p55 Tumor necrosis factor receptor fusion protein in the treatment of patients with severe sepsis and septic shock. A randomized controlled multicenter trial. Ro 45-2081 Study Group

E. Abraham, M. P. Glauser, T. Butler, J. Garbino, D. Gelmont, P. F. Laterre, K. Kudsk, H. A. Bruining, C. Otto, E. Tobin, C. Zwingelstein, W. Lesslauer and A. Leighton
Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver 80262, USA.

OBJECTIVE: To evaluate the safety and efficacy of p55 tumor necrosis factor receptor fusion protein, a recombinant chimeric protein of human p55 (type I) tumor necrosis factor receptor (CD120a) extracellular domain and IgG1 sequences (referred to as p55-IgG), in the treatment of patients with severe sepsis or septic shock. DESIGN: Randomized, prospective, multicenter, double-blind, placebo-controlled clinical trial. SETTING: Forty-four community and university-affiliated hospitals in the United States and Europe. PATIENTS: There were 498 patients enrolled in this clinical trial. INTERVENTION: Patients prospectively stratified within each site into refractory shock or severe sepsis groups were randomized to receive a single infusion of p55-IgG, 0.083 mg/kg, 0.042 mg/kg, or 0.008 mg/kg, or placebo. Patients received standard aggressive medical/surgical care during the 28-day postinfusion period. OUTCOME MEASURE: Twenty-eight-day all-cause mortality. RESULTS: The distribution of variables describing demographics, organ system dysfunction or failure, infecting microorganisms, predicted mortality, plasma interleukin 6 levels, and plasma tumor necrosis factor alpha (TNF-alpha) levels were similar among patients in the p55-IgG and placebo treatment arms. A planned interim analysis was performed after 201 patients were enrolled. Because a statistically nonsignificant trend toward increased mortality was present in patients who had received 0.008 mg/kg, this treatment arm was discontinued, and the study continued with 3 arms. Among all infused patients, there was a statistically nonsignificant trend toward reduced 28-day all-cause mortality in those who received p55-IgG compared with placebo-treated patients (5% reduction, 0.042 mg/kg vs placebo; 15% reduction, 0.083 mg/kg vs placebo; P=.30). However, in patients with severe sepsis and early septic shock (n=247), therapy with p55-IgG, 0.083 mg/kg, was associated with a 36% reduction in 28-day all-cause mortality compared with placebo (P=.07): 20 (23%) of 87 patients died among those treated with p55-IgG, 0.083 mg/kg; 30 (37%) of 82 among those treated with p55-IgG, 0.042 mg/kg; and 28 (36%) of 78 in the placebo group. A prospectively planned logistic regression analysis to assess treatment effect on 28-day all-cause mortality by means of predicted mortality and serum interleukin 6 levels as continuous covariates demonstrated a significant improvement in outcome for the patients with severe sepsis treated with p55-IgG, 0.083 mg/kg, compared with placebo (P=.01). Serious adverse events, including death and the development of new organ system dysfunction, were reported in 65% of patients infused with placebo, with no increased frequency (56%) present in the 2 p55-IgG treatment arms. There were no reports of immediate hypersensitivity reactions caused by p55-IgG. CONCLUSIONS: In this dose-finding study, there was no decrease in mortality between placebo and p55-IgG in all infused patients. In the prospectively defined population of patients with severe sepsis who received p55-IgG, 0.083 mg/kg, there was a trend toward reduced mortality at day 28 that became significant when predicted mortality and plasma interleukin 6 levels were included in a logistic regression analysis.

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

Sepsis and the Heart
Merx and Weber
Circulation 2007;116:793-802.
ABSTRACT | FULL TEXT  

Chronic Sepsis Mortality Characterized by an Individualized Inflammatory Response
Osuchowski et al.
J. Immunol. 2007;179:623-630.
ABSTRACT | FULL TEXT  

Selective clearance of glycoforms of a complex glycoprotein pharmaceutical caused by terminal N-acetylglucosamine is similar in humans and cynomolgus monkeys
Jones et al.
Glycobiology 2007;17:529-540.
ABSTRACT | FULL TEXT  

Pathophysiology of Sepsis
Remick
Am. J. Pathol. 2007;170:1435-1444.
ABSTRACT | FULL TEXT  

Cell Response to Surgery
Ni Choileain and Redmond
Arch Surg 2006;141:1132-1140.
ABSTRACT | FULL TEXT  

Review: Infection, fever, and exogenous and endogenous pyrogens: some concepts have changed
Dinarello
Innate Immunity 2004;10:201-222.
ABSTRACT  

Plasminogen activator inhibitor type-1 deficiency does not influence the outcome of murine pneumococcal pneumonia
Rijneveld et al.
Blood 2003;102:934-939.
ABSTRACT | FULL TEXT  

The Problems and Challenges of Immunotherapy in Sepsis
Nasraway
Chest 2003;123:451S-459S.
ABSTRACT | FULL TEXT  

Risk and the Efficacy of Antiinflammatory Agents: Retrospective and Confirmatory Studies of Sepsis
Eichacker et al.
Am. J. Respir. Crit. Care Med. 2002;166:1197-1205.
ABSTRACT | FULL TEXT  

Cardiac Inflammation and Innate Immunity in Septic Shock* : Is There a Role for Toll-Like Receptors?
Knuefermann et al.
Chest 2002;121:1329-1336.
ABSTRACT | FULL TEXT  

Development of a novel, nonimmunogenic, soluble human TNF receptor type I (sTNFR-I) construct in the baboon
Rosenberg et al.
J. Appl. Physiol. 2001;91:2213-2223.
ABSTRACT | FULL TEXT  

Countervailing Influence of Tumor Necrosis Factor-{{alpha}} and Nitric Oxide in Endotoxemia
JAIMES et al.
J. Am. Soc. Nephrol. 2001;12:1204-1210.
ABSTRACT | FULL TEXT  

Role of p38 mitogen-activated protein kinase in cardiac myocyte secretion of the inflammatory cytokine TNF-{alpha}
Ballard-Croft et al.
Am. J. Physiol. Heart Circ. Physiol. 2001;280:H1970-H1981.
ABSTRACT | FULL TEXT  

Suppression of Endotoxin- and Staphylococcal Exotoxin-Induced Cytokines and Chemokines by a Phospholipase C Inhibitor in Human Peripheral Blood Mononuclear Cells
Krakauer
CVI 2001;8:449-453.
ABSTRACT | FULL TEXT  

Septic Shock and Acute Lung Injury in Rabbits with Peritonitis . Failure of the Neutrophil Response to Localized Infection
MATUTE-BELLO et al.
Am. J. Respir. Crit. Care Med. 2001;163:234-243.
ABSTRACT | FULL TEXT  

Clinically-oriented therapies in sepsis: a review
Dubois and Vincent
Innate Immunity 2000;6:463-469.
ABSTRACT  

Intensive Care Medicine 2000: First Signs of Maturity?
Suter
Anesth. Analg. 2000;90:1236-1237.
FULL TEXT  

Cytokine Blockade as a New Strategy to Treat Rheumatoid Arthritis: Inhibition of Tumor Necrosis Factor
Fox
Arch Intern Med 2000;160:437-444.
ABSTRACT | FULL TEXT  

Impact of Immunomodulating Therapy on Morbidity in Patients with Severe Sepsis
PITTET et al.
Am. J. Respir. Crit. Care Med. 1999;160:852-857.
ABSTRACT | FULL TEXT  

Sepsis: Lessons Learned in the Last Century and Future Directions
Chaudry
Arch Surg 1999;134:922-929.
FULL TEXT  

Altered Immune Responses and Susceptibility to Leishmania major and Staphylococcus aureus Infection in IL-18-Deficient Mice
Wei et al.
J. Immunol. 1999;163:2821-2828.
ABSTRACT | FULL TEXT  

Acute Systemic Reaction and Lung Alterations Induced by an Antiplatelet Integrin gpIIb/IIIa Antibody in Mice
Nieswandt et al.
Blood 1999;94:684-693.
ABSTRACT | FULL TEXT  

Lung Cytokines and ARDS: Roger S. Mitchell Lecture
Martin
Chest 1999;116:2S-8S.
FULL TEXT  

Roles of IL-1 and TNF in the decreased ileal muscle contractility induced by lipopolysaccharide
Lodato et al.
Am. J. Physiol. Gastrointest. Liver Physiol. 1999;276:G1356-G1362.
ABSTRACT | FULL TEXT  

Variables Affecting Outcome in Critically Ill Patients
Chernow
Chest 1999;115:71S-76S.
ABSTRACT | FULL TEXT  

Immunological evaluation of cytokine and anticytokine immunotherapy in vivo: what have we learnt?
Jorgensen et al.
Ann Rheum Dis 1999;58:136-141.
FULL TEXT  

Animal Pharmacokinetics of the Tumor Necrosis Factor Receptor-Immunoglobulin Fusion Protein Lenercept and Their Extrapolation to Humans
Richter et al.
Drug Metab. Dispos. 1999;27:21-25.
ABSTRACT | FULL TEXT  

Tumor Necrosis Factor Alpha Enhances Antifungal Activities of Polymorphonuclear and Mononuclear Phagocytes against Aspergillus fumigatus
Roilides et al.
Infect. Immun. 1998;66:5999-6003.
ABSTRACT | FULL TEXT  

Feedback Inhibition of Macrophage Tumor Necrosis Factor- Production by Tristetraprolin
Carballo et al.
Science 1998;281:1001-1005.
ABSTRACT | FULL TEXT  

Discussion Sections in Reports of Controlled Trials Published in General Medical Journals: Islands in Search of Continents?
Clarke and Chalmers
JAMA 1998;280:280-282.
ABSTRACT | FULL TEXT  

Essential Role of Gamma Interferon in Survival of Colon Ascendens Stent Peritonitis, a Novel Murine Model of Abdominal Sepsis
Zantl et al.
Infect. Immun. 1998;66:2300-2309.
ABSTRACT | FULL TEXT  

Revisiting the Role of Tumor Necrosis Factor {alpha} and the Response to Surgical Injury and Inflammation
Ksontini et al.
Arch Surg 1998;133:558-567.
ABSTRACT | FULL TEXT  

Pharmacokinetics, immunogenicity, and efficacy of dimeric TNFR binding proteins in healthy and bacteremic baboon
Solorzano et al.
J. Appl. Physiol. 1998;84:1119-1130.
ABSTRACT | FULL TEXT  

Tumor necrosis factor in the heart
Meldrum
Am. J. Physiol. Regul. Integr. Comp. Physiol. 1998;274:R577-R595.
ABSTRACT | FULL TEXT  

Encouraging Results with Treatment for Septic Shock
Journal Watch Dermatology 1997;1997:18-18.
FULL TEXT  

ENCOURAGING RESULTS WITH TREATMENT FOR SEPTIC SHOCK
JWatch General 1997;1997:3-3.
FULL TEXT  

Shedding of TNF-alpha receptors, blood pressure, and insulin sensitivity in type 2 diabetes mellitus
Fernandez-Real et al.
Am. J. Physiol. Endocrinol. Metab. 2002;282:E952-E959.
ABSTRACT | FULL TEXT