Remdesivir for the treatment of COVID-19.

Remdesivir is an antiviral medicine with properties to inhibit viral replication of SARS-CoV-2. Positive results from early studies attracted media attention and led to emergency use authorisation of remdesivir in COVID-19.  A thorough understanding of the current evidence regarding the effects of remdesivir as a treatment for SARS-CoV-2 infection based on randomised controlled trials (RCTs) is required. To assess the effects of remdesivir compared to placebo or standard care alone on clinical outcomes in hospitalised patients with SARS-CoV-2 infection, and to maintain the currency of the evidence using a living systematic review approach. We searched the Cochrane COVID-19 Study Register (which comprises the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Embase, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, and medRxiv) as well as Web of Science (Science Citation Index Expanded and Emerging Sources Citation Index) and WHO COVID-19 Global literature on coronavirus disease to identify completed and ongoing studies without language restrictions. We conducted the searches on 16 April 2021. We followed standard Cochrane methodology. We included RCTs evaluating remdesivir for the treatment of SARS-CoV-2 infection in hospitalised adults compared to placebo or standard care alone irrespective of disease severity, gender, ethnicity, or setting.  We excluded studies that evaluated remdesivir for the treatment of other coronavirus diseases. We followed standard Cochrane methodology. To assess risk of bias in included studies, we used the Cochrane RoB 2 tool for RCTs. We rated the certainty of evidence using the GRADE approach for outcomes that were reported according to our prioritised categories: all-cause mortality at up to day 28, duration to liberation from invasive mechanical ventilation, duration to liberation from supplemental oxygen, new need for mechanical ventilation (high-flow oxygen or non-invasive or invasive mechanical ventilation), new need for invasive mechanical ventilation, new need for non-invasive mechanical ventilation or high-flow oxygen, new need for oxygen by mask or nasal prongs, quality of life, adverse events (any grade), and serious adverse events. We included five RCTs with 7452 participants diagnosed with SARS-CoV-2 infection and a mean age of 59 years, of whom 3886 participants were randomised to receive remdesivir. Most participants required low-flow oxygen (n=4409) or mechanical ventilation (n=1025) at baseline. We identified two ongoing studies, one was suspended due to a lack of COVID-19 patients to recruit. Risk of bias was considered to be of some concerns or high risk for clinical status and safety outcomes because participants who had died did not contribute information to these outcomes. Without adjustment, this leads to an uncertain amount of missing values and the potential for bias due to missing data. Effects of remdesivir in hospitalised individuals  Remdesivir probably makes little or no difference to all-cause mortality at up to day 28 (risk ratio (RR) 0.93, 95% confidence interval (CI) 0.81 to 1.06; risk difference (RD) 8 fewer per 1000, 95% CI 21 fewer to 7 more; 4 studies, 7142 participants; moderate-certainty evidence). Considering the initial severity of condition, only one study showed a beneficial effect of remdesivir in patients who received low-flow oxygen at baseline (RR 0.32, 95% CI 0.15 to 0.66, 435 participants), but conflicting results exists from another study, and we were unable to validly assess this observations due to limited availability of comparable data. Remdesivir may have little or no effect on the duration to liberation from invasive mechanical ventilation (2 studies, 1298 participants, data not pooled, low-certainty evidence). We are uncertain whether remdesivir increases or decreases the chance of clinical improvement in terms of duration to liberation from supplemental oxygen at up to day 28 (3 studies, 1691 participants, data not pooled, very low-certainty evidence).   We are very uncertain whether remdesivir decreases or increases the risk of clinical worsening in terms of new need for mechanical ventilation at up to day 28 (high-flow oxygen or non-invasive ventilation or invasive mechanical ventilation) (RR 0.78, 95% CI 0.48 to 1.24; RD 29 fewer per 1000, 95% CI 68 fewer to 32 more; 3 studies, 6696 participants; very low-certainty evidence); new need for non-invasive mechanical ventilation or high-flow oxygen (RR 0.70, 95% CI 0.51 to 0.98; RD 72 fewer per 1000, 95% CI 118 fewer to 5 fewer; 1 study, 573 participants; very low-certainty evidence); and new need for oxygen by mask or nasal prongs (RR 0.81, 95% CI 0.54 to 1.22; RD 84 fewer per 1000, 95% CI 204 fewer to 98 more; 1 study, 138 participants; very low-certainty evidence). The evidence suggests that remdesivir may decrease the risk of clinical worsening in terms of new need for invasive mechanical ventilation (67 fewer participants amongst 1000 participants; RR 0.56, 95% CI 0.41 to 0.77; 2 studies, 1159 participants; low-certainty evidence).  None of the included studies reported quality of life. Remdesivir probably decreases the serious adverse events rate at up to 28 days (RR 0.75, 95% CI 0.63 to 0.90; RD 63 fewer per 1000, 95% CI 94 fewer to 25 fewer; 3 studies, 1674 participants; moderate-certainty evidence). We are very uncertain whether remdesivir increases or decreases adverse events rate (any grade) (RR 1.05, 95% CI 0.86 to 1.27; RD 29 more per 1000, 95% CI 82 fewer to 158 more; 3 studies, 1674 participants; very low-certainty evidence). Based on the currently available evidence, we are moderately certain that remdesivir probably has little or no effect on all-cause mortality at up to day 28 in hospitalised adults with SARS-CoV-2 infection. We are uncertain about the effects of remdesivir on clinical improvement and worsening. There were insufficient data available to validly examine the effect of remdesivir on mortality in subgroups depending on the extent of respiratory support at baseline.  Future studies should provide additional data on efficacy and safety of remdesivir for defined core outcomes in COVID-19 research, especially for different population subgroups. This could allow us to draw more reliable conclusions on the potential benefits and harms of remdesivir in future updates of this review. Due to the living approach of this work, we will update the review periodically.

Ansems K ，Grundeis F ，Dahms K ，Mikolajewska A ，Thieme V ，Piechotta V ，Metzendorf MI ，Stegemann M ，Benstoem C ，Fichtner F ... -  《Cochrane Database of Systematic Reviews》

Remdesivir for the treatment of COVID-19.

Remdesivir is an antiviral medicine approved for the treatment of mild-to-moderate coronavirus disease 2019 (COVID-19). This led to widespread implementation, although the available evidence remains inconsistent. This update aims to fill current knowledge gaps by identifying, describing, evaluating, and synthesising all evidence from randomised controlled trials (RCTs) on the effects of remdesivir on clinical outcomes in COVID-19. To assess the effects of remdesivir and standard care compared to standard care plus/minus placebo on clinical outcomes in patients treated for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We searched the Cochrane COVID-19 Study Register (which comprises the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Embase, ClinicalTrials.gov, World Health Organization (WHO) International Clinical Trials Registry Platform, and medRxiv) as well as Web of Science (Science Citation Index Expanded and Emerging Sources Citation Index) and WHO COVID-19 Global literature on coronavirus disease to identify completed and ongoing studies, without language restrictions. We conducted the searches on 31 May 2022. We followed standard Cochrane methodology. We included RCTs evaluating remdesivir and standard care for the treatment of SARS-CoV-2 infection compared to standard care plus/minus placebo irrespective of disease severity, gender, ethnicity, or setting. We excluded studies that evaluated remdesivir for the treatment of other coronavirus diseases. We followed standard Cochrane methodology. To assess risk of bias in included studies, we used the Cochrane RoB 2 tool for RCTs. We rated the certainty of evidence using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach for outcomes that were reported according to our prioritised categories: all-cause mortality, in-hospital mortality, clinical improvement (being alive and ready for discharge up to day 28) or worsening (new need for invasive mechanical ventilation or death up to day 28), quality of life, serious adverse events, and adverse events (any grade). We differentiated between non-hospitalised individuals with asymptomatic SARS-CoV-2 infection or mild COVID-19 and hospitalised individuals with moderate to severe COVID-19. We included nine RCTs with 11,218 participants diagnosed with SARS-CoV-2 infection and a mean age of 53.6 years, of whom 5982 participants were randomised to receive remdesivir. Most participants required low-flow oxygen at baseline. Studies were mainly conducted in high- and upper-middle-income countries. We identified two studies that are awaiting classification and five ongoing studies. Effects of remdesivir in hospitalised individuals with moderate to severe COVID-19 With moderate-certainty evidence, remdesivir probably makes little or no difference to all-cause mortality at up to day 28 (risk ratio (RR) 0.93, 95% confidence interval (CI) 0.81 to 1.06; risk difference (RD) 8 fewer per 1000, 95% CI 21 fewer to 6 more; 4 studies, 7142 participants), day 60 (RR 0.85, 95% CI 0.69 to 1.05; RD 35 fewer per 1000, 95% CI 73 fewer to 12 more; 1 study, 1281 participants), or in-hospital mortality at up to day 150 (RR 0.93, 95% CI 0.84 to 1.03; RD 11 fewer per 1000, 95% CI 25 fewer to 5 more; 1 study, 8275 participants). Remdesivir probably increases the chance of clinical improvement at up to day 28 slightly (RR 1.11, 95% CI 1.06 to 1.17; RD 68 more per 1000, 95% CI 37 more to 105 more; 4 studies, 2514 participants; moderate-certainty evidence). It probably decreases the risk of clinical worsening within 28 days (hazard ratio (HR) 0.67, 95% CI 0.54 to 0.82; RD 135 fewer per 1000, 95% CI 198 fewer to 69 fewer; 2 studies, 1734 participants, moderate-certainty evidence). Remdesivir may make little or no difference to the rate of adverse events of any grade (RR 1.04, 95% CI 0.92 to 1.18; RD 23 more per 1000, 95% CI 46 fewer to 104 more; 4 studies, 2498 participants; low-certainty evidence), or serious adverse events (RR 0.84, 95% CI 0.65 to 1.07; RD 44 fewer per 1000, 95% CI 96 fewer to 19 more; 4 studies, 2498 participants; low-certainty evidence). We considered risk of bias to be low, with some concerns for mortality and clinical course. We had some concerns for safety outcomes because participants who had died did not contribute information. Without adjustment, this leads to an uncertain amount of missing values and the potential for bias due to missing data. Effects of remdesivir in non-hospitalised individuals with mild COVID-19 One of the nine RCTs was conducted in the outpatient setting and included symptomatic people with a risk of progression. No deaths occurred within the 28 days observation period. We are uncertain about clinical improvement due to very low-certainty evidence. Remdesivir probably decreases the risk of clinical worsening (hospitalisation) at up to day 28 (RR 0.28, 95% CI 0.11 to 0.75; RD 46 fewer per 1000, 95% CI 57 fewer to 16 fewer; 562 participants; moderate-certainty evidence). We did not find any data for quality of life. Remdesivir may decrease the rate of serious adverse events at up to 28 days (RR 0.27, 95% CI 0.10 to 0.70; RD 49 fewer per 1000, 95% CI 60 fewer to 20 fewer; 562 participants; low-certainty evidence), but it probably makes little or no difference to the risk of adverse events of any grade (RR 0.91, 95% CI 0.76 to 1.10; RD 42 fewer per 1000, 95% CI 111 fewer to 46 more; 562 participants; moderate-certainty evidence). We considered risk of bias to be low for mortality, clinical improvement, and safety outcomes. We identified a high risk of bias for clinical worsening. Based on the available evidence up to 31 May 2022, remdesivir probably has little or no effect on all-cause mortality or in-hospital mortality of individuals with moderate to severe COVID-19. The hospitalisation rate was reduced with remdesivir in one study including participants with mild to moderate COVID-19. It may be beneficial in the clinical course for both hospitalised and non-hospitalised patients, but certainty remains limited. The applicability of the evidence to current practice may be limited by the recruitment of participants from mostly unvaccinated populations exposed to early variants of the SARS-CoV-2 virus at the time the studies were undertaken.  Future studies should provide additional data on the efficacy and safety of remdesivir for defined core outcomes in COVID-19 research, especially for different population subgroups.

Grundeis F ，Ansems K ，Dahms K ，Thieme V ，Metzendorf MI ，Skoetz N ，Benstoem C ，Mikolajewska A ，Griesel M ，Fichtner F ，Stegemann M ... -  《Cochrane Database of Systematic Reviews》

Colchicine for the treatment of COVID-19.

The development of severe coronavirus disease 2019 (COVID-19) and poor clinical outcomes are associated with hyperinflammation and a complex dysregulation of the immune response. Colchicine is an anti-inflammatory medicine and is thought to improve disease outcomes in COVID-19 through a wide range of anti-inflammatory mechanisms. Patients and healthcare systems need more and better treatment options for COVID-19 and a thorough understanding of the current body of evidence. To assess the effectiveness and safety of Colchicine as a treatment option for COVID-19 in comparison to an active comparator, placebo, or standard care alone in any setting, and to maintain the currency of the evidence, using a living systematic review approach. We searched the Cochrane COVID-19 Study Register (comprising CENTRAL, MEDLINE (PubMed), Embase, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, and medRxiv), Web of Science (Science Citation Index Expanded and Emerging Sources Citation Index), and WHO COVID-19 Global literature on coronavirus disease to identify completed and ongoing studies without language restrictions to 21 May 2021. We included randomised controlled trials evaluating colchicine for the treatment of people with COVID-19, irrespective of disease severity, age, sex, or ethnicity. We excluded studies investigating the prophylactic effects of colchicine for people without severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection but at high risk of SARS-CoV-2 exposure. We followed standard Cochrane methodology. We used the Cochrane risk of bias tool (ROB 2) to assess bias in included studies and GRADE to rate the certainty of evidence for the following prioritised outcome categories considering people with moderate or severe COVID-19: all-cause mortality, worsening and improvement of clinical status, quality of life, adverse events, and serious adverse events and for people with asymptomatic infection or mild disease: all-cause mortality, admission to hospital or death, symptom resolution, duration to symptom resolution, quality of life, adverse events, serious adverse events. We included three RCTs with 11,525 hospitalised participants (8002 male) and one RCT with 4488 (2067 male) non-hospitalised participants. Mean age of people treated in hospital was about 64 years, and was 55 years in the study with non-hospitalised participants. Further, we identified 17 ongoing studies and 11 studies completed or terminated, but without published results. Colchicine plus standard care versus standard care (plus/minus placebo) Treatment of hospitalised people with moderate to severe COVID-19 All-cause mortality: colchicine plus standard care probably results in little to no difference in all-cause mortality up to 28 days compared to standard care alone (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.93 to 1.08; 2 RCTs, 11,445 participants; moderate-certainty evidence). Worsening of clinical status: colchicine plus standard care probably results in little to no difference in worsening of clinical status assessed as new need for invasive mechanical ventilation or death compared to standard care alone (RR 1.02, 95% CI 0.96 to 1.09; 2 RCTs, 10,916 participants; moderate-certainty evidence). Improvement of clinical status: colchicine plus standard care probably results in little to no difference in improvement of clinical status, assessed as number of participants discharged alive up to day 28 without clinical deterioration or death compared to standard care alone (RR 0.99, 95% CI 0.96 to 1.01; 1 RCT, 11,340 participants; moderate-certainty evidence). Quality of life, including fatigue and neurological status: we identified no studies reporting this outcome. Adverse events: the evidence is very uncertain about the effect of colchicine on adverse events compared to placebo (RR 1.00, 95% CI 0.56 to 1.78; 1 RCT, 72 participants; very low-certainty evidence). Serious adverse events: the evidence is very uncertain about the effect of colchicine plus standard care on serious adverse events compared to standard care alone (0 events observed in 1 RCT of 105 participants; very low-certainty evidence). Treatment of non-hospitalised people with asymptomatic SARS-CoV-2 infection or mild COVID-19 All-cause mortality: the evidence is uncertain about the effect of colchicine on all-cause mortality at 28 days (Peto odds ratio (OR) 0.57, 95% CI 0.20 to 1.62; 1 RCT, 4488 participants; low-certainty evidence). Admission to hospital or death within 28 days: colchicine probably slightly reduces the need for hospitalisation or death within 28 days compared to placebo (RR 0.80, 95% CI 0.62 to 1.03; 1 RCT, 4488 participants; moderate-certainty evidence). Symptom resolution: we identified no studies reporting this outcome. Quality of life, including fatigue and neurological status: we identified no studies reporting this outcome. Adverse events: the evidence is uncertain about the effect of colchicine on adverse events compared to placebo . Results are from one RCT reporting treatment-related events only in 4412 participants (low-certainty evidence). Serious adverse events: colchicine probably slightly reduces serious adverse events (RR 0.78, 95% CI 0.61 to 1.00; 1 RCT, 4412 participants; moderate-certainty evidence). Colchicine versus another active treatment (e.g. corticosteroids, anti-viral drugs, monoclonal antibodies) No studies evaluated this comparison. Different formulations, doses, or schedules of colchicine No studies assessed this. Based on the current evidence, in people hospitalised with moderate to severe COVID-19 the use of colchicine probably has little to no influence on mortality or clinical progression in comparison to placebo or standard care alone. We do not know whether colchicine increases the risk of (serious) adverse events. We are uncertain about the evidence of the effect of colchicine on all-cause mortality for people with asymptomatic infection or mild disease. However, colchicine probably results in a slight reduction of hospital admissions or deaths within 28 days, and the rate of serious adverse events compared with placebo. None of the studies reported data on quality of life or compared the benefits and harms of colchicine versus other drugs, or different dosages of colchicine. We identified 17 ongoing and 11 completed but not published RCTs, which we expect to incorporate in future versions of this review as their results become available. Editorial note: due to the living approach of this work, we monitor newly published results of RCTs on colchicine on a weekly basis and will update the review when the evidence or our certainty in the evidence changes.

Mikolajewska A ，Fischer AL ，Piechotta V ，Mueller A ，Metzendorf MI ，Becker M ，Dorando E ，Pacheco RL ，Martimbianco ALC ，Riera R ，Skoetz N ，Stegemann M ... -  《Cochrane Database of Systematic Reviews》

Early versus late tracheostomy in critically ill COVID-19 patients.

The role of early tracheostomy as an intervention for critically ill COVID-19 patients is unclear. Previous reports have described prolonged intensive care stays and difficulty weaning from mechanical ventilation in critically ill COVID-19 patients, particularly in those developing acute respiratory distress syndrome. Pre-pandemic evidence on the benefits of early tracheostomy is conflicting but suggests shorter hospital stays and lower mortality rates compared to late tracheostomy. To assess the benefits and harms of early tracheostomy compared to late tracheostomy in critically ill COVID-19 patients. We searched the Cochrane COVID-19 Study Register, which comprises CENTRAL, PubMed, Embase, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, and medRxiv, as well as Web of Science (Science Citation Index Expanded and Emerging Sources Citation Index) and WHO COVID-19 Global literature on coronavirus disease to identify completed and ongoing studies without language restrictions. We conducted the searches on 14 June 2022. We followed standard Cochrane methodology. We included randomized controlled trials (RCTs) and non-randomized studies of interventions (NRSI) evaluating early tracheostomy compared to late tracheostomy during SARS-CoV-2 infection in critically ill adults irrespective of gender, ethnicity, or setting. We followed standard Cochrane methodology. To assess risk of bias in included studies, we used the Cochrane RoB 2 tool for RCTs and the ROBINS-I tool for NRSIs. We used the GRADE approach to assess the certainty of evidence for outcomes of our prioritized categories: mortality, clinical status, and intensive care unit (ICU) length of stay. As the timing of tracheostomy was very heterogeneous among the included studies, we applied GRADE only to studies that defined early tracheostomy as 10 days or less, which was chosen according to clinical relevance. We included one RCT with 150 participants diagnosed with SARS-CoV-2 infection and 24 NRSIs with 6372 participants diagnosed with SARS-CoV-2 infection. All participants were admitted to the ICU, orally intubated and mechanically ventilated. The RCT was a multicenter, parallel, single-blinded study conducted in Sweden. Of the 24 NRSIs, which were mostly conducted in high- and middle-income countries, eight had a prospective design and 16 a retrospective design. We did not find any ongoing studies. RCT-based evidence We judged risk of bias for the RCT to be of low or some concerns regarding randomization and measurement of the outcome. Early tracheostomy may result in little to no difference in overall mortality (RR 0.82, 95% CI 0.52 to 1.29; RD 67 fewer per 1000, 95% CI 178 fewer to 108 more; 1 study, 150 participants; low-certainty evidence). As an indicator of improvement of clinical status, early tracheostomy may result in little to no difference in duration to liberation from invasive mechanical ventilation (MD 1.50 days fewer, 95%, CI 5.74 days fewer to 2.74 days more; 1 study, 150 participants; low-certainty evidence). As an indicator of worsening clinical status, early tracheostomy may result in little to no difference in the incidence of adverse events of any grade (RR 0.94, 95% CI 0.79 to 1.13; RD 47 fewer per 1000, 95% CI 164 fewer to 102 more; 1 study, 150 participants; low-certainty evidence); little to no difference in the incidence of ventilator-associated pneumonia (RR 1.08, 95% CI 0.23 to 5.20; RD 3 more per 1000, 95% CI 30 fewer to 162 more; 1 study, 150 participants; low-certainty evidence). None of the studies reported need for renal replacement therapy. Early tracheostomy may result in little benefit to no difference in ICU length of stay (MD 0.5 days fewer, 95% CI 5.34 days fewer to 4.34 days more; 1 study, 150 participants; low-certainty evidence). NRSI-based evidence We considered risk of bias for NRSIs to be critical because of possible confounding, study participant enrollment into the studies, intervention classification and potentially systematic errors in the measurement of outcomes. We are uncertain whether early tracheostomy (≤ 10 days) increases or decreases overall mortality (RR 1.47, 95% CI 0.43 to 5.00; RD 143 more per 1000, 95% CI 174 less to 1218 more; I2 = 79%; 2 studies, 719 participants) or duration to liberation from mechanical ventilation (MD 1.98 days fewer, 95% CI 0.16 days fewer to 4.12 more; 1 study, 50 participants), because we graded the certainty of evidence as very low. Three NRSIs reported ICU length of stay for 519 patients with early tracheostomy (≤ 10 days) as a median value, which we could not include in the meta-analyses. We are uncertain whether early tracheostomy (≤ 10 days) increases or decreases the ICU length of stay, because we graded the certainty of evidence as very low. We found low-certainty evidence that early tracheostomy may result in little to no difference in overall mortality in critically ill COVID-19 patients requiring prolonged mechanical ventilation compared with late tracheostomy. In terms of clinical improvement, early tracheostomy may result in little to no difference in duration to liberation from mechanical ventilation compared with late tracheostomy. We are not certain about the impact of early tracheostomy on clinical worsening in terms of the incidence of adverse events, need for renal replacement therapy, ventilator-associated pneumonia, or the length of stay in the ICU. Future RCTs should provide additional data on the benefits and harms of early tracheostomy for defined main outcomes of COVID-19 research, as well as of comparable diseases, especially for different population subgroups to reduce clinical heterogeneity, and report a longer observation period. Then it would be possible to draw conclusions regarding which patient groups might benefit from early intervention. Furthermore, validated scoring systems for more accurate predictions of the need for prolonged mechanical ventilation should be developed and used in new RCTs to ensure safer indication and patient safety. High-quality (prospectively registered) NRSIs should be conducted in the future to provide valuable answers to clinical questions. This could enable us to draw more reliable conclusions about the potential benefits and harms of early tracheostomy in critically ill COVID-19 patients.

Szafran A ，Dahms K ，Ansems K ，Skoetz N ，Monsef I ，Breuer T ，Benstoem C ... -  《Cochrane Database of Systematic Reviews》

Ivermectin for preventing and treating COVID-19.

Ivermectin, an antiparasitic agent used to treat parasitic infestations, inhibits the replication of viruses in vitro. The molecular hypothesis of ivermectin's antiviral mode of action suggests an inhibitory effect on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication in the early stages of infection. Currently, evidence on efficacy and safety of ivermectin for prevention of SARS-CoV-2 infection and COVID-19 treatment is conflicting. To assess the efficacy and safety of ivermectin compared to no treatment, standard of care, placebo, or any other proven intervention for people with COVID-19 receiving treatment as inpatients or outpatients, and for prevention of an infection with SARS-CoV-2 (postexposure prophylaxis). We searched the Cochrane COVID-19 Study Register, Web of Science (Emerging Citation Index and Science Citation Index), medRxiv, and Research Square, identifying completed and ongoing studies without language restrictions to 26 May 2021. We included randomized controlled trials (RCTs) comparing ivermectin to no treatment, standard of care, placebo, or another proven intervention for treatment of people with confirmed COVID-19 diagnosis, irrespective of disease severity, treated in inpatient or outpatient settings, and for prevention of SARS-CoV-2 infection. Co-interventions had to be the same in both study arms.  We excluded studies comparing ivermectin to other pharmacological interventions with unproven efficacy. We assessed RCTs for bias, using the Cochrane risk of bias 2 tool. The primary analysis excluded studies with high risk of bias. We used GRADE to rate the certainty of evidence for the following outcomes 1. to treat inpatients with moderate-to-severe COVID-19: mortality, clinical worsening or improvement, adverse events, quality of life, duration of hospitalization, and viral clearance; 2. to treat outpatients with mild COVID-19: mortality, clinical worsening or improvement, admission to hospital, adverse events, quality of life, and viral clearance; (3) to prevent SARS-CoV-2 infection: SARS-CoV-2 infection, development of COVID-19 symptoms, adverse events, mortality, admission to hospital, and quality of life. We found 14 studies with 1678 participants investigating ivermectin compared to no treatment, placebo, or standard of care. No study compared ivermectin to an intervention with proven efficacy. There were nine studies treating participants with moderate COVID-19 in inpatient settings and four treating mild COVID-19 cases in outpatient settings. One study investigated ivermectin for prevention of SARS-CoV-2 infection. Eight studies had an open-label design, six were double-blind and placebo-controlled. Of the 41 study results contributed by included studies, about one third were at overall high risk of bias.  Ivermectin doses and treatment duration varied among included studies.  We identified 31 ongoing and 18 studies awaiting classification until publication of results or clarification of inconsistencies. Ivermectin compared to placebo or standard of care for inpatient COVID-19 treatment We are uncertain whether ivermectin compared to placebo or standard of care reduces or increases mortality (risk ratio (RR) 0.60, 95% confidence interval (CI) 0.14 to 2.51; 2 studies, 185 participants; very low-certainty evidence) and clinical worsening up to day 28 assessed as need for invasive mechanical ventilation (IMV) (RR 0.55, 95% CI 0.11 to 2.59; 2 studies, 185 participants; very low-certainty evidence) or need for supplemental oxygen (0 participants required supplemental oxygen; 1 study, 45 participants; very low-certainty evidence), adverse events within 28 days (RR 1.21, 95% CI 0.50 to 2.97; 1 study, 152 participants; very low-certainty evidence), and viral clearance at day seven (RR 1.82, 95% CI 0.51 to 6.48; 2 studies, 159 participants; very low-certainty evidence). Ivermectin may have little or no effect compared to placebo or standard of care on clinical improvement up to 28 days (RR 1.03, 95% CI 0.78 to 1.35; 1 study; 73 participants; low-certainty evidence) and duration of hospitalization (mean difference (MD) -0.10 days, 95% CI -2.43 to 2.23; 1 study; 45 participants; low-certainty evidence). No study reported quality of life up to 28 days. Ivermectin compared to placebo or standard of care for outpatient COVID-19 treatment We are uncertain whether ivermectin compared to placebo or standard of care reduces or increases mortality up to 28 days (RR 0.33, 95% CI 0.01 to 8.05; 2 studies, 422 participants; very low-certainty evidence) and clinical worsening up to 14 days assessed as need for IMV (RR 2.97, 95% CI 0.12 to 72.47; 1 study, 398 participants; very low-certainty evidence) or non-IMV or high flow oxygen requirement (0 participants required non-IMV or high flow; 1 study, 398 participants; very low-certainty evidence). We are uncertain whether ivermectin compared to placebo reduces or increases viral clearance at seven days (RR 3.00, 95% CI 0.13 to 67.06; 1 study, 24 participants; low-certainty evidence). Ivermectin may have little or no effect compared to placebo or standard of care on the number of participants with symptoms resolved up to 14 days (RR 1.04, 95% CI 0.89 to 1.21; 1 study, 398 participants; low-certainty evidence) and adverse events within 28 days (RR 0.95, 95% CI 0.86 to 1.05; 2 studies, 422 participants; low-certainty evidence). None of the studies reporting duration of symptoms were eligible for primary analysis. No study reported hospital admission or quality of life up to 14 days. Ivermectin compared to no treatment for prevention of SARS-CoV-2 infection We found one study. Mortality up to 28 days was the only outcome eligible for primary analysis. We are uncertain whether ivermectin reduces or increases mortality compared to no treatment (0 participants died; 1 study, 304 participants; very low-certainty evidence). The study reported results for development of COVID-19 symptoms and adverse events up to 14 days that were included in a secondary analysis due to high risk of bias. No study reported SARS-CoV-2 infection, hospital admission, and quality of life up to 14 days. Based on the current very low- to low-certainty evidence, we are uncertain about the efficacy and safety of ivermectin used to treat or prevent COVID-19. The completed studies are small and few are considered high quality. Several studies are underway that may produce clearer answers in review updates. Overall, the reliable evidence available does not support the use ivermectin for treatment or prevention of COVID-19 outside of well-designed randomized trials.

Popp M ，Stegemann M ，Metzendorf MI ，Gould S ，Kranke P ，Meybohm P ，Skoetz N ，Weibel S ... -  《Cochrane Database of Systematic Reviews》