TRONARTO: A Randomized, Placebo-Controlled Study of Tiotropium/Olodaterol Delivered via Soft Mist Inhaler in COPD Patients Stratified by Peak Inspiratory Flow.

Background: Inhaled bronchodilator therapy is currently the mainstay of treatment for patients with chronic obstructive pulmonary disease (COPD). Some inhalers require patients to achieve certain inhalation efforts either to activate the device or to deliver medication to the site of action. For dry powder inhalers, low peak inspiratory flow (PIF) can result in poor medication delivery but the clinical significance of this is not well understood.
Methods: TRONARTO was a 4-week, randomized, double-blind, placebo-controlled, multicenter, parallel-group study which stratified patients with moderate-to-severe COPD according to their PIF against medium-low resistance at screening. Patients were randomized to receive tiotropium/olodaterol (5 μg/5 μg) or matched placebo delivered via the Respimat ^® Soft Mist™ inhaler (SMI). After 4 weeks of treatment, we assessed change from baseline in forced expiratory volume in 1 second (FEV ₁ ) area under the curve 0-3 hours (FEV ₁ AUC _0-3h ) and trough FEV ₁ .
Results: Overall, 213 patients were randomized, of whom 106 received tiotropium/olodaterol (PIF <60 L/min, 55; PIF ≥60 L/min, 51) and 107 received placebo (PIF <60 L/min, 55; PIF ≥60 L/min, 52). For FEV ₁ AUC _0-3h , the adjusted mean change from baseline versus placebo was 336 mL (95% confidence interval [CI] 246-425 mL; P<0.0001) in the PIF <60 L/min group and 321 mL (95% CI 233-409 mL; P<0.0001) in the PIF ≥60 L/min group. For trough FEV ₁ , the adjusted mean change from baseline versus placebo was 201 mL (95% CI 117-286 mL; P<0.0001) in the PIF <60 L/min group and 217 mL (95% CI 135-299 mL; P<0.0001) in the PIF ≥60 L/min group.
Conclusion: In the TRONARTO study, which included patients with moderate-to-severe COPD and varying inspiratory flow abilities, treatment with tiotropium/olodaterol resulted in significant lung function improvements versus placebo. This SMI can be used irrespective of the PIF that a patient can generate.
Competing Interests: Donald A. Mahler, M.D., FCCP reports fees for advisory boards from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Mylan, Teva, Theravance, and Verona; royalties from Salem Media Group – COPD: Answers to Your Questions (2015); work with pharmaceutical companies on the use of BDI/TDI; and participation in speaker’s bureau for AstraZeneca, Boehringer Ingelheim and Teva; and https://www.donaldmahler.com – an educational website for those with COPD and their families. Andrea Ludwig-Sengpiel reports investigator fees from Boehringer Ingelheim, paid to her institution during the conduct of the study; investigator fees from AstraZeneca, GlaxoSmithKline, Sanofi, Teva, Avillion, IONIS, Gossamer, Chiesi, Verona, Insmed and Novartis paid to her institution. Gary T. Ferguson reports grants, personal fees and non-financial support from Boehringer Ingelheim, during the conduct of the study; grants, personal fees and non-financial support from Teva Pharmaceuticals, Novartis, AstraZeneca, Pearl Therapeutics, Sunovion, Verona, Theravance, Mylan, Verona, and GlaxoSmithKline; grants and personal fees from Sanofi, grants from Altavant, Chiesi, and Knopp; personal fees from DevPro, Galderma, Ionis, and Orpheris, outside the submitted work. Alberto de la Hoz, John Ritz and Asif Shaikh are all employees of Boehringer Ingelheim. Henrik Watz reports grants from Boehringer Ingelheim for conductance of the study paid to his institution, consulting fees, honoraria payments, support for attending meetings and participation on a data safety monitoring or advisory board from AstraZeneca, Bayer, Boehringer Ingelheim, Chiesi, Novartis, Takeda, Verona Pharma, and GlaxoSmithKline. The authors report no other conflicts of interest in this work.
(© 2021 Mahler et al.)