Emmanuel Weiss1,2, Jean-Ralph Zahar3,4, Jeff Alder5, Karim Asehnoune6, Matteo Bassetti7, Marc J M Bonten8, Jean Chastre9, Jan De Waele10, George Dimopoulos11, Philippe Eggimann12, Marc Engelhardt13, Santiago Ewig14, Marin Kollef15, Jeffrey Lipman16,17, Carlos Luna18, Ignacio Martin-Loeches19, Leonardo Pagani20, Lucy B Palmer21, Laurent Papazian22, Garyphallia Poulakou23,24, Philippe Prokocimer25, Jordi Rello26, John H Rex27, Andrew F Shorr28, George H Talbot29, Visanu Thamlikitkul30, Antoni Torres31, Richard G Wunderink32, Jean-François Timsit33,34. 1. Department of Anesthesiology and Critical Care, Assistance Publique-Hôpitaux de Paris (AP-HP), Beaujon Hospital, Clichy. 2. Unité Mixte de Recherche (UMR) 1149, Centre for Research on Inflammation, Institut national de la santé et de la recherche médicale (INSERM)/Université Paris Diderot, Paris. 3. Department of Clinical Microbiology and Infection Control Unit, Avicennes Hospital, AP-HP, Bobigny. 4. Infection, Antibiotics, Modelisation, Epidemiology (IAME), UMR 1137, Université Paris 13, Sorbonne Paris Cité, France. 5. Bayer US LLC, Parsippany, New Jersey. 6. University Hospital of Nantes, Intensive Care Unit, Anesthesia and Critical Care Department, Hôtel Dieu, Nantes, France. 7. Infectious Diseases Division, Department of Medicine, University of Udine and Santa Maria Misericordia University Hospital, Italy. 8. Department of Medical Microbiology and Julius Center for Health Science and Primary Care, University Medical Center Utrecht, The Netherlands. 9. Service de Réanimation Médicale, Institut de Cardiologie, Groupe Hospitalier Pitié-Salpêtrière, AP-HP, Paris, France. 10. Department of Critical Care Medicine, Ghent University Hospital, Belgium. 11. Department of Critical Care, University Hospital Attikon, National and Kapodistrian University of Athens, Greece. 12. Department of Critical Care, Centre Hospitalier Universitaire Vaudois, Lausanne. 13. Basilea Pharmaceutica International Ltd, Basel, Switzerland. 14. Department of Respiratory Medicine and Infectious Diseases, Evangelic Hospital in Herne and Augusta Hospital, Bochum, Germany. 15. Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St Louis, Missouri. 16. Royal Brisbane and Womens Hospital, Australia. 17. University of the Witwatersrand, Johannesburg, South Africa. 18. Department of Medicine, Pulmonary Diseases Division, Hospital de Clínicas, Universidad de Buenos Aires, Argentina. 19. Department of Clinical Medicine, Multidisciplinary Intensive Care Research Organization, St James's Hospital, Trinity Centre for Health Sciences, Dublin, Ireland. 20. Infectious Diseases Unit, Bolzano Central Hospital, Italy. 21. Pulmonary, Critical Care and Sleep Division, State University of New York at Stony Brook, France. 22. Médecine Intensive-Réanimation, Assistance Publique-Hôpitaux de Marseille, Hôpital Nord, France. 23. Third Department of Medicine, Sotiria General Hospital, Greece. 24. Medical School, National and Kapodistrian University of Athens, Greece. 25. Merck & Co, Inc, Kenilworth, New Jersey. 26. Centro Investigacion Biomedica En Red de Enfermedades Respiratorias (CIBERES), Vall d'Hebron Barcelona Hospital Campus, Spain. 27. F2G, Ltd, Eccles, United Kingdom. 28. Medstar Washington Hospital Center, Washington, District of Columbia. 29. Talbot Advisors LLC, Anna Maria, Florida. 30. Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand. 31. Servei de Pneumologia, Hospital Clinic, Universitat de Barcelona, Institut De Investigacio Biomedica Agusti Pi i Sunyer, CIBERES, Spain. 32. Feinberg School of Medicine, Northwestern University, Chicago, Illinois. 33. AP-HP, Medical and Infectious Diseases Intensive Care Unit, Bichat Hospital, Paris. 34. UMR 1137 IAME, INSERM, Université Paris Diderot, France.
Abstract
BACKGROUND: Randomized clinical trials (RCTs) in hospital-acquired and ventilator-associated bacterial pneumonia (HABP and VABP, respectively) are important for the evaluation of new antimicrobials. However, the heterogeneity in endpoints used in RCTs evaluating treatment of HABP/VABP may puzzle clinicians. The aim of this work was to reach a consensus on clinical endpoints to consider in future clinical trials evaluating antimicrobial treatment efficacy for HABP/VABP. METHODS: Twenty-six international experts from intensive care, infectious diseases, and the pharmaceutical industry were polled using the Delphi method. RESULTS: The panel recommended a hierarchical composite endpoint including, by priority order, (1) survival at day 28, (2) mechanical ventilation-free days through day 28, and (3) clinical cure between study days 7 and 10 for VABP; and (1) survival (day 28) and (2) clinical cure (days 7-10) for HABP. Clinical cure was defined as the combination of resolution of signs and symptoms present at enrollment and improvement or lack of progression of radiological signs. More than 70% of the experts agreed to assess survival and mechanical ventilation-free days though day 28, and clinical cure between day 7 and day 10 after treatment initiation. Finally, the hierarchical order of endpoint components was reached after 3 Delphi rounds (72% agreement). CONCLUSIONS: We provide a multinational expert consensus on separate hierarchical composite endpoints for VABP and HABP, and on a definition of clinical cure that could be considered for use in future HABP/VABP clinical trials.
BACKGROUND: Randomized clinical trials (RCTs) in hospital-acquired and ventilator-associated bacterial pneumonia (HABP and VABP, respectively) are important for the evaluation of new antimicrobials. However, the heterogeneity in endpoints used in RCTs evaluating treatment of HABP/VABP may puzzle clinicians. The aim of this work was to reach a consensus on clinical endpoints to consider in future clinical trials evaluating antimicrobial treatment efficacy for HABP/VABP. METHODS: Twenty-six international experts from intensive care, infectious diseases, and the pharmaceutical industry were polled using the Delphi method. RESULTS: The panel recommended a hierarchical composite endpoint including, by priority order, (1) survival at day 28, (2) mechanical ventilation-free days through day 28, and (3) clinical cure between study days 7 and 10 for VABP; and (1) survival (day 28) and (2) clinical cure (days 7-10) for HABP. Clinical cure was defined as the combination of resolution of signs and symptoms present at enrollment and improvement or lack of progression of radiological signs. More than 70% of the experts agreed to assess survival and mechanical ventilation-free days though day 28, and clinical cure between day 7 and day 10 after treatment initiation. Finally, the hierarchical order of endpoint components was reached after 3 Delphi rounds (72% agreement). CONCLUSIONS: We provide a multinational expert consensus on separate hierarchical composite endpoints for VABP and HABP, and on a definition of clinical cure that could be considered for use in future HABP/VABP clinical trials.
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