Single inhaler extrafine triple therapy in uncontrolled asthma (TRIMARAN and TRIGGER): two double-blind, parallel-group, randomised, controlled phase 3 trials

摘要: Summary Background To date, no studies have assessed the efficacy of single-inhaler triple therapy in asthma. Here we report on two that compared extrafine combination beclometasone dipropionate (BDP; inhaled corticosteroid), formoterol fumarate (FF; long-acting β2 agonist), and glycopyrronium (G; muscarinic antagonist) with BDP FF. Methods Two parallel-group, double-blind, randomised, active-controlled, phase 3 trials (Triple Asthma With Uncontrolled Patients Medium Strength ICS + LABA [TRIMARAN] Triple High Versus ICS/LABA HS Tiotropium [TRIGGER]) recruited patients from 171 sites across 16 countries (TRIMARAN), 221 17 (TRIGGER). The were a mixture secondary tertiary care centres specialised investigation units. Eligible adults (aged 18–75 years) uncontrolled asthma, history one or more exacerbations previous year, previously treated corticosteroid (TRIMARAN: medium dose; TRIGGER: high dose) plus agonist. Enrolled initially BDP/FF 100 μg 6 FF; 200 FF) for 2 weeks, then randomly assigned to treatment using an interactive response technology system balanced block randomisation scheme stratified by country. Patients, investigators, site staff, sponsor staff masked BDP/FF/G assignment. In TRIMARAN, (1:1) 52 weeks (100 BDP, FF, 10 G) FF), inhalations twice daily. TRIGGER, (2:2:1) (200 both daily, open-label daily tiotropium 2·5 once Coprimary endpoints (BDP/FF/G vs BDP/FF) pre-dose forced expiratory volume 1 s (FEV1) at week 26 rate moderate severe over weeks. Safety was all who received least dose study treatment. These registered ClinicalTrials.gov , NCT02676076 NCT02676089 Findings Between Feb 17, 2016, May 2018, 1155 TRIMARAN given (n=579) (n=576). April 6, 28, 1437 TRIGGER (n=573), (n=576), (n=288). Compared group, predose FEV1 improved group 57 mL (95% CI 15–99; p=0·0080) 73 (26–120; p=0·0025) reductions 15% (rate ratio 0·85, 95% 0·73–0·99; p=0·033) 12% (0·88, 0·75–1·03; p=0·11) TRIGGER. Four had treatment-related serious adverse events, three TRIGGER—one group. Three group—had events leading death. None deaths considered as related Interpretation addition antagonist β2-agonist improves lung function reduces exacerbations. Funding Chiesi Farmaceutici.