【The New England Journal of Medicine】2025年8-9月文献导读
期刊介绍：
《新英格兰医学杂志》（The New England Journal of Medicine，简称NEJM），是由美国麻州医学协会（Massachusetts Medical Society）所出版的评审性质医学期刊（medical journal）和综合性医学期刊，创刊于1812年，创始人为美国波士顿著名外科医生约翰·科林斯·瓦伦和麻省总医院创始人詹姆斯·杰克逊，始称《新英格兰医学与外科杂志》。《新英格兰医学杂志》是全球影响因子最高的医学学术期刊，影响因子大概为70。本期共27篇Articles。
八月第二期共4篇Articles.
1.Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity
卡格林肽和索马鲁肽在超重或肥胖成人中的联合给药
阿拉巴马大学伯明翰分校
Abstract
Background:
Semaglutide at a dose of 2.4 mg has established weight-loss and cardiovascular benefits, and cagrilintide at a dose of 2.4 mg has shown promising results in early-phase trials; the efficacy of the combination (known as CagriSema) on weight loss in persons with either overweight and coexisting conditions or obesity is unknown.
Methods:
In a phase 3a, 68-week, multicenter, double-blind, placebo-controlled and active-controlled trial, we enrolled adults without diabetes who had a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of 30 or higher or a BMI of 27 or higher with at least one obesity-related complication. Participants were randomly assigned in a ratio of 21:3:3:7 to receive the combination of semaglutide at a dose of 2.4 mg and cagrilintide at a dose of 2.4 mg, semaglutide alone at a dose of 2.4 mg, cagrilintide alone at a dose of 2.4 mg, or placebo, plus lifestyle interventions for all groups. The coprimary end points were the relative change in body weight and a reduction of 5% or more in body weight from baseline to week 68 with cagrilintide–semaglutide as compared with placebo. Body-weight reductions of 20% or more, 25% or more, and 30% or more were assessed as confirmatory secondary end points. Effect estimates were assessed with the treatment-policy estimand (consistent with the intention-to-treat principle). Safety was assessed.
Results:
A total of 3417 participants underwent randomization, with 2108 assigned to receive cagrilintide–semaglutide, 302 to receive semaglutide, 302 to receive cagrilintide, and 705 to receive placebo. The estimated mean percent change in body weight from baseline to week 68 was –20.4% with cagrilintide–semaglutide as compared with –3.0% with placebo (estimated difference, –17.3 percentage points; 95% confidence interval, –18.1 to –16.6; P<0.001). Participants receiving cagrilintide–semaglutide were more likely than those receiving placebo to reach weight-loss targets of 5% or more, 20% or more, 25% or more, and 30% or more (P<0.001 for all comparisons). Gastrointestinal adverse events (affecting 79.6% in the cagrilintide–semaglutide group and 39.9% in the placebo group), including nausea, vomiting, diarrhea, constipation, or abdominal pain, were mainly transient and mild-to-moderate in severity.
Conclusions:
Cagrilintide–semaglutide provided significant and clinically relevant body-weight reductions in adults with overweight or obesity, as compared with placebo.
摘要：
背景：
2.4 mg剂量的索马鲁肽已证实具有减肥功效及心血管益处，而相同剂量的卡格林肽在早期试验中也显示出一定减肥潜力，但该组合（称为CagriSema）在减重及肥胖相关疾病的疗效方面尚不清楚。
方法：
在一项为期68周的3a期、多中心、双盲、安慰剂对照和主动对照试验中，研究者招募了两类不同体重指数（BMI=体重（kg）/身高2（m2））的志愿者，一类是BMI≥30的非糖尿病成人，另外一类是BMI≥27且至少有一种肥胖相关并发症的患者。参与者以21：3：3：7的比例随机分配接受CagriSema组合、单独使用2.4 mg索马鲁肽、单独使用2.4 mg卡格林肽或安慰剂，同时所有组别均接受生活方式干预。与安慰剂相比，所有组别的主要终点是使用卡格林肽或索马鲁肽后，从基线至第64周的体重变化百分比和体重减少≥5%。体重≥20%、体重≥25%和体重≥30% 被认定为次要终点。采用治疗策略估计量（与意向性治疗原则一致）对效应估计值进行评估。同时对安全性进行了评估。
结果：
共有3417名受试者接受了随机分组，其中2108名接受卡格林肽-索马鲁肽治疗，302名接受索马鲁肽治疗，302名接受卡格林肽治疗，705名接受安慰剂治疗。卡格林肽-索马鲁肽组从基线到第68周的体重估计平均变化百分比为-20.4%，而安慰剂组为-3.0%，组间差异为-17.3%（95% 置信区间，-18.1至-16.6;P<0.001）。接受卡格林肽-索马鲁肽的受试者达到体重减轻≥5%、20%、25%和30%的概率显著高于比接受安慰剂的受试者（P<0.001）。卡格林肽-索马鲁肽组的胃肠道不良事件发生概率为79.6%，高于安慰剂组的39.9%，包括恶心、呕吐、腹泻、便秘或腹痛，多为轻至中度且具有自限性。
结论：
与安慰剂相比，卡格林肽-索马鲁肽在超重或肥胖的成年人中提供了显著且临床相关的体重减轻。
2.Cagrilintide–Semaglutide in Adults with Overweight or Obesity and Type 2 Diabetes
卡格林肽-索马鲁肽在超重或肥胖和2型糖尿病成人中的应用
英国莱斯特大学糖尿病研究中心
Abstract
Background:
Cagrilintide and semaglutide have each been shown to induce weight loss as monotherapies. Data are needed on the coadministration of cagrilintide and semaglutide (called CagriSema) for weight management in adults with type 2 diabetes, including those in a subgroup who are undergoing continuous glucose monitoring.
Methods:
In this phase 3a, double-blind, randomized, placebo-controlled trial conducted in 12 countries, we assigned adults with a body-mass index of 27 or more, a glycated hemoglobin level of 7 to 10%, and type 2 diabetes in a 3:1 ratio to receive once-weekly cagrilintide–semaglutide (2.4 mg each) or placebo, along with lifestyle intervention, for 68 weeks. The two primary end points were the percent change in body weight and the percentage of patients with a weight reduction of at least 5%. Additional end points were changes in glycemic measures and safety assessments. Effect estimates were calculated with the use of the treatment-policy estimand (consistent with the intention-to-treat principle).
Results:
A total of 1206 patients underwent randomization to either the cagrilintide–semaglutide group (904 patients) or the placebo group (302 patients). The estimated mean change in body weight from baseline to week 68 was −13.7% in the cagrilintide–semaglutide group and −3.4% in the placebo group (estimated difference, −10.4 percentage points; 95% confidence interval, −11.2 to −9.5; P<0.001). More patients in the cagrilintide–semaglutide group than in the placebo group had a weight reduction of 5% or more (P<0.001); the same was true of reductions of at least 10%, 15%, and 20% (P<0.001 for the last comparison). The percentage of patients who had a glycated hemoglobin level of 6.5% or less was 73.5% in the cagrilintide–semaglutide group and 15.9% in the placebo group. Gastrointestinal adverse events were reported by 72.5% of the patients in the cagrilintide–semaglutide group and 34.4% in the placebo group, most of which were transient and mild or moderate in severity.
Conclusions:
Once-weekly cagrilintide–semaglutide (at a dose of 2.4 mg each) resulted in a significantly lower body weight than placebo in adults with obesity and type 2 diabetes.
摘要：
背景：
卡格林肽和索马鲁肽均已被证明可以通过单一作用诱导体重减轻。卡格林肽和索马鲁肽（称为CagriSema）联合给药用于成人2型糖尿病体重管理尚缺乏相关研究，研究对象同时包括正在接受连续血糖监测的亚组患者。
方法：
在这项在12个国家进行的3a期、双盲、随机、安慰剂对照试验中，我们以3：1的比例分配BMI≥27、糖化血红蛋白水平为7%~10%和2型糖尿病的成年人接受每周一次的卡格林肽-索马鲁肽CagriSema给药（各2.4毫克）或安慰剂处理，同时均接受生活方式干预。该疗程持续68周。两个主要终点是体重变化百分比和体重减轻≥5%的患者百分比。其他终点是血糖测量和安全性评估的变化。使用治疗政策估计值计算效果估计值（符合意向治疗原则）。
结果：
共有1206名患者接受随机分配至卡格林肽-索马鲁肽组（904名患者）或安慰剂组（302名患者）。到第68周后，卡格林肽-索马鲁肽组的估计体重平均变化为-13.7%，安慰剂组为-3.4%，组间差异为-10.4%（95% 置信区间， -11.2~-9.5，P<0.001）。卡格林肽-索马鲁肽组的体重减轻≥5%的患者多于安慰剂组（P<0.001）;体重减少≥10%、15%和20%的情况也是如此（P<0.001）。糖化血红蛋白水平≦6.5%的患者比例在卡格林肽-索马鲁肽组中为73.5%，安慰剂组为15.9%。报告胃肠道不良事件的人群比列在卡格林肽-索马鲁肽组为72.5%，在安慰剂组为34.4%，其中大多数是轻度或中度且短期发生。
结论：
每周一次的卡格林肽-索马鲁肽（每次剂量为2.4毫克）导致肥胖和2型糖尿病成人的体重显着低于安慰剂。
3.A Crossover Trial of Hospital-Wide Lactated Ringer’s Solution versus Normal Saline
全院乳酸林格氏液与生理盐水的交叉试验
渥太华医院研究所
Abstract
Background:
Whether lactated Ringer’s solution is clinically superior to normal saline for routine intravenous administration of fluids is uncertain.
Methods:
In an open-label, two-period, two-sequence, cross-sectional, cluster-randomized, crossover trial, we assigned hospitals in Ontario, Canada, to use either lactated Ringer’s solution or normal saline hospital-wide for a period of 12 weeks. After a washout period, hospitals switched to the other fluid for 12 weeks. The primary outcome was a composite of death or readmission to the hospital within 90 days after the index admission. Secondary outcomes were the individual components of the primary outcome, as well as the length of stay in the hospital, initiation of dialysis within 90 days after the index admission, a visit to the emergency department within 90 days, and discharge to a facility other than home. Data on outcomes were obtained from health administrative databases. The analyses were conducted at the hospital level, and the primary estimand was the effect of the use of lactated Ringer’s solution as compared with normal saline averaged across all participating hospitals.
Results:
Seven hospitals completed both 12-week periods before the trial was interrupted owing to the coronavirus disease 2019 pandemic. Data on the primary outcome were available for 43,626 eligible patients. The mean (±SD) incidence of the composite of death or readmission to the hospital within 90 days after the index admission was 20.3±3.5% with lactated Ringer’s solution and 21.4±3.3% with normal saline (adjusted difference, −0.53 percentage points; 95% confidence interval, −1.85 to 0.79; P=0.35). Results for all secondary outcomes were consistent with those for the primary outcome. No serious adverse events were reported.
Conclusions:
A hospital-wide policy to administer lactated Ringer’s solution rather than normal saline did not result in a significantly lower incidence of death or readmission to the hospital within 90 days after the index admission.
摘要：
背景：
乳酸林格氏液和生理盐水均为临床常规静脉输液制剂，但前者的临床疗效是否优于后者尚不确定。
方法：
本研究采用开放标签、两期两序列、横断面、整群随机交叉设计，纳入加拿大安大略省多家医院作为研究单位，每家医院在12周内先推行使用乳酸林格氏液或生理盐水的单一输液方案。在洗脱期之后，切换为另一种输液方案并再次持续12周。主要结局指标是患者首次住院后90天内死亡或再次入院的复合终点。次要结局指标包括主要结局指标的单独组成部分（90天死亡率、90天再入院率），住院时长、首次住院后90天内开始透析的情况、90天内急诊科就诊次数，以及出院后转入非居家设施的比例。结局数据来源于健康行政数据库。统计分析在医院层面开展，主要效应指标是在所有参与医院乳酸林格氏液与生理盐水的平均疗效差异。
结果：
研究纳入7家医院，完成了2个为期12周的试验，后因2019年冠状病毒大流行终止。43,626名符合条件的患者的主要结局数据可用。指数入院后90天内死亡或再入院的平均（±SD）发生率为乳酸林格氏液组20.3±3.5%，生理盐水组为21.4±3.3%（调整后差异，-0.53个百分点;95%置信区间，-1.85至0.79;P=0.35）。所有次要结局的结果与主要结局的结果一致。没有报告严重不良事件。
结论：
全院范围内使用乳酸林格氏液而不是生理盐水的政策并没有显着降低指数入院后90天内的死亡或再入院率。
4.Risdiplam in Presymptomatic Spinal Muscular Atrophy
Risdiplam 治疗症状前脊髓性肌萎缩症
圣裘德儿童研究医院儿科医学部实验神经治疗中心
Abstract
Background:
Risdiplam, an oral pre–messenger RNA splicing modifier, is an efficacious treatment for persons with symptomatic spinal muscular atrophy (SMA). The safety and efficacy of risdiplam in presymptomatic disease are unclear.
Methods:
We conducted an open-label study of daily oral risdiplam (with the dose adjusted to 0.2 mg per kilogram of body weight) in infants 1 day (birth) to 42 days of age with genetically diagnosed SMA but without strongly suggestive clinical signs or symptoms. The primary outcome, assessed in infants with two SMN2 copies and a baseline ulnar compound muscle action potential (CMAP) amplitude of at least 1.5 mV, was the ability to sit without support at month 12. Natural history studies have shown that the majority of infants with two SMN2 copies who are untreated would have a severe SMA phenotype (type 1), would never sit independently, would receive permanent ventilation and feeding support, or would die by 13 months of age. Secondary outcomes that were assessed over a period of 24 months included survival, ventilatory support, motor milestones, the development of clinically manifested SMA, feeding, and growth.
Results:
A total of 26 infants with two, three, or four or more copies of SMN2 were enrolled. After 12 months of treatment, 21 infants (81%) could sit unsupported for 30 seconds, 14 (54%) could stand alone, and 11 (42%) could walk alone. A total of 4 of 5 infants (80%; 95% confidence interval, 28 to 100) with two SMN2 copies and a baseline ulnar CMAP amplitude of at least 1.5 mV were able to sit without support for at least 5 seconds. Three infants were withdrawn from the study by a parent or caregiver after the month 12 visit. Of 23 infants who completed 24 months of treatment, all were alive without the use of permanent ventilation or feeding support. Over a period of 24 months, nine treatment-related adverse events were reported in 7 infants; none of these events were serious.
Conclusions:
Infants up to 6 weeks of age with genetically diagnosed SMA who were treated with risdiplam before the development of clinical signs or symptoms appeared to have better functional and survival outcomes at 12 and 24 months than untreated infants in natural history studies. Larger, controlled studies with longer follow-up are needed to further understand the relative efficacy and safety of presymptomatic treatment of SMA with risdiplam.
摘要：
背景：
利司普兰（Risdiplam）是一种口服信使前RNA剪接修饰剂，对有症状的脊髓性肌萎缩症（SMA）患者具有确切治疗效果。但该药物在症状前SMA人群中的安全性和有效性尚不清楚。
方法：
本研究为一项开放标签，纳入1日（出生）至42日龄、基因诊断为SMA但未出现典型临床症状的婴儿，给药剂量调整为0.2mg/kg。研究主要结局指标设定为：在携带2个SMN2拷贝且基线尺骨复合动作电位（CMAP）振幅≥1.5mV的婴儿中，治疗12个月时能够在没有支撑的情况下坐着。自然病史研究表明，大多数未经治疗的此类婴儿多表现为重型SMA（1型），往往不能独立稳坐，需要接受永久通气和喂养支持，且多数在13个月大时死亡。次要结局指标包括24个月内的生存、通气支持、运动里程碑、临床症状性的SMA的发生情况、喂养和生长。
结果：
研究共招募了26名携带2个、3个或4个或更多SMN2拷贝的婴儿。治疗12个月后，21名（81%）婴儿可以无支撑稳坐30秒，14名（54%）可以独立站立，11名（42%）可以独自行走。5名婴儿中有4名（80%;95%置信区间，28至100）具有两个SMN2拷贝且基线尺骨CMAP振幅至少为1.5mV，能够在没有支撑的情况下坐着至少5秒。在第12个月的访问后，父母或看护人将三名婴儿退出了研究。在完成24个月治疗的23名婴儿中，所有婴儿在没有使用永久通气或喂养支持的情况下都存活着。在24个月的时间里，7名婴儿报告了9例与治疗相关的不良事件;这些事件都不严重。
结论：
对于出生6周内、经基因确诊但尚未出现临床症状的SMA婴儿，早期给予Risdiplam治疗，其12个月及24个月的预后与生存结局，均显著优于自然病史研究中未经治疗的同类患儿。未来需要更大规模的对照研究和更长时间的随访，以进一步了解Risdiplam对SMA的症状前治疗的相对疗效和安全性。
八月第三期共4篇Articles
1.Overall Survival with Neoadjuvant Nivolumab plus Chemotherapy in Lung Cancer
新辅助 Nivolumab 联合化疗治疗肺癌的总生存期
都柏林圣三一大学圣詹姆斯癌症研究所
Abstract
Background:
Neoadjuvant nivolumab plus chemotherapy significantly improved pathological complete response and event-free survival in patients with resectable non–small-cell lung cancer (NSCLC) in a phase 3 trial. Data are needed on overall survival.
Methods:
In this open-label, phase 3 trial, patients with stage IB to IIIA resectable NSCLC were randomly assigned to receive nivolumab plus chemotherapy or chemotherapy alone for three cycles, followed by surgery. The primary end points were event-free survival and pathological complete response. Here, we report the results of the planned analysis of overall survival.
Results:
A total of 358 patients were concurrently assigned to receive nivolumab plus chemotherapy (179 patients) or chemotherapy alone (179 patients). The final analysis of overall survival significantly favored neoadjuvant nivolumab plus chemotherapy over chemotherapy (hazard ratio for death, 0.72; 95% confidence interval [CI], 0.523 to 0.998; P=0.048). At a median follow-up of 68.4 months, the 5-year overall survival was 65.4% with nivolumab plus chemotherapy and 55.0% with chemotherapy alone, with consistency across most subgroups. In exploratory analyses, the 5-year overall survival in the nivolumab-plus-chemotherapy group was 95.3% (95% CI, 82.7 to 98.8) among the patients with a pathological complete response and 55.7% (95% CI, 46.9 to 63.7) among those without such a response; survival was 75.0% among the patients with presurgery clearance of circulating tumor DNA (ctDNA) and 52.6% among those without such clearance. No new safety signals were observed.
Conclusions:
Three cycles of neoadjuvant nivolumab plus chemotherapy significantly improved overall survival among patients with resectable NSCLC as compared with chemotherapy alone.
摘要：
背景：
在一项3期试验中，新辅助纳武利尤单抗联合化疗显着改善了可切除非小细胞肺癌（NSCLC）患者的病理完全缓解和无事件生存期，但关于该治疗方案对患者总生存期的影响，尚缺乏相应数据支撑。
方法：
在这项开放标签的3期试验中，IB至IIIA期可切除NSCLC患者被随机分配接受三个周期的纳武利尤单抗联合或单独化疗，后续均接受手术治疗。主要终点是无事件生存期和病理完全缓解。在这里，作者报告了总生存期的计划分析结果。
结果：
研究共纳入358名患者，纳武利尤单抗联合化疗组和单独化疗组各179名患者。总生存期的最终分析显示，纳武利尤单抗联合化疗的疗效显著优于单独化疗组（死亡风险比HR=0.72;95% 置信区间=0.523~0.998;P=0.048）。在中位随访68.4个月时，纳武利尤单抗联合化疗组的5年总生存率为65.4%，显著高于单独化疗组的55.0%，大多数亚组的生存率一致。在探索性分析中，纳武利尤单抗联合化疗组的5年总生存率为95.3%（95%[CI]：82.7-98.8），无病理完全缓解的患者为55.7%（95%[CI]：46.9-63.7）;术前循环肿瘤DNA（ctDNA）清除患者的生存率为75.0%，未清除循环肿瘤DNA（ctDNA）的患者存活率为52.6%。没有观察到新的不良事件信号。
结论：
与单独化疗相比，三个周期的新辅助纳武单抗联合化疗显着提高了可切除NSCLC患者的总生存期。
2.Elinzanetant for Vasomotor Symptoms from Endocrine Therapy for Breast Cancer
Elinzanetant 治疗乳腺癌内分泌治疗引起的血管舒缩症状
葡萄牙里斯本尚帕利莫基金会尚帕利莫临床中心乳腺科
Abstract
Background:
Women receiving endocrine therapy for hormone receptor (HR)–positive breast cancer or its prevention among those at high risk for breast cancer commonly have vasomotor symptoms. Data are lacking on the effects of elinzanetant, a neurokinin-targeted therapy shown to be effective in treating vasomotor symptoms, in this population.
Methods:
We performed a phase 3 trial involving women 18 to 70 years of age with moderate-to-severe vasomotor symptoms associated with endocrine therapy for HR-positive breast cancer or its prevention. Women were randomly assigned in a 2:1 ratio to receive once-daily elinzanetant at a dose of 120 mg for 52 weeks or once-daily placebo for 12 weeks followed by once-daily elinzanetant at a dose of 120 mg for 40 weeks. The primary end points were the change in the mean daily frequency of moderate-to-severe vasomotor symptoms from baseline to week 4 and to week 12.
Results:
A total of 316 participants were assigned to the elinzanetant group and 158 to the placebo–elinzanetant group. At baseline, the mean daily frequency of moderate-to-severe vasomotor symptoms was 11.4 episodes (95% confidence interval [CI], 10.7 to 12.2) in the elinzanetant group and 11.5 episodes (95% CI, 10.5 to 12.5) in the placebo–elinzanetant group. At week 4, the mean change from baseline in the mean daily frequency of moderate-to-severe vasomotor symptoms was −6.5 episodes (95% CI, −7.2 to −5.8) among those who were receiving elinzanetant and −3.0 episodes (95% CI, −3.9 to −2.2) among those who were receiving placebo (least-squares mean difference, −3.5 episodes; 95% CI, −4.4 to −2.6; P<0.001). At week 12, the mean change was −7.8 episodes (95% CI, −8.5 to −7.1) among those receiving elinzanetant and −4.2 episodes (95% CI, −5.2 to −3.2) among those receiving placebo (least-squares mean difference, −3.4 episodes; 95% CI, −4.2 to −2.5; P<0.001). During weeks 1 through 12, a total of 220 participants (69.8%) receiving elinzanetant and 98 (62.0%) receiving placebo reported at least one adverse event that occurred while receiving elinzanetant or placebo, with the most common being headache, fatigue, and somnolence. Serious adverse events occurred during weeks 1 through 12 in 8 participants (2.5%) receiving elinzanetant and 1 participant (0.6%) receiving placebo.
Conclusions:
Elinzanetant led to a significantly lower frequency of vasomotor symptoms associated with endocrine therapy than placebo.
摘要：
背景：
激素受体（HR）阳性乳腺癌患者在接受内分泌治疗时，或乳腺癌其他高危人群在接受预防内分泌治疗时，通常会出现血管舒缩症状。艾林泽坦（Elinzanetant）是一种神经激肽靶向治疗药物，其被证明可有效治疗血管舒缩症状。但该药物缺乏在此类人群中的疗效数据。
方法：
本研究为一项3期试验，纳入18至70岁、接受HR阳性乳腺癌内分泌治疗或预防治疗而出现中度至重度血管舒缩症状的女性。受试者以2：1的比例随机分配，一组接受每天一次120mg elinzanetant治疗，持续52周；另一组接受每天一次120mg安慰剂治疗，持续12周，再序贯每日一次120mg艾林泽坦治疗，持续40周。主要终点是从基线到第4周、第12周时中度至重度血管舒缩症状的平均每日发作频率变化。
结果：
共有316名参与者被分配到elinzanetant组，158名参与者被分配到安慰剂-elinzanetant组。基线时，elinzanetant组中度至重度血管舒缩症状的平均每日发作频率为11.4次（95%置信区间[CI]，10.7-12.2），安慰剂-elinzanetant组为11.5次（95%[CI]：10.5-12.5）。在第4周时，接受elinzanetant治疗的患者中，中度至重度血管舒缩症状的平均每日频率相对于基线的平均变化为-6.5次（95%[CI]：-7.2至-5.8），接受安慰剂的患者为-3.0次（95%[CI]：-3.9至-2.2）（最小二乘平均差，-3.5次;95%[CI]：-4.4至-2.6;第<0.001页）。在第12周，接受elinzanetant的患者的平均变化为-7.8次（95%[CI]：-8.5至-7.1），接受安慰剂的患者的平均变化为-4.2次（95%[CI]：-5.2至-3.2）（最小二乘均数差，-3.4次;95%[CI]：-4.2至-2.5;第<0.001页）。在第1周至第12周期间，共有220名接受elinzanetant的受试者（69.8%）和接受安慰剂的98名（62.0%）参与者报告了在接受elinzanetant或安慰剂治疗时发生的至少一次不良事件，最常见的是头痛、疲劳和嗜睡。在第1周至第12周期间，8名接受elinzanetant的参与者（2.5%）和1名接受安慰剂的参与者（0.6%）发生了严重不良事件。
结论：
与安慰剂相比，Elinzanetant导致与内分泌治疗相关的血管舒缩症状的频率显着降低。
3.Phase 3 Trial of Inhaled Molgramostim in Autoimmune Pulmonary Alveolar Proteinosis
吸入 molgramostim 治疗自身免疫性肺泡蛋白沉着症的 3 期试验
美国辛辛那提儿童医院医疗中心呼吸转化医学研究中心
Abstract
Background:
Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease characterized by progressive surfactant accumulation and hypoxemia caused by autoantibodies against granulocyte–macrophage colony-stimulating factor (GM-CSF), which alveolar macrophages require to clear surfactant. Molgramostim is a formulation of inhaled recombinant human GM-CSF, but its efficacy and safety in patients with aPAP have not been studied sufficiently.
Methods:
In this phase 3, double-blind, placebo-controlled trial, we randomly assigned patients with aPAP to receive molgramostim at a dose of 300 μg or placebo once daily for 48 weeks. The primary end point was the change from baseline to week 24 in the diffusing capacity of the lungs for carbon monoxide (DLCO), which was adjusted for hemoglobin concentration and expressed as a percentage of the predicted value. Secondary end points adjusted for multiplicity were the change from baseline in DLCO at 48 weeks and the change from baseline in the St. George’s Respiratory Questionnaire total (SGRQ-T) and activity (SGRQ-A) scores (scores range from 0 to 100, with lower scores indicating better quality of life) and in exercise capacity at 24 and 48 weeks.
Results:
A total of 164 patients underwent randomization: 81 were assigned to receive molgramostim and 83 to receive placebo. The least-squares mean change in DLCO from baseline to week 24 was 9.8 percentage points (95% confidence interval [CI], 7.3 to 12.3) with molgramostim and 3.8 percentage points (95% CI, 1.4 to 6.3) with placebo (estimated treatment difference, 6.0 percentage points; 95% CI, 2.5 to 9.4; P<0.001). The least-squares mean change in DLCO from baseline to week 48 was 11.6 percentage points (95% CI, 8.7 to 14.5) with molgramostim and 4.7 percentage points (95% CI, 1.8 to 7.6) with placebo (P<0.001), and the least-squares mean change in the SGRQ-T score at week 24 was −11.5 points (95% CI, −15.0 to −8.0) and −4.9 points (95% CI, −8.3 to −1.5), respectively (P=0.007). No significant between-group difference in the change in SGRQ-A score was observed at 24 weeks, so no statistical inference was drawn with respect to subsequent secondary end points. The percentage of patients with at least one adverse event and the percentage with at least one serious adverse event were similar in the two groups.
Conclusions:
Once-daily inhaled molgramostim led to a greater increase in pulmonary gas transfer than placebo in patients with aPAP.
摘要：
背景：
自身免疫性肺泡蛋白沉着症（autoimmunepulmonaryalveolarproteinosis，aPAP）是一种罕见的疾病，其机制是机体产生的针对粒细胞-巨噬细胞集落刺激因子（genelolocy-macrophagecolony-stimulatingfactor，GM-CSF）的自身抗体，其会可阻碍肺泡巨噬细胞清除肺表面活性物质，进而引发进行性表面活性物质蓄积及低氧血症。莫格莫司亭（Molgramostim）是一种吸入重组人GM-CSF的制剂，但其在aPAP患者中的疗效和安全性尚未得到充分研究。
方法：
在这项3期双盲安慰剂对照试验中，作者随机分配aPAP患者接受剂量为300μg的molgramostim或安慰剂，每天一次，持续48周。主要终点是经血红蛋白浓度校正后，从基线至第 24 周时肺一氧化碳弥散能力（DLCO）占预测值百分比的变化值。根据多重性调整的次要终点是48周时DLCO相对于基线的变化，以及圣乔治呼吸问卷总分（SGRQ-T）和活动（SGRQ-A）评分相对于基线的变化（分数范围从0到100，分数越低表示生活质量越好）以及24周和48周时的运动能力。
结果：
共有164名患者接受了随机分组：81名患者接受摩格莫司亭治疗，83名患者接受安慰剂治疗。DLCO从基线到第24周的最小二乘平均变化为9.8个百分点（95%置信区间[CI]，7.3-12.3），安慰剂组为3.8个百分点（95%[CI]：1.4-6.3）（估计治疗差异，6.0个百分点;95%[CI]：2.5-9.4;P<0.001）。DLCO从基线到第48周的最小二乘平均变化为11.6个百分点（95%[CI]：8.7至14.5），安慰剂组为4.7个百分点（95%[CI]：1.8至7.6）（P<0.001），第24周时SGRQ-T评分的最小二乘平均变化为-11.5分（95%[CI]：-15.0至-8.0）和-4.9分（95%[CI]：-8.3至-1.5），分别为（P=0.007）。在24周时，SGRQ-A评分的变化没有观察到显着的组间差异，因此没有对随后的次要终点进行统计推断。两组发生至少1例不良事件的患者百分比和发生至少1例严重不良事件的患者百分比相似。
结论：
与安慰剂相比，每天一次吸入molgramostim导致aPAP患者的肺气体转移增加更大。
4.Adjuvant Cemiplimab or Placebo in High-Risk Cutaneous Squamous-Cell Carcinoma
辅助 Cemiplimab 或安慰剂治疗高危皮肤鳞状细胞癌
澳大利亚墨尔本彼得·麦卡勒姆癌症中心肿瘤内科
Abstract
Background:
Patients who have cutaneous squamous-cell carcinoma with high-risk features are at risk for recurrence after definitive local therapy. The benefit of systemic adjuvant therapy options has not been well established in clinical trials.
Methods:
In a phase 3, randomized trial, we enrolled patients with local or regional cutaneous squamous-cell carcinoma, after surgical resection and postoperative radiotherapy, at high risk for recurrence owing to nodal features (extracapsular extension with largest node ≥20 mm in diameter or at least three involved nodes) or nonnodal features (in-transit metastases, T4 lesion [with bone invasion], perineural invasion, or locally recurrent tumor with ≥1 additional risk feature). Patients were assigned in a 1:1 ratio to receive adjuvant cemiplimab (350 mg) or placebo, administered intravenously every 3 weeks for 12 weeks, followed by a dose increase to 700 mg administered every 6 weeks for up to 36 weeks (≤48 weeks total). The primary end point was disease-free survival. Secondary end points included freedom from locoregional recurrence, freedom from distant recurrence, and safety.
Results:
A total of 415 patients were assigned to cemiplimab (209) or placebo (206). The median follow-up was 24 months. Cemiplimab was superior to placebo with respect to disease-free survival (24 vs. 65 events; hazard ratio for disease recurrence or death, 0.32; 95% confidence interval [CI], 0.20 to 0.51; P<0.001). The estimated 24-month disease-free survival was 87.1% (95% CI, 80.3 to 91.6) with cemiplimab and 64.1% (95% CI, 55.9 to 71.1) with placebo. Cemiplimab led to lower risks of locoregional recurrence (9 events, vs. 40 with placebo; hazard ratio, 0.20; 95% CI, 0.09 to 0.40) and distant recurrence (10 vs. 26 events; hazard ratio, 0.35; 95% CI, 0.17 to 0.72). Adverse events of grade 3 or higher occurred in 23.9% of the patients who received cemiplimab and in 14.2% of those who received placebo; discontinuation due to adverse events occurred in 9.8% and 1.5%, respectively.
Conclusions:
Adjuvant cemiplimab therapy led to longer disease-free survival than placebo among patients at high risk for recurrence of cutaneous squamous-cell carcinoma.
摘要：
背景：
具有高危特征的皮肤鳞状细胞癌患者，在接受根治性局部治疗后仍存在复发的风险，而全身辅助治疗方案对该类患者的益处，尚未在临床试验中得到充分证实。
方法：
在一项3期随机试验中，作者招募了经手术切除联合术后放疗的后局部或区域皮肤鳞状细胞癌患者，入组患者需满足高位风险特征：淋巴结相关特征（最大淋巴结囊外延伸≥直径20毫米，或≥3个淋巴结受累），或非淋巴结特征（肿瘤转移、T4期伴骨侵犯、神经周围浸润，或具有≥1个额外风险特征的局部复发性肿瘤）。患者以1：1的比例分配接受辅助cemiplimab（350mg）或安慰剂，每3周静脉注射一次，持续12周，然后剂量增加至700mg，每6周给药一次，持续长达36周（总共≤48周）。主要终点是无病生存期。次要终点包括无局部区域复发、无远处复发和安全性。
结果：
共有415名患者被分配到西米普利单抗（209）或安慰剂组（206）。中位随访时间为24个月。在无病生存期方面，Cemiplimab优于安慰剂（24vs65事件;疾病复发或死亡风险比，0.32;95%[CI]：0.20至0.51;P<0.001）。cemiplimab组估计的24个月无病生存率为87.1%（95%[CI]：80.3-91.6），安慰剂组估计为64.1%（95%[CI]：55.9-71.1）。西米利单抗可降低局部区域复发的风险（9例，安慰剂组为40例;风险比为0.20;95%[CI]：0.09-0.40）和远处复发（10例vs.26例;风险比为0.35;95%[CI]：0.17-0.72）。接受cemiplimab治疗的患者中有23.9%发生3级或更高级别的不良事件，在接受安慰剂治疗的患者中，14.2%发生了3级或更高级别的不良事件;因不良事件而停药的比例分别为9.8%和1.5%。
结论：
在皮肤鳞状细胞癌复发高危患者中，辅助cemiplimab治疗比安慰剂治疗的无病生存期更长。
九月第一期共5篇Articles
1.Once-Monthly Maridebart Cafraglutide for the Treatment of Obesity — A Phase 2 Trial
每月一次的 Maridebart Cafraglutide 治疗肥胖症 — 2 期试验
美国康涅狄格州纽黑文市耶鲁大学医学院内科系内分泌与代谢科
Abstract
Background:
Maridebart cafraglutide (known as MariTide) is a long-acting peptide–antibody conjugate that combines glucagon-like peptide-1 receptor agonism and glucose-dependent insulinotropic polypeptide receptor antagonism and that is intended for the treatment of obesity.
Methods:
We conducted a phase 2, double-blind, randomized, placebo-controlled, dose-ranging trial that included 11 groups as two cohorts. Participants with obesity (obesity cohort) were randomly assigned in a 3:3:3:2:2:2:3 ratio to receive maridebart cafraglutide subcutaneously at a dose of 140, 280, or 420 mg every 4 weeks without dose escalation; 420 mg every 8 weeks without dose escalation; 420 mg every 4 weeks with 4-week dose escalation; 420 mg every 4 weeks with 12-week dose escalation; or placebo. Participants with obesity with type 2 diabetes (obesity–diabetes cohort) were randomly assigned in a 1:1:1:1 ratio to receive maridebart cafraglutide at a dose of 140, 280, or 420 mg every 4 weeks (all without dose escalation) or placebo. The primary end point was the percent change in body weight from baseline to week 52.
Results:
We enrolled 592 participants. In the obesity cohort (465 participants; female sex, 63%; mean age, 47.9 years; mean body-mass index [BMI, the weight in kilograms divided by the square of the height in meters], 37.9), the mean percent change in body weight from baseline to week 52 on the basis of the treatment policy estimand (intention-to-treat approach) ranged from −12.3% (95% confidence interval [CI], −15.0 to −9.7) to −16.2% (95% CI, −18.9 to −13.5) with maridebart cafraglutide, as compared with −2.5% (95% CI, −4.2 to −0.7) with placebo. In the obesity–diabetes cohort (127 participants; female sex, 42%; mean age, 55.1 years; mean BMI, 36.5), the mean percent change in body weight from baseline to week 52 on the basis of the treatment policy estimand ranged from −8.4% (95% CI, −11.0 to −5.7) to −12.3% (95% CI, −15.3 to −9.2) with maridebart cafraglutide, as compared with −1.7% (95% CI, −2.9 to −0.6) with placebo. The mean change in the glycated hemoglobin level on the basis of the treatment policy estimand in this cohort was −1.2 to −1.6 percentage points in the maridebart cafraglutide groups and 0.1 percentage points in the placebo group. Gastrointestinal adverse events were common with maridebart cafraglutide, although less frequent with dose escalation and a lower starting dose. No unexpected safety signals emerged.
Conclusions:
In this phase 2 trial, once-monthly maridebart cafraglutide resulted in substantial weight reduction in participants with obesity with or without type 2 diabetes.
摘要：
背景：
Maridebartcafraglutide（称为MariTide）是一种长效肽-抗体偶联物，兼具胰高血糖素样肽-1受体激动活性和葡萄糖依赖性促胰岛素多肽受体拮抗活性，适用于治疗肥胖症。
方法：
本研究为进行了一项2期、双盲、随机、安慰剂对照、剂量范围探究试验，共设置了11个实验组，并分为2个队列。肥胖队列纳入单纯性肥胖患者，以3：3：3：2：2：2：3的比例随机分配，接受每4周皮下注射MariTide140mg、280mg或420mg（无需剂量递增）;每8周皮下注射420mg（无剂量递增）;每4周皮下注射420mg，剂量递增4周;每4周皮下注射420mg，剂量递增12周;或皮下注射安慰剂。肥胖-糖尿病队列纳入肥胖合并2型糖尿病的受试者，以1：1：1：1的比例随机分配接受每4周140mg、280mg或420mg剂量的maridebartcafraglutide（均不增加剂量）或安慰剂。主要终点是体重从基线到第52周的百分比变化。
结果：
研究招募了592名参与者。肥胖队列纳入465名受试者，其中女性占比63%，平均年龄为47.9岁，平均体重指数[BMI，体重（公斤）/身高2（米2）]为37.9，基于治疗政策估计（意向治疗方法）的体重从基线到第52周的平均百分比变化范围为-12.3%（95% [CI]：-15.0至-9.7）至-16.2%（95%[CI]：-18.9至-13.5），而安慰剂组的-2.5%（95% [CI]：-4.2至-0.7）。肥胖-糖尿病队列纳入127名受试者，其中女性占比为42%，平均年龄为55.1岁，平均BMI为36.5，根据治疗政策估计，体重从基线到第52周的平均百分比变化范围为-8.4%（95% [CI]：-11.0至-5.7）至-12.3%（95% [CI]：-15.3至-9.2），而maridebartcafraglutide组为-1.7%（95% [CI]：-2.9至-0.6）与安慰剂。根据治疗政策估计，该队列中糖化血红蛋白水平的平均变化在maridebartcafraglutide组中为-1.2%至-1.6%，安慰剂组中则为0.1%。maridebart卡夫鲁肽的胃肠道不良事件很常见，但采用剂量递增方案或降低起始剂量时，发生频率有所降低。研究过程中没有出现预期外的安全信号。
结论：
在这项2期试验中，每月一次的maridebart卡夫鲁肽可显着减轻肥胖参与者的体重，无论是否患有2型糖尿病。
2.Stem Cell–Derived, Fully Differentiated Islets for Type 1 Diabetes
干细胞来源的全分化胰岛用于 1 型糖尿病
多伦多大学大学健康网络-多伦多综合医院
Abstract
Background:
Zimislecel is an allogeneic stem cell–derived islet-cell therapy. Data on the safety and efficacy of zimislecel in persons with type 1 diabetes are needed.
Methods:
We conducted a phase 1–2 study of zimislecel in persons with type 1 diabetes. In part A, participants received a half dose of zimislecel (0.4×109 cells) as a single infusion into the portal vein, with an option for a second half dose within 2 years. In parts B and C, participants received a full dose of zimislecel (0.8×109 cells) as a single infusion. All the participants also received glucocorticoid-free immunosuppressive therapy. The primary end point in part A was safety. The primary end point in part C was freedom from severe hypoglycemic events during days 90 through 365, with a glycated hemoglobin level of less than 7% or a decrease of at least 1 percentage point from baseline in the glycated hemoglobin level at one or more time points between days 180 and 365. Secondary end points in part C included safety and insulin independence between days 180 and 365. Assessment of the primary and secondary end points in part C involved the participants who received the full dose of zimislecel as a single infusion in part B or C. Detection of serum C-peptide during a 4-hour mixed-meal tolerance test was used to assess engraftment and islet function. All the analyses were interim and not prespecified.
Results:
A total of 14 participants (2 in part A and 12 in parts B and C) completed at least 12 months of follow-up and were included in the analyses. C-peptide was undetectable at baseline in all 14 participants. After zimislecel infusion, all the participants had engraftment and islet function, as evidenced by the detection of C-peptide. Neutropenia was the most common serious adverse event, occurring in 3 participants. Two deaths occurred — one caused by cryptococcal meningitis and one by severe dementia with agitation owing to the progression of preexisting neurocognitive impairment. All 12 participants in parts B and C were free of severe hypoglycemic events and had a glycated hemoglobin level of less than 7%; these participants spent more than 70% of the time in the target glucose range (70 to 180 mg per deciliter). Ten of the 12 participants (83%) had insulin independence and were not using exogenous insulin at day 365.
Conclusions:
The results of this small, short-term study involving persons with type 1 diabetes support the hypothesis that zimislecel can restore physiologic islet function, warranting further clinical investigation.
摘要：
背景：
齐米来塞（Zimislecel）是一种基于同种异体干细胞的胰岛细胞疗法，为1型糖尿病的治疗提供了新方向，但目前尚缺乏齐米来塞在1型糖尿病患者中的安全性和有效性数据。
方法：
本研究为一项的1-2期研究，纳入1型糖尿病患者并分为A、B、C三部分，在A部分中，受试者接受半剂量zimislecel（0.4×109个细胞）单次门静脉输注，并可选择在2年内接受另一半剂量输注。在B部分和C部分，受试者均接受全剂量的zimislecel（0.8×109细胞）单次输注。所有参与者均接受不含糖皮质激素的免疫抑制治疗。研究设置差异化终点：A部分以安全性为主要终点。C部分主要终点是第90~365天无严重低血糖事件发生，且在第180~第365天任意时间点，糖化血红蛋白水平＜7% 或较基线下降≥1%。C部分的次要终点包括试验期间的安全性和胰岛素独立性。针对C部分主要和次要终点评估，纳入了B、C部分中接受全剂量齐米来塞单次输注的参与者。在4小时混餐耐受性试验中检测血清C肽，评估胰岛细胞植入情况和胰岛功能恢复情况。本研究所有分析均为探索性分析，无预先指定的统计假设。
结果：
共有14名参与者（A部分2名，B部分和C部分12名）完成了至少12个月的随访并被纳入分析。所有14名参与者的C肽在基线时均未检测到。输注zimislecel后，所有参与者都有植入和胰岛功能，C肽的检测证明了这一点。中性粒细胞减少症是最常见的严重不良事件，发生在3名受试者中；研究期间报告两例死亡事件——一例由隐球菌性脑膜炎引起，另一例由先前存在的神经认知障碍进展导致的严重痴呆伴躁动。B部分和C部分的所有12名参与者均未发生严重低血糖事件，糖化血红蛋白水平低于7%;这些参与者超过70%的时间都在目标葡萄糖范围内（每分升70至180毫克）度过。12名参与者中有10名（83%）具有胰岛素独立性，并且在第365天没有使用外源性胰岛素。
结论：
这项涉及1型糖尿病患者的小型短期研究的结果支持了齐米来塞可以恢复生理胰岛功能的假设，值得进一步的临床研究。
3.One Dose versus Three Doses of Benzathine Penicillin G in Early Syphilis
早期梅毒中一剂与三剂苄星青霉素G对比
美国阿拉巴马州伯明翰市阿拉巴马大学伯明翰分校医学系
Abstract
Background:
Controversy persists regarding the appropriate duration of therapy with benzathine penicillin G in persons with early (i.e., primary, secondary, or early latent) syphilis (Treponema pallidum infection).
Methods:
In a multicenter, randomized, controlled, noninferiority trial, we assigned persons who had early syphilis, with or without human immunodeficiency virus (HIV) infection, to receive intramuscular injections of benzathine penicillin G in a one-time dose of 2.4 million units or in doses of 2.4 million units administered at three successive weekly intervals. The primary end point was seroreversion to nonreactive status or a decrease in the rapid plasma reagin titer by two or more dilutions at 6 months, referred to here as a serologic response (noninferiority margin, 10 percentage points). A key secondary end point was a serologic response within subgroups defined according to HIV status, also assessed in a noninferiority analysis.
Results:
A total of 249 persons with early syphilis were enrolled. Most participants were men (97%), 62% were Black, and 153 (61%) were living with HIV infection. The distribution according to syphilis stage was 19% with primary syphilis, 47% with secondary syphilis, and 33% with early latent syphilis. The percentage of participants with a serologic response at 6 months was 76% (95% confidence interval [CI], 68 to 82) in the single-dose group and 70% (95% CI, 61 to 77) in the three-dose group (difference, −6 percentage points; 90% CI, −15 to 3, indicating noninferiority). No clinical relapse or treatment failure occurred in either group. In the one-dose group, a serologic response at 6 months was observed in 76% of participants who had HIV infection and 76% of those who did not, and in the three-dose group, a serologic response at 6 months was observed in 71% of participants who had HIV infection and 70% of those who did not. Most participants in each group had local injection-site pain and tenderness with treatment (76% with a single dose and 85% with three doses).
Conclusions:
Treatment with one dose of 2.4 million units of benzathine penicillin G was noninferior to treatment with three doses with regard to serologic response 6 months after treatment.
摘要：
背景：
苄星青霉素G是治疗早期梅毒（一期、二期及早期潜伏性）螺旋体感染的常用药物，但其对患者的适当治疗疗程尚存在争议。
方法：
一项多中心、随机、对照、非劣效性试验纳入伴或不伴人类免疫缺陷病毒（humanimmunodefiencyvirus，HIV）感染的早期梅毒患者，随机分配为两组，一组接受单次肌肉注射240万单位苄星青霉素G，另一组接受每周一次，连续三次肌肉注射给药240万单位苄星青霉素G。主要终点是血清反应恢复到阴性非应答状态，或在6个月时快速反应素滴度较基线降低≥2个稀释度；非劣效性范围界定为10个百分点。关键次要终点是根据HIV状态定义的亚组血清学应答反应，同样采用非劣效性分析进行评估。
结果：
共入组了249名早期梅毒患者。大多数参与者是男性（97%），62%是黑人，153人（61%）感染了HIV。按梅毒分期分布，一期梅毒占19%，二期梅毒占47%，早期潜伏梅毒占33%。单剂量组在6个月时出现血清学反应的受试者百分比为76%（95%置信区间[CI]，68-82），三剂组为70%（95%[CI]：61-77）（差异，-6个百分点;90%CI，-15-3，表明非劣效性）。两组均未发生临床复发或治疗失败状况。在一剂组中，76%的HIV感染者和76%的未感染者在6个月时观察到血清学反应，在三剂组中，在6个月时观察到血清学反应在71%的HIV感染者和70%的未感染者中观察到血清学反应。每组的大多数受试者在治疗后出现局部注射部位疼痛和压痛（单剂76%，三剂85%）。
结论：
在治疗后6个月的血清学反应方面，一剂240万单位苄星青霉素G治疗不劣于三剂治疗。
4.Monoclonal Antibodies in the Pathogenesis of Heparin-Induced Thrombocytopenia
单克隆抗体在肝素诱导的血小板减少症发病机制中的应用
加拿大安大略省汉密尔顿市麦克马斯特大学生物化学与生物医学科学系
Abstract
Background:
Heparin-induced thrombocytopenia (HIT) is an immune-mediated platelet disorder caused by antibodies that target complexes of platelet factor 4 (PF4) and heparin. HIT has been characterized as a polyclonal immune response; however, studies of other rare anti-PF4 disorders have identified clonally restricted antibodies.
Methods:
In this study, we investigated the clonality of pathogenic HIT antibodies. Antibodies against PF4–heparin were affinity-purified with the use of PF4–heparin beads from serum samples obtained from nine patients with clinically and serologically confirmed HIT. Antibody clonality was assessed by means of immunofixation electrophoresis and mass spectrometry. Antibody binding to PF4 was evaluated by an enzyme immunoassay, and functional platelet activation was evaluated with the use of a P-selectin expression assay. HIT antibody epitopes were mapped in two patients with the use of a PF4 mutant library.
Results:
Serum samples from all nine patients with HIT were positive for platelet-activating antibodies against PF4–heparin by enzyme immunoassay, as well as the P-selectin expression assay, and six samples (67%) had a monoclonal antibody detectable by immunofixation electrophoresis. The affinity-purified antibodies against PF4–heparin from all nine samples activated platelets in the P-selectin expression assay, and mass spectrometry showed monoclonality. After affinity purification, antibody-depleted serum samples lost binding activity in the enzyme immunoassay and functional activity in the P-selectin expression assay, which confirmed the removal of the pathogenic antibodies. The epitopes on PF4 targeted by anti–PF4–heparin antibodies from serum samples were the same as those targeted by the affinity-purified monoclonal antibodies.
Conclusions:
The pathogenic antibodies in all nine patients with HIT were found to be monoclonal. This finding provides insight into the pathogenesis of HIT and has implications for improved diagnostics and targeted therapeutics.
摘要：
背景：
肝素诱导的血小板减少症（HIT）是一种免疫介导的血小板疾病，由靶向血小板因子4（PF4）和肝素复合物的抗体引起。既往研究中HIT被描述为多克隆免疫反应，但对其他罕见抗PF4疾病的研究已经确定，此类疾病中存在克隆限制性抗体，而 HIT致病性抗体的克隆性特征尚未明确。
方法：
本研究旨在调查致病性HIT抗体的克隆性，纳入9例经临床和血清学证实的HIT患者，获取其血清样本中的PF4-肝素珠，亲和纯化了针对PF4-肝素的抗体。通过免疫固定、电泳和质谱法评估抗体克隆性。通过酶免疫测定法评估抗体与PF4的结合，并使用P-选择素表达测定法评估功能性血小板活化。使用PF4突变体文库在两名患者中绘制HIT抗体表位。
结果：
本研究共874例患者完成随机分组：伊姆仑斯特单药组331例，标准治疗组330例，伊姆仑斯特-阿贝西利联合组213例。在256例ESR1突变患者中，伊姆仑斯特组中位无进展生存期为5.5个月，标准治疗组为3.8个月。19.4个月时的估计限制性平均生存时间：伊姆仑斯特组7.9个月（95%置信区间[CI]6.8-9.1），标准治疗组5.4个月（95%[CI]4.6-6.2）（组间差异2.6个月；95%[CI]1.2-3.9；P<0.001）。全体患者中，伊姆仑斯特组与标准治疗组的中位无进展生存期分别为5.6个月和5.5个月（疾病进展或死亡风险比0.87；95%[CI]0.72-1.04；P=0.12）。在伊姆仑斯特-阿贝西利联合组与伊姆仑斯特单药组比较的426例患者中，中位无进展生存期分别为9.4所有9名HIT患者的血清样本均通过酶免疫测定和P-选择素表达测定对PF4-肝素的血小板激活抗体呈阳性，6份样本（67%）具有可通过免疫固定电泳检测到的单克隆抗体。所有9个样品中针对PF4-肝素的亲和纯化抗体在P-选择素表达测定中激活血小板，质谱显示单克隆性。亲和纯化后，抗体耗尽的血清样品在酶免疫测定中失去结合活性，在P-选择素表达测定中失去功能活性，证实了致病性抗体的去除。血清样本中抗PF4-肝素抗体靶向的PF4表位与亲和纯化单克隆抗体靶向的表位相同。
结论：
所有9名HIT患者的致病性抗体均被发现为单克隆抗体。这一发现提供了对HIT发病机制的深入了解，并对改进诊断和靶向治疗具有重要意义。
5.Survival of Transplanted Allogeneic Beta Cells with No Immunosuppression
无免疫抑制的移植同种异体 β 细胞的存活率
瑞典乌普萨拉大学医学细胞生物学系
Summary:
The need to suppress a patient’s immune system after the transplantation of allogeneic cells is associated with wide-ranging side effects. We report the outcomes of transplantation of genetically modified allogeneic donor islet cells into a man with long-standing type 1 diabetes. We used clustered regularly interspaced short palindromic repeats (CRISPR)–CRISPR-associated protein 12b (Cas12b) editing and lentiviral transduction to genetically edit the cells to avoid rejection; the cells were then transplanted into the participant’s forearm muscle. He did not receive any immunosuppressive drugs and, at 12 weeks after transplantation, showed no immune response against the gene-edited cells. C-peptide measurements showed stable and glucose-responsive insulin secretion. A total of four adverse events occurred, none of which were serious or related to the study drug.
总结：
同种异体细胞移植术后需要需长期进行免疫抑制治疗，而这往往伴随广泛的副作用。研究团队报告了一例将基因编辑同种异体供体胰岛细胞移植治疗长期1型糖尿病男性患者的结果。通过使用成簇规则间隔短回文重复序列（CRISPR）-CRISPR相关蛋白12b（Cas12b）编辑，联合慢病毒转导，对供体胰岛细胞进行靶向修饰，以避免排斥反应;然后将细胞移植到参与者的前臂肌肉中，全程未接受任何免疫抑制药物。术后12周随访结果表示，患者未出现针对基因编辑细胞的免疫排斥反应。C肽测量显示稳定且对葡萄糖有反应的胰岛素分泌。共发生四起不良事件，均不严重或与研究药物相关。
九月第二期共4篇Articles
1.Aficamten or Metoprolol Monotherapy for Obstructive Hypertrophic Cardiomyopathy
Aficamten 或美托洛尔单药治疗梗阻性肥厚型心肌病
马德里铁门大学医院（马哈达翁达）- 铁门-塞哥维亚德阿拉纳卫生研究所 - 心血管疾病生物医学研究网络中心
Abstract
Background:
Beta-blockers have been the initial treatment for symptomatic obstructive hypertrophic cardiomyopathy (HCM) despite limited evidence of their efficacy. Aficamten is a cardiac myosin inhibitor that reduces left ventricular outflow tract gradients, improves exercise capacity, and decreases HCM symptoms when added to standard medications. Whether aficamten as monotherapy provides greater clinical benefit than beta-blockers as monotherapy remains unknown.
Methods:
We conducted an international, double-blind, double-dummy trial in which adults with symptomatic obstructive HCM were randomly assigned in a 1:1 ratio to receive aficamten (at a daily dose of 5 mg to 20 mg) plus placebo or metoprolol (at a daily dose of 50 mg to 200 mg) plus placebo. The primary end point was the change in peak oxygen uptake at week 24; secondary end points were improvement at week 24 in New York Heart Association (NYHA) functional class and changes at week 24 in Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), left ventricular outflow tract gradient after the Valsalva maneuver, N-terminal pro–B-type natriuretic peptide (NT-proBNP) level, left atrial volume index, and left ventricular mass index.
Results:
Among A total of 88 patients were assigned to the aficamten group and 87 to the metoprolol group. The mean age of the patients was 58 years, 58.3% were men, and the mean left ventricular outflow tract gradient was 47 mm Hg at rest and 74 mm Hg after the Valsalva maneuver. At 24 weeks, the change in the peak oxygen uptake was 1.1 ml per kilogram of body weight per minute (95% confidence interval [CI], 0.5 to 1.7) in the aficamten group and −1.2 ml per kilogram per minute (95% CI, −1.7 to −0.8) in the metoprolol group (least-squares mean between-group difference, 2.3 ml per kilogram per minute; 95% CI, 1.5 to 3.1; P<0.001). Patients who received aficamten had significantly greater improvements in NYHA class, KCCQ-CSS, left ventricular outflow tract gradient, NT-proBNP level, and left atrial volume index than patients who received metoprolol. No significant difference in left ventricular mass index was observed. Adverse events appeared to be similar in the two treatment groups.
Conclusions:
Among patients with symptomatic obstructive HCM, aficamten monotherapy was superior to metoprolol monotherapy in improving peak oxygen uptake and hemodynamics and decreasing symptoms.
摘要：
背景：
β受体阻滞剂长期作为症状性阻塞性肥厚型心肌病（HCM）的初始治疗药物，但其疗效的缺乏充足试验证据。Aficamten是一种心脏肌球蛋白抑制剂，当添加到标准药物中时，可降低左心室流出道梯度，提高运动能力并减轻HCM症状。Aficamten作为单药治疗与β受体阻滞剂作为单药治疗的临床获益差异尚未明确。
方法：
本研究为一项国际、双盲、双模拟试验，其中有症状的阻塞性HCM成人以1：1的比例随机分配接受Aficamten（每日剂量为5mg至20mg）加安慰剂或美托洛尔（每日剂量为50mg至200mg）加安慰剂。主要终点是第24周摄氧峰值的变化;次要终点是纽约心脏协会（NYHA）功能分级在第24周时的改善和堪萨斯城心肌病问卷临床总分（KCCQ-CSS）在第24周时的变化、Valsalva动作后的左心室流出道梯度、N末端B型利钠肽前体（NT-proBNP）水平、左心房容积指数和左心室质量指数。
结果：
共有88名患者被分配到Aficamten组，87名患者被分配到美托洛尔组。患者平均年龄为58岁，男性占58.3%，静息时平均左心室流出道梯度为47mmHg，Valsalva动作后平均为74mmHg。在24周时，Aficamten组的摄氧峰值变化为1.1mL/kg/min（95%[CI]：0.5~1.7），美托洛尔组为-1.2mL/kg/min（95%[CI]：-1.7~-0.8）（最小二乘平均组间差异=2.3mL/kg/min;95%[CI]：1.5~3.1;P<0.001）。与接受美托洛尔治疗的患者相比，接受Aficamten的患者在NYHA等级、KCCQ-CSS、左心室流出道梯度、NT-proBNP水平和左心房容积指数方面有明显更大的改善。左心室质量指数无显著差异。两个治疗组的不良事件似乎相似。
结论：
在有症状的梗阻性HCM患者中，非卡坦单药治疗在改善峰值摄氧量和血流动力学以及减轻症状方面优于美托洛尔单药治疗。
2.Mavacamten in Symptomatic Nonobstructive Hypertrophic Cardiomyopathy
Mavacamten 治疗有症状的非阻塞性肥厚型心肌病
克利夫兰诊所心脏、血管和胸科研究所-肥厚型心肌病中心
Abstract
Background:
Mavacamten is approved to treat adults with symptomatic obstructive hypertrophic cardiomyopathy (HCM). However, its effects in nonobstructive HCM remain uncertain.
Methods:
We conducted a phase 3, international, double-blind, placebo-controlled, clinical trial to determine whether mavacamten improves functional capacity and patient-reported health status among adults with symptomatic nonobstructive HCM. Patients were randomly assigned in a 1:1 ratio to receive mavacamten (starting at 5 mg per day and adjusted up to a maximum of 15 mg per day on the basis of left ventricular ejection fraction) or placebo (with sham dose adjustment) for 48 weeks. The two primary end points were the change from baseline to week 48 in peak oxygen uptake and in the 23-item Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS; scores range from 0 to 100, with higher scores indicating better health status).
Results:
We randomly assigned 289 patients to receive mavacamten and 291 to receive placebo. The mean (±SD) age of the patients was 56±15 years, and 46% were women. From baseline to week 48, the least-squares mean change in peak oxygen uptake was 0.52 ml per kilogram of body weight per minute (95% confidence interval [CI], 0.09 to 0.95) in the mavacamten group and 0.05 ml per kilogram per minute (95% CI, −0.38 to 0.47) in the placebo group (between-group difference, 0.47 ml per kilogram per minute; 95% CI, −0.03 to 0.98; P=0.07). The least-squares mean change in the KCCQ-CSS was 13.1 points (95% CI, 10.7 to 15.5) in the mavacamten group and 10.4 points (95% CI, 8.0 to 12.8) in the placebo group (between-group difference, 2.7 points; 95% CI, −0.1 to 5.6; P=0.06). Reductions in ejection fraction and interruptions in the trial regimen were more common with mavacamten than with placebo.
Conclusions:
Among patients with nonobstructive HCM, mavacamten did not result in a significantly greater improvement in peak oxygen uptake or decrease in symptoms than placebo.
摘要：
背景：
Mavacamten作为一种心脏肌球蛋白抑制剂，被批准用于治疗患有症状性阻塞性肥厚型心肌病（HCM）的患者。然而，其对非阻塞性HCM的影响仍不确定。
方法：
本研究为一项国际、双盲、安慰剂对照的3期临床试验，以确定mavacamten是否能改善有症状的非阻塞性HCM成人患者的功能能力和患者报告的健康状况。患者以1：1的比例随机分配至 Mavacamten 组与安慰剂组，mavacamten组初始剂量为每日5 mg，根据左心室射血分数调整至每天最多15mg，安慰剂接受匹配的假剂量调整，两组均为持续48周。两个主要终点是峰值摄氧量从基线到第48周的变化，以及堪萨斯城心肌病问卷临床总分23项（KCCQ-CSS;分数范围从0到100，分数越高表示健康状况越好）。
结果：
研究纳入289名患者接受mavacamten治疗，291名患者接受安慰剂治疗。患者的平均年龄（±SD）为56±15岁，其中46%为女性。从基线到第48周，mavacamten组的峰值摄氧量的最小二乘平均变化为0.52ml/kg/min（95%置信区间[CI]，0.09-0.95），安慰剂组为0.05ml/kg/min（95%[CI]:-0.38~0.47）（组间差异=0.47ml/kg/min;95%[CI]：−0.03~0.98;P=0.07）。mavacamten组KCCQ-CSS的最小二乘平均值变化为13.1分（95%[CI]:10.7~15.5），安慰剂组为10.4分（95%[CI]:8.0~12.8）（组间差异=2.7;95%[CI]：-0.1~5.6;P=0.06）。射血分数降低和试验方案中断在mavacamten组比安慰剂组更常见。
结论：
在非阻塞性HCM患者中，与安慰剂相比，mavacamten并没有显着改善峰值摄氧量或减轻症状。
3.Multidomain Rehabilitation for Older Patients with Myocardial Infarction
老年心肌梗死患者的多领域康复
意大利费拉拉大学医院心脏病科
Abstract
Background:
The benefit of rehabilitation interventions in patients who are 65 years of age or older with myocardial infarction and impaired physical performance remains unclear.
Methods:
In this multicenter, randomized trial conducted in Italy, we assigned older patients with impaired physical performance 1 month after myocardial infarction in a 2:1 ratio to receive either an intervention consisting of control of cardiovascular risk factors, dietary counseling, and exercise training (intervention group) or usual care (control group). The primary outcome was a composite of cardiovascular death or unplanned hospitalization for cardiovascular causes within 1 year.
Results:
A total of 512 patients underwent randomization (342 to the intervention group and 170 to the control group). The median age of the patients was 80 years, and 36% were women. A primary-outcome event occurred in 43 patients (12.6%) in the intervention group and in 35 patients (20.6%) in the control group (hazard ratio, 0.57; 95% confidence interval [CI], 0.36 to 0.89; P=0.01). Cardiovascular death occurred in 14 patients (4.1%) in the intervention group and in 10 patients (5.9%) in the control group (hazard ratio, 0.69; 95% CI, 0.31 to 1.55). Unplanned hospitalization for cardiovascular causes occurred in 31 patients (9.1%) in the intervention group and in 30 patients (17.6%) in the control group (hazard ratio, 0.48; 95% CI, 0.29 to 0.79). There were no serious adverse events associated with the intervention.
Conclusions:
Among older patients with impaired physical performance 1 month after myocardial infarction, a multidomain rehabilitation intervention resulted in a lower incidence of cardiovascular death or unplanned cardiovascular hospitalization within 1 year than usual care.
摘要：
背景：
传统心脏康复干预多聚焦于一般心梗人群，对65岁或以上心肌梗死和身体机能受损患者的益处仍不清楚。
方法：
本研究为一项意大利多中心随机试验中，纳入对象为心肌梗死后1个月、身体机能受损的老年患者，按2：1比例接受包括控制心血管危险因素、饮食咨询和运动训练在内的干预（干预组）或常规护理（对照组）。主要结局是心血管死亡或1年内因心血管原因意外住院的复合结局。
结果：
研究共有512名患者接受了随机分组（干预组342名，对照组170名）。患者中位年龄为80岁，36%为女性，其中干预组43例（12.6%），对照组35例（20.6%）发生主要结局事件（风险比=0.57;95%[CI]：0.36-0.89;P=0.01）。干预组14例（4.1%）和对照组10例（5.9%）发生心血管死亡（风险比=0.69; 95%[CI]：0.31-1.55）。干预组31例（9.1%）和对照组30例（17.6%）患者因心血管原因意外住院（风险比=0.48; 95%[CI]：0.29-0.79）。没有与干预相关的严重不良事件。
结论：
在心肌梗死后1个月身体机能受损的老年患者中，多域康复干预导致1年内心血管死亡或计划外心血管住院的发生率低于常规护理。
4.Marburg Virus Disease in Rwanda, 2024 — Public Health and Clinical Responses
2024年卢旺达马尔堡病毒病 — 公共卫生和临床应对
卢旺达基加利卫生部
Abstract
Background:
On September 27, 2024, Rwanda reported an outbreak of Marburg virus disease (MVD), after a cluster of cases of viral hemorrhagic fever was detected at two urban hospitals.
Methods:
We report key aspects of the epidemiology, clinical manifestations, and treatment of MVD during this outbreak, as well as the overall response to the outbreak. We performed a retrospective epidemiologic and clinical analysis of data compiled across all pillars of the outbreak response and a case-series analysis to characterize clinical features, disease progression, and outcomes among patients who received supportive care and investigational therapeutic agents.
Results:
Among the 6340 patients with suspected MVD who underwent testing, 66 had laboratory-confirmed MVD, 51 (77%) of whom were health care workers. The median estimated incubation period was 10 days (interquartile range, 8 to 13), and symptom onset occurred a median of 2 days (interquartile range, 1 to 3) before hospital admission. The results of epidemiologic investigations were highly suggestive of a zoonotic origin of the outbreak: an index patient was identified who had been exposed to Egyptian fruit bats at a mining site. The case fatality rate in the outbreak was 23% (15 deaths among 66 patients). Remdesivir and the monoclonal antibody MBP091 were used under expanded access and clinical trial protocols. In addition, 1710 frontline workers and high-risk contacts received the chimpanzee adenovirus 3–vectored vaccine ChAd3-MARV under emergency use authorization in a phase 2 clinical trial.
Conclusions:
Implementation of containment measures, advanced supportive care, and access to investigational countermeasures may have contributed to reduced mortality from MVD in this outbreak. Enhancing surveillance, improving infection prevention and control in health care settings, and ensuring timely deployment of medical countermeasures will be critical for mitigating the effects of future filovirus disease outbreaks.
摘要：
背景：
2024年9月27日，卢旺达报告了马尔堡病毒病（MVD）的疫情，此前两家城市医院发现了一组聚集性病毒性出血热病例。
方法：
本研究采用回顾性流行病学和临床病例系列分析，整合疫情应对所有支柱数据，报告了本次马尔堡病毒病的流行病学、临床表现和治疗的关键信息，以及对疫情的总体反应，以表征接受支持性治疗和研究性治疗药物的患者的临床特征、疾病进展和结局。
结果：
在接受检测的6340名疑似马尔堡病患者中，66例经实验室确诊为马尔堡病，其中51例（77%）为医护人员。中位估计潜伏期为10天（四分位距，8~13天），症状发作发生在入院前中位2天（四分位距，1~3天）。流行病学调查的结果高度表明疫情是人畜共患的：患者为采矿场埃及果蝠（Rousettus aegyptiacus）接触者。疫情中的病死率为23%（66名患者中有15人死亡）。瑞德西韦和单克隆抗体MBP091在扩大准入和临床试验方案下使用。此外，1710名一线工作人员和高风险接触者在一项2期临床试验中获得了紧急使用授权的黑猩猩腺病毒3载体疫苗ChAd3-MARV。
结论：
在本次疫情中，实施防控措施、先进支持性治疗和及时部署研究性措施可能有助于降低马尔堡病的死亡率。加强监测、改善卫生保健机构的感染预防和控制以及确保及时部署医疗对策对于减轻未来丝状病毒病暴发的影响至关重要。
九月第三期共4篇Articles
1.Low-Dose Aspirin for PI3K-Altered Localized Colorectal Cancer
低剂量阿司匹林治疗 PI3K 改变的局限性结直肠癌
瑞典斯德哥尔摩卡罗林斯卡学院分子医学与外科系
Abstract
Background:
Aspirin reduces the incidence of colorectal adenoma and colorectal cancer among high-risk persons. Observational studies suggest that aspirin may also improve disease-free survival after diagnosis, particularly among patients with tumors harboring somatic PIK3CA mutations. However, data from randomized trials are lacking.
Methods:
We conducted a double-blind, randomized, placebo-controlled trial involving patients with stage I, II, or III rectal cancer or stage II or III colon cancer with somatic alterations in PI3K pathway genes. The patients were assigned in a 1:1 ratio to receive 160 mg of aspirin or matched placebo once daily for 3 years. Patients with prespecified PIK3CA hotspot mutations in exon 9 or 20 (group A alterations) and those with other moderate- or high-impact somatic variants in PIK3CA, PIK3R1, or PTEN (group B alterations) were eligible for randomization. The primary end point was colorectal cancer recurrence, assessed in a time-to-event analysis, in patients with group A alterations. Secondary end points included colorectal cancer recurrence in patients with group B alterations, disease-free survival, and safety.
Results:
Alterations in PI3K pathway genes were detected in 1103 of 2980 patients (37.0%) with complete genomic data. Of 515 patients with group A alterations and 588 patients with group B alterations, 314 and 312, respectively, were assigned to receive aspirin or placebo. The estimated 3-year cumulative incidence of recurrence was 7.7% with aspirin and 14.1% with placebo (hazard ratio, 0.49; 95% confidence interval [CI], 0.24 to 0.98; P=0.04) among patients with group A alterations and 7.7% and 16.8%, respectively (hazard ratio, 0.42; 95% CI, 0.21 to 0.83), among those with group B alterations. The estimated 3-year disease-free survival was 88.5% with aspirin and 81.4% with placebo (hazard ratio, 0.61; 95% CI, 0.34 to 1.08) among patients with group A alterations and 89.1% and 78.7%, respectively (hazard ratio, 0.51; 95% CI, 0.29 to 0.88), among those with group B alterations. Severe adverse events occurred in 16.8% of aspirin recipients and 11.6% of placebo recipients.
Conclusions:
Aspirin led to a significantly lower incidence of colorectal cancer recurrence than placebo among patients with PIK3CA hotspot mutations in exon 9 or 20 and appeared to have a similar benefit among those with other somatic alterations in PI3K pathway genes.
摘要：
背景：
阿司匹林可降低高危人群中结直肠腺瘤和结直肠癌的发病率。观察性研究表明，阿司匹林还可以提高诊断后的无病生存期，特别是在携带体细胞PIK3CA突变的肿瘤患者中，但缺乏随机试验的数据。
方法：
本研究进行了一项双盲、随机、安慰剂对照试验，涉及PI3K通路基因体细胞改变的I~III期直肠癌或II~III期结肠癌患者。患者以1：1比例随机分配至阿司匹林组（每日一次160mg）或安慰剂组，持续3年。纳入标准分为两类：A组为肿瘤携带 PI3KCA 外显子 9 或 20 预先指定热点突变，B组为肿瘤携带 PIK3CA、PIK3R1 或 PTEN 基因的其他中度或高影响体细胞变异。主要终点是结直肠癌复发，在事件发生时间分析中评估，在A组改变的患者中进行评估。次要终点包括B组改变患者的结直肠癌复发、无病生存期和安全性。
结果：
在2980名患者中，有1103名（37.0%）检测到PI3K通路基因的改变，并具有完整的基因组数据。在515名A组改变患者和588名B组改变患者中，分别有314名和312名患者被分配接受阿司匹林或安慰剂治疗。阿司匹林组估计的3年累积复发发生率为7.7%，安慰剂组为14.1%（风险比，0.49;95%置信区间[CI]，0.24-0.98;P=0.04），在A组改变的患者中分别为7.7%和16.8%（风险比，0.42;95%[CI]：0.21至0.83）。A组改变患者的估计3年无病生存率为88.5%，安慰剂组为81.4%（风险比，0.61;95%[CI]：0.34-1.08），B组改变患者的3年无病生存率分别为89.1%和78.7%（风险比，0.51;95%[CI]：0.29-0.88）。16.8%的阿司匹林接受者和11.6%的安慰剂接受者发生严重不良事件。
结论：
在外显子9或20中具有PIK3CA热点突变的患者中，阿司匹林导致结直肠癌复发率显着低于安慰剂，并且在PI3K通路基因具有其他体细胞改变的患者中似乎具有类似的益处。
2.Orforglipron, an Oral Small-Molecule GLP-1 Receptor Agonist, in Early Type 2 Diabetes
Orforglipron，一种口服小分子 GLP-1 受体激动剂，用于早期 2 型糖尿病
达拉斯医疗城维洛西蒂临床研究中心
Abstract
Background:
Orforglipron is a small-molecule, nonpeptide glucagon-like peptide-1 (GLP-1) receptor agonist in clinical development for type 2 diabetes and weight management. Additional data on the efficacy and safety of orforglipron are needed.
Methods:
In this phase 3, double-blind, placebo-controlled trial, we randomly assigned participants in a 1:1:1:1 ratio to receive orforglipron at one of three doses (3 mg, 12 mg, or 36 mg) or placebo once daily for 40 weeks. Participants had type 2 diabetes treated only with diet and exercise, a glycated hemoglobin level of at least 7.0% but no more than 9.5%, and a body-mass index (the weight in kilograms divided by the square of the height in meters) of at least 23.0. The primary end point was the change from baseline to week 40 in the glycated hemoglobin level. A key secondary end point was the percent change in body weight from baseline to week 40.
Results:
A total of 559 participants underwent randomization. The mean glycated hemoglobin level at baseline was 8.0%. At week 40, the estimated mean change from baseline in the glycated hemoglobin level was −1.24 percentage points with the 3-mg dose, −1.47 percentage points with the 12-mg dose, −1.48 percentage points with the 36-mg dose, and −0.41 percentage points with placebo. All three doses of orforglipron were superior to placebo with respect to the primary end point; the estimated mean difference from placebo was −0.83 percentage points (95% confidence interval [CI], −1.10 to −0.56) with the 3-mg dose, −1.06 percentage points (95% CI, −1.33 to −0.79) with the 12-mg dose, and −1.07 percentage points (95% CI, −1.33 to −0.81) with the 36-mg dose (P<0.001 for all comparisons). The mean glycated hemoglobin level at week 40 was 6.5 to 6.7% with orforglipron. The percent change in body weight from baseline to week 40 was −4.5% with the 3-mg dose, −5.8% with the 12-mg dose, −7.6% with the 36-mg dose, and −1.7% with placebo. The most common adverse events were mild-to-moderate gastrointestinal events, most of which occurred during dose escalation. No episodes of severe hypoglycemia were reported. Permanent discontinuation of orforglipron or placebo due to adverse events occurred in 4.4 to 7.8% of participants receiving orforglipron and 1.4% of participants receiving placebo.
Conclusions:
In adults with early type 2 diabetes, orforglipron significantly reduced the glycated hemoglobin level over a period of 40 weeks.
摘要：
背景：
奥格列普隆（Orforglipron）是一种小分子非肽胰高血糖素样肽-1（GLP-1）受体激动剂，目前正针对2型糖尿病治疗和体重管理进行临床开发实验。有关奥格列普隆疗效和安全性的数据有待补充。
方法：
本研究为一项3期双盲安慰剂对照试验，受试者以1：1：1：1的比例随机分配参与接受三种剂量（3mg、12mg或36mg）之一的奥格列普隆或安慰剂，每天一次，持续40周。纳入标准为：确诊2型糖尿病，仅通过饮食和运动干预治疗，糖化血红蛋白水平为7.0%~9.5%，BMI≥23.0。主要终点是糖化血红蛋白水平从基线到第40周的变化。关键次要终点是体重从基线到第40周的百分比变化。
结果：
研究共纳入559名参与者接受了随机分组。基线时的平均糖化血红蛋白水平为8.0%。在第40周时，糖化血红蛋白水平相对于基线的估计平均变化为3mg剂量为-1.24个百分点，12mg剂量为-1.47个百分点，36mg剂量为-1.48个百分点，安慰剂为-0.41个百分点。所有三种剂量的奥格列普隆在主要终点方面均优于安慰剂;3mg剂量与安慰剂组的平均差异估计为-0.83个百分点（95%[CI]：-1.10至-0.56），12mg剂量为-1.06个百分点（95%[CI]：-1.33至-0.79），36mg剂量为-1.07个百分点（95%[CI]：-1.33至-0.81）（所有比较P<0.001）。奥格列普隆组第40周时的平均糖化血红蛋白水平为6.5%至6.7%。3mg剂量组从基线到第40周体重变化百分比为-4.5%，12mg剂量组为-5.8%，36mg剂量组为-7.6%，安慰剂组为-1.7%。最常见的不良事件是轻度至中度胃肠道事件，其中大多数发生在剂量递增期间。没有报告严重低血糖发作。接受奥格列普隆治疗的受试者中有4.4%至7.8%和接受安慰剂的参与者中有1.4%因不良事件而永久停用奥格列普隆或安慰剂。
结论：
在患有早期2型糖尿病的成人中，orforglipron在40周内显着降低了糖化血红蛋白水平。
3.Oral Semaglutide at a Dose of 25 mg in Adults with Overweight or Obesity
口服索马鲁肽，剂量为 25 mg，用于超重或肥胖的成人
多伦多大学
Abstract
Background:
Oral semaglutide at a dose of 25 mg may provide an alternative treatment option to injectable semaglutide (2.4 mg) and higher-dose oral semaglutide (50 mg) for persons with overweight or obesity.
Methods:
In a 71-week, double-blind, randomized, placebo-controlled trial conducted at 22 sites in four countries, we enrolled persons without diabetes who had a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of 30 or higher or a BMI of 27 or higher with at least one obesity-related complication. The participants were randomly assigned in a 2:1 ratio to receive oral semaglutide (25 mg) or placebo once daily, plus lifestyle interventions. The coprimary end points at week 64 were the percent change in body weight and a reduction of 5% or more in body weight; confirmatory secondary end points included reductions in body weight of 10% or more, 15% or more, and 20% or more and the change in the Impact of Weight on Quality of Life–Lite Clinical Trials Version (IWQOL-Lite-CT) Physical Function score.
Results:
A total of 205 participants were randomly assigned to receive oral semaglutide, and 102 to receive placebo. The estimated mean change in body weight from baseline to week 64 was −13.6% in the oral semaglutide group and −2.2% in the placebo group (estimated difference, −11.4 percentage points; 95% confidence interval, −13.9 to −9.0; P<0.001). Participants in the oral semaglutide group were significantly more likely than those in the placebo group to have body-weight reductions of 5% or more, 10% or more, 15% or more, and 20% or more (P<0.001 for all comparisons) and to have an improved IWQOL-Lite-CT Physical Function score (P<0.001). Gastrointestinal adverse events were more common with oral semaglutide than with placebo (74.0% vs. 42.2%).
Conclusions:
Oral semaglutide at a dose of 25 mg once daily resulted in a greater mean reduction in body weight than placebo in participants with overweight or obesity.
摘要：
背景：
对于超重或肥胖者，口服索马鲁肽（25mg）可为超重或肥胖者提供注射索马鲁肽（2.4mg）和更高剂量口服索马鲁肽（50mg）的替代治疗选择。
方法：
本研究为一项在四个国家的22个地点进行、为期71周的双盲、随机、安慰剂对照试验，招募了体重指数（BMI=体重（kg）/身高2（m2））≥30 kg/m²，或BMI ≥27 kg/m²且至少合并一种肥胖相关并发症的非糖尿病患者.受试者以2：1的比例随机分配接受口服索马鲁肽25 mg组或安慰剂，每天一次，两组均同步实施生活方式干预。共同主要终点是从基线至第64周的体重变化百分比，以及体重减轻≥5%的受试者比例;次要终点包括体重减轻≥10%、≥15% 及≥20%的受试者比例，以及体重对生活质量的影响–Lite临床试验版（IWQOL-Lite-CT）身体功能评分的变化。
结果：
研究共纳入307名受试者，其中口服索马鲁肽组205名，安慰剂组102名。至第64周，口服索马鲁肽组受试者体重平均变化为-13.6%，安慰剂组为-2.2%，组间估计差异为-11.4个百分点（95%置信区间：-13.9~-9.0，P＜0.001）。口服索马鲁肽组的体重减轻≥5%、≥10%、≥15% 及≥20%的受试者比例均显著高于安慰剂组（P<0.001），且IWQOL-Lite-CT身体机能评分较安慰剂组显著提高（P<0.001）。与安慰剂相比，口服索马鲁肽组的胃肠道不良事件更常见（74.0%vs.42.2%）。
结论：
在超重或肥胖的参与者中，口服索马鲁肽，剂量为25毫克，每天一次，与安慰剂相比，平均体重减轻幅度更大。
4.Proportional-Assist Ventilation for Minimizing the Duration of Mechanical Ventilation
比例辅助通气，可最大限度地缩短机械通气的持续时间
加拿大安大略省伦敦市西安大略大学舒立克医学与牙科学院内科-西部危重症医学科
Abstract
Background:
In critically ill patients, acceleration of liberation from mechanical ventilation is important in order to reduce the risk of complications and to improve long-term outcomes. Whether the use of proportional-assist ventilation with load-adjustable gain factors (PAV+) results in a shorter time to successful liberation from mechanical ventilation than pressure-support ventilation (PSV) is unclear.
Methods:
In this international clinical trial, we randomly assigned adult patients who had been receiving mechanical ventilation for at least 24 hours and were able to undergo partial ventilatory support with PSV but were not yet ready for liberation from ventilation to undergo PAV+ (which targeted normal work of breathing) or PSV (which targeted a normal respiratory rate and tidal volume). The primary outcome was the time from randomization to successful liberation from mechanical ventilation.
Results:
Across 23 centers in seven countries, 722 patients were enrolled, and 573 underwent randomization and were included in the analysis. The median time to successful liberation from mechanical ventilation was 7.3 days (95% confidence interval [CI], 6.2 to 9.7) in the PAV+ group and 6.8 days (95% CI, 5.4 to 8.8) in the PSV group (P=0.58). The median number of ventilator-free days, the incidence of reintubation and tracheostomy, and the incidence of death by day 90 (29.6% in the PAV+ group and 26.6% in the PSV group), all of which were secondary outcomes, were similar in the two groups. With respect to sedative drugs, the mean (±SD) difference in the midazolam-equivalent dose at day 28 relative to the baseline dose was −1.51±3.28 mg per kilogram of body weight in the PAV+ group and 0.04±0.97 mg per kilogram in the PSV group. Serious adverse events occurred in 31 patients (10.8%) in the PAV+ group and in 28 patients (9.8%) in the PSV group (P=0.79).
Conclusions:
The time to liberation from mechanical ventilation did not differ significantly between the group that underwent PAV+ and the group that underwent PSV.
摘要：
背景：
加速危重患者的机械通气脱机进程，是降低并发症风险、改善长期预后的关键措施。与压力支持通气（pressure-supportventilation，PSV）相比，使用具有负荷可调增益因子（PAV+）的比例辅助通气是否能缩短成功从机械通气中解放出来的时间，尚不清楚。
方法：
本研究为一项国际临床试验，涉及7个国家的23个中心。纳入对象为已接受机械通气≥24小时、且能够接受PSV部分通气支持但尚未达到脱机标准的成年患者，受试者被随机分配接受PAV+（针对正常呼吸功）或PSV（针对正常呼吸频率和潮气量）治疗。主要结局指标是从随机分组到成功从机械通气中解放出来的时间。次要结局指标包括无呼吸机支持中位天数、再插管率、气管切开术发生率、第90天死亡率，以及第28天镇静药物（咪达唑仑当量）剂量相对于基线的变化。
结果：
本研究共纳入722例患者，573例接受随机分组并纳入分析。PAV+组成功摆脱机械通气的中位时间为7.3d（95%置信区间[CI]，6.2-9.7），PSV组为6.8d（95%[CI]：5.4-8.8）（P=0.58）。第90天的死亡发生率PAV+组为29.6%，PSV组为26.6%。镇静药物方面，第28天咪达唑仑当量剂量相对于基线剂量的平均（±SD）差异为-1.51±3.28mg/kg体重，PSV组为0.04±0.97mg/kg。PAV+组31例（10.8%）发生严重不良事件，PSV组28例（9.8%）发生严重不良事件（P=0.79）。
结论：
接受PAV+的组和接受PSV的组之间从机械通气中解放出来的时间没有显着差异。
汇报人：李向东
导师：陈飞
审核：张子妍、代一冯、任建君
