A Randomized, Placebo Controlled, Double‐Blind, Crossover Trial of the Effect of Stiolto Respimat on Neuromuscular Performance During Cycling in COPD

Abstract

RATIONALEExercise intolerance in COPD patients is associated with reduced inspiratory reserve volume (IRV) and dyspnea. The mechanisms by which exercise is limited are unknown. Intolerance may occur due to: limiting symptoms (e.g. pain, dyspnea); reduced neural motor activation and/or excitability (activation fatigue, AF); reduced muscular power for a given muscle activation (muscle fatigue, MF). The sum of activation and muscle fatigue describes overall exercise‐induced reduction in neuromuscular performance, and is termed performance fatigue (PF; watts). In moderate to severe COPD, PF is associated negatively with resting FEV1/FVC and positively with peak exercise VE/MVV. We postulated that this was due to greater activation fatigue when IRV was low. Thus, this study determined the effect of bronchodilation on mechanisms limiting cycling exercise in COPD. We hypothesized that, compared with placebo, combination LAMA+LABA therapy would increase pre‐exercise FEV1, increase isotime IRV during exercise, leading to reduced performance fatigue and prolonged exercise endurance.METHODSFourteen COPD patients (4 female) volunteered for this single center, randomized, placebo controlled, double blind, crossover trial of once‐daily Stiolto Respimat (tiotropium bromide and olodaterol) (ClinicalTrials.gov: NCT02845752). Pulmonary function and cardiopulmonary exercise responses were assessed before and after 1 week of treatment, with 2 weeks washout between treatment periods. PF (and its subcomponents, AF and MF) were assessed using a 4‐second maximal isokinetic cycling effort (Cannon et al. J Appl Physiol 121:1365–1373, 2016) at baseline, isotime and intolerance during a constant work rate exercise test at 80% peak incremental power. Isotime was the shorter exercise duration of the two treatment conditions. Muscle activity was assessed by surface EMG on 5 leg muscles. Significance was assessed in Box‐Cox transformed data using a univariate general linear model ANOVA with treatment as fixed factor and subject as random factor.RESULTSPatients were 64[58,72] years old with FEV1 67[56,75]% predicted at baseline (median[IQR]). Peak incremental exercise responses included: 79[70,99] W; VO2peak 14.0[12.9,18.0] mL.min−1.kg−1; IRV 0.59[0.34,0.95] L. Pre‐exercise FEV1 was significantly greater with LAMA+LABA vs placebo (1.81[1.58,1.98] vs. 1.72[1.29,1.99] L; p=0.006). However, IRV at isotime (0.54[0.23,0.90] vs. 0.46[0.29,0.85] L; p=0.391), PF at isotime (76.1[45.9,103.7] vs 68.5[54.0,116.6] W; p=0.248) and constant work rate endurance time (297[253,351] vs 274[222,326] s; p=0.228) were not significantly different between LAMA+LABA vs. placebo.CONCLUSIONA modest (~95 mL) FEV1 increase in following 1 week of combination LAMA+LABA treatment did not detectably alleviate neuromuscular performance fatigue or enhance cycle exercise tolerance in moderate to severe COPD patients.Support or Funding InformationBoehringer Ingelheim, Investigator Initiated Study 1237.55