INTRODUCTION: Effective management of seasonal and pandemic influenza is a high priority internationally. Guidelines in many countries recommend antiviral treatment for older people and individuals with comorbidity at increased risk of complications. However, antivirals are not often prescribed in primary care in Europe, partly because its clinical and cost effectiveness has been insufficiently demonstrated by non-industry funded and pragmatic studies. METHODS AND ANALYSIS: Antivirals for influenza-Like Illness? An rCt of Clinical and Cost effectiveness in primary CarE is a European multinational, multicentre, open-labelled, non-industry funded, pragmatic, adaptive-platform, randomised controlled trial. Initial trial arms will be best usual primary care and best usual primary care plus treatment with oseltamivir for 5 days. We aim to recruit at least 2500 participants ≥1 year presenting with influenza-like illness (ILI), with symptom duration ≤72 hours in primary care over three consecutive periods of confirmed high influenza incidence. Participant outcomes will be followed up to 28 days by diary and telephone. The primary objective is to determine whether adding antiviral treatment to best usual primary care is effective in reducing time to return to usual daily activity with fever, headache and muscle ache reduced to minor severity or less. Secondary objectives include estimating cost-effectiveness, benefits in subgroups according to age (<12, 12-64 and >64 years), severity of symptoms at presentation (low, medium and high), comorbidity (yes/no), duration of symptoms (≤48 hours/>48-72 hours), complications (hospital admission and pneumonia), use of additional prescribed medication including antibiotics, use of over-the-counter medicines and self-management of ILI symptoms. ETHICS AND DISSEMINATION: Research ethics committee (REC) approval was granted by the NRES Committee South Central (Oxford B) and Clinical Trial Authority (CTA) approval by The Medicines and Healthcare products Regulatory Agency. All participating countries gained national REC and CTA approval as required. Dissemination of results will be through peer-reviewed scientific journals and conference presentations. TRIAL REGISTRATION NUMBER: ISRCTN27908921; Pre-results.

Basel Institute for Clinical Epidemiology and Biostatistics University Hospital Basel Basel Switzerland

Berry Consultants Austin Texas USA

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

Centre for Health Economics Research and Modelling Infectious Diseases 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 University of Crete Heraklion Greece

Department of Biostatistics Vanderbilt University School of Medicine Nashville Tennessee USA

Department of Family and Community Medicine Medical University of Lodz Lodz Poland

Department of Family Medicine and Community Nursing Medical University of Bialystok Bialystok Poland

Department of Family Medicine and Primary Health Care Ghent University Ghent Belgium

Department of General Practice Institute of Health and Society University of Oslo Oslo Norway

Department of General Practice Royal College of Surgeons in Ireland School of Medicine Dublin Ireland

Department of Medical Microbiology Academic Medical Center Amsterdam The Netherlands

Department of Population Medicine Cardiff University School of Medicine Cardiff UK

Department of Public Health and Community Medicine Sahlgrenska Academy at the University of Gothenburg Gothenburg Sweden

Department of Public Health University Hospital of Nice Nice France

Department of Pulmonology Hospital Clínic de Barcelona Universitat de Barcelona and IDIBAPS Barcelona Spain

Department of Teaching and Research in General Practice University of Côte d'Azur Nice France

Drug Research Centre LLC Balatonfüred Hungary

Ely Bridge Surgery Ely UK

Institute for Public Health University of Copenhagen Copenhagen Denmark

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

JSC Mano Seimos Gydytojas Klaipėda Lithuania

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

Laboratory of Medical Microbiology Vaccine and Infectious Disease Institute University of Antwerp Antwerp Belgium

Närhälsan Research and Development Primary Health Care Region Västra Götaland Research and Development Center Södra Älvsborg Borås Sweden

Primary Care and Population Science University of Southampton Southampton UK

Primary Healthcare Centre Jaume 1 Universitat Rovira i Virgili Tarragona Catalonia Spain

SERGAS Hospital Clinico Universitario de Santiago de Compostela Santiago de Compostela Spain

The Nuffield Department of Primary Care Health Sciences University of Oxford Oxford UK

University of Basel Basel Switzerland

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ISRCTN
ISRCTN27908921