D Average e-RS dyspnea score during the remedy period Average e-RS total score for the duration of the remedy period Exploratory endpoints Alter in SP-D and CCl-18 from baseline to week 6 in a subset of patientsAbbreviations: precise, eXAcerbations of Chronic pulmonary illness tool; e-RS, eXACt-Respiratory Symptoms; SgRQ-C, St george’s Respiratory Questionnaire for COPD; SP-D, surfactant protein D; CCl-18, CC chemokine ligand-18.Other efficacy assessmentsSpirometry might be performed at all visits, while the St George’s Respiratory Questionnaire for COPD (SGRQ-C) along with the COPD Assessment Test (CAT) will be administered at baseline and week six, 23, and 52 (Figure 1). All through the study, patients will complete an electronic diary daily, which involves the EXACT-Patient-Reported Outcome (EXACT-PRO) questionnaire and added concerns on rescue medication use, sleep disturbance, and study medication compliance. Blood samples for the assessment of serum SP-D (sandwich ELISA; BioVendor, Brno, Czech Republic) and CCL-18 (sandwich ELISA; Myriad RBM, Austin, TX, USA) levels will likely be collected at baseline and week 6 in aInternational Journal of COPD 2015:submit your manuscript | www.dovepress.comDovepressPapi et alDovepressand a two-sided alpha of 0.05. Assuming 5 of individuals won’t be a part of the modified intent-to-treat population (the principal evaluation population), a total of 1,758 sufferers might be randomized (586 per therapy group). The study protocol was amended to raise the original sample size of 486 sufferers per group, as a planned interim review from the pooled exacerbation rate when 50 of sufferers had been recruited revealed a lower than anticipated event price. The main endpoint may be the annualized rate of moderate and severe exacerbations (defined per HCU criteria), analyzed using a adverse binomial regression model with fixed terms for treatment, FEV1 predicted category, variety of exacerbations inside the previous year category, smoking status, prior ICS use, and country, along with the logarithm of time on remedy as an offset variable. The secondary comparison (fluticasone propionate/formoterol 250/10 versus formoterol 12 ) are going to be analyzed in a confirmatory manner only when the main comparison (fluticasone propionate/formoterol 500/20 versus formoterol 12 ) is considerable at the 0.1450879-67-0 supplier 05 alpha level.1178566-52-3 Purity Only if each these major endpoint final results are important at the 0.PMID:23672196 05 level will the first important secondary endpoint (Table 1) be analyzed within a confirmatory manner making use of a Hochberg closed testing procedure. This stepwise strategy, ie, major comparison followed by secondary comparison along with the requirement for each to be substantial prior to proceeding to test the subsequent endpoint inside a confirmatory manner, will be employed hierarchically all through the essential secondary endpoints per the order listed in Table 1. Spirometry, SGRQ-C, CAT, and EXACT-Respiratory Symptoms (E-RS) might be analyzed working with repeated measures analysis of covariance (ANCOVA) with fixed terms for remedy, FEV1 predicted category, quantity of exacerbations inside the earlier year category, baseline value, smoking status, prior ICS use, country, time-point, and therapy by time-point interaction. The price of EXACT-PRO exacerbations will probably be analyzed employing the exact same model as the major endpoint evaluation. Adjustments inside the biomarker levels (SP-D and CCL-18) from baseline will probably be analyzed making use of a Kruskal allis test. The adjustments from baseline to week 6 will also be divided into quintiles t.