A randomized, placebo-controlled repeat-dose thorough QT study of inhaled loxapine in healthy volunteers

Abstract

Objective: This randomized, double-blind, active- and placebo-controlled, crossover, thorough QT study assessed the effect of two inhaled loxapine doses on cardiac repolarization as measured by corrected QT (QTc) interval in healthy subjects (ClinicalTrials.gov NCT01854710).

Methods: Subjects received two doses of inhaled loxapine (10 mg) 2 hours apart+oral placebo, two doses of inhaled placebo+oral placebo, or two doses of inhaled placebo+oral moxifloxacin (400 mg; positive control), with ≥3 days washout between treatments. Two-sided 90% confidence intervals (CIs) were calculated around least-squares mean predose placebo-subtracted individually corrected QT durations (ΔΔTcIs) at 12 time points throughout 24 hours after dosing. A ΔΔTcI 95% upper CI exceeding 10 msec was the threshold indicating QTc prolongation (primary endpoint). Secondary endpoints included Fridericia- and Bazett-corrected QT duration and QTcI outliers. Pharmacokinetics and adverse events (AEs) were also assessed.

Results: Of 60 subjects enrolled (mean age, 33.8 years; 52% male), 44 completed the study. Post loxapine dosing, no ΔΔTcI 95% upper CI exceeded 10 msec; the largest was 6.31 msec 5 minutes post dose 2. Methodology was validated by ΔΔTcI 95% lower CIs exceeding 5 msec at 9 of 12 time points after moxifloxacin dosing. Loxapine plasma concentrations increased rapidly (mean Cmax, 177 ng/mL; median tmax 2 minutes after dose 2, 2.03 hours after dose 1). There were no deaths, serious AEs, or AEs leading to discontinuation, and one severe AE.

Conclusions: Primary and secondary endpoints indicated two therapeutic doses of inhaled loxapine did not cause threshold QTc prolongation in this study.

Figures

Figure 1.. Subject disposition (safety population). Treatment: A = inhaled loxapine 2 × 10 mg; B = placebo; C = oral moxifloxacin 400 mg. aTwo subjects withdrawn owing to procedural error by the CRU and two subjects withdrawn owing to subject request after treatment A. bTwo subjects withdrawn owing to procedural error by the CRU and one subject withdrawn owing to subject request after treatment A. cTwo subjects withdrawn owing to procedural error by the CRU. CRU = clinical research unit.

Figure 2.. Least-squares mean ΔΔQTcI (predose subtracted individually corrected QT duration compared with placebo) and two-sided 90% CIs, primary analysis model (QT population). A: Inhaled loxapine. *Reference line at 10 msec shows the threshold of regulatory concern for the upper bound of the 95% CI on the mean effect of the primary outcome measure (QTcI). B: Oral moxifloxacin. **Reference line shows the threshold for concluding suitable assay sensitivity if any moxifloxacin QTcI lower 95% CI exceeds 5 msec. CI = confidence interval.

Figure 3.. Predose subtracted individually corrected QT duration compared with placebo (ΔΔQTcI, msec) vs. loxapine concentrations (ng/mL) and fitted linear regression (ΔΔQTcI = –1.1 + 1.64 (log (loxapine)); p = 0.013).

Figure 4.. Predose subtracted individually corrected QT duration compared with placebo (ΔΔQTcI, msec) vs. 8-OH-loxapine concentrations (ng/mL) and fitted linear regression (ΔΔQTcI = 1.7 – 0.561 (log (loxapine)); p = not significant). 8-OH-loxapine = 8-hydroxy loxapine.