Clinical Bioequivalence of Wixela Inhub and Advair Diskus in Adults With Asthma

Abstract

Background: Wixela® Inhub® is a dry powder inhaler approved as a generic equivalent to Advair® Diskus® (fluticasone propionate [FP]/salmeterol fixed-dose combination) for patients with asthma or chronic obstructive pulmonary disease (COPD). This study aimed at confirming the local (lung) therapeutic equivalence of both the FP and salmeterol components of Wixela Inhub (test [T]) to Advair Diskus (reference [R]) after inhalation. Methods: This randomized, double-blind, double-dummy, placebo-controlled, parallel-group study in patients ≥18 years with mild-to-moderate persistent asthma compared the local therapeutic equivalence (using forced expiratory volume in 1 second [FEV1]) of FP/salmeterol (100/50 μg) after inhaled delivery via T and R. Results: Randomized patients (N = 1127) received T (n = 512), R (n = 512), or placebo (n = 103). T and R significantly increased day 1 FEV1 area under the effect curve over 12 hours of the change from baseline (AUC[0-12]) and day 29 trough FEV1 over placebo, indicating that these endpoints were sufficiently sensitive for evaluation of bioequivalence. On day 1, T and R each increased FEV1 AUC(0-12) over placebo (3.134 L•h [T], 2.677 L•h [R]; each p < 0.0001). Following twice-daily dosing for 28 days, T and R also each increased trough FEV1 (measured on day 29) over placebo (235 mL [T], 215 mL [R]; each p < 0.0001). Least-squares mean T/R ratios (90% confidence intervals) for day 1 FEV1 AUC(0-12) and day 29 trough FEV1 were 1.120 (1.016-1.237) and 1.069 (0.938-1.220), respectively, indicating that T and R were bioequivalent for both co-primary endpoints. FP/salmeterol was well tolerated when administered via either T or R. Conclusions: These results demonstrate that the therapeutic effects of Wixela Inhub are bioequivalent to Advair Diskus in the lung. Wixela Inhub represents a therapeutically equivalent new FP/salmeterol treatment option for use in the treatment of asthma and COPD.

Keywords: Advair Diskus; Wixela Inhub; fluticasone propionate; generic drugs; local bioequivalence; salmeterol.

Conflict of interest statement

D.N., S.H., J.K.W., and R.A. are employees of Mylan and have stock ownership in Mylan.

E.M.K. has participated in consulting, advisory boards, speaker panels, or received travel reimbursement for Amphastar, Astra Zeneca, Boehringer Ingelheim, GlaxoSmithKline, Mylan, Novartis, Oriel, Pearl, Sunovion, Teva, and Theravance. He has conducted multicenter clinical research trials for ∼40 pharmaceutical companies.

M.V.W. reports grants from Mylan, during the conduct of the study; personal fees from Mylan; grants from Sanofi-Aventis; and grants from Genentech, outside the submitted work.

S.D.M. has no disclosures to declare.

Figures

FIG. 1.

Patient flow. One of the patients randomized to the reference product (Advair Diskus) was not treated because of a failure to meet the inclusion/exclusion criteria, which resulted in 512 patients treated with Advair Diskus and 1127 total treated patients. All 1127 patients receiving a study treatment (Wixela Inhub [T], Advair Diskus [R], or placebo) were analyzed for safety. The FAS consisted of 1122 patients (509 [R], 511 [T], and 102 [placebo]); 5 treated patients (3 [T], 1 [R], and 1 [placebo]) were excluded from the FAS due to being enrolled into the study twice and so the second participations were excluded from the FAS. The PPS consisted of 1105 patients (502 [T and R], 101 [placebo]); 17 patients (7 [T], 9 [R], and 1 [placebo]) were excluded from the PPS due to ≥1 significant protocol deviation. FAS, full analysis set; PPS, per protocol set; R, reference product (Advair Diskus); T, test product (Wixela Inhub).

FIG. 2.

Change from baseline in FEV1 over time on day 1 with placebo (open squares), test (open circles), and reference (open triangles) FPS. Test FPS, Wixela Inhub; reference FPS, Advair Diskus. Data are mean and 95% CI. CI, confidence interval; FEV1, forced expiratory volume in 1 second. FPS, fluticasone propionate/salmeterol.

FIG. 3.

Day 1 (A) and day 29 (B) improvement in lung function after treatment with test and reference FPS and placebo. Baseline-subtracted data presented as LS mean and 95% CI. Test, Wixela Inhub; Reference, Advair Diskus. *Difference from placebo p < 0.0001. AUC(0–12), area under the effect curve over 12 hours; LS, least squares.

FIG. 4.

Day 1 and day 29 bioequivalence test. T/R FEV1 LS mean ratio and 90% CI for both day 1 (FEV1 AUC(0–12)) and day 29 (trough FEV1) co-primary endpoints were within the standard bioequivalence limits, shown as dotted lines. AUC(0–12), area under the effect curve over 12 hours postdose; R, reference product (Advair Diskus); T, test product (Wixela Inhub).