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Background: The assessment of QTc changes after the intake of a standardized meal has been proposed as an alternative approach to prove assay sensitivity when the proarrhythimic potential of a drug is to be excluded in either TQT or intensive Phase I QT studies., Methods: In this article, an analysis of the food effect at baseline across periods in two different studies is presented to support the robustness of the method., Results: The results show that the time-effect attributed to food is stable over different study periods demonstrating consistency of the physiological response triggered by food., Conclusions: Stability and reproducibility of the effect is comparable with moxifloxacin., (© 2016 Wiley Periodicals, Inc.)

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.

This study was performed to determine the efficacy and safety of oral cizolirtine citrate, a novel agent, in the treatment of chronic neuropathic pain. Cizolirtine was tested in a double-blind, placebo-controlled, two-way crossover study, having previously been shown to have significant analgesic and anti-hyperalgesic action in neuropathic pain models and preliminary human studies. Twenty-five patients with neuropathic pain, which was persistent for at least three months, and scored > 30 mm on a 100 mm visual analogue scale (VAS), were included. A subgroup of five patients had primary skin allodynia, i.e. pain evoked by non-noxious stimuli in the territory of the injured nerve. Cizolirtine 200 mg or placebo was administered twice daily for a treatment period of 21 days, each separated by a washout interval of 7 days. Assessments of skin allodynia were performed using the graded monofilaments (von Frey hairs) on days 1 (predose), 14 and 21 (90 min postdose). All patients were instructed to maintain a daily pain diary throughout the study. Results showed that the differences in VAS and allodynia scores between cizolirtine and placebo treatments were not significant in the overall analysis (p > or = 0.05); cizolirtine was well tolerated. In a subgroup of five patients with primary allodynia, a 53% reduction in VAS score from baseline at rest (p = 0.007) and 55% on movement (p = 0.0002) at day 21 was observed with cizolirtine, as compared to 8% at rest (p = 0.5215) and 13% on movement (p = 0.4187) with placebo. Similarly, allodynia improved with cizolirtine (p = 0.03) but not with placebo (p = 0.9) in this subgroup. Cizolirtine may be effective in primary allodynia after peripheral nerve injury, and a further trial in a larger number of such subjects is warranted.