Abstract: Research JAMA Internal Medicine | Original Investigation Efficacy of Inhaled Ciclesonide for Outpatient Treatment of Adolescents and Adults With Symptomatic COVID-19 A Randomized Clinical Trial Brian M. Clemency, DO; Renoj Varughese, MD; Yaneicy Gonzalez-Rojas, MD; Caryn G. Morse, MD, MPH; Wanda Phipatanakul, MD, MS; David J. Koster, MS; Michael S. Blaiss, MD Visual Abstract IMPORTANCE Systemic corticosteroids are commonly used in treating severe COVID-19. However, the role of inhaled corticosteroids in the treatment of patients with mild to moderate disease is less clear. Supplemental content OBJECTIVE To determine the efficacy of the inhaled steroid ciclesonide in reducing the time to alleviation of all COVID-19–related symptoms among nonhospitalized participants with symptomatic COVID-19 infection. DESIGN, SETTING, AND PARTICIPANTS This phase 3, multicenter, double-blind, randomized clinical trial was conducted at 10 centers throughout the US and assessed the safety and efficacy of a ciclesonide metered-dose inhaler (MDI) for treating nonhospitalized participants with symptomatic COVID-19 infection who were screened from June 11, 2020, to November 3, 2020. INTERVENTIONS Participants were randomly assigned to receive ciclesonide MDI, 160 μg per actuation, for a total of 2 actuations twice a day (total daily dose, 640 μg) or placebo for 30 days. MAIN OUTCOMES AND MEASURES The primary end point was time to alleviation of all COVID-19–related symptoms (cough, dyspnea, chills, feeling feverish, repeated shaking with chills, muscle pain, headache, sore throat, and new loss of taste or smell) by day 30. Secondary end points included subsequent emergency department visits or hospital admissions for reasons attributable to COVID-19. RESULTS A total of 413 participants were screened and 400 (96.9%) were enrolled and randomized (197 [49.3%] in the ciclesonide arm and 203 [50.7%] in the placebo arm; mean [SD] age, 43.3 [16.9] years; 221 [55.3%] female; 2 [0.5%] Asian, 47 [11.8%] Black or African American, 3 [0.8%] Native Hawaiian or other Pacific Islander, 345 [86.3%] White, and 1 multiracial individuals [0.3%]; 172 Hispanic or Latino individuals [43.0%]). The median time to alleviation of all COVID-19–related symptoms was 19.0 days (95% CI, 14.0-21.0) in the ciclesonide arm and 19.0 days (95% CI, 16.0-23.0) in the placebo arm. There was no difference in resolution of all symptoms by day 30 (odds ratio, 1.28; 95% CI, 0.84-1.97). Participants who were treated with ciclesonide had fewer subsequent emergency department visits or hospital admissions for reasons related to COVID-19 (odds ratio, 0.18; 95% CI, 0.04-0.85). No participants died during the study. CONCLUSIONS AND RELEVANCE The results of this randomized clinical trial demonstrated that ciclesonide did not achieve the primary efficacy end point of reduced time to alleviation of all COVID-19–related symptoms. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT04377711 JAMA Intern Med. doi:10.1001/jamainternmed.2021.6759 Published online November 22, 2021. Author Affiliations: Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York (Clemency, Varughese); Verus Clinical Research Corporation, Coral Gables, Florida (Gonzalez-Rojas); Wake Forest School of Medicine, Winston-Salem, North Carolina (Morse); Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts (Phipatanakul); Instat Clinical Research, Chatham, New Jersey (Koster);..