A Randomized, Double-Blind, Placebo- and Active Comparator-Controlled Phase I Study of Analgesic/Antihyperalgesic Properties of ASP8477, a Fatty Acid Amide Hydrolase Inhibitor, in Healthy Female Subjects

Abstract

Objectives: To evaluate the analgesic/antihyperalgesic effect of ASP8477.

Design: Randomized, double-blind, double-dummy, cross-over, placebo- and active comparator-controlled study.

Setting: HPR Dr. Schaffler GmbH, Munich, Germany.

Subjects: Healthy female subjects aged 18-65 years.

Methods: Eligible subjects were randomly assigned to one of six treatment sequences and received multiple ascending doses of ASP8477, duloxetine, and placebo over three treatment periods (each consisting of 21-day dosing separated by 14-day washout periods). On the last day of each dose level, laser evoked potentials (LEPs) and visual analog scales (VAS pain) on capsaicin-treated skin at baseline and at multiple postdose time points were assessed. The primary end point was the difference in LEP N2-P2 peak-to-peak (PtP) amplitudes for ASP8477 100 mg vs placebo.

Results: Twenty-five subjects were randomized. In all subjects, LEP N2-P2 PtP amplitudes were numerically lower for ASP8477 100 mg vs placebo (P = 0.0721); in subjects who demonstrated positive capsaicin skin effects, a greater mean difference of -2.24 µV (P = 0.0146) was observed. Across all doses, LEP N2-P2 PtP amplitudes were lower for duloxetine compared with ASP8477 (mean difference -3.80 µV; P < 0.0001) or placebo (mean difference -5.21 µV; P < 0.0001). The effect of ASP8477 (all doses) on down-scoring the VAS pain score was significant compared with placebo (mean difference -2.55%; P < 0.0007).

Conclusions: ASP8477 was well tolerated in this study. Analysis of all subjects did not demonstrate a significant difference in LEP for ASP8477 100 mg over placebo but did in subjects who demonstrated positive capsaicin skin effects.

Figure 1

Study design. *ASP8477 low-dose 20 mg once daily, duloxetine low-dose 30 mg once daily; ^†ASP8477 mid-dose 60 mg once daily, duloxetine mid-dose 60 mg once daily; ^‡ASP8477 high-dose 100 mg once daily, duloxetine mid-dose 60 mg once daily; ^§washout for 14 days following each treatment period. ESV = end of study visit; LEP = laser evoked potential; MAD = main assessment day; VAS = visual analog scale; WO = washout.

Figure 2

Overall postadministration mean plus 95% confidence interval for laser evoked potential (LEP) N2-P2 peak-to-peak (PtP) amplitudes and visual analog scale (VAS) pain by treatment group in all subjects (FAS). Overall postadministration mean plus 95% confidence interval for (A) LEP N2-P2 PtP amplitudes and (B) VAS pain by treatment groups in all subjects. *P = 0.0054 relative to placebo. ^†P < 0.0001 relative to ASP8477 or placebo. ^‡P < 0.0007 relative to placebo. FAS = full analysis set.

Figure 3

Time course of action of the treatment groups in laser evoked potential (LEP) N2-P2 peak-to-peak (PtP) amplitudes and visual analog scale (VAS) by assessment days (FAS). Time course of action of the treatment groups on (A) LEP N2-P2 PtP amplitudes and (B) VAS pain by assessment days. Time after dose = 0 refers to predose assessment on days 7, 14, or 21, assessed directly following removal of capsaicin. By convention, the predose value day 7 (at steady state) was defined as 0% change. FAS = full analysis set.

Figure 4

Laser evoked potential (LEP) N2-P2 peak-to-peak (PtP) cumulative magnitude of response (AUC) for ASP8477 vs duloxetine. LEP N2-P2 PtP cumulative magnitude of response (AUC) for ASP8477 vs duloxetine in (A) full analysis set (all patients treated) and (B) capsaicin subgroup analysis. AUC = area under curve.

Figure 5

Laser evoked potential (LEP) N2-P2 peak-to-peak (PtP) duration of response (AUC) for ASP8477 vs duloxetine. LEP N2-P2 PtP duration of response (AUC) for ASP8477 vs duloxetine in (A) full analysis set (all subjects treated) and (B) capsaicin subgroup analysis. Results shown are predose values on days 7, 14, and 21. AUC = area under curve.