Long-Term Once-Daily Tiotropium Respimat® Is Well Tolerated and Maintains Efficacy over 52 Weeks in Patients with Symptomatic Asthma in Japan: A Randomised, Placebo-Controlled Study

Abstract

Background: This study assessed the long-term safety and efficacy of tiotropium Respimat, a long-acting inhaled anticholinergic bronchodilator, in asthma, added on to inhaled corticosteroids (ICS) with or without long-acting β2-agonist (LABA).

Methods: 285 patients with symptomatic asthma, despite treatment with ICS±LABA, were randomised 2:2:1 to once-daily tiotropium 5 μg, tiotropium 2.5 μg or placebo for 52 weeks (via the Respimat SoftMist inhaler) added on to ICS±LABA, in a double-blind, placebo-controlled, parallel-group study (NCT01340209).

Primary objective: to describe the long-term safety profile of tiotropium. Secondary end points included: trough forced expiratory volume in 1 second (FEV1) response; peak expiratory flow rate (PEFR) response; seven-question Asthma Control Questionnaire (ACQ-7) score.

Results: At Week 52, adverse-event (AE) rates with tiotropium 5 μg, 2.5 μg and placebo were 88.6%, 86.8% and 89.5%, respectively. Commonly reported AEs with tiotropium 5 μg, 2.5 μg and placebo were nasopharyngitis (48.2%, 44.7%, 42.1%), asthma (28.9%, 29.8%, 38.6%), decreased PEFR (15.8%, 7.9%, 21.1%), bronchitis (9.6%, 13.2%, 7.0%), pharyngitis (7.9%, 13.2%, 3.5%) and gastroenteritis (10.5%, 3.5%, 5.3%). In the tiotropium 5 μg, 2.5 μg and placebo groups, 8.8%, 5.3% and 5.3% of patients reported drug-related AEs; 3.5%, 3.5% and 15.8% reported serious AEs. Asthma worsening was the only serious AE reported in more than one patient. At Week 52, adjusted mean trough FEV1 and trough PEFR responses were significantly higher with tiotropium 5 μg (but not 2.5 μg) versus placebo. ACQ-7 responder rates were higher with tiotropium 5 μg and 2.5 μg versus placebo at Week 24.

Conclusions: The long-term tiotropium Respimat safety profile was comparable with that of placebo Respimat, and associated with mild to moderate, non-serious AEs in patients with symptomatic asthma despite ICS±LABA therapy. Compared with placebo, tiotropium 5 μg, but not 2.5 μg, significantly improved lung function and symptoms, supporting the long-term efficacy of the 5 μg dose.

Trial registration: ClinicalTrials.gov NCT01340209.

Conflict of interest statement

Competing Interests: The authors have the following interests: this work was supported by Boehringer Ingelheim, the employer of Michael Engel and Petra Moroni-Zentgraf. Satoko Kunimitsu and Wataru Sakamoto are employed by Nippon Boehringer Ingelheim Co., Ltd. All were involved in the study design, analysis and interpretation of the manuscript. Tiotropium Respimat is a Boehringer Ingelheim product. Ken Ohta has served on advisory boards for Boehringer Ingelheim and received lecture fees from Boehringer Ingelheim, GlaxoSmithKline, AstraZeneca, MSD, Novartis, Astellas, Kyorin and Ono. Masakazu Ichinose has served on advisory boards for Boehringer Ingelheim Pharma GmbH and received lecture fees from Nippon Boehringer Ingelheim Co., Ltd. Yuji Tohda has received lecture fees from Nippon Boehringer Ingelheim Co., Ltd, Kyorin, MSD and TEIJIN Pharma. Mitsuru Adachi has received lecture honoraria from Boehringer Ingelheim, GlaxoSmithKline, Novartis, Astellas, Kyorin, Torii and Kyowa Hakko Kirin Pharma. There are no further patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

Figures

Fig 1. CONSORT diagram.

Fig 2. Trough FEV1 response for patients receiving tiotropium Respimat add-on or placebo Respimat add-on.

Trough FEV1 response for patients receiving tiotropium Respimat or placebo Respimat as add-on to maintenance therapy of inhaled corticosteroids, with or without a long-acting β2-agonist, over the 52-week study period (full analysis set). Tiotropium Respimat and placebo Respimat dosed once-daily in the evening. Common baseline mean (standard deviation) at visit 2 (randomisation), mL: 2285 (645). FEV1, forced expiratory volume in 1 second.

Fig 3. In-clinic trough PEFR response for patients receiving tiotropium Respimat add-on or placebo Respimat add-on.

In-clinic trough PEFR response for patients receiving tiotropium Respimat or placebo Respimat as add-on to maintenance therapy of inhaled corticosteroids, with or without a long-acting β2-agonist, over the 52-week study period (full analysis set). Tiotropium Respimat and placebo Respimat dosed once-daily in the evening. Baseline mean (standard deviation) at visit 2 (randomisation), L/min: 371.0 (120.2). PEFR, peak expiratory flow rate.