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Treatment of Septic Shock with Human Monoclonal Antibody HA-1A: A Randomized, Double-Blind, Placebo-Controlled Trial

Richard V. McCloskey, MD; Richard C. Straube, MD; Corazon Sanders, PhD; Susan M. Smith, RN; Craig R. Smith, MD, CHESS Trial Study Group.
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From Centocor, Inc., Malvern, Pennsylvania. Requests for Reprints: Richard V. McCloskey, MD, Vice President, Clinical Research, Centocor, Inc., 200 Great Valley Parkway, Malvern, PA 19355. Acknowledgments: The members of the Safety and Efficacy Monitoring Committee were Richard Platt, MD, Channing Laboratories, 180 Longwood Avenue, Boston, MA 02115; Rob Roy MacGregor, MD, Chief, Department of Infectious Disease, University of Pennsylvania, 536 Johnson—6073, Philadelphia, PA 19103; Frank Cerra, MD, Professor of Surgery, University of Minnesota Hospital & Clinic, Box 42 Mayo, 406 Harvard Street SE, Minneapolis, MN 55455; Kuang-Kuo Gordon Lan, PhD, Professor, Statistics, George Washington University Biostatistics Center, 6110 Executive Building, Suite 750, Rockville, MD 20852; Canon Michael Hamilton, Washington National Cathedral, Massachusetts and Wisconsin Avenues, NW, Washington, DC 20016; and Richard V. McCloskey, MD, Vice President, Clinical Research, Centocor, Inc., 200 Great Valley Parkway, Malvern, PA 19355. Grant Support: By Centocor, Inc.

Copyright ©2004 by the American College of Physicians

Ann Intern Med. 1994;121(1):1-5. doi:10.7326/0003-4819-121-1-199407010-00001
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Objective: To compare the effectiveness of 100 mg of HA-1A and placebo in reducing the 14-day all-cause mortality rate in patients with septic shock and gram-negative bacteremia in the Centocor: HA-1A Efficacy in Septic Shock (CHESS) trial, and to assess the safety of 100 mg of HA-1A given to patients with septic shock who did not have gram-negative bacteremia.

Design: Large, simple, group-sequential, randomized, double-blind, multicenter, placebo-controlled trial.

Setting: 603 investigators at 513 community and university-affiliated hospitals in the United States.

Patients: Within 6 hours before enrollment, the patients had been in shock with a systolic blood pressure of less than 90 mm Hg after adequate fluid challenge or had received vasopressors to maintain blood pressure. These episodes of shock began within 24 hours of enrollment. A presumptive clinical diagnosis of gram-negative infection as the cause of the shock episode and a commitment from the patients' physicians to provide full supportive care were required.

Measurements: Blood cultures were obtained within 48 hours of enrollment, and death at day 14 after treatment was recorded. Adverse events occurring within 14 days after enrollment were also tabulated.

Results: 2199 patients were enrolled; 621 (28.2%) met all enrollment criteria, received HA-1A or placebo, and had confirmed gram-negative bacteremia. Mortality rates in this group were as follows: placebo, 32% (95 of 293) and HA-1A, 33% (109 of 328) (P = 0.864, Fisher exact test, two-tailed; 95% CI for the difference, −6.2% to 8.6%). Mortality rates in the patients without gram-negative bacteremia were as follows: placebo, 37% (292 of 793) and HA-1A, 41% (318 of 785) (P = 0.073, Fisher exact test, one-tailed; CI, −0.8% to 8.8%).

Conclusions: In this trial, HA-1A was not effective in reducing the 14-day mortality rate in patients with gram-negative bacteremia and septic shock. These data do not support using septic shock as an indication for HA-1A treatment. If HA-1A is effective in reducing the mortality rate in patients dying from endotoxemia, these patients must be identified using other treatment criteria.





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