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Recombinant Human Interleukin 1 Receptor Antagonist in the Treatment of Patients With Sepsis SyndromeResults 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;
the Phase III rhIL-1ra Sepsis Syndrome Study Group;
The Phase III rhIL-1ra Sepsis Syndrome Study Group;
Mark Astiz, MD;
Eric C. Rackow, MD;
Charles Carpati, MD;
Robert A. Balk, MD;
Roger C. Bone, MD;
Gus J. Slotman, MD;
Bruce Friedman, MD;
Anthony J. Mure, MD;
Collin Brathwaite, MD;
Eugenia Shapiro, MD;
Laura Melhorn;
Marc J. Shapiro, MD;
Robert Taylor, MD;
Mary Keegan, RN, MSN;
Jacklyn O'Brien, RN;
Richard L. Greenman, MD;
Roland Schein, MD;
Maria Pena, RN;
Monina Wasserlouf, RN;
Thomas J. Iberti, MD;
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;
Steven M. Opal, 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;
Charles J. Fisher, Jr, MD;
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;
H. David Reines, 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;
Maire P. Shelly, FRCA;
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;
Clinical Evaluation Committee;
Charles J. Fisher, Jr, MD;
Jean-Francois Dhainaut, MD, PhD;
Steven M. Opal, MD;
Robert A. Balk, MD;
Gus J. Slotman, MD;
Thomas J. Iberti, MD;
H. David Reines, MD;
Maire P. Shelly, FRCA;
Jerald C. Sadoff, MD;
John P. Pribble, PharmD;
David M. Stiles, MS;
Bruce W. Thompson, PhD;
Mary Jane Prior, PhD;
Genell Knatterud, PhD;
Michael Terrin, MD;
Joseph Kufera, MA;
Patricia Wilkens;
Knut Ra, MD;
Lee Monroe;
Safety and Efficacy Monitoring Committee;
Charles Sprung, MD;
Cannon Michael Hamilton;
Richard Matthay, MD;
William McCabe, MD;
James Tonascia, PhD;
Herbert Wiedeman, MD;
Janet Wittes, PhD;
Bruce W. Thompson, PhD;
Genell Knatterud, PhD.;
John P. Pribble, PharmD;
David M. Stiles, MS;
John F. LaBrecque, PhD;
Michael A. Catalano, MD;
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;
William A. Knaus, MD;
Douglas Wagner, PhD;
Frank Harrell, PhD;
Dona Stablein, RN.
JAMA. 1994;271(23):1836-1843.
Abstract
| |
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)
Author Affiliations
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Investigative Centers: St Vincent's Hospital and Medical Center of New York, NY; Rush Presbyterian-St Luke's Medical Center, Chicago, Ill; Cooper Hospital/University Medical Center, Camden, NJ; St Louis (Mo) Health Sciences Center; Veterans Affairs Medical Center and University of Miami (Fla) School of Medicine; Mt Sinai Medical Center, New York, NY; Veterans Affairs Medical Center, Bay Pines, Fla, and University of South Florida, Tampa; Toronto (Ontario) General Hospital; UCLA Medical Center, Los Angeles, Calif; University of New Mexico Medical Center, Albuquerque; Veterans Affairs Medical Center and St Luke's and St Alphonsus Regional Medical Centers, Boise, Idaho; Chirurgische Universitätsklinik Erlangen, Germany; University of California—Davis Medical Center, Sacramento; University of Cincinnati (Ohio) Medical Center; Massachusetts General Hospital, Boston; Carolinas Medical Center, Charlotte, NC; John Radcliffe Hospital, Oxford, England; Chest, Infectious Diseases, Critical Care Associates, Des Moines, Iowa; Zentralkrankenhaus "Links der Weser," Bremen, Germany; Hershey (Pa) Medical Center; Hospital Erasme, Free University of Brussels, Belgium; University of South Alabama Medical Center, Mobile; University of Kentucky A. B. Chandler Medical Center, Lexington; Duke University Medical Center, Durham, NC; Brown University Medical School, Providence, RI; Medizinische Universität zu Lübeck, Germany; Winthrop University Hospital, Mineola, NY; Free University Hospital, Amsterdam, the Netherlands; Harper Hospital, Wayne State University, Detroit, Mich; Vanderbilt Medical School, Nashville, Tenn; University of Minnesota Medical School, Minneapolis; Veterans Affairs Medical Center, Bronx, NY; Victoria Hospital, London, Ontario; St Paul's Hospital, Vancouver, British Columbia; The Cleveland (Ohio) Clinic Foundation; Hôpital Calmette, Lille, France; Hôpital Louise Michel, Evry, France; Cornell University Medical Center, New York, NY; Medical College of Virginia, Richmond; New England Medical Center, Boston, Mass; Louisiana State University Medical Center, New Orleans; University of Göteborg, Sweden; University of Wisconsin Medical School, Madison; Hahnemann University, Philadelphia, Pa; Guy's Hospital, London, England; Centre Hospitalier D'Argenteuil, France; University Health Center, Detroit, Mich; University of Chicago, Ill; University of Iowa Hospitals and Clinics, Iowa City; University of Texas Southwestern Medical Center, Dallas; Hartford Hospital, University of Connecticut Medical Center; University Hospital of South Manchester, England; Linkoping (Sweden) University Hospital; George Washington University Medical Center, Washington, DC; Baylor College of Medicine, Houston, Tex; Lund (Sweden) University Hospital; Hôpital Cochin, Paris, France; Veterans Affairs Medical Center, Washington, DC; University of Maryland Hospital, Baltimore; St George's Hospital, London, England; Malmo (Sweden) General Hospital; University Hospital of Wales, Cardiff; Ealing Hospital, Middlesex, England; Maryland Medical Research Institute, Baltimore; Synergen Inc, Boulder Colo; Pharmaco LSR, Austin, Tex; APACHE Medical Systems Inc, Washington, DC
From the Department of Pulmonary and Critical Care Medicine, The Cleveland (Ohio) Clinic Foundation (Dr Fisher); the Department of Intensive Care Medicine, Cochin Port-Royal Hospital, Paris V University, France (Dr Dhainaut); the Department of Medicine, Brown University Medical School, Providence, RI (Dr Opal); the Department of Clinical Research, Synergen Inc, Boulder, Colo (Drs Pribble, LaBrecque, and Catalano); the Department of Medicine, Rush Presbyterian—St Luke's Medical Center, Chicago, Ill (Dr Balk); the Department of Surgery, Cooper Hospital/University Medical Center, Camden, NJ (Dr Slotman); the Department of Surgery, Mt Sinai Medical Center, New York, NY (Dr Iberti); the Department of Medicine, St Vincent's Hospital and Medical Center, New York, NY (Dr Rackow); the Department of Surgery, St Louis (Mo) University Medical Center (Dr Shapiro); the Department of Medicine, Veterans Affairs Medical Center and University of Miami (Fla) School of Medicine (Dr Greenman); the Department of Surgery, Medical College of Virginia, Richmond (Dr Reines); the Intensive Care Unit, University Hospital of South Manchester, England (Dr Shelly); the Maryland Medical Research Institute, Baltimore (Dr Thompson); the Intensive Care Research Unit, George Washington University Medical Center, Washington, DC (Dr Knaus); and the Division of Communicable Diseases and Immunology, Walter Reed Army Institute of Research, Washington, DC (Dr Sadoff). Members of the Phase III rhIL-1ra Sepsis Syndrome Study Group are listed at the end of this article.
Footnotes
 Deceased.
Drs Fisher and Opal have functioned as paid consultants to Synergen Inc, Boulder, Colo, for the development of rhIL-1ra. Drs Pribble and LaBrecque are employees of Synergen Inc and receive stock options in the company. Dr Knaus is a founder and shareholder in APACHE Medical Systems Inc, Washington, DC, which received payment from Synergen Inc for consulting services provided. Dr Knaus received no direct payments from Synergen Inc.
Reprint requests to Critical Care Research Unit, Department of Pulmonary and Critical Care Medicine (G-62), The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195 (Dr Fisher).
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Natural Cytokine Antagonists and Endogenous Antiendotoxin Core Antibodies in Sepsis Syndrome
Goldie et al.
JAMA 1995;274:172-177.
ABSTRACT
Interleukin-1 Blockade Attenuates Mediator Release and Dysregulation of the Hemostatic Mechanism During Human Sepsis
Boermeester et al.
Arch Surg 1995;130:739-748.
ABSTRACT
Editorial
Morrison
Innate Immunity 1995;2:149-150.
Blocking interleukin-1 in sepsis
Dinarello
Innate Immunity 1995;2:157-162.
ABSTRACT
Risk assessment in recent clinical trials in sepsis/SIRS: lessons learned and future directions
Knaus et al.
Innate Immunity 1995;2:169-175.
ABSTRACT
Physiological classification and stratification of illness severity of posttrauma 'sepsis' patients as a basis for randomization of clinical trials
Siegel et al.
Innate Immunity 1995;2:177-188.
Preclinical and clinical evaluation of carbohydrate immunopharmaceuticals in the prevention of sepsis and septic sequelae
Williams et al.
Innate Immunity 1995;2:203-208.
ABSTRACT
Applying lessons learned from anti-endotoxin therapy
Scannon
Innate Immunity 1995;2:217-220.
Lessons learned from clinical trials of sepsis
Opal
Innate Immunity 1995;2:221-226.
ABSTRACT
Can second-generation versions of existing therapeutics be successful in clinical trials of sepsis?
Fisher
Innate Immunity 1995;2:227-232.
ABSTRACT
Efficacy and Safety of Monoclonal Antibody to Human Tumor Necrosis Factor {alpha} in Patients With Sepsis Syndrome: A Randomized, Controlled, Double-blind, Multicenter Clinical Trial
Abraham et al.
JAMA 1995;273:934-941.
ABSTRACT
Effects of bactericidal/permeability-increasing protein on endotoxin-induced fever and Escherichia coli-induced shock in rabbits
Porat et al.
Innate Immunity 1995;2:9-18.
ABSTRACT
Defining Sepsis
Knaus et al.
JAMA 1994;272:1901-1901.
ABSTRACT
Shifting Ground: Enteral vs Parenteral Nutrition in Critically Ill Patients
Dahn
Nutr Clin Pract 1994;9:163-164.
THE SEARCH FOR ANTISEPSIS AGENTS CONTINUES. ..NS. Human interleukin 1 receptor antagonist is a natural substance produced by macrophages and other cells in response to endotoxin and other products that play a role in the pathogenesis of sepsis syndrome. T
JWatch General 1994;1994:6-6.
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Sepsis Therapy Trials: Continued Disappointment or Reason for Hope?
Abraham and Raffin
JAMA 1994;271:1876-1878.
ABSTRACT
Apolipoprotein E Protects Against Bacterial Lipopolysaccharide-induced Lethality. A NEW THERAPEUTIC APPROACH TO TREAT GRAM-NEGATIVE SEPSIS
Van Oosten et al.
J. Biol. Chem. 2001;276:8820-8824.
ABSTRACT
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Targeted adenovirus-induced expression of IL-10 decreases thymic apoptosis and improves survival in murine sepsis
Oberholzer et al.
Proc. Natl. Acad. Sci. USA 2001;98:11503-11508.
ABSTRACT
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When Sleeping Beauty Turns Ugly: Mitochondria in Hypoxia
Warnholtz et al.
Arterioscler. Thromb. Vasc. Bio. 2002;22:525-527.
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