Christopher C Butler1, Alike W van der Velden2, Emily Bongard3, Benjamin R Saville4, Jane Holmes5, Samuel Coenen6, Johanna Cook3, Nick A Francis7, Roger J Lewis8, Maciek Godycki-Cwirko9, Carl Llor10, Sławomir Chlabicz11, Christos Lionis12, Bohumil Seifert13, Pär-Daniel Sundvall14, Annelies Colliers6, Rune Aabenhus15, Lars Bjerrum15, Nicolay Jonassen Harbin16, Morten Lindbæk16, Dominik Glinz17, Heiner C Bucher17, Bernadett Kovács18, Ruta Radzeviciene Jurgute19, Pia Touboul Lundgren20, Paul Little7, Andrew W Murphy21, An De Sutter22, Peter Openshaw23, Menno D de Jong24, Jason T Connor25, Veerle Matheeussen26, Margareta Ieven26, Herman Goossens26, Theo J Verheij2. 1. Department of Primary Care Health Services, University of Oxford, Oxford, UK. Electronic address: christopher.butler@phc.ox.ac.uk. 2. Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands. 3. Department of Primary Care Health Services, University of Oxford, Oxford, UK. 4. Berry Consultants, Austin, Texas; Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA. 5. Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK. 6. Centre for General Practice, Department of Primary and Interdisciplinary Care, University of Antwerp, Antwerp, Belgium. 7. Primary Care and Population Sciences, University of Southampton, Southampton, UK. 8. Harbor-UCLA Medical Center, Torrance, CA, USA; David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Berry Consultants, Austin, TX, USA. 9. Centre for Family and Community Medicine, Faculty of Health Sciences, Medical University of Lodz, Lodz, Poland. 10. University Institute in Primary Care Research Jordi Gol, Via Roma Health Centre, Barcelona, Spain. 11. Department of Family Medicine, Medical University of Bialystok, Bialystok, Poland. 12. Clinic of Social and Family Medicine, Faculty of Medicine, University of Crete, Crete, Greece. 13. Department of General Practice, First Faculty of Medicine, Charles University, Prague, Czech Republic. 14. Research and Development Primary Health Care-Region Västra Götaland, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden. 15. Section and Research Unit of General Practice, Department of Public Health, University of Copenhagen, Copenhagen, Denmark. 16. Antibiotic Center for Primary Care, Department of General Practice, Institute of Health and Society, University of Oslo, Oslo, Norway. 17. Basel Institute for Clinical Epidemiology and Biostatistics, Department of Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland. 18. Drug Research Centre, Balatonfüred, Hungary. 19. JSC Mano seimos gydytojas (My family doctor), Klaipeda, Lithuania. 20. Département de Santé Publique, Université Côte d'Azur, Centre Hospitalier Universitaire de Nice, Nice, France. 21. Health Research Board Primary Care Clinical Trial Network Ireland, National University of Ireland Galway, Galway, Ireland. 22. Center for Family Medicine UGent, Department of Public Health and Primary Care, Ghent University, Ghent, Belgium. 23. National Heart and Lung Institute, Imperial College London, London, UK. 24. Department of Medical Microbiology, Amsterdam UMC, University of Amsterdam, Netherlands. 25. ConfluenceStat, Orlando, FL, USA; College of Medicine, University of Central Florida, Orlando, FL, USA. 26. Laboratory of Medical Microbiology, Vaccine & Infectious Disease Institute, University of Antwerp, Antwerp, Belgium; Laboratory of Clinical Microbiology, Antwerp University Hospital, Edegem, Belgium.
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 previoussymptom duration recovered 2-3 days sooner. FUNDING: European Commission's Seventh Framework Programme.
RCT Entities:
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.
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