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

¹ University of Nebraska Medical Center, Omaha, Nebraska; ² Spartanburg Pharmaceutical Research, Spartanburg, South Carolina; ³ Temple University Medical Center, Philadelphia, Pennsylvania; ⁴ Neem Research Group, Charlotte, North Carolina; ⁵ University of California, San Diego, Clinical Trials Center, San Diego, California; ⁶ Neem Research Group, Columbia, South Carolina; ⁷ Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire; ⁸ Amarillo Center for Clinical Research, Ltd., Amarillo, Texas; ⁹ Midwest Chest Consultants, P.C., St. Charles, Missouri; ¹⁰ Mountain View Clinical Research, Inc., Greer, South Carolina; ¹¹ The Clinical Research Center, LLC, St. Louis, Missouri; ¹² New Orleans Center for Clinical Research, New Orleans, Louisiana; ¹³ Minnesota Lung Center, Minneapolis, Minnesota; ¹⁴ Pulmonary Research Associates, LLC, Larchmont, New York; ¹⁵ Lung Diagnostics, Ltd., San Antonio, Texas; ¹⁶ Red Rock Research Center, Las Vegas, Nevada; ¹⁷ University of North Carolina, Chapel Hill, North Carolina; ¹⁸ Centocor Research and Development, Inc., Malvern, Pennsylvania; and ¹⁹ Vanderbilt University Medical Center, Nashville, Tennessee

Correspondence and requests for reprints should be addressed to Stephen I. Rennard, M.D., University of Nebraska Medical Center, 985125 Nebraska Medical Center, Omaha, NE 68198. E-mail: srennard{at}unmc.edu

Rationale: Chronic obstructive pulmonary disease (COPD) is a progressive, smoking-related, inflammatory lung disease in which tumor necrosis factor- is overexpressed and has been suggested to play a pathogenic role.

Objectives: To determine if infliximab, an anti–TNF- antibody, results in clinical benefit and has an acceptable safety profile in patients with moderate to severe COPD.

Methods: In 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, but showed no treatment benefit as measured by the primary endpoint, Chronic Respiratory Questionnaire total score. Similarly, there was no change in secondary measures, including prebronchodilator FEV₁, 6-min walk distance, SF-36 physical score, transition dyspnea index, or moderate-to-severe COPD exacerbations. Post hoc analysis revealed that subjects who were younger or cachectic showed improvement in the 6-min walk distance. Malignancies were diagnosed during the study in 9 of 157 infliximab-treated subjects versus 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 the study agent due to adverse events (20–27%) than did placebo-treated subjects (9%).

Conclusions: Subjects with moderate to severe COPD did not benefit from treatment with infliximab. Although not statistically significant, more cases of cancer and pneumonia were observed in the infliximab-treated subjects. The impact of infliximab on malignancy risk in patients with COPD needs to be further elucidated.

Key Words: chronic obstructive pulmonary disease • infliximab • tumor necrosis factor-

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Tumor necrosis factor (TNF)- has been suggested to play a pathophysiologic role in chronic obstructive pulmonary disease. The therapeutic benefit of TNF- antagonism is unknown. What This Study Adds to the Field This study demonstrates lack of clinical effect of anti-TNF antibody (infliximab) in patients with moderate to severe chronic obstructive pulmonary disease.

 

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