PGx7703_BRL49653_PHNA_Exploratory Pharmacogenomics analysis of Alzheimer’s Disease in Studies AVA102670 and AVA102672

Trial description: The purpose of this exploratory pharmacogenetics (PGx) study, PGx7703, is to investigate the genetic association between genetic variants and Disease Progression using data from studies AVA102670 and AVA102672, here after referred to as the Rosiglitazone (RSG) trials. The primary objective is to test for genetic effects on ADAS-Cog change from baseline and ADAS-Cog responder status in participants treated with rosiglitazone (RSG) and/or placebo at 12 weeks. The analysis populations consist of subjects in both studies that received at least one treatment dose of placebo or RSG, provided written informed consent for genetics research and a DNA sample, and were successfully genotyped. The populations will be based on the actual treatment the subject received. The following dosages will be included alone or in combination: RSG 8mg, RSG 2mg, Placebo. As a preliminary step, we will assess if there are treatment effects on change from baseline in ADAS-Cog at week 12. If no treatment effects are observed (p≤0.05), then the treatments will be pooled for the genome-wide analyses. Otherwise, the genome-wide analyses will be conducted within each separate treatment group. ADAS-Cog and Covariates, which will be evaluated for inclusion in the analysis models, will include study, APOE e4 status, gender, age, treatment, years of education, and baseline ADAS-cog score. If analyses are conducted within each separate treatment group, then a fixed effects variance weighted meta-analysis will be conducted using the effect estimates from each underlying group. A type 1 error rate of 0.05, adjusting for multiple genetic variants, will be maintained by using the standard significance threshold for genome-wide variants of 5x10-8. No adjustment will be made for multiple endpoints or subgroup analyses.The genotyping platform is the Affymetrix Axiom Precision Medicine Research Array. Genotype imputation for genetic variants that were not directly genotyped (“untyped variants”) will be performed using a cosmopolitan haplotype reference panel from the 1000 Genomes Project.