Efficacy and safety of single-inhaler extrafine triple therapy versus inhaled corticosteroid plus long-acting beta2 agonist in eastern Asian patients with COPD: the TRIVERSYTI randomised controlled trial

Abstract

Background: A single-inhaler extrafine triple combination of beclometasone dipropionate (BDP), formoterol fumarate (FF) and glycopyrronium (G) has been developed for maintenance therapy of chronic obstructive pulmonary disease (COPD). This study evaluated the efficacy and safety of BDP/FF/G in patients in three eastern Asian areas: China, Republic of Korea and Taiwan.

Methods: TRIVERSYTI was a double-blind, randomised, active-controlled, parallel-group study in patients with COPD, post-bronchodilator forced expiratory volume in 1 s (FEV1) < 50% predicted, ≥ 1 exacerbation in the previous 12 months, and receiving inhaled maintenance medication. Patients received either extrafine BDP/FF/G 100/6/10 µg via pressurised metered-dose inhaler, or non-extrafine budesonide/formoterol (BUD/FF) 160/4.5 µg via dry-powder inhaler, both administered as two puffs twice-daily for 24 weeks. The co-primary objectives (analysed in the overall population) were to demonstrate superiority of BDP/FF/G over BUD/FF for change from baseline in pre-dose morning and 2-h post-dose FEV1 at Week 24 (these were analysed as key secondary objectives in the China subgroup). The rate of moderate/severe COPD exacerbations was a secondary endpoint.

Results: Of 708 patients randomised, 88.8% completed. BDP/FF/G was superior to BUD/FF for pre-dose and 2-h post-dose FEV1 at Week 24 [adjusted mean differences 62 (95% CI 38, 85) mL and 113 (87, 140) mL; both p < 0.001]. The annualised moderate/severe exacerbation rate was 43% lower with BDP/FF/G [rate ratio 0.57 (95% CI 0.42, 0.77); p < 0.001]. Adverse events were reported by 61.1% and 67.0% patients with BDP/FF/G and BUD/FF. Results were similar in the China subgroup.

Conclusions: In patients with COPD, FEV1 < 50% and an exacerbation history despite maintenance therapy, treatment with extrafine BDP/FF/G improved bronchodilation, and was more effective at preventing moderate/severe COPD exacerbations than BUD/FF. Trial registration CFDA CTR20160507 (registered 7 Nov 2016, http://www.chinadrugtrials.org.cn/index.html ).

Keywords: Airway obstruction; Chronic bronchitis; Chronic obstructive pulmonary disease; Extrafine; Triple inhalation therapy.

Conflict of interest statement

JZ has no relevant conflicts to disclose. LZ has no relevant conflicts to disclose. HL has no relevant conflicts to disclose. K-HL has no relevant conflicts to disclose. DS reports personal fees from Chiesi during the conduct of the study. Outside the submitted work, he reports personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, Genentech, GlaxoSmithKline, Glenmark, Menarini, Mundipharma, Novartis, Peptinnovate, Pfizer, Pulmatrix, Theravance, and Verona. AP reports grants, personal fees, non-financial support and payment for advisory board membership, consultancy, payment for lectures, grants for research, and travel expenses reimbursement from Chiesi, AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, Mundipharma and TEVA, and personal fees and non-financial support from Menarini, Novartis, Zambon and Sanofi, all outside the submitted work. SB, FG, AG and GG are employees of Chiesi, the sponsor of the study.

Figures

Fig. 1

Patient flow through the study (overall population). COPD chronic obstructive pulmonary disease, BDP beclometasone dipropionate, FF formoterol fumarate, G glycopyrronium, BUD budesonide, ITT intention-to-treat, PP per protocol

Fig. 2

Adjusted mean change from baseline in a pre-dose morning FEV1, and b 2-h post-dose FEV1 (overall population, ITT). ‡p < 0.001. Data are adjusted mean and 95% CI. The N values are the number of patients included in the statistical model. FEV1 forced expiratory volume in 1 s, ITT intention-to-treat, BDP beclometasone dipropionate, FF formoterol fumarate, G glycopyrronium, BUD budesonide, CI confidence interval

Fig. 3

Adjusted mean change from baseline in IC (overall population, ITT). *p < 0.05; †p < 0.01; ‡p < 0.001. Data are adjusted mean and 95% CI. The N values are the number of patients included in the statistical model. IC inspiratory capacity, ITT intention-to-treat, BDP beclometasone dipropionate, FF formoterol fumarate, G glycopyrronium, BUD budesonide, CI confidence interval

Fig. 4

Annualised moderate/severe COPD exacerbation rates (ITT population). Bars represent adjusted exacerbation rate per patient per year and 95% CI. The N values are for the ITT population. COPD chronic obstructive pulmonary disease, ITT intention-to-treat, BDP beclometasone dipropionate, FF formoterol fumarate, G glycopyrronium, BUD budesonide, CI confidence interval

Fig. 5

Adjusted mean change from baseline in a SGRQ and b CAT total scores (overall population, ITT). †p < 0.01; ‡p < 0.001. Data are adjusted mean and 95% CI. The N values are the number of patients included in the statistical model. SGRQ St George’s Respiratory Questionnaire, CAT COPD Assessment Test, ITT intention-to-treat, BDP beclometasone dipropionate, FF formoterol fumarate, G glycopyrronium, BUD budesonide, CI confidence interval