Adding long-acting muscarinic antagonists to the treatment regimens of patients with uncontrolled asthma taking inhaled corticosteroids (ICS) plus long-acting β2 agonists (LABA) reduces exacerbations and improves lung function, according to study results published in The Lancet.

Until now, no study has evaluated the efficacy of single-inhaler triple therapy in adults aged 18 to 75 years with asthma. The current study reports on 2 parallel-group, phase 3, randomized double-blind active-controlled clinical trials (Triple in Asthma With Uncontrolled Patients on Medium Strength of ICS + LABA [TRIMARAN] and Triple in Asthma High Strength vs ICS/LABA HS and Tiotropium [TRIGGER]) comparing the extrafine, single-inhaler combination of glycopyrronium (G; long-acting muscarinic antagonist), beclomethasone dipropionate (BDP; ICS), and formoterol fumarate (FF; LABA), with a BDP/FF combination (TRIMARAN; Identifier:NCT02676076; TRIGGER; Identifier: NCT02676089). Participants were recruited from 221 sites across 17 countries (TRIGGER), and 171 sites across 16 countries (TRIMARAN). Participants were adults with uncontrolled asthma and >1 previous-year exacerbations, who were previously treated with medium- to high-dose ICS plus a LABA.

Participants initially received treatment with BDP/FF (TRIMARAN: 100 μg BDP and 6 μg FF; TRIGGER: 200 μg BDP and 6 μg FF) for 2 weeks, then were randomly assigned to treatment groups masked to investigators and staff. In TRIGGER, participants were randomly assigned (2:2:1) to 52 weeks of 2 twice-daily inhalations of BDP/FF/G (200 μg BDP, 6 μg FF, and 10 μg G; n=573) or BDP/FF (200 μg BDP and 6 μg FF; n=576), or 2 twice-daily inhalations of open-label BDP/FF (200 μg BDP and 6 μg FF) plus 2 once-daily inhalations of tiotropium 2.5 μg (n=288). In TRIMARAN, participants were assigned (1:1) to 52 weeks of 2 twice-daily inhalations of BDP/FF/G (100 μg BDP, 6 μg FF, and 10 μg G; n=579) or BDP/FF (100 μg BDP and 6 μg FF; n=576). For both trials, coprimary end points were predose forced expiratory volume in 1 second (FEV1) at week 26, and rate of moderate to severe exacerbations over the 52-week study period.

Both studies met the coprimary end point of predose FEV1 change at week 26. In TRIMARAN, week 26 FEV1 improved in the BDP/FF/G group by 57 mL (95% CI, 15-99; P =.0080) compared with the BDP/FF group, and in TRIGGER, it was by 73 mL (95% CI, 26-120; P =.0025). No difference was found between the BDP/FF/G and the BDP/FF plus tiotropium groups in the week 26 predose FEV1 in TRIGGER (-45 mL, 95% CI, -103 to 13; P =.13). Moderate and severe exacerbations were reduced by 15% (rate ratio [RR], 0.85; 95% CI, 0.73-0.99; P =.033) in TRIMARAN and 12% (RR, 0.88; 95% CI, 0.75-1.03; P =.11) in TRIGGER, although not significantly. Again, no difference was found in TRIGGER between the BDP/FF/G group and BDP/FF plus tiotropium group (RR, 1.07; 95% CI, 0.88-1.30; P =.50). All 5 groups showed a similar rate of adverse events, most of them mild, with 2 TRIGGER participants and 3 TRIMARAN participants experiencing fatal adverse events, none of which were considered treatment-related.

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Study investigators concluded, “Taken together, these data indicate that in adults with uncontrolled asthma treated with a medium­to­high dose of [ICS] plus a [LABA] the addition of a long­acting muscarinic antagonist in a single inhaler BDP/FF/G triple therapy mainly improves lung function with an associated positive effect on severe exacerbations and some benefit in terms of asthma symptoms and control.”

Disclosure: The clinical trials were supported by Chiesi Farmaceutici. Please see the original reference for a full list of authors’ disclosures.


Virchow JC, Kuna P, Paggiaro P, et al. Single inhaler extrafine triple therapy in uncontrolled asthma (TRIMARAN and TRIGGER): two double-blind, parallel-group, randomised, controlled phase 3 trials [published online September 30, 2019]. Lancet. doi:10.1016/S0140-6736(19)32215-9