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接受经导管主动脉瓣植入术患者的PCI
PCI in Patients Undergoing Transcatheter Aortic-Valve Implantation
背景
对于接受经导管主动脉瓣植入术（TAVI）的稳定型冠心病合并重度主动脉瓣狭窄患者，经皮冠状动脉介入治疗（PCI）的益处仍不明确。
The benefit of percutaneous coronary intervention (PCI) in patients with stable coronary artery disease and severe aortic stenosis who are undergoing transcatheter aortic-valve implantation (TAVI) remains unclear.
方法
在一项国际性试验中，我们以1:1比例将患重度有症状主动脉瓣狭窄且至少有一处冠状动脉狭窄（血流储备分数≤0.80或直径狭窄至少达90%）的患者随机分组，分别接受PCI或保守治疗，并且所有患者均接受TAVI治疗。主要终点是主要心脏不良事件，即由全因死亡、心肌梗死或紧急血运重建构成的复合终点。本试验对安全性进行了评估，包括出血事件和手术并发症。
In an international trial, we randomly assigned, in a 1:1 ratio, patients with severe symptomatic aortic stenosis and at least one coronary-artery stenosis with a fractional flow reserve of 0.80 or less or a diameter stenosis of at least 90% either to undergo PCI or to receive conservative treatment, with all patients also undergoing TAVI. The primary end point was a major adverse cardiac event, defined as a composite of death from any cause, myocardial infarction, or urgent revascularization. Safety, including bleeding events and procedural complications, was assessed.
结果
共计455例患者接受了随机分组：227人被分配到PCI组，228人被分配到保守治疗组。患者中位年龄为82岁（四分位距，78~85），胸外科医师学会-手术死亡风险（Society of Thoracic Surgeons–Procedural Risk of Mortality）中位评分（评分范围为0~100%，评分较高表示术后30天内死亡风险较大）为3%（四分位距，2~4）。在中位2年（四分位距，1~4）随访时，PCI组60例患者（26%）和保守治疗组81例患者（36%）发生了主要心脏不良事件（主要终点）（风险比，0.71；95%置信区间[CI]，0.51~0.99；P=0.04）。PCI组64例患者（28%）和保守治疗组45例患者（20%）发生了出血事件（风险比，1.51；95% CI，1.03~2.22）。在PCI组中，7例患者（3%）发生了PCI手术相关并发症。
Result
A total of 455 patients underwent randomization: 227 to the PCI group and 228 to the conservative-treatment group. The median age of the patients was 82 years (interquartile range, 78 to 85), and the median Society of Thoracic Surgeons–Procedural Risk of Mortality score (on a scale from 0 to 100%, with higher scores indicating a greater risk of death within 30 days after the procedure) was 3% (interquartile range, 2 to 4). At a median follow-up of 2 years (interquartile range, 1 to 4), a major adverse cardiac event (primary end point) had occurred in 60 patients (26%) in the PCI group and in 81 (36%) in the conservative-treatment group (hazard ratio, 0.71; 95% confidence interval [CI], 0.51 to 0.99; P=0.04). A bleeding event occurred in 64 patients (28%) in the PCI group and in 45 (20%) in the conservative-treatment group (hazard ratio, 1.51; 95% CI, 1.03 to 2.22). In the PCI group, 7 patients (3%) had PCI procedure–related complications.
结论
在接受TAVI的冠心病患者中，中位2年随访时，与保守治疗相比，PCI与较低的复合终点（全因死亡、心肌梗死或紧急血运重建）风险相关。（由Boston Scientific和丹麦心脏基金会[Danish Heart Foundation]资助；NOTION-3在ClinicalTrials.gov注册号为NCT03058627）
Conclusions
Among patients with coronary artery disease who were undergoing TAVI, PCI was associated with a lower risk of a composite of death from any cause, myocardial infarction, or urgent revascularization at a median follow-up of 2 years than conservative treatment. (Funded by Boston Scientific and the Danish Heart Foundation; NOTION-3 ClinicalTrials.gov number, NCT03058627.)
既往未经胰岛素治疗的2型糖尿病患者应用efsitora胰岛素与德谷胰岛素的比较
Insulin Efsitora versus Degludec in Type 2 Diabetes without Previous Insulin Treatment
背景
efsitora alfa（efsitora）胰岛素是一种设计为每周给药一次的新型基础胰岛素。目前安全性和疗效数据仅限于小型1期或2期试验。
我们开展了一项为期52周的3期、平行设计、开放标签、达标治疗试验，该试验纳入既往未接受过胰岛素治疗的成人2型糖尿病患者。以1:1比例将参与者随机分配接受efsitora或德谷胰岛素治疗。主要终点是糖化血红蛋白水平从基线到第52周的变化；我们假设efsitora疗效不劣于德谷胰岛素（非劣效性界值，0.4个百分点）。次要终点和安全性终点包括应用和未应用胰高血糖素样肽-1（GLP-1）受体激动剂的亚组参与者的糖化血红蛋白水平变化、第48~52周期间血糖水平位于70~180 mg/dL目标范围的时间百分比以及低血糖发作。
Methods
We conducted a 52-week, phase 3, parallel-design, open-label, treat-to-target trial involving adults with type 2 diabetes who had not previously received insulin. Participants were randomly assigned in a 1:1 ratio to receive efsitora or degludec. The primary end point was the change in the glycated hemoglobin level from baseline to week 52; we hypothesized that efsitora would be noninferior to degludec (noninferiority margin, 0.4 percentage points). Secondary and safety end points included the change in the glycated hemoglobin level in subgroups of participants using and not using glucagon-like peptide-1 (GLP-1) receptor agonists, the percentage of time that the glucose level was in the target range of 70 to 180 mg per deciliter in weeks 48 through 52, and hypoglycemic episodes.
共计928名参与者接受了随机分组（efsitora组466人，德谷胰岛素组462人）。efsitora组的平均糖化血红蛋白水平从基线时的8.21%降至第52周时的6.97%（最小二乘均值变化，－1.26个百分点），而德谷胰岛素组从8.24%降至7.05%（最小二乘均值变化，－1.17个百分点）（估计组间差异，－0.09个百分点；95%置信区间[CI]，－0.22~0.04），这些结果达到非劣效性。在应用和未应用GLP-1受体激动剂的参与者中，在糖化血红蛋白水平的变化方面，efsitora不劣于德谷胰岛素。efsitora组血糖水平位于目标范围的时间百分比为64.3%，德谷胰岛素组为61.2%（估计组间差异，3.1个百分点；95% CI，0.1~6.1）。efsitora组有临床意义或重度低血糖的总发生率为0.58起事件/参与者-年暴露，德谷胰岛素组为0.45起事件/参与者-年暴露（估计率比，1.30；95% CI，0.94~1.78）。根据报告，efsitora组未发生重度低血糖，德谷胰岛素组发生6次低血糖。两组的不良事件发生率相似。
Result
A total of 928 participants underwent randomization (466 to the efsitora group and 462 to the degludec group). The mean glycated hemoglobin level decreased from 8.21% at baseline to 6.97% at week 52 with efsitora (least-squares mean change, −1.26 percentage points) and from 8.24% to 7.05% with degludec (least-squares mean change, −1.17 percentage points) (estimated treatment difference, −0.09 percentage points; 95% confidence interval [CI], −0.22 to 0.04), findings that showed noninferiority. Efsitora was noninferior to degludec with respect to the change in the glycated hemoglobin level in participants using and not using GLP-1 receptor agonists. The percentage of time that the glucose level was within the target range was 64.3% with efsitora and 61.2% with degludec (estimated treatment difference, 3.1 percentage points; 95% CI, 0.1 to 6.1). The rate of combined clinically significant or severe hypoglycemia was 0.58 events per participant-year of exposure with efsitora and 0.45 events per participant-year of exposure with degludec (estimated rate ratio, 1.30; 95% CI, 0.94 to 1.78). No severe hypoglycemia was reported with efsitora; six episodes were reported with degludec. The incidence of adverse events was similar in the two groups.
结论
对于既往未接受过胰岛素治疗的成人2型糖尿病患者，在降低糖化血红蛋白水平方面，每周一次efsitora不劣于每日一次德谷胰岛素。（由礼来公司资助；QWINT-2在ClinicalTrials.gov注册号为NCT05362058）。
贝达喹啉单药治疗多菌型麻风病
Bedaquiline Monotherapy for Multibacillary Leprosy
背景
麻风病的标准多药治疗方案可能会产生严重副作用，这加剧了麻风病患者承受的污名和歧视。此外，耐药性麻风病所带来的威胁表明，有必要采用替代性联合用药方案以及更短程、更安全的多药治疗方案。
在此项于巴西进行的开放标签、概念验证研究中，我们安排既往未经治疗的多菌型麻风病患者接受贝达喹啉单药治疗，疗程为8周。完成8周贝达喹啉疗程后，患者开始接受麻风病标准多药治疗方案（根据世界卫生组织的定义），并接受112周随访。主要终点是贝达喹啉治疗8周后，小鼠足垫中麻风分枝杆菌阳性生长几率与基线相比的变化。次要终点是安全性。探索性终点包括麻风病临床症状和体征的变化，以及分子水平下麻风分枝杆菌生存力的变化（通过定量反转录聚合酶链反应方法测定）。
Methods
In this open-label, proof-of-concept study conducted in Brazil, we assigned patients with previously untreated multibacillary leprosy to receive bedaquiline monotherapy for 8 weeks. After completing the 8-week course of bedaquiline, the patients started standard multidrug therapy (as defined by the World Health Organization) for leprosy and were followed for 112 weeks. The primary end point was the change from baseline in the odds of positive growth of Mycobacterium leprae in mouse footpads after 8 weeks of bedaquiline therapy. The secondary end point was safety. Exploratory end points included change in the clinical signs and symptoms of leprosy and in the molecular viability of M. leprae (measured by a quantitative reverse-transcriptase–polymerase-chain-reaction assay).
共计9例患者被纳入改良意向性治疗分析。接受贝达喹啉单药治疗4周后，所有患者的麻风分枝杆菌阳性生长几率从基线时的100%降至无生长。治疗7周后，与基线相比，所有患者的皮损外观均有所改善。7例患者在治疗期间发生了至少一起不良事件（均为1级或2级）。
Result
A total of nine patients were included in the modified intention-to-treat analysis. The odds of positive M. leprae growth had decreased from 100% in all the patients at baseline to no growth after 4 weeks of bedaquiline monotherapy. After 7 weeks of treatment, all the patients showed improvement in the appearance of skin lesions as compared with baseline. Seven patients had at least one adverse event (all grade 1 or 2) during treatment
结论
在多菌型麻风病患者中，贝达喹啉单药治疗4周后即可清除麻风分枝杆菌，治疗7周后皮损外观有所改善。（由Janssen Research and Development资助；在ClinicalTrials.gov注册号为NCT03384641）。
obecabtagene autoleucel治疗B细胞急性淋巴细胞白血病成人患者试验
Obecabtagene Autoleucel in Adults with B-Cell Acute Lymphoblastic Leukemia
背景
obecabtagene autoleucel（obe-cel）是一种自体41BB-ζ抗CD19嵌合抗原受体（CAR）T细胞疗法，它使用中等亲和力CAR来降低毒性效应并改善持久性。
我们在复发或难治性B细胞急性淋巴细胞白血病（ALL）成人患者（≥18岁）中对obe-cel进行了一项1b~2期多中心研究。主要队列（队列2A）包括有形态学病变的患者；队列2B患者有可测量残留病变。主要终点是队列2A的总体缓解（完全缓解或完全缓解伴血液学不完全恢复）。次要终点包括无事件生存期、总生存期和安全性。
Methods
We conducted a phase 1b–2 multicenter study of obe-cel in adults (≥18 years of age) with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). The main cohort, cohort 2A, included patients with morphologic disease; patients in cohort 2B had measurable residual disease. The primary end point was overall remission (complete remission or complete remission with incomplete hematologic recovery) in cohort 2A. Secondary end points included event-free survival, overall survival, and safety.
在纳入试验的153例患者中，127人（83.0%）接受了至少一次obe-cel输注，并且可以评估。在队列2A（94例患者；中位随访时间，20.3个月）中，总体缓解率为77%（95%置信区间[CI]，67~85），完全缓解率为55%（95% CI，45~66），完全缓解伴血液学不完全恢复率为21%（95% CI，14~31）。总体缓解率（≤40%）和完全缓解率（≤20%）的预设无效假设被拒绝（P<0.001）。在接受至少一次obe-cel输注的127例患者中（中位随访时间，21.5个月），中位无事件生存期为11.9个月（95% CI，8.0~22.1）；估计6个月和12个月无事件生存率分别为65.4%和49.5%。中位总生存期为15.6个月（95% CI，12.9个月至无法评估）；估计6个月和12个月总生存率分别为80.3%和61.1%。3级或更高级别细胞因子释放综合征发生率为2.4%，3级或更高级别免疫效应细胞相关神经毒性综合征发生率为7.1%。
Result
Of the 153 enrolled patients, 127 (83.0%) received at least one infusion of obe-cel and were evaluable. In cohort 2A (94 patients; median follow-up, 20.3 months), overall remission occurred in 77% (95% confidence interval [CI], 67 to 85), with complete remission in 55% (95% CI, 45 to 66) and complete remission with incomplete hematologic recovery in 21% (95% CI, 14 to 31). The prespecified null hypotheses of overall remission (≤40%) and complete remission (≤20%) were rejected (P<0.001). In the 127 patients who received at least one obe-cel infusion (median follow-up, 21.5 months), the median event-free survival was 11.9 months (95% CI, 8.0 to 22.1); estimated 6- and 12-month event-free survival was 65.4% and 49.5%, respectively. The median overall survival was 15.6 months (95% CI, 12.9 to not evaluable); estimated 6- and 12-month overall survival was 80.3% and 61.1%, respectively. Grade 3 or higher cytokine release syndrome developed in 2.4% of the patients, and grade 3 or higher immune effector cell–associated neurotoxicity syndrome developed in 7.1% of the patients.
结论
在复发或难治性B细胞ALL成人患者中，obe-cel治疗后持久缓解率较高，并且3级或更高级别免疫相关毒性效应发生率较低。（由Autolus Therapeutics资助；FELIX在ClinicalTrials.gov注册号为NCT04404660）。
应用nexiguran ziclumeran进行CRISPR-Cas9基因编辑，治疗ATTR心肌病
CRISPR-Cas9 Gene Editing with Nexiguran Ziclumeran for ATTR Cardiomyopathy
背景
转甲状腺素蛋白淀粉样变性伴心肌病（ATTR-CM）是一种进展性疾病，通常会导致死亡。nexiguran ziclumeran（nex-z）是一种基于CRISPR-Cas9（规律成簇的间隔短回文重复序列和相关Cas9核酸内切酶），靶向转甲状腺素蛋白（TTR）编码基因的在研疗法。
在此项1期开放标签试验中，我们为ATTR-CM患者单次静脉输注nex-z。主要目的包括评估nex-z对安全性和药效学（包括血清TTR水平）的影响。次要终点包括N末端B型钠尿肽前体（NT-proBNP）水平、高敏心肌肌钙蛋白T水平、6分钟步行距离和纽约心脏学会（NYHA，New York Heart Association）心功能分级的变化。
Methods
In this phase 1, open-label trial, we administered a single intravenous infusion of nex-z to patients with ATTR-CM. Primary objectives included assessment of the effect of nex-z on safety and pharmacodynamics, including the serum TTR level. Secondary end points included changes in N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels, high-sensitivity cardiac troponin T levels, the 6-minute walk distance, and the New York Heart Association (NYHA) class.
共计36例患者接受nex-z治疗，并完成至少12个月随访。在这些患者中，50%属于NYHA心功能Ⅲ级，31%患变异型ATTR-CM。28天时，血清TTR水平与基线相比的平均变化百分比为－89%（95%置信区间[CI]，－92~－87），12个月时为－90%（95% CI，－93~－87）。据报告，34例患者发生了不良事件。5例患者发生了一过性输液相关反应，2例患者发生了被判定为与治疗相关的一过性肝酶升高。14例患者报告了严重不良事件，其中大部分与ATTR-CM相符。从基线到第12个月，NT-proBNP水平的几何平均变化倍数为1.02（95% CI，0.88~1.17），高敏心肌肌钙蛋白T水平的几何平均变化倍数为0.95（95% CI，0.89~1.01）。从基线到第12个月，6分钟步行距离的变化中位数为5米（四分位距，－33~49）。共计92%患者的NYHA心功能分级改善或无变化。
Result
A total of 36 patients received nex-z and completed at least 12 months of follow-up. Of these patients, 50% were in NYHA class III and 31% had variant ATTR-CM. The mean percent change from baseline in the serum TTR level was −89% (95% confidence interval [CI], −92 to −87) at 28 days and −90% (95% CI, −93 to −87) at 12 months. Adverse events were reported in 34 patients. Five had transient infusion-related reactions, and two had transient liver-enzyme elevations that were assessed as treatment-related. Serious adverse events, most of which were consistent with ATTR-CM, were reported in 14 patients. The geometric mean factor change from baseline to month 12 was 1.02 (95% CI, 0.88 to 1.17) in the NT-proBNP level and 0.95 (95% CI, 0.89 to 1.01) in the high-sensitivity cardiac troponin T level. The median change from baseline to month 12 in the 6-minute walk distance was 5 m (interquartile range, −33 to 49). A total of 92% of the patients had either improvement or no change in their NYHA class.
结论
在此项纳入ATTR-CM患者的1期研究中，单剂nex-z治疗与一过性输液相关反应相关，并且与血清TTR水平一致、迅速且持久下降相关。（由Intellia Therapeutics和Regeneron Pharmaceuticals资助；在ClinicalTrials.gov注册号为NCT04601051）。
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