Modification of Asthma Clinical Trial Treatment Efficacy by Social and Environmental Exposures

Abstract

BACKGROUND AND AIM: Randomized controlled trials (RCTs) are considered the gold standard for examining effectiveness of clinical interventions, though they rarely evaluate social and environmental exposures that may modify underlying disease states. This is a particular concern for asthma, which is consistently linked to air pollution and social stressors. METHODS: We reexamined the AsthmaNet Step-up Yellow Zone Inhaled Corticosteroids to Prevent Exacerbations (STICS) trial, in which participants were randomly assigned to low (44 ug/inhalation) or high (220 ug/inhalation) dose of fluticasone inhaled corticosteroid treatment (ICS) upon asthma exacerbation, and followed to assess subsequent exacerbations. AsthmaNet reported no significant differences between dose groups in number of exacerbations, or time to first rescue prednisone use (Jackson et al, NEJM 2018). We geocoded participant residences, estimated mean exposures over follow-up using a validated national spatiotemporal model for fine particles (PM2.5), and derived census tract-level indicators for poverty rates and medically-underserved areas (MUAs). We used Cox proportional hazard models to assess time-to-prednisone use, and tested whether co-exposures modified associations between treatment arm and outcomes. RESULTS:Individuals with above-median (7.4 µg/m3) PM2.5 exposures had, on average, more exacerbation events over the study, than did those with below-median PM2.5 [µ= 1.75 events (SD = 1.84) vs. µ= 1.45 events (SD = 1.71)]. The high ICS dose was associated with shorter time-to-prednisone-use, compared to low ICS dose, {only} among those with above-median PM2.5 exposure (p =.048), or living in lower-poverty areas (p =.08) or non-MUAs (p =.02). CONCLUSIONS:While the overall impact of quintupling ICS dose on exacerbations was null, specific social and environmental factors modified observed treatment effects. In high-PM2.5 or less-deprived areas, higher ICS doses conferred shorter times to exacerbation. Clinical trials should account for social and environmental exposures, to better understand intervention impacts and identify sub-groups for whom interventions may be particularly effective. KEYWORDS: asthma exacerbations, PM2.5, inhaled corticosteroids, RCT