Background We and others have previously demonstrated that the endothelium is a primary target of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and L-arginine has been shown to improve endothelial dysfunction. However, the effects of L-arginine have never been evaluated in coronavirus disease 2019 (COVID-19). Methods This is a parallel-group, double-blind, randomized, placebo-controlled trial conducted on patients hospitalized for severe COVID-19. Patients received 1.66 g L-arginine twice a day or placebo, administered orally. The primary efficacy endpoint was a reduction in respiratory support assessed 10 and 20 days after randomization. Secondary outcomes were the length of in-hospital stay, the time to normalization of lymphocyte number, and the time to obtain a negative real-time reverse transcription polymerase chain reaction (RT-PCR) for SARS-CoV-2 on nasopharyngeal swab. This clinical trial had been registered at ClinicalTrials.gov, identifier: NCT04637906. Findings We present here the results of the initial interim analysis on the first 101 patients. No treatment-emergent serious adverse events were attributable to L-arginine. At 10-day evaluation, 71.1% of patients in the L-arginine arm and 44.4% in the placebo arm ( p < 0.01) had the respiratory support reduced; however, a significant difference was not detected 20 days after randomization. Strikingly, patients treated with L-arginine exhibited a significantly reduced in-hospital stay vs placebo, with a median (interquartile range 25 th ,75 th percentile) of 46 days (45,46) in the placebo group vs 25 days (21,26) in the L-arginine group ( p < 0.0001); these findings were also confirmed after adjusting for potential confounders including age, duration of symptoms, comorbidities, D-dimer, as well as antiviral and anticoagulant treatments. The other secondary outcomes were not significantly different between groups. Interpretation In this interim analysis, adding oral L-arginine to standard therapy in patients with severe COVID-19 significantly decreases the length of hospitalization and reduces the respiratory support at 10 but not at 20 days after starting the treatment. Funding Both placebo and L-arginine were kindly provided by Farmaceutici Damor S.p.A., Naples
【저자키워드】 COVID-19, SARS-CoV-2, coronavirus, immune response, clinical trial, arginine, Endothelial dysfunction, 【초록키워드】 Treatment, coronavirus disease, randomization, severe COVID-19, Antiviral, Hospitalization, Comorbidities, D-dimer, outcome, RT-PCR, Endothelium, Randomized, Nasopharyngeal swab, lymphocyte, placebo-controlled trial, Patient, age, Placebo, reverse transcription, patients, funding, Anticoagulant, Standard therapy, Respiratory Support, double-blind, In-hospital, interquartile range, Serious Adverse Event, acute respiratory syndrome, L-Arginine, significant difference, Registered, parallel-group, secondary outcome, primary efficacy endpoint, interim analysis, finding, Administered, Effect, confounder, secondary, decrease, polymerase chain, initial, IMPROVE, shown, significantly, evaluated, conducted, provided, reduced, exhibited, median, demonstrated, reduce, groups, reduction in, duration of symptoms, Naple, not significantly different, patients hospitalized, patients treated, the placebo group, 【제목키워드】 Trial, Randomized, Patient, placebo-controlled, Standard therapy, double-blind, L-Arginine, parallel-group, interim analysis, Effect, Result,