A randomized, parallel-group study to evaluate the efficacy of umeclidinium/vilanterol 62.5/25 µg on health-related quality of life in patients with COPD

Thomas M Siler,1 Alison C Donald,2 Dianne O’Dell,2,3 Alison Church,2 William A Fahy4 1Midwest Chest Consultants, PC, St Charles, MO, 2GSK, Research Triangle Park, NC, USA; 3Pearl Therapeutics, Inc., Durham, NC, USA; 4GSK, Respiratory Medicines Development Centre, Stockley Park, Middlesex, UK Background: The combination of the inhaled muscarinic antagonist umeclidinium (UMEC) with the long-acting β2-agonist vilanterol (VI) has been shown to provide significant improvements in lung function compared with UMEC, VI, or placebo (PBO) in patients with chronic obstructive pulmonary disease (COPD). This study was specifically designed to support these findings by assessing health-related quality of life and symptomatic outcomes in a similar population. Methods: This was a 12-week multicenter, randomized, double-blind, parallel-group, placebo-controlled study. Eligible patients were randomized 1:1 to receive once-daily UMEC/VI 62.5/25 µg (via ELLIPTA® dry powder inhaler) or PBO for 12 weeks. The primary endpoint was St George’s Respiratory Questionnaire (SGRQ) total score at day 84. Secondary efficacy endpoints included rescue albuterol use (puffs/day) over weeks 1–12 and trough forced expiratory volume in 1 second on day 84. Adverse events were also assessed. Results: A total of 496 patients were included in the intent-to-treat population in the UMEC/VI (n=248) and PBO (n=248) treatment groups. UMEC/VI 62.5/25 µg provided a significant and clinically meaningful improvement in SGRQ total score at day 84 versus PBO (difference between treatments in SGRQ total score change from baseline: -4.03 [95% confidence interval {CI}: -6.28, -1.79]; P<0.001). UMEC/VI 62.5/25 µg resulted in a statistically significant reduction in rescue albuterol use versus PBO (-0.7 puffs/day [95% CI: -1.1, -0.4]; P<0.001). UMEC/VI 62.5/25 µg provided a significant and clinically meaningful improvement in trough forced expiratory volume in 1 second on day 84 versus PBO (122 mL [95% CI: 71, 172]; P<0.001). The incidence of adverse events was similar between treatments (32% and 30% of patients in the UMEC/VI 62.5/25 µg and PBO groups, respectively). Conclusion: The results of this study demonstrate that treatment with UMEC/VI 62.5/25 µg provides clinically important improvements in SGRQ and rescue medication use versus PBO in patients with moderate-to-very-severe COPD. Keywords: COPD, umeclidinium, vilanterol, health-related quality of life, SGRQ, long-acting bronchodilato

Developmentally regulated interactions of human thymocytes with different laminin isoforms

The gene family of heterotrimeric laminin molecules consists of at least 15 naturally occurring isoforms which are formed by five different α, three β and three γ subunits. The expression pattern of the individual laminin chains in the human thymus was comprehensively analysed in the present study. Whereas laminin isoforms containing the laminin α1 chain (e.g. LN-1) were not present in the human thymus, laminin isoforms containing the α2 chain (LN-2/4) or the α5 chain (LN-10/11) were expressed in the subcapsular epithelium and in thymic blood vessels. Expression of the laminin α4 chain seemed to be restricted to endothelial cells of the thymus, whereas the LN-5 isoform containing the α3 chain could be detected on medullary thymic epithelial cells and weakly in the subcapsular epithelium. As revealed by cell attachment assays, early CD4(−) CD8(−) thymocytes which are localized in the thymus beneath the subcapsular epithelium adhered strongly to LN-10/11, but not to LN-1, LN-2/4 or LN-5. Adhesion of these thymocytes to LN-10/11 was mediated by the integrin α6β1. During further development, the cortically localized CD4(+) CD8(+) thymocytes have lost the capacity to adhere to laminin-10/11. Neither do these cells adhere to any other laminin isoform tested. However, the more differentiated single positive CD8(+) thymocytes which were mainly found in the medulla were able to bind to LN-5 which is expressed by medullary epithelial cells. Interactions of CD8(+) thymocytes with LN-5 were integrin α6β4-dependent. These results show that interactions of developing human thymocytes with different laminin isoforms are spatially and developmentally regulated