Effect of IL-4RαR576 polymorphism on response to dupilumab in asthma, a genotype-stratified, randomized, placebo- controlled trial (IDEA Trial): Design, Rationale, Methods, Strategies, and Lessons Learned.

BACKGROUND: Asthma is a heterogeneous chronic disease, disproportionately affecting racial and ethnic minorities, with persistence and severity influenced by both environmental and genetic factors. The IL-4RαR576 variant occurs more commonly in racially minoritized, and the genotype, independent of race, is associated with severe, exacerbation-prone asthma. IDEA (Investigating Dupilumab's Effect in Asthma by genotype) NCT02570984 is a multicenter, randomized, placebo-controlled trial designed to determine whether dupilumab, a monoclonal antibody that directly inhibits the IL-4 receptor, has differential efficacy according to IL-4Rα genotype, and to better understand genotype-specific asthma outcomes in adolescents and adults. At the time of this design and methods report, while enrollment is complete, the trial is ongoing and clinical outcome results are not yet available. METHODS: IDEA enrolled participants aged 12 years and above with uncontrolled asthma. Eligible participants are genotyped for the IL-4RαR576 allele and stratified into wild-type, heterozygous, and homozygous groups. A total of 120 participants (goal of 48 wild-type, 48 heterozygous, 24 homozygous) are being randomized 1:1 to receive dupilumab or placebo in addition to guidelines-based therapy for 48 weeks. The primary endpoint is reduction in asthma exacerbations. Digitalized strategies to address adherence in home administration of biologics are employed. Strategies to boost recruitment include new electronic health medical record tools, community advertising on public transportation and subway systems, and team members and sites in culturally attuned neighborhoods. DISCUSSION: IDEA evaluates response to a biologic by genotype. Results will inform future targeted therapies in genetically susceptible populations, with potential implications for reducing asthma disparities.Clinical Trials.gov NCT02570984.