Effect of Bamlanivimab as Monotherapy or in Combination With Etesevimab on Viral Load in Patients With Mild to Moderate COVID-19 A Randomized Clinical Trial
Effect of Bamlanivimab as Monotherapy or in Combination With Etesevimab on Viral Load in Patients With Mild to Moderate COVID-19 A Randomized Clinical Trial
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DOI：
10.1001/jama.2021.0202
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发表时间：
2021-01-21
影响因子：
120.7
通讯作者：
Skovronsky, Daniel M.
中科院分区：
文献类型：
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作者：
Gottlieb, Robert L.;Nirula, Ajay;Skovronsky, Daniel M.
2019冠状病毒病（COVID-19）继续在全球迅速蔓延。中和抗体是治疗COVID-19的一种潜在方法。目的观察bamlanivimab单药治疗和bamlanivimab与etesevimab联合治疗严重急性呼吸综合征冠状病毒2型（SARS冠状病毒2型）的疗效（SARS-CoV-2）病毒载量在轻至中度COVID-19中的作用。设计，地点，BLAZE-1研究是一项在49个美国中心进行的随机2/3期试验，包括SARS-CoV检测阳性的非卧床患者（N = 613）。2例感染，并有1个或多个轻度至中度症状。首先入组接受bamlanivimab单药治疗或安慰剂治疗的患者（2020年6月17日至8月21日），然后入组接受bamlanivimab和etesevimab或安慰剂治疗的患者（8月22日至9月3日）。这些是最终分析，代表了截至2020年10月6日的结果。干预患者随机接受单次bamlanivimab输注（700 mg [n = 101]、2800 mg [n = 107]或7000 mg [n = 101]），联合治疗（2800 mg bamlanivimab和2800 mg etesevimab [n = 112]）或安慰剂（n = 156）。主要结果和测量主要终点是第11天（+/-4天）SARS-CoV-2病毒载量对数的变化。通过比较每个治疗组和安慰剂组，评价了9个预先设定的次要结局指标，包括3个其他病毒载量指标，5个症状指标和1个临床结局指标（与COVID-19相关的住院、急诊[艾德]就诊、结果577例患者随机接受静脉滴注，（平均年龄，44.7 [SD，15.7]岁; 315例[54.6%]女性），533例（92.4%）完成疗效评价期（第29天）。第11天，700 mg组、2800 mg组、7000 mg组、联合治疗组和安慰剂组的病毒载量对数相对于基线的变化分别为-3.72、-4.08、-3.49、-4.37和-3.80。与安慰剂相比，第11天病毒载量对数变化的差异为0.09（95% CI，-0.35至0.52; P = .69）700 mg，-0.27（95% CI，-0.71至0.16; P = .21），7000 mg为0.31（95% CI，-0.13至0.76; P = .16），联合治疗为-0.57（95% CI，-1.00至0.14; P = .01）。在次要结局指标中，各治疗组与安慰剂组之间的差异在84个终点中有10个具有统计学意义。安慰剂组发生COVID-19相关住院或艾德访视的患者比例为5.8%（9起事件），700 mg组为1.0%（1起事件），2800 mg组为1.9%（2起事件），7000 mg组为2.0%（2起事件），联合治疗组为0.9%（1起事件）。9例患者报告了速发型超敏反应（6例bamlanivimab，2例联合治疗，1例安慰剂）。结论和相关性在轻度至中度COVID-19疾病的非住院患者中，与安慰剂相比，bamlanivimab和etesevimab治疗与第11天SARS-CoV-2病毒载量的统计学显著降低相关; bamlanivimab单药治疗在病毒载量降低方面没有观察到显著差异。进一步正在进行的临床试验将重点评估抗刺突中和抗体在COVID-19患者中的临床获益，并将其作为主要终点。
IMPORTANCE Coronavirus disease 2019 (COVID-19) continues to spread rapidly worldwide. Neutralizing antibodies are a potential treatment for COVID-19.OBJECTIVE To determine the effect of bamlanivimab monotherapy and combination therapy with bamlanivimab and etesevimab on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load in mild to moderate COVID-19.DESIGN, SETTING, AND PARTICIPANTS The BLAZE-1 study is a randomized phase 2/3 trial at 49 US centers including ambulatory patients (N = 613) who tested positive for SARS-CoV-2 infection and had 1 or more mild to moderate symptoms. Patients who received bamlanivimab monotherapy or placebo were enrolled first (June 17-August 21, 2020) followed by patients who received bamlanivimab and etesevimab or placebo (August 22-September 3). These are the final analyses and represent findings through October 6, 2020.INTERVENTIONS Patients were randomized to receive a single infusion of bamlanivimab (700 mg [n = 101], 2800 mg [n = 107], or 7000 mg [n = 101]), the combination treatment (2800 mg of bamlanivimab and 2800 mg of etesevimab [n = 112]), or placebo (n = 156).MAIN OUTCOMES AND MEASURES The primary end point was change in SARS-CoV-2 log viral load at day 11 (+/- 4 days). Nine prespecified secondary outcome measures were evaluated with comparisons between each treatment group and placebo, and included 3 other measures of viral load, 5 on symptoms, and 1 measure of clinical outcome (the proportion of patients with a COVID-19-related hospitalization, an emergency department [ED] visit, or death at day 29).RESULTS Among the 577 patients who were randomized and received an infusion (mean age, 44.7 [SD, 15.7] years; 315 [54.6%] women), 533 (92.4%) completed the efficacy evaluation period (day 29). The change in log viral load from baseline at day 11 was -3.72 for 700 mg, -4.08 for 2800 mg, -3.49 for 7000 mg, -4.37 for combination treatment, and -3.80 for placebo. Compared with placebo, the differences in the change in log viral load at day 11 were 0.09 (95% CI, -0.35 to 0.52; P = .69) for 700 mg, -0.27 (95% CI, -0.71 to 0.16; P = .21) for 2800 mg, 0.31 (95% CI, -0.13 to 0.76; P = .16) for 7000 mg, and -0.57 (95% CI, -1.00 to -0.14; P = .01) for combination treatment. Among the secondary outcome measures, differences between each treatment group vs the placebo group were statistically significant for 10 of 84 end points. The proportion of patients with COVID-19-related hospitalizations or ED visits was 5.8% (9 events) for placebo, 1.0% (1 event) for 700 mg, 1.9% (2 events) for 2800 mg, 2.0% (2 events) for 7000 mg, and 0.9% (1 event) for combination treatment. Immediate hypersensitivity reactions were reported in 9 patients (6 bamlanivimab, 2 combination treatment, and 1 placebo). No deaths occurred during the study treatment.CONCLUSIONS AND RELEVANCE Among nonhospitalized patients with mild to moderate COVID-19 illness, treatment with bamlanivimab and etesevimab, compared with placebo, was associated with a statistically significant reduction in SARS-CoV-2 viral load at day 11; no significant difference in viral load reduction was observed for bamlanivimab monotherapy. Further ongoing clinical trials will focus on assessing the clinical benefit of antispike neutralizing antibodies in patients with COVID-19 as a primary end point.