A repeat-dose thorough QT study of inhaled fluticasone furoate/vilanterol combination in healthy subjects

Rodger Kempsford, Ann Allen, Kathryn Kelly, Parminder Saggu, Courtney Crim, Rodger Kempsford, Ann Allen, Kathryn Kelly, Parminder Saggu, Courtney Crim

Abstract

Aims: This study was designed as a thorough QT (TQT) study to evaluate the effects of fluticasone furoate (FF)/vilanterol (VI) in healthy subjects. Supportive data from a TQT study conducted with FF are also presented.

Methods: This was a randomized, placebo- and positive-controlled, double-dummy, double-blind, four-way crossover study, in which healthy subjects (n = 85) were randomized to 7 days of once-daily treatment of FF/VI (200/25 or 800/100 μg) or placebo or single-dose oral moxifloxacin (single-blind, 400 mg). In the supportive TQT study, subjects (n = 40) were randomized to single-dose inhaled FF (4000 μg), oral moxifloxacin (400 mg) or placebo.

Results: There was a lack of effect of FF/VI (200/25 μg) on QTcF (Fridericia's correction); all time-matched mean differences from baseline relative to placebo (0-24 h) were <5 ms, with upper 90% confidence intervals (CI) of <10 ms. At 800/100 μg, FF/VI had no significant clinical effect on QTcF except at 30 min postdose when the 90% CI was >10 ms [mean (90% CI), 9.6 ms (7.2, 12.0)]. No effect on QTci (individually corrected) was observed at either strength of FF/VI, with mean time-matched treatment differences <5 ms at all time points [upper 90% CIs <10 ms (0-24 h)]. Assay sensitivity was confirmed; moxifloxacin prolonged QTcF and QTci, with time-matched mean differences from baseline relative to placebo of >10 ms (1-8 h postdose).

Conclusions: Repeat once-daily dosing of FF/VI (200/25 μg), which is the highest therapeutic strength used in phase III studies, is not associated with QTc prolongation in healthy subjects. Supratherapeutic strength FF/VI (800/100 μg) demonstrated a small transient effect on QTcF but not on QTci.

Trial registration: ClinicalTrials.gov NCT01209026.

Keywords: fluticasone furoate; healthy subjects; moxifloxacin; thorough QT; vilanterol.

© 2013 GlaxoSmithKline. The British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.

Figures

Figure 1
Figure 1
QTcF (Fridericia's correction) adjusted mean (90% CI) change from baseline (difference from placebo) 0–24 h after dosing on day 7 with FF/VI (800/100 and 200/25 μg) and single dose moxifloxacin (400 mg) (per protocol population). , FF/VI 200/25 μg; , FF/VI 800/100 μg; , moxifloxacin 400 mg
Figure 2
Figure 2
QTci (individually corrected) adjusted mean (90% CI) change from baseline (difference from placebo) 0–24 h after dosing on day 7 with FF/VI (800/100 and 200/25 μg) and single-dose moxifloxacin (400 mg) (‘all subjects’ population). , FF/VI 200/25 μg; , FF/VI 800/100 μg; , moxifloxacin 400 mg
Figure 3
Figure 3
QTcF (Fridericia's correction) adjusted mean (90% CI) change from baseline (difference from placebo) 0–24 h after single dose FF (4000 μg) and single dose moxifloxacin (400 mg) ('all subjects' population). , FF 4000 μg; , Moxi 400 mg

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