Results From a Phase 4, Open-Label, Multicenter, Two-Cohort, Two-Period, Slow-Titration and Food Effect Trial to Assess the Safety and Efficacy of Xanomeline and Trospium Chloride in Schizophrenia

Background: In pharmacokinetic studies of xanomeline and trospium chloride (X/T), dosing with food reduced trospium bioavailability, potentially impacting tolerability. This study was designed to demonstrate taking X/T with food after a slow up-titration is safe and tolerable.

Methods: An inpatient, open-label, 2-cohort trial (NCT06572449) enrolled adults with schizophrenia and PANSS total score ≤80. In period 1, participants began X/T BID treatment on an empty stomach at 50mg/20mg and uptitrated to a maximum 125mg/30mg (cohort 1) or 100mg/20mg (cohort 2). In period 2, treatment was administered within 30 minutes of food intake. Safety, efficacy, and X/T pharmacokinetics pooled from both cohorts in both periods were assessed.

Results: 64.2% and 39.0% of participants reported ≥1 TEAE during periods 1 and 2, respectively. The most common TEAEs (≥5%) in period 1 were nausea (22.5%), dyspepsia (15.6%), headache (15.0%), constipation (12.7%), and vomiting (11.6%); the incidence of all new onset TEAEs was less in period 2 when taken with food. All TEAEs were mild or moderate in intensity none were serious. PANSS total score decreased over periods 1 and 2; CGI-S score decreased over period 1 with no further change over period 2. Dose-normalized AUC and Cmax of trospium pooled from cohorts 1 and 2 decreased by 36% and 43%, respectively, when taken with food vs fasting. No clinically significant differences were observed in xanomeline exposure.

Conclusion: After slow uptitration on an empty stomach, there was no increase in the incidence or severity of TEAEs when taking X/T with food; efficacy was maintained.