TNF-α阻滞剂治疗重症持续期哮喘患者的随机、双盲、安慰剂对照研究
2009/03/18
理论基础：golimumab是一种人类抗肿瘤坏死因子α（TNF-α）的单克隆抗体，它在重症哮喘持续期患者治疗中的作用目前还不清楚。
目的：评价golimumab在治疗一个大样本的、未控制的重症持续期哮喘患者的安全性和有效性。
方法：在2004～2006年期间，选择309名重症哮喘患者，他们尽管使用了大剂量的吸入性糖皮质激素和长效β2受体激动剂，但其哮喘仍得不到控制，以1:1:1:1的比例随机分为4组，分别给予皮下注射安慰剂或50 mg、100 mg、200 mg的golimumab，每月注射1次，治疗52周。主要终点是治疗24周后使用支气管扩张剂前FEV1占预计值百分比和重症哮喘恶化的次数，与基线水平相比而发生的变化。
检测主要结果：治疗24周后FEV1占预计值百分比（最小二乘均数：安慰剂对照组为2.44 [95% CI，-0.574-5.461]；100 mg和200 mg golimumab治疗组为2.91 [95% CI，0.696-5.116]），及重症哮喘恶化的次数（均数±标准差：安慰剂对照组为0.5±1.07；100 mg和200 mg golimumab治疗组为0.5±0.97）均无显著变化。24周期间，安慰剂对照组和golimumab治疗组中分别有2.6%和19.5%的患者停止服药，分别有1.3%和7.8%的患者退出研究。在24周数据库锁定后风险—效益评估不太令人满意，因此患者很早就停止服药。至76周时，安慰剂对照组和golimumab治疗组中分别有20.5%和30.3%的患者发生严重不良反应（SAEs），golimumab治疗组中发生严重感染的患者更多。1例死亡和8例恶性肿瘤均发生在治疗组。
结论：总的说来，在本研究选取的重症哮喘持续期患者的人群中，golimumab治疗的风险—疗效评估并不令人满意。
（苏楠 审校）
Am J Respir Crit Care Med. 2009 Jan 8.
Wenzel SE, et al. Am J Respir Crit Care Med. 2009 Jan 8. [Epub ahead of print]
A Randomized, Double-blind, Placebo-controlled Study of TNF-{alpha} Blockade in Severe Persistent Asthma.
RATIONALE: The treatment effect of golimumab, a human monoclonal antibody against tumor necrosis factor-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 asthma, uncontrolled despite high-dose inhaled corticosteroids and long-acting beta2 agonists, were randomized 1:1:1:1 to monthly subcutaneous injections of placebo or golimumab (50, 100, or 200mg) through week 52. Co-primary endpoints were change from baseline through week 24 in prebronchodilator percent-predicted FEV1 and number of severe asthma exacerbations through week 24.
MEASUREMENTS AND MAIN RESULTS: No significant differences were observed for change in percent-predicted FEV1 (LS mean: placebo 2.44 [95% CI -0.574-5.461], combined 100 and 200mg 2.91 [0.696-5.116]) or severe exacerbations (mean+/-SD: placebo 0.5+/-1.07 versus combined 100 and 200 mg 0.5+/-0.97) through week 24. Through week 24, 2.6% of placebo- versus 19.5% of golimumab-treated patients discontinued study agent, and 1.3% and 7.8%, respectively, discontinued study participation. An unfavorable risk-benefit profile led to early discontinuation of study-agent administration after the week-24 database lock. Through week 76, 20.5% placebo- and 30.3% golimumab-treated patients experienced SAEs, with serious infections occurring more frequently in golimumab-treated patients. One death and all 8 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 Registration: NCT00207740 registered at www.clinicaltrials.gov.
