Occurrence of urinary retention-related adverse events with xanomeline and trospium chloride: results from the 52-week, open-label EMERGENT-5 trial

Introduction

Xanomeline and trospium chloride (KarXT) combines the dual M₁/M₄-preferring muscarinic receptor agonist xanomeline and the peripherally restricted muscarinic receptor antagonist trospium. The efficacy and safety of KarXT, the first non-dopaminergic therapy for schizophrenia approved in the United States, were shown in the phase 3, 5-week, randomized, double-blind, placebo-controlled EMERGENT-1 (NCT03697252), EMERGENT-2 (NCT04659161), and EMERGENT-3 (NCT04738123) trials and the 52-week, open-label EMERGENT-4 (NCT04659174) and EMERGENT-5 (NCT04820309) trials. Trospium chloride alone is an approved treatment for overactive bladder. Consistent with guidance on trospium use, KarXT is contraindicated in individuals with urinary retention.

Aims

To examine the occurrence of urinary retention-related adverse events (AEs) with KarXT in the EMERGENT-5 trial.

Methods

The EMERGENT-5 trial enrolled adults aged 18-65 years with schizophrenia, no prior KarXT exposure, and stable symptoms appropriate for outpatient care. Eligible participants had received oral antipsychotic therapy within 30 days of screening and discontinued these medications prior to baseline visits. KarXT treatment started at 50 mg/20 mg (xanomeline/trospium) twice daily and increased to a maximum of 125 mg/30 mg (xanomeline/trospium) twice daily based on tolerability. Analyses were conducted in the overall safety population, defined as all participants who received ≥1 dose of KarXT; post hoc analysis examined subgroups based on sex and age (<55 vs ≥55 years).

Results

The safety population (N=566) included 375 males and 191 females, with 369 participants aged <55 years and 197 participants aged ≥55 years. A total of 16 (2.8%) and 14 (2.5%) participants experienced ≥1 treatment-emergent AE (TEAE) or treatment-related AE (TRAE) of urinary retention, respectively, and 18 (3.2%) and 3 (0.5%) experienced a urinary tract infection (UTI) TEAE or TRAE, respectively. Males and females reported similar incidences of urinary retention TEAEs (2.9% vs 2.6%) and TRAEs (2.4% vs 2.6%). However, both urinary retention TEAEs (4.6% vs 1.9%) and TRAEs (3.6% vs 1.9%) were more frequent in participants aged ≥55 years compared with those aged <55 years, respectively. UTI TEAEs were more common in females than males (5.8% vs 1.9%), whereas the incidences of UTI TRAEs were similar for both groups (0.5% vs 0.5%). UTI TEAEs (3.3% vs 3.0%) and TRAEs (0.3% vs 1.0%) were also similar in both the older and younger age groups. Most urinary retention (14/16) and UTI (17/18) TEAEs were mild or moderate in intensity, with median durations of 30 and 15 days, respectively.

Conclusions

Incidences of urinary retention and UTI TEAEs/TRAEs with KarXT were low and generally mild or moderate in intensity in the 52-week EMERGENT-5 trial of adults with schizophrenia. Although subgroup analyses showed slightly greater incidences of urinary retention TEAEs in participants aged ≥55 vs <55 years, and of UTI TEAEs in females vs males, incidences of these expected TEAEs remained low regardless of sex and age.

References

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