Key result
Single-dose E-52862 up to 800 mg fails to prolong the QTc interval versus placebo.
Why the study?
E-52862 is a Sigma-1 receptor antagonist under investigation as a potential analgesic, and its effects on QTc interval needed evaluation to assess cardiac safety.
RCT (n=32)
Double-blind
Randomized
No
Mean Difference: 1.32 (95% CI -1.89–4.53)
Supports cardiac safety for single doses up to 800 mg; confirms no QTc effect in this RCT.
BACKGROUND: E-52862 is a Sigma-1 receptor antagonist (S1RA) currently under investigation as a potential analgesic medicine. We successfully applied a concentration-effect model retrospectively to a four-way crossover Phase I single ascending dose study and utilized the QTc shortening effects of a meal to demonstrate assay sensitivity by establishing the time course effects from baseline in all four periods, independently from any potential drug effects. METHODS: Thirty two healthy male and female subjects were included in four treatment periods to receive single ascending doses of 500 mg, 600 mg or 800 mg of E-52862 or placebo. PK was linear over the dose range investigated and doses up to 600 mg were well tolerated. The baseline electrocardiography (ECG) measurements on Day-1 were time-matched with ECG and pharmacokinetic (PK) samples on Day 1 (dosing day). RESULTS: In this conventional mean change to time-matched placebo analysis, the largest time-matched difference to placebo QTcI was 1.44 ms (90% CI: -4.04, 6.93 ms) for 500 mg; -0.39 ms (90% CI: -3.91, 3.13 ms) for 600 mg and 1.32 ms (90% CI: -1.89, 4.53 ms) for 800 mg of E-52862, thereby showing the absence of any QTc prolonging effect at the doses tested. In addition concentration-effect models, one based on the placebo corrected change from baseline and one for the change of QTcI from average baseline with time as fixed effect were fitted to the data confirming the results of the time course analysis. CONCLUSION: The sensitivity of this study to detect small changes in the QTc interval was confirmed by demonstrating a shortening of QTcF of -8.1 (90% CI: -10.4, -5.9) one hour and -7.2 (90% CI: -9.4, -5.0) three hours after a standardised meal. TRIAL REGISTRATION: EU Clinical Trials Register EudraCT 2010 020343 13.
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Täubel et al. (2015) conducted an RCT in Healthy volunteers (n=32). E-52862 vs. Placebo was evaluated on Largest time-matched difference to placebo QTcI (MD 1.32 ms, 95% CI -1.89, 4.53). Single doses up to 800 mg of E-52862 did not prolong the QTc interval, with the largest time-matched difference to placebo QTcI being 1.32 ms for the 800 mg dose.
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