Background The role of ivermectin in the treatment of COVID-19 is still under debate, yet the drug has been widely used in some parts of the world, as shown by impressive market data. The available body of evidence may have changed over the last months, as studies have been retracted and “standards of care” (SOC) used in control groups have changed with rapidly evolving knowledge on COVID-19. This review aims to summarize and critically appraise the evidence of randomized controlled trials (RCTs) of ivermectin, assessing clinical outcomes in COVID-19 patients. Methods RCTs evaluating the effects of ivermectin in adult patients with COVID-19 were searched through June 22, 2022, in four databases, L.OVE platform, clinical trial registries and pre-prints platforms. Primary endpoints included all-cause mortality and invasive ventilation requirement. Secondary endpoint was the occurrence of adverse events. Risk of bias was evaluated using the Cochrane Risk of Bias 2.0 tool. Meta-analysis included only studies which compared ivermectin to placebo or SOC. Random-effects were used to pool the risk ratios (RRs) of individual trials. The quality of evidence was evaluated using GRADE. The protocol was register in PROSPERO (CRD42021257471). Results Twenty-five RCTs fulfilled inclusion criteria (n = 6310). Of those, 14 compared ivermectin with placebo, in night ivermectin associated with SOC was compared to SOC and two studies compared ivermectin to an active comparator. Most RCTs had some concerns or high risk of bias, mostly due to lack of concealment of the randomization sequence and allocation, lack of blinding and high number of missing cases. Ivermectin did not show an effect in reducing mortality (RR = 0.76; 95%CI: 0.52–1.11) or mechanical ventilation (RR = 0.74; 95%CI: 0.48–1.16). This effect was consistent when comparing ivermectin vs. placebo, and ivermectin associated with SOC vs. SOC, as well as in sensitivity analysis. Additionally, there was very low quality of evidence regarding adverse effects (RR = 1.07; 95%CI: 0.84–1.35). Conclusions The evidence suggests that ivermectin does not reduce mortality risk and the risk of mechanical ventilation requirement. Although we did not observe an increase in the risk of adverse effects, the evidence is very uncertain regarding this endpoint.

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Background: The role of ivermectin in the treatment of COVID-19 is still under debate, yet the drug has been widely used in some parts of the world, as shown by impressive market data and ivermectin-related adverse event reports. The available body of evidence may have changed over the last months, as studies have been retracted and "standards of care" (SOC) used in control groups have changed with rapidly evolving knowledge on COVID-19 rapidly. This review aims to summarize and critically appraise the evidence of randomized controlled trials (RCTs) of ivermectin, assessing clinical outcomes in COVID-19 patients.Methods: RCTs evaluating the effects of ivermectin in adult patients with COVID-19 were searched through December 14, 2021, in four databases, L.OVE platform, clinical trial registries and pre-prints platforms. Primary endpoints included all-cause mortality and invasive ventilation requirement. Secondary endpoint was the occurrence of adverse events. Risk of bias was evaluated using the Cochrane Risk of Bias 2.0 tool. Random-effects were used to pool the risk ratios (RRs) of individual trials. The quality of evidence was evaluated using GRADE. Subgroup and sensitivity analysis were performed. The protocol was register in PROSPERO (CRD42021257471)Results: Twenty-one RCTs fulfilled inclusion criteria (n=2592). Of those, 12 compared ivermectin with placebo and in seven ivermectin associated with SOC was compared to SOC. Most RCTs had some concerns or high risk of bias, mostly due to lack of concealment of the randomization sequence and allocation, lack of blinding and high number of missing cases. Ivermectin did not show an effect in reducing mortality (RR=0.76; 95%CI:0.44 to 1.32) or mechanical ventilation (RR=0.83; 95%CI:0.31 to 2.22) in COVID-19 patients. This effect was consistent when comparing ivermectin vs. placebo, and ivermectin associated with SOC vs. SOC, as well as in sensitivity analysis. Additionally, there was very low quality of evidence regarding adverse effects (RR=0.95; 95%CI: 0.86 to 1.04).Conclusions: The evidence suggests that ivermectin does not reduce mortality risk and the risk of mechanical ventilation requirement. Although we did not observe an increase in the risk of adverse effects, the evidence is very uncertain regarding this endpoint.Funding: Research agencies FAPEMIG and CNPq.

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