沙丁胺醇-布地奈德固定剂量复方救援吸入剂治疗哮喘
Albuterol–Budesonide Fixed-Dose Combination Rescue Inhaler for Asthma
背景
随着哮喘症状恶化，患者通常依赖短效β2受体激动剂（SABA）救援治疗，但SABA无法解决炎症恶化的问题，因此患者仍面临哮喘重度发作的风险。与单纯使用沙丁胺醇相比，使用沙丁胺醇和布地奈德固定剂量复方药物作为救援用药有可能降低哮喘重度发作的风险。
As asthma symptoms worsen, patients typically rely on short-acting β2-agonist (SABA) rescue therapy, but SABAs do not address worsening inflammation, which leaves patients at risk for severe asthma exacerbations. The use of a fixed-dose combination of albuterol and budesonide, as compared with albuterol alone, as rescue medication might reduce the risk of severe asthma exacerbation.
方法
我们开展了一项多国、3期、双盲、随机、事件驱动的试验，该试验纳入正在接受吸入性糖皮质激素维持治疗（整个试验期间继续接受该治疗），但病情未受到控制的中度至重度哮喘患者，目的是与单纯使用沙丁胺醇作为救援用药相比，评估沙丁胺醇-布地奈德的疗效和安全性。我们以1:1:1的比例将成人和青少年患者（≥12岁）随机分配到三个试验组之一：180 μg沙丁胺醇和160 μg布地奈德固定剂量复方药物（每剂两揿，每揿分别90 μg和80 μg上述药物[大剂量复方组]），180 μg沙丁胺醇和80μg布地奈德固定剂量复方药物（每剂两揿，每揿分别90 μg和40 μg上述药物[小剂量复方组]），或者180 μg沙丁胺醇（每剂两揿，每揿90 μg沙丁胺醇[单纯沙丁胺醇组]）。将4~11岁儿童随机分配到小剂量复方组或单纯沙丁胺醇组。主要疗效终点是在至事件发生时间分析中，哮喘首次重度发作事件（在意向治疗人群中进行分析）。
We conducted a multinational, phase 3, double-blind, randomized, event-driven trial to evaluate the efficacy and safety of albuterol–budesonide, as compared with albuterol alone, as rescue medication in patients with uncontrolled moderate-to-severe asthma who were receiving inhaled glucocorticoid-containing maintenance therapies, which were continued throughout the trial. Adults and adolescents (≥12 years of age) were randomly assigned in a 1:1:1 ratio to one of three trial groups: a fixed-dose combination of 180 μg of albuterol and 160 μg of budesonide (with each dose consisting of two actuations of 90 μg and 80 μg, respectively [the higher-dose combination group]), a fixed-dose combination of 180 μg of albuterol and 80 μg of budesonide (with each dose consisting of two actuations of 90 μg and 40 μg, respectively [the lower-dose combination group]), or 180 μg of albuterol (with each dose consisting of two actuations of 90 μg [the albuterol-alone group]). Children 4 to 11 years of age were randomly assigned to only the lower-dose combination group or the albuterol-alone group. The primary efficacy end point was the first event of severe asthma exacerbation in a time-to-event analysis, which was performed in the intention-to-treat population.
结果
共计3132例患者接受了随机分组，其中97%的患者年龄≥12岁。大剂量复方组的哮喘重度发作风险显著低于单纯沙丁胺醇组（低26%；风险比，0.74；95%置信区间[CI]，0.62~0.89；P=0.001）。小剂量复方组与单纯沙丁胺醇组相比的风险比为0.84（95% CI，0.71~1.00；P=0.052）。3个试验组的不良事件发生率相似。
Result
A total of 3132 patients underwent randomization, among whom 97% were 12 years of age or older. The risk of severe asthma exacerbation was significantly lower, by 26%, in the higher-dose combination group than in the albuterol-alone group (hazard ratio, 0.74; 95% confidence interval [CI], 0.62 to 0.89; P=0.001). The hazard ratio in the lower-dose combination group, as compared with the albuterol-alone group, was 0.84 (95% CI, 0.71 to 1.00; P=0.052). The incidence of adverse events was similar in the three trial groups.
结论
对于接受各种吸入性糖皮质激素维持治疗，但病情未受到控制的中度至重度哮喘患者，按需使用180 μg沙丁胺醇和160 μg布地奈德固定剂量复方药物时，哮喘重度发作的风险显著低于按需单纯使用沙丁胺醇。（由Avillion资助；MANDALA在ClinicalTrials.gov注册号为NCT03769090。）
Conclusions
The risk of severe asthma exacerbation was significantly lower with as-needed use of a fixed-dose combination of 180 μg of albuterol and 160 μg of budesonide than with as-needed use of albuterol alone among patients with uncontrolled moderate-to-severe asthma who were receiving a wide range of inhaled glucocorticoid-containing maintenance therapies. (Funded by Avillion; MANDALA ClinicalTrials.gov number, NCT03769090.)
Alberto Papi, Bradley E. Chipps, Richard Beasley, Albuterol–Budesonide Fixed-Dose Combination Rescue Inhaler for Asthma. DOI: 10.1056/NEJMoa2203163
基于植物的含佐剂重组COVID-19疫苗的效力和安全性
Efficacy and Safety of a Recombinant Plant-Based Adjuvanted Covid-19 Vaccine
背景
研究者将在植物中制造，显示SARS-CoV-2原始毒株融合前刺突糖蛋白的冠状病毒样颗粒（CoVLP）与佐剂（佐剂系统03[AS03]）组合，制成候选疫苗。
Coronavirus-like particles (CoVLP) that are produced in plants and display the prefusion spike glycoprotein of the original strain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are combined with an adjuvant (Adjuvant System 03 [AS03]) to form the candidate vaccine.
我们在85个研究中心开展了此项3期、多国、随机、安慰剂对照试验，并且以1:1的比例将成人（≥18岁）随机分组，两组分别以21天的间隔期肌内注射两剂CoVLP+AS03疫苗或安慰剂。试验的主要目的是确定CoVLP+AS03疫苗对注射第2剂至少7天之后出现的有症状COVID-19的预防效力；我们在检出至少160个病例之后进行分析。
In this phase 3, multinational, randomized, placebo-controlled trial conducted at 85 centers, we assigned adults (≥18 years of age) in a 1:1 ratio to receive two intramuscular injections of the CoVLP+AS03 vaccine or placebo 21 days apart. The primary objective of the trial was to determine the efficacy of the CoVLP+AS03 vaccine in preventing symptomatic coronavirus disease 2019 (Covid-19) beginning at least 7 days after the second injection, with the analysis performed after the detection of at least 160 cases.
共计24,141名志愿者参与了试验；参与者的中位年龄是29岁。在意向治疗人群中，聚合酶链反应检测法将165名参与者确诊为COVID-19；可测序的所有病毒样本均含有原始毒株的变异株。对于测序鉴定出的5种变异株引起的有症状COVID-19，疫苗的预防效力为69.5%（95%置信区间[CI]，56.7~78.8）。在事后分析中，疫苗对中度至重症疾病的预防效力为78.8%（95% CI，55.8~90.8），在基线血清反应阴性参与者中的预防效力为74.0%（95% CI，62.1~82.5）。疫苗组未出现重症COVID-19病例，突破性感染病例的中位病毒载量是安慰剂组的1/100以下。征集的不良事件大多为轻度或中度且为暂时性，并且疫苗组的发生率高于安慰剂组；两组中局部不良事件发生率分别为92.3%和45.5%，全身不良事件发生率分别为87.3%和65.0%。在注射每剂后21天内（22.7%和20.4%）以及从第43天至第201天（4.2%和4.0%），两组中非征集的不良事件发生率相似。
Result
A total of 24,141 volunteers participated in the trial; the median age of the participants was 29 years. Covid-19 was confirmed by polymerase-chain-reaction assay in 165 participants in the intention-to-treat population; all viral samples that could be sequenced contained variants of the original strain. Vaccine efficacy was 69.5% (95% confidence interval [CI], 56.7 to 78.8) against any symptomatic Covid-19 caused by five variants that were identified by sequencing. In a post hoc analysis, vaccine efficacy was 78.8% (95% CI, 55.8 to 90.8) against moderate-to-severe disease and 74.0% (95% CI, 62.1 to 82.5) among the participants who were seronegative at baseline. No severe cases of Covid-19 occurred in the vaccine group, in which the median viral load for breakthrough cases was lower than that in the placebo group by a factor of more than 100. Solicited adverse events were mostly mild or moderate and transient and were more frequent in the vaccine group than in the placebo group; local adverse events occurred in 92.3% and 45.5% of participants, respectively, and systemic adverse events in 87.3% and 65.0%. The incidence of unsolicited adverse events was similar in the two groups up to 21 days after each dose (22.7% and 20.4%) and from day 43 through day 201 (4.2% and 4.0%).
结论
CoVLP+AS03疫苗可有效预防多种变异株引起的COVID-19，其预防效力范围是从针对有症状感染的69.5%至针对中度至重症疾病的78.8%。（由Medicago资助；在ClinicalTrials.gov注册号为NCT04636697。）
Conclusions
The CoVLP+AS03 vaccine was effective in preventing Covid-19 caused by a spectrum of variants, with efficacy ranging from 69.5% against symptomatic infection to 78.8% against moderate-to-severe disease. (Funded by Medicago; ClinicalTrials.gov number, NCT04636697.)
Karen J. Hager, Gonzalo Pérez Marc, Philipe Gobeil, Efficacy and Safety of a Recombinant Plant-Based Adjuvanted Covid-19 Vaccine. DOI: 10.1056/NEJMoa2201300
成人接种基于RBD二聚体的COVID-19疫苗ZF2001的效力和安全性
Efficacy and Safety of the RBD-Dimer–Based Covid-19 Vaccine ZF2001 in Adults
背景
ZF2001疫苗包含严重急性呼吸综合征冠状病毒2（SARS-CoV-2）受体结合结构域二聚体和氢氧化铝佐剂；1期和2期临床试验已证明成人接种该疫苗安全、副作用可接受且具有免疫原性。
The ZF2001 vaccine, which contains a dimeric form of the receptor-binding domain of severe acute respiratory syndrome coronavirus 2 and aluminum hydroxide as an adjuvant, was shown to be safe, with an acceptable side-effect profile, and immunogenic in adults in phase 1 and 2 clinical trials.
我们开展了一项旨在研究ZF2001效力并确认其安全性的随机、双盲、安慰剂对照3期试验。该试验在乌兹别克斯坦、印度尼西亚、巴基斯坦和厄瓜多尔的31个临床中心进行；此外，中国的一个临床中心仅被纳入安全性分析。成人参与者（年龄≥18岁）以1:1的比例被随机分配接种3剂25 μg剂量（间隔30天）ZF2001疫苗或安慰剂。主要终点是接种第3剂至少7天之后，发生聚合酶链反应确诊的有症状2019冠状病毒病（COVID-19）。一项关键次要效力终点是接种第3剂至少7天之后，发生重症至危重症COVID-19（包括COVID-19相关死亡）。
We conducted a randomized, double-blind, placebo-controlled, phase 3 trial to investigate the efficacy and confirm the safety of ZF2001. The trial was performed at 31 clinical centers across Uzbekistan, Indonesia, Pakistan, and Ecuador; an additional center in China was included in the safety analysis only. Adult participants (≥18 years of age) were randomly assigned in a 1:1 ratio to receive a total of three 25-μg doses (30 days apart) of ZF2001 or placebo. The primary end point was the occurrence of symptomatic coronavirus disease 2019 (Covid-19), as confirmed on polymerase-chain-reaction assay, at least 7 days after receipt of the third dose. A key secondary efficacy end point was the occurrence of severe-to-critical Covid-19 (including Covid-19–related death) at least 7 days after receipt of the third dose.
结果
从2020年12月12日至2021年12月15日，共计28,873名参与者接种了至少1剂ZF2001或安慰剂，并被纳入安全性分析；完成3剂接种方案的25,193名参与者被纳入在第二个数据截止日期2021年12月15日进行的最新主要疗效分析，这些参与者有约6个月的随访数据。在最新分析中，ZF2001组12,625名参与者中的158名和安慰剂组12,568名参与者中的580名发生了主要终点，疫苗效力为75.7%（95%置信区间[CI]，71.0~79.8）。ZF2001组6名参与者和安慰剂组43名参与者发生了重症至危重症COVID-19，疫苗效力为87.6%（95% CI，70.6~95.7）；两组分别有2名和12名参与者发生COVID-19相关死亡，疫苗效力为86.5%（95% CI，38.9~98.5），两组的不良事件和严重不良事件发生率平衡，未发生与疫苗相关的死亡。大多数不良反应（98.5%）为1级或2级。
Result
Between December 12, 2020, and December 15, 2021, a total of 28,873 participants received at least one dose of ZF2001 or placebo and were included in the safety analysis; 25,193 participants who had completed the three-dose regimen, for whom there were approximately 6 months of follow-up data, were included in the updated primary efficacy analysis that was conducted at the second data cutoff date of December 15, 2021. In the updated analysis, primary end-point cases were reported in 158 of 12,625 participants in the ZF2001 group and in 580 of 12,568 participants in the placebo group, for a vaccine efficacy of 75.7% (95% confidence interval [CI], 71.0 to 79.8). Severe-to-critical Covid-19 occurred in 6 participants in the ZF2001 group and in 43 in the placebo group, for a vaccine efficacy of 87.6% (95% CI, 70.6 to 95.7); Covid-19–related death occurred in 2 and 12 participants, respectively, for a vaccine efficacy of 86.5% (95% CI, 38.9 to 98.5). The incidence of adverse events and serious adverse events was balanced in the two groups, and there were no vaccine-related deaths. Most adverse reactions (98.5%) were of grade 1 or 2.
结论
在大规模成人队列中，在全程接种疫苗后至少6个月内，ZF2001疫苗安全，并且可有效预防有症状以及重症至危重症COVID-19。（由中国国家科技重大专项等资助；在ClinicalTrials.gov注册号为NCT04646590。）
Conclusions
In a large cohort of adults, the ZF2001 vaccine was shown to be safe and effective against symptomatic and severe-to-critical Covid-19 for at least 6 months after full vaccination. (Funded by the National Science and Technology Major Project and others; ClinicalTrials.gov number, NCT04646590.)
