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Recombinant Human Interleukin 1 Receptor Antagonist in the Treatment of Patients With Sepsis Syndrome Results From a Randomized, Double-blind, Placebo-Controlled Trial

Charles J. Fisher Jr, MD; Jean-Francois A. Dhainaut, MD, PhD; Steven M. Opal, MD; John P. Pribble, PharmD; Robert A. Balk, MD; Gus J. Slotman, MD; Thomas J. Iberti, MD; Eric C. Rackow, MD; Marc J. Shapiro, MD; Richard L. Greenman, MD; H. David Reines, MD; Maire P. Shelly, FRCA; Bruce W. Thompson, PhD; John F. LaBrecque, PhD; Michael A. Catalano, MD; William A. Knaus, MD; Jerald C. Sadoff, MD; Mark Astiz, MD; Charles Carpati, MD; Roger C. Bone, MD; Bruce Friedman, MD; Anthony J. Mure, MD; Collin Brathwaite, MD; Eugenia Shapiro, MD; Laura Melhorn; Robert Taylor, MD; Mary Keegan, RN, MSN; Jacklyn O'Brien, RN; Roland Schein, MD; Maria Pena, RN; Monina Wasserlouf, RN; John Oropello, MD; Ernest Benjamin, MD; Rosanna DelGuidice, RN; George Emmanuel, MD; Thiam Lie, MD; Lynn Anderson, MD; John Marshall, MD; Wilfred De Majo, MD; Ori Rotstein, MD; Debra Foster, RN; Edward Abraham, MD; Harold Middleton, RN; Cindy Perry, RN; Howard Levy, MD; Donald E. Fry, MD; Steven Q. Simpson, MD; Richard E. Crowell, MD; Mary Neidhart, RN; Dennis Stevens, MD, PhD; Thomas Coffman, MD; Nagraj Narasimhan, MD; David K. Merrick, MD; William Bergquist, MD; Klaus E. Matzel, MD; Matthias Huebler, MD; Garrett E. Foulke, MD; Timothy E. Albertson, MD, PhD; William F. Walby, MS; Roblee P. Allen, MD; Robert Baughman, MD; Per-Olof Hasselgren, MD; Mitchell P. Fink, MD; Felicia Favorito, RN, BSN; B. Taylor Thompson, MD; Richard Corbin, MD; G. Yovonne Shellhorse, MD; Arnold Frazier, MD; Sandy White, RN; Christopher Garrard, MD, PhD; Christine A'Court, MD; Shirley Storer, RN; Daniel H. Gervich, MD; Debra Foshe, RN; Rainer Brase, MD; Andreas Bagdahn, MD; Robert Cooney, MD; J. Stanley Smith Jr, MD; Louis F. Martin, MD; Jean-Louis Vincent, MD, PhD; Gilberto Friedman, MD; Giorgio Berlot, MD; J. Raymond Fletcher, MD, PhD; Mark D. Williams, MD; Theresa F. Wright, RN; Steven Johnson, MD; Carinda Feild, PharmD; Karen Wolf, MD; Neil MacIntyre, MD; Howard G. Dubin, MD; Margaret R. Durkin, MD; Penelope K. Dubin, RN; Karl Hermann Staubach, MD; Alan M. Fein, MD; Debra B. Schulman, RN; Michael S. Niederman, MD; Donald B. Chalfin, MD; Paul A. M. van; Leeuwen, MD, PhD; Marja A. Boermeester, MD; Anton J. Schneider, MD, PhD; Joseph Bander, MD; Amy Imm, MD; Gordon Bernard, MD; Loren Nelson, MD; Mary Stroud, RN; Karen Safcsak, RN; Frank Cerra, MD; Jean Rindal, RN, MS; Henry Mann, PharmD; Neil Halpern, MD; Jeffrey Silverstein, MD; Margarita Alicea, RN; William J. Sibbald, MD; Claudio M. Martin, MD; Frank S. Rutledge, MD; Kathryn Petti, RN; James A. Russell, MD; Robert Kruger, RN; Alana Drummond, RN; Paul Lange, MD; Tracy Seifert, RN, MSN; Alain Durocher, MD; Alain Tenaillon, MD; Richard Boiteau, PhD; Thierry Lherm, MD; Stephen F. Lowry, MD; Susette M. Coyle, RN; Philip S. Barie, MD; Eric DeMaria, MD; David R. Snydman, MD; Steven D. Schwaitzberg, MD; Stanley A. Nasraway Jr, MD; Jeanne Grindlinger, RN; Warren Summer, MD; Benjamen de Boisblanc, MD; Martin Wahl, MD; Kjell Alestig, MD; Jeffrey Grossman, MD; Dennis Maki, MD; Harold L. Paz, MD, MS; Martha Weiner, RN, MS; David Bihari, MA, FRCP; David Campbell, FRCA; Gerard Bleichner, MD; Michael S. Dahn, MD, PhD; M. Patricia Lange, RN, PhD; Jesse Hall, MD; Anne Pohlman, RN, MSN; Richard P. Wenzel, MD, MS; Mark Grosserode, MD; Michele Costigan, RN; William Mileski, MD; John Weigelt, MD; Neil Yeston, MD; Cheryl Irizarry, RN; Jack Ross, MD; James Robbins, MD; Peter Nightingale, FRCA; Kate Owen; Stefan Sandstedt, MD, PhD; Soren Berg, MD; Gary L. Simon, MD, PhD; Michael G. Seneff, MD; Kathleen M. Conry, RN, MSN; Janice L. Zimmerman, MD; R. Phillip Dellinger, MD; Robert Johnston Jr, MD; Patricia Allee, RN; Per-Olof Grande, MD; Erling Myhre, MD; Jean-Francois Dhainaut, MD, PhD; Isabelle Hamy, MD; Jean-Paul Mira, MD; John Harmon, MD; Jon White, MD; Lloyd McKie, MD; Henry Silverman, MD; Pamela Tuma, RN, BSN; David Bennett, MD; J. C. Porter, MD; Martin H. Laurell, MD, PhD; Sidney Jacobs, MD; Stephen Ash, MD; David M. Stiles, MS; Mary Jane Prior, PhD; Genell Knatterud, PhD; Michael Terrin, MD; Joseph Kufera, MA; Patricia Wilkens; Knut Ra, MD; Lee Monroe; Charles Sprung, MD; Cannon Michael Hamilton; Richard Matthay, MD; William McCabe, MD; James Tonascia, PhD; Herbert Wiedeman, MD; Janet Wittes, PhD; Genell Knatterud, PhD.; Giles V. Campion, MD; Carol R. Croft; Richard Lustick; Janice Lookabaugh, MS; Gilad S. Gordon, MD, MBA; Leslie Noe, RPh, MPA; Duane Bloedow, PhD; Smith G. Christopher; Dennis Brannon, RPh; Rebecca Kush, PhD; David Ng, PhD; Elizabeth Moore, MEd; Karen Bazemore, MS; Michael Galvan; Douglas Wagner, PhD; Frank Harrell, PhD; Dona Stablein, RN.
JAMA. 1994;271(23):1836-1843. doi:10.1001/jama.1994.03510470040032.
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Objective.  —To further define the safety and efficacy of recombinant human interleukin 1 receptor antagonist (rhIL-1ra) in the treatment of sepsis syndrome.

Study Design.  —Randomized, double-blind, placebo-controlled, multicenter, multinational clinical trial.

Population.  —A total of 893 patients with sepsis syndrome received an intravenous loading dose of rhIL-1ra, 100 mg, or placebo followed by a continuous 72-hour intravenous infusion of rhIL-1ra (1.0 or 2.0 mg/kg per hour) or placebo.

Outcome Measure.  —Twenty-eight—day all-cause mortality.

Results.  —There was not a significant increase in survival time for rhIL-1ra treatment compared with placebo among all patients who received the study medication (n=893; generalized Wilcoxon statistic, P=.22) or among patients with shock at study entry (n=713; generalized Wilcoxon statistic, P=.23), the two primary efficacy analyses specified a priori for this trial. Results from secondary analyses suggest an increase in survival time with rhIL-1ra treatment among patients with dysfunction of one or more organs (n=563; linear dose-response, P=.009). Retrospective analysis demonstrated an increase in survival time with rhIL-1ra treatment among patients with a predicted risk of mortality of 24% or greater (n=580; linear dose-response, P=.005) as well as among patients with both dysfunction of one or more organs and a predicted risk of mortality of 24% or greater (n=411; linear dose-response, P=.002).

Conclusions.  —There was not a statistically significant increase in survivial time for rhIL-1ra treatment compared with placebo among all patients who received the study medication or among patients with shock at study entry. Secondary and retrospective analyses of efficacy suggest that treatment with rhIL-1ra results in a dose-related increase in survival time among patients with sepsis who have organ dysfunction and/or a predicted risk of mortality of 24% or greater.(JAMA. 1994;271:1836-1843)


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