Appraisal of ICH E14/S7B Q&As adopted in February 2022 using thorough QT/QTc study data for a4-integrin antagonist carotegrast methyl in Japanese healthy subjects

We investigated how a lack of placebo control affects the interpretation of results of thorough QT/QTc (TQT) study. Results of TQT study in 48 healthy Japanese subjects assessing the effects of 480 and 960 mg of carotegrast methyl (test drug) and 400 mg of moxifloxacin (positive control) on the time-matched changes in corrected QT from baseline (Delta QTcF) and the placebo-adjusted Delta QTcF (Delta Delta QTcF) were analyzed with central-tendency and concentration-response analyses. In central-tendency analysis, moxifloxacin prolonged Delta QTcF and Delta Delta QTcF with the largest mean values (90% confidence interval) of 12.1 ms (9.3, 14.8) and 15.4 ms (12.6, 18.1), respectively. Meanwhile, carotegrast methyl hardly altered Delta QTcF and Delta Delta QTcF with the largest mean values of 0.8 ms (-2.3, 3.9) and 2.1 ms (-0.7, 4.8) for the low dose, and-0.2 ms (-3.4, 3.0) and 1.6 ms (-0.9, 4.2) for the high dose, respectively. In concentration-response analysis, moxifloxacin attained the estimated mean values for Delta QTcF and Delta Delta QTcF of 11.4 ms (8.5, 14.4) and 16.7 ms (14.0, 19.4) at the mean C-max, whereas carotegrast methyl provided those of -4.6 ms (-7.3,-1.9) and 0.7 ms (-1.4, 2.8), respectively. Thus, lack of placebo control did not influence the interpretation of TQT study with either of the analysis in line with updated E14/S7B Q & As.(c) 2022 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society.

Automated summary

This study investigated the impact of a lack of placebo control on the interpretation of results in thorough QT/QTc (TQT) studies. The analysis showed that the lack of placebo control did not influence the interpretation of TQT study results in both central-tendency and concentration-response analyses, in line with the updated E14/S7B Q & As.