Efficacy of umeclidinium bromide and vilanterol (UMEC/VI) for the slowing of chronic obstructive pulmonary disease (COPD) development in smokers

Cigarette smoking produces inflammation in small airways and development of emphysema in about 20-40% of susceptible individuals. The presence of small airway pathology leads to uneven distribution of ventilation in the lungs as well as excessive airway closure which may produce excessive biomechanical stress leading to further progression of pathology. These changes produce a greater than the normal age-related rate of decline of lung function as measured by the FEV1 and this can lead to the clinical features of COPD. We hypothesise that: 1. The early pathological changes can be identified by tests derived from the multiple breath nitrogen washout (MBNW) and these tests may identify individuals at risk of developing COPD. 2. Bronchodilatation will reduce airway closure and normalise the distribution of ventilation thereby reducing biomechanical stress and may thus lead to reduction in the rate of decline of lung function. The primary objective is to asses the rate of decline of FEV1 during and at the end of a 12 month intervention with or without active study treatment. The secondary objective is to assess the change from baseline in small airway function and ventilation heterogeneity, change in FOT, and the effect of bronchodilators on spirometry, DLCO and BCSS symptoms. The study is a double-blind, placebo controlled, parallel design study comparing: 1. Umeclidinium bromide with vilanterol (Anoro) via the Ellipta dry powder inhalation device at a dose of 62.5mcg/25mcg once daily with 2. Matched placebo once daily A total of 100 participants will be randomised from four centres in NSW, Australia. Subject will attend clinic visits at screening, randomisation, 26 weeks and 52 weeks. Monthly telephone calls will be made to each participant to record adverse events, concomitant medications, adherence to medication and current smoking status. Study measurements will include spirometry pre and post bronchodilator, body plethysmography to measure lung volumes and DLCO, MBNW, FOT and BCSS symptoms. The student t-test will be used to compare the annual rate of decline of the FEV1 between the active treatment and placebo groups. Statistical methods for analysing the secondary outcomes will be by a linear regression model adjusted for baseline measurements if applicable