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

Author(s): Virchow JC, Kuna P, Paggiaro P et al

Lancet 2019; 394: P1737-1749

Airway diseases
General respiratory patient care

Digest Author(s): Stylianos Loukides, e-Learning Director / 10 November, 2019

Two parallel-group, double-blind, randomised, active-controlled, phase 3 trials (Triple in Asthma With Uncontrolled Patients on Medium Strength of ICS + LABA [TRIMARAN] and Triple in Asthma High Strength Versus ICS/LABA HS and Tiotropium [TRIGGER]). The study population consisted of adults aged 18-75 years. Patients had uncontrolled asthma and a history of one or more exacerbations in the previous year. They previously treated with inhaled corticosteroid (TRIMARAN: medium dose; TRIGGER: high dose) plus a long-acting β2 agonist. after a run-in phase of 15 days patients were randomly assigned (1:1) to 52 weeks of triple therapy with medium dose beclomethasone (400μg), formoterol, glycopyronium (BDP/FF/G) or BDP/FF in Trimaran and or were randomly assigned (2:2:1) to 52 weeks of high dose BDP(800μg)/FF/G or open-label high dose BDP/FF (800 μg ) tplus tiotropium5 μg once daily. Summarizing the two studies there was a direct comparison between ICS/LABA at different ICS doses with open and closed triple therapy. Co-primary endpoints for both trials were pre-dose FEV1 at week 26 and rate of moderate and severe exacerbations over 52 weeks. Safety was assessed in all patients who received at least one dose of study treatment.

The findings of this study showed that in patients with uncontrolled asthma addition of a long acting muscarinic antagonist to ICS/LABA improved lung function and decreased the rate of moderate to severe exacerbations. The above findings were observed for both open and closed triple therapy regimes.


This is the first close triple therapy for uncontrolled asthma with two main messages. The first one is that triple therapy represents an effective and safe approach in pateints not controlled with ICS/LABA for both steps 4 &5. The above strategy is not alternative to biologics but an additive one. The second message which is equally important refers to no significant differences between closed and open triple. The latest is quite similar to that observed in COPD. However, an issue which needs further clarification in a real life setting is whether the first approach would lead to an increased adherence.