PGx_208826_Confirmatory PGx evaluation of IL13 association with GSK2285997 (fluticasone furoate/vilanterol) efficacy in inadequately controlled asthma pts in study 205715

Trial description: The purpose of this study is to confirm the association of the rs2243204 T allele with mean change from baseline in trough Forced Expiratory Volume (FEV1) (week 24) in subjects with asthma treated with FF/VI in study 205715. The association of the rs2243204 T allele to trough FEV1 was first identified in study 206822. In study 206822, an exploratory pharmacogenetic investigation of efficacy response to FF/VI in subjects with asthma enrolled in 5 other studies (HZA106827, HZA106829, HZA106837, HZA113091 and HZA116863) was conducted.Study 205715 is a phase IIIA, randomized, double-blind, active controlled 6-arm parallel group, global multicentre study evaluating FF/umeclidinium bromide (UMEC)/VI (100/31.25/25, 100/62.5/25, 200/31.25/25 and 200/62.5/25 mcg) versus FF/VI (100/25 and 200/25 mcg), dosing given once daily in the morning. The duration of the treatment period is variable but will be a minimum of 24 weeks and a maximum of 52 weeks. The study completion date will be determined based on the date of last subject randomized in the study, who will be on the double-blinded treatment for 24 weeks with a follow up visit 1-week post treatment.The null hypothesis to be tested is that genetic variation at rs2243204 does not have a positive effect size on mean change from baseline in trough FEV1 (week 24) in subjects with asthma treated with FF/VI.Subjects in the ‘Genetics’ population will be those who received at least one dose of FF/VI, provided written informed consent for genetics research, were successfully genotyped, and for whom change in baseline FEV1 data through week 24 in 205715 is available.Mean change from baseline in trough FEV1 (week 24) will be analyzed as the endpoint in study 205715.The genetic variant rs2243204 T allele will be analyzed for effect on mean change from baseline FEV1 data at week 24. The Affymetrix Precision Medicine Research Array (PMRA) in conjunction with the phase 3 haplotype reference panel from the 1000 Genomes Project will be used to impute genetic variants across the genome. This analysis will be used to confirm earlier findings of the association of the candidate variant with the endpoint in study 206822.The genetic main effect of candidate variant rs2243204 T allele on mean change from baseline FEV1 at week 24 will be tested assuming an additive genetic effect, using linear regression. Covariates may include dose, sex, age, baseline value (change trough FEV1), region, and ancestry PCs. In addition, sensitivity analysis will be done using mixed model repeated measures (MMRM), on mean change from baseline of trough FEV1 at weeks 4, 12, and 24. Similar covariates as those used in the primary endpoint analysis will be used for sensitivity analysis.Candidate variant main positive effect, one-sided p≤0.05 will be used as statistical significance threshold.