ImportanceA significant need exists for new antipsychotic medications with different mechanisms of action, greater efficacy, and better tolerability than existing agents. Xanomeline is a dual M1/M4 preferring muscarinic receptor agonist with no direct D2 dopamine receptor blocking activity. KarXT combines xanomeline with the peripheral muscarinic receptor antagonist trospium chloride with the goal of reducing adverse events due to xanomeline-related peripheral muscarinic receptor activation. In prior trials, xanomeline-trospium chloride was effective in reducing symptoms of psychosis and generally well tolerated in people with schizophrenia.ObjectiveTo evaluate the efficacy and safety of xanomeline-trospium vs placebo in adults with schizophrenia.Design, Setting, and ParticipantsEMERGENT-3 (NCT04738123) was a phase 3, multicenter, randomized, double-blind, placebo-controlled, 5-week trial of xanomeline-trospium in people with schizophrenia experiencing acute psychosis, conducted between April 1, 2021, and December 7, 2022, at 30 inpatient sites in the US and Ukraine. Data were analyzed from February to June 2023.InterventionsParticipants were randomized 1:1 to receive xanomeline-trospium chloride (maximum dose xanomeline 125 mg/trospium 30 mg) or placebo for 5 weeks.Main Outcomes and MeasuresThe prespecified primary end point was change from baseline to week 5 in Positive and Negative Syndrome Scale (PANSS) total score. Secondary outcome measures were change from baseline to week 5 in PANSS positive subscale score, PANSS negative subscale score, PANSS Marder negative factor score, Clinical Global Impression–Severity score, and proportion of participants with at least a 30% reduction in PANSS total score. Safety and tolerability were also evaluated.ResultsA total of 256 participants (mean [SD] age, 43.1 [11.8] years; 191 men [74.6%]; 156 of 256 participants [60.9%] were Black or African American, 98 [38.3%] were White, and 1 [0.4%] was Asian) were randomized (125 in xanomeline-trospium group and 131 in placebo group). At week 5, xanomeline-trospium significantly reduced PANSS total score compared with placebo (xanomeline-trospium , −20.6; placebo, −12.2; least squares mean difference, −8.4; 95% CI, −12.4 to −4.3; P < .001; Cohen d effect size, 0.60). Discontinuation rates due to treatment-emergent adverse events (TEAEs) were similar between the xanomeline-trospium (8 participants [6.4%]) and placebo (7 participants [5.5%]) groups. The most common TEAEs in the xanomeline-trospium vs placebo group were nausea (24 participants [19.2%] vs 2 participants [1.6%]), dyspepsia (20 participants [16.0%] vs 2 participants [1.6%]), vomiting (20 participants [16.0%] vs 1 participant [0.8%]), and constipation (16 participants [12.8%] vs 5 participants [3.9%]). Measures of extrapyramidal symptoms, weight gain, and somnolence were similar between treatment groups.Conclusions and RelevanceXanomeline-trospium was efficacious and well tolerated in people with schizophrenia experiencing acute psychosis. These findings, together with the previously reported and consistent results from the EMERGENT-1 and EMERGENT-2 trials, support the potential of xanomeline-trospium to be the first in a putative new class of antipsychotic medications without D2 dopamine receptor blocking activity.Trial RegistrationClinicalTrials.gov Identifier: NCT04738123

中文翻译：

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呫诺美林-曲司氯铵治疗精神分裂症的疗效和安全性

重要性与现有药物相比，迫切需要具有不同作用机制、更高功效和更好耐受性的新型抗精神病药物。 Xanomeline 是一种双 M1/米4首选毒蕈碱受体激动剂，无直接D2多巴胺受体阻断活性。 KarXT 将 xanomeline 与外周毒蕈碱受体拮抗剂曲司氯铵相结合，旨在减少 xanomeline 相关外周毒蕈碱受体激活引起的不良事件。在之前的试验中，xanomeline-trospium 氯化物可有效减轻精神病症状，并且在精神分裂症患者中通常具有良好的耐受性。目的评估 xanomeline-trospium 与安慰剂相比，对成人精神分裂症患者的疗效和安全性。设计、设置和参与者EMERGENT-3 (NCT04738123）是一项 3 期、多中心、随机、双盲、安慰剂对照、为期 5 周的 xanomeline-trospium 试验，用于治疗患有急性精神病的精神分裂症患者，于 2021 年 4 月 1 日至 2022 年 12 月 7 日期间在 30 名住院患者中进行美国和乌克兰的站点。数据分析时间为 2023 年 2 月至 6 月。干预措施参与者以 1:1 的比例随机接受呫诺美林-曲司氯铵（最大剂量呫诺美林 125 mg/曲司氯铵 30 mg）或安慰剂，为期 5 周。主要结果和措施预先设定的主要终点是相对于基线的变化到第 5 周的阳性和阴性症状量表 (PANSS) 总分。次要结局指标是从基线到第 5 周 PANSS 阳性子量表评分、PANSS 阴性子量表评分、PANSS Marder 阴性因素评分、临床总体印象-严重性评分以及 PANSS 总分至少降低 30% 的参与者比例的变化。还评估了安全性和耐受性。 结果共有 256 名参与者（平均 [SD] 年龄，43.1 [11.8] 岁；191 名男性 [74.6%]；256 名参与者中有 156 名 [60.9%] 是黑人或非裔美国人，98 名 [38.3%] ] 为白人，1 名 [0.4%] 为亚洲人）被随机分配（xanomeline-trospium 组有 125 名，安慰剂组有 131 名）。第5周时，与安慰剂相比，xanomeline-trospium显着降低了PANSS总分（xanomeline-trospium，-20.6；安慰剂，-12.2；最小二乘均差，-8.4；95% CI，-12.4至-4.3；磷< .001;科恩d效应大小，0.60）。 xanomeline-trospium（8 名受试者 [6.4%]）和安慰剂组（7 名受试者 [5.5%]）之间因治疗引起的不良事件 (TEAE) 导致的停药率相似。 xanomeline-trospium 与安慰剂组中最常见的 TEAE 是恶心（24 名受试者 [19.2%] vs 2 名受试者 [1.6%]）、消化不良（20 名受试者 [16.0%] vs 2 名受试者 [1.6%]）、呕吐（20参与者[16.0%] vs 1名参与者[0.8%]），以及便秘（16名参与者[12.8%] vs 5名参与者[3.9%]）。治疗组之间锥体外系症状、体重增加和嗜睡的测量结果相似。结论和相关性Xanomeline-trospium 对于患有急性精神病的精神分裂症患者有效且耐受性良好。这些发现，加上之前报道的 EMERGENT-1 和 EMERGENT-2 试验的一致结果，支持 xanomeline-trospium 有可能成为推定的新型抗精神病药物中第一个不含 D 的药物。2多巴胺受体阻断活性。试验注册ClinicalTrials.gov 标识符：NCT04738123