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

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

doi:10.1016/S0140-6736(19)32982-4

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

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

19 Citations (Scopus)

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.

Original language	English
Journal	Lancet Oncology
ISSN	1470-2045
DOIs	https://doi.org/10.1016/S0140-6736(19)32982-4
Publication status	Published - 4 Jan 2020

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Butler, C. C., van der Velden, A. W., Bongard, E., Saville, B. R., Holmes, J., Coenen, S., Cook, J., Francis, N. A., Lewis, R. J., Godycki-Cwirko, M., Llor, C., Chlabicz, S., Lionis, C., Seifert, B., Sundvall, P-D., Colliers, A., Aabenhus, R., Bjerrum, L., Jonassen Harbin, N., ... Verheij, T. J. (2020). Oseltamivir plus usual care versus usual care for influenza-like illness in primary care: an open-label, pragmatic, randomised controlled trial. Lancet Oncology. https://doi.org/10.1016/S0140-6736(19)32982-4

Butler, CC, van der Velden, AW, Bongard, E, Saville, BR, Holmes, J, Coenen, S, Cook, J, Francis, NA, Lewis, RJ, Godycki-Cwirko, M, Llor, C, Chlabicz, S, Lionis, C, Seifert, B, Sundvall, P-D, Colliers, A, Aabenhus, R , Bjerrum, L, Jonassen Harbin, N, Lindbæk, M, Glinz, D, Bucher, HC, Kovács, B, Radzeviciene Jurgute, R, Touboul Lundgren, P, Little, P, Murphy, AW, De Sutter, A, Openshaw, P, de Jong, MD, Connor, JT, Matheeussen, V, Ieven, M, Goossens, H & Verheij, TJ 2020, 'Oseltamivir plus usual care versus usual care for influenza-like illness in primary care: an open-label, pragmatic, randomised controlled trial', Lancet Oncology. https://doi.org/10.1016/S0140-6736(19)32982-4

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

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.",

author = "Butler, {Christopher C} and {van der Velden}, {Alike W} and Emily Bongard and Saville, {Benjamin R} and Jane Holmes and Samuel Coenen and Johanna Cook and Francis, {Nick A} and Lewis, {Roger J} and Maciek Godycki-Cwirko and Carl Llor and S{\l}awomir Chlabicz and Christos Lionis and Bohumil Seifert and P{\"a}r-Daniel Sundvall and Annelies Colliers and Rune Aabenhus and Lars Bjerrum and {Jonassen Harbin}, Nicolay and Morten Lindb{\ae}k and Dominik Glinz and Bucher, {Heiner C} and Bernadett Kov{\'a}cs and {Radzeviciene Jurgute}, Ruta and {Touboul Lundgren}, Pia and Paul Little and Murphy, {Andrew W} and {De Sutter}, An and Peter Openshaw and {de Jong}, {Menno D} and Connor, {Jason T} and Veerle Matheeussen and Margareta Ieven and Herman Goossens and Verheij, {Theo J}",

year = "2020",

month = jan,

day = "4",

doi = "10.1016/S0140-6736(19)32982-4",

language = "English",

journal = "The Lancet Oncology",

issn = "1470-2045",

publisher = "TheLancet Publishing Group",

}

TY - JOUR

T1 - Oseltamivir plus usual care versus usual care for influenza-like illness in primary care

T2 - an open-label, pragmatic, randomised controlled trial

AU - Butler, Christopher C

AU - van der Velden, Alike W

AU - Bongard, Emily

AU - Saville, Benjamin R

AU - Holmes, Jane

AU - Coenen, Samuel

AU - Cook, Johanna

AU - Francis, Nick A

AU - Lewis, Roger J

AU - Godycki-Cwirko, Maciek

AU - Llor, Carl

AU - Chlabicz, Sławomir

AU - Lionis, Christos

AU - Seifert, Bohumil

AU - Sundvall, Pär-Daniel

AU - Colliers, Annelies

AU - Aabenhus, Rune

AU - Bjerrum, Lars

AU - Jonassen Harbin, Nicolay

AU - Lindbæk, Morten

AU - Glinz, Dominik

AU - Bucher, Heiner C

AU - Kovács, Bernadett

AU - Radzeviciene Jurgute, Ruta

AU - Touboul Lundgren, Pia

AU - Little, Paul

AU - Murphy, Andrew W

AU - De Sutter, An

AU - Openshaw, Peter

AU - de Jong, Menno D

AU - Connor, Jason T

AU - Matheeussen, Veerle

AU - Ieven, Margareta

AU - Goossens, Herman

AU - Verheij, Theo J

PY - 2020/1/4

Y1 - 2020/1/4

N2 - 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.

AB - 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.

U2 - 10.1016/S0140-6736(19)32982-4

DO - 10.1016/S0140-6736(19)32982-4

M3 - Journal article

C2 - 31839279

SN - 1470-2045

JO - The Lancet Oncology

JF - The Lancet Oncology

ER -

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

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