Determinants of response to inhaled extrafine triple therapy in asthma: analyses of TRIMARAN and TRIGGER

Abstract

Background: A number of single-inhaler triple therapies are being developed for asthma, including the extrafine formulation of beclometasone dipropionate (BDP), formoterol fumarate (FF), and glycopyrronium (G). Given asthma is a heterogenous disease, we investigated whether the clinical response to the addition of the long-acting muscarinic antagonist component within inhaled triple therapy was impacted by a range of clinical characteristics.

Methods: These were pre-specified and post-hoc sub-group analyses of TRIMARAN and TRIGGER, which were double-blind, 52-week studies comparing medium-strength (100/6/10 µg; TRIMARAN) and high-strength (200/6/10 µg; TRIGGER) BDP/FF/G with the respective BDP/FF strengths in adults with uncontrolled asthma and a history of ≥ 1 exacerbation. Co-primary endpoints were pre-dose forced expiratory volume in 1 s (FEV1) at Week 26 and the rate of moderate-to-severe exacerbations over 52 weeks. Key secondary endpoints: peak FEV1 at Week 26 and average morning peak expiratory flow over the first 26 weeks in each study, and severe exacerbation rate over 52 weeks (pooled data).

Results: Baseline clinical characteristics (pre-specified analyses) had no consistent effect on the lung function improvements with BDP/FF/G. For the exacerbation endpoints, sub-groups with higher reversibility gained greatest relative benefit from BDP/FF/G versus BDP/FF. In post-hoc analyses with patients sub-grouped by screening blood eosinophil values, in TRIMARAN the greatest relative effect of BDP/FF/G versus BDP/FF on the lung function endpoints was in the ≤ 300 cells/µL group; in TRIGGER, eosinophil levels did not markedly influence the relative efficacy of BDP/FF/G versus BDP/FF. Eosinophil levels did not influence relative efficacy on moderate-to-severe or severe exacerbations.

Conclusion: Overall, the relative efficacy of extrafine BDP/FF/G versus BDP/FF was not influenced by a range of clinical characteristics. However, some patient sub-groups gained additional benefit from BDP/FF/G for certain endpoints. In particular, for exacerbations the relative efficacy of BDP/FF/G was greater in more reversible patients. Trial registration ClinicalTrials.gov: TRIMARAN, NCT02676076 (registered February 8, 2016, https://ichgcp.net/clinical-trials-registry/NCT02676076?term=NCT02676076&draw=2&rank=1 ,); TRIGGER, NCT02676089 (registered February 8, 2016, https://ichgcp.net/clinical-trials-registry/NCT02676089?term=NCT02676089&draw=2&rank=1 ).

Keywords: Asthma; Eosinophils; Inhaled corticosteroids; Long-acting muscarinic antagonists; Long-acting β2-agonists; Pharmacotherapy; Subgroup analyses.

Conflict of interest statement

DS reports personal fees from Chiesi during the conduct of the studies. 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. JCV reports personal fees from Chiesi during the conduct of the studies. In the past JCV has lectured and received honoraria from AstraZeneca, Avontec, Bayer, Bencard, Bionorica, Boehringer-Ingelheim, Chiesi, Essex/Schering-Plough, GSK, Janssen-Cilag, Leti, MEDA, Merck, MSD, Mundipharma, Novartis, Nycomed/Altana, Pfizer, Revotar, Sanofi/Regeneron, Sandoz-Hexal, Stallergens, TEVA, UCB/Schwarz-Pharma, Zydus/Cadila and possibly others, and participated in advisory boards and received honoraria from Avontec, Boehringer-Ingelheim, Chiesi, Essex/Schering-Plough, GSK, Janssen-Cilag, MEDA, MSD, Mundipharma, Novartis, Paul-Ehrlich Institut, Regeneron, Revotar, Roche, Sanofi-Aventis, Sanofi/Regeneron, Sandoz-Hexal, TEVA, UCB/Schwarz-Pharma and possibly others, and received funding for research from Deutsche Forschungsgesellschaft, Land Mecklenburg-Vorpommern, GSK, and MSD, and has advised the Gemeinsame Bundesausschuss (GBA). GWC reports personal fees from A. Menarini, Alk-Abello, Allergy Therapeutics, AstraZeneca-Medimmune, Boehringer Ingelheim, Chiesi Farmaceutici, Genentech, Guidotti-Malesci, Glaxo Smith Kline, Hal Allergy, Merck Sharp & Dome, Mundipharma, Novartis, Orion, Sanofi-Aventis, Sanofi Genzyme/Regeneron, Stallergenes-Greer, Uriach Pharma, Teva, Valeas, ViforPharma, all outside the submitted work. AV and MK are employees of Chiesi, the sponsor of the studies. GG is an employee of Chiesi USA, Inc. 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.

Figures

Fig. 1

Change from baseline in pre-dose FEV1 at Week 26, adjusted least squares mean difference BDP/FF/G versus BDP/FF in patient sub-groups. *p < 0.05. FEV1 forced expiratory volume in 1 s, BDP beclometasone dipropionate, FF formoterol fumarate, G glycopyrronium, BMI body mass index

Fig. 2

Moderate-to-severe and severe exacerbations, adjusted rate ratio BDP/FF/G versus BDP/FF in patient sub-groups. During the studies, moderate-to-severe exacerbations were experienced by 58.6% and 66.0% patients in the BDP/FF/G and BDP/FF groups, respectively, in TRIMARAN, and by 56.6% and 63.7%, respectively, in TRIGGER; severe exacerbations were experienced by 18.2% and 22.4% patients, respectively, in the pooled population. *p BDP beclometasone dipropionate, FF formoterol fumarate, G glycopyrronium, BMI body mass index

Fig. 3

Change from baseline in peak FEV1 at Week 26, adjusted least squares mean difference BDP/FF/G versus BDP/FF in patient sub-groups. *p < 0.05. FEV1 forced expiratory volume in 1 s, BDP beclometasone dipropionate, FF formoterol fumarate, G glycopyrronium, BMI body mass index

Fig. 4

Change from baseline in average morning PEF over the first 26 weeks, adjusted least squares mean difference BDP/FF/G versus BDP/FF in patient sub-groups. *p PEF peak expiratory flowm BDP beclometasone dipropionate, FF formoterol fumarate, G glycopyrronium, BMI body mass index

Fig. 5

Severe exacerbations, adjusted rate ratio BDP/FF/G versus BDP/FF (pooled analysis) across eosinophil values. Analysed using a negative binomial model including treatment, country, number of exacerbations in the previous year (1 or > 1) and study as fixed effects, and log-time on study as offset. BDP beclometasone dipropionate, FF formoterol fumarate, G glycopyrronium