A Randomized, Double-Blind, Placebo- and Positive-Controlled, Three-Way Crossover Study in Healthy Participants to Investigate the Effect of Savolitinib on the QTc Interval
Abstract
Savolitinib (AZD6094, HMPL-504, volitinib) is an oral, bioavailable, selective MET-tyrosine kinase inhibitor. This randomized, double-blind, 3-way, crossover phase 1 study of savolitinib versus moxifloxacin (positive control) and placebo-evaluated effects on the QT interval after a single savolitinib dose. Healthy non-Japanese men were randomized to 1 of 6 treatment sequences, receiving single doses of savolitinib 600 mg, moxifloxacin 400 mg, and placebo. The primary end point was time-matched, placebo-adjusted change from baseline in the QT interval corrected for the time between corresponding points on 2 consecutive R waves on electrocardiogram (RR) by the Fridericia formula (ΔΔQTcF). Secondary end points included 12-lead electrocardiogram (ECG) variables, pharmacokinetics, and safety. All 3 treatment periods were completed by 44 of 45 participants (98%). Baseline demographics were balanced across treatment groups. After a single savolitinib 600-mg dose, the highest least-squares mean ΔΔQTcF of 12 milliseconds was observed 5 hours postdose. Upper limits of the 2-sided 90% confidence interval for ΔΔQTcF exceeded 10 milliseconds (the prespecified International Council for Harmonisation limit) 3-6 hours postsavolitinib but otherwise remained less than the threshold. Savolitinib showed no additional effect on PR, QRS, QT, or RR intervals. A positive ΔΔQTcF signal from the moxifloxacin group confirmed study validity. Savolitinib was well tolerated, with a low incidence of…
How strong is the evidence?
Evidence Hub reads this as a randomized trial, done in people. Its evidence level is 2 of 5 (High · randomized trial). Randomized trials of a reasonable size are the strongest single-study design. Reported size: 44 participants or records.
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