QVA149

FEV1 was measured with spirometry conducted according to internationally accepted standards. The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time over an entire day (AUC 0-24h). A positive change from baseline indicates improvement.

Inspiratory capacity (IC) will be measured with spirometry conducted according to internationally accepted standards. The mean of 3 acceptable measurements will be calculated and reported in liters. In this cross-over trial, we had two baselines collected at day 1 and collected at day 36. From the IC measurements collected on either Day 22 or 57, respectively, the appropriate baseline measurements were subtracted - so either Day 22-Day1 or Day 57-Day36

Average physical activity level is defined by average daily activity-related energy consumption \[Kcal/day\], measured via Actinography device. In this cross-over trial, we had two baselines collected at day 1 and collected at day 36. From the activity measurements collected on either Day 22 or 57, respectively, the appropriate baseline measurements were subtracted - so either Day 22-Day1 or Day 57-Day36

COPD exacerbations starting between first dose and one day after last treatment are included. COPD exacerbations that occurred within 7 days of each other are collapsed as one event. Estimates are from a generalized linear model assuming a negative binomial distribution with terms for treatment, baseline total symptom score, baseline COPD exacerbation history (i.e. number of COPD exacerbations during the past 12 months prior to study), smoking status at screening, ICS use at screening, airflow limitation severity, and region. As the offset variable log(exposure time in years) was used.

Pulmonary function assessments were performed using centralized spirometry according to international standards. Baseline FEV1 was defined as the average of the pre-dose FEV1 measured at -45 minutes (min) and -15 min at day 1. A mixed model for repeated measures (MMRM), used for this analysis, included terms of treatment, baseline FEV1 measurements, smoking status at baseline, baseline inhaled corticosteroid (ICS) use, region, baseline FEV1 \* visit interaction, and visit, treatment \* visit interaction. Missing values of FEV1 AUC0-12 at Day 1 and Week 12 will not imputed. The trapezoidal rule was used to calculate FEV1 AUC and then normalized to the length of time.

Measurement of QVA149 110/50 μg o.d. to fluticasone/salmeterol 500/50 μg b.i.d. in terms of trough FEV1 (mean of 23 h 15 min and 23 h 45 min post QVA149 dose) following 26 weeks of treatment in patients with moderate to severe COPD.

Pulmonary function assessments were performed using centralized spirometry according to international standards. Baseline FEV1 was defined as the average of the pre-dose FEV1 measured at -45 minutes (min) and -15 min at day 1. A mixed model for repeated measures (MMRM), used for this analysis, included terms of treatment, baseline FEV1 measurements, smoking status at baseline, baseline inhaled corticosteroid (ICS) use, region, baseline FEV1 \* visit interaction, and visit, treatment \* visit interaction. Missing values of FEV1 AUC0-12 at Day 1 and Week 12 will not imputed. The trapezoidal rule was used to calculate FEV1 AUC and then normalized to the length of time.

The overall rate of serious adverse events reported from initiation through 30 days post last dose.

The overall rate of adverse events reported from initiation through 30 days post last dose.

Spirometry was conducted according to internationally accepted standards. Trough FEV1 is defined as the average of the 23 hour 15 minute and 23 hour 45 minute post-dose FEV1 readings measured at day 29, after 28 days of treatment. Mixed model: Trough FEV1 = treatment + baseline FEV1 + FEV1 reversibility components + baseline smoking status + baseline ICS use + country + center (country) + error. Center was included as a random effect nested within country.

SGRQ is a health related quality of life questionnaire consisting of 40 items in three areas: symptoms (respiratory symptoms and severity), activity (activities that cause or are limited by breathlessness) and impacts (social functioning and psychological disturbances due to airway disease). The total score is 0 to 100 with a higher score indicating poorer health status. For patients who completed the study but with missing SGRQ-C during treatment, the missing SGRQ-C were replaced by the last observation carried forward (LOCF). Symptom scores were expected to improve over treatment, therefore the replacement of missing values with earlier measurements did not result in overoptimistic imputation and this procedure could be regarded as conservative.

Total Transient Dyspnea Index (TDI) is part of the BDI/TDI questionnaire where participants indicated whether they improved or deteriorated since their Baseline Dyspnea Index (BDI). The BDI and TDI each had 3 domains: activities, tasks, and effort. BDI domains were rated from 0 (very severe) to 4 (none) and the rates summed for the total BDI score ranging from 0 to 12; the lower the score the worse the severity of dyspnea. TDI domains were rated from -6 (major deterioration) to 6 (major improvement) and the rates summed for the total TDI score ranging from -18 to 18. However, to ensure comparability with the TDI paper version, all TDI values were divided by 2 before the analysis. If data was missing or insufficient for any one of the domains a BDI/TDI was calculated. BDI = Baseline Dyspnea Index taken 75 min prior to the first dose in each treatment period. TDI = Transition Dyspnea Index taken after 6 weeks of treatment 75 min prior to the last dose in each treatment period.

An AE was the appearance or worsening of any undesirable sign, symptom, or medical condition occurring after starting the study drug even if the event was not considered to be related to study drug. Study drug includes the investigational drug under evaluation and the comparator drug or placebo that was given during any phase of the study. Adverse events starting on or after the time of the first inhalation of study drug were classified as a treatment emergent adverse event.

A Chronic Obstructive Pulmonary Disease (COPD) exacerbation was defined as a worsening of two or more of the following major symptoms for at least 2 consecutive days: dyspnea, sputum volume or sputum purulence OR a worsening of any 1 major symptom together with an increase in any 1 of the following minor symptoms for at least 2 consecutive days: sore throat, colds (nasal discharge and/or nasal congestion), fever without other cause, cough or wheezing. A COPD exacerbation was considered of moderate severity if treatment with systemic glucocorticosteroids or antibiotics or both was required and severe if hospitalization was required. An emergency room (ER) visit of longer than 24 hours was considered a hospitalization. Rate of moderate or severe exacerbations per year = total number of moderate or severe exacerbations / total number of treatment years

Adverse events are defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal lab finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. Serious adverse events are any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgments of the investigators represent significant hazards.