评估两种剂量的多克隆抗肿瘤坏死因子-α 片段抗体 AZD9773 治疗成人严重脓毒症和/或脓毒性休克患者的疗效和安全性：随机、双盲、安慰剂对照的 IIb 期研究*。

Evaluating the efficacy and safety of two doses of the polyclonal anti-tumor necrosis factor-α fragment antibody AZD9773 in adult patients with severe sepsis and/or septic shock: randomized, double-blind, placebo-controlled phase IIb study*.

机构信息

1Division of Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, TN. 2Service de Réanimation Polyvalente, CIC-P 0801, CHU Dupuytren, Limoges, Cedex, France. 3Hôpitaux Paris Centre, AP-HP; Université Paris Descartes, Faculté de médecine, Paris, France and Cochin Institute, INSERM U567, CNRS UMR 8104, Paris, France. 4Department of Intensive Care, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium. 5Department of Medicine, Cooper University Hospital, Camden, NJ. 6Centre for Heart Lung Innovation, University of British Columbia, Vancouver, BC, Canada. 7Division of Infectious Diseases, Beverly Hospital, Beverly, MA. 8Critical Care Department, St Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium. 9Department of Medicine, Brown University, Providence, RI. 10Worldwide Medical Services Department, PAREXEL International, Durham, NC. 11AstraZeneca, Alderley Park, Macclesfield, United Kingdom.

出版信息

Crit Care Med. 2014 Mar;42(3):504-11. doi: 10.1097/CCM.0000000000000043.

DOI:10.1097/CCM.0000000000000043

PMID:24335445

Abstract

OBJECTIVE

This trial compared the efficacy/safety of two IV doses of AZD9773, a polyclonal antibody to tumor necrosis factor-α, in adult patients with severe sepsis/septic shock.

DESIGN

Multicenter, randomized, double-blind, placebo-controlled phase IIb trial.

SETTING

ICUs in seven countries (Australia, Belgium, Canada, Czech Republic, Finland, France, and Spain).

PATIENTS

Patients 18 years old or older with severe sepsis and/or septic shock. Patients were required to have 1) objective clinical evidence of infection; 2) at least two of four systemic inflammatory response syndrome criteria; and 3) cardiovascular and/or respiratory sepsis-related failure.

INTERVENTIONS

Patients were randomized 1:1:1 to a single loading infusion of AZD9773 250 U/kg followed by 50 U/kg every 12 hours (low dose, n = 100), a single loading infusion of AZD9773 500 U/kg followed by 100 U/kg every 12 hours (high dose, n = 100), or placebo (n = 100) for 5 days. Follow-up assessments were performed up to day 90.

MEASUREMENTS AND MAIN RESULTS

Mean number of ventilator-free days (primary endpoint) did not differ between low-dose (19.7 d) or high-dose AZD9773 (17.3 d) and placebo (18.3 d) (one-sided p = 0.18 and 0.74, respectively). Mortality rates were comparable across treatment groups; relative risk of death versus placebo at day 29 was 0.80 for low-dose AZD9773 (one-sided p = 0.25) and 1.64 for high-dose AZD9773 (p = 0.97). Most patients experienced at least one treatment-emergent adverse event (87.8% in AZD9773-treated patients, 92.9% in placebo patients) although most were mild/moderate in nature. No differences in the incidence of adverse events or laboratory or vital sign abnormalities were observed between groups.

CONCLUSIONS

AZD9773 rapidly and efficiently decreased plasma tumor necrosis factor-α concentration in patients with severe sepsis/septic shock, but this effect did not translate into clinical benefit.

摘要

目的

本试验比较了两种静脉剂量的 AZD9773（一种针对肿瘤坏死因子-α 的多克隆抗体）在成年严重脓毒症/脓毒性休克患者中的疗效/安全性。

设计

多中心、随机、双盲、安慰剂对照的 2b 期试验。

设置

七个国家（澳大利亚、比利时、加拿大、捷克共和国、芬兰、法国和西班牙）的 ICU。

患者

18 岁或以上的严重脓毒症和/或脓毒性休克患者。患者需要有 1）感染的客观临床证据；2）全身炎症反应综合征标准中的至少两个；3）心血管和/或呼吸与脓毒症相关的衰竭。

干预

患者随机分为 1:1:1 接受 AZD9773 250 U/kg 的单次负荷输注，然后每 12 小时给予 50 U/kg（低剂量组，n=100）、AZD9773 500 U/kg 的单次负荷输注，然后每 12 小时给予 100 U/kg（高剂量组，n=100）或安慰剂（n=100），连续 5 天。随访评估至第 90 天。

测量和主要结果

无机械通气天数（主要终点）在低剂量（19.7 天）或高剂量 AZD9773（17.3 天）和安慰剂（18.3 天）之间无差异（单侧 p=0.18 和 0.74，分别）。治疗组死亡率相当；低剂量 AZD9773 与安慰剂相比，第 29 天的死亡相对风险为 0.80（单侧 p=0.25），高剂量 AZD9773 为 1.64（p=0.97）。大多数患者发生至少一次治疗中出现的不良事件（AZD9773 治疗患者中为 87.8%，安慰剂患者中为 92.9%），但大多数为轻度/中度。各组间不良事件发生率、实验室或生命体征异常无差异。