Browsing by Author "Targum, Steven D."

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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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    Site-independent confirmation of primary site-based PANSS ratings in a schizophrenia trial
    (Elsevier, 2021) Targum, Steven D.; Murphy, Christopher; Breier, Alan; Brannan, Stephen K.; Psychiatry, School of Medicine
    Blinded, site-independent (remote) ratings from audio-digital recordings of site-based Positive and Negative Syndrome Scale (PANSS) interviews were obtained in a 5-week, randomized, double-blinded study assessing the safety, tolerability, and efficacy of KarXT (a fixed combination of xanomeline and trospium chloride) in hospitalized adults with schizophrenia experiencing an acute exacerbation of psychosis (EMERGENT-1; ClinicalTrials.gov identifier: NCT3697252). The blinded site-independent raters had no knowledge of site location, study visit, drug vs. placebo assignment, or any treatment emergent adverse events (TEAEs). Concordance analyses of 561 paired site-based and site-independent PANSS ratings across all visits revealed a high correlation (ICC = 0.775). Paired scoring differences were positively correlated with the PANSS total score (Spearman's rho = 0.37, p < 0.0001). Paired PANSS scores were available from 148 subjects at both the baseline and end of study visits (KarXT = 72, Placebo = 76). Site-based PANSS total scores (primary aim) revealed a significantly greater improvement from baseline in the KarXT group compared to the placebo group (p < 0.0001). The blinded site-independent PANSS total scores derived from listening to and scoring the recorded site-based PANSS interviews replicated this finding (p < 0.001) and yielded an overall predictive value of 85.1% for matching the site-based response/non-response outcomes. TEAE's have the potential to "unblind" site-based ratings. In this study, the site-independent raters were blinded to TEAEs, affirmed the site-based PANSS ratings, and mitigated concerns about possible functional unblinding of site-based raters. This method of blinded assessment via audio-digital recordings may have utility for other studies concerned with ratings precision and/or functional unblinding.