OBJECTIVE: This study assesses the potential of the phosphodiesterase 4 inhibitor roflumilast to affect cardiac repolarization. METHODS: In this randomized, placebo-controlled study (n = 80), 40 healthy subjects receivedmoxifloxacin 400 mg p.o. (positive control for prolongation of QT/heart-rate corrected QT [QTc]) and another 40 received placebo. After a 1-day washout, subjects received placebo or ascending doses of roflumilast 500 (therapeutic dose), 750 or 1000 μg/day p.o., for 14, 7 and 14 days, respectively. QT intervals were measured and corrected for heart rate with a Fridericia algorithm (QTc(F)). The primary endpoint was the largest mean time-matched change in QTc(F) from baseline (day 1). Safety and tolerability were monitored. RESULTS:Moxifloxacin gave a maximum time-matched change in QTc(F) versus baseline of 6.79 ms. Repeated administration of roflumilast500 and 1000 μg resulted in maximum QTc(F) changes from baseline of -3.23 and -4.81 ms, respectively, confirming the absence of any QT/QTc prolongation at therapeutic and supra-therapeutic dosing. There were no changes in other electrocardiographic variables or time intervals, and roflumilast was well tolerated. CONCLUSIONS: Repeated administration of roflumilast at doses ≤ 1000 μg/day had no effect on cardiac repolarization or overall cardiac safety evaluations in healthy subjects. CLINICAL TRIAL REGISTRATION NUMBER: ISRCTN63818313
RCT Entities:
OBJECTIVE: This study assesses the potential of the phosphodiesterase 4 inhibitor roflumilast to affect cardiac repolarization. METHODS: In this randomized, placebo-controlled study (n = 80), 40 healthy subjects received moxifloxacin 400 mg p.o. (positive control for prolongation of QT/heart-rate corrected QT [QTc]) and another 40 received placebo. After a 1-day washout, subjects received placebo or ascending doses of roflumilast 500 (therapeutic dose), 750 or 1000 μg/day p.o., for 14, 7 and 14 days, respectively. QT intervals were measured and corrected for heart rate with a Fridericia algorithm (QTc(F)). The primary endpoint was the largest mean time-matched change in QTc(F) from baseline (day 1). Safety and tolerability were monitored. RESULTS:Moxifloxacin gave a maximum time-matched change in QTc(F) versus baseline of 6.79 ms. Repeated administration of roflumilast 500 and 1000 μg resulted in maximum QTc(F) changes from baseline of -3.23 and -4.81 ms, respectively, confirming the absence of any QT/QTc prolongation at therapeutic and supra-therapeutic dosing. There were no changes in other electrocardiographic variables or time intervals, and roflumilast was well tolerated. CONCLUSIONS: Repeated administration of roflumilast at doses ≤ 1000 μg/day had no effect on cardiac repolarization or overall cardiac safety evaluations in healthy subjects. CLINICAL TRIAL REGISTRATION NUMBER: ISRCTN63818313