Albuterol–Budesonide Fixed-Dose Combination Rescue Inhaler for Asthma
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.
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.
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.
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。）
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
Efficacy and Safety of a Recombinant Plant-Based Adjuvanted Covid-19 Vaccine
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.
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。
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%).
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
Efficacy and Safety of the RBD-Dimer–Based Covid-19 Vaccine ZF2001 in Adults
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.
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.
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。
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.
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.)