PGx_213170_GSK3772847_PHNA_Exploratory analysis of efficacy on sST2 levels in study 207597

Trial description: The purpose of this study is to describe the effect of genetic variation on free baseline sST2 levels and on change from baseline in free and total sST2 levels to aid in understanding target engagement in study 207597.GSK3772847 is an IgG2σ monoclonal antibody currently in clinical development for the treatment of asthma. In study 207597 eligible subjects were randomized to receive either GSK3772847 or placebo administered via intravenous (IV) route every 4 weeks in addition to open-label background therapy of fluticasone propionate/ salmeterol (FP/Sal) 500/50 micrograms (mcg) twice daily. During the treatment phase, the background therapy was switched to FP 500 mcg for 2 weeks and the dose of FP was reduced by approximately 50 percent at every 2 weeks until complete FP discontinuation.The following analysis populations are drawn from modified Intent-to-Treat (mITT) populations from 207597. The mITT population consists of all randomized participants who took at least 1 dose of study treatment.• Genetics Baseline: Subjects in the Modified Intent-to-treat (mITT) population of 207597 who took at least 1 dose of study treatment (GSK3772847 or placebo).• Genetics GSK3772847: Subjects in Genetics Baseline treated with at least one dose of GSK3772847• Genetics Placebo: Subjects in Genetics Baseline treated with at least one dose of Placebo. Note: this population will be analyzed to aid in the interpretation of results using the Genetics GSK3772847 populationThree endpoints will be examined. Following the approach in the clinical statistical analysis in study 207957, these endpoints will be log transformed for analysis:• Free sST2 levels at baseline• Change from baseline in free sST2 levels during treatment (weeks 4, 8, 12, 16)• Change from baseline in total sST2 levels during treatment (weeks 4, 8, 12, 16)The effect of 12 candidate variants in IL1RL1 and IL33 on baseline free sST2 levels and on change from baseline in free and total sST2 levels will be examined. 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 will be used to 1) provide genetics data on candidate variants and 2) be used in generation of genetic ancestry principal components (PCs). Data on one candidate variant will be generated using a Taqman assay as it will not be covered within the PMRA data.The genetic main effect on free sST2 baseline levels in the Genetics Baseline population will be conducted testing for an additive genetic effect by variant using a generalized linear regression. Covariates will include genetic ancestry PCs and eosinophil strata at baseline (<150 cells/ul vs >=150 cells/ul). Additional covariates such as age, sex and BMI may be evaluated for inclusion in the model. The genetic main effect on change from baseline free and total sST2 levels (log transformed) will be conducted testing for an additive genetic effect by variant using a mixed model with repeated measures. Covariates will include genetic ancestry PCs, baseline free or total sST2 levels and eosinophil strata at baseline (<150 cells/ul vs >=150 cells/ul). Additional covariates such as age, sex and BMI may be evaluated for inclusion in the model.The significance threshold for candidate variants will be 0.0042 (0.05/12 variants). No adjustment will be made for multiple endpoints. Assuming a minor allele frequency of 0,15, there is 80% power to detect an effect of >=0.65 standard deviation (SD) units for baseline free sST2 levels and >=0.95 SD units for change from baseline in sST2 levels.