Johannesen Lars, Vicente Jose, Hosseini Meisam, Strauss David G
Office of Clinical Pharmacology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, United States of America.
BSICoS Group, Aragón Institute for Engineering Research (I3A), IIS Aragón, University of Zaragoza, Zaragoza, Spain.
PLoS One. 2016 Dec 30;11(12):e0166925. doi: 10.1371/journal.pone.0166925. eCollection 2016.
Prolongation of the heart rate corrected QT (QTc) interval is a sensitive marker of torsade de pointes risk; however it is not specific as QTc prolonging drugs that block inward currents are often not associated with torsade. Recent work demonstrated that separate analysis of the heart rate corrected J-Tpeakc (J-Tpeakc) and Tpeak-Tend intervals can identify QTc prolonging drugs with inward current block and is being proposed as a part of a new cardiac safety paradigm for new drugs (the "CiPA" initiative).
In this work, we describe an automated measurement methodology for assessment of the J-Tpeakc and Tpeak-Tend intervals using the vector magnitude lead. The automated measurement methodology was developed using data from one clinical trial and was evaluated using independent data from a second clinical trial.
Comparison between the automated and the prior semi-automated measurements shows that the automated algorithm reproduces the semi-automated measurements with a mean difference of single-deltas <1 ms and no difference in intra-time point variability (p for all > 0.39). In addition, the time-profile of the baseline and placebo-adjusted changes are within 1 ms for 63% of the time-points (86% within 2 ms). Importantly, the automated results lead to the same conclusions about the electrophysiological mechanisms of the studied drugs.
We have developed an automated algorithm for assessment of J-Tpeakc and Tpeak-Tend intervals that can be applied in clinical drug trials. Under the CiPA initiative this ECG assessment would determine if there are unexpected ion channel effects in humans compared to preclinical studies. The algorithm is being released as open-source software.
NCT02308748 and NCT01873950.
心率校正QT（QTc）间期延长是尖端扭转型室速风险的敏感标志物；然而，它并不具有特异性，因为阻断内向电流的QTc延长药物通常与尖端扭转型室速无关。最近的研究表明，分别分析心率校正的J-Tpeakc（J-Tpeakc）和Tpeak-Tend间期可以识别具有内向电流阻断作用的QTc延长药物，并且有人提议将其作为新药心脏安全新范式（“CiPA”倡议）的一部分。
在本研究中，我们描述了一种使用向量幅度导联评估J-Tpeakc和Tpeak-Tend间期的自动测量方法。该自动测量方法是利用一项临床试验的数据开发的，并使用另一项临床试验的独立数据进行评估。
自动测量与先前半自动测量之间的比较表明，自动算法再现了半自动测量结果，平均单差值<1 ms，时间点内变异性无差异（所有p>0.39）。此外，63%的时间点基线和安慰剂校正变化的时间曲线在1 ms以内（86%在2 ms以内）。重要的是，自动测量结果对所研究药物的电生理机制得出了相同的结论。
我们开发了一种用于评估J-Tpeakc和Tpeak-Tend间期的自动算法，可应用于临床药物试验。根据CiPA倡议，这种心电图评估将确定与临床前研究相比，人体是否存在意外的离子通道效应。该算法将作为开源软件发布。
NCT02308748和NCT01873950。
