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急性冠脉综合征事件后的milvexian联合抗血小板治疗试验
Milvexian with Antiplatelet Therapy after Acute Coronary Syndrome Event
背景
急性冠脉综合征事件后，患者发生缺血性事件复发的风险增加。milvexian是一种口服凝血因子Ⅺa抑制剂，它有可能在出血风险极小的情况下降低主要不良临床事件的风险。
Background
Patients are at increased risk for recurrent ischemic events after an acute coronary syndrome event. Milvexian, an oral factor XIa inhibitor, may reduce the risk of major adverse clinical events with minimal bleeding risk.
方法
在此项3期、随机、安慰剂对照试验中，我们评估了在急性冠脉综合征事件后7天内将milvexian联合标准抗血小板治疗的疗效和安全性。患者按1:1比例分配至口服milvexian（25 mg，每日两次）组或匹配安慰剂组。主要疗效结局为心血管原因死亡、心肌梗死或缺血性卒中的复合结局，采用至事件发生时间分析法进行评估。主要安全性结局为出血学术研究联合会（BARC，Bleeding Academic Research Consortium）3c型或5型出血（损害视力的颅内或眼内出血，或致死性出血）。Methods
In this phase 3, randomized, placebo-controlled trial, we evaluated the efficacy and safety of milvexian when added to standard antiplatelet therapy within 7 days after an acute coronary syndrome event. Patients were assigned in a 1:1 ratio to receive oral milvexian (25 mg twice daily) or matched placebo. The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, or ischemic stroke as evaluated in a time-to-event analysis. The principal safety outcome was Bleeding Academic Research Consortium (BARC) type 3c or 5 bleeding (intracranial or intraocular bleeding that compromises vision or fatal bleeding).
结果
在基于556例经裁定的疗效终点进行计划的期中分析后，该试验因无效而终止。试验共入组14,194例患者，其中7094例分配至milvexian组，7100例分配至安慰剂组。中位随访12.2个月后，milvexian组384例患者（5.4%）和安慰剂组365例患者（5.1%）发生主要疗效结局事件（风险比，1.05；95%置信区间，0.91~1.21；P=0.50）。milvexian组23例患者（0.3%）和安慰剂组22例患者（0.3%）发生BARC 3c型或5型出血（P=0.88）。
Results
After a planned interim analysis that was based on 556 adjudicated efficacy end points, the trial was terminated for futility. A total of 14,194 patients had been enrolled, with 7094 assigned to receive milvexian and 7100 to receive placebo. After a median follow-up of 12.2 months, a primary efficacy outcome event had occurred in 384 patients (5.4%) in the milvexian group and in 365 patients (5.1%) in the placebo group (hazard ratio, 1.05; 95% confidence interval, 0.91 to 1.21; P=0.50). BARC type 3c or 5 bleeding occurred in 23 patients (0.3%) in the milvexian group and in 22 patients (0.3%) in the placebo group (P=0.88).
结论
Conclusions
Among patients with a recent acute coronary syndrome event, milvexian did not decrease the risk of cardiovascular death, myocardial infarction, or ischemic stroke but did not increase the risk of intracranial or fatal bleeding, as compared with placebo. (Funded by Janssen Research and Development and Bristol Myers Squibb; LIBREXIA ACS ClinicalTrials.gov number, NCT05754957.)
C. Michael Gibson, P. Gabriel Steg, M. Cecilia Bahit, et al. Milvexian with Antiplatelet Therapy after Acute Coronary Syndrome Event. DOI:10.1056/NEJMoa2608717
ianalumab治疗干燥综合征患者试验
Ianalumab for the Treatment of Patients with Sjögrens Disease
背景
Background
Sjögrens disease is a complex, systemic autoimmune disease with no approved targeted therapies. Ianalumab is an IgG1 monoclonal antibody with a dual mechanism of action, depleting B cells through antibody-dependent cellular cytotoxicity and inhibiting B-cell activation and survival through blockade of B-cell activating factor receptor.
方法
我们对活动性干燥综合征患者开展了两项为期52周、双盲、随机、安慰剂对照试验。NEPTUNUS-1试验中的患者按1:1比例随机分配至皮下注射ianalumab组（每月一次300 mg）或安慰剂组；NEPTUNUS-2试验中的患者按1:1:1比例随机分配至每月一次300 mg ianalumab组、每3个月一次300 mg ianalumab组或安慰剂组。主要终点是第48周时欧洲风湿病学会联盟（EULAR，European Alliance of Associations for Rheumatology）干燥综合征疾病活动指数（ESSDAI，Sjögren’s Syndrome Disease Activity Index）评分相较基线的变化（评分范围为0~123，评分越高表明疾病活动度越高）。在NEPTUNUS-1试验的层级检验计划中，第一项关键次要终点是第48周时的ESSDAI应答（降低≥5分）；NEPTUNUS-2试验的关键次要终点是第48周时干燥综合征症状日记（SSSD，Sjögren’s Syndrome Symptom Diary）或EULAR干燥综合征患者报告指数（ESSPRI，Sjögren’s Syndrome Patient Reported Index）评分相较基线的变化。
Methods
We conducted two 52-week, double-blind, randomized, placebo-controlled trials involving patients with active Sjögrens disease. Patients in the NEPTUNUS-1 trial were assigned in a 1:1 ratio to receive subcutaneous ianalumab (300 mg monthly) or placebo; patients in the NEPTUNUS-2 trial were assigned in a 1:1:1 ratio to receive 300 mg of ianalumab monthly or every 3 months or placebo. The primary end point was the change from baseline in the score on the European Alliance of Associations for Rheumatology (EULAR) Sjögrens Syndrome Disease Activity Index (ESSDAI) at week 48 (scores range from 0 to 123, with higher scores indicating greater disease activity). The first key secondary end point in the hierarchical plan for the NEPTUNUS-1 trial was an ESSDAI response (5-point reduction) at week 48; for the NEPTUNUS-2 trial, it was the change from baseline in the score on the Sjögrens Syndrome Symptom Diary (SSSD) or EULAR Sjögrens Syndrome Patient Reported Index (ESSPRI) at week 48.
结果
Results
Overall, 275 patients underwent randomization in the NEPTUNUS-1 trial (ianalumab monthly, 137 patients; placebo, 138 patients) and 504 in the NEPTUNUS-2 trial (ianalumab monthly, 168 patients; ianalumab every 3 months, 167 patients; and placebo, 169 patients). In both trials, ianalumab monthly led to a significantly greater decrease in the ESSDAI score at week 48 than placebo, with a between-group difference of 1.3 points (95% confidence interval [CI], 2.6 to 0.0; P=0.0496) in NEPTUNUS-1 and 1.0 points (95% CI, 2.0 to 0.0; P=0.04) in NEPTUNUS-2. No significant differences in the incidence of an ESSDAI response or in the change from baseline in SSSD or ESSPRI scores were observed at week 48. The incidence of serious adverse events was similar with ianalumab and placebo. Nonserious local injection-site and systemic injection-related reactions were more common in the ianalumab groups.
结论
Conclusions
In these two trials involving patients with active Sjögrens disease, ianalumab at a dose of 300 mg monthly resulted in a significantly greater decrease in disease activity at week 48 than placebo, although there were no significant differences in the incidence of an ESSDAI response or in the change from baseline in SSSD or ESSPRI symptom scores. (Funded by Novartis Pharma; NEPTUNUS-1 and NEPTUNUS-2 ClinicalTrials.gov numbers, NCT05350072 and NCT05349214, respectively.)
Xavier Mariette, Thomas Grader-Beck, Stephanie Finzel, et al.Ianalumab for the Treatment of Patients with Sjögrens Disease. DOI: 10.1056/NEJMoa2601088
感染性心内膜炎：根据临床应答调整疗程与标准疗程抗生素治疗的比较试验
Response-Tailored or Standard-Duration Antibiotic Treatment for Infective Endocarditis
背景
Background
In patients with infective endocarditis on the left side of the heart, the current recommendation of up to 6 weeks of antibiotic therapy is based largely on expert consensus opinion. Whether a clinical responsetailored antibiotic management strategy can shorten treatment duration without compromising safety is unclear.
方法
Methods
In this international, open-label, randomized trial, we assigned adults in stable condition with infective endocarditis caused by Staphylococcus aureus, Enterococcus faecalis, or streptococcus species to receive either response-tailored or standard-duration antibiotic therapy. Before randomization, all the patients received at least the prespecified 2 to 4 weeks of therapy and met criteria for clinical stabilization. After randomization, patients in the tailored-therapy group discontinued antibiotics and those in the standard-therapy group continued standard treatment (total duration, 4 to 6 weeks). The primary efficacy end point was days alive without antibiotic treatment for infective endocarditis or bacteremia within 6 months after randomization (tested for superiority). The primary safety end point was a composite of death from any cause, unplanned cardiac surgery, or symptomatic embolic events within 6 months after randomization (tested for noninferiority; margin, 7.5 percentage points). Relapse of bacteremia or infective endocarditis was a key secondary end point.
结果
Results
A total of 508 patients underwent randomization, with 255 assigned to response-tailored therapy and 253 to standard-duration therapy. The median time alive without antibiotic treatment was 183 days (interquartile range, 181 to 183) with tailored therapy and 169 days (interquartile range, 166 to 171) with standard therapy (HodgesLehmann estimated difference, 13 days; 95% confidence interval [CI], 12 to 13; P<0.001 for superiority). A primary safety end-point event occurred in 21 patients (8.2%) with tailored therapy and in 27 patients (10.7%) with standard therapy (absolute between-group difference, －2.4 percentage points; 95% CI, －7.7 to 2.7; P<0.001 for noninferiority), indicating noninferiority. Relapse occurred in 13 patients (5.1%) with tailored therapy and in 4 patients (1.6%) with standard therapy (P=0.04).
结论
Conclusions
Henning Bundgaard, Mia Pries-Heje, Julie Hjulmand, et al.Response-Tailored or Standard-Duration Antibiotic Treatment for Infective Endocarditis. DOI: 10.1056/NEJMoa2607887
Tambotatug Pelitecan in Small-Cell Lung Cancer after Platinum-Based Therapy
背景
依康坦博妥塔单抗（简称Tam-Peli，一种靶向免疫检查点分子B7-H3的新型抗体药物偶联物）在早期临床试验中对复发性广泛期小细胞肺癌患者显示出令人鼓舞的临床疗效。
Background
Tambotatug pelitecan (known as Tam-Peli, a new antibodydrug conjugate that targets the immune-checkpoint molecule B7-H3) showed promising clinical efficacy in patients with relapsed extensive-stage small-cell lung cancer in early-phase trials.
方法
Methods
In this phase 3, multicenter, open-label, randomized trial, we assigned eligible patients with small-cell lung cancer that had progressed after first-line platinum-based therapy in a 1:1 ratio to receive tambotatug pelitecan or topotecan. The primary end point was overall survival. The key secondary end points were progression-free survival and objective response as assessed by investigators. Here, we report the results from the prespecified interim analysis.
结果
Results
A total of 451 patients underwent randomization: 225 were assigned to receive tambotatug pelitecan and 226 to receive topotecan. Overall survival was significantly longer with tambotatug pelitecan than with topotecan a median of 13.3 months (95% confidence interval [CI], 12.1 to could not be estimated), as compared with 9.4 months (95% CI, 7.7 to 10.5); the stratified hazard ratio for death was 0.46 (95% CI, 0.35 to 0.62; P<0.001). Treatment with tambotatug pelitecan also resulted in significantly longer progression-free survival than treatment with topotecan (median, 7.4 months [95% CI, 6.1 to 7.6] vs. 2.8 months [95% CI, 1.8 to 3.0]; stratified hazard ratio, 0.29 [95% CI, 0.23 to 0.37]; P<0.001). A confirmed objective response occurred in 59.1% of the patients in the tambotatug pelitecan group, as compared with 9.7% of those in the topotecan group (P<0.001). The overall incidence of adverse events of grade 3 or higher was lower with tambotatug pelitecan than with topotecan (55.4% vs. 77.9%).
结论
Conclusions
Yuanyuan Zhao, Hongxu Liu, Xiangjiao Meng, et al.Tambotatug Pelitecan in Small-Cell Lung Cancer after Platinum-Based Therapy.DOI: 10.1056/NEJMoa2610229
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