Benefits of Centralized ECG Reading in Clinical Oncology Studies

Abstract

While on average ECG machine-measured QTcF values were very similar to the central core lab measurements; there were very significant discrepancies which will have important implications for patient recruitment for clinical oncology trials as well as for patient safety during dosing with new oncologic agents. Reliance on ECG machine QTc measurements during clinical oncology trials may lead to unnecessary exclusion of patients as well as unneeded treatment interruptions.

Evaluation of the potential for QTc prolongation with avelumab

“…Based on these data, it was concluded that the frequency of QTc outliers in both short and long ranges was likely overestimated by local ECG reads. This is in line with previous studies, which have also reported potential overestimation of abnormalities in locally read ECGs compared with centralized reading [24].…”

“…All patients in the dose-escalation cohort of JAVELIN Solid Tumor also had their ECGs reevaluated by central read. These analyses were similar to those of a previous study that compared QTc measurements from digital ECG machines and a centralized core laboratory [24] and were performed to investigate the variability and quality of local reads compared with central reads.…”

“…This variability could have been caused by concomitant medicines (e.g., antiemetics), known effects of diphenhydramine premedication [25], or underlying cardiovascular conditions; however, the analysis of this variation was not possible due to the lack of a placebo or control arm. Despite the aspects of the study design being suboptimal for exposure–QTc and ECG outlier analyses, the analysis objectives were met in accordance with ICH recommendations [19]: data were pooled from multiple studies that used the same methods of ECG measurement and analysis, and covered a wide range of avelumab doses; the exposure–QTc analysis used a robust modeling approach that included diphenhydramine premedication as a covariate; and locally read ECG data were reevaluated in a central laboratory, and the results of which, in line with reports from the previous studies [24], highlight the benefits of centrally read ECGs compared with locally read ECGs.…”

“…Since it has been previously reported that larger variability is associated with local reading of ECGs compared with centralized reading [24], outlier ECGs were subsequently reevaluated by central read. In two further analyses, to compare the outliers from locally and centrally read ECGs, patients were re-sampled and their ECGs were reevaluated by central read; one analysis included a random sampling of patients with two available ECG measurements (one taken at baseline and one at an on-treatment timepoint thereafter) from JAVELIN Solid Tumor and JAVELIN Merkel 200 ( n = 180 patients; 360 total ECGs were planned to be analyzed; however, only 264 were available for reevaluation by central read), while the second sample analysis included all patients in the dose-escalation cohorts of JAVELIN Solid Tumor (483 total ECGs taken at screening or baseline or during treatment were analyzed from 53 patients).…”

Opções Contemporâneas de Rastreio da Cardiotoxicidade Relacionada a Tratamentos Oncológicos

“…É importante para monitorização de alterações prévias, pois o surgimento de novas alterações pode sugerir injúria cardiovascular aguda e/ou subaguda 23 . As principais variações incluem alteração da repolarização ventricular, intervalo QT, síndromes coronarianas agudas, arritmias supraventriculares e ventriculares, sendo ainda possível sugerir pericardite e miocardite 24 .…”