Xanomeline and Trospium Chloride for the Treatment of Agitation Associated With Schizophrenia

Objective: To further characterize the efficacy of oral xanomeline and trospium chloride in the treatment of agitation associated with schizophrenia. Methods: Analyses were performed on the change from baseline of the Positive and Negative Syndrome Scale-Excited Component (PANSS-EC; composed of excitement, tension, hostility, uncooperativeness, and poor impulse control items) data from the 5-week, randomized, double-blind, placebo controlled, inpatient EMERGENT-1, EMERGENT-2, and EMERGENT-3 trials of xanomeline/trospium in adults with schizophrenia with a recent worsening of psychosis requiring hospitalization. The 3 trials met the primary endpoint of reduction from baseline to week 5 in PANSS total score. Data were analyzed from individual studies and were also pooled. Results: The population comprised 640 participants from the pivotal trials which were conducted from September 2018 to December 2022. PANSS-EC scores were significantly reduced with xanomeline/trospium vs placebo at week 5 across all 3 EMERGENT trials. In EMERGENT-1, xanomeline/trospium (n = 83) was statistically significantly superior (Cohen's d =0.62, P = .0002) to placebo (n = 87) in improvement (decrease) of PANSS-EC score at week 5. In EMERGENT-2, xanomeline/trospium (n = 117) was significantly superior (d = 0.43, P = .0026) to placebo (n = 119) at week 5. In EMERGENT-3, xanomeline/ trospium (n = 114) was significantly superior (d = 0.62, P < .0001) to placebo (n = 120) at week 5. Pooled results were consistent with the individual trials. Conclusion: Xanomeline/trospium showed improvement in agitation as measured by PANSS-EC in participants with acute exacerbations of schizophrenia. Xanomeline/trospium is the first in a new class of treatments for schizophrenia based on muscarinic receptor agonism. Trial Registration: ClinicalTrials.gov identifiers: NCT03697252, NCT04659161, NCT04738123.