Antiviral effect of high-dose ivermectin in adults with COVID-19: A proof-of-concept randomized trial

Abstract

Background: There are limited antiviral options for the treatment of patients with COVID-19. Ivermectin (IVM), a macrocyclic lactone with a wide anti-parasitary spectrum, has shown potent activity against SARS-CoV-2 in vitro. This study aimed at assessing the antiviral effect of IVM on viral load of respiratory secretions and its relationship with drug concentrations in plasma.

Methods: Proof-of-concept, pilot, randomized, controlled, outcome-assessor blinded trial to evaluate antiviral activity of high-dose IVM in 45 COVID-19 hospitalized patients randomized in a 2:1 ratio to standard of care plus oral IVM at 0·6 mg/kg/day for 5 days versus standard of care in 4 hospitals in Argentina. Eligible patients were adults with RT-PCR confirmed SARS-CoV-2 infection within 5 days of symptoms onset. The primary endpoint was the difference in viral load in respiratory secretions between baseline and day-5, by quantitative RT-PCR. Concentrations of IVM in plasma were measured. Study registered at ClinicalTrials.gov: NCT04381884.

Findings: 45 participants were recruited (30 to IVM and 15 controls) between May 18 and September 9, 2020. There was no difference in viral load reduction between groups but a significant difference was found in patients with higher median plasma IVM levels (72% IQR 59-77) versus untreated controls (42% IQR 31-73) (p = 0·004). Mean ivermectin plasma concentration levels correlated with viral decay rate (r: 0·47, p = 0·02). Adverse events were similar between groups. No differences in clinical evolution at day-7 and day-30 between groups were observed.

Interpretation: A concentration dependent antiviral activity of oral high-dose IVM was identified at a dosing regimen that was well tolerated. Large trials with clinical endpoints are necessary to determine the clinical utility of IVM in COVID-19.

Funding: This work was supported by grant IP-COVID-19-625, Agencia Nacional de Promoción de la Investigación, el Desarrollo Tecnológico y la Innovación, Argentina and Laboratorio ELEA/Phoenix, Argentina.

Conflict of interest statement

AK reports grants and lecture fees from Laboratorio Elea/Phoenix and a grant from Agencia Nacional de Promoción de la Investigación, el Desarrollo Tecnológico y la Innovación, Argentina. DFA reports personal fees from Laboratorio ELEA-Phoenix outside the submitted work; RV, RS and JF report personal fees from Elea Phoenix Laboratory during the conduct of the study. MT report personal fees from Elea/Phoenix. MAT and ES are employees of Laboratorios Elea/Phoenix. SG is a member of the Board of Directors of Laboratorio Elea/Phoenix. All other authors declare no competing interests.

© 2021 The Author(s).

Figures

Fig. 1

Trial profile.

Fig. 2

Viral load by quantitative RT-PCR on upper respiratory tract secretions since baseline in patients receiving IVM 0•6 mg/kg/day for 5 days versus untreated controls.

Fig. 3

Viral load reduction between baseline and day-5 (median and IQR) in untreated controls and IVM treated patients discriminated by their median IVM plasma concentrations.

Fig. 4

Viral load decay rates by quantitative RT-PCR on upper respiratory tract secretions in untreated controls and IVM treated patients according to median plasma concentrations of IVM. Data are expressed as median (IQR).