Indacaterol 110µg/ Glycopyrronium 50µg (Ultibro®) Versus Tiotropium (Spiriva®) Alone to Reduce Exertional Dyspnea in Patients With Moderate to Severe COPD

The foundation of COPD therapy is to combine inhaled therapy to optimize benefits as it was done several years ago by associating short-acting β2-agonists and muscarinic antagonist. The recent availability of once-daily LABA/LAMA fixed combination products makes this therapeutic strategy even more appealing and appears as a promising treatment option in COPD. One relevant question regarding these new LABA/LAMA combinations is whether they provide superior benefits compared to a single agent. Once-daily LABA/LAMA fixed combinations consistently improves lung function compared to monotherapy. The key question is whether they provide superior efficacy to monotherapy on patient's oriented clinical outcomes, beyond lung function improvement. In regards, once-daily LABA/LAMA fixed combinations can reduce exacerbation rate and perception of dyspnea, further to what can be obtained with the monocomponents. Once-daily LABA/LAMA fixed combinations also improve exercise tolerance compared to placebo but whether they provide additional benefit over monotherapy is uncertain.

Dyspnea is the most troublesome symptom in COPD and it is felt that the main mechanism through which bronchodilators improve exercise tolerance is by reducing dyspnea. As such, dyspnea measurement appears a valid surrogate of exercise tolerance. One advantage of dyspnea measurement over the measurement of exercise endurance is that it does not require a maximal effort. In this regard, it may be a less noisy outcome than exercise duration. Dyspnea can be quantified during the 6-min walking test but pre and post-intervention comparisons are made difficult since the walking speed and thus the exercise stimulus is not controlled during the test. Another strategy to evaluate the effects of interventions on exertional dyspnea is to compare dyspnea at isotime while controlling the walking or cycling speed during the endurance shuttle walking test or the constant rate cycling test. One limitation of this approach is that pre and post intervention dyspnea measurement is not always obtained at the same time point since the duration of the test is variable. To overcome this problem, linear interpolation can be used to estimate of dyspnea. However, this approach is not as robust as when a "real" dyspnea score is directly obtained from the patients.

To circumvent these difficulties, the investigators have recently developed a strong and simple exercise methodology whose primary objective is to assess exertional dyspnea in patients with COPD: the 3-min constant rate shuttle walking test. During this test, which is a modification of the endurance shuttle walking test, patients are asked to walk around two cones set-up in a flat corridor and separated by 10m. An audio signal is used to impose the walking speed and the test ends at a fixed duration of 3 minutes or until symptoms become intolerable. At pre-specified time point during the test, and at the end of the test (3 min), patients are asked to score their perception of dyspnea on a Borg scale. The feasibility and reproducibility of this test in providing a standardized physical stimulus and a measurable level of dyspnea in patients with moderate to severe COPD has been reported. In one study, the investigators also confirmed the responsiveness of this test to bronchodilation, reporting statistically and clinically significant reduction in Borg dyspnea score with ipratropium bromide compared to placebo.

Methodology:

The study will require 7 visits; the run-in and familiarization phase (visits #1-3), the treatment A phase (visits #4-5), and the treatment B phase (visits #6-7).