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PurposeTo assess the trustworthiness and impact of preprint trial reports during the COVID-19 pandemic. Data sourcesWHO COVID-19 database and the L-OVE COVID-19 platform by the Epistemonikos Foundation (up to August 3rd, 2021) DesignWe compare the characteristics of COVID-19 trials with and without preprints, estimate time to publication of COVID-19 preprint reports, describe discrepancies in key methods and results between preprint and published trial reports, report the number of retracted preprints and publications, and assess whether including versus excluding preprint reports affects meta-analytic estimates and the certainty of evidence. For the effects of eight therapies on mortality and mechanical ventilation, we performed meta-analyses including preprints and excluding preprints at 1 month, 3 months, and 6 months after the first trial addressing the therapy became available either as a preprint or publication (120 meta-analyses in total). ResultsWe included 356 trials, 101 of which are only available as preprints, 181 as journal publications, and 74 as preprints first and subsequently published in journals. Half of all preprints remain unpublished at six months and a third at one year. There were few important differences in key methods and results between trial preprints and their subsequent published reports. We identified four retracted trials, three of which were published in peer-reviewed journals. With two exceptions (2/60; 3.3%), point estimates were consistent between meta-analyses including versus excluding preprints as to whether they indicated benefit, no appreciable effect, or harm. There were nine comparisons (9/60; 15%) for which the rating of the certainty of evidence differed when preprints were included versus excluded, for four of these comparisons the certainty of evidence including preprints was higher and for five of these comparisons the certainty of evidence including preprints was lower. LimitationsThe generalizability of our results is limited to COVID-19. Preprints that are subsequently published in journals may be the most rigorous and may not represent all trial preprints. ConclusionWe found no compelling evidence that preprints provide less trustworthy results than published papers. We show that preprints remain the only source of findings of many trials for several months, a length of time that is unacceptable in a health emergency. We show that including preprints may affect the results of meta-analyses and the certainty of evidence. We encourage evidence users to consider data from preprints in contexts in which decisions are being made rapidly and evidence is being produced faster than can be peer-reviewed. O_TEXTBOXSummary Box 1O_ST_ABSWhat is already known on this topicC_ST_ABSO_LIClinicians and decision-makers need rapidly available and credible data addressing the comparative effectiveness of treatments and prophylaxis for COVID-19. C_LIO_LIInvestigators have adopted preprint servers, which allow the rapid dissemination of research findings before publication in peer-reviewed journals. C_LI What this study addsO_LIWe found no compelling evidence that preprints provide less trustworthy results than published papers. C_LIO_LIWe show that including preprints may affect the results of meta-analyses and the certainty of evidence and we encourage evidence users to consider data from preprints in contexts in which decisions are being made rapidly and evidence is being produced faster than can be peer-reviewed. C_LI C_TEXTBOX
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ObjectiveCOVID-19 Living OVerview of Evidence (COVID-19 L{middle dot}OVE) is a public repository and classification platform for COVID-19 articles. The repository contains over 430,000 articles as of 20 September 2021 and intends to provide a one-stop shop for COVID-19 evidence. Considering that systematic reviews conduct high-quality searches, this study assesses the comprehensiveness and currency of the repository against the total number of studies in a representative sample of COVID-19 systematic reviews. MethodsOur sample was generated from all the studies included in the systematic reviews of COVID-19 published during April 2021. We estimated the comprehensiveness of COVID-19 L{middle dot}OVE repository by determining how many of the individual studies in the sample were included in the COVID-19 L{middle dot}OVE repository. We estimated the currency as the percentage of studies that were available in the COVID-19 L{middle dot}OVE repository at the time the systematic reviews conducted their own search. ResultsWe identified 83 eligible systematic reviews that included 2132 studies. COVID-19 L{middle dot}OVE had an overall comprehensiveness of 99.67% (2125/2132). The overall currency of the repository, that is, the proportion of articles that would have been obtained if the search of the reviews was conducted in COVID-19 L{middle dot}OVE instead of searching the original sources, was 96.48% (2057/2132). Both the comprehensiveness and the currency were 100% for randomised trials (82/82). ConclusionThe COVID-19 L{middle dot}OVE repository is highly comprehensive and current. Using this repository instead of traditional manual searches in multiple databases can save a great amount of work to people conducting systematic reviews and would improve the comprehensiveness and timeliness of evidence syntheses. This tool is particularly important for supporting living evidence synthesis processes
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Background and purposeThe objective of this systematic review is to summarize the effects of ivermectin for the prevention and treatment of patients with COVID-19 and to assess inconsistencies in results from individual studies with focus on risk of bias due to methodological limitations. Evidence reviewWe searched the L.OVE platform through July 6, 2021 and included randomized trials (RCTs) comparing ivermectin to standard or other active treatments. We conducted random-effects pairwise meta-analysis, assessed the certainty of evidence using the GRADE approach and performed sensitivity analysis excluding trials with risk of bias. ResultsWe included 29 RCTs which enrolled 5592 cases. Overall, the certainty of the evidence was very low to low. Compared to standard of care, ivermectin may reduce mortality, may increase symptom resolution or improvement, may increase viral clearance, may reduce infections in exposed individuals and may decrease hospitalizations (Risk difference (RD) 21 fewer per 1000, 95%CI: 35 fewer to 4 more). However, after excluding trials classified as "high risk" or "some concerns" in the risk of bias assessment, most estimates of effect changed substantially: Compared to standard of care, low certainty evidence suggests that ivermectin may not significantly reduce mortality (RD 7 fewer per 1000, 95%CI: 77 fewer to 108 more) nor mechanical ventilation (RD 6 more per 1000, 95%CI: 43 fewer to 86 more), and moderate certainty evidence shows that it probably does not significantly increase symptom resolution or improvement (RD 14 more per 1000, 95%CI: 29 fewer to 71 more) nor viral clearance (RD 12 fewer per 1000, 95%CI: 84 fewer to 76 more). It is uncertain if ivermectin increases or decreases severe adverse events and symptomatic infections in exposed individuals. Conclusions and RelevanceIvermectin may not improve clinically important outcomes in patients with COVID-19 and its effects as a prophylactic intervention in exposed individuals are uncertain. Previous reports concluding significant benefits associated with ivermectin are based on potentially biased results reported by studies with substantial methodological limitations. Further research is needed.
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ObjectiveTo determine and compare the effects of drug prophylaxis on severe acute respiratory syndrome coronavirus virus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (covid-19). DesignLiving systematic review and network meta-analysis. Data sourcesWHO covid-19 database, a comprehensive multilingual source of global covid-19 literature to 19 January 2021, and six additional Chinese databases to 20 January 2021. Study selectionRandomized trials in which people at risk of covid-19 were randomized to drug prophylaxis or no prophylaxis (standard care or placebo). Pairs of reviewers independently screened potentially eligible articles. MethodsAfter duplicate data abstraction, we conducted random-effects bayesian network meta-analysis. We assessed risk of bias of the included studies using a modification of the Cochrane risk of bias 2.0 tool and assessed the certainty of the evidence using the grading of recommendations assessment, development and evaluation (GRADE) approach. ResultsThe first iteration of this living network meta-analysis includes nine randomized trials - six addressing hydroxychloroquine (6,059 participants), one addressing ivermectin combined with iota-carrageenan (234 participants) and two addressing ivermectin alone (540 participants), all compared to standard care or placebo. Hydroxychloroquine has no important effect on admission to hospital (risk difference (RD) 1 fewer per 1,000, 95% credible interval (CrI) 3 fewer to 4 more, high certainty) or mortality (RD 1 fewer per 1,000, 95% CrI 2 fewer to 3 more, high certainty). Hydroxychloroquine probably has no important effect on laboratory-confirmed infection (RD 2 more per 1,000, 95% CrI 18 fewer to 28 more, moderate certainty), probably increases adverse effects leading to drug discontinuation (RD 19 more per 1,000, 95% CrI 1 fewer to 70 more, moderate certainty) and may have no important effect on suspected, probable or laboratory-confirmed infection (RD 15 fewer per 1,000, 95% CrI 64 fewer to 41 more, low certainty). Due to serious risk of bias and very serious imprecision - and thus very low certainty evidence, the effects of ivermectin combined with iota-carrageenan on laboratory-confirmed infection (RD 52 fewer per 1,000, 95% CrI 58 fewer to 37 fewer), and ivermectin alone on laboratory-confirmed infection (RD 50 fewer per 1,000, 95% CrI 59 fewer to 16 fewer) and suspected, probable or laboratory-confirmed infection (RD 159 fewer per 1,000, 95% CrI 165 fewer to 144 fewer) remain uncertain. ConclusionHydroxychloroquine prophylaxis does not have an important effect on hospital admission and mortality, probably increases adverse effects, and probably does not have an important effect on laboratory-confirmed SARS-CoV-2 infection. Because of serious risk of bias and very serious imprecision, we are highly uncertain whether ivermectin combined with iota-carrageenan and ivermectin alone reduce the risk of SARS-CoV-2 infection. Systematic review registrationThis review was not registered. The protocol established a priori is included as a supplement. FundingThis study was supported by the Canadian Institutes of Health Research (grant CIHR-IRSC:0579001321). Readers noteThis article is a living systematic review that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication.
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Objective This living systematic review aims to provide a timely, rigorous and continuously updated summary of the evidence available on the role of remdesivir in the treatment of patients with COVID-19 Methods We adapted an already published common protocol for multiple parallel systematic reviews to the specificities of this question. Eligible studies were randomised trials evaluating the effect of remdesivir versus placebo or no treatment. We conducted searches in the LOVE (Living OVerview of Evidence) platform for COVID-19, a system that maps PICO questions to a repository maintained through regular searches in electronic databases, preprint servers, trial registries and other resources relevant to COVID-19. All the searches covered the period until 25 August 2020. No date or language restrictions were applied. Two reviewers independently evaluated potentially eligible studies according to predefined selection criteria, and extracted data on study characteristics, methods, outcomes, and risk of bias, using a predesigned, standardised form. We performed meta-analyses using random-effect models and assessed overall certainty in evidence using the GRADE approach. A living, web-based version of this review will be openly available during the COVID-19 pandemic. We will resubmit it every time the conclusions change or whenever there are substantial updates. Results Our search strategy yielded 574 references. Finally, we included 3 randomised trials evaluating remdesivir in addition to standard care versus standard care alone. The evidence is very uncertain about the effect of remdesivir on mortality (RR 0.7, 95% CI 0.46 to 1.05; very low certainty evidence) and the need for invasive mechanical ventilation (RR 0.69, 95% CI 0.39 to 1.24; very low certainty evidence). On the other hand, remdesivir likely results in a large reduction in the incidence of adverse effects in patients with COVID-19 (RR 1.29, 95% CI 0.58 to 2.84; moderate certainty evidence). Conclusions The evidence is insufficient for the outcomes critical for making decisions about the role of remdesivir in the treatment of patients with COVID-19, so it is not possible to balance the potential benefits, if any, with the adverse effects and costs. PROSPERO Registration number CRD42020183384 Keywords COVID-19, Coronavirus disease, Severe Acute Respiratory Syndrome Coronavirus 2, Coronavirus Infections, Systematic Review, Remdesivir, Antivirals
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ObjectiveThis living systematic review aims to provide a timely, rigorous and continuously updated summary of the evidence available on the role of vitamin C in the treatment of patients with COVID-19. Data sourcesWe will conduct searches in PubMed/Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), grey literature and in a centralised repository in L{middle dot}OVE (Living OVerview of Evidence). L{middle dot}OVE is a platform that maps PICO questions to evidence from Epistemonikos database. In response to the COVID-19 emergency, L{middle dot}OVE was adapted to expand the range of evidence it covers and customised to group all COVID-19 evidence in one place. The search will coverthe period until the day before submission to a journal. Eligibility criteria for selecting studies and methodsWe adapted an already published common protocol for multiple parallel systematic reviews to the specificities of this question. We will include randomised trials evaluating the effect of vitamin C, as monotherapy or in combination with other drugs, versus placebo or no treatment in patients with COVID-19. Randomised trials evaluating vitamin C in infections caused by other coronaviruses, such as MERS-CoV and SARS-CoV, and non-randomised studies in COVID-19 will be searched in case no direct evidence from randomised trials is found, or if the direct evidence provides low- or very low-certainty for critical outcomes. Two reviewers will independently screen each study for eligibility, extract data, and assess the risk of bias. We will pool the results using meta-analysis and will apply the GRADE system to assess the certainty of the evidence for each outcome. A living, web-based version of this review will be openly available during the COVID-19 pandemic. We will resubmit it every time the conclusions change or whenever there are substantial updates. Ethics and disseminationNo ethics approval is considered necessary. The results of this review will be widely disseminated via peer-reviewed publications, social networks and traditional media. PROSPERO RegistrationSubmitted to PROSPERO (awaiting ID allocation) COVID-19 L OVE Working Group
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ObjectiveThis living systematic review aims to provide a timely, rigorous and continuously updated summary of the available evidence on the role of cell-based therapies in the treatment of patients with COVID-19. Data sourcesWe conducted searches in PubMed/Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), grey literature and in a centralised repository in L-OVE (Living OVerview of Evidence). L-OVE is a platform that maps PICO questions to evidence from Epistemonikos database. In response to the COVID-19 emergency, L-OVE was adapted to expand the range of evidence it covers and customised to group all COVID-19 evidence in one place. All the searches covered the period until April 23, 2020 (one day before submission). Eligibility criteria for selecting studies and methodsWe adapted an already published common protocol for multiple parallel systematic reviews to the specificities of this question. We searched for randomised trials evaluating the effect of cell-based therapies versus placebo or no treatment in patients with COVID-19. Anticipating the lack of randomised trials directly addressing this question, we also searched for trials evaluating other coronavirus infections, such as MERS-CoV and SARS-CoV, and non-randomised studies in COVID-19. Two reviewers independently screened each study for eligibility. A living, web-based version of this review will be openly available during the COVID-19 pandemic. We will resubmit it every time the conclusions change or whenever there are substantial updates. ResultsWe screened 1,043 records but no study was considered eligible. We identified 61 ongoing studies, including 39 randomised trials evaluating different types of cell-based therapies in COVID-19. ConclusionsWe did not find any studies that met our inclusion criteria and hence there is no evidence to support or refute the use of cell-based therapies in the treatment of patients with COVID-19. A substantial number of ongoing studies should provide valuable evidence to inform researchers and decision makers in the near future. PROSPERO Registration numberCRD42020179711 O_TEXTBOXO_TEXTBOXNOBox 1C_TEXTBOXNO Linked resources in this Living Systematic Review Common protocolCommon protocol for the systematic reviews and overviews of systematic reviews being conducted by the COVID-19 L{middle dot}OVE Working Group. Available here Living reviewWeb version of this systematic review, presented in a living systematic review format. This means it is continuously updated as soon as new evidence emerges. Available here Living OVerview of Evidence - L{middle dot}OVEAn open platform that uses artificial intelligence and a broad network of contributors to identify all of the evidence relevant to this and other healthcare questions, including those related to COVID-19. Available here C_TEXTBOX
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ObjectiveTo determine the impact of mesenchymal stromal cells outcomes important to patients with COVID-19. DesignThis is the protocol of a living systematic review. Data sourcesWe will conduct searches in PubMed/Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), grey literature and in a centralised repository in L{middle dot}OVE (Living OVerview of Evidence). L{middle dot}OVE is a platform that maps PICO questions to evidence from Epistemonikos database. In response to the COVID-19 emergency, L{middle dot}OVE was adapted to expand the range of evidence it covers and customised to group all COVID-19 evidence in one place. The search will cover the period until the day before submission to a journal. Eligibility criteria for selecting studies and methodsWe adapted an already published common protocol for multiple parallel systematic reviews to the specificities of this question. We will include randomised trials evaluating the effect of mesenchymal stromal cells versus placebo or no treatment in patients with COVID-19. Randomised trials evaluating other coronavirus infections, such as MERS-CoV and SARS-CoV, and non-randomised studies in COVID-19 will be searched in case we find no direct evidence from randomised trials, or if the direct evidence provides low- or very low-certainty for critical outcomes. Two reviewers will independently screen each study for eligibility, extract data, and assess the risk of bias. We will pool the results using meta-analysis and will apply the GRADE system to assess the certainty of the evidence for each outcome. A living, web-based version of this review will be openly available during the COVID-19 pandemic. We will resubmit it every time the conclusions change or whenever there are substantial updates. Ethics and disseminationNo ethics approval is considered necessary. The results of this review will be widely disseminated via peer-reviewed publications, social networks and traditional media. PROSPERO RegistrationSubmitted to PROSPERO (awaiting ID allocation).
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ObjectiveTo assess the efficacy and safety of lopinavir/ritonavir for the treatment of patients with COVID-19. DesignThis is the protocol of a living systematic review. Data sourcesWe will conduct searches in PubMed/Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), grey literature and in a centralised repository in L{middle dot}OVE (Living OVerview of Evidence). L{middle dot}OVE is a platform that maps PICO questions to evidence from Epistemonikos database. In response to the COVID-19 emergency, L{middle dot}OVE was adapted to expand the range of evidence it covers and customised to group all COVID-19 evidence in one place. The search will cover the period until the day before submission to a journal. Eligibility criteria for selecting studies and methodsWe adapted an already published common protocol for multiple parallel systematic reviews to the specificities of this question. We will include randomised trials evaluating the effect of lopinavir/ritonavir-- as monotherapy or in combination with other drugs -- versus placebo or no treatment in patients with COVID-19. Randomised trials evaluating lopinavir/ritonavir in infections caused by other coronaviruses, such as MERS-CoV and SARS-CoV, and non-randomised studies in COVID-19 will be searched in case no direct evidence from randomised trials is found, or if the direct evidence provides low- or very low-certainty for critical outcomes. Two reviewers will independently screen each study for eligibility, extract data, and assess the risk of bias. We will perform random-effects meta-analyses and use GRADE to assess the certainty of the evidence for each outcome. A living, web-based version of this review will be openly available during the COVID-19 pandemic. We will resubmit it if the conclusions change or there are substantial updates. Ethics and disseminationNo ethics approval is considered necessary. The results of this review will be widely disseminated via peer-reviewed publications, social networks and traditional media. PROSPERO RegistrationSubmitted to PROSPERO (awaiting ID allocation).
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ObjectiveThe objective of our systematic review is to identify prognostic factors that can potentially be used in decision-making related to the care of patients infected with COVID-19. DesignThis is the protocol of a living systematic review. Data sourcesWe will conduct searches in PubMed/Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), grey literature and in a centralised repository in L{middle dot}OVE (Living OVerview of Evidence). L{middle dot}OVE is a platform that maps PICO questions to evidence from Epistemonikos database. In response to the COVID-19 emergency, L{middle dot}OVE was adapted to expand the range of evidence covered and customised to group all COVID-19 evidence in one place. The search will continue until the day before submission to a journal. Eligibility criteria for selecting studies and methodsWe will follow a common protocol for multiple parallel systematic reviews, already published and submitted to PROSPERO (awaiting ID allocation). We will include studies that assess patients with confirmed or suspected SARS-CoV-2 infection and inform the relation between potential prognostic factors and death or disease severity. Two groups of two reviewers will independently screen studies for eligibility, extract data and assess the risk of bias. We will perform meta-analyses and use GRADE to assess the certainty of evidence for each prognostic factor and outcome. A living, web-based version of this review will be openly available during the COVID-19 pandemic. We will resubmit it if the conclusions change or there are substantial updates. Ethics and disseminationNo ethics approval is considered necessary. The results of this review will be widely disseminated via peer-reviewed publications, social networks and traditional media. PROSPERO RegistrationSubmitted to PROSPERO (awaiting ID allocation).
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ObjectiveTo determine the relative impact of the use of chloroquine and hydroxychloroquine on outcomes important to patients with COVID 19. DesignThis is the protocol of a living systematic review. Data sourcesWe will conduct searches in PubMed/Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), trial registries, grey literature and in a centralised repository in L{middle dot}OVE (Living OVerview of Evidence). L{middle dot}OVE is a platform that maps PICO questions to evidence from Epistemonikos database. In response to the COVID-19 emergency, L{middle dot}OVE was adapted to expand the range of evidence it covers and customised to group all COVID-19 evidence in one place. The search will cover the period until the day before submission to a journal. Eligibility criteria for selecting studies and methodsWe will follow a common protocol for multiple parallel systematic reviews, already published and submitted to PROSPERO (awaiting ID allocation). We will include randomised controlled trials evaluating the effect of chloroquine and hydroxychloroquine -- as monotherapy or in combination with other drugs -- versus placebo or no treatment in patients with COVID-19. Randomised trials evaluating chloroquine and hydroxychloroquine in infections caused by other coronaviruses, such as MERS-CoV and SARS-CoV, and non-randomised studies in COVID-19 will be searched in case no direct evidence from randomised trials is found, or if the direct evidence provides low- or very low-certainty for critical outcomes. Two reviewers will independently screen each study for eligibility, extract data, and assess the risk of bias. We will perform random-effects meta-analyses and use GRADE to assess the certainty of the evidence for each outcome. A living, web-based version of this review will be openly available during the COVID-19 pandemic. We will resubmit it if the conclusions change or there are substantial updates. Ethics and disseminationNo ethics approval is considered necessary. The results of this review will be widely disseminated via peer-reviewed publications, social networks and traditional media.
