A randomized, double-blind, placebo-controlled study of tumor necrosis factor-alpha blockade in severe persistent asthma.

RATIONALE The treatment effect of golimumab, a human monoclonal antibody against tumor necrosis factor (TNF)-alpha, 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 beta(2) 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 FEV(1) 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).

[1]  E. Bleecker,et al.  Pharmacogenetic Identification of Increased Responsiveness in Severe Asthma with anti-TNF (Golimumab) Therapy , 2008 .

[2]  H. Wajant,et al.  Anti-tumor necrosis factor therapy inhibits pancreatic tumor growth and metastasis. , 2008, Cancer research.

[3]  R. Panettieri,et al.  Mitogenic Effects of Cytokines on Smooth Muscle Are Critically Dependent on Protein Kinase A and Are Unmasked by Steroids and Cyclooxygenase Inhibitors , 2008, Molecular Pharmacology.

[4]  S. Holgate,et al.  The role of a soluble TNFα receptor fusion protein (etanercept) in corticosteroid refractory asthma: a double blind, randomised, placebo controlled trial , 2008, Thorax.

[5]  M. Gore,et al.  Tumor necrosis factor alpha as a new target for renal cell carcinoma: two sequential phase II trials of infliximab at standard and high dose. , 2007, Journal of Clinical Oncology.

[6]  Stanley B. Cohen,et al.  Pharmacokinetics and Safety of Golimumab, a Fully Human Anti‐TNF‐α Monoclonal Antibody, in Subjects With Rheumatoid Arthritis , 2007, Journal of clinical pharmacology.

[7]  D. Curran‐Everett,et al.  Characterization of the severe asthma phenotype by the National Heart, Lung, and Blood Institute's Severe Asthma Research Program. , 2007, The Journal of allergy and clinical immunology.

[8]  P. Barnes,et al.  The Effects of a Monoclonal Antibody Directed against Tumor Necrosis Factor-α in Asthma , 2006 .

[9]  C. Iribarren,et al.  Risk factors for work disability in severe adult asthma. , 2006, The American journal of medicine.

[10]  S. Antoniu.  Targeting tumour necrosis factor-α in corticosteroid-dependent asthma , 2006 .

[11]  I. Buchan,et al.  Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. , 2006, JAMA.

[12]  M. Leinonen,et al.  Pathogenic bacteria and viruses in induced sputum or pharyngeal secretions of adults with stable asthma , 2006, Thorax.

[13]  I. Pavord,et al.  Evidence of a role of tumor necrosis factor alpha in refractory asthma. , 2006, The New England journal of medicine.

[14]  L. G. García Rodríguez,et al.  Cancer incidence in a general population of asthma patients , 2006, Pharmacoepidemiology and drug safety.

[15]  Yu Wang,et al.  TSLP-activated dendritic cells induce an inflammatory T helper type 2 cell response through OX40 ligand , 2005, The Journal of experimental medicine.

[16]  B. Sherrill,et al.  Cancer risk in asthmatic populations. , 2005, Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology.

[17]  P. Howarth,et al.  Tumour necrosis factor (TNFalpha) as a novel therapeutic target in symptomatic corticosteroid dependent asthma. , 2005, Thorax.

[18]  J. Bousquet,et al.  The public health implications of asthma. , 2005, Bulletin of the World Health Organization.

[19]  M. Mills,et al.  Prevalence of gastroesophageal reflux in difficult asthma: relationship to asthma outcome. , 2005, Chest.

[20]  C. Tai,et al.  Neuropathology in rhinosinusitis. , 2005, American journal of respiratory and critical care medicine.

[21]  C. Bucca,et al.  Asthma severity and medical resource utilisation , 2004, European Respiratory Journal.

[22]  C. Jenkins,et al.  Systematic review of prevalence of aspirin induced asthma and its implications for clinical practice , 2004, BMJ : British Medical Journal.

[23]  S. Wenzel,et al.  Distinguishing severe asthma phenotypes: role of age at onset and eosinophilic inflammation. , 2004, The Journal of allergy and clinical immunology.

[24]  R. Panettieri,et al.  Tumor Necrosis Factor α Modulates Airway Smooth Muscle Function via the Autocrine Action of Interferon β* , 2003, Journal of Biological Chemistry.

[25]  D. Postma,et al.  The ENFUMOSA cross-sectional European multicentre study of the clinical phenotype of chronic severe asthma , 2003, European Respiratory Journal.

[26]  I. Tillie‐Leblond,et al.  Chronic bronchial allergic inflammation increases alveolar liquid clearance by TNF-alpha -dependent mechanism. , 2002, American journal of physiology. Lung cellular and molecular physiology.

[27]  P. Thomas,et al.  Effects of inhaled tumour necrosis factor alpha in subjects with mild asthma , 2002, Thorax.

[28]  P Godard,et al.  Costs of asthma are correlated with severity: a 1-yr prospective study , 2002, European Respiratory Journal.

[29]  A. Draper,et al.  Occupational Asthma , 2002, The Journal of asthma : official journal of the Association for the Care of Asthma.

[30]  E. Bleecker,et al.  Subjects with mild and moderate asthma respond to segmental allergen challenge with similar, reproducible, allergen-specific inflammation. , 2001, The Journal of allergy and clinical immunology.

[31]  A. Zwinderman,et al.  Factors associated with persistent airflow limitation in severe asthma. , 2001, American journal of respiratory and critical care medicine.

[32]  A. Zwinderman,et al.  Persistent airflow limitation in adult-onset nonatopic asthma is associated with serologic evidence of Chlamydia pneumoniae infection. , 2001, The Journal of allergy and clinical immunology.

[33]  S. Wenzel,et al.  Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. , 1999, American journal of respiratory and critical care medicine.

[34]  V. Plaza,et al.  Costs of asthma according to the degree of severity. , 1998, The European respiratory journal.

[35]  G. Bonsignore,et al.  Effect of age upon airway obstruction and reversibility in adult patients with asthma. , 1998, Chest.

[36]  S. Szefler,et al.  Difficult-to-control asthma: clinical characteristics of steroid-insensitive asthma. , 1998, The Journal of allergy and clinical immunology.

[37]  D. Yates,et al.  Tumor necrosis factor-alpha increases airway responsiveness and sputum neutrophilia in normal human subjects. , 1995, American journal of respiratory and critical care medicine.

[38]  C. Bronner,et al.  Potentiation by tumour necrosis factor‐α of calcium signals induced by bradykinin and carbachol in human tracheal smooth muscle cells , 1995, British journal of pharmacology.

[39]  P. Mäkelä,et al.  Risk factors for pneumonia in the elderly. , 1994, The American journal of medicine.

[40]  E. Pukkala,et al.  Cancer incidence among 78,000 asthmatic patients. , 1993, International journal of epidemiology.

[41]  B. Källén,et al.  Cancer risk in asthmatic subjects selected from hospital discharge registry. , 1993, The European respiratory journal.

[42]  A. Inglot,et al.  Elevated release of tumor necrosis factor-alpha and interferon-gamma by bronchoalveolar leukocytes from patients with bronchial asthma. , 1993, The American review of respiratory disease.

[43]  C. Smith,et al.  Induction of ICAM-1 expression on human airway epithelial cells by inflammatory cytokines: effects on neutrophil-epithelial cell adhesion. , 1992, American journal of respiratory cell and molecular biology.

[44]  D. Broide,et al.  Cytokines in symptomatic asthma airways. , 1992, The Journal of allergy and clinical immunology.

[45]  G. Guyatt,et al.  Evaluation of impairment of health related quality of life in asthma: development of a questionnaire for use in clinical trials. , 1992, Thorax.

[46]  A. Capron,et al.  Potential implication of endothelial cells in bronchial asthma. , 1991, International archives of allergy and applied immunology.

[47]  Y. Hochberg.  A sharper Bonferroni procedure for multiple tests of significance , 1988 .

[48]  D. Rubin,et al.  Statistical Analysis with Missing Data. , 1989 .

[49]  S. Pocock,et al.  Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial. , 1975, Biometrics.