A randomized, double-blind, placebo-controlled study of tumor necrosis factor-alpha blockade in severe persistent asthma.
BACKGROUND
The treatment effect of golimumab, a human monoclonal antibody against tumor necrosis factor (TNF)-alpha, in severe persistent asthma is unknown.


OBJECTIVE
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.


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).
Wenzel
Sally E
SE
Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213, USA. wenzelse@upmc.edu
Barnes
Peter J
PJ
Bleecker
Eugene R
ER
Bousquet
Jean
J
Busse
William
W
Dahlén
Sven-Erik
SE
Holgate
Stephen T
ST
Meyers
Deborah A
DA
Rabe
Klaus F
KF
Antczak
Adam
A
Baker
James
J
Horvath
Ildiko
I
Mark
Zsuzsanna
Z
Bernstein
David
D
Kerwin
Edward
E
Schlenker-Herceg
Rozsa
R
Lo
Kim Hung
KH
Watt
Rosemary
R
Barnathan
Elliot S
ES
Chanez
Pascal
P
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D001249:Asthma / Q000188:drug therapy* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D007239:Infections / Q000209:etiology; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D000911:Antibodies, Monoclonal; D014409:Tumor Necrosis Factor-alpha; C529000:golimumab