Early treatment with baloxavir marboxil in high-risk adolescent and adult outpatients with uncomplicated influenza (CAPSTONE-2): a randomised, placebo-controlled, phase 3 trial
Early treatment with baloxavir marboxil in high-risk adolescent and adult outpatients with uncomplicated influenza (CAPSTONE-2): a randomised, placebo-controlled, phase 3 trial
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DOI：
10.1016/51473-3099(20)30004-9
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发表时间：
2020-10-01
影响因子：
56.3
通讯作者：
Hayden, Frederick G.
中科院分区：
文献类型：
--
作者：
Ison, Michael G.;Portsmouth, Simon;Hayden, Frederick G.
Baloxavir marboxil（以下简称Baloxavir）是一种流感帽依赖性核酸内切酶的选择性抑制剂，于2018年在美国和日本被批准用于治疗12岁及以上健康个体的无并发症流感。我们的目的是研究巴洛韦在发生流感相关并发症的高风险门诊患者中的疗效。方法我们在17个国家和地区的551个地点对12岁及以上的门诊患者进行了双盲、安慰剂对照和奥司他尼韦对照试验。符合条件的患者临床诊断为流感样疾病，至少有一个流感相关并发症的危险因素（例如，年龄大于65岁），症状持续时间小于48小时。根据基线症状评分（= 15）、发病时与流感前相比已存在和恶化的症状（是或否）、地区（亚洲、北美和欧洲或南半球）和体重（= 80 kg）对患者进行分层。并通过互动网络反应系统随机分配（1:1:1），以体重为基础的单剂量baloxavir（体重= 80 kg的患者40 mg； baloxavir组），oseltamivir 75 mg，每天两次，持续5天（oseltamivir组），或匹配安慰剂（安慰剂组）。在数据库锁定之前，所有患者、研究者、研究人员和数据分析人员对治疗分配进行屏蔽。主要终点是修改意向治疗人群中流感症状（TTIIS）改善的时间，其中包括所有接受至少一剂研究药物且经rt - pcr确认的流感病毒感染的患者。对所有接受至少一剂研究药物的患者进行安全性评估。该试验已在ClinicalTrials.gov注册，编号NCT02949011。从2017年1月11日至2018年3月30日，2184名患者入组，随机分配接受巴洛昔韦（n=730）、安慰剂（n=729）或奥司他韦（n=725）治疗。修改意向治疗人群包括1163例患者：巴洛韦组388例，安慰剂组386例，奥司他韦组389例。1163例患者中，甲型H3N2感染557例（48%），乙型流感感染484例（42%），甲型H1N1流感感染80例（7%），混合感染14例，非分型病毒感染28例。巴洛韦组的中位TTIIS （73.2 h [95% CI 67.2 ~ 85.1]）短于安慰剂组(102.3 h[92.7 ~ 113.1]；差异29.1h [95% CI 14.6 ~ 42.8]
Background Baloxavir marboxil (hereafter baloxavir), a selective inhibitor of influenza cap-dependent endonuclease, was approved in 2018 in the USA and Japan for the treatment of uncomplicated influenza in otherwise healthy individuals aged 12 years and older. We aimed to study the efficacy of baloxavir in outpatients at high risk of developing influenza-associated complications.Methods We did a double-blind, placebo-controlled and oseltatnivir-controlled trial in outpatients aged 12 years and older in 551 sites in 17 countries and territories. Eligible patients had clinically diagnosed influenza-like illness, at least one risk factor for influenza-associated complications (eg, age older than 65 years), and a symptom duration of less than 48 h. Patients were stratified by baseline symptom score (= 15), pre-existing and worsened symptoms at onset of illness compared with pre-influenza (yes or no), region (Asia, North America and Europe, or southern hemisphere), and weight (= 80 kg), and randomly assigned (1:1:1) via an interactive web-response system to either a single weight-based dose of baloxavir (40 mg for patients weighing = 80 kg; baloxavir group), oseltamivir 75 mg twice daily for 5 days (oseltamivir group), or matching placebo (placebo group). All patients, investigators, study personnel, and data analysts were masked to treatment assignment until database lock. The primary endpoint was time to improvement of influenza symptoms (TTIIS) in the modified intention-to-treat population, which included all patients who received at least one dose of study drug and had RT-PCR-confirmed influenza virus infection. Safety was assessed in all patients who receved at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02949011.Findings 2184 patients were enrolled from Jan 11, 2017, to March 30, 2018, and randomly assigned to receive baloxavir (n=730), placebo (n=729), or oseltamivir (n=725). The modified intention-to-treat population included 1163 patients: 388 in the baloxavir group, 386 in the placebo group, and 389 in the oseltamivir group. 557 (48%) of 1163 patients had influenza A H3N2, 484 (42%) had influenza B, 80 (7%) had influenza A H1N1, 14 patients had a mixed infection, and 28 had infections with non-typable viruses. The median TTIIS was shorter in the baloxavir group (73.2 h [95% CI 67.2 to 85.1]) than in the placebo group (102.3 h [92.7 to 113.1]; difference 29.1h [95% CI 14.6 to 42.8]; p