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

Tom Smith

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 […]

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.

1. Introduction

The emergence of a novel coronavirus, Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) in Wuhan in December 2019 and its pandemic spread causing COVID-19 at a global scale, with over 85 million reported cases and 1.7 million deaths by the end of 2020 has prompted the search for pharmacologic interventions to treat, prevent and mitigate the consequences of this potentially devastating acute respiratory infection. Several therapeutic agents have been evaluated at different disease stages as potential antiviral therapies; most of them as part of a drug repurposing strategy for active principles already used in other therapeutic indications. Although different molecules such as hydroxychloroquine, lopinavir and remdesivir have demonstrated antiviral activity against SARS-CoV-2 in vitro, evidence from randomized controlled clinical trials has only demonstrated clinical benefits for intravenous remdesivir in some groups of hospitalized patients [

[1]

National Institutes of Health
COVID-19 treatment guidelines panel. Coronavirus disease 2019 (COVID-19) treatment guidelines.