significantly longer (median difference 4 days) to achieve symptom resolution. Although azithromycin is noninferior to amoxicillin-clavulanate, no superiority RCTs comparing either of these antibiotics to placebo have been done to address the important clinical question of whether oral antibiotics are necessary to treat all nonsevere acute exacerbations of bronchiectasis.…”

Section: Introductionmentioning

confidence: 99%

“…12 In children, almost half of acute exacerbations are associated with viruses. 11,13 As antimicrobial resistance is of increasing global concern, it is important to determine the efficacy of antibiotics for treating exacerbations. 14 Thus, in the absence of any published randomised placebocontrolled trials of oral antibiotics in either children or adults with an acute exacerbation of bronchiectasis, we aimed to test whether two commonly used but different classes of oral antibiotics, namely amoxicillin-clavulanate and azithromycin, were superior to placebo in achieving resolution of nonsevere exacerbations by day 14 of treatment.…”

Section: Introductionmentioning

confidence: 99%

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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

Grimwood

Ware

et al. 2019

The Lancet Respiratory Medicine

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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 CTconfirmed 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 amoxicillinclavulanate 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 bronchiec...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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

Grimwood

Ware

et al. 2019

The Lancet Respiratory Medicine

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“…BEST‐1, the first placebo‐controlled RCT for exacerbations, showed the efficacy of amoxicillin‐clavulanate and azithromycin over placebo (relative risk of bronchiectasis resolution by day 14 was 1.50 (95% CI: 1.08–2.09; P = 0.015) and 1.41 (95% CI: 1.01–1.97; P = 0.042), respectively) . BEST‐2 described that although azithromycin was non‐inferior (within a 20% margin) to amoxicillin‐clavulanate for resolving exacerbations in children with non‐severe bronchiectasis, children on azithromycin had a longer exacerbation duration and increased risk of inducing macrolide resistance . Data over the last decade have shown that bronchiectasis exacerbations can be successfully reduced by 40–50% (using long‐term oral azithromycin for 6–26 months in children and adults) by using inhaled fluoroquinolones (rate ratio = 0.74, 95% CI: 0.62–0.87) …”

Section: Disclosure Statementmentioning

confidence: 99%

Twenty‐five years of Respirology: Advances in bronchiectasis

Chotirmall

Chang

2019

Respirology

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A fiducial approach for testing the non‐inferiority of proportion difference in matched‐pairs design

Wan

et al. 2023

Pharmaceutical Statistics

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The non‐inferiority of one treatment/drug to another is a common and important issue in medical and pharmaceutical fields. This study explored a fiducial approach for testing the non‐inferiority of proportion difference in matched‐pairs design. Approximate tests constructed using fiducial quantities with a combination of different parameters were proposed. Four simulation studies were employed to compare the performance of fiducial tests by comparing their type I errors and powers. The results showed that fiducial quantities with parameter 0.6≤w1≤0.8 performed satisfactorily from small to large samples. Therefore, the fiducial tests could be recommended for practical applications. The recommended fiducial tests might be a competitive alternative to other available tests. Three real data sets were analyzed to illustrate the proposed methods were competitive or even better than other tests.

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Amoxicillin–clavulanate versus azithromycin for respiratory exacerbations in children with bronchiectasis (BEST-2): a multicentre, double-blind, non-inferiority, randomised controlled trial

Abstract: Australian National Health and Medical Research Council.

Cited by 57 publications

References 31 publications

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

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

Twenty‐five years of Respirology: Advances in bronchiectasis

A fiducial approach for testing the non‐inferiority of proportion difference in matched‐pairs design

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