Targum Steven D, Horan William P, Davis Vicki G, Breier Alan, Brannan Stephen K
, Boston, MA, USA.
Bristol Myers Squibb, Princeton, NJ, USA.
Transl Psychiatry. 2025 Feb 7;15(1):47. doi: 10.1038/s41398-025-03262-1.
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 M/M 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.
与药品独特性质相关的治疗中出现的不良事件（TEAE）可能会在功能上使临床医生的评分失去盲态，掩盖真正的药物效果，并影响对临床试验结果的信心。中枢神经系统研究尤其容易出现功能上的非盲态，因为它们依赖相对主观的症状评估。在三项针对患有急性精神病的精神分裂症患者进行的为期五周的双盲、安慰剂对照的 xanomeline 和氯化曲司氯铵（原称 KarXT）试验的汇总数据中，使用了两种不同方法来检查可能存在的功能非盲态。Xanomeline/曲司氯铵是一种 M/M 毒蕈碱受体激动剂，可能会产生胆碱能副作用。首先，我们比较了对 TEAE 不知情的远程（与研究地点无关）评分者的分数，这些评分者收听了基于研究地点的阳性和阴性症状量表（PANSS）访谈的录音。其次，我们对报告了或未报告与胆碱能相关的 TEAE 的参与者亚组进行了事后分析，以确定胆碱能 TEAE 是否影响试验结果。远程评分在基线和终点时紧密复制了 575 个可用的“配对”基于研究地点的 PANSS 总分（组内相关系数分别为 0.88 和 0.93）。基于研究地点和远程的 PANSS 评分均显示，与安慰剂相比，xanomeline/曲司氯铵有显著改善（均 p < 0.0001），且治疗反应（相对于基线改善≥30%）显著大于安慰剂（均 p < 0.0001）。无论参与者是否报告了与胆碱能相关的 TEAE 或任何 TEAE，所有亚组中 PANSS 评分显示 xanomeline/曲司氯铵优于安慰剂的显著改善程度相当（均 p < 0.001）。总之，在这些研究中用于评估功能非盲态的两种不同方法发现，胆碱能 TEAE 或任何 TEAE 对试验结果均无影响。这些方法可能在所有临床试验中都有用。
