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Effects of combined tiotropium/olodaterol on inspiratory capacity and exercise endurance in COPD.

ABSTRACT: Two replicate, double-blind, 6-week, incomplete-crossover studies (MORACTO 1 and 2) assessed the effects of tiotropium/olodaterol on inspiratory capacity and exercise endurance time in patients with moderate to severe chronic obstructive pulmonary disease.For each patient, four of five treatments were administered once daily for 6 weeks, with a 21-day washout between treatments: tiotropium/olodaterol 2.5/5 µg or 5/5 µg, tiotropium 5 µg, olodaterol 5 µg or placebo, all via the Respimat inhaler. Primary outcomes were inspiratory capacity prior to exercise and exercise endurance time during constant work-rate cycle ergometry to symptom limitation at 75% of peak incremental work rate after 6 weeks (2 h post-dose).295 and 291 patients were treated in MORACTO 1 and 2, respectively. Tiotropium/olodaterol 2.5/5 and 5/5 µg provided significant improvements in inspiratory capacity versus placebo and monotherapies (p<0.0001), and significant improvements in exercise endurance time versus placebo (p<0.0001). Intensity of breathing discomfort was reduced following both doses of tiotropium/olodaterol versus placebo (p<0.0001).Once-daily tiotropium/olodaterol yielded improvements in lung hyperinflation versus placebo and statistically significant improvements versus monotherapies. Tiotropium/olodaterol also showed improvements in dyspnoea and exercise tolerance versus placebo but not consistently versus monotherapies.

SUBMITTER: O'Donnell DE

PROVIDER: S-EPMC5898947 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Effects of combined tiotropium/olodaterol on inspiratory capacity and exercise endurance in COPD.

O'Donnell Denis E DE Casaburi Richard R Frith Peter P Kirsten Anne A De Sousa Dorothy D Hamilton Alan A Xue Wenqiong W Maltais François F

The European respiratory journal 20170419 4

Two replicate, double-blind, 6-week, incomplete-crossover studies (MORACTO 1 and 2) assessed the effects of tiotropium/olodaterol on inspiratory capacity and exercise endurance time in patients with moderate to severe chronic obstructive pulmonary disease.For each patient, four of five treatments were administered once daily for 6 weeks, with a 21-day washout between treatments: tiotropium/olodaterol 2.5/5 µg or 5/5 µg, tiotropium 5 µg, olodaterol 5 µg or placebo, all <i>via</i> the Respimat inh ...[more]

PMID: 28424359

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Project description:Exercise intolerance in chronic obstructive pulmonary disease (COPD) is associated with dyspnea, reduced inspiratory capacity (IC) and occurs with a neuromuscular "power reserve," i.e., an acute ability to increase isokinetic locomotor power. This power reserve is associated with resting forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) suggesting that treatments to target pulmonary function may protect neuromuscular performance and extend whole body exercise in COPD. We, therefore, tested whether combination long-acting β-agonist and muscarinic antagonist bronchodilator therapy [long-acting muscarinic antagonist (LAMA) + long-acting β-agonist (LABA); Stiolto Respimat] would ameliorate the decline in neuromuscular performance and increase endurance time during constant power cycling at 80% peak incremental power. Fourteen patients with COPD (4 female; 64 [58, 72] yr; FEV1 67% [56%, 75%] predicted; median [25th, 75th percentile]) participated in a randomized, placebo-controlled crossover trial (NCT02845752). Pulmonary function and cardiopulmonary exercise responses were assessed before and after 1 wk of treatment, with 2 wk washout between conditions. Performance fatigue was assessed using an ∼4-s maximal isokinetic cycling effort at preexercise, isotime, and intolerance. Isotime was the shorter exercise duration of the two treatment conditions. Significance was assessed using ANOVA with treatment as fixed factor and subject as random factor. FEV1 was greater with LAMA + LABA versus placebo (1.81 [1.58, 1.98] L vs. 1.72 [1.29, 1.99] L; P = 0.006), but IC at isotime, performance fatigue at isotime, and constant power endurance time were not different between conditions (each P > 0.05). A modest (∼95 mL) increase in FEV1 following 1 wk of combination LAMA + LABA treatment did not alleviate neuromuscular performance fatigue or enhance cycle exercise tolerance in patients with mild-to-severe COPD with largely preserved "static" lung volumes.NEW & NOTEWORTHY Bronchodilation is known to increase forced expiratory volume in 1 s (FEV1) and reduce hyperinflation in COPD. In a randomized controlled trial, we investigated whether combined inhaled long-acting β-agonist and muscarinic antagonist would alleviate maximal voluntary neuromuscular performance fatigue or enhance maximal muscle activation during cycling in patients with COPD. Despite increased FEV1, combination bronchodilator therapy did not reduce neuromuscular performance fatigue or enhance muscle activity or exercise tolerance in patients with mild-to-severe COPD.

Project description:BackgroundAs lung function declines rapidly in the early stages of chronic obstructive pulmonary disease (COPD), the effects of bronchodilators in patients with moderate disease and those who have not previously received maintenance therapy are of interest. OTEMTO® 1 and 2 were two replicate, 12-week, Phase III studies investigating the benefit of tiotropium + olodaterol on lung function and quality of life in patients with moderate to severe disease. Post hoc analyses were performed to assess the benefits for patients according to disease severity and treatment history.MethodsFour subgroup analyses were performed: Global initiative for chronic Obstructive Lung Disease (GOLD) 2/3, GOLD A/B/C/D, treatment naive/not treatment naive and receiving inhaled corticosteroids (ICS) at baseline/not receiving ICS at baseline. Primary end points were change in forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 3 h response, change in trough FEV1 and St George's Respiratory Questionnaire (SGRQ) total score. Transition Dyspnoea Index (TDI) focal score was a secondary end point, and SGRQ and TDI responder analyses were further end points; all were assessed at 12 weeks.ResultsIn all subgroups, patients receiving tiotropium + olodaterol responded better overall than those receiving tiotropium monotherapy. Improvements with tiotropium + olodaterol over placebo or tiotropium monotherapy were noted across GOLD 2/3 and GOLD A/B/C/D; however, improvements in SGRQ total score were most evident in the GOLD B subgroup. Moreover, lung-function outcomes were generally greater in those patients who had been receiving previous long-acting bronchodilator and/or ICS maintenance treatment.ConclusionsThese data suggest that tiotropium + olodaterol should be considered as a treatment option in patients with moderate COPD who are initiating maintenance therapy, as well as those with more severe disease.Trial registrationClinicalTrials.gov: NCT01964352 and NCT02006732 .

Project description:PurposeThis study aims to assess the effect of inspiratory muscle training (IMT) combined with endurance training (ET) on balance in patients with chronic obstructive pulmonary disease (COPD).MethodsWe studied 32 male patients (62 ± 6 years) with moderate to very severe COPD. They were randomly assigned to an experimental group (IMT+ET) n = 16 or a control group (ET) n = 16 with similar characteristics. The evaluations were carried out at inclusion and after eight weeks of the training period. Functional balance was assessed by the Berg Balance Scale (BBS), the Timed-up and Go (TUG), the Single Leg Stance test (SLS), and the Activities-specific Balance Confidence (ABC) scale. The strength of the inspiratory muscles (PImax) was assessed by maximal inspiratory mouth pressure. Functional exercise performance was assessed by the 6 minutes walking test (6MWT). IMT program consists in performing two daily sets of 30 inspirations with 50% of PImax increased by 10% every two weeks. ET program consists in performing 30 min treadmill exercise at 60% to 80% of the average speed achieved during the 6MWT three days per week.ResultsAfter the training period, the experimental group demonstrated greater improvements in BBS (IMT+ET vs. ET; p = 0.019), and in ABC (IMT+ET vs. ET; p = 0.014). However, no significant differences between groups were observed for TUG, SLS, and 6MWT. There was a significant difference between groups in PImax (IMT+ET vs. ET; p = 0.030). Significant moderate correlations were obtained between ΔPImax and ΔBBS for both groups (IMT+ET: r = 0.624, p = 0.010; ET r = 0.550, p = 0.027) as well as for ΔABC but only in the experimental group (IMT+ET: r = 0.550, p = 0.027).ConclusionCompared to ET alone, the results suggest that IMT combined with ET enhances inspiratory muscle function and functional balance according to BBS and ABC in patients with COPD. We suggest that inspiratory muscle training might be introduced as additional training to pulmonary rehabilitation programs aimed at improving balance in COPD patients.Trial registrationThe trial registry name: Clinical Trials; Registration number: NCT04084405; URL: https://clinicaltrials.gov/ct2/show/NCT04084405.

Project description:BackgroundLong-acting bronchodilators are the cornerstone of pharmacologic treatment of COPD. The new combination of long-acting muscarinic antagonist (LAMA) tiotropium (TIO) and long acting beta-agonists (LABA) olodaterol (OLO) has been introduced as fist line therapy for COPD. This article analyses the evidence of efficacy and safety of the TIO/OLO combination.MethodsA systematic review and metaanalysis of randomized controlled trials (RCT) with a period of treatment of at least 6 weeks, in patients with COPD confirmed by spirometry, comparing combined treatment with TIO/OLO (approved doses only), with any of the mono-components or any other active comparator administered as an inhalator.ResultsA total of 10 Randomized controlled trials (RCT) were identified (N = 10,918). TIO/OLO significantly improved trough FEV1 from baseline to week 12 versus TIO, OLO and LABA/ICS (0.06 L, 0.09 L and between 0.04 and 0.05 L, respectively). TIO/OLO improved transitional dyspnea index (TDI) and St. George's Respiratory Questionnaire (SGRQ) compared with mono-components, with patients more likely to achieve clinically important improvements in TDI (risk ratio [RR]: 1.17, 95% confidence interval [CI]: [1.07, 1.28] versus TIO and RR: 1.14, 95%CI: [1.01, 1.28] versus OLO) and in SGRQ (RR: 1.21, 95%CI: [1.12, 1.30] versus TIO and RR: 1.28, 95%CI: [1.18, 1.40] versus OLO). Patients treated with TIO/OLO showed a significant reduction in the use of rescue medication and no significant differences in frequency of general and serious adverse events were observed between TIO/OLO and mono-components.ConclusionsTreatment with TIO/OLO provided significant improvements in lung function versus mono-components and LABA/ICS with more patients achieving significant improvements in dyspnea and health status. No differences in adverse events were observed compared with other active treatments.Clinical trial registrationPROSPERO register of systematic reviews ( CRD42016040162 ).

Dataset Information

Effects of combined tiotropium/olodaterol on inspiratory capacity and exercise endurance in COPD.

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Effects of combined tiotropium/olodaterol on inspiratory capacity and exercise endurance in COPD.

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