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A Randomized, Double-blind, Placebo-controlled Study of Tumor Necrosis Factor- Blockade in Severe Persistent Asthma

Sally E. Wenzel^1,*, Peter J. Barnes², Eugene R. Bleecker³, Jean Bousquet⁴, William Busse⁵, Sven-Erik Dahlén⁶, Stephen T. Holgate⁷, Deborah A. Meyers³, Klaus F. Rabe⁸, Adam Antczak^9,, James Baker¹⁰, Ildiko Horvath¹¹, Zsuzsanna Mark¹², David Bernstein^13,, Edward Kerwin¹⁴, Rozsa Schlenker-Herceg¹⁵, Kim Hung Lo¹⁵, Rosemary Watt¹⁵, Elliot S. Barnathan¹⁵, Pascal Chanez^16,|| on behalf of the T03 Asthma Investigators

¹ Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; ² Airway Disease Section, National Heart & Lung Institute, Imperial College, London, United Kingdom; ³ Pulmonary/Critical Care Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina; ⁴ Clinique des Maladies Respiratoires, Hôpital Arnaud de Villeneuve, Montpellier, France; ⁵ Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin; ⁶ Unit for Experimental Asthma and Allergy Research, Karolinska Institutet, Stockholm, Sweden; ⁷ AIR Division, Southampton General Hospital, Southampton, United Kingdom; ⁸ Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands; ⁹ Prywatny Gabinet Specjalistyczny, Lodz, Poland; ¹⁰ Allergy, Asthma and Dermatology Research Center, LLC, Oswego, Oregon; ¹¹ National Koranyi TBC and Pulmonology Institute and Institute of Clinical Experimental Research, Semmelweis University, Budapest, Hungary; ¹² Pulmonary Medicine Institute Torokbalint, Torokbalint, Hungary; ¹³ Bernstein Allergy Group, Cincinnati, Ohio; ¹⁴ The Clinical Research Institute of Southern Oregon, PC, Medford, Oregon; and ¹⁵ Centocor Research & Development, Inc., Malvern, Pennsylvania; ¹⁶ Hôpital Arnaud de Villeneuve, Montpellier, France

Correspondence and requests for reprints should be addressed to Sally E. Wenzel, M.D., University of Pittsburgh Medical Center, NW 628 Montefiore, 3459 Fifth Avenue, Pittsburgh, PA 15213. E-mail: wenzelse{at}upmc.edu

Rationale: The treatment effect of golimumab, a human monoclonal antibody against tumor necrosis factor (TNF)-, in severe persistent asthma is unknown.

Objectives: To assess the safety and efficacy of golimumab in a large population of patients with uncontrolled, severe persistent asthma.

Methods: From 2004 to 2006, 309 patients with severe and uncontrolled asthma, despite high-dose inhaled corticosteroids and long-acting β₂ agonists, were randomized 1:1:1:1 to monthly subcutaneous injections of placebo or golimumab (50, 100, or 200 mg) through Week 52. Coprimary endpoints were the change from baseline through Week 24 in prebronchodilator percent-predicted FEV₁ and the number of severe asthma exacerbations through Week 24.

Measurements and Main Results: No significant differences were observed for the change in percent-predicted FEV₁ (least squares mean: placebo, 2.44 [95% confidence interval (CI) –0.574 to 5.461]; combined 100-mg and 200-mg, 2.91 [0.696–5.116]) or severe exacerbations (mean ± SD: placebo, 0.5 ± 1.07 vs. combined 100-mg and 200-mg 0.5 ± 0.97) through week 24. Through Week 24, 2.6% of patients treated with placebo vs. 19.5% of those treated with golimumab discontinued the study agent, and 1.3% and 7.8% discontinued study participation, respectively. An unfavorable risk–benefit profile led to early discontinuation of study-agent administration after the Week-24 database lock. Through Week 76, 20.5% of patients treated with placebo and 30.3% of patients treated with golimumab experienced serious adverse events, with serious infections occurring more frequently in golimumab-treated patients. One death and all eight malignancies occurred in the active groups.

Conclusions: Overall, treatment with golimumab did not demonstrate a favorable risk–benefit profile in this study population of patients with severe persistent asthma.

Clinical trial registered with www.clinicaltrials.gov (NCT00207740).

Key Words: golimumab • asthma • tumor necrosis factor-

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject The treatment effect of golimumab, a human monoclonal antibody against tumor necrosis factor-, in severe persistent asthma is unknown. What This Study Adds to the Field The unfavorable risk-benefit profile for golimumab in the overall population suggests that this therapeutic approach may not be suitable for all patients with asthma.

 

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