Kathryn WheelerOne treatment option recommended by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines for patients with symptomatic COPD at high risk for exacerbations is “triple therapy,” the combination of an inhaled corticosteroid (ICS)/long acting beta agonist (LABA) inhaler with a long acting muscarinic antagonist (LAMA).
Triple therapy is not uncommon in clinical practice, although lack of extensive research to date has resulted in only limited demonstration of benefit.
Two 12-week, randomized, double-blind, parallel-group studies assessed the efficacy and safety of daily inhaled doses of 62.5 mcg and 125 mcg of the LAMA umeclidinium vs. placebo, in COPD patients administered baseline therapy of fluticasone priopionate/salmeterol, an ICS/LABA combination inhaler, at 250 mcg/50 mcg inhaled twice daily.
Patients included in the study were at least 40 years old and had a history of COPD, defined by the American Thoracic Society/European Respiratory Society as including:
- A minimum 10 pack-years of tobacco use
- A ratio of forced expiratory volume in one second to forced vital capacity (FEV1/FVC) less than 0.7, assessed both before and after albuterol use
- A FEV1 of 70% or less of the predicted normal values
- A minimum score of 2 on the modified Medical Research Council Dyspnea Scale at the first study visit
Patients were excluded if they had been admitted for COPD or pneumonia within the 12 weeks before the first visit, or had a diagnosis of another respiratory disease.
All patients received four weeks of therapy with fluticasone propionate/salmeterol 250 mcg/50 mcg and then were randomized to receive umeclidinium 62.5 mcg, 125 mcg, or placebo once daily for 12 weeks. Albuterol use was permitted as a rescue therapy as needed any time during the study.
Trough FEV1 at day 85 assessed the primary outcome, improvement in lung function.
Secondary endpoints assessed lung function at various points throughout the study; before-and-after administration of study drug; use of albuterol rescue therapy; and the proportion of patients achieving a clinically relevant improvement in FEV1 and FVC.
Researchers assessed health-related quality-of-life measures for each patient, starting with a baseline after four weeks of fluticasone propionate/salmeterol administration.
The incidents of adverse effects and COPD exacerbations, as well as vital sign assessments, were tracked for safety and tolerability of umeclidinium use.
The primary outcome analysis was performed using data from all patients randomized to treatment who received at least one dose of study drug.
Overall, lung function improved in both trials for both doses of umeclidinium used compared to placebo.
Both studies demonstrated statistical improvements in trough FEV1 at day 85.
Use of umeclidinium for either dose in both studies improved a patient’s odds of achieving a trough FEV1 greater than baseline at any visit, an improved FEV1 ≥12% and 0.2 L above baseline any time within six hours after administration on day 1, improvements in FEV1 and trough FVC at each visit, and greater improvements in serial FEV1 measurements sustained for 24 hours. The magnitude of effect was similar for both doses of umeclidinium studied.
Overall, patients receiving either dose of umeclidinium had a larger proportion of rescue-free days from baseline compared to those receiving placebo in addition to the background therapy.
Treatment was well tolerated. Incidence of adverse effects was similar among treatment groups except for the incidence of serious adverse effects in study 2, which was higher among patients receiving placebo.
Headache and nasopharyngitis were the most commonly reported adverse effects among all treatment groups.
Vital-sign assessment indicated no clinically relevant treatment-related changes.
The results of these studies demonstrate that an improvement in lung function that is statistically significant as well as clinically meaningful may be obtained by adding umeclidinium therapy to inhaled ICS/LABA therapy.
Despite the demonstrated benefits on lung function, these studies did not demonstrate consistent benefit of umeclidinium over placebo added to a baseline ICS/LABA on health-related quality-of-life scores or exacerbations. The studies were designed to investigate impact on lung function and may not have been large enough or conducted long enough to assess these outcomes.
These studies support the rationale for triple therapy as further benefit to patients with COPD.
Source: Siler TM, Kerwin E, Singletary K, et al. Efficacy and safety of umeclidinium added to fluticasone propionate/salmeterol in patients with COPD: Results of two randomized, double-blind studies. COPD: Journal of Chronic Obstructive Pulmonary Disease (2016). 13:1, 1–10, DOI: 10.3109/15412555.2015.1034256.
Kathryn Wheeler is associate clinical professor, Pharmacy Practice, University of Connecticut School of Pharmacy, Storrs, Conn.