PGx7665: Exploratory Pharmacogenetic analysis of response to GSK2269557, a PI3 kinase delta inhibitor in patients from study 116678 with COPD

Trial description: GSK2269557 is a potent and highly selective inhaled Phosphoinositide 3-Kinase Delta (PI3Kd) inhibitor being developed as an anti-inflammatory and anti-infective agent for the treatment of inflammatory airways diseases. Clinical study PII116678 is a phase IIa randomized, double-blind (sponsor unblinded), placebo controlled, parallel-group, multicenter study to evaluate the efficacy and safety of GSK2269557 administered in addition to standard of care in adult subjects diagnosed with an acute exacerbation of COPD. Subjects included in study PII116678 were between 40 and 80 years of age with an acute exacerbation of COPD. Intended treatment duration was 84 days, high resolution computed tomography (HRCT) scans taken at Baseline, Day 12 and Day 28.This exploratory pharmacogenetic study includes subjects enrolled in GSK clinical study PII116678, who provided optional written consent, a blood sample for genetic research, and were successfully genotyped. Study samples will be genotyped by BioStorage Technologies/ Bioprocessing Solutions Alliance (Piscataway,NJ, USA) using the Affymetrix Axiom Biobank Genotyping Array with GlaxoSmithKline (GSK) custom content version 2. Haplotype reference data from the 1000 Genomes phase 3 project will be used to impute variants for analysis across the genome including the human leukocyte antigen (HLA) region. The purpose of this pharmacogenetic study is to evaluate the genetic effects of genome-wide variation on response to GSK2269557 in study PII116678, as assessed by change in forced expiratory volume in 1 second (FEV1) in milliliter (mL) at Day 84, and by change from Baseline in siVaw as determined by HRCT scans after normal exhalation (functional residual capacity [FRC]).The genetics analysis populations (Genetics GSK2269557 population and Genetics placebo population) will include subjects in the PII116678 Intent-to-treat population who provided informed consent for genetics research, a genetics sample and were successfully genotyped. The Genetics GSK2269557 population received at least one dose of GSK2269557 while the Genetics placebo population received at least one dose of placebo.Genetic main effects on efficacy endpoints will be assessed using the Genetics GSK2269557 population. The Genetics Placebo arm will also be analyzed to aid in interpretation of the Genetics GSK2269557 results and to allow for estimation of genotype by treatment interactions using appropriate contrasts or linear combinations of the genetic effect size estimates obtained within the treatment arms.Two co-primary endpoints will be analyzed: Change from Baseline in FEV1 in mL after 84 days of treatment and Change from Baseline in untrimmed siVaw distal region at FRC after 28 days of treatment. The two endpoints will be analyzed using linear regression models with an inverse normal transformation. Genomic control adjustments will be applied to control for test statistic inflation. For each endpoint, two models will be run with and without clinical covariates. Both models will include the first three genetic ancestry principal components. Covariates will include age, gender, body mass index (BMI) and Baseline measures (FEV1 or distal siVaw). Given the small sample size, residuals will be analyzed in the models with clinical covariates.The pre-specified thresholds regarding what constitutes a significant result will be p <=5 multiplied by 10^-8 for main effects in the Genetics GSK2296557 population and p <=5 multiplied by 10^-8 for genotype by treatment effects.