Antiviral Effect of High-Dose Ivermectin in Adults with COVID-19: A Pilot Randomised, Controlled, Open Label, Multicentre Trial

Background: There are limited antiviral options for the treatment of patients with coronavirus disease 2019 (COVID-19) that have demonstrated clinical efficacy and none of them is an oral drug. Ivermectin (IVM), a macrocytic lactone with a wide anti-parasitary spectrum, has shown potent in vitro activity against SARS-CoV-2 in cell cultures.  Methods: We completed a pilot, randomized, controlled, outcome-assessor blinded clinical trial with the goal of evaluating the antiviral activity of high dose IVM in COVID-19 patients. Eligible patients were adults (aged 18 to 69 years) with mild or moderate RT-PCR confirmed SARS-CoV-2 infection within 5 days of symptoms onset. 45 patients were 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. The primary endpoint was viral load reduction in respiratory secretions at day-5. Viral load in respiratory secretions was measured through quantitative RT-PCR. Concentrations of IVM in plasma were measured on multiple treatment days. Findings: The trial run between May 18 and September 29, 2020 with 45 randomized patients (30 in the IVM group and 15 controls). There was no difference in viral load reduction between groups but a significant difference in reduction was found in patients with higher median plasma IVM levels (72% IQR 59 – 77) versus untreated controls (42% IQR 31 – 73) (p=0·004). The mean ivermectin plasma concentration levels also showed a positive correlation with viral decay rate (r:0·47, p=0·02). Adverse events were reported in 5 (33%) patients in the controls and 13 (43%) in the IVM treated group, without a relationship between IVM plasma levels and adverse events. Interpretation: A concentration dependent antiviral activity of oral high dose IVM was identified in this pilot trial 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. Trial Registration: This trial is registered with ClinicalTrials.gov, NCT004381884. Funding Statement: This work was supported by grant IP-COVID-19-625 from Agencia Nacional de Promocion de la Investigacion, el Desarrollo Tecnologico y la Innovacion, Argentina and Laboratorio ELEA/Phoenix, Argentina. Declaration of Interests: AK reports grants from Laboratorio Elea/Phoenix. MAT, MDG and ES are employees of Laboratorios Elea/Phoenix. SG is a moember of the Board of Directors of Laboratorio Elea/Phoenix. All other authors declare no competing interests. Ethics Approval Statement: Ethical approval was obtained from the Institutional Independent Ethics Committees and from district and national regulatory agencies. All participating individuals provided written informed consent. The trial was done in accordance with the principles of the Declaration of Helsinki.