The Impact of Xanomeline and Trospium Chloride on Cognitive Impairment in Acute Schizophrenia: Replication in Pooled Data From Two Phase 3 Trials.

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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. 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. 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. 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.