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Antivirals for influenza-Like Illness? A randomised Controlled trial of Clinical and Cost effectiveness in primary CarE (ALIC4 E): the ALIC4 E protocol
  1. Emily Bongard1,
  2. Alike W van der Velden2,
  3. Johanna Cook1,
  4. Ben Saville3,4,
  5. Philippe Beutels5,
  6. Rune Munck Aabenhus6,
  7. Curt Brugman2,
  8. Slawomir Chlabicz7,
  9. Samuel Coenen8,9,
  10. Annelies Colliers8,
  11. Melanie Davies10,
  12. Muireann De Paor11,
  13. An De Sutter12,
  14. Nick A Francis13,
  15. Dominik Glinz14,15,
  16. Maciek Godycki-ćwirko16,
  17. Herman Goossens9,
  18. Jane Holmes17,
  19. Margareta Ieven9,
  20. Menno de Jong18,
  21. Morten Lindbaek19,
  22. Paul Little20,
  23. Frederico Martinón-Torres21,
  24. Ana Moragas22,
  25. József Pauer23,
  26. Markéta Pfeiferová24,
  27. Ruta Radzeviciene-Jurgute25,
  28. Pär-Daniel Sundvall26,27,
  29. Antoni Torres28,
  30. Pia Touboul29,30,
  31. Dionyssios Varthalis31,
  32. Theo Verheij2,
  33. Christopher C Butler1
  1. 1 The Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK
  2. 2 Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
  3. 3 Berry Consultants, Austin, Texas, USA
  4. 4 Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
  5. 5 Centre for Health Economics Research and Modelling Infectious Diseases (CHERMID), Vaccine and Infectious Disease Institute (VAXINFECTIO), University of Antwerp, Antwerp, Belgium
  6. 6 Institute for Public Health, University of Copenhagen, Copenhagen, Denmark
  7. 7 Department of Family Medicine and Community Nursing, Medical University of Bialystok, Bialystok, Poland
  8. 8 Centre for General Practice, Department of Primary and Interdisciplinary Care (ELIZA), University of Antwerp, Antwerp, Belgium
  9. 9 Laboratory of Medical Microbiology, Vaccine and Infectious Disease Institute (VAXINFECTIO), University of Antwerp, Antwerp, Belgium
  10. 10 Ely Bridge Surgery, Ely, UK
  11. 11 Department of General Practice, Royal College of Surgeons in Ireland School of Medicine, Dublin, Ireland
  12. 12 Department of Family Medicine and Primary Health Care, Ghent University, Ghent, Belgium
  13. 13 Department of Population Medicine, Cardiff University School of Medicine, Cardiff, UK
  14. 14 University of Basel, Basel, Switzerland
  15. 15 Basel Institute for Clinical Epidemiology and Biostatistics, University Hospital Basel, Basel, Switzerland
  16. 16 Department of Family and Community Medicine, Medical University of Lodz, Lodz, Poland
  17. 17 Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
  18. 18 Department of Medical Microbiology, Academic Medical Center, Amsterdam, The Netherlands
  19. 19 Department of General Practice, Institute of Health and Society, University of Oslo, Oslo, Norway
  20. 20 Primary Care and Population Science, University of Southampton, Southampton, UK
  21. 21 SERGAS, Hospital Clinico Universitario de Santiago de Compostela, Santiago de Compostela, Spain
  22. 22 Primary Healthcare Centre Jaume I, Universitat Rovira i Virgili, Tarragona, Catalonia, Spain
  23. 23 Drug Research Centre LLC, Balatonfüred, Hungary
  24. 24 Institute of General Practice, First Faculty of Medicine, Charles University, Prague, Czech Republic
  25. 25 JSC Mano Seimos Gydytojas, Klaipėda, Lithuania
  26. 26 Närhälsan, Research and Development Primary Health Care, Region Västra Götaland, Research and Development Center Södra Älvsborg, Borås, Sweden
  27. 27 Department of Public Health and Community Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
  28. 28 Department of Pulmonology, Hospital Clínic de Barcelona, Universitat de Barcelona and IDIBAPS, Barcelona, Spain
  29. 29 Department of Public Health, University Hospital of Nice, Nice, France
  30. 30 Department of Teaching and Research in General Practice, University of Côte d’Azur, Nice, France
  31. 31 Clinic of Social and Family Medicine, University of Crete, Heraklion, Greece
  1. Correspondence to Dr Emily Bongard; emily.bongard{at}


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.

  • influenza
  • oseltamivir
  • primary healthcare
  • cost-benefit analysis
  • adaptive clinical trial

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  • EB and AWV contributed equally.

  • Contributors CCB and TV are cochief investigators of this trial, act as guarantors of the study in its entirety and led the development of the research question, study design and obtaining the funding along with AWvdV, JC, PB, HG, MdJ and PL. EB, JC and AWvdV manage the trial and coordinate the operational delivery of the study protocol to the networks co-ordinating centres. BS and JH are the trial statisticians. PB provides health economics input. MI provides support with sampling and analysis. RMA, CB, SCh, SCo, AC, MD, MDP, ADS, NAF, DG, MG-ć, ML, FMT, AM, JP, MP, RR-J, P-DS, AT, PT and DV are representatives of the collaborating co-ordinating centres responsible for their networks participation in the trial. EB and AWvdV drafted the manuscript and supervised by CCB. All other authors provided critical review and final approval of the manuscript.

  • Funding This work was supported by the European Commission FP7 Programme grant no HEALTH-F3-2013-602525.

  • Competing interests None declared.

  • Patient consent Not required.

  • Ethics approval NRES Committee South Central (Oxford B)

  • Provenance and peer review Not commissioned; externally peer reviewed.