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Oseltamivir plus usual care versus usual care for influenza-like illness in primary care: an open-label, pragmatic, randomised controlled trial

Oseltamivir plus usual care versus usual care for influenza-like illness in primary care: an open-label, pragmatic, randomised controlled trial
Oseltamivir plus usual care versus usual care for influenza-like illness in primary care: an open-label, pragmatic, randomised controlled trial

Background: Antivirals are infrequently prescribed in European primary care for influenza-like illness, mostly because of perceived ineffectiveness in real world primary care and because individuals who will especially benefit have not been identified in independent trials. We aimed to determine whether adding antiviral treatment to usual primary care for patients with influenza-like illness reduces time to recovery overall and in key subgroups. Methods: We did an open-label, pragmatic, adaptive, randomised controlled trial of adding oseltamivir to usual care in patients aged 1 year and older presenting with influenza-like illness in primary care. The primary endpoint was time to recovery, defined as return to usual activities, with fever, headache, and muscle ache minor or absent. The trial was designed and powered to assess oseltamivir benefit overall and in 36 prespecified subgroups defined by age, comorbidity, previous symptom duration, and symptom severity, using a Bayesian piece-wise exponential primary analysis model. The trial is registered with the ISRCTN Registry, number ISRCTN 27908921. Findings: Between Jan 15, 2016, and April 12, 2018, we recruited 3266 participants in 15 European countries during three seasonal influenza seasons, allocated 1629 to usual care plus oseltamivir and 1637 to usual care, and ascertained the primary outcome in 1533 (94%) and 1526 (93%). 1590 (52%) of 3059 participants had PCR-confirmed influenza infection. Time to recovery was shorter in participants randomly assigned to oseltamivir (hazard ratio 1·29, 95% Bayesian credible interval [BCrI] 1·20–1·39) overall and in 30 of the 36 prespecified subgroups, with estimated hazard ratios ranging from 1·13 to 1·72. The estimated absolute mean benefit from oseltamivir was 1·02 days (95% [BCrI] 0·74–1·31) overall, and in the prespecified subgroups, ranged from 0·70 (95% BCrI 0·30–1·20) in patients younger than 12 years, with less severe symptoms, no comorbidities, and shorter previous illness duration to 3·20 (95% BCrI 1·00–5·50) in patients aged 65 years or older who had more severe illness, comorbidities, and longer previous illness duration. Regarding harms, an increased burden of vomiting or nausea was observed in the oseltamivir group. Interpretation: Primary care patients with influenza-like illness treated with oseltamivir recovered one day sooner on average than those managed by usual care alone. Older, sicker patients with comorbidities and longer previous symptom duration recovered 2–3 days sooner. Funding: European Commission's Seventh Framework Programme.

Adolescent, Adult, Aged, Antiviral Agents/administration & dosage, Child, Child, Preschool, Combined Modality Therapy, Europe, Female, Humans, Infant, Influenza, Human/therapy, Male, Middle Aged, Oseltamivir/administration & dosage, Primary Health Care/methods, Severity of Illness Index, Time Factors, Treatment Outcome, Young Adult
0140-6736
42-52
Butler, Christopher C.
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van der Velden, Alike W.
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Bongard, Emily
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Saville, Benjamin R.
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Holmes, Jane
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Coenen, Samuel
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Cook, Johanna
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Francis, Nick A.
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Lewis, Roger J.
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Godycki-Cwirko, Maciek
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Llor, Carl
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Chlabicz, Sławomir
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Lionis, Christos
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Seifert, Bohumil
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Sundvall, Pär Daniel
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Colliers, Annelies
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Aabenhus, Rune
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Bjerrum, Lars
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Jonassen Harbin, Nicolay
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Lindbæk, Morten
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Glinz, Dominik
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Bucher, Heiner C.
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Kovács, Bernadett
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Radzeviciene Jurgute, Ruta
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Touboul Lundgren, Pia
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Little, Paul
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Murphy, Andrew W.
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De Sutter, An
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Openshaw, Peter
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de Jong, Menno D.
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Connor, Jason T.
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Matheeussen, Veerle
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Ieven, Margareta
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Goossens, Herman
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Verheij, Theo J.
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Butler, Christopher C.
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van der Velden, Alike W.
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Bongard, Emily
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Saville, Benjamin R.
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Holmes, Jane
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Coenen, Samuel
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Cook, Johanna
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Francis, Nick A.
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Lewis, Roger J.
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Godycki-Cwirko, Maciek
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Llor, Carl
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Chlabicz, Sławomir
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Lionis, Christos
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Seifert, Bohumil
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Sundvall, Pär Daniel
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Colliers, Annelies
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Aabenhus, Rune
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Bjerrum, Lars
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Jonassen Harbin, Nicolay
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Lindbæk, Morten
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Glinz, Dominik
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Bucher, Heiner C.
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Kovács, Bernadett
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Radzeviciene Jurgute, Ruta
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Touboul Lundgren, Pia
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Little, Paul
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Murphy, Andrew W.
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De Sutter, An
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Openshaw, Peter
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de Jong, Menno D.
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Connor, Jason T.
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Matheeussen, Veerle
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Ieven, Margareta
c138048d-d838-4c8e-848d-a43e309f4cf0
Goossens, Herman
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Verheij, Theo J.
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Butler, Christopher C., van der Velden, Alike W., Bongard, Emily, Saville, Benjamin R., Holmes, Jane, Coenen, Samuel, Cook, Johanna, Francis, Nick A., Lewis, Roger J., Godycki-Cwirko, Maciek, Llor, Carl, Chlabicz, Sławomir, Lionis, Christos, Seifert, Bohumil, Sundvall, Pär Daniel, Colliers, Annelies, Aabenhus, Rune, Bjerrum, Lars, Jonassen Harbin, Nicolay, Lindbæk, Morten, Glinz, Dominik, Bucher, Heiner C., Kovács, Bernadett, Radzeviciene Jurgute, Ruta, Touboul Lundgren, Pia, Little, Paul, Murphy, Andrew W., De Sutter, An, Openshaw, Peter, de Jong, Menno D., Connor, Jason T., Matheeussen, Veerle, Ieven, Margareta, Goossens, Herman and Verheij, Theo J. (2020) Oseltamivir plus usual care versus usual care for influenza-like illness in primary care: an open-label, pragmatic, randomised controlled trial. The Lancet, 395 (10217), 42-52. (doi:10.1016/S0140-6736(19)32982-4).

Record type: Article

Abstract

Background: Antivirals are infrequently prescribed in European primary care for influenza-like illness, mostly because of perceived ineffectiveness in real world primary care and because individuals who will especially benefit have not been identified in independent trials. We aimed to determine whether adding antiviral treatment to usual primary care for patients with influenza-like illness reduces time to recovery overall and in key subgroups. Methods: We did an open-label, pragmatic, adaptive, randomised controlled trial of adding oseltamivir to usual care in patients aged 1 year and older presenting with influenza-like illness in primary care. The primary endpoint was time to recovery, defined as return to usual activities, with fever, headache, and muscle ache minor or absent. The trial was designed and powered to assess oseltamivir benefit overall and in 36 prespecified subgroups defined by age, comorbidity, previous symptom duration, and symptom severity, using a Bayesian piece-wise exponential primary analysis model. The trial is registered with the ISRCTN Registry, number ISRCTN 27908921. Findings: Between Jan 15, 2016, and April 12, 2018, we recruited 3266 participants in 15 European countries during three seasonal influenza seasons, allocated 1629 to usual care plus oseltamivir and 1637 to usual care, and ascertained the primary outcome in 1533 (94%) and 1526 (93%). 1590 (52%) of 3059 participants had PCR-confirmed influenza infection. Time to recovery was shorter in participants randomly assigned to oseltamivir (hazard ratio 1·29, 95% Bayesian credible interval [BCrI] 1·20–1·39) overall and in 30 of the 36 prespecified subgroups, with estimated hazard ratios ranging from 1·13 to 1·72. The estimated absolute mean benefit from oseltamivir was 1·02 days (95% [BCrI] 0·74–1·31) overall, and in the prespecified subgroups, ranged from 0·70 (95% BCrI 0·30–1·20) in patients younger than 12 years, with less severe symptoms, no comorbidities, and shorter previous illness duration to 3·20 (95% BCrI 1·00–5·50) in patients aged 65 years or older who had more severe illness, comorbidities, and longer previous illness duration. Regarding harms, an increased burden of vomiting or nausea was observed in the oseltamivir group. Interpretation: Primary care patients with influenza-like illness treated with oseltamivir recovered one day sooner on average than those managed by usual care alone. Older, sicker patients with comorbidities and longer previous symptom duration recovered 2–3 days sooner. Funding: European Commission's Seventh Framework Programme.

Text
05.11.2019 THELANCET-D-19-05658 R3 Clean - Accepted Manuscript
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Accepted/In Press date: 1 January 2019
e-pub ahead of print date: 12 December 2019
Published date: 4 January 2020
Keywords: Adolescent, Adult, Aged, Antiviral Agents/administration & dosage, Child, Child, Preschool, Combined Modality Therapy, Europe, Female, Humans, Infant, Influenza, Human/therapy, Male, Middle Aged, Oseltamivir/administration & dosage, Primary Health Care/methods, Severity of Illness Index, Time Factors, Treatment Outcome, Young Adult

Identifiers

Local EPrints ID: 437317
URI: http://eprints.soton.ac.uk/id/eprint/437317
ISSN: 0140-6736
PURE UUID: c1499fff-fbe2-4b03-9247-cb8ba3674ceb
ORCID for Nick A. Francis: ORCID iD orcid.org/0000-0001-8939-7312

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Date deposited: 24 Jan 2020 17:31
Last modified: 03 Sep 2022 04:09

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Contributors

Author: Christopher C. Butler
Author: Alike W. van der Velden
Author: Emily Bongard
Author: Benjamin R. Saville
Author: Jane Holmes
Author: Samuel Coenen
Author: Johanna Cook
Author: Nick A. Francis ORCID iD
Author: Roger J. Lewis
Author: Maciek Godycki-Cwirko
Author: Carl Llor
Author: Sławomir Chlabicz
Author: Christos Lionis
Author: Bohumil Seifert
Author: Pär Daniel Sundvall
Author: Annelies Colliers
Author: Rune Aabenhus
Author: Lars Bjerrum
Author: Nicolay Jonassen Harbin
Author: Morten Lindbæk
Author: Dominik Glinz
Author: Heiner C. Bucher
Author: Bernadett Kovács
Author: Ruta Radzeviciene Jurgute
Author: Pia Touboul Lundgren
Author: Paul Little
Author: Andrew W. Murphy
Author: An De Sutter
Author: Peter Openshaw
Author: Menno D. de Jong
Author: Jason T. Connor
Author: Veerle Matheeussen
Author: Margareta Ieven
Author: Herman Goossens
Author: Theo J. Verheij

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