Project Summary Chronic Obstructive Pulmonary Disease (COPD) is a heterogeneous disease with significant variation in disease manifestation, progression, and outcomes. There is increasing interest in precision medicine strategies in COPD to identify disease traits that, when targeted for treatment, result in improved outcomes. There has been increasing recognition of the prevalence of allergic disease and allergic sensitization in COPD, but the clinical significance of this overlapping trait has been unclear. Blood eosinophils have been recognized as a trait to help target treatment with inhaled corticosteroids among individuals with COPD but are imprecise as a biomarker of type 2 inflammation. We recently published compelling results showing that individuals with COPD having both allergic sensitization as well as concomitant exposure to common indoor aeroallergens, also having elevated total IgE, have a substantially higher risk of adverse outcomes. It is also well established that individuals with allergic asthma having sensitization with exposure to common indoor aeroallergens have significant benefit from treatment with omalizumab. Accordingly, we propose the Clinical trial of omalizumab for allergen sensitized and exposed individuals with COPD (COPD OMA) a masked, randomized, placebo- controlled multi-center phase 2 clinical trial of omalizumab versus placebo among individuals with COPD having sensitization with concomitant exposure to common indoor allergens. The trial will enroll 330 individuals with moderate to severe COPD in partnership with the American Lung Association-Airways Clinical Research Centers (ALA-ACRC) and will test whether omalizumab leads to treatment response, including improvement in exacerbation risk (primary outcome), disease status (measured by St. George's Respiratory Questionnaire and COPD Assessment Test Score), and lung function (secondary outcomes) over the course of 12 months. The study will be conducted at twenty centers throughout the US. In a mechanistic aim, we also propose to explore molecular signatures of IL-4 and IL-13 cytokines to understand drivers of disease morbidity as well as treatment response in this population. Accordingly, this is an ideal phase II clinical trial with the goals of detecting a signal for efficacy of omalizumab in improving relevant clinical outcomes among a high-risk subgroup of individuals; and understanding relevant biologic endotypes with increased responsiveness to treatment.