OPEN-LABEL, RANDOMIZED STUDY TO ASSESS SAFETY AND EFFICACY OF SLOW AND ACCELERATED SWITCHING TO XANOMELINE/TROSPIUM FROM STANDARD OF CARE ATYPICAL ANTIPSYCHOTICS IN PARTICIPANTS WITH SCHIZOPHRENIA

Antipsychotic (AP) medications may cause significant side effects resulting in treatment discontinuation and relapse. Xanomeline/trospium chloride (KarXT), a dual M1/M4 muscarinic receptor agonist combined with a peripheral pan muscarinic receptor antagonist, does not block D2 dopamine receptors, potentially lowering the risk of cardiometabolic and extrapyramidal adverse events (AEs). Medication switching is common among those with schizophrenia, and healthcare providers may benefit from clinical data on how to switch patients from APs to KarXT.

Methods

This 8-week, multicenter, randomized, open-label, outpatient trial assessed the efficacy and safety of a switch from atypical APs to KarXT monotherapy in adults aged 1865 years with schizophrenia based on DSM-5 criteria. Participants were randomized 1:1 to 2 treatment groups: slower transition from AP to KarXT over 4 weeks (25% reduction in AP dose/week) or faster transition from AP to KarXT over 2 weeks (50% reduction in AP dose/week). Participants in both treatment groups followed the same KarXT titration schedule and were initiated at KarXT 50 mg/20 mg (xanomeline/trospium) twice daily for 7 days then titrated to 100 mg/20 mg twice daily for 7 days. If tolerated, participants could then titrate to a maximum dose of 125 mg/30 mg on day 15 . The primary endpoint was all-cause discontinuation of KarXT. Secondary endpoints included change from baseline to week 8 in Positive and Negative Syndrome Scale (PANSS), Clinical Global Impressions-Severity (CGI-S), and Personal and Social Performance (PSP) scores. Secondary safety endpoints were KarXT AE-related discontinuation and AE incidence. Results from the trial were based on descriptive analyses and stratified by prior AP (-pine APs [pAPs, olanzapine/quetiapine] or non-pine APs [npAPs, aripiprazole/lurasidone/risperidone]) at the time of switching.

Results

A total of 53 participants (52 with AP data) were enrolled in the slower transition group (pAPs: n=35; npAPs: n=17) and 52 in the faster transition group (pAPs: n=31; npAPs: n=21). Approximately 86% of participants completed 8 weeks of treatment, with discontinuation rates of 15.1% (pAPs: 11.4%; npAPs: 17.6%) and 13.5% (pAPs: 12.9%; npAPs: 14.3%) in the slower and faster transition groups, respectively. No participant discontinued due to lack of efficacy. Mean changes in PANSS total scores from baseline to week 8 were −4.2 in the slower transition group (pAPs: −3.7; npAPs: −5.8) and −3.1 in the faster transition group (pAPs: −2.8; npAPs: −3.4). Mean change in CGI-S scores was −0.2 in both the slower (pAPs: −0.2; npAPs: −0.3) and faster (pAPs: −0.1; npAPs: −0.3) transition groups. From baseline to week 8, mean PSP scores increased by 1.1 (pAPs: 1.3; npAPs: 1.0) and 0.7 (pAPs: 0.0; npAPs: 2.0) in the slower and faster transition groups, respectively. Forty-nine percent of participants (pAPs: 50.0%; npAPs: 47.4%) had ≥1 treatment-emergent AE (TEAE); none were serious. TEAE rates were consistent with pooled analyses from EMERGENT-1–3. In the slower and faster transition groups, 1.9% and 3.8%, respectively, discontinued treatment early due to TEAEs.

Conclusions

Overall, both slower (4 week) and faster (2 week) transitions from atypical APs to KarXT were generally safe and effective among participants with schizophrenia, suggesting that either transition method may be considered. These results may aid clinical decision-making, providing evidence-based guidance on how to switch to KarXT from oral atypical APs.