Key result
Carotegrast methyl did not prolong QTcF (largest mean ΔΔQTcF 2.1 ms and 1.6 ms for 480 and 960 mg doses), demonstrating that lack of placebo control did not influence TQT study interpretation.
Why the study?
The study investigated how a lack of placebo control affects the interpretation of results in a thorough QT/QTc study.
Does the lack of placebo control affect the interpretation of thorough QT/QTc study results for carotegrast methyl in healthy subjects?
Does the lack of placebo control affect the interpretation of thorough QT/QTc study results for carotegrast methyl in healthy subjects?
The lack of a placebo control does not negatively impact the interpretation of thorough QT/QTc studies when analyzed using central-tendency and concentration-response analyses, aligning with updated ICH E14/S7B guidelines.
Reassures cardiac safety of carotegrast methyl; confirms placebo omission does not compromise TQT interpretability under ICH E14/S7B.
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 (ΔQTcF) and the placebo-adjusted ΔQTcF (ΔΔQTcF) were analyzed with central-tendency and concentration-response analyses. In central-tendency analysis, moxifloxacin prolonged ΔQTcF and ΔΔQTcF 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 ΔQTcF and ΔΔQTcF 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 ΔQTcF and ΔΔQTcF of 11.4 ms (8.5, 14.4) and 16.7 ms (14.0, 19.4) at the mean Cmax, 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.
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Kambayashi et al. (2022) studied Healthy subjects (n=48). Carotegrast methyl vs. Moxifloxacin 400 mg was evaluated on Time-matched changes in corrected QT from baseline (ΔQTcF) and placebo-adjusted ΔQTcF (ΔΔQTcF). Carotegrast methyl did not prolong QTcF (largest mean ΔΔQTcF 2.1 ms and 1.6 ms for 480 and 960 mg doses), demonstrating that lack of placebo control did not influence TQT study interpretation.
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