OBJECTIVE Xanomeline and trospium chloride (formerly known as KarXT), a novel M1/M4 muscarinic receptor agonist, demonstrated efficacy across phase 2 and 3 trials as monotherapy for the treatment of inpatients with acute schizophrenia on the Positive and Negative Syndrome Scale total score primary endpoint. In the phase 2 trial, xanomeline/trospium improved performance on a cognitive outcome measure in the subgroup of participants with clinically significant baseline cognitive impairment. The authors sought to confirm this finding using data from two phase 3 trials. METHODS Data were pooled from two 5-week inpatient trials of xanomeline/trospium monotherapy in patients with acute schizophrenia. The statistical analysis plan prespecified comparisons of cognitive composite score changes between xanomeline/trospium and placebo in the full sample and the cognitively impaired (≤1 SD below norms at baseline) subgroup. RESULTS There was no significant xanomeline/trospium effect in the full sample (N=357); however, in the impaired subgroup, xanomeline/trospium (N=71) had a significantly greater benefit for cognition compared with placebo (N=66; least squares mean difference=0.31, SE=0.10; d=0.54). The xanomeline/trospium effect size increased significantly with a more stringent baseline impairment threshold (≤-1.5 SD; d=0.80). Improvements in cognition were minimally correlated with concurrent changes in total, positive, and negative symptoms in both treatment groups. CONCLUSIONS Participants with acute schizophrenia with prespecified impairments demonstrated significant cognitive improvement with xanomeline/trospium compared with placebo. This result directly confirms earlier findings. This benefit is not attributable to changes in symptoms, despite substantial evidence of efficacy for psychosis. Evaluation of xanomeline/trospium's potential for cognitive enhancement in a well-controlled trial of stable patients with cognitive impairment is warranted.

中文翻译：

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Xanomeline 和 Trospium Chloride 对急性精神分裂症认知障碍的影响：来自两项 3 期试验的汇总数据中的复制。


目的 Xanomeline 和 trospium chloride （以前称为 KarXT） 是一种新型 M1/M4 毒蕈碱受体激动剂，在 2 期和 3 期试验中作为单一疗法治疗急性精神分裂症住院患者的阳性和阴性综合征总分主要终点的疗效。在 2 期试验中，xanomeline/trospium 改善了具有临床意义基线认知障碍的参与者亚组的认知结果测量表现。作者试图使用来自两项 3 期试验的数据来证实这一发现。方法 汇总了两项为期 5 周的急性精神分裂症患者 xanomeline/trospium 单药治疗住院试验的数据。统计分析计划预先指定了 xanomeline/trospium 和安慰剂在完整样本和认知障碍 （基线时低于正常值 ≤1 SD ） 亚组中的认知综合评分变化的预先指定比较。结果 全样本中没有显着的 xanomeline/trospium 效应 （N=357）;然而，在受损亚组中，与安慰剂相比，xanomeline/trospium （N=71） 对认知的益处显著更大 （N=66;最小二乘均数差 = 0.31，SE=0.10;d=0.54）。xanomeline/trospium 效应量随着更严格的基线损伤阈值 （≤-1.5 SD;d=0.80） 而显著增加。认知改善与两个治疗组的总、阳性和阴性症状的并发变化的相关性最小。结论 与安慰剂相比，xanomeline/trospium 治疗具有预先指定障碍的急性精神分裂症参与者表现出显着的认知改善。这一结果直接证实了早期的发现。 尽管有大量证据表明对精神病有效，但这种益处并非归因于症状的变化。在一项针对稳定认知障碍患者的对照试验中，有必要评估 xanomeline/trospium 增强认知能力的潜力。