The early use of Antibiotics for at Risk CHildren with InfluEnza-like illness (ARCHIE): a double-blind randomised placebo-controlled trial
The early use of Antibiotics for at Risk CHildren with InfluEnza-like illness (ARCHIE): a double-blind randomised placebo-controlled trial
Introduction The UK government stockpiles co-amoxiclav to treat bacterial complications during influenza pandemics. This pragmatic trial examines whether early co-amoxiclav use reduces reconsultation due to clinical deterioration in "at risk"children presenting with influenza-like illness (ILI) in primary or ambulatory care. Methods "At risk"children aged from 6 months to 12 years presenting within 5 days of ILI onset were randomly assigned to oral co-amoxiclav 400/57 or a placebo twice daily for 5 days (dosing based on age±weight). "At risk"groups included children with respiratory, cardiac and neurological conditions. Randomisation was stratified by region and used a non-deterministic minimisation algorithm to balance age and current seasonal influenza vaccination status. Our target sample size was 650 children which would have allowed us to detect a reduction in the proportion of children reconsulting due to clinical deterioration from 40% to 26%, with 90% power and 5% two-tailed alpha error (including allowance for 25% loss to follow-up and an inflation factor of 1.041). Participants, caregivers and investigators were blinded to treatment allocation. Intention-to-treat analysis included all randomised participants with primary outcome data on reconsultation due to clinical deterioration within 28 days. Safety analysis included all randomised participants. Trial registration: ISRCTN 70714783. EudraCT 2013-002822-21. Results We recruited 271 children between February 11, 2015 and April 20, 2018. Primary outcome data were available for 265 children. Only 61 out of 265 children (23.0%) reconsulted due to clinical deterioration. No evidence of a treatment effect was observed for reconsultation due to clinical deterioration (33 out of 133 for co-amoxiclav (24.8%) and 28 out of 132 (21.2%) for placebo; adjusted risk ratio (RR) 1.16, 95% confidence interval (CI) 0.75-1.80). There was also no evidence of a difference between groups in the proportion of children for whom one or more adverse events (AEs) were reported (32 out of 136 (23.5%) for co-amoxiclav and 22 out of 135 (16.3%) for placebo; adjusted RR 1.45, 95% CI 0.90-2.34). In total, 66 AEs were reported (co-amoxiclav, n=37; placebo, n=29). Nine serious AEs were reported per group, although none were considered related to study medication. Conclusion Our trial did not find evidence that treatment with co-amoxiclav reduces risk of reconsultation due to clinical deterioration in "at risk"children who present early with ILI during influenza season. Our findings therefore do not support early co-amoxiclav use in children with seasonal ILI.
Little, Paul
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Moore, Michael
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Wang, Kay
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Hay, Alistair D.
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Butler, Christopher C.
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1 October 2021
Little, Paul
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Moore, Michael
1be81dad-7120-45f0-bbed-f3b0cc0cfe99
Wang, Kay
d5db72ee-6755-4f79-b8ce-d04e47167927
Hay, Alistair D.
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Butler, Christopher C.
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Little, Paul, Moore, Michael, Wang, Kay, Hay, Alistair D. and Butler, Christopher C.
(2021)
The early use of Antibiotics for at Risk CHildren with InfluEnza-like illness (ARCHIE): a double-blind randomised placebo-controlled trial.
European Respiratory Journal, 58 (4), [2002819].
(doi:10.1183/13993003.02819-2020).
Abstract
Introduction The UK government stockpiles co-amoxiclav to treat bacterial complications during influenza pandemics. This pragmatic trial examines whether early co-amoxiclav use reduces reconsultation due to clinical deterioration in "at risk"children presenting with influenza-like illness (ILI) in primary or ambulatory care. Methods "At risk"children aged from 6 months to 12 years presenting within 5 days of ILI onset were randomly assigned to oral co-amoxiclav 400/57 or a placebo twice daily for 5 days (dosing based on age±weight). "At risk"groups included children with respiratory, cardiac and neurological conditions. Randomisation was stratified by region and used a non-deterministic minimisation algorithm to balance age and current seasonal influenza vaccination status. Our target sample size was 650 children which would have allowed us to detect a reduction in the proportion of children reconsulting due to clinical deterioration from 40% to 26%, with 90% power and 5% two-tailed alpha error (including allowance for 25% loss to follow-up and an inflation factor of 1.041). Participants, caregivers and investigators were blinded to treatment allocation. Intention-to-treat analysis included all randomised participants with primary outcome data on reconsultation due to clinical deterioration within 28 days. Safety analysis included all randomised participants. Trial registration: ISRCTN 70714783. EudraCT 2013-002822-21. Results We recruited 271 children between February 11, 2015 and April 20, 2018. Primary outcome data were available for 265 children. Only 61 out of 265 children (23.0%) reconsulted due to clinical deterioration. No evidence of a treatment effect was observed for reconsultation due to clinical deterioration (33 out of 133 for co-amoxiclav (24.8%) and 28 out of 132 (21.2%) for placebo; adjusted risk ratio (RR) 1.16, 95% confidence interval (CI) 0.75-1.80). There was also no evidence of a difference between groups in the proportion of children for whom one or more adverse events (AEs) were reported (32 out of 136 (23.5%) for co-amoxiclav and 22 out of 135 (16.3%) for placebo; adjusted RR 1.45, 95% CI 0.90-2.34). In total, 66 AEs were reported (co-amoxiclav, n=37; placebo, n=29). Nine serious AEs were reported per group, although none were considered related to study medication. Conclusion Our trial did not find evidence that treatment with co-amoxiclav reduces risk of reconsultation due to clinical deterioration in "at risk"children who present early with ILI during influenza season. Our findings therefore do not support early co-amoxiclav use in children with seasonal ILI.
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ARCHIE MS v0.13 clean copy for ERJ
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Accepted/In Press date: 18 February 2021
e-pub ahead of print date: 18 March 2021
Published date: 1 October 2021
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Funding Information:
Conflict of interest: K. Wang held a National Institute for Health Research (NIHR) Academic Clinical Lectureship during the conduct of the study and currently holds a NIHR Postdoctoral Fellowship. M.G. Semple reports grants from the UK NIHR Health Protection Research Unit in Emerging and Zoonotic Infections at the University of Liverpool and the Wellcome Trust Enhancing Research Activity in Epidemic Situations (ERAES) Programme during the conduct of the study, and grants from the Wellcome Trust and the Bill & Melinda Gates Foundation, as well as grants from UK NIHR Efficacy and Mechanism Evaluation, outside the submitted work; and is a minority owner of Integrum Scientific LLC, Greensboro, NC, USA, outside the submitted work. M. Moore has nothing to disclose. A.D. Hay has nothing to disclose. S. Tonner has nothing to disclose. U. Galal has nothing to disclose. J. Grabey has nothing to disclose. T. Carver has nothing to disclose. R. Perera receives funding from the NIHR Oxford Biomedical Research Centre (BRC), the NIHR Oxford Medtech and In-Vitro Diagnostics Cooperative (MIC), the NIHR Applied Research Collaboration (ARC) Oxford and Thames Valley, and the Oxford Martin School. L-M. Yu has nothing to disclose. J. Mollison has nothing to disclose. P. Little has nothing to disclose. A. Farmer receives funding from the NIHR Oxford BRC and is a NIHR Senior Investigator. C.C. Butler reports grants from the NIHR as an NIHR Senior Investigator and the NIHR Health Technology Assessment Programme to support the study, as well as grants from the NIHR Health Protection Research Unit on Health Care Associated Infections and Antimicrobial Resistance and grants from NIHR Health for the MIC for innovative diagnostics and monitoring technology to enhance community healthcare, during the conduct of the study; personal fees for advisory board work from Roche Molecular Systems and Pfizer, and grants from Roche Molecular Diagnostics, outside the submitted work. Afinion CRP devices and associated training to participating general practices were provided at no cost to the study by Alere and was part of a publicly funded research consortia that include industrial partners. A. Harnden has nothing to disclose.
Funding Information:
Support statement: This project is funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research Programme (project reference RP-PG-1210-12012). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. The funder of the study had no role in the design and conduct of the study; the collection, management, analysis and interpretation of the data; the preparation, review and approval of the manuscript; or the decision to submit the manuscript for publication. K. Wang and U. Galal had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Funding information for this article has been deposited with the Crossref Funder Registry.
Publisher Copyright:
© The authors 2021.
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Local EPrints ID: 447566
URI: http://eprints.soton.ac.uk/id/eprint/447566
ISSN: 0903-1936
PURE UUID: 0c362408-2b3b-4c3b-ab54-e22d68478187
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Date deposited: 16 Mar 2021 17:32
Last modified: 17 Mar 2024 06:24
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Kay Wang
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Alistair D. Hay
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Christopher C. Butler
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