OBJECTIVE: Test the hypothesis that trospium can mitigate cholinergic AEs associated with xanomeline.
METHODS: Healthy volunteers enrolled in this phase 1 (NCT02831231), single-site, 9-day, double-blind comparison of xanomeline alone (n = 33) versus KarXT (n = 35). Rates of five prespecified cholinergic AEs (nausea, vomiting, diarrhea, excessive sweating, salivary hypersecretion) were compared between treatment arms. Vital signs, electrocardiograms (ECGs), safety laboratory values, and pharmacokinetic (PK) analyses were assessed. A self-administered visual analog scale (VAS) and clinician-administered scales were employed.
RESULTS: Compared with xanomeline alone, KarXT reduced composite incidences of the five a priori selected cholinergic AEs by 46% and each individual AE by ≥ 29%. There were no episodes of syncope in KarXT-treated subjects; two cases occurred in the xanomeline-alone arm. The rate of postural dizziness was 11.4% in the KarXT arm versus 27.2% with xanomeline alone. ECG, vital signs, and laboratory values were not meaningfully different between treatment arms. The VAS and clinician-administered scales tended to favor KarXT. PK analysis revealed that trospium did not affect xanomeline\'s PK profile.
CONCLUSIONS: Trospium was effective in mitigating xanomeline-related cholinergic AEs. KarXT had an improved safety profile compared with xanomeline alone.
目的:检验曲司铵可以减轻与黄嘌呤相关的胆碱能AE的假设。
方法:健康志愿者参加此阶段1(NCT02831231),单站点,9天,单用xanomeline(n=33)与KarXT(n=35)的双盲比较。五种预设胆碱能AE的发生率(恶心,呕吐,腹泻,出汗过多,唾液分泌过多)在治疗组之间进行比较。生命体征,心电图(ECG),安全实验室值,和药代动力学(PK)分析进行评估。采用自我管理的视觉模拟量表(VAS)和临床医生管理的量表。
结果:与单独的xanomeline相比,KarXT将五种先验胆碱能AE的复合发生率降低了46%,每个单独的AE降低了≥29%。在KarXT治疗的受试者中没有晕厥发作;仅在xanomeline臂中发生了2例。KarXT臂的姿势性头晕率为11.4%,而仅xanomeline为27.2%。心电图,生命体征,和实验室值在治疗组之间没有显著差异.VAS和临床医生管理的量表倾向于支持KarXT。PK分析显示,曲司汀不影响xanomeline的PK谱。
结论:Trospium可有效缓解黄霉素相关的胆碱能AE。与单独使用xanomeline相比,KarXT具有改善的安全性。