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      Design, conduct, analysis and reporting of a multi-national placebo-controlled trial of activated protein C for persistent septic shock


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          The role of drotrecogin alfa (activated) (DAA) in severe sepsis remains controversial and clinicians are unsure whether or not to treat their patients with DAA. In response to a request from the European Medicines Agency, Eli Lilly will sponsor a new placebo-controlled trial and history suggests the results will be subject to great scrutiny. An academic steering committee will oversee the conduct of the study and will write the study manuscripts. The steering committee intends that the study will be conducted with the maximum possible transparency; this includes publication of the study protocol and a memorandum of understanding which delineates the role of the sponsor. The trial has the potential to provide clinicians with valuable data but patients will only benefit if clinicians have confidence in the conduct, analysis and reporting of the trial. This special article describes the process by which the trial was developed, major decisions regarding trial design, and plans for independent analysis, interpretation and reporting of the data.

          Electronic supplementary material

          The online version of this article (doi:10.1007/s00134-008-1266-6) contains supplementary material, which is available to authorized users.

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          Most cited references 33

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          Pharmaceutical industry sponsorship and research outcome and quality: systematic review.

          To investigate whether funding of drug studies by the pharmaceutical industry is associated with outcomes that are favourable to the funder and whether the methods of trials funded by pharmaceutical companies differ from the methods in trials with other sources of support. Medline (January 1966 to December 2002) and Embase (January 1980 to December 2002) searches were supplemented with material identified in the references and in the authors' personal files. Data were independently abstracted by three of the authors and disagreements were resolved by consensus. 30 studies were included. Research funded by drug companies was less likely to be published than research funded by other sources. Studies sponsored by pharmaceutical companies were more likely to have outcomes favouring the sponsor than were studies with other sponsors (odds ratio 4.05; 95% confidence interval 2.98 to 5.51; 18 comparisons). None of the 13 studies that analysed methods reported that studies funded by industry was of poorer quality. Systematic bias favours products which are made by the company funding the research. Explanations include the selection of an inappropriate comparator to the product being investigated and publication bias.
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            Rapid increase in hospitalization and mortality rates for severe sepsis in the United States: a trend analysis from 1993 to 2003.

            To determine recent trends in rates of hospitalization, mortality, and hospital case fatality for severe sepsis in the United States. Trend analysis for the period from 1993 to 2003. U.S. community hospitals from the Nationwide Inpatient Sample that is a 20% stratified sample of all U.S. community hospitals. Subjects of any age with sepsis including severe sepsis who were hospitalized in the United States during the study period. None. Utilizing International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes for septicemia and major organ dysfunction, we identified 8,403,766 patients with sepsis, including 2,857,476 patients with severe sepsis, who were hospitalized in the United States from 1993 to 2003. The percentage of severe sepsis cases among all sepsis cases increased continuously from 25.6% in 1993 to 43.8% in 2003 (p < .001). Age-adjusted rate of hospitalization for severe sepsis grew from 66.8 +/- 0.16 to 132.0 +/- 0.21 per 100,000 population (p < .001). Age-adjusted, population-based mortality rate within these years increased from 30.3 +/- 0.11 to 49.7 +/- 0.13 per 100,000 population (p < .001), whereas hospital case fatality rate fell from 45.8% +/- 0.17% to 37.8% +/- 0.10% (p < .001). During each study year, the rates of hospitalization, mortality, and case fatality increased with age. Hospitalization and mortality rates in males exceeded those in females, but case fatality rate was greater in females. From 1993 to 2003, age-adjusted rates for severe sepsis hospitalization and mortality increased annually by 8.2% (p < .001) and 5.6% (p < .001), respectively, whereas case fatality rate decreased by 1.4% (p < .001). The rate of severe sepsis hospitalization almost doubled during the 11-yr period studied and is considerably greater than has been previously predicted. Mortality from severe sepsis also increased significantly. However, case fatality rates decreased during the same study period.
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              Management of Sepsis

              New England Journal of Medicine, 355(16), 1699-1713

                Author and article information

                +61-2-96570348 , +61-2-96570301 , sfinfer@george.org.au
                Intensive Care Med
                Intensive Care Medicine
                Springer-Verlag (Berlin/Heidelberg )
                7 October 2008
                7 October 2008
                November 2008
                : 34
                : 11
                : 1935-1947
                [1 ]Critical Care and Trauma, The George Institute for International Health, University of Sydney, PO Box M201, Missenden Road, Sydney, NSW 2050 Australia
                [2 ]Ospedale S. Giovanni Battista-Molinette, Università di Torino, Torino, Italy
                [3 ]Pulmonary and Critical Care Unit, Bullfinch Building, Room 148, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114 USA
                [4 ]Department of Surgery, P713A, Weill Cornell Medical College, 525 East 68 St, New York, NY 10065 USA
                [5 ]Cochin Port Royal Hospital-Paris Descartes University, Paris, France
                [6 ]Denver Health and University of Colorado, Denver, USA
                [7 ]Department of Infectious Diseases, Karolinska University Hospital, 14186 Stockholm, Sweden
                [8 ]Departments of Surgery and Critical Care Medicine, St Michael’s Hospital, 4th Floor Bond Wing, Rm. 4-007, 30 Bond Street, Toronto, ON M5B 1W8 Canada
                [9 ]Department of Intensive Care Medicine and Anaesthesia, St George’s Hospital, London, SW17 0QT UK
                © Springer-Verlag 2008
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                © Springer-Verlag 2008


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