key: cord-0064665-fien6nra authors: Hariyanto, Timotius Ivan; Halim, Devina Adella; Rosalind, Jane; Gunawan, Catherine; Kurniawan, Andree title: Ivermectin and outcomes from Covid‐19 pneumonia: A systematic review and meta‐analysis of randomized clinical trial studies date: 2021-06-06 journal: Rev Med Virol DOI: 10.1002/rmv.2265 sha: 55d8324c548db44445c3152cdd64e3e1978476cb doc_id: 64665 cord_uid: fien6nra Ivermectin is an FDA‐approved drug for a parasitic disease that has broad antiviral activity. This study aims to analyse the efficacy of ivermectin in improving the Covid‐19 outcomes. We systematically searched the PubMed, Europe PMC and ClinicalTrials.gov database using specific keywords related to our aims until 10th May 2021. All published randomized clinical trial studies on Covid‐19 and ivermectin were retrieved. The quality of the study was assessed using Jadad scale assessment tool for clinical trial studies. Statistical analysis was done using Review Manager 5.4 software. A total of 19 studies with 2768 Covid‐19 patients were included in this meta‐analysis. This meta‐analysis showed that ivermectin was associated with reduction in severity of Covid‐19 (RR 0.43 [95% CI 0.23–0.81], p = 0.008), reduction of mortality (RR 0.31 [95% CI 0.15–0.62], p = 0.001), higher negative RT‐PCR test results rate (RR 1.23 [95% CI 1.01–1.51], p = 0.04), shorter time to negative RT‐PCR test results (mean difference [MD] −3.29 [95% CI −5.69, −0.89], p = 0.007), higher symptoms alleviations rate (RR 1.23 [95% CI 1.03−1.46], p = 0.02), shorter time to symptoms alleviations (MD −0.68 [95% CI −1.07, −0.29], p = 0.0007) and shorter time to hospital discharge (MD −2.66 [95% CI −4.49, −0.82], p = 0.004). Our study suggests that ivermectin may offer beneficial effects towards Covid‐19 outcomes. More randomized clinical trial studies are still needed to confirm the results of our study. At the end of 2019, the first cases of a newly discovered acute respiratory illness, named coronavirus disease 2019 (Covid- 19) , were reported in Wuhan, China. As of 22 December 2020, a total of about 75.1 million cases and 1,680,794 deaths were identified across the world. 1 Covid-19 has various clinical manifestations, ranging from mild respiratory manifestations such as fever, cough, anosmia to severe or life-threatening conditions such as shock, respiratory distress, arrhythmia, sepsis, loss of consciousness. [2] [3] [4] [5] Previous published meta-analysis studies have identified several comorbidities, 6-10 home medications 11, 12 and laboratory values 13, 14 which are associated with severe outcomes and the risk of dying from Covid-19. To reduce the severity and mortality rate of Covid-19, many attempts have been undertaken, including to discover the potential therapy. There were many therapeutic agents evaluated in clinical trials and suggested for Covid-19 therapy, such as remdesivir, dexamethasone, colchicine and tocilizumab. [15] [16] [17] These drugs may be beneficial for Covid-19 treatment because of their effects on the cytokine storm syndrome which may cause progression of the disease into more severe outcome. 18 Ivermectin is a drug that is used to manage parasitic infections with broad-spectrum effectivity and has been approved by The United States Food and Drug Administration (FDA). It has been long known for the treatment of onchocerciasis, strongyloidiasis, lymphatic filariasis and/or scabies. 19 Besides its potential as anti-parasitic agents, several articles have demonstrated the antiviral activity of ivermectin against various viruses. [20] [21] [22] Ivermectin has also been suggested to offer benefit in improving the outcomes from Covid-19 because of its action on prevention of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) proteins from entering the host cell nucleus in vitro. 23 Nonetheless, the evidence concerning the advantage of ivermectin, specifically in patients with SARS-CoV-2 infections, remains unclear. The objective of this meta-analysis is to explore the potential advantage of ivermectin to improve the outcomes of Covid-19 based on available randomized clinical trial studies. The protocol of this study has been registered in PROSPERO (3) ratio of the partial pressure of arterial oxygen (PaO2) to a fractional concentration of oxygen inspired air (FiO2) ≤300 mmHg; or (4) critical complication (respiratory failure, septic shock and or multiple organ dysfunction/failure) or intensive care unit admission. The total of dead patients due to Covid-19 was described as the mortality outcome. The other two authors assessing each included studies' quality independently, using the Jadad scale assessment. 24 The random allocation, allocation concealment, blindness and withdrawals and In electronic databases, 1612 studies were found. A total of 1237 records remained following the elimination of duplicates. By Jadad scale assessments were used to assess clinical trial studies ( Eight studies (n = 1638) reported on the severe Covid-19 outcome. Our pooled analysis showed that ivermectin administration was associated with reduction of severe Covid-19 outcome (RR 0.43 [95% CI 0.23-0.81], p = 0.008, I 2 = 65%, random-effect modelling; Figure 2a ). Eight studies (n = 1726) reported on the mortality outcome. Our pooled analysis showed that ivermectin administration was associ- Figure 2d ). Eight studies (n = 1535) reported on the symptoms alleviations rate outcome. Our pooled analysis showed that ivermectin administration was associated with higher rate of symptoms alleviations (RR 1.23 [95% CI 1.03-1.46), p = 0.02, I 2 = 85%, random-effect modelling; Figure 2e ). Quality appraisal of studies included in the meta-analysis using Jadad scale assessment Subgroup analysis revealed that ivermectin administration in mild to moderate patients showed a lower RR, therefore was associated with On the other side, subgroup analysis also revealed that ivermectin administration in severe patients showed a higher RR and higher MD in terms of negative RT-PCR test results rate (n = 224; RR Funnel plot analysis showed a relatively symmetrical inverted-plot for the negative RT-PCR test results rate (Figure 5c studies, the funnel plots and statistical tests for detecting publication bias are not much reliable when compared with whenever there are more than 10 included studies in each outcomes. 46 This study has several limitations. First, significant heterogeneities were found on most of the outcomes of interests included in this study. This was probably caused by the difference in the given ivermectin doses and the medications used as a standard of care or placebo. Second, the total number of patients included in this study was relatively small because at this time, ivermectin is still considered as new repurposed drug for Covid-19 where early trials still show conflicting results and there is still no meta-analysis study to support its efficacy, therefore it may be difficult to collect the participants and receiving their consent to participate in the trials. Third, we include some pre-print studies to minimize the risk of publication bias; however, the authors have made exhaustive efforts to ensure that only sound studies were included, and we expect that most of those studies currently available in pre-print form will eventually be published and that we will identify them through ongoing electronic literature surveillances. We hope that this study can give further insight into the management of Covid-19 patients. Our meta-analysis of randomized clinical trial studies indicates that ivermectin administration had an association with favourable out- World Health Organization. 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The Authors declare that there is no conflict of interest.