Effects of adding L-arginine orally to standard therapy in patients with COVID-19: A randomized, double-blind, placebo-controlled, parallel-group trial. Results of the first interim analysis

Giuseppe Fiorentino, Antonietta Coppola, Raffaele Izzo, Anna Annunziata, Mariano Bernardo, Angela Lombardi, Valentina Trimarco, Gaetano Santulli, Bruno Trimarco, Giuseppe Fiorentino, Antonietta Coppola, Raffaele Izzo, Anna Annunziata, Mariano Bernardo, Angela Lombardi, Valentina Trimarco, Gaetano Santulli, Bruno Trimarco

Abstract

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 25th,75th 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.

Keywords: Arginine; COVID-19; Clinical trial; Coronavirus; Endothelial dysfunction; Immune response; SARS-CoV-2.

Conflict of interest statement

We declare no competing interests.

© 2021 The Author(s).

Figures

Fig. 1
Fig. 1
Study flowchart.
Fig. 2
Fig. 2
Respiratory support at baseline and at day 10 (A) and percentage of patients in which the respiratory support was reduced, evaluated 10 days after randomization (B) in the per-protocol analysis; *: p < 0.01. CPAP: continuous positive airway pressure; HFNC: high-flow nasal cannula; LTOT: long-term oxygen therapy; NIV: non-invasive ventilation.
Fig. 3
Fig. 3
Kaplan-Meier curves assessing in the per-protocol analysis the length of in-hospital stay.

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