Dataset Information

Effectiveness and safety of ivermectin in the treatment of COVID-19: protocol for a systematic review and meta-analysis.

ABSTRACT:

Introduction

Ivermectin is a drug with antiviral properties and has been proposed as an alternative treatment for patients with COVID-19, in some countries; however, there is limited evidence to support its clinical use. Accordingly, the aim of this review and meta-analysis is to obtain superior evidence on the effectiveness and safety of ivermectin in treatment of COVID-19.

Methods and analysis

We will search in the medical databases and International Clinical Trials Registry Platform databases for randomised clinical trials and quasi-randomised trials published from December 2019. The criteria for inclusion are that infection needs to be confirmed by a real-time PCR or serology test, and the effect of ivermectin has been compared with placebo, symptomatic treatment or no treatment. We will exclude observational studies and clinical trials that involved patients with symptoms suggestive of COVID-19, but without a laboratorial diagnosis. Outcomes of interest include mortality, time to symptom resolution, time of hospitalisation, frequency of invasive mechanical ventilation and extracorporeal membrane oxygenation, incidence of severe acute respiratory syndrome, admission to intensive care unit, viral load, PCR-negative status, percentage of infection after prophylactic use, and total incidence of adverse and side effects. Study selection will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Two reviewers will independently select the studies and assess their eligibility. Two other reviewers will independently extract data from each study. Meta-analysis will then be carried out using fixed-effects or random-effects model, using the mean difference for continuous outcomes and the relative risk for dichotomous outcomes. Bias risk will be assessed using the Cochrane risk-of-bias tool. The quality of evidence for each outcome will be assessed using GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology. Review Manager V.5.3.5 will be used for synthesis and subgroup analysis.

Ethics and dissemination

Owing to the nature of the review, ethical approval is not required. The results will be disseminated through peer-reviewed publications.

Prospero registration number

CRD42020197395.

SUBMITTER: Machado MLL

PROVIDER: S-EPMC8450968 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Ivermectin has received particular attention as a potential treatment for COVID-19. However, the evidence to support its clinical efficacy is controversial. We undertook a new systematic review of ivermectin for the treatment and prophylaxis of COVID-19, including new primary studies, outcomes other than mortality, and grading the quality of the available evidence following the Cochrane guidance for methodology. We searched electronic databases, repository databases, and clinical trial registries (up to June 2021). The measure of treatment effect was risk difference (RD) with 95% confidence intervals (CIs). The GRADE system was used to assess the certainty of the evidence. The review includes 11 RCTs (2436 participants). The certainty of the available evidence was quite low or very low due to risk of bias, inconsistency, and imprecision. When the analysis was limited to patients with baseline mild or moderate disease (8 reports, 1283 patients), there were no differences in mortality between ivermectin and control groups (low level of certainty); in patients with baseline severe diseases (3 reports, 304 patients), the use of ivermectin significantly decreased mortality compared to the controls (RD -0.17; 95% CIs, -0.24/-0.10; p = 0.00001; low level of certainty). In terms of disease progression (to severe pneumonia, admission to intensive care unit, and/or mechanical ventilation), the results were much the same. At day 14, the rate of patients with a negative RT-PCR test was 21% higher (from 5 to 36% higher) for ivermectin recipients than it was for the controls (low quality of evidence). Three studies (736 subjects) indicated that prophylaxis with ivermectin increased the likelihood of preventing COVID-19 compared to controls (low quality of evidence). Serious adverse events were rarely reported. There is limited evidence for the benefit of ivermectin for COVID-19 treatment and prophylaxis, and most of this evidence is of low quality. Further evidence is needed to fine-tune potential indications and optimal treatment protocols for ivermectin as a treatment for COVID-19.

Project description:BackgroundThe 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.MethodsRCTs 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).ResultsTwenty-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).ConclusionsThe 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.

Project description:Background and objectivesAn effective treatment option is not yet available for SARS-CoV2, which causes the COVID-19 pandemic and whose effects are felt more and more every day. Ivermectin is among the drugs whose effectiveness in treatment has been investigated. In this study; it was aimed to investigate the presence of gene mutations that alter ivermectin metabolism and cause toxic effects in patients with severe COVID-19 pneumonia, and to evaluate the effectiveness and safety of ivermectin use in the treatment of patients without mutation.Materials and methodsPatients with severe COVID19 pneumonia were included in the study, which was planned as a prospective, randomized, controlled, single-blind phase 3 study. Two groups, the study group and the control group, took part in the study. Ivermectin 200 mcg/kg/day for 5 days in the form of a solution prepared for enteral use added to the reference treatment protocol -hydroxychloroquine + favipiravir + azithromycin- of patients included in the study group. Patients in the control group were given only reference treatment with 3 other drugs without ivermectin. The presence of mutations was investigated by performing sequence analysis in the mdr1/abcab1 gene with the Sanger method in patients included in the study group according to randomization. Patients with mutations were excluded from the study and ivermectin treatment was not continued. Patients were followed for 5 days after treatment. At the end of the treatment and follow-up period, clinical response and changes in laboratory parameters were evaluated.ResultsA total of 66 patients, 36 in the study group and 30 in the control group were included in the study. Mutations affecting ivermectin metabolism was detected in genetic tests of six (16.7%) patients in the study group and they were excluded from the study. At the end of the 5-day follow-up period, the rate of clinical improvement was 73.3% (22/30) in the study group and was 53.3% (16/30) in the control group (p = 0.10). At the end of the study, mortality developed in 6 patients (20%) in the study group and in 9 (30%) patients in the control group (p = 0.37). At the end of the follow-up period, the average peripheral capillary oxygen saturation (SpO2) values of the study and control groups were found to be 93.5 and 93.0%, respectively. Partial pressure of oxygen (PaO2)/FiO2 ratios were determined as 236.3 ± 85.7 and 220.8 ± 127.3 in the study and control groups, respectively. While the blood lymphocyte count was higher in the study group compared to the control group (1698 ± 1438 and 1256 ± 710, respectively) at the end of the follow-up period (p = 0.24); reduction in serum C-reactive protein (CRP), ferritin and D-dimer levels was more pronounced in the study group (p = 0.02, p = 0.005 and p = 0.03, respectively).ConclusionsAccording to the findings obtained, ivermectin can provide an increase in clinical recovery, improvement in prognostic laboratory parameters and a decrease in mortality rates even when used in patients with severe COVID-19. Consequently, ivermectin should be considered as an alternative drug that can be used in the treatment of COVID-19 disease or as an additional option to existing protocols.

Project description:BackgroundAbout 3·7 billion doses of ivermectin have been distributed in mass drug administration (MDA) campaigns globally over the past 30 years. At 10-100 times higher than current human doses, ivermectin is a known teratogen in mammals. During these campaigns with recommended doses, pregnant women might be inadvertently exposed. We therefore aimed to evaluate the existing evidence for serious and non-serious adverse events after ivermectin exposure in pregnant women.MethodsFor this systematic review and meta-analysis, we searched relevant databases and trial registry platforms on July 15, 2018, for randomised controlled trials (RCTs) and observational studies that reported adverse events in pregnant women. We did not use language or date restrictions. Outcomes of interest were spontaneous abortions, stillbirths, congenital anomalies, and neonatal death (serious adverse events), as well as maternal morbidity, preterm births, and low birthweight (adverse events). The risk of bias was assessed using the Newcastle-Ottawa Scale for observational studies and the Cochrane Risk of Bias Tool for RCTs. We did the meta-analysis of observational studies and RCTs separately. The quality of evidence was assessed using the GRADE approach. The study protocol is registered with PROSPERO, protocol CRD42016046914.FindingsWe identified 147 records, of which only five observational studies and one RCT were included for quantitative analysis; these studies were published between 1990 and 2008, and were done in six African countries. 893 women with 899 pregancy outcomes were included, of whom 496 pregnant women (500 pregnancy outcomes) received ivermectin inadvertently during MDA campaigns in the observational studies and 397 pregnant women (399 pregnancy outcomes) purposely received ivermectin as part of the open-label RCT. No study reported neonatal deaths, maternal morbidity, preterm births, or low birthweight. It is unclear whether exposure to ivermectin during pregnancy increases the risk of spontaneous abortions and stillbirths (odds ratio [OR] 1·15 [95% CI 0·75-1·78] with very low certainty of evidence for the four observational studies and 0·62 [0·18-2·14] with very low certainty of evidence for the RCT) or congenital anomalies (OR 1·69 [95% CI 0·83-3·41] with very low certainty of evidence for the five observational studies and 1·10 [0·07-17·65] with very low certainty of evidence for the RCT).InterpretationThere is insufficient evidence to conclude on the safety profile of ivermectin during pregnancy. Treatment campaigns should focus additional efforts on preventing inadvertent treatment of pregnant women.FundingUnitaid.