Normalisation of airflow limitation in asthma: Post-hoc analyses of TRIMARAN and TRIGGER

Abstract

Background: In asthma, persistent airflow limitation (PAL) is associated with poorer control, lung function decline and exacerbations. Using post-hoc analyses we evaluated: the relationship between post-salbutamol PAL at screening, airflow limitation (AL) during 52 weeks treatment with extrafine beclometasone dipropionate/formoterol fumarate/glycopyrronium (BDP/FF/G) versus BDP/FF and the risk of moderate/severe asthma exacerbations.

Methods: TRIMARAN and TRIGGER were double-blind studies comparing BDP/FF/G with BDP/FF (TRIMARAN medium-dose ICS; TRIGGER high-dose) in adults with uncontrolled asthma. Patients were subgrouped according to post-salbutamol PAL status at screening, and AL over the 52-week treatment period.

Results: Most patients with post-salbutamol PAL at screening had AL at all on-treatment visits (TRIMARAN 62.8%; TRIGGER 66.8%). A significantly higher proportion of patients had normalised airflow on ≥1 follow-up visit when receiving BDP/FF/G than BDP/FF (TRIMARAN 44.1 vs. 33.1% [p = 0.003]; TRIGGER 40.1 vs. 26.0% [p < 0.001]). In patients with post-salbutamol PAL at screening and normalised AL at ≥1 follow-up visit, exacerbation rates were 15% (p = 0.105) and 19% (p = 0.039) lower in TRIMARAN and TRIGGER versus those with AL on all visits. There was a trend to lower exacerbation rates in patients receiving BDP/FF/G than BDP/FF, particularly in patients in whom AL was normalised.

Conclusion: In these analyses, AL in asthma was associated with an increased exacerbation incidence. Inhaled triple therapy with extrafine BDP/FF/G was more likely to normalise airflow, and was associated with a trend to a lower exacerbation rate than BDP/FF, particularly in the subgroup of patients in whom treatment was associated with airflow normalisation.ClinicalTrials.gov: TRIMARAN, NCT02676076; TRIGGER, NCT02676089.

Keywords: exacerbations; inhaled corticosteroid; inhaled triple therapy; long‐acting beta2‐agonist; long‐acting muscarinic antagonist.

Conflict of interest statement

Alberto Papi 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. Dave Singh 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. J. Christian Virchow reports personal fees from Chiesi during the conduct of the studies. In the past J. Christian Virchow 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 Bemeinsame Bundesausschuss (GBA). G. Walter Canonica 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. Andrea Vele is an employee of Chiesi, the sponsor of the studies. George Georges is an employee of Chiesi USA, Inc.

© 2022 The Authors. Clinical and Translational Allergy published by John Wiley & Sons Ltd on behalf of European Academy of Allergy and Clinical Immunology.

Figures

FIGURE 1

Patients in TRIMARAN and TRIGGER subgrouped by post‐salbutamol persistent airflow limitation (PAL) status at screening (top panel), and the subgroup of patients with post‐salbutamol PAL at screening then subgrouped by on‐treatment 3‐h post‐dose airflow limitation status during the studies. Screening: PAL, persistent airflow limitation, defined as post‐salbutamol FEV1/FVC <0.7; No PAL, no persistent airflow limitation, defined as post‐salbutamol FEV1/FVC ≥0.7. On‐treatment: AL+, airflow limitation, defined as all available post‐randomisation 3 h post‐dose FEV1/FVC <0.7; AL‐, normalisation of airflow limitation, defined as at least one post‐randomisation 3 h post‐dose FEV1/FVC ≥0.7

FIGURE 2

Adjusted rate of moderate/severe exacerbations in the subgroup of patients with post‐salbutamol PAL at screening, comparing patients by on‐treatment 3‐h post‐dose airflow limitation status. Data plotted are adjusted exacerbation rate and 95% confidence interval comparing patients without versus with on‐treatment airflow limitation. AL+, airflow limitation, defined as all available post‐randomisation 3 h post‐dose FEV1/FVC <0.7; AL‐, normalisation of airflow limitation, defined as at least one post‐randomisation 3 h post‐dose FEV1/FVC ≥0.7. PAL, persistent airflow limitation, defined as post‐salbutamol FEV1/FVC <0.7 at screening. RR, rate ratio (95% confidence interval)

FIGURE 3

Relationship between study treatment received and normalisation of airflow limitation. OR, odds ratio for the proportion of patients with AL– at ≥1 on‐treatment visit, comparing BDP/FF/G versus BDP/FF. Screening: PAL, persistent airflow limitation, defined as post‐salbutamol FEV1/FVC <0.7; No PAL, no persistent airflow limitation, defined as post‐salbutamol FEV1/FVC ≥0.7. On‐treatment: AL+, airflow limitation, defined as all available post‐randomisation 3 h post‐dose FEV1/FVC <0.7; AL‐, normalisation of airflow limitation, defined as at least one post‐randomisation 3 h post‐dose FEV1/FVC ≥0.7. BDP, beclometasone dipropionate; FF, formoterol fumarate; G, glycopyrronium

FIGURE 4

Adjusted rate of moderate/severe exacerbations in the subgroup of patients with post‐salbutamol PAL at screening, with patients subgrouped by on‐treatment 3‐h post‐dose airflow limitation status and by treatment. Data plotted are adjusted exacerbation rate and 95% confidence interval from the statistical model subgrouping patients by on‐treatment AL and comparing BDP/FF/G versus BDP/FF (the rates from the statistical model subgrouping patients by the treatment received and comparing patients without vs. with on‐treatment airflow limitation were 2.02, 1.64, 2.32, 2.07, 2.02, 1.32, 2.10, and 2.15). AL+, airflow limitation, defined as all available post‐randomisation 3 h post‐dose FEV1/FVC <0.7; AL‐, normalisation of airflow limitation, defined as at least one post‐randomisation 3 h post‐dose FEV1/FVC ≥0.7. PAL, persistent airflow limitation, defined as post‐salbutamol FEV1/FVC <0.7 at screening. RR, rate ratio (95% confidence interval); BDP, beclometasone dipropionate; FF, formoterol fumarate; G, glycopyrronium