英文音频来自NEJM官网nejm.org
1
背景
斑秃是一种自身免疫性疾病，其特征是头发、眉毛和睫毛的快速脱落，治疗方法有限。巴瑞替尼是一种口服、选择性、可逆Janus激酶1和2抑制剂，可能会阻断参与斑秃发病的细胞因子信号转导。
Background
Alopecia areata is an autoimmune condition characterized by rapid hair loss in the scalp, eyebrows, and eyelashes, for which treatments are limited. Baricitinib, an oral, selective, reversible inhibitor of Janus kinases 1 and 2, may interrupt cytokine signaling implicated in the pathogenesis of alopecia areata.
方法
我们在脱发严重程度工具（Severity of Alopecia Tool，SALT）评分≥50分（范围，0[无头发丢失]~100分[头发完全丢失]）的重度斑秃成人患者中开展了两项随机、安慰剂对照、3期试验（BRAVE-AA1和BRAVE-AA2）。我们以3:2:2的比例将患者随机分组，分别接受巴瑞替尼 4 mg，巴瑞替尼2 mg或安慰剂每日1次给药。主要结局是第36周时SALT评分≤20分。
Methods
We conducted two randomized, placebo-controlled, phase 3 trials (BRAVE-AA1 and BRAVE-AA2) involving adults with severe alopecia areata with a Severity of Alopecia Tool (SALT) score of 50 or higher (range, 0 [no scalp hair loss] to 100 [complete scalp hair loss]). Patients were randomly assigned in a 3:2:2 ratio to receive once-daily baricitinib at a dose of 4 mg, baricitinib at a dose of 2 mg, or placebo. The primary outcome was a SALT score of 20 or less at week 36.
结果
在BRAVE-AA1试验和BRAVE-AA2试验中，我们分别纳入了654例患者和546例患者。在BRAVE-AA1试验中，在巴瑞替尼4 mg组、巴瑞替尼2 mg组和安慰剂组中，第36周时SALT评分≤20分的患者的估计百分比分别为38.8%、22.8%和6.2%，在BRAVE-AA2试验中，分别为35.9%、19.4%和3.3%。在BRAVE-AA1试验中，4 mg巴瑞替尼组与安慰剂组之间的差异为32.6个百分点（95%置信区间[CI]，25.6~39.5），2 mg巴瑞替尼组与安慰剂组之间的差异为16.6个百分点（95% CI，9.5~23.8）（各剂量组vs.安慰剂的P<0.001）。在BRAVE-AA2试验中，相应数值分别为32.6个百分点（95% CI，25.6~39.6）和16.1个百分点（95% CI，9.1~23.2）（各剂量组vs.安慰剂的P<0.001）。在次要结局方面，巴瑞替尼4 mg通常优于安慰剂，但巴瑞替尼2 mg一般不优于安慰剂。与安慰剂组相比，巴瑞替尼组痤疮、肌酸激酶水平升高、低密度脂蛋白胆固醇和高密度脂蛋白胆固醇水平升高较常见。
Result
We enrolled 654 patients in the BRAVE-AA1 trial and 546 in the BRAVE-AA2 trial. The estimated percentage of patients with a SALT score of 20 or less at week 36 was 38.8% with 4-mg baricitinib, 22.8% with 2-mg baricitinib, and 6.2% with placebo in BRAVE-AA1 and 35.9%, 19.4%, and 3.3%, respectively, in BRAVE-AA2. In BRAVE-AA1, the difference between 4-mg baricitinib and placebo was 32.6 percentage points (95% confidence interval [CI], 25.6 to 39.5), and the difference between 2-mg baricitinib and placebo was 16.6 percentage points (95% CI, 9.5 to 23.8) (P<0.001 for each dose vs. placebo). In BRAVE-AA2, the corresponding values were 32.6 percentage points (95% CI, 25.6 to 39.6) and 16.1 percentage points (95% CI, 9.1 to 23.2) (P<0.001 for each dose vs. placebo). Secondary outcomes for baricitinib at a dose of 4 mg but not at a dose of 2 mg generally favored baricitinib over placebo. Acne, elevated levels of creatine kinase, and increased levels of low- and high-density lipoprotein cholesterol were more common with baricitinib than with placebo.
结论
在重度斑秃患者中进行的两项3期试验中，在36周时的头发再生方面，口服巴瑞替尼优于安慰剂。需要更长时间的试验来评估巴瑞替尼治疗斑秃的疗效和安全性。（由因赛特[Incyte]授权礼来公司资助；BRAVE-AA1和BRAVE-AA2在ClinicalTrials.gov注册号分别为NCT03570749和NCT03899259。）
Conclusions
In two phase 3 trials involving patients with severe alopecia areata, oral baricitinib was superior to placebo with respect to hair regrowth at 36 weeks. Longer trials are required to assess the efficacy and safety of baricitinib for alopecia areata. (Funded by Eli Lilly under license from Incyte; BRAVE-AA1 and BRAVE-AA2 ClinicalTrials.gov numbers, NCT03570749 and NCT03899259.)
2
背景
多克隆恢复期血浆可从COVID-19已康复的供者获取。目前尚不明确将该血浆用于新发COVID-19门诊患者可否有效预防严重并发症。
Background
Polyclonal convalescent plasma may be obtained from donors who have recovered from coronavirus disease 2019 (Covid-19). The efficacy of this plasma in preventing serious complications in outpatients with recent-onset Covid-19 is uncertain.
方法
在此项多中心、双盲、随机、对照试验中，我们在SARS-CoV-2检测结果呈阳性的有症状成人（≥18岁，不考虑疾病进展的危险因素或疫苗接种状态）中比较了COVID-19恢复期血浆与对照血浆的效力和安全性。参与者在症状出现后8日内被纳入试验，并在随机分组后1日内输入血浆。主要结局是输入血浆后28日内的COVID-19相关住院。
Methods
In this multicenter, double-blind, randomized, controlled trial, we evaluated the efficacy and safety of Covid-19 convalescent plasma, as compared with control plasma, in symptomatic adults (≥18 years of age) who had tested positive for severe acute respiratory syndrome coronavirus 2, regardless of their risk factors for disease progression or vaccination status. Participants were enrolled within 8 days after symptom onset and received a transfusion within 1 day after randomization. The primary outcome was Covid-19–related hospitalization within 28 days after transfusion.
结果
参与者在2020年6月3日至2021年10月1日被纳入试验。共计1225名参与者接受了随机分组，1181名输入了血浆。在仅包含输入血浆参与者的预设改良意向治疗分析中，恢复期血浆组592名参与者中的17名（2.9%）和对照血浆组589名参与者中的37名（6.3%）发生了主要结局（绝对危险度降幅，3.4个百分点；95%置信区间，1.0~5.8；P=0.005），对应的相对危险度降幅为54%。我们无法根据这些数据推断接种疫苗者的效力证据，因为54名住院的COVID-19患者中有53人未接种疫苗，1人部分接种疫苗。在未住院的参与者中，共发生16起3级或4级不良事件（恢复期血浆组7起，对照血浆组9起）。
Result
Participants were enrolled from June 3, 2020, through October 1, 2021. A total of 1225 participants underwent randomization, and 1181 received a transfusion. In the prespecified modified intention-to-treat analysis that included only participants who received a transfusion, the primary outcome occurred in 17 of 592 participants (2.9%) who received convalescent plasma and 37 of 589 participants (6.3%) who received control plasma (absolute risk reduction, 3.4 percentage points; 95% confidence interval, 1.0 to 5.8; P=0.005), which corresponded to a relative risk reduction of 54%. Evidence of efficacy in vaccinated participants cannot be inferred from these data because 53 of the 54 participants with Covid-19 who were hospitalized were unvaccinated and 1 participant was partially vaccinated. A total of 16 grade 3 or 4 adverse events (7 in the convalescent-plasma group and 9 in the control-plasma group) occurred in participants who were not hospitalized.
结论
在大多数未接种疫苗的COVID-19患者中，在症状出现后9日内输入恢复期血浆可降低需要住院的疾病进展风险。（由美国国防部等资助；CSSC-004在ClinicalTrials.gov注册号为NCT04373460。）
Conclusions
In participants with Covid-19, most of whom were unvaccinated, the administration of convalescent plasma within 9 days after the onset of symptoms reduced the risk of disease progression leading to hospitalization. (Funded by the Department of Defense and others; CSSC-004 ClinicalTrials.gov number, NCT04373460.)
David J. Sullivan, Kelly A. Gebo, Shmuel Shoham, Early Outpatient Treatment for Covid-19 with Convalescent Plasma. DOI: 10.1056/NEJMoa2119657
3
背景
2022年1月2日，以色列开始为60岁及以上人群接种第4剂BNT162b2疫苗。我们需要第4剂疫苗对确诊SARS-CoV-2感染率和重症COVID-19发病率的效力数据。
Background
On January 2, 2022, Israel began administering a fourth dose of BNT162b2 vaccine to persons 60 years of age or older. Data are needed regarding the effect of the fourth dose on rates of confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and of severe coronavirus disease 2019 (Covid-19).
方法
通过以色列卫生部数据库，我们提取了在SARS-CoV-2 B.1.1.529（omicron）变异株为主要流行株的时期（2022年1月10日至3月2日），年龄60岁及以上并且符合第4剂疫苗接种条件的1,252,331人的数据。我们估算了从接种第4剂（4剂组）后8天开始，作为时间函数的确诊感染率和重症COVID-19发病率，并且与仅接种3剂（3剂组）的人群和在3~7天前接种第4剂（内部对照组）的人群进行了比较。估算感染率和发病率时，我们采用了根据年龄、性别、人口统计学群组和日历日进行校正的准泊松回归方法。
Methods
Using the Israeli Ministry of Health database, we extracted data on 1,252,331 persons who were 60 years of age or older and eligible for the fourth dose during a period in which the B.1.1.529 (omicron) variant of SARS-CoV-2 was predominant (January 10 through March 2, 2022). We estimated the rate of confirmed infection and severe Covid-19 as a function of time starting at 8 days after receipt of a fourth dose (four-dose groups) as compared with that among persons who had received only three doses (three-dose group) and among persons who had received a fourth dose 3 to 7 days earlier (internal control group). For the estimation of rates, we used quasi-Poisson regression with adjustment for age, sex, demographic group, and calendar day.
结果
每100,000人-天的重症COVID-19病例数（未校正的发病率）如下：4剂组为1.5，3剂组为3.9，内部对照组为4.2。在准泊松分析中，接种第4剂后第4周的校正后重症COVID-19发病率比3剂组低3.5倍（95%置信区间[CI]，2.7~4.6），比内部对照组低2.3倍（95% CI，1.7~3.3）。在接种第4剂后6周内，疫苗对重症疾病的防护力未减弱。每100,000人-天的确诊感染病例数（未校正的感染率）如下：4剂组为177，3剂组为361，内部对照组为388。在准泊松分析中，接种第4剂后第4周的校正后确诊感染率比3剂组低2.0倍（95% CI，1.9~2.1），比内部对照组低1.8倍（95% CI，1.7~1.9）。然而，这一防护力在后面几周减弱。
Result
The number of cases of severe Covid-19 per 100,000 person-days (unadjusted rate) was 1.5 in the aggregated four-dose groups, 3.9 in the three-dose group, and 4.2 in the internal control group. In the quasi-Poisson analysis, the adjusted rate of severe Covid-19 in the fourth week after receipt of the fourth dose was lower than that in the three-dose group by a factor of 3.5 (95% confidence interval [CI], 2.7 to 4.6) and was lower than that in the internal control group by a factor of 2.3 (95% CI, 1.7 to 3.3). Protection against severe illness did not wane during the 6 weeks after receipt of the fourth dose. The number of cases of confirmed infection per 100,000 person-days (unadjusted rate) was 177 in the aggregated four-dose groups, 361 in the three-dose group, and 388 in the internal control group. In the quasi-Poisson analysis, the adjusted rate of confirmed infection in the fourth week after receipt of the fourth dose was lower than that in the three-dose group by a factor of 2.0 (95% CI, 1.9 to 2.1) and was lower than that in the internal control group by a factor of 1.8 (95% CI, 1.7 to 1.9). However, this protection waned in later weeks.
结论
接种第4剂BNT162b2疫苗后，确诊SARS-CoV-2感染率和重症COVID-19发病率低于仅接种3剂疫苗。疫苗对确诊感染的防护力似乎是短暂的，但对重症疾病的防护力在研究期间没有减弱。
Conclusions
Rates of confirmed SARS-CoV-2 infection and severe Covid-19 were lower after a fourth dose of BNT162b2 vaccine than after only three doses. Protection against confirmed infection appeared short-lived, whereas protection against severe illness did not wane during the study period.
Yinon M. Bar-On, Yair Goldberg, Micha Mandel, Protection by a Fourth Dose of BNT162b2 against Omicron in Israel. DOI: 10.1056/NEJMoa2201570
4
背景
目前尚不明确对于急性有症状COVID-19门诊患者，伊维菌素可否有效预防住院或急诊观察时间延长。
Background
The efficacy of ivermectin in preventing hospitalization or extended observation in an emergency setting among outpatients with acutely symptomatic coronavirus disease 2019 (Covid-19), the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is unclear.
方法
我们从巴西12个公共健康诊所招募了有症状的SARS-CoV-2阳性成人，并对其开展了一项双盲、随机、安慰剂对照、适应性平台试验。本试验纳入出现COVID-19症状后7日内，并且有疾病进展的至少一项危险因素的患者，并将其随机分配接受连续3天的每日一次伊维菌素（400 μg/kg体重）或安慰剂治疗。（该试验还评估了本文未报告结果的其他干预措施）。主要复合结局是随机分组后28日内因COVID-19住院，或者随机分组后28日内因COVID-19临床恶化到急诊就诊（定义为受试者接受>6小时观察）。
Methods
We conducted a double-blind, randomized, placebo-controlled, adaptive platform trial involving symptomatic SARS-CoV-2–positive adults recruited from 12 public health clinics in Brazil. Patients who had had symptoms of Covid-19 for up to 7 days and had at least one risk factor for disease progression were randomly assigned to receive ivermectin (400 μg per kilogram of body weight) once daily for 3 days or placebo. (The trial also involved other interventions that are not reported here.) The primary composite outcome was hospitalization due to Covid-19 within 28 days after randomization or an emergency department visit due to clinical worsening of Covid-19 (defined as the participant remaining under observation for >6 hours) within 28 days after randomization.
结果
共计3515例患者被随机分配接受伊维菌素（679例患者）、安慰剂（679例）或另外一种干预措施（2157例）。伊维菌素组100例患者（14.7%）发生了主要结局事件，而安慰剂组为111例（16.3%）（相对危险度，0.90；95%贝叶斯可信区间，0.70~1.16）。在211起主要结局事件中，171起（81.0%）为住院。在改良意向治疗分析（仅纳入接受至少一剂伊维菌素或安慰剂的患者[相对危险度，0.89；95%贝叶斯可信区间，0.69~1.15]）和符合方案分析（仅纳入据报告100%依从分配方案的患者[相对危险度，0.94；95%贝叶斯可信区间，0.67~1.35]）中，结果与主要分析的结果相似。使用伊维菌素对次要结局和不良事件均无显著影响。
Result
A total of 3515 patients were randomly assigned to receive ivermectin (679 patients), placebo (679), or another intervention (2157). Overall, 100 patients (14.7%) in the ivermectin group had a primary-outcome event, as compared with 111 (16.3%) in the placebo group (relative risk, 0.90; 95% Bayesian credible interval, 0.70 to 1.16). Of the 211 primary-outcome events, 171 (81.0%) were hospital admissions. Findings were similar to the primary analysis in a modified intention-to-treat analysis that included only patients who received at least one dose of ivermectin or placebo (relative risk, 0.89; 95% Bayesian credible interval, 0.69 to 1.15) and in a per-protocol analysis that included only patients who reported 100% adherence to the assigned regimen (relative risk, 0.94; 95% Bayesian credible interval, 0.67 to 1.35). There were no significant effects of ivermectin use on secondary outcomes or adverse events.
结论
在诊断为早期COVID-19的门诊患者中，伊维菌素未降低COVID-19进展导致的住院率，也未降低急诊观察时间延长的发生率。（由FastGrants和Rainwater慈善基金会资助；TOGETHER在ClinicalTrials.gov注册号为NCT04727424。）
Conclusions
Treatment with ivermectin did not result in a lower incidence of medical admission to a hospital due to progression of Covid-19 or of prolonged emergency department observation among outpatients with an early diagnosis of Covid-19. (Funded by FastGrants and the Rainwater Charitable Foundation; TOGETHER ClinicalTrials.gov number, NCT04727424.)
Gilmar Reis, Eduardo A.S.M. Silva, Daniela C.M. Silva, Effect of Early Treatment with Ivermectin among Patients with Covid-19. DOI: 10.1056/NEJMoa2115869
