PGx7687: Exploratory Pharmacogenetic Study to Investigate Efficacy of SB252263 Tafenoquine on relapse of P Vivax Malaria in TAF112582 and TAF115654

Trial description: The purpose of this exploratory pharmacogenetics (PGx) study, 208099, is to evaluate the genetic effects of genome-wide germline genetic variation on response to tafenoquine+chloroquine (TQ+CQ) in studies TAF112582 and TAF116564 in subjects infected with P vivax malaria. The primaquine+chloroquine (PQ+CQ) arm and the chloroquine alone (CQ) arm will also be analyzed to aid in interpretation of the TQ+CQ arm results and to allow for estimation of genotype by treatment interactions using appropriate contrasts of linear combinations of the genetic effect size estimates obtained within the treatment arms.The following analysis populations are drawn from the microbiological Intent-to-Treat (mITT) populations from TAF112582 and TAF116564. mITT is defined as all randomized subjects who receive at least one dose of blinded study medication and have microscopically-confirmed vivax parasitemia. Subjects will be pooled across studies by their actual treatment.• Genetics TQ: Subjects treated with 300 milligram (mg) or 600 mg TQ• Genetics PQ: Subjects treated with primaquine (PQ)• Genetics CQ: Subjects treated with chloroquine alone (CQ)Note: Subjects treated with TQ or with PQ were also treated with CQ on Days 1-3. Three endpoints will be examined:• Relapse-free efficacy response six months post-dosing• Relapse-free efficacy response four months post-dosing• Time to relapse up to 6 months post dosingGenetic main effect on relapse free efficacy response six months or four months post dosing in the Genetics TQ population will be assessed using logistic regression analysis to generate odds ratios (OR) and 95% confidence intervals (CI). Genetic main effects on relapse free efficacy response six months or four months post dosing will also be assessed in the Genetics PQ and Genetics CQ populations to aid in interpretation of the Genetics TQ results, and to allow for estimation of genotype by treatment interactions using appropriate contrasts of linear combinations of the genetic effect size estimates obtained within the treatment arms.Genetic main effect on time to relapse in the Genetics TQ population will be assessed using a Cox proportional hazards regression model to generate hazards ratios (HR) and 95% confidence intervals (CI). Genetic main effects on time to relapse will also be assessed in the Genetics PQ and Genetics CQ populations to aid in interpretation of the Genetics TQ results, and to allow for estimation of genotype by treatment interactions using appropriate contrasts of linear combinations of the genetic effect size estimates obtained within the treatment arms.The Affymetrix Axiom Biobank array with GSK custom content v2 in conjunction with a reference set of haplotypes will be used to impute approximately 30+ million genetic variants across the genome including the HLA region. Analysis will be conducted on genome-wide germline genetic variants with a minor allele frequency >=0.01 and an imputation r2 >=0.30. An additive genetic model will be used for all variants. The significance threshold for genome-wide variants is <=5x10-8 (conventional genome-wide analysis threshold). No adjustment will be made for multiple endpoints.