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Published ahead of print on February 8, 2007, doi:10.1164/rccm.200607-995OC

Am. J. Respir. Crit. Care Med., Volume 175, Number 9, May 2007, 926-934

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Submitted on July 21, 2006
Accepted on February 8, 2007

The Safety and Efficacy of Infliximab in Moderate-To-Severe Chronic Obstructive Pulmonary Disease

Stephen I Rennard1*, Charles Fogarty2, Steven Kelsen3, Wiliam Long4, Joe Ramsdell5, James Allison6, Donald Mahler7, Constantine Saadeh8, Thomas Siler9, Phillip Snell10, Phillip Korenblat11, William Smith12, Mitchell Kaye13, Michael Mandel14, Charles Andrews15, Rachakonda Prabhu16, James F Donohue17, Rosemary Watt18, Kim Hung Lo18, and Rozsa Schlenker-Herceg18

1 University of Nebraska Medical Center, Omaha, NE, USA, 2 Spartanburg Pharmaceutical Research, Spartanburg, SC, USA, 3 Temple University Medical Center, Philadelphia, PA, USA, 4 Neem Research Group, Charlotte, NC, USA, 5 UCSD Clinical Trials Center, San Diego, CA, USA, 6 Neem Research Group, Columbia, SC, USA, 7 Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA, 8 Amarillo Center for Clinical Research, Ltd., Amarillo, TX, USA, 9 Midwest Chest Consultants, P.C., St. Charles, MO, USA, 10 Mountain View Clinical Research, Inc., Greer, SC, USA, 11 The Clinical Research Center, LLC, St. Louis, MO, USA, 12 New Orleans Center for Clinical Research, New Orleans, LA, USA, 13 Minnesota Lung Center, Minneapolis, MN, USA, 14 Pulmonary Research Associates, LLC, Larchmont, NY, USA, 15 Lung Diagnostics, Ltd., San Antonio, TX, USA, 16 Red Rock Research Center, Las Vegas, NV, USA, 17 University of North Carolina, Chapel Hill, NC, USA, 18 Centocor, Inc., Malvern, PA, USA

* To whom correspondence should be addressed. E-mail: srennard{at}unmc.edu.

Rationale: Chronic obstructive pulmonary disease (COPD) is a progressive, smoking-related, inflammatory lung disease in which TNF{alpha} has been suggested to play a pathogenic role. Methods: A multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-finding study, subjects with moderate-to-severe COPD received infliximab (3 mg/kg [n=78] or 5 mg/kg [n=79]) or placebo (n=77) at weeks 0, 2, 6, 12, 18, and 24. Efficacy, health status and safety were assessed through week 44. Measurements and Main Results: Infliximab was generally well tolerated. However, infliximab showed no treatment benefit as measured by the primary endpoint, Chronic Respiratory Questionnaire total score. Similarly, there was no change in secondary measures, including pre-bronchodilator FEV1, 6-minute walk distance, SF-36 physical score, transition dyspnea index or in moderate/severe COPD exacerbations. Post-hoc analysis revealed that subjects who were younger or cachectic showed improvement in the 6-minute walk distance. Malignancies were diagnosed during the study in 9 of 157 infliximab-treated subjects vs. 1 of 77 placebo-treated subjects. No opportunistic infections were observed and there were no differences in the occurrence of antibiotic-requiring infections, although the incidence of pneumonia was higher in infliximab-treated subjects. No infection-related mortality was observed. Higher proportions of infliximab-treated subjects discontinued study agent due to adverse events (20-27%) than did placebo-treated (9%). Conclusions: Subjects with moderate-to severe-COPD did not benefit from treatment with infliximab. While not statistically significant, more cases of cancer and pneumonia were observed in the infliximab-treated subjects. The impact of infliximab on malignancy risk in COPD subjects needs to be further elucidated.
Key words: COPD, infliximab, TNF-[(alpha)]




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