Xanomeline combined with trospium in treatment of patients with schizophrenia resulted in a greater decrease in the Positive and Negative Syndrome Scale (PANSS) total score but was associated with cholinergic and anticholinergic adverse events, the researchers found in a phase 2 trial designed and sponsored by Karuna Therapeutics and the Wellcome Trust. Their work was published in The New England Journal of Medicine.
The trial (ClinicalTrials.gov: NCT03697252) included adult patients with a baseline PANSS total score of at least 80 points and a Clinical Global Impression-Severity (CGI-S) score of at least 4, who had also experienced acute exacerbation or relapse of psychosis requiring hospitalization within 2 months before screening. The patients were free of antipsychotic medication for at least 2 weeks before the baseline assessment.
A total of 90 patients were randomly assigned to receive twice-daily xanomeline-trospium (increased to a maximum of 125 mg of xanomeline and 30 mg of trospium per dose) while another 92 were to receive placebo for 5 weeks. Of the patients, 72 in the xanomeline-trospium group and 73 in the placebo group completed the trial while 179 patients received at least 1 dose of either and therefore were included in the safety population.
Mean PANSS total scores at baseline were 97.7 points in the xanomeline-trospium group and 96.6 points in the placebo group. From baseline to week 5, PANSS total scores decreased by 17.4 points in the xanomeline-trospium group and decreased by 5.9 points in the placebo group (least-squares mean difference, -11.6 points; 95% CI, -16.1 to -7.1). PANSS positive symptom subscores decreased by 5.6 points in the xanomeline-trospium group and 2.4 points in the placebo group (least-squares mean difference, -3.2 points; 95% CI, -4.8 to -1.7).
The categorical distribution of scores on the CGI-S scale favored xanomeline-trospium as compared with placebo ; the change from baseline in the PANSS negative symptom subscore was -3.2 points and -0.9 points, respectively (least-squares mean difference, −2.3 points; 95% CI, -3.5 to -1.1); the change from baseline in the PANSS Marder negative symptom subscore was -3.9 points and -1.3 points, respectively (least-squares mean difference, -2.5 points; 95% CI, -3.9 to -1.2; P <.001 for all).
Constipation (17%), nausea (17%), dry mouth (9%), dyspepsia (9%), and vomiting (9%) were the most common adverse events in the xanomeline-trospium group; 54% of patients in the group experienced adverse events (compared with 43% in the placebo group). Nausea, vomiting, and dry mouth occurred most frequently early in the trial and occurred less often at week 5, while constipation incidence was constant throughout the trial. Of the patients in the xanomeline-trospium group, 2% (compared with 6% in the placebo group) experienced a more than 7% weight increase.
Limitations of the trial included its brevity and inability to address the durability of the effect of the active drug in a lifelong illness.
“None of these adverse events resulted in the discontinuation of xanomeline-trospium, and all were rated by site investigators as mild or moderate in severity,” the study authors said.
Disclosure: This study was sponsored by Karuna Therapeutics and the Wellcome Trust, and the study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.
Brannan SK, Sawchak S, Miller AC, Lieberman JA, Paul SM, Breier A. Muscarinic cholinergic receptor agonist and peripheral antagonist for schizophrenia. N Engl J Med. 2021;384(8):717-726. doi:10.1056/NEJMoa2017015