Lim Jeremy J, Nilsson Anna C, Silverman Michael, Assy Nimer, Kulkarni Priya, McBride Jacqueline M, Deng Rong, Li Chloe, Yang Xiaoying, Nguyen Allen, Horn Priscilla, Maia Mauricio, Castro Aide, Peck Melicent C, Galanter Joshua, Chu Tom, Newton Elizabeth M, Tavel Jorge A
Genentech, Inc., South San Francisco, California, USA
Department of Translational Medicine, Infectious Diseases Research Unit, Lund University, Malmö, Sweden.
Antimicrob Agents Chemother. 2020 Jun 23;64(7). doi: 10.1128/AAC.00352-20.
For patients hospitalized with severe influenza A virus infection, morbidity and mortality remain high. MHAA4549A, a human monoclonal antibody targeting the influenza A virus hemagglutinin stalk, has demonstrated pharmacological activity in animal studies and in a human influenza A challenge study. We evaluated the safety and efficacy of MHAA4549A plus oseltamivir against influenza A virus infection in hospitalized patients. The CRANE trial was a phase 2b randomized, double-blind, placebo-controlled study of single intravenous (i.v.) doses of placebo, 3,600 mg MHAA4549A, or 8,400 mg MHAA4549A each combined with oral oseltamivir (+OTV) in patients hospitalized with severe influenza A virus infection. Patients, enrolled across 68 clinical sites in 18 countries, were randomized 1:1:1. The primary outcome was the median time to normalization of respiratory function, defined as the time to removal of supplemental oxygen support to maintain a stable oxygen saturation (SpO) of ≥95%. Safety, pharmacokinetics, and effects on influenza viral load were also assessed. One hundred sixty-six patients were randomized and analyzed during a preplanned interim analysis. Compared to placebo+OTV, MHAA4549A+OTV did not significantly reduce the time to normalization of respiratory function (placebo+OTV, 4.28 days; 3,600 mg MHAA4549A+OTV, 2.78 days; 8,400 mg MHAA4549A+OTV, 2.65 days), nor did it improve other secondary clinical outcomes. Adverse event frequency was balanced across cohorts. MHAA4549A+OTV did not further reduce viral load versus placebo+OTV. In hospitalized patients with influenza A virus infection, MHAA4549A did not improve clinical outcomes over OTV alone. Variability in patient removal from oxygen supplementation limited the utility of the primary endpoint. Validated endpoints are needed to assess novel treatments for severe influenza A virus infection. (This study has been registered at ClinicalTrials.gov under registration no. NCT02293863.).
对于因感染甲型流感病毒而住院的患者，其发病率和死亡率仍然很高。MHAA4549A是一种靶向甲型流感病毒血凝素茎部的人源单克隆抗体，已在动物研究和一项人类甲型流感激发试验中显示出药理活性。我们评估了MHAA4549A联合奥司他韦治疗住院患者甲型流感病毒感染的安全性和有效性。CRANE试验是一项2b期随机、双盲、安慰剂对照研究，对因严重甲型流感病毒感染住院的患者单次静脉注射安慰剂、3600mg MHAA4549A或8400mg MHAA4549A，每种药物均联合口服奥司他韦（+OTV）。在18个国家的68个临床地点招募患者，随机分为1:1:1。主要结局是呼吸功能恢复正常的中位时间，定义为停止补充氧气支持以维持稳定的氧饱和度（SpO）≥95%的时间。还评估了安全性、药代动力学以及对流感病毒载量的影响。在一项预先计划的中期分析中，对166名患者进行了随机分组和分析。与安慰剂+OTV相比，MHAA4549A+OTV并未显著缩短呼吸功能恢复正常的时间（安慰剂+OTV为4.28天；3600mg MHAA4549A+OTV为2.78天；8400mg MHAA4549A+OTV为2.65天），也未改善其他次要临床结局。各队列的不良事件发生率相当。与安慰剂+OTV相比，MHAA4549A+OTV并未进一步降低病毒载量。在感染甲型流感病毒的住院患者中，与单独使用OTV相比，MHAA4549A并未改善临床结局。患者停止吸氧的差异限制了主要终点的效用。需要经过验证的终点来评估严重甲型流感病毒感染的新疗法。（本研究已在ClinicalTrials.gov注册，注册号为NCT02293863。）
