Browsing by Subject "Muscarinic agonists"

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    Methods to address functional unblinding of raters in CNS trials
    (Springer Nature, 2025-02-07) Targum, Steven D.; Horan, William P.; Davis, Vicki G.; Breier, Alan; Brannan, Stephen K.; Psychiatry, School of Medicine
    Treatment-emergent adverse events (TEAEs) associated with the unique properties of a pharmaceutical product may functionally unblind clinician ratings, obscure true medication effects, and affect confidence about clinical trial results. Central nervous system studies are particularly susceptible to functional unblinding because they rely on relatively subjective symptom assessments. Two different methods were used to examine possible functional unblinding in pooled data from three recent five-week, double-blind, placebo-controlled trials of xanomeline and trospium chloride (formerly known as KarXT) in participants with schizophrenia experiencing acute psychosis. Xanomeline/trospium is an M1/M4 muscarinic receptor agonist that may produce cholinergic side effects. First, we compared the scores of remote (site-independent) raters, blinded to TEAEs, who listened to audio recorded, site-based Positive and Negative Syndrome Scale (PANSS) interviews. Second, we conducted a post hoc analysis of participant subgroups with or without reported cholinergic-related TEAEs to ascertain whether cholinergic TEAEs influenced trial outcome. Remote ratings closely replicated 575 available "paired" site-based PANSS total scores at baseline and endpoint (intraclass correlation coefficient = 0.88 and 0.93, respectively). Both site-based and remote PANSS scores yielded significant improvement favouring xanomeline/trospium over placebo (both p < 0.0001) and yielded significantly greater treatment response (≥30% improvement from baseline) than placebo (both p < 0.0001). The significant improvement of PANSS scores favouring xanomeline/trospium over placebo was comparable in magnitude for all subgroups regardless of whether participants reported cholinergic-related TEAEs, or any TEAEs at all (all p < 0.001). In sum, the two different methods used to assess functional unblinding in these studies found no impact of cholinergic TEAEs, or any TEAEs, on the trial results. These methods may have utility across all clinical trials.
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    Muscarinic Cholinergic Receptor Agonist and Peripheral Antagonist for Schizophrenia
    (Massachusetts Medical Society, 2021-02-25) Brannan, Stephen K.; Sawchak, Sharon; Miller, Andrew C.; Lieberman, Jeffrey A.; Paul, Steven M.; Breier, Alan; Psychiatry, School of Medicine
    Background: The muscarinic receptor agonist xanomeline has antipsychotic properties and is devoid of dopamine receptor-blocking activity but causes cholinergic adverse events. Trospium is a peripherally restricted muscarinic receptor antagonist that reduces peripheral cholinergic effects of xanomeline. The efficacy and safety of combined xanomeline and trospium in patients with schizophrenia are unknown. Methods: In this double-blind, phase 2 trial, we randomly assigned patients with schizophrenia in a 1:1 ratio to receive twice-daily xanomeline-trospium (increased to a maximum of 125 mg of xanomeline and 30 mg of trospium per dose) or placebo for 5 weeks. The primary end point was the change from baseline to week 5 in the total score on the Positive and Negative Syndrome Scale (PANSS; range, 30 to 210, with higher scores indicating more severe symptoms of schizophrenia). Secondary end points were the change in the PANSS positive symptom subscore, the score on the Clinical Global Impression-Severity (CGI-S) scale (range, 1 to 7, with higher scores indicating greater severity of illness), the change in the PANSS negative symptom subscore, the change in the PANSS Marder negative symptom subscore, and the percentage of patients with a response according to a CGI-S score of 1 or 2. Results: A total of 182 patients were enrolled, with 90 assigned to receive xanomeline-trospium and 92 to receive placebo. The PANSS total score at baseline was 97.7 in the xanomeline-trospium group and 96.6 in the placebo group. The change from baseline to week 5 was -17.4 points with xanomeline-trospium and -5.9 points with placebo (least-squares mean difference, -11.6 points; 95% confidence interval, -16.1 to -7.1; P<0.001). The results for the secondary end points were significantly better in the xanomeline-trospium group than in the placebo group, with the exception of the percentage of patients with a CGI-S response. The most common adverse events in the xanomeline-trospium group were constipation, nausea, dry mouth, dyspepsia, and vomiting. The incidences of somnolence, weight gain, restlessness, and extrapyramidal symptoms were similar in the two groups. Conclusions: In a 5-week trial, xanomeline-trospium resulted in a greater decrease in the PANSS total score than placebo but was associated with cholinergic and anticholinergic adverse events. Larger and longer trials are required to determine the efficacy and safety of xanomeline-trospium in patients with schizophrenia.