BackgroundSphingosine-1-phosphate receptor ligands (SRLs) dampen immunopathological damages in models of viral pneumonia. Research QuestionIs it feasible to administer an SRL therapy, here ozanimod, to acutely ill SARS-CoV-2-infected patients? Study Design and MethodsThe prospective, randomized, open-label, COVID-19 Ozanimod Intervention (COZI) pilot trial was conducted in three Canadian hospitals. Patients admitted for COVID-19 requiring oxygen were eligible. Randomization was stratified for risk factors of poor outcome and oxygen needs at inclusion. Participants were allocated to standard of care (SOC), or to standard of care plus ozanimod (OZA). Ozanimod (oral, once daily, incremental dosage) was administered for a maximum of 14 days. Primary endpoint investigated for size effect and variance over time was the assessment of safety and efficacy, evaluated by the daily score on the WHO-adapted 6-points ordinal scale for clinical improvement analyzed under the intention-to-treat principle. ResultsTwenty-three patients were randomized to SOC arm and 20, in the OZA arm from September 2020 to February 2022. Evaluation of efficacy showed non-significant reductions of median duration of respiratory support (6 (3-10) vs 9 (4-12) days, P=0.34), median duration of hospitalization (9 (6-12) vs 10 (6-18) days, P=0.20) and median time to clinical improvement (4 (3-7) vs 7 (3-11) days, P=0.12) for OZA compared to SOC. Heart rate was significantly lower with ozanimod (65 (63-67) vs. 71 (69-72) bpm, P<0.0001). However, QT and PR intervals were not affected. No severe adverse drug reaction was reported. InterpretationSRLs utility in severe pneumonia had never been tested in patients. We show for the first time that this new pharmacological agent can safely be administered to patients hospitalized for viral pneumonia, with potential clinical benefits. Bradycardia was frequent but well tolerated. Clinical Trial RegistrationClinicalTrials.gov number NCT04405102