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For numbered affiliations see end of article. Drug treatments for covid-19: living and network BMJ: first published as 10.1136/bmj.m2980 on 30 July 2020. Downloaded from Correspondence to: R Siemieniuk [email protected] meta-analysis https://orcid.org/0000-0002-3725-3031 1 , * 1 , * 2 , * 1 , * 3 1 Cite this as: BMJ 2020;370:m2980 Reed AC Siemieniuk, Jessica J Bartoszko, Long Ge, Dena Zeraatkar, Ariel Izcovich, Elena Kum, http://dx.doi.org/10.1136/bmj.m2980 Hector Pardo-Hernandez, 4, 5 Anila Qasim, 1 Juan Pablo Díaz Martinez, 1 Bram Rochwerg, 1, 6 Accepted: 2319 March July 2020 2021 Francois Lamontagne, 7 Mi Ah Han, 8 Qin Liu, 9, 10 Arnav Agarwal, 1, 11 Thomas Agoritsas, 1, 12 Derek K Chu, 1, Published: 30 July 2020 6 Rachel Couban, 13 Ellen Cusano, Andrea Darzi, 1 Tahira Devji, 1 Bo Fang, 9, 10 Carmen Fang, 15 Signe Agnes Flottorp, 16, 17 Farid Foroutan, 1, 18 Maryam Ghadimi, 1 Diane Heels-Ansdell, 1 Kimia Honarmand, 19 Liangying Hou, 2 Xiaorong Hou, 20 Quazi Ibrahim, 1 Assem Khamis, 33 Bonnie Lam, 1 Mark Loeb, 1, 6 Maura Marcucci, 1, 6 Shelley L McLeod, 21, 22 Sharhzad Motaghi, 1 Srinivas Murthy, 23 Reem A Mustafa, 1, 24 John D Neary, 6 Gabriel Rada, 25, 26 Irbaz Bin Riaz, 27 Behnam Sadeghirad, 1, 13 Nigar Sekercioglu, 1 Lulu Sheng, 9, 10 Ashwini Sreekanta, 1 Charlotte Switzer, 1 Britta Tendal, 28 Lehana Thabane, 1 George Tomlinson, 29 Tari Turner, 28 Per O Vandvik, 15 Robin WM Vernooij, 30, 31 Andrés Viteri-García, 25, 32 Ying Wang, 1 Liang Yao, 1 Zhikang Ye, 1 Gordon H Guyatt, 1, 6 Romina Brignardello-Petersen1 ABSTRACT (30 fewer per 1000, 46 fewer to 10 fewer, moderate OBJECTIVE certainty) and may reduce length of hospital stay (4.3 To compare the effects of treatments for coronavirus days fewer, 8.1 fewer to 0.5 fewer, low certainty), but disease 2019 (covid-19). whether or not they reduce mortality is uncertain (15 DESIGN fewer per 1000, 30 fewer to 6 more, low certainty). Living systematic review and network meta-analysis. Janus kinase inhibitors may reduce mortality (50 DATA SOURCES fewer per 1000, 84 fewer to no difference, low certainty), mechanical ventilation (46 fewer per 1000, WHO covid-19 database, a comprehensive 74 fewer to 5 fewer, low certainty), and duration of multilingual source of global covid-19 literature, up mechanical ventilation (3.8 days fewer, 7.5 fewer to to 1 March 2021 and six additional Chinese databases 0.1 fewer, moderate certainty). The impact of up to 20 February 2021. Studies identified as of 12 on mortality and most other outcomes is February 2021 were included in the analysis. uncertain. The effects of ivermectin were rated as http://www.bmj.com/ STUDY SELECTION very low certainty for all critical outcomes, including Randomised clinical trials in which people with mortality. In patients with non-severe disease, suspected, probable, or confirmed covid-19 were colchicine may reduce mortality (78 fewer per 1000, randomised to drug treatment or to standard care or 110 fewer to 9 fewer, low certainty) and mechanical placebo. Pairs of reviewers independently screened ventilation (57 fewer per 1000, 90 fewer to 3 more, potentially eligible articles. low certainty). Azithromycin, hydroxychloroquine, METHODS lopinavir-, and -beta do not appear After duplicate data abstraction, a bayesian network to reduce risk of death or have an effect on any other on 2 October 2021 by guest. Protected copyright. meta-analysis was conducted. Risk of bias of the patient-important outcome. The certainty in effects included studies was assessed using a modification for all other interventions was low or very low. of the Cochrane risk of bias 2.0 tool, and the certainty CONCLUSION of the evidence using the grading of Corticosteroids and interleukin-6 inhibitors probably recommendations assessment, development, and confer important benefits in patients with severe evaluation (GRADE) approach. For each outcome, covid-19. Janus kinase inhibitors appear to have interventions were classified in groups from the most promising benefits, but certainty is low. Azithromycin, to the least beneficial or harmful following GRADE hydroxychloroquine, lopinavir-ritonavir, and guidance. interferon-beta do not appear to have any important RESULTS benefits. Whether or not remdesivir, ivermectin, and 196 trials enrolling 76 767 patients were included; other drugs confer any patient-important benefit 111 (56.6%) trials and 35 098 (45.72%) patients are remains uncertain. new from the previous iteration; 113 (57.7%) trials SYSTEMATIC REVIEW REGISTRATION evaluating treatments with at least 100 patients or This review was not registered. The is 20 events met the threshold for inclusion in the publicly available in the supplementary material. analyses. Compared with standard care, READERS’ NOTE corticosteroids probably reduce death ( This article is a living systematic review that will be 20 fewer per 1000 patients, 95% credible interval 36 updated to reflect emerging evidence. Updates may fewer to 3 fewer, moderate certainty), mechanical occur for up to two years from the date of original ventilation (25 fewer per 1000, 44 fewer to 1 fewer, publication. This is the fourth version of the original moderate certainty), and increase the number of days article published on 30 July 2020 (BMJ free from mechanical ventilation (2.6 more, 0.3 more 2020;370:m2980), and previous versions can be to 5.0 more, moderate certainty). Interleukin-6 found as data supplements. When citing this paper inhibitors probably reduce mechanical ventilation the bmj | BMJ 2020;370:m2980 | doi: 10.1136/bmj.m2980 1 RESEARCH

please consider adding the version number and date of access for • clarity. Siemieniuk RAC, Bartoszko JJ, Ge L, et al. Drug treatments for covid-19: living systematic review and network meta-analysis [Update 3]. BMJ BMJ: first published as 10.1136/bmj.m2980 on 30 July 2020. Downloaded from Introduction 2020;370:m2980, doi:10.1136/bmj.m2980 As of 28 March 2021, more than 127 million people have been infected ‐ Review and network meta-analysis of all available randomised with severe acute respiratory syndrome coronavirus virus 2 trials that assessed drug treatments for covid-19 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 • MAGICapp (https://app.magicapp.org/#/guideline/nBkO1E) (covid-19); of these, more than 2.7 million have died.1 Despite global efforts to identify effective interventions for the prevention and ‐ Expanded version of the methods, processes, and results with treatment of covid-19, which have resulted in 2800 trials completed multilayered recommendations, evidence summaries, and decision or underway,2 evidence for effective treatment remains limited. aids for use on all devices Faced with the pressures of a global pandemic, healthcare workers • Author website (https://www.covid19lnma.com) around the world are prescribing drugs off-label for which there is ‐ Interim updates will be available here only very low quality evidence. Timely evidence summaries and associated guidelines could ameliorate the problem.3 Clinicians, patients, guideline bodies, and government agencies are also facing Methods the challenges of interpreting the results from trials that are being A protocol provides the detailed methods of this systematic review, published at a rate never encountered previously. This environment including all updates (see supplementary appendix). We report this makes it necessary to produce well developed summaries that living systematic review following the guidelines of the preferred distinguish more trustworthy evidence from less trustworthy reporting items for systematic reviews and meta-analyses (PRISMA) evidence. checklist for network meta-analyses.11 A living systematic review Living systematic reviews deal with the main limitation of traditional is a cumulative synthesis that is updated regularly as new evidence 12 reviews—that of providing an overview of the relevant evidence becomes available. The linked BMJ Rapid Recommendations only at a specific time.4 This is crucial in the context of covid-19, in guideline panels approved all decisions relevant to data synthesis. which the best evidence is constantly changing. The ability of a Eligibility criteria living network meta-analysis to present a complete, broad, and updated view of the evidence makes it the best type of evidence We included randomised clinical trials in people with suspected, synthesis to inform the development of practice recommendations. probable, or confirmed covid-19 that compared drugs for treatment Network meta-analysis, rather than pairwise meta-analysis, provides against one another or against no intervention, placebo, or standard useful information about the comparative effectiveness of treatments care. We included trials regardless of publication status (peer that have not been tested head to head. The lack of such direct reviewed, in press, or preprint) or language. No restrictions were comparisons is certain to limit inferences in the covid-19 setting. applied based on severity of illness or setting and we included trials http://www.bmj.com/ Moreover, the incorporation of indirect evidence can strengthen of Chinese medicines if the drug comprised one or more specific evidence in comparisons that were tested head to head.5 molecules with a defined molecular weight dosing. In this living systematic review and network meta-analysis we We excluded randomised trials evaluating vaccination, blood compare the effects of drug treatments for covid-19. This review is products and antibody-based antiviral therapies (such as part of the BMJ Rapid Recommendations project, a collaborative virus-specific monoclonal antibodies), nutrition, traditional Chinese effort from the MAGIC Evidence Ecosystem Foundation herbal or alternative medicines that include more than one molecule (www.magicproject.org) and The BMJ.6 This living systematic review or a molecule without specific molecular weighted dosing, and on 2 October 2021 by guest. Protected copyright. and network meta-analysis informs World Health Organization and non-drug supportive care interventions. Trials that evaluated these BMJ Rapid Recommendations6 on covid-19 treatments, initiated to interventions were identified and categorised separately. provide trustworthy, actionable, and living guidance to clinicians Information sources and patients soon after new and potentially practice-changing We perform daily searches from Monday to Friday in the World evidence becomes available. The first covid-19 BMJ Rapid Health Organization (WHO) covid-19 database for eligible studies Recommendation considered the role of remdesivir.7 Subsequent – a comprehensive multilingual source of global literature on guidance addressed the role of hydroxychloroquine, corticosteroids, covid-19. Prior to its merge with the WHO covid-19 database on 9 lopinavir-ritonavir, and updated guidance for remdesivir (box 1).8 October 2020, we performed daily searches from Monday to Friday The latest recommendation covers ivermectin. This living network in the US Centers for Disease Control and Prevention (CDC) COVID-19 meta-analysis is the fourth version. The previous versions are Research Articles Downloadable Database for eligible studies.13 The available in the supplementary material. Drugs for prophylaxis9 10 database includes, but is not limited to the following 25 and antibody-based treatments will be addressed separately. bibliographic and grey literature sources: Medline (Ovid and Box 1: Linked resources in this BMJ Rapid Recommendations cluster PubMed), PubMed Central, Embase, CAB Abstracts, Global Health, PsycInfo, Cochrane Library, Scopus, Academic Search Complete, • Siemieniuk R, Rochwerg B, Agoritsas T, et al. A living WHO guideline Africa Wide Information, CINAHL, ProQuest Central, SciFinder, the on drugs for covid-19 [Update 3]. BMJ 2020;370:m3379, Virtual Health Library, LitCovid, WHO covid-19 website, CDC doi:10.1136/bmj.m3379 covid-19 website, Eurosurveillance, China CDC Weekly, Homeland ‐ Living WHO BMJ Rapid Recommendations guidance on drugs for Security Digital Library, ClinicalTrials.gov, bioRxiv (preprints), covid-19 medRxiv (preprints), chemRxiv (preprints), and SSRN (preprints). The supplementary material contains the WHO literature search • World Health Organization. Therapeutics and COVID-19. Living strategy. guideline. 31 March 2021. https://www.who.int/publica- tions/i/item/therapeutics-and-covid-19-living-guideline. The daily searches are designed to match the update schedule of the database and to capture eligible studies the day of or the day

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after publication. To identify randomised trials, we filtered the because both may be surrogates for transmissibility, although this results from the WHO’s database through a validated and highly is uncertain.18 sensitive machine learning model.14 We tracked preprints of BMJ: first published as 10.1136/bmj.m2980 on 30 July 2020. Downloaded from Mechanical ventilation includes both invasive and non-invasive randomised trials for updates and through publication: when data mechanical ventilation. We used a hierarchy for the outcome was discrepant, we used the most recent data. mechanical ventilation in which we preferentially used the total In addition, we search six Chinese databases monthly: Wanfang, number of patients who received mechanical ventilation over the Chinese Biomedical Literature, China National Knowledge study. We used the number of patients ventilated at the time point Infrastructure, VIP, Chinese Medical Journal Net (preprints), and that the largest number of the patients were ventilated if the trial ChinaXiv (preprints). We adapted the search terms for covid-19 reported the number of patients ventilated at specific timepoints. developed by the CDC to the Chinese language. For the Chinese Risk of bias within individual studies literature search, we also included search terms for randomised trials. The supplementary appendix includes the Chinese literature For each eligible trial, reviewers, following training and calibration search strategy. exercises, used a revision of the Cochrane tool for assessing risk of bias in randomised trials (RoB 2.0)19 to rate trials as either at (i) low We monitor living evidence retrieval services on an ongoing basis. risk of bias, (ii) some concerns—probably low risk of bias, (iii) some These included the Living Overview of the Evidence (L-OVE) concerns—probably high risk of bias, or (iv) high risk of bias, across COVID-19 Repository by the Epistemonikos Foundation15 and the the following domains: bias arising from the randomisation process; Systematic and Living Map on COVID-19 Evidence by the Norwegian bias owing to departures from the intended intervention; bias from Institute of Public Health, in collaboration with the Cochrane Canada missing outcome data; bias in measurement of the outcome; bias Centre at McMaster University.16 in selection of the reported results, including deviations from the We searched WHO information sources from 1 December 2019 to 1 registered protocol; bias due to competing risks; and bias arising March 2021, and the Chinese literature from conception of the from early termination for benefit. We rated trials at high risk of databases to 20 February 2021. bias overall if one or more domains were rated as probably high risk of bias or as high risk of bias and as low risk of bias if all Study selection domains were rated as probably low risk of bias or low risk of bias. Using a systematic review software, Covidence,17 pairs of reviewers, For ivermectin, the linked guideline panel also requested a review following training and calibration exercises, independently screened of the study protocols to check that trial registration occurred prior all titles and abstracts, followed by full texts of trials that were to patient recruitment. Reviewers resolved discrepancies by identified as potentially eligible. A third reviewer adjudicated discussion and, when not possible, with adjudication by a third conflicts. party.

Data collection Data synthesis http://www.bmj.com/ For each eligible trial, pairs of reviewers, following training and We conducted the network meta-analysis using a bayesian calibration exercises, extracted data independently using a framework.20 In this report, we conducted a network meta-analysis standardised, pilot tested data extraction form. Reviewers collected of drug treatments for covid-19 that included all patients, regardless information on trial characteristics (trial registration, publication of severity of disease. status, study status, design), patient characteristics (country, age, Summary measures sex, smoking habits, comorbidities, setting and type of care, and severity of covid-19 symptoms for studies of treatment), and We summarised the effect of interventions on dichotomous outcomes on 2 October 2021 by guest. Protected copyright. outcomes of interest (means or medians and measures of variability using the and corresponding 95% credible interval. For for continuous outcomes and the number of participants analysed continuous outcomes, we used the mean difference and and the number of participants who experienced an event for corresponding 95% credible interval in days for ICU length of stay, dichotomous outcomes). Reviewers resolved discrepancies by length of hospital stay, and duration of mechanical ventilation discussion and, when necessary, with adjudication by a third party. because we expected similar durations across randomised trials. We updated the data collected from included preprints as soon as For time to symptom resolution and time to viral clearance, we first the peer review publication became available. performed the analyses using the relative effect measure ratio of means and corresponding 95% credible interval before calculating Outcomes of interest were selected based on importance to patients the mean difference in days because we expected substantial and were informed by clinical expertise in the systematic review variation between studies.21 team and in the linked guideline panel responsible for the WHO-BMJ Rapid Recommendations.7 8 The panel includes unconflicted clinical Treatment nodes and methodology experts, recruited to ensure global representation, Treatments were grouped into common nodes based on molecule and patient-partners. All panel members rated outcomes from 1 to and not on dose or duration. For intervention arms with more than 9 based on importance to individual patients (9 being most one drug, we created a separate node. Chloroquine and important), and we included any outcome rated 7 or higher by any hydroxychloroquine were included in the same node for covid-19 panel member. Selected outcomes included mortality (closest to 90 specific effects and separated for disease independent adverse days), mechanical ventilation (total number of patients, over 90 effects. We drew network plots using the networkplot command of days), adverse events leading to discontinuation (within 28 days), Stata version 15.1 (StataCorp, College Station, TX), with thickness viral clearance (closest to 7 days, 3 days either way), admission to of lines between nodes and size of the nodes based on the inverse hospital, duration of hospital stay, intensive care unit (ICU) length of the variance of the direct comparison.22 of stay, duration of mechanical ventilation, time to symptom resolution or clinical improvement, time to viral clearance, and days free from mechanical ventilation (within 28 days). Viral clearance at seven days and time to viral clearance were included the bmj | BMJ 2020;370:m2980 | doi: 10.1136/bmj.m2980 3 RESEARCH

Statistical analysis mechanical ventilation, duration of hospitalisation, and ICU length of stay we used baseline risks from the International Severe Acute

For most outcomes, we conducted network meta-analyses and BMJ: first published as 10.1136/bmj.m2980 on 30 July 2020. Downloaded from Respiratory and Emerging COVID-19 database.31 For all pairwise meta-analyses using a bayesian framework with the same other outcomes, we used the median from all studies in which priors for the variance and effect parameters.20 In previous versions, participants received standard of care to calculate the baseline risk we used fixed effects for some outcomes because data was sparse for each outcome, with each study weighed equally. We calculated or dominated by a single trial. As per our protocol, we used random absolute effects using the transitive risks model32 using R2jags effects for all outcomes. We used a plausible prior for variance package in R.33 parameter and a uniform prior for the effect parameter suggested in a previous study based on empirical data.23 For all analyses, we For each outcome, we classified treatments in groups from the most used three Markov chains with 100 000 iterations after an initial to the least effective using the minimally contextualised framework, burn-in of 10 000 and a thinning of 10. We used node splitting which focuses on the treatment effect estimates and the certainty models to assess local incoherence and to obtain indirect of the evidence.34 estimates.24 All network meta-analyses were performed using the Subgroup and sensitivity analysis gemtc package of R version 3.6.3 (RStudio, Boston, MA)25 and all pairwise meta-analyses using the bayesmeta package.20 Subgroup analyses were performed for specific interventions of interest at the direction of the linked WHO living guideline panel. In the first iteration of this living network meta-analysis, some In this iteration, we performed subgroup analyses for ivermectin treatment nodes with few total participants and few total events and interleukin-6 inhibitors for the pairwise comparison against resulted in highly implausible and extremely imprecise effect standard care. Previous iterations included subgroup analyses for estimates. We therefore decided to include only treatments that corticosteroids, hydroxychloroquine, lopinavir-ritonavir, and included at least 100 patients or had at least 20 events, based on remdesivir. The panel requested subgroup analyses by age (children our impression of the minimum number of patients/events to v non-elderly adults v elderly), severity (non-severe v severe v possibly provide meaningful results. critical), concomitant use of corticosteroids (for interleukin-6 Certainty of the evidence inhibitors), dose (for ivermectin; by cumulative dose and by single v multiple dosing regimens), higher v lower C reactive protein (for We assessed the certainty of evidence using the grading of interleukin-6 inhibitors), and risk of bias (for ivermectin) for the recommendations assessment, development and evaluation following outcomes: adverse events leading to discontinuation, (GRADE) approach for network meta-analysis.5 26 27 Two people hospital admission (for ivermectin), mortality, and mechanical with experience in using GRADE rated each domain for each ventilation. We performed bayesian hierarchical meta-regression comparison separately and resolved discrepancies by consensus. with study as a random effect. Where possible, we performed within We rated the certainty for each comparison and outcome as high, rather than between trial analyses.

moderate, low, or very low, based on considerations of risk of bias, http://www.bmj.com/ inconsistency, indirectness, publication bias, intransitivity, Patient and public involvement incoherence (difference between direct and indirect effects), and Patients were involved in outcome selection, interpretation of imprecision.27 We rated down for risk of bias if the interpretation results, and the generation of parallel recommendations, as part of of the effect would change if only studies at low risk of bias would the BMJ Rapid Recommendations initiative. have been considered. For example, if the credible interval of the pooled effect from studies at low risk of bias would have crossed Results the threshold for imprecision, we rated down for risk of bias.

After screening 31 848 titles and abstracts and 611 full texts, 206 on 2 October 2021 by guest. Protected copyright. Judgments of imprecision for this systematic review were made unique randomised trials from 189 publications were identified that using a minimally contextualised approach, with a null effect as evaluated drug treatments as of 1 March 2021 (fig 1). A table of the threshold of importance.28 The minimally contextualised excluded full texts is provided in the supplementary appendix. approach considers only whether credible intervals include the null Searches of living evidence retrieval services identified 84 effect and thus does not consider whether plausible effects, captured publications of eligible randomised trials, which were reconciled by credible intervals, include both important and trivial effects.28 with our formal search strategy when necessary. One hundred and To evaluate certainty of no benefit (or no effect), we used a 2% risk thirty randomised trials have been published in peer reviewed difference threshold of the 95% credible interval for mortality and journals, 53 as preprints, 17 within three meta-analyses, three as mechanical ventilation. In other words, if the entire 95% credible correspondence from study authors, one as a presentation, one as interval was within 2% of the null effect, we would not rate down a conference abstract and one as a registry reporting for imprecision. We decided on this preliminary threshold based results. Most of the trials were registered (181/206; 88%), published on a survey of the authors. Interim updates and additional study in English (197/206; 96%), and evaluated treatment in patients data will be posted on our website (www.covid19lnma.com). admitted to hospital with covid-19 (168/206; 82%). China, Iran, Interpretation of results Brazil, United States and Spain were the five most common countries in which randomised trials were conducted. Eighty-four different To facilitate interpretation of the results, we calculated absolute drug treatments were evaluated. The five most common drug effects for outcomes in which the summary measure was an odds treatments evaluated, based on number of randomised trials, were ratio or ratio of means. When available, we inferred baseline risk (hydroxy)chloroquine (37/206; 18%), ivermectin (16/206, 7.8%), in the usual care group for each outcome from representative corticosteroids (14/206; 6.8%), lopinavir-ritonavir (14/206, 6.8%) observational data (supplementary material). For mortality, we and interleukin-6 inhibitors (tocilizumab and sarilumab) (11/206; used data from the CDC on patients who were hospitalised with 5.3%). covid-19.29 30 For mechanical ventilation, duration of invasive

4 the bmj | BMJ 2020;370:m2980 | doi: 10.1136/bmj.m2980 RESEARCH BMJ: first published as 10.1136/bmj.m2980 on 30 July 2020. Downloaded from http://www.bmj.com/ on 2 October 2021 by guest. Protected copyright.

Fig 1 | Study selection

One hundred and ninety six randomised trials that evaluated drug that evaluated different durations or doses of the same drug, because treatments were identified up until the date of analysis (12 February both arms would have been classified within the same treatment 2021) (table 1; supplementary appendix).35 -211 Several of these trials node; two trials145 146 with insufficient data; and ten could not be included in the analysis: nine trials69 77 90 129 130 158 181 212 trials38 56 87 101 172 192 198 204 209 211 that reported no outcomes of the bmj | BMJ 2020;370:m2980 | doi: 10.1136/bmj.m2980 5 RESEARCH

interest. Of the remaining 175 trials, we analysed 113 (69.8%) presents the characteristics of the 196 included studies. Additional reporting on treatments with at least 100 patients or 20 events to study characteristics, outcome data, and risk of bias assessments avoid implausible and extremely imprecise estimates. Table 1 for each study are available in the supplementary appendix. BMJ: first published as 10.1136/bmj.m2980 on 30 July 2020. Downloaded from

Table 1 | Study characteristics. Values are numbers (percentages) of studies unless stated otherwise

Characteristic Registered 175 (89.3%) Publication status: Preprint 52 (26.5%) Published 121 (61.7%) Unpublished 23 (11.7%) Median (SD) No of patients 87.5 (145.2) Country: China 38 (19.4%) Iran 28 (14.3%) Brazil 26 (13.3%) United States 26 (13.3%) Spain 19 (9.7%) Intensity of care: Outpatient 33 (16.8%) Inpatient 156 (79.6%) ICU 8 (4.1%) Severity: Mild/moderate 57 (29.1%) Severe/critical 35 (17.9%) Median (SD) percentage of patients mechanically ventilated at baseline 3.9 (37.7) http://www.bmj.com/

Table 2 describes the 10 randomised trials that were identified after the data analysis and that will be included in the next update.213 -222

Table 2 | Randomised trials identified after data analysis, which will be included in the next update

Study Publication status, registration No No of participants Treatments on 2 October 2021 by guest. Protected copyright. Yadegarinia 2020213 Published, NR 34 ; standard care Balykova 2020214 Published, NCT04542694 39 ; standard care Thomas 2021215 Published, NCT04342728 214 Zinc, ascorbic acid; zinc; ascorbic acid; standard care Baratt-Due 2021217 Preprint, NCT04321616 185 Hydroxychloroquine; remdesivir; standard care Purwati 2021222 Published, INA-TX6YYSS 754 Lopinavir-ritonavir, azithromycin; lopinavir-ritonavir, doxycycline; hydroxychloroquine, azithromycin Jamaati 2021219 Published, IRCT20151227025726N17 50 Dexamethasone; standard care Migled 2020220 Published, NR 60 Methisoprinol; standard care Balykova 2020216 Published, NR 200 Favipiravir; standard care Patel 2021221 Published, ACTRN12620000454976 33 Zinc; placebo Cadegiani 2021218 Published, NR 236 Proxalutamide; placebo

Of the randomised trials included in the analyses, eight did not were allocated by preference; the authors shared outcome data with have publicly accessible protocols or registrations. Of the trials with us among patients who were truly randomised.64 publicly accessible protocols or registrations, 79 reported results Thirty five studies were initially posted as preprints and for one or more of our outcomes of interest that were not prespecified subsequently published after peer review. The supplementary in protocols or registrations. No other discrepancies between the material presents the differences between study preprint and peer reporting of our outcomes of interest in trial reports and protocols reviewed publications. Eighteen studies had discrepancies in or registrations were noted. One trial did not stratify reporting of outcome reporting between the preprint and peer-reviewed outcomes for those who were truly randomised versus those who publication. Fourteen studies had discrepancies with patient

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baseline characteristics. Six studies had discrepancies in reporting judged at low risk of bias in all domains. All other studies had that led to changes in risk of bias ratings. No substantive differences probably high or high risk of bias in at least one of the domains. were found for 11 studies. BMJ: first published as 10.1136/bmj.m2980 on 30 July 2020. Downloaded from Effects of the interventions All analyses reached convergence based on trace plots and a The supplementary material presents the network plots depicting Brooks-Gelman-Rubin statistic less than 1.05, except comparisons the interventions included in the network meta-analysis of each including umifenovir for mortality because no patients randomised outcome. Figure 2 presents a summary of the effects of the to either of these drugs died, interleukin-6 inhibitors and interventions on the outcomes. The supplementary appendix also doxycycline with ivermectin for adverse events, proxalutamide for presents detailed relative and absolute effect estimates and certainty hospital admission, and sulodexide for clinically important bleeding. of the evidence for all comparisons and outcomes. We did not detect Risk of bias in included studies statistical incoherence in any of the network meta-analyses. The supplementary material presents the assessment of risk of bias of the included studies for each outcome. Thirty-seven studies were http://www.bmj.com/ on 2 October 2021 by guest. Protected copyright.

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Fig 2 | Summary of effects compared with standard care

Mortality hundred and one trials with 67 491 participants met the threshold of analysing treatments with a minimum of 100 patients or 20 events One hundred and forty eight randomised trials including 71 468 and were included in the network meta-analysis (supplementary participants reported mortality (supplementary appendix). One appendix). Figure 3 shows the network plot for mortality, with each

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edge representing a direct comparison between two interventions. with non-severe disease; odds ratio 0.37, 0.13 to 0.92; low certainty), The most common interventions were standard care/placebo (95 and janus kinase (JAK) inhibitors (baricitinib and ruxolitinib, odds trials, 36 166 participants), hydroxychloroquine (33 trials, 4902 ratio 0.58, 0.33 to 1.00; low certainty). Patients randomised to BMJ: first published as 10.1136/bmj.m2980 on 30 July 2020. Downloaded from participants), remdesivir (4 trials, 3826 participants), azithromycin (odds ratio 0.97, 0.78 to 1.19; low certainty), lopinavir-ritonavir (7 trials, 3557 participants), interleukin-6 hydroxychloroquine (odds ratio 1.09, 0.93 to 1.27; moderate certainty inhibitors (9 trials, 3642 participants), azithromycin (6 trials, 2982 of no benefit), lopinavir-ritonavir (odds ratio 1.02, 0.85 to 1.23; low participants), and corticosteroids (11 trials, 2975 participants). certainty), full dose anticoagulation (odds ratio 0.98, 0.72 to 1.32; Random effects network meta-analysis showed that corticosteroids low certainty), and interferon beta (odds ratio 0.99, 0.71 to 1.26; low probably reduce deaths compared with standard care (odds ratio certainty) did not have a lower risk of death than those randomised 0.83, 95% credible interval 0.69 to 0.98; moderate certainty) (fig 2). to standard care. Although the 95% credible intervals did not include Evidence was less certain for remdesivir (odds ratio 0.90, 0.72 to harm for ivermectin and recombinant human granulocyte colony 1.11; low certainty), interleukin-6 inhibitors (odds ratio 0.87, 0.74 stimulating factor (rhG-CSF), the evidence was very low certainty to 1.05; low certainty), colchicine (evidence primarily from patients because of risk of bias and extremely low total number of events. http://www.bmj.com/ on 2 October 2021 by guest. Protected copyright.

Fig 3 | Network plot for mortality. The size of the circles is proportional to the number of patients randomised to that intervention and the size of the lines is proportional to the inverse of the standard error of the effect estimate.

Mechanical ventilation low certainty). Patients randomised to several interventions did not have a lower chance of mechanical ventilation compared to standard Eighty seven randomised trials including 56 560 participants care: hydroxychloroquine (odds ratio 1.15, 0.92 to 1.46; low reported mechanical ventilation (supplementary appendix). Sixty certainty), azithromycin (odds ratio 0.95, 0.69 to 1.28), six trials with 55 174 participants met the threshold of analysing lopinavir-ritonavir (odds ratio 1.10, 0.84 to 1.42; low certainty). The treatments with a minimum of 100 patients or 20 events and were effect of ivermectin was very uncertain (odds ratio 0.51, 0.13 to 1.86; included in the network meta-analysis (supplementary appendix). very low certainty). The most common interventions were standard care (64 trials, 30 339 participants), remdesivir (4 trials, 3433 participants), Adverse events leading to discontinuation hydroxychloroquine (11 trials, 3155 participants), lopinavir-ritonavir Fifty nine randomised trials including 10 314 participants reported (4 trials, 3086 participants), interleukin-6 inhibitors (9 trials, 3056 adverse effects leading to discontinuation of the study drug participants), and corticosteroids (8 trials, 2425 participants). (supplementary appendix). Twenty five trials with 6999 participants Random effects network meta-analysis showed that, compared with met the threshold of analysing treatments with a minimum of 100 standard care, two interventions probably reduce risk of mechanical patients or 20 events and were included in the network ventilation: corticosteroids (odds ratio 0.76, 0.59 to 0.99; moderate meta-analysis (supplementary appendix). The most common certainty) and interleukin-6 inhibitors (odds ratio 0.72, 0.57 to 0.90; interventions were standard care (24 trials, 2866 participants), moderate certainty) (fig 2). Treatments that may reduce mechanical hydroxychloroquine (8 trials, 893 participants), and remdesivir (2 ventilation, with lower certainty, were remdesivir (odds ratio 0.75, trials, 699 participants). Moderate certainty evidence showed that 0.52 to 0.98; low certainty), JAK inhibitors (odds ratio 0.57, 0.33 to remdesivir did not result in a substantial increase in adverse effects 0.95; low certainty), and colchicine (odds ratio 0.48, 0.21 to 1.03; leading to drug discontinuation compared with standard care (odds the bmj | BMJ 2020;370:m2980 | doi: 10.1136/bmj.m2980 9 RESEARCH

ratio 1.00, 0.36 to 4.06). Certainty in evidence for all of the other ICU length of stay interventions was low or very low (fig 2).

Fourteen randomised trials including 1784 participants reported BMJ: first published as 10.1136/bmj.m2980 on 30 July 2020. Downloaded from Viral clearance at 7 days (± 3 days) length of ICU stay (supplementary appendix). Three interventions had at least 100 patients including standard care (3 trials, 609 Forty three randomised trials including 5136 participants measured participants), interleukin-6 inhibitors (2 trials, 598 participants), viral clearance with polymerase chain reaction cut-off points and corticosteroids (1 trial, 278 participants). Most of these trials (supplementary appendix). Thirty one trials with 4383 participants did not report estimates of variance. Therefore, we did not perform met the threshold of analysing treatments with a minimum of 100 a meta-analysis (fig 2). The REMAP-CAP trial found a large reduction patients or 20 events and were included in the network in median duration of ICU stay with interleukin-6 inhibitors (−9 meta-analysis (supplementary appendix). The most common days).93 interventions were standard care (29 trials, 1741 participants), hydroxychloroquine (10 trials, 756 participants), lopinavir-ritonavir Duration of mechanical ventilation (6 trials, 450 participants), and ivermectin (7 trials, 291 participants). Thirteen randomised trials including 1138 participants reported We did not find evidence that any of the interventions increased duration of mechanical ventilation (supplementary appendix). Four the rate of viral clearance: hydroxychloroquine (odds ratio 1.01, trials with 966 participants met the threshold of analysing 0.69 to 1.56; very low certainty), lopinavir-ritonavir (odds ratio 0.92, treatments with a minimum of 100 patients and were included in 0.50 to 1.49; very low certainty), ivermectin (odds ratio 1.62, 0.95 to the network meta-analysis (supplementary appendix). The included 2.86; low certainty), and remdesivir (odds ratio 1.06, 0.35 to 3.20) interventions were standard care (4 trials, 521 participants), (fig 2). remdesivir (2 trials, 194 participants), corticosteroids (1 trial, 151 Admission to hospital participants), and JAK inhibitors (1 trial, 100 participants). JAK inhibitors probably reduce the duration of mechanical ventilation Sixteen randomised trials including 8307 participants reported (−3.8 days, −7.5 to −0.1, moderate certainty). There was no admission to hospital among outpatients at baseline (supplementary convincing evidence that corticosteroids (mean difference −1.4 days, appendix). Nine trials with 7655 participants met the threshold of −3.2 to 0.4; low certainty) or remdesivir (mean difference −1.4 days, analysing treatments with a minimum of 100 patients or 20 events −3.2 to 1.5; low certainty) reduce duration of mechanical ventilation and were included in the network meta-analysis (supplementary (fig 2). appendix). The most common interventions were standard care (9 trials, 3603 participants), colchicine (1 trial, 2235 participants), Ventilator-free days hydroxychloroquine (4 trials, 668 participants), and Ten randomised trials including 2495 participants reported lopinavir-ritonavir (1 trial, 244 participants). There was insufficient ventilator-free days (supplementary appendix). Seven studies with evidence to know if any of the interventions reduce hospitalisation 1835 participants met the threshold of analysing treatments with a

(fig 2). http://www.bmj.com/ minimum of 100 patients and were included in the network Venous thromboembolism meta-analysis (supplementary appendix). The most common interventions were standard care (6 trials, 783 participants), Two trials including a total of 2523 participants43 126 reported venous interleukin-6 inhibitors (3 trials, 652 participants), azithromycin (2 thromboembolism in patients who received full dose anticoagulation trials, 155 participants), and corticosteroids (1 trial, 151 participants). versus prophylactic dose anticoagulation (odds ratio 0.57, 0.21 to Compared with standard care, corticosteroids probably increase 1.73; low certainty). ventilator-free days (mean difference 2.6 days, 0.3 to 4.9; moderate Clinically important bleeding certainty). There was no evidence that interleukin-6 inhibitors (low on 2 October 2021 by guest. Protected copyright. Two trials including 2523 participants43 126 reported clinically certainty), hydroxychloroquine (very low certainty), or azithromycin important bleeding in patients who received full dose (very low certainty) increase ventilator-free days (fig 2). anticoagulation versus prophylactic dose anticoagulation (odds Time to symptom resolution ratio 2.00, 0.70 to 5.98; low certainty). Fifty nine randomised trials including 9846 participants reported Duration of hospital stay time to symptom resolution (supplementary appendix). Thirty one Eighty two randomised trials including 54 277 participants reported trials including 7639 participants met the threshold of analysing duration of hospital stay (supplementary appendix). Fifty eight treatments with a minimum of 100 patients and were included in trials with 52 518 participants met the threshold of analysing the network meta-analysis (supplementary appendix). The most treatments with a minimum of 100 patients and were included in common interventions were standard care (29 trials, 3155 the network meta-analysis (supplementary appendix). The most participants), remdesivir (3 trials, 1083 participants), interleukin-6 common interventions were standard care (56 trials, 29 443 inhibitors (5 trials, 1070 participants), hydroxychloroquine (9 trials, participants), interleukin-6 inhibitors (9 trials, 3583 participants), 706 participants), and JAK inhibitors (2 trials, 535 participants). remdesivir (4 trials, 3826 participants), hydroxychloroquine (12 Favipiravir may reduce time to symptom resolution (ratio of mean trials, 3226 participants), azithromycin (3 trials, 2780 participants), days between intervention and standard care 0.62, 0.48 to 0.81; low and corticosteroids (5 trials, 2669 participants). Compared with certainty). The 95% credible interval for all other interventions standard care, duration of hospitalisation was shorter in patients included no effect, and certainty was low or very low for all who received interleukin-6 inhibitors (mean difference −4.5 days, interventions except remdesivir (ratio of mean days between −6.7 to −2.3; low certainty), colchicine (mean difference −1.7 days, intervention and standard care, 0.82, 0.64 to 1.06; moderate −2.8 to −0.7; low certainty), and favipiravir (mean difference −1.3 certainty) (fig 2). days, −2.4 to −0.1; low certainty). There was no evidence that any Time to viral clearance of the other interventions reduce length of stay, but certainty was Thirty-five randomised trials including 2933 participants reported low or very low (fig 2). time to viral clearance (supplementary appendix). Thirteen trials

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including 1444 participants met the threshold of analysing These results were driven in large part by the COLCORONA study,185 treatments with at least 100 patients and were included in the which enrolled outpatients with non-severe disease. The RECOVERY network meta-analysis (supplementary appendix). The treatments trial randomised 11 162 inpatients to colchicine or standard care BMJ: first published as 10.1136/bmj.m2980 on 30 July 2020. Downloaded from analysed include standard care (12 trials, 485 participants), and was not included in this analysis because the study was hydroxychloroquine (7 trials, 482 participants), favipiravir (4 trials, published after conducting the analysis. Colchicine did not appear 243 participants), and ivermectin (3 trials, 234 participants). The to have an effect on mortality in the RECOVERY trial, which was 95% credible interval for all other interventions included no effect, limited to inpatients with mostly severe or critical disease.224 and certainty was low or very low for all interventions (fig 2). Substantial uncertainty about the effect of colchicine on patients with non-severe disease remains. Subgroups Several small trials have examined the effect of ivermectin, and the Previous iterations of this living systematic review explored pooled result suggests a possible reduction in mortality. However, subgroup effects for remdesivir, lopinavir-ritonavir, the data are limited by extremely few events (very serious hydroxychloroquine, and corticosteroids. In this iteration, we imprecision) and serious risk of bias (several of the studies were explored subgroup effects for ivermectin and interleukin-6 inhibitors not pre-registered prior to enrolling patients or were not adequately (supplementary material). For ivermectin, there was no difference blinded). The effect of ivermectin on all other outcomes was similarly in relative effects for any of the subgroups tested, including uncertain, with 95% credible intervals that include substantial cumulative dose, single versus multiple doses of ivermectin, or risk harm. of bias. There was insufficient information to examine the effect of age or severity of illness. For interleukin-6 inhibitors, there was no Two trials examined the effect of JAK inhibitors and appear to show difference in relative effects between sarilumab and tocilizumab, promising results. JAK inhibitors may reduce mortality, mechanical by disease severity, or concomitant corticosteroid use on mortality, ventilation, and duration of hospitalisation. They probably reduce mechanical ventilation, or adverse effects. There was insufficient the duration of mechanical ventilation. Further trials are needed to information to examine the effect of age on any of these outcomes. confirm these promising effects. There was also no credible effect difference between patients with Full dose anticoagulation did not appear to show any important higher versus lower C reactive protein on a composite of mortality effect. A separate meta-analysis of four trials that examined full and mechanical ventilation. dose anticoagulation versus prophylactic dose anticoagulation Discussion appeared to show a reduction in mortality in patients with severe but not critical illness43; but these trials are not yet published in This living systematic review and network meta-analysis provides full and the data available is insufficient to judge whether or not it a comprehensive overview of the evidence for drug treatments of is a credible subgroup effect. covid-19 up to 12 February 2021 and a comprehensive list of drug

trials to 1 March 2021. There are now more than 200 randomised Several interventions do not appear to have important impact on http://www.bmj.com/ trials examining many different interventions for treating covid-19, any patient-important outcomes, including angiotensin-converting and, as a result, the certainty in evidence for multiple interventions enzyme inhibitors, azithromycin, hydroxychloroquine, is improving. interferon-beta, lopinavir-ritonavir, vitamin C, and vitamin D. For other interventions, there remains substantial uncertainty. Corticosteroids probably reduce the risk of death and mechanical ventilation and probably increase ventilator-free days. The evidence Compared with the second iteration, there are several important for corticosteroids comes primarily from patients who are hypoxic updates (box 2). We now have evidence from several large-scale

and admitted to hospital. Whether corticosteroids have any international trials on azithromycin, interleukin-6 inhibitors, full on 2 October 2021 by guest. Protected copyright. important effect on patients with non-severe disease remains dose anticoagulation, and colchicine. uncertain. Box 2: Summary of changes since last iteration Interleukin-6 inhibitors are likely to have some benefits, although the evidence regarding their impact on mortality remains of low • One hundred and eleven additional randomised trials (35 038 certainty. Other meta-analyses using fixed effects (that is, they do participants) not consider between-trial heterogeneity) found a significant • Angiotensin-converting enzyme inhibitors, anakinra, full dose mortality reduction.105 223 Interleukin-6 inhibitors probably reduce anticoagulation, ivermectin, ivermectin plus doxycycline, JAK risk of mechanical ventilation and may reduce duration of inhibitors, lopinavir-ritonavir plus interferon-beta, peginterferon hospitalisation. The evidence for interleukin-6 inhibitors comes lambda, proxalutamide, sulodexide, vitamin C, and vitamin D are new primarily from patients who are admitted to hospital and are interventions included in the analyses, but certainty is low or very low for the effects of the most of these interventions hypoxic. The use (or not) of corticosteroids, and baseline C reactive protein levels did not appear to modify their effects, however data • New evidence suggests that azithromycin may not have an impact on available for subgroup analyses was limited. any patient-important outcome, when combined with usual care. • New evidence suggests that interleukin-6 inhibitors probably reduce Whether or not remdesivir has any effect on mortality remains mechanical ventilation (moderate certainty) and may reduce duration uncertain. If one believes the subgroup effect previously reported, of hospitalisation (low certainty). remdesivir may reduce or have no effect mortality in patients with • New evidence suggests that JAK inhibitors probably reduce duration less severe disease and may increase or have no effect on mortality of mechanical ventilation (moderate certainty) and may reduce in patients with critical illness. The subgroup effect however has mortality (low certainty), mechanical ventilation (low certainty), and only moderate credibility and whether or not remdesivir reduces duration of hospitalisation (low certainty). or increases mortality in any subgroup is uncertain. Remdesivir • New evidence suggests that colchicine may reduce mortality (low may reduce risk of mechanical ventilation. certainty) and mechanical ventilation (low certainty) in outpatients Evidence from our analyses suggests that colchicine may reduce with non-severe disease, however our analysis does not include recent mortality, mechanical ventilation, and duration of hospitalisation. the bmj | BMJ 2020;370:m2980 | doi: 10.1136/bmj.m2980 11 RESEARCH

Our living systematic review and network meta-analysis will evidence from the RECOVERY trial, which did not find any effect on continue to inform the development of the WHO living guidelines mortality in hospitalised patients. and BMJ Rapid Recommendations.6 -8 An important difference in BMJ: first published as 10.1136/bmj.m2980 on 30 July 2020. Downloaded from • There is some new evidence on ivermectin and ivermectin plus the methods for assessing the certainty of the evidence does, doxycycline, however whether or not they have an important impact however, exist between the two. In this living systematic review on any patient-important outcome remains very uncertain. and network meta-analysis, we use a minimally contextualised • Evidence for other interventions is similar to the previous version approach for rating the certainty of the evidence, whereas the guideline panels use a fully contextualised approach in which the Strengths and limitations of this review thresholds of importance of magnitudes of effects depend on all 28 Our search strategy and eligibility criteria were comprehensive, other outcomes and factors involved in the decision. The without restrictions on language of publication or publication status. contextualisation explains differences in the certainty of the To ensure expertise in all areas, our team is composed of clinical evidence between the two. and methods experts who have undergone training and calibration To date, we are aware of two other similar efforts to ours.228 229 Our exercises for all stages of the review process. To minimise problems intention is different in that the results fully inform clinical decision with counterintuitive results, we anticipated challenges that arise making for the associated living guidance.6 We also include a more in network meta-analysis when data are sparse.225 Many of the comprehensive search for the evidence and several differences in results for comparisons with sparse data were uninformative and analytical methods, which we believe are best suited for this were sometimes implausible. For that reason, we decided to report evidence. For example, some others use fixed rather than random evidence on treatments for which at least 100 people were effects meta-analysis and provide estimates for pairwise randomised or for which there were at least 20 events. comparisons only. It is also important to evaluate the The main limitation of the data is that only thirty-seven studies were and replicability of findings from different scientific approaches. judged to be at low risk of bias. The primary limitation of the We will periodically update this living systematic review and evidence is lack of blinding, which might introduce bias through network meta-analysis. The changes from each version will be differences in co-interventions between randomised groups. We highlighted for readers and the most updated version will be the chose to consider the treatment arms that did not receive an active one available in the publication platform. Previous versions will be experimental drug (that is, placebo or standard care) within the archived in the supplementary material. This living systematic same node: it is possible that the unblinded standard care groups review and network meta-analysis will also be accompanied by an received systematically different co-interventions than groups interactive infographic and a website for users to access the most randomised to receive a placebo. Direct comparisons in which the updated results in a user-friendly format (magicapp.org). evidence is dominated by unblinded studies were rated down, Conclusions

consistent with GRADE, for risk of bias and that is reflected in the http://www.bmj.com/ rating of the quality of evidence from the network estimate.226 Many Evidence from this living systematic review and network of the data also had reporting concerns. For some outcomes, the meta-analysis suggests that corticosteroids probably reduce method in which the researchers measured and reported outcomes mortality, mechanical ventilation, and ventilator-free days in proved inconsistent across studies. This led the team to propose a patients with severe covid-19. Remdesivir may reduce the need for hierarchy for the outcome mechanical ventilation, as described in mechanical ventilation but does not appear to have an impact on the methods. mortality. Interleukin-6 inhibitors (sarilumab and tocilizumab) probably reduce mechanical ventilation and ICU length of stay, and

The living nature of our systematic review and network on 2 October 2021 by guest. Protected copyright. may reduce duration of hospitalisation. JAK inhibitors (baricitinib meta-analysis could conceivably (at least temporarily) amplify and ruxolitinib) may reduce mortality, mechanical ventilation, publication bias, because studies with promising results are more duration of hospitalisation. Azithromycin, hydroxychloroquine, likely to be published and are published sooner than studies with lopinavir-ritonavir, and interferon beta seem unlikely to have any negative results. The inclusion of preprints, many of which have benefits. The effects of many other drug interventions are currently negative results, might reduce this risk. However, the inclusion of highly uncertain (including ivermectin), and no definitive evidence preprints in our network meta-analysis might introduce bias from exists that these interventions result in important benefits and simple errors and the reporting limitations of preprints. We include harms for any outcomes. preprints because of the urgent need for information and because so many of the studies on covid-19 are published first as preprints. What is already known on this topic So far, differences between preprints and peer reviewed publications • have been mostly been limited to additional baseline patient Despite huge efforts to identify effective drug interventions for information, clarification on study design, and outcomes reported coronavirus disease 2019 (covid-19), evidence for effective treatment remains limited in the peer reviewed publications. None of these changes would have resulted in a meaningful change to pooled effect estimates or What this study adds certainty for any outcome. • This living systematic review and network meta-analysis provides a comprehensive overview and assessment of the evidence published It is possible that we did not detect important subgroup as of 1 March 2021 and will be updated periodically modification.227 For example, the RECOVERY trial suggested that • patients with more severe disease might obtain a greater benefit The certainty of the evidence for most interventions is low or very low, 103 including ivermectin from dexamethasone than patients with less severe disease. Full dose anticoagulation may be beneficial in patients with severe but • In patients with severe covid-19, glucocorticoids probably decrease not critical disease, and harmful in patients with critical disease. mortality, mechanical ventilation. However, these subgroup effects only have moderate credibility at • In patients with severe covid-19, interleukin-6 inhibitors probably best. Users should carefully consider the characteristics of the reduce mechanical ventilation and ICU length of stay, and may improve patients included in the trials for each intervention. ventilator-free days and duration of hospitalisation.

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AUTHOR AFFILIATIONS 30 Department of Nephrology and Hypertension, University Medical Center Utrecht, 1 Department of Health Research Methods, Evidence, and Impact, McMaster University, Utrecht, Netherlands BMJ: first published as 10.1136/bmj.m2980 on 30 July 2020. Downloaded from 1280 Main St W, Hamilton, ON L8S 4L8, Canada 31 Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, 2 Evidence Based Social Science Research Center, School of Public Health, Lanzhou Utrecht University, Utrecht, Netherlands University, Lanzhou, Gansu, China 32 Centro de Investigación de Salud Pública y Epidemiología Clínica (CISPEC), Facultad 3 Servicio de Clinica Médica del Hospital Alemán, Buenos Aires, Argentina de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador 33 4 Iberoamerican Cochrane Centre, Sant Pau Biomedical Research Institute (IIB Sant Wolfson Palliative Care Research Centre, Hull York Medical School, Hull, UK Pau), Barcelona, Spain * Joint first authors 5 CIBER de Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain Contributors: RACS, JJB, LG, and DZ contributed equally to the systematic review and are joint first 6 authors. RACS, JJB, DZ, EK, LG, and RB-P were the core team leading the systematic review. JJB, RC, Department of Medicine, McMaster University, Hamilton, ON, Canada SAF, MG, RWMV, SM, YW, ZY, CS, LY, QL, XH, LS, BF, and AV-G identified and selected the studies. 7 DZ, EK, NS, RWMV, AA, YW, KH, HP-H, MAH, CF, SLM, QL, AS, AQ, LY, BL, MG, EC, and FF collected Department of Medicine and Centre de recherche du CHU de Sherbrooke, Sherbrooke, the data. LG, AK, AQ, JPDM, BS, LH, QI, DH-A, GHG, GT, and LT analysed the data. RB-P, HPH, AI, RAM, Quebec, Canada TD, NS, and DC assessed the certainty of the evidence. SLM, FL, BR, TA, POV, GHG, MM, JDN, ML, TT, BT, FF, and GR provided advice at different stages. RACS, RB-P, and GHG drafted the manuscript. All 8 authors approved the final version of the manuscript. RACS is the guarantor. The corresponding author Department of Preventive Medicine, College of Medicine, Chosun University, Gwangju, attests that all listed authors meet authorship criteria and that no others meeting the criteria have been Republic of Korea omitted. 9 Cochrane China Network Affiliate, Chongqing Medical University, Chongqing, China Funder: This study was supported by the Canadian Institutes of Health Research CIHR-IRSC:057900132 and Coronavirus Rapid Research Funding Opportunity - OV2170359. 10 School of Public Health and Management, Chongqing Medical University, Chongqing, Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icm- China je.org/coi_disclosure.pdf and declare: support from the Canadian Institutes of Health Research; no 11 financial relationships with any organisations that might have an interest in the submitted work in the Department of Medicine, University of Toronto, Toronto, ON, Canada previous three years; no other relationships or activities that could appear to have influenced the 12 submitted work. Division of General Internal Medicine & Division of Clinical , University Hospitals of Geneva, Geneva, Switzerland Ethical approval: Not applicable. All the work was developed using published data. 13 Data sharing: No additional data available. Department of Anesthesia, McMaster University, Hamilton, ON, Canada 14 RACS affirms that this manuscript is an honest, accurate, and transparent account of the study being Department of Medicine, University of Calgary, Calgary, AB, Canada reported; that no important aspects of the study have been omitted; and that any discrepancies from http://www.bmj.com/ 15 the study as planned have been explained. William Osler Health Network, Toronto, ON, Canada Dissemination to participants and related patient and public communities: The infographic and MAGICapp 16 decision aids (available at www.magicapp.org/) were created to facilitate conversations between Norwegian Institute of Public Health, Oslo, Norway healthcare providers and patients or their surrogates. The MAGICapp decision aids were co-created 17 with people who have lived experience of covid-19. Institute of Health and Society, University of Oslo, Oslo, Norway 18 Provenance and peer review: Not commissioned; externally peer reviewed.

Ted Rogers Center for Heart Research, Toronto General Hospital, ON, Canada on 2 October 2021 by guest. Protected copyright. We thank Kevin Cheung and Paul Alexander (who was an author in the previous version of this review) 19 Department of Medicine, Western University, London, ON, Canada for input and early contributions. 20 1 John Hopkins University. Coronavirus Resource Center 2020 https://coronavirus.jhu.edu/map.html. College of Medical Informatics, Chongqing Medical University, Chongqing, China 2 Cytel. Global coronavirus COVID-19 clinical trial tracker. 2020 https://www.covid19-trials.org/. 21 3 Schwartz/Reisman Emergency Medicine Institute, Sinai Health, Toronto, ON, Canada Djulbegovic B, Guyatt G. Evidence-based medicine in times of crisis. J Clin Epidemiol 2020. doi: 10.1016/j.jclinepi.2020.07.002 pmid: 32659364 22 4 Vandvik PO, Brignardello-Petersen R, Guyatt GH. Living cumulative network meta-analysis to Department of Family and Community Medicine, University of Toronto, Toronto, ON, reduce waste in research: a paradigmatic shift for systematic reviews?BMC Med 2016;14:59. Canada doi: 10.1186/s12916-016-0596-4 pmid: 27025849 23 5 Puhan MA, Schünemann HJ, Murad MH, etalGRADE Working Group. A GRADE Working Group Department of Pediatrics, Faculty of Medicine, University of British Columbia, approach for rating the quality of treatment effect estimates from network meta-analysis. BMJ Vancouver, BC, Canada 2014;349:g5630. doi: 10.1136/bmj.g5630 pmid: 25252733 24 6 Siemieniuk RA, Agoritsas T, Macdonald H, Guyatt GH, Brandt L, Vandvik PO. Introduction to BMJ Department of Medicine, University of Kansas Medical Center, Kansas City, MO, USA Rapid Recommendations. BMJ 2016;354:i5191. doi: 10.1136/bmj.i5191 pmid: 27680768 25 7 Rochwerg B, Agarwal A, Zeng L, etal. Remdesivir for severe covid-19: a clinical practice guideline. Epistemonikos Foundation, Santiago, Chile BMJ 2020;370:m2924. doi: 10.1136/bmj.m2924 pmid: 32732352 26 8 Siemieniuk R, Rochwerg B, Agoritsas T, etal. A living WHO guideline on drugs for covid-19. BMJ UC Evidence Center, Cochrane Chile Associated Center, Pontificia Universidad Católica 2020;370:m3379. doi: 10.1136/bmj.m3379 pmid: 32887691 de Chile, Santiago, Chile 9 Bartoszko JJ, Siemieniuk RA, Kum E, etal. Prophylaxis for covid-19: living systematic review and 27 network meta-analysis.MedRxiv 2021 Hematology and Oncology, Mayo Clinic Rochester, Rochester, MN, USA 10 Lamontagne F, Agoritsas T, Siemieniuk R, etal. A living WHO guideline on drugs to prevent 28 covid-19. BMJ 2021;372:n526. doi: 10.1136/bmj.n526 pmid: 33649077 School of Public Health and Preventative Medicine, Monash University, Melbourne, 11 Hutton B, Salanti G, Caldwell DM, etal. The PRISMA extension statement for reporting of Australia systematic reviews incorporating network meta-analyses of health care interventions: checklist 29 and explanations. Ann Intern Med 2015;162:777-84. doi: 10.7326/M14-2385 pmid: 26030634 Department of Medicine, University Health Network, Toronto, ON, Canada 12 Elliott JH, Synnot A, Turner T, etalLiving Systematic Review Network. Living systematic review: 1. Introduction-the why, what, when, and how. J Clin Epidemiol 2017;91:23-30. doi: 10.1016/j.jclinepi.2017.08.010 pmid: 28912002 the bmj | BMJ 2020;370:m2980 | doi: 10.1136/bmj.m2980 13 RESEARCH

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