Effect of 12 weeks of once-daily tiotropium/olodaterol on exercise endurance during constant work-rate cycling and endurance shuttle walking in chronic obstructive pulmonary disease

François Maltais, Denis O'Donnell, Juan Bautista Gáldiz Iturri, Anne-Marie Kirsten, Dave Singh, Alan Hamilton, Kay Tetzlaff, Yihua Zhao, Richard Casaburi, François Maltais, Denis O'Donnell, Juan Bautista Gáldiz Iturri, Anne-Marie Kirsten, Dave Singh, Alan Hamilton, Kay Tetzlaff, Yihua Zhao, Richard Casaburi

Abstract

Background: The TORRACTO® study evaluated the effects of tiotropium/olodaterol versus placebo on endurance time during constant work-rate cycling and constant speed shuttle walking in patients with chronic obstructive pulmonary disease (COPD) after 12 weeks of treatment.

Methods: The effects of once-daily tiotropium/olodaterol (2.5/5 and 5/5 μg) on endurance time during constant work-rate cycle ergometry (CWRCE) after 6 and 12 weeks of treatment were compared with placebo in patients with COPD in a randomized, double-blind, placebo-controlled, parallel-group clinical trial. Endurance time during the endurance shuttle walk test (ESWT) after 6 and 12 weeks of treatment was also evaluated in a subset of patients.

Results: A total of 404 patients received treatment, with 165 participating in the ESWT substudy. A statistically significant improvement in endurance time during CWRCE was observed after 12 weeks (primary endpoint) with tiotropium/olodaterol 5/5 µg [14% ( p = 0.02)] but not with tiotropium/olodaterol 2.5/5 µg [9% ( p = 0.14)] versus placebo. In the ESWT substudy, a trend to improvement in endurance time during ESWT after 12 weeks (key secondary endpoint) was observed with tiotropium/olodaterol 5/5 µg [21% ( p = 0.055)] and tiotropium/olodaterol 2.5/5 µg [21% ( p = 0.056)] versus placebo.

Conclusion: Tiotropium/olodaterol 5/5 µg improved endurance time during cycle ergometry versus placebo, with a strong tendency to also improve walking endurance time. [ ClinicalTrials.gov identifier: NCT01525615.].

Keywords: COPD; bronchodilator; constant work-rate cycling; endurance shuttle walking; olodaterol; tiotropium.

Conflict of interest statement

Conflict of interest statement: FM has received research support and speaker fees from AstraZeneca, Novartis, and Grifols, and research support, advisory board participation, and speaker fees from Boehringer Ingelheim and GlaxoSmithKline. DO’D has received research grants via his institution from AstraZeneca, Boehringer Ingelheim, and GlaxoSmithKline, and has served on speaker bureaus, consultation panels, and advisory boards for Almirall, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Pfizer. JBGI has nothing to disclose. A-MK has received payment for lectures from Boehringer Ingelheim, AstraZeneca, and Novartis, and her institution has received compensation for the conduct of clinical studies from AstraZeneca, Boehringer Ingelheim, Roche, GlaxoSmithKline, Novartis, Chiesi, Takeda, Bayer, Sterna Biologicals, Johnson & Johnson, and Sanofi. DS has received personal fees from Apellis, Cipla, Genentech, Peptinnovate, and SkyePharma, and grants and personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Glenmark, Merck, Mundipharma, Novartis, Pfizer, Pulmatrix, Teva, Theravance, and Verona. RC has received personal fees from Sunovion and Theravance, and grants and personal fees from Boehringer Ingelheim, AstraZeneca, and Astellas. AH, KT, and YZ are employees of Boehringer Ingelheim.

Figures

Figure 1.
Figure 1.
Study design. *Cycle ergometry testing; $endurance shuttle walk test; ‡primary endpoint assessment. R, randomization.
Figure 2.
Figure 2.
CONSORT diagram. CONSORT, Consolidated Standards of Reporting Trials; O, olodaterol; T, tiotropium.
Figure 3.
Figure 3.
Geometric mean exercise endurance time during constant work-rate cycle ergometry after 6 and 12 weeks. *Geometric mean results are reported as the primary analysis based on log10-transformed data; week 6 data are not included in hierarchical testing sequence and should be considered descriptive only. Common geometric mean baseline EET: 443.0 s. Placebo, n = 121; T/O 2.5/5 μg, n = 129; T/O 5/5 μg, n = 135. EET, exercise endurance time; O, olodaterol; SE, standard error; T, tiotropium.
Figure 4.
Figure 4.
Mean inspiratory capacity (a) and slope of intensity (b) of breathing discomfort after 12 weeks. Mean baseline IC: pre-exercise, 2397 ml; isotime, 2131 ml; end-exercise, 2111 ml. T/O 2.5/5 µg versus placebo, p = 0.0218; T/O 5/5 µg versus placebo, p = 0.0598. IC, inspiratory capacity; O, olodaterol; SE, standard error; T, tiotropium.
Figure 5.
Figure 5.
Geometric mean endurance shuttle walk test endurance time after 6 and 12 weeks in the endurance shuttle walk test subgroup. *Geometric mean results reported as primary analysis based on log10-transformed data; week 6 data are not included in hierarchical testing sequence and should be considered descriptive only. Common geometric mean baseline ESWT endurance time: 311.2 s. Placebo, n = 50; T/O 2.5/5 μg, n = 56; T/O 5/5 μg, n = 59. ESWT, endurance shuttle walk test; O, olodaterol; SE, standard error; T, tiotropium.

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