Kerr Wesley T, Ngo Leock Y, Zhu Liang, Patten Anna, Cheng Jocelyn Y, Biju Lavanya, French Jacqueline A
Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Epilepsia. 2025 May 15. doi: 10.1111/epi.18460.
In traditionally designed randomized clinical trials of antiseizure medications, participants take a blinded treatment for a prespecified number of weeks, irrespective of continued seizures. The alternative design time to prerandomization monthly seizure count (T-PSC) allows participants to end the blinded treatment after an individually prespecified number of seizures, which shortens exposure to placebo and ineffective treatment. Previous reanalyses have shown that T-PSC replicated the efficacy conclusions of trials; therefore, we evaluated whether T-PSC also could replicate tolerability and safety conclusions.
We retrospectively applied the T-PSC design to analyze treatment-emergent adverse events (TEAEs) from three blinded, placebo-controlled trials of perampanel for focal onset seizures (NCT00699972, NCT00699582, NCT00700310). We evaluated the incidences of TEAEs, treatment-related TEAEs, serious TEAEs, and TEAEs that prompted medication adjustment compared to those observed during the full-length trial.
Of the 1480 participants in the three trials, 1093 experienced any TEAE, of whom 1006 (92%) had onset prior to T-PSC. When evaluating the differences in each type of TEAE for each dose of perampanel from placebo within each trial, there was no consistent pattern of under- or overestimation. Across the three studies, 23 of 79 (29%) serious TEAEs, most requiring hospitalization, occurred after T-PSC.
Almost all TEAEs occurred before T-PSC. Similar conclusions regarding the tolerability and safety of perampanel would have been reached if the T-PSC design had been used. This suggests that the T-PSC design may potentially benefit participants by allowing earlier change from an ineffective treatment to an alternate treatment, which could reduce the risk of serious consequences of ineffective treatment, such as hospitalization.
在传统设计的抗癫痫药物随机临床试验中，参与者需接受预先指定周数的盲法治疗，无论癫痫是否持续发作。另一种设计——随机分组前每月癫痫发作计数时间（T-PSC）允许参与者在个体预先指定的发作次数后结束盲法治疗，这缩短了安慰剂和无效治疗的暴露时间。先前的重新分析表明，T-PSC重复了试验的疗效结论；因此，我们评估了T-PSC是否也能重复耐受性和安全性结论。
我们回顾性应用T-PSC设计，分析了三项关于吡仑帕奈治疗局灶性发作的盲法、安慰剂对照试验（NCT00699972、NCT00699582、NCT00700310）中治疗中出现的不良事件（TEAE）。我们评估了TEAE、治疗相关TEAE、严重TEAE以及导致药物调整的TEAE的发生率，并与全长试验期间观察到的情况进行比较。
在三项试验的1480名参与者中，1093人经历了任何TEAE，其中1006人（92%）在T-PSC之前发作。在评估每项试验中每种剂量的吡仑帕奈与安慰剂相比的每种TEAE差异时，没有一致的低估或高估模式。在三项研究中，79例严重TEAE中有23例（29%）在T-PSC之后发生，其中大多数需要住院治疗。
几乎所有TEAE都发生在T-PSC之前。如果使用T-PSC设计，关于吡仑帕奈耐受性和安全性会得出类似结论。这表明T-PSC设计可能通过允许更早地从无效治疗改为替代治疗而使参与者受益，这可以降低无效治疗的严重后果（如住院）的风险。
