High-dose ivermectin for early treatment of COVID-19 (COVER study): a randomised, double-blind, multicentre, phase II, dose-finding, proof-of-concept clinical trial

Abstract

High concentrations of ivermectin demonstrated antiviral activity against SARS-CoV-2 in vitro . Aim of this study was to assess safety and efficacy of high-dose ivermectin in reducing viral load in individuals with early SARS-CoV-2 infection. Randomised, double-blind, multicentre, phase II, dose-finding, proof-of-concept clinical trial. Participants: adults recently diagnosed with asymptomatic/oligosymptomatic SARS-CoV-2 infection, providing informed consent. Exclusion criteria: pregnant or lactating women; CNS diseases; dialysis; severe medical condition with prognosis < 6 months; warfarin treatment; antiviral/chloroquine phosphate/hydroxychloroquine treatment. Participants were assigned according to a randomized permuted block procedure to one of the following arms with allocation ratio 1:1:1: placebo (arm A); single dose ivermectin 600 μg/kg plus placebo for 5 days (arm B); single dose ivermectin 1200 μg/kg for 5 days (arm C). Primary outcomes: serious adverse drug reactions (SADR) and change of viral load at Day 7. From 31 th July, 2020 to 26 th May, 2021, 32 participants were randomized to arm A, 29 to arm B and 32 to arm C. The recruitment was stopped on 10 th June, because of a dramatic drop of cases. Eighty-nine participants were included in the safety analysis set, the change in viral load was calculated on 87 participants. No SADR were registered. The mean log10 viral load reduction was 2.9 in arm C (SD 1.6), 2.5 (2.2) in arm B and 2.0 (2.1) in arm A, with no significant differences (p=0.099 and 0.122 for C versus A and B versus A, respectively). High-dose ivermectin was safe, but did not prove efficacy to reduce viral load.

Ivermectin under scrutiny: a systematic review and meta-analysis of efficacy and possible sources of controversies in COVID-19 patients

“…These studies were included in a number of systematic reviews and meta-analyses that reported the beneficial effect of this medication [ 14 , 16 – 18 ]. Furthermore, recent RCTs have shown that ivermectin is ineffective in the treatment of COVID-19 [ 19 , 20 ]. Since the beginning of the pandemic, all of these have caused controversy regarding the possible effects of this drug.…”

“…There are some concerns regarding the accuracy of the results of previous studies that should be addressed. The most important concerns are several retractions of clinical trials [ 21 ], the availability of inaccurate or outdated meta-analyses [ 14 , 22 , 23 ], and three RCTs recently published in 2022 [ 19 , 20 , 24 ] which their final results were not included in previous meta-analyses. Considering these issues, we set out to conduct a comprehensive systematic review and meta-analysis of current peer-reviewed randomized controlled trials to assess the possible effect of ivermectin in patients with COVID-19.…”

Systematic Review and Meta-Analysis of Ivermectin for Treatment of COVID-19: Evidence Beyond the Hype

“…No additional articles were retrieved from the reference lists of the included studies. Of the 21 included studies, 04 were available as preprints upon the time of submission of the present study [45][46][47][48].…”

“…In nine of them, the registration was done after the beginning of recruitment, in one of them the recruitment period was not mentioned, and the protocols of three studies could not be retrieved for the registration date to be checked. In eight studies, there were amends in the protocol after the registration [19,45,47,48,49,50,51,52]. * The nal sample for adverse effects is different to the nal sample for our primary outcomes ** This arm was not included in the meta-analysis 1 Lopinavir/ritonavir.…”

COVID-19 at a Glance: An Up-to-Date Overview on Variants, Drug Design and Therapies

“…Whether this drug might have clinical efficacy at lower doses remains debated. The recommendation of the WHO suggests that it is currently advisable to refrain from administrating ivermectin for the treatment of COVID-19 outside clinical trials [ 156 ]. These studies are summarized in Table 4 .…”