""Randomized, placebo-controlled trial of the anti-tumor necrosis factor antibody fragment afelimomab in hyperinflammatory response during severe sepsis: The RAMSES Study
Konrad Reinhart, MD; Thilo Menges, MD; Bengt Gardlund, MD; Jan Harm Zwaveling, MD; Mark Smithes, MD; Jean-Louis Vincent, MD, PhD; Jose Maria Tellado, MD; Antonio Salgado-Remigio, MD; Reuven Zimlichman, MD; Stuart Withington, MD; Klaus Tschaikowsky, MD; Rainer Brase, MD; Pierre Damas, MD; Hartmut Kupper, MD; Joachim Kempeni, MD; Juergen Eiselstein, MD; Martin Kaul, MD; The AFELIMOMAB Sepsis Study Group
From the Department of Anesthesia and Operative Intensive Care (Dr. Reinhart), Friedrich-Schiller University, Jena, Germany; the Department of Anesthesia and Intensive Care (Dr. Menges), Gieen University, Gieen, Germany; the Section of Infectious Diseases (Dr. Gardlund), Karolinska Hospital, Stockholm, Sweden; the Department of Surgery (Dr. Zwaveling), Academisch Ziekenhuis Groningen, Groningen, The Netherlands; the Intensive Therapy Unit (Dr. Smithes), University Hospital of Wales, Cardiff, Great Britain; the Department of Intensive Care (Dr. Vincent), Erasmus University Hospital, Brussels, Belgium; the Department of General Surgery (Dr. Tellado), Hospital Gregorio Maranon, Madrid, Spain; the Department of Internal Medicine (Dr. Salgado-Remigio), Valle Hebron Hospital, Barcelona, Spain; the Department of Intensive Medicine (Dr. Zimlichman), Wolfson Hospital, Holon, Israel; the Department of Anesthetics (Dr. Withington), Royal London Hospital, London, Great Britain; the Institute of Anesthesia (Dr. Tschaikowsky), Erlangen University, Erlangen, Germany; the Department of Anesthesia (Dr. Brase), Hospital “Links der Weser,” Bremen, Germany; the Intensive Care Unit (Dr. Damas), CHU Liège, Liège, Belgium; and the Department of Research & Development (Drs. Kupper, Kempeni, Eiselstein, and Kaul), Knoll AG, Ludwigshafen, Germany.
CRITICAL CARE MEDICINE 2001;29:765-769
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Objective: This study investigated whether treatment with the anti-tumor necrosis factor- monoclonal antibody afelimomab would improve survival in septic patients with serum interleukin (IL)-6 concentrations of >1000 pg/mL.
Design: Multicenter, double-blind, randomized, placebo-controlled study.
Setting: Eighty-four intensive care units in academic medical centers in Europe and Israel.
Patients: A total of 944 septic patients were screened and stratified by the results of a rapid qualitative immunostrip test for serum IL-6 concentrations. Patients with a positive test kit result indicating IL-6 concentrations of >1000 pg/mL were randomized to receive either afelimomab (n = 224) or placebo (n = 222). Patients with a negative IL-6 test (n = 498) were not randomized and were followed up for 28 days.
Interventions: Treatment consisted of 15-min infusions of 1 mg/kg afelimomab or matching placebo every 8 hrs for 3 days. Standard surgical and intensive care therapy was otherwise delivered.
Measurements and Main Results: The study was terminated prematurely after an interim analysis estimated that the primary efficacy end points would not be met. The 28-day mortality rate in the nonrandomized patients (39.6%, 197 of 498) was significantly lower (p < .001) than that found in the randomized patients (55.8%, 249 of 446). The mortality rates in the IL-6 test kit positive patients randomized to afelimomab and placebo were similar, 54.0% (121 of 224) vs. 57.7% (128 of 222), respectively. Treatment with afelimomab was not associated with any particular adverse events.
Conclusions: The IL-6 immunostrip test identified two distinct sepsis populations with significantly different mortality rates. A small (3.7%) absolute reduction in mortality rate was found in the afelimomab-treated patients. The treatment difference did not reach statistical significance.
Key Words: sepsis; interleukin-6; tumor necrosis factor; monoclonal antibody; cytokines; infection; critical illness; clinical trial; septic shock
Crit Care Med 2001 April;29(4):765-769
Copyright © 2001 Lippincott Williams & Wilkins
All rights reserved ""
There was a 3% to 4% absolute difference between placebo and treatment group favoring the use of the drug, but not statistically significant...
link at : ipsapp003.lwwonline.com
There is also a critical review of study design and how to
design for best results, elaboration over many anti-tnf treatments that after about 7 studies put together at the same absolute differences add on to several thousands of patients and Statistical significance is achieved, something like good ideas for bpi designs. And several nice graphics on intent to treat and who could benefit.
They mentioned the Lilly trial and the problems it will bring to new drugs (bpi will be in the "new" group)in terms of designing studies, ehthics and costs (aka more difficult to prove a new drug once Zovant comes to market).
Interestingly, they advocate even a "proven" (statistically significant ) absolute difference of 1% !!!! as quite good, but they say as long as the power of the study is increased and this means THOUSANDS of patients in studies.
Next the critical review:
""New strategies for clinical trials in patients with sepsis and septic shock
Jonathan Cohen, MB; Gordon Guyatt, MD; Gordon R. Bernard, MD; Thierry Calandra, MD; Deborah Cook, MD; Diana Elbourne, PhD; John Marshall, MD; Andrew Nunn, MSc; Steven Opal, MD; on behalf of a UK Medical Research Council International Working Party
From the Department of Infectious Diseases (Dr. Cohen), Imperial College School of Medicine, London, England; the Departments of Medicine, Clinical Epidemiology, and Biostatistics (Drs. Guyatt and Cook), McMaster University, Hamilton, ON, Canada; the Division of Allergy, Pulmonary, and Critical Care Medicine (Dr. Bernard), Vanderbilt University, Nashville, TN; the Division of Infectious Diseases (Dr. Calandra), CHUV, Lausanne, Switzerland; the Department of Epidemiology and Population Health (Dr. Elbourne), London School of Hygiene and Tropical Medicine, London, UK; the Division of Surgery (Dr. Marshall), University of Toronto, Toronto, ON, Canada; the Medical Research Council Clinical Trials Unit (Mr. Nunn), London, UK; and the Department of Infectious Diseases (Dr. Opal), Brown University, RI.
CRITICAL CARE MEDICINE 2001;29:880-886
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Objective: The difficulty in identifying new treatment modalities that significantly reduce the mortality and morbidity rates associated with sepsis has highlighted the need to reevaluate the approach to clinical trial design. The United Kingdom Medical Research Council convened an International Working Party to address these issues.
Data Sources: The subject areas that were to be the focus of discussion were identified by the co-chairs, and group leaders were nominated. Preconference reading material was circulated to group members.
Study Selection and Data Extraction: Small-group discussion fed into an iterative process of feedback from plenary sessions, followed by the formulation of recommendations. Finally, each working group prepared a summary of its recommendations and these are reported herein.
Data Synthesis: There were five key recommendations. First, investigators should no longer rely solely on the American College of Chest Physicians/Society of Critical Care Medicine definitions of sepsis or sepsis syndrome as the basis of trial entry. Entry criteria should be based on three principles: a) All patients should have infection; b) there should be evidence of a pathologic process that represents a biologically plausible target for the proposed intervention, for example, an abnormal circulating level of a biological marker pertinent to the study drug; and c) patients should fall into an appropriate category of severity (usually severe sepsis). Second, investigators should use a scoring system for organ dysfunctions that has been validated and that can be incorporated into all sepsis studies; agreement on the use of a single system would simplify comparisons between studies. Third, the primary outcome measure generally should be mortality rates, but under appropriate circumstances major morbidities could be considered as primary end points. Regardless of choice of the duration to primary end point, patients should be followed for 90 days. Fourth, sample size needs to be based on a realistic assessment of achievable effect size based on knowledge of the at-risk population. Fifth, subgroups should be few in number and should be defined a priori on the basis of variables present before randomization.
Conclusions: Important changes in several aspects of trial design may improve the quality of clinical studies in sepsis and maximize the chance of identifying effective therapeutic agents.
Key Words: sepsis; septic shock; clinical trial; statistics; methods; meta-analysis
Crit Care Med 2001 April;29(4):880-886
Copyright © 2001 Lippincott Williams & Wilkins
All rights reserved ""
Blue they agree with your green sunny bpi views, but they are not the FDA.
Long Live The FDA. |
