The effect of early treatment with ivermectin on viral load, symptoms and humoral response in patients with non-severe COVID-19: A pilot, double-blind, placebo-controlled, randomized clinical trial

Abstract

Background: Ivermectin inhibits the replication of SARS-CoV-2 in vitro at concentrations not readily achievable with currently approved doses. There is limited evidence to support its clinical use in COVID-19 patients. We conducted a Pilot, randomized, double-blind, placebo-controlled trial to evaluate the efficacy of a single dose of ivermectin reduce the transmission of SARS-CoV-2 when administered early after disease onset.

Methods: Consecutive patients with non-severe COVID-19 and no risk factors for complicated disease attending the emergency room of the Clínica Universidad de Navarra between July 31, 2020 and September 11, 2020 were enrolled. All enrollments occurred within 72 h of onset of fever or cough. Patients were randomized 1:1 to receive ivermectin, 400 mcg/kg, single dose (n = 12) or placebo (n = 12). The primary outcome measure was the proportion of patients with detectable SARS-CoV-2 RNA by PCR from nasopharyngeal swab at day 7 post-treatment. The primary outcome was supported by determination of the viral load and infectivity of each sample. The differences between ivermectin and placebo were calculated using Fisher's exact test and presented as a relative risk ratio. This study is registered at ClinicalTrials.gov: NCT04390022.

Findings: All patients recruited completed the trial (median age, 26 [IQR 19-36 in the ivermectin and 21-44 in the controls] years; 12 [50%] women; 100% had symptoms at recruitment, 70% reported headache, 62% reported fever, 50% reported general malaise and 25% reported cough). At day 7, there was no difference in the proportion of PCR positive patients (RR 0·92, 95% CI: 0·77-1·09, p = 1·0). The ivermectin group had non-statistically significant lower viral loads at day 4 (p = 0·24 for gene E; p = 0·18 for gene N) and day 7 (p = 0·16 for gene E; p = 0·18 for gene N) post treatment as well as lower IgG titers at day 21 post treatment (p = 0·24). Patients in the ivermectin group recovered earlier from hyposmia/anosmia (76 vs 158 patient-days; p < 0.001).

Interpretation: Among patients with non-severe COVID-19 and no risk factors for severe disease receiving a single 400 mcg/kg dose of ivermectin within 72 h of fever or cough onset there was no difference in the proportion of PCR positives. There was however a marked reduction of self-reported anosmia/hyposmia, a reduction of cough and a tendency to lower viral loads and lower IgG titers which warrants assessment in larger trials.

Funding: ISGlobal, Barcelona Institute for Global Health and Clínica Universidad de Navarra.

Keywords: Anosmia; COVID-19; Hyposmia; Ivermectin; SARS-CoV-2.

Fig. 1

Enrollment and patient flow. ^a One presented with pneumonia in the ER and one had a compatible X-ray during screening. ^b Formally screened based on epidemiological and clinical suspicion but had a negative PCR.

Fig. 2

Viral load evolution by study arm. Viral load values were log-transformed. The boxes show the interquartile range. Dots represent each individual value.

Fig. 3

Daily proportion of any self-reported symptoms, self-reported cough and self-reported anosmia/hyposmia by study arm. Each graph represents the daily proportion of individuals (n/N) who suffered from each symptom in the corresponding study arm for a 28 day follow up. Missing answers were replaced by the value in the immediately preceding day.

Fig. 4

IgG titers by study arm. The boxes show the interquartile range. Dots represent each individual value (p = 0·24, Wilcoxon rank-sum test).

Fig. 5

Kaplan-Meier curves for viral load. A survival threshold of Ct ≥ 30 was used. Log-Rank test yielded significance for the difference in gene E (p = 0·0358) and borderline significance for the difference in gene N (p = 0·0550).