Patients with uncontrolled asthma may decrease severe exacerbations and improve lung function with a triple combination therapy that involves either: 1) adding a long-acting muscarinic receptor antagonist (LAMA) to fixed-dose combination (FDC) therapy of inhaled corticosteroid (ICS)/long-acting β2-adrenoceptor agonist (LABA); or 2) escalating ICS on a background of ICS/LABA/LAMA FDC therapy. These were among the findings of a network meta-analysis of phase 3 randomized controlled trials (RCTs) published in the European Respiratory Journal.

For their analysis, the investigators selected phase 3 RCTs in which: 1) patients had asthma for at least 24 weeks, and 2) at least 1 study arm evaluated the effect of any triple combination therapy on asthma outcomes. The study compared triple combination treatments and other comparative treatments with respect to the risk for moderate to severe asthma exacerbation and change from baseline in trough forced expiratory volume in 1 second (FEV1). Other endpoints included the patient’s change from baseline in Asthma Control Questionnaire responses and the risk for serious adverse events.

A total of 9535 patients with asthma from 5 phase 3 RCTs were included in the meta-analysis. All 5 studies involved symptomatic patients with uncontrolled asthma. The triple combination ICS/LABA/LAMA FDC therapies evaluated included: 1) beclomethasone dipropionate (BDP)/formeterol fumarate (FOR)/glycoprotein bromide (GLY) (in 2 studies); 2) mometasone furoate (MF)/indacterol (IND)/GLY (in 2 studies); and 3) fluticasone furoate (FF)/vilanterol (VI)/umeclidinium (UMEC) (in 1 study). The investigated free combination ICS/LABA FDC plus tiotropium (TIO) included BDP/FOR plus TIO in 1 study and FP/salmeterol (SAL) + TIO in 1 study. Active comparators included the ICS/LABA FDCs BDP/FOR, FF/VI, MF/IND, and FP/SAL.


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Results of the study demonstrated that triple combination therapies with an ICS given at a high dose were significantly more effective than medium-dose ICS/LABA/LAMA FDC therapies (P <.05). This high-dose triple combination therapy was also more effective than medium- and high-dose ICS/LABA FDC therapies against moderate to severe asthma exacerbations (relative risk [RR], from 0.61 to 0.80) and in increasing trough FEV1 (from +33 mL to +114 mL).

Further, triple combination treatments containing high-dose ICS were significantly superior (P <.05) to medium-dose ICS/LABA/LAMA FDC therapies in preventing severe exacerbations (RR from 0.46 to 0.65) but were not significantly superior with respect to prevention of moderate exacerbations (P >.05). Triple combination therapies were equally effective with respect to asthma control with no safety concerns reported.

Based on their analysis, researchers concluded ICS/LABA/LAMA FDC therapies appeared to be safe and effective for the treatment of uncontrolled asthma. The dose of ICS used in the combination therapies represents the discriminating factor for treating patients with a history of moderate or severe asthma exacerbations.

Disclosure: Some of the study authors have declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 

Reference                                                                                                                                                                             

Rogliani P, Ritondo BL, Calzetta L. Triple therapy in uncontrolled asthma: a network meta-analysis of phase III studies. Eur Respir J. 2021;58(3):2004233. doi:10.1183/13993003.04233-2020