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EClinicalMedicine

EClinicalMedicine

Available online 9 September 2021, 101125
In Press, Corrected ProofWhat are Corrected Proof articles?
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Research Paper
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

Author links open overlay panelGiuseppeFiorentino^a^1Antonietta
Coppola^a^1RaffaeleIzzo^bAnnaAnnunziata^aMarianoBernardo^aAngela
Lombardi^c^dValentinaTrimarco^eGaetanoSantulli^b^c^f^gBrunoTrimarco^b
^g
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https://doi.org/10.1016/j.eclinm.2021.101125Get rights and content
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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 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.

Keywords

COVID-19
Endothelial dysfunction
SARS-CoV-2
Arginine
Clinical trial
Coronavirus
Immune response
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^1

    These authors contributed equally to this work.

(c) 2021 The Author(s). Published by Elsevier Ltd.

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