A randomized, controlled, repeat-dose study of batefenterol/fluticasone furoate compared with placebo in the treatment of COPD

Abstract

Background: Batefenterol (BAT) is a bi-functional molecule with both muscarinic antagonist and β2-adrenoceptor agonist pharmacology. This Phase II, randomized, placebo-controlled, double-blind study evaluated the safety and tolerability of BAT 300 μg with fluticasone furoate (FF) 100 μg administered via the ELLIPTA inhaler (BAT/FF 300/100).

Methods: Subjects with stable chronic obstructive pulmonary disease were randomized 2:1 to receive BAT/FF 300/100 or placebo once daily for 6 weeks. The primary endpoint was change from baseline in 0-4-h weighted mean (WM) heart rate (HR, measured by electrocardiogram [ECG]) on Day 42. Other endpoints included WM and maximum 0-4-h corrected QT interval (ECG on Days 1, 28, and 42), HR measured by Holter monitoring (Day 42), and standard safety assessments. Study protocol was approved by an Investigational Review Board.

Results: Sixty-two patients were randomized and received ≥1 dose of study medication (BAT/FF 300/100 n = 42; placebo n = 20). Mean age was 62.5 years (standard deviation [SD] 8.17). Study completion rates were 83% (BAT/FF 300/100) and 100% (placebo). Screening mean (SD) post-bronchodilator percentage-predicted forced expiratory volume in 1 s was 57.57 (11.42) in the BAT/FF 300/100 group and 55.68 (14.03) in the placebo group. BAT/FF 300/100 was non-inferior to placebo for the primary endpoint, treatment difference: - 2.2 beats per minute (bpm), 95% confidence interval [CI]: - 6.2, 1.7). There were no clinically relevant differences between treatment groups in WM or maximum 0-4-h corrected QT interval, or mean HR based on Holter monitoring on Day 42 (BAT/FF 300/100: 76.3 bpm [SD 11.38]; placebo: 84.8 bpm [SD 9.87]). Adverse events (AEs) occurred in 38% (BAT/FF 300/100) and 35% (placebo) of patients. AEs in ≥2 subjects with BAT/FF 300/100 were dysgeusia (10%), diarrhea (7%), nasopharyngitis (7%), and cough (5%). AEs leading to discontinuation occurred in two subjects who received BAT/FF 300/100: post-treatment severe pneumonia (serious AE) and non-serious AEs of moderate vomiting and severe gastroenteritis; both were not considered drug-related. No deaths occurred.

Conclusions: Six weeks of BAT/FF 300/100 treatment was non-inferior to placebo for change from baseline in HR, with no new clinically relevant general or cardiovascular safety signals.

Trial registration: Clinicaltrials.gov: NCT02573870 (submitted October 12, 2015).

Keywords: Bi-functional molecule; Bronchodilator; Safety; Triple therapy.

Conflict of interest statement

CB, RC-S, C Crim, C Crawford and MW are employees of, and hold shares, in GSK. AE is a former employee of, and holds shares in, GSK. MG has participated in speakers’ bureau for GSK, and has received grants from Boehringer Ingelheim, Sunvovion, AstraZeneca, Theravance, Pearl, and Chiesi. SS has received personal fees from GSK in connection with participation in a speakers’ bureau.

Figures

Fig. 1

Study design (a) and participant flow diagram (b). BAT/FF, batefenterol/fluticasone furoate; PRN, Pro re nata (when necessary); QD, once daily; V, visit

Fig. 2

LS mean change from baseline in 0–4-h WM HR (bpm). BAT/FF 300/100, batefenterol/fluticasone furoate 300/100 μg; bpm, beats per minute; HR, heart rate; LS, least squares; WM, weighted mean

Fig. 3

WM and maximum QTc(F) change from baseline to Day 42 (MMRM analyses). BAT/FF 300/100, batefenterol/fluticasone furoate 300/100 μg; QTc(F), QT interval corrected by Fridericia’s method; MMRM, mixed models repeated measures; WM, weighted mean

Fig. 4

LS mean change from baseline in trough FEV1. BAT/FF 300/100, batefenterol/fluticasone furoate 300/100 μg; FEV1, forced expiratory volume in 1 s; LS, least squares