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.

Antibiotic Center for Primary Care Department of General Practice Institute of Health and Society University of Oslo Oslo Norway

Basel Institute for Clinical Epidemiology and Biostatistics Department of Clinical Research University Hospital Basel and University of Basel Basel Switzerland

Berry Consultants Austin Texas; Department of Biostatistics Vanderbilt University School of Medicine Nashville Tennessee USA

Center for Family Medicine UGent Department of Public Health and Primary Care Ghent University Ghent Belgium

Centre for Family and Community Medicine Faculty of Health Sciences Medical University of Lodz Lodz Poland

Centre for General Practice Department of Primary and Interdisciplinary Care University of Antwerp Antwerp Belgium

Centre for Statistics in Medicine Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences University of Oxford Oxford UK

Clinic of Social and Family Medicine Faculty of Medicine University of Crete Crete Greece

ConfluenceStat Orlando FL USA; College of Medicine University of Central Florida Orlando FL USA

Département de Santé Publique Université Côte d'Azur Centre Hospitalier Universitaire de Nice Nice France

Department of Family Medicine Medical University of Bialystok Bialystok Poland

Department of General Practice 1st Faculty of Medicine Charles University Prague Czech Republic

Department of Medical Microbiology Amsterdam UMC University of Amsterdam Netherlands

Department of Primary Care Health Services University of Oxford Oxford UK

Drug Research Centre Balatonfüred Hungary

Harbor UCLA Medical Center Torrance CA USA; David Geffen School of Medicine at UCLA Los Angeles CA USA; Berry Consultants Austin TX USA

Health Research Board Primary Care Clinical Trial Network Ireland National University of Ireland Galway Galway Ireland

JSC Mano seimos gydytojas Klaipeda Lithuania

Julius Center for Health Sciences and Primary Care University Medical Center Utrecht Utrecht Netherlands

Laboratory of Medical Microbiology Vaccine and Infectious Disease Institute University of Antwerp Antwerp Belgium; Laboratory of Clinical Microbiology Antwerp University Hospital Edegem Belgium

National Heart and Lung Institute Imperial College London London UK

Primary Care and Population Sciences University of Southampton Southampton UK

Research and Development Primary Health Care Region Västra Götaland Institute of Medicine Sahlgrenska Academy at the University of Gothenburg Gothenburg Sweden

Section and Research Unit of General Practice Department of Public Health University of Copenhagen Copenhagen Denmark

University Institute in Primary Care Research Jordi Gol Via Roma Health Centre Barcelona Spain

Lancet. 2020 Jan 4;395(10217):4-6. doi: 10.1016/S0140-6736(19)33097-1. PubMed

Ann Intern Med. 2020 Apr 21;172(8):JC43. doi: 10.7326/ACPJ202004210-043. PubMed

J Pediatr. 2020 May;220:264-267. doi: 10.1016/j.jpeds.2020.02.064. PubMed

References provided by Crossref.org

Cost-effectiveness of adding oseltamivir to primary care for influenza-like-illness: economic evaluation alongside the randomised controlled ALIC4E trial in 15 European countries

Clinical presentation, microbiological aetiology and disease course in patients with flu-like illness: a post hoc analysis of randomised controlled trial data

Direct and Indirect Costs of Influenza-Like Illness Treated with and Without Oseltamivir in 15 European Countries: A Descriptive Analysis Alongside the Randomised Controlled ALIC4E Trial