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Rochwerg, B., Siemieniuk, R. A., Agoritsas, T., Lamontagne, F., Askie, L., Lytvyn, L., Agarwal, A., Leo, Y., Macdonald, H., Zeng, L., Amin, W., Burhan, E., Bausch, F. J., Calfee, C. S., Cecconi, M., Chanda, D., Du, B., Geduld, H., Gee, P., . . . Vandvik, P. O. (2020). A living WHO guideline on drugs for covid-19. BMJ (Online), 370.
Authors
Rochwerg, Bram
Siemieniuk, Reed A. C.
Agoritsas, Thomas
Lamontagne, François
Askie, Lisa
Lytvyn, Lyubov
Agarwal, Arnav
Leo, Yee-Sin
Macdonald, Helen
Zeng, Linan
Amin, Wagdy
Burhan, Erlina
Bausch, Frederique Jacquerioz
Calfee, Carolyn S.
Cecconi, Maurizio
Chanda, Duncan
Du, Bin
Geduld, Heike
Gee, Patrick
Harley, Nerina
Hashimi, Madiha
Hunt, Beverly
Kabra, Sushil K.
Kanda, Seema
Kawano-Dourado, Leticia
Kim, Yae-Jean
Kissoon, Niranjan
Kwizera, Arthur
Mahaka, Imelda
Manai, Hela
Mino, Greta
Nsutebu, Emmanuel
Pshenichnaya, Natalia
Qadir, Nida
Sabzwari, Saniya
Sarin, Rohit
Shankar-Hari, Manu
Sharland, Michael
Shen, Yinzhong
Sri Ranganathan, Shalini
Souza, Joao P.
Stegemann, Miriam
De Sutter, An
Ugarte, Sebastian
Venkatapuram, Sridhar
Quoc Dat, Vu
Vuyiseka, Dubula
Wijewickrama, Ananda
Maguire, Brittany
Zeraatkar, Dena
Bartoszko, Jessica J.
Ge, Long
Brignardello-Petersen, Romina
Owen, Andrew
Guyatt, Gordon H.
Diaz, Janet
Jacobs, Michael
Vandvik, Per Olav
Clinical question What is the role of drug interventions in the treatment of patients with covid-19? New recommendation Increased attention on ivermectin as a potential treatment for covid-19 triggered this recommendation. The panel made a recommendation against ivermectin in patients with covid-19 regardless of disease severity, except in the context of a clinical trial. Prior recommendations (a) a strong recommendation against the use of hydroxychloroquine in patients with covid-19, regardless of disease severity; (b) a strong recommendation against the use of lopinavir-ritonavir in patients with covid-19, regardless of disease severity; (c) a strong recommendation for systemic corticosteroids in patients with severe and critical covid-19; (d) a conditional recommendation against systemic corticosteroids in patients with non-severe covid-19, and (e) a conditional recommendation against remdesivir in hospitalised patients with covid-19. How this guideline was created This living guideline is from the World Health Organization (WHO) and provides up to date covid-19 guidance to inform policy and practice worldwide. Magic Evidence Ecosystem Foundation (MAGIC) provided methodological support. A living systematic review with network analysis informed the recommendations. An international guideline development group (GDG) of content experts, clinicians, patients, an ethicist and methodologists produced recommendations following standards for trustworthy guideline development using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Understanding the new recommendation There is insufficient evidence to be clear to what extent, if any, ivermectin is helpful or harmful in treating covid-19. There was a large degree of uncertainty in the evidence about ivermectin on mortality, need for mechanical ventilation, need for hospital admission, time to clinical improvement, and other patient-important outcomes. There is potential for harm with an increased risk of adverse events leading to study drug discontinuation. Applying pre-determined values and preferences, the panel inferred that almost all well informed patients would want to receive ivermectin only in the context of a randomised trial, given that the evidence left a very high degree of uncertainty on important effects. Updates This is a living guideline. It replaces earlier versions (4 September, 20 November, and 17 December 2020) and supersedes the BMJ Rapid Recommendations on remdesivir published on 2 July 2020. The previous versions can be found as data supplements. New recommendations will be published as updates to this guideline. Readers note This is the fourth version (update 3) of the living guideline (BMJ 2020;370:m3379). When citing this article, please consider adding the update number and date of access for clarity.
RAPID RECOMMENDATIONSA living WHO guideline on drugs for covid-19Bram Rochwerg, 1, 2, a, c Reed AC Siemieniuk, 1, 2, a, * Thomas Agoritsas, 1, 3, 4, *, b François Lamontagne, 5, *, bLisa Askie, 6 Lyubov Lytvyn, 1, * Arnav Agarwal, 7, * Yee-Sin Leo, 8, a, b, c Helen Macdonald, 9, * Linan Zeng, 1,* Wagdy Amin, 10, a, c Erlina Burhan, 11, a, c Frederique Jacquerioz Bausch, 12, a, c Carolyn S Calfee, 13, b, cMaurizio Cecconi, 14, a, b, c Duncan Chanda, 15, a, c Bin Du, 16, a, c Heike Geduld, 17, a, b, c Patrick Gee, 18, a, b, cNerina Harley, 19, c Madiha Hashimi, 20, a, c Beverly Hunt, 21, c Sushil K Kabra, 22, a, c Seema Kanda, 23, a, b, cLeticia Kawano-Dourado, 24, a, b, c Yae-Jean Kim, 25, a, b, c Niranjan Kissoon, 26, a, b, c Arthur Kwizera, 27, a, b, cImeldaMahaka, 28, a, cHelaManai, 29, a, b, cGretaMino, 30, a, c Emmanuel Nsutebu, 31, a, cNatalia Pshenichnaya, 32,a, cNida Qadir, 33, a, b, c Saniya Sabzwari, 34, a, c Rohit Sarin, 35, a, b, cManu Shankar-Hari, 36, cMichael Sharland, 37,a, c Yinzhong Shen, 38, a, b, c Shalini Sri Ranganathan, 39, a, c Joao P Souza, 40, a, c Miriam Stegemann, 41, c An DeSutter, 42, c Sebastian Ugarte, 43, a, c Sridhar Venkatapuram, 44, a, c Vu Quoc Dat, 45, a, c Dubula Vuyiseka, 46, a,c Ananda Wijewickrama, 47, a, c Brittany Maguire, 48, * Dena Zeraatkar, 1, * Jessica J Bartoszko, 1, * Long Ge, 1,49, * Romina Brignardello-Petersen, 1, * Andrew Owen, 50, * Gordon Guyatt, 1, 2, * Janet Diaz, 6, *, dMichael Jacobs, 51, a, c, d Per Olav Vandvik4, 52, *, dABSTRACTCLINICAL QUESTIONWhat is the role of drug interventions in the treatmentof patients with covid-19?NEW RECOMMENDATIONIncreased attention on ivermectin as a potentialtreatment for covid-19 triggered this recommendation.The panel made a recommendation againstivermectin in patients with covid-19 regardless ofdisease severity, except in the context of a clinicaltrial.PRIOR RECOMMENDATIONS(a) a strong recommendation against the use ofhydroxychloroquine in patients with covid-19,regardless of disease severity; (b) a strongrecommendationagainst theuseof lopinavir-ritonavirin patients with covid-19, regardless of diseaseseverity; (c) a strong recommendation for systemiccorticosteroids in patients with severe and criticalcovid-19; (d) a conditional recommendation againstsystemic corticosteroids in patients with non-severecovid-19, and (e) a conditional recommendationagainst remdesivir in hospitalised patients withcovid-19.HOW THIS GUIDELINE WAS CREATEDThis living guideline is from the World HealthOrganization (WHO) andprovides up to date covid-19guidance to inform policy and practice worldwide.Magic Evidence Ecosystem Foundation (MAGIC)providedmethodological support. A living systematicreview with network analysis informed therecommendations. An international guidelinedevelopment group (GDG) of content experts,clinicians, patients, an ethicist and methodologistsproduced recommendations following standards fortrustworthy guideline development using theGradingof RecommendationsAssessment, Development andEvaluation (GRADE) approach.UNDERSTANDING THE NEW RECOMMENDATIONThere is insufficient evidence to be clear to whatextent, if any, ivermectin is helpful or harmful intreating covid-19. There was a large degree ofuncertainty in the evidence about ivermectin onmortality, need for mechanical ventilation, need forhospital admission, time to clinical improvement,and other patient-important outcomes. There ispotential for harm with an increased risk of adverseevents leading to study drug discontinuation.Applying pre-determined values andpreferences, thepanel inferred that almost all well informed patientswould want to receive ivermectin only in the contextof a randomised trial, given that the evidence left avery high degree of uncertainty on important effects.UPDATESThis is a living guideline. It replaces earlier versions(4 September, 20November, and 17December 2020)and supersedes theBMJRapid Recommendations onremdesivir published on 2 July 2020. The previousversions can be found as data supplements. Newrecommendations will be published as updates tothis guideline.READERS NOTEThis is the fourth version (update 3) of the livingguideline (BMJ 2020;370:m3379). When citing thisarticle, please consider adding the update numberand date of access for clarity.This living guideline responds to emerging evidencefrom randomised controlled trials (RCTs) on existingandnewdrug treatments for covid-19. Although casenumbers are falling in some regions, they are risingin others. Vaccines are linked to falling case numbersand hospitalisations, but most people remainunvaccinated. It is unclear how long protectionfollowing vaccination or natural infection will last,or how this might alter with the emergence of newvariants. Therefore, the potential for drugs to treatpeople infectedwith covid-19 remains of interest andis the focus of this guideline. A linked guidelineaddresses the role of drugs in the prevention ofcovid-19 among people who are not infected.1More than 3800 trials on covid-19 interventions havebeen registered or are ongoing (see section on1the bmj | BMJ 2020;370:m3379 | doi: 10.1136/bmj.m3379PRACTICEFor numbered affiliations see end ofarticle.Correspondence to: Bram Rochwergrochwerg@mcmaster.ca or MichaelJacobs michael.jacobs@ucl.ac.ukAdditional material is published onlineonly. To view please visit the journalonlineCite this as: BMJ 2020;370:m3379http://dx.doi.org/10.1136/bmj.m3379copyright. on 16 June 2021 at The University of British Columbia Library. Protected byhttp://www.bmj.com/BMJ: first published as 10.1136/bmj.m3379 on 4 September 2020. Downloaded from emerging evidence2). Among these are large national andinternationalplatformtrials (suchasRECOVERY,WHOSOLIDARITY,DISCOVERY, REMAP-CAP and ACTIV) that recruit large numbersof patients in many countries, with a pragmatic and adaptivedesign.3 4 These platform trials are currently investigating andreporting on numerous interventions, including antiviralmonoclonal antibodies and immunomodulators. This rapidlyevolving evidence landscape requires trustworthy interpretationand expeditious clinical practice guidelines to inform cliniciansand health care decision-makers.A living network meta-analysis associated with this guideline willincorporate new trial data as the evidence base increases andallowsfor analysis of comparative effectiveness of multiple covid-19treatments.5 This network meta-analysis and other relatedpublications are included in box 1. We also use additional relevantevidence on safety, prognosis, and patient values and preferencesrelated to covid-19 treatments to inform the living guidance.Box 1: Linked resources in this BMJ Rapid Recommendations cluster• Siemieniuk RAC, Rochwerg B, Agoritsas T, et al. A livingWHOguidelineon drugs for covid-19 [Update 3]. BMJ 2020;370:m3379• World Health Organization. Therapeutics and COVID-19. Livingguideline. 31 March 2021. https://www.who.int/publica-tions/i/item/therapeutics-and-covid-19-living-guideline.• MAGICapp (https://app.magicapp.org/#/guideline/nBkO1E)‐ Expanded version of the methods, processes, and results withmultilayered recommendations, evidencesummaries, anddecisionaids for use on all devices• Siemieniuk RAC, Bartoszko JJ, Ge L, et al. Drug treatments for covid-19:living systematic review and network meta-analysis [Update 3]. BMJ2020;370:m2980, doi:10.1136/bmj.m2980• Izcovich A, Siemieniuk RAC, Bartoszko JJ, et al. Adverse effects ofremdesivir, hydroxychloroquine, and lopinavir/ritonavir when usedfor COVID-19: systematic review and meta-analysis of randomizedtrials. Preprint available at: https://www.medrxiv.org/con-tent/10.1101/2020.11.16.20232876v1What triggered this version of the guideline?This is the fourth version of this guideline, and it addresses the useof ivermectin in patientswith covid-19. Itwas triggered by increasedinternational attention on ivermectin as a potential treatment.How to use this guidelineThis is a living guideline, so the recommendations included herewill be updated, and new recommendationswill be added for otherdrugs for covid-19. The infographic provides a summary of therecommendations and includes links to the MAGICapp for moredetails on the evidence and rationale for the recommendation, aswell as patient decision aids. Box 2 outlines key methodologicalaspects of the guideline process.Box 2: How this living guideline was created (see MAGICapp for fulldetails https://app.magicapp.org/#/guideline/nBkO1E)This guidelinewasdevelopedbyWHOand theMAGICEvidenceEcosystemFoundation (MAGIC), with support from The BMJ. It is driven by an urgentneed for trustworthy and living guidance to rapidly inform policy andpractice worldwide during the covid-19 pandemic. WHO has partneredwith MAGIC for their methodologic support in the development anddissemination of living guidance for covid-19 drug treatments, in the formof BMJ Rapid Recommendations, to provide patients, clinicians, andpolicy makers with up to date, evidence based, and user friendlyguidelines.Standards,methods, andprocesses for living and trustworthyguidanceThe panel produced the recommendations following standards fortrustworthy guideline development using the GRADE (Grading ofRecommendationsAssessment, Development andEvaluation) approach,in compliance with theWHO Handbook for Guideline Development 2ndEdition,6 the Institute of Medicine, and the Guideline InternationalNetwork (G-I-N).7 Details are provided in the WHO guideline(https://www.who.int/publications/i/item/therapeutics-and-covid-19-living-guideline) and MAGICapp (https://app.magicapp.org/#/guide-line/nBkO1E).Selection and support of the panelFor the ivermectin recommendation, WHO convened an internationalguideline development panel (GDG)with 34 individuals, of whom28werecontent experts (clinicians, methodologists, scientists) and four werepatients who had survived covid-19. Themethods chair (methodologicalexpertise) and a clinical chair (content expertise) guided the paneldiscussions. Panel members were invited by WHO, after consultationwith the methods chair and MAGIC, with the aim of achieving gender,geography, expertise, and patient representation balance in the panel.No relevant conflict of interest was identified for any panel member.As recommended by the WHO handbook, the panel aimed to create arecommendation based on consensus but elected, at the beginning ofthe first panelmeeting, to call a vote if a consensus could not be reached.These procedures proved unnecessary for this recommendation.Guideline perspective, outcomes, and values and preferencesThe target audience for this guidance consists primarily of clinicians, butsecondarily of patients and healthcare decision makers. The panelconsidered an individual patient perspective but also took account ofcontextual factors (such as resources, feasibility, acceptability, equity)to accommodate global re-use and adaptation for countries andhealthcare systems.During a pandemic, access to healthcaremay vary over time andbetweendifferent countries. The panel defined covid-19 by clinical severity, andmutually exclusive definitions are provided in box 3.There were insufficient published data to provide the GDG with aninformative systematic reviewof studies describing patients’ experiencesor values and preferences on treatment decisions for covid-19 drugtreatments. The GDG therefore relied on their own judgments of whatwell informedpatientswould value after carefully balancing the benefits,harms, and burdens of treatment and their subsequent treatmentpreferences. The GDG included four patient representatives who hadlived experience with covid-19.The GDG agreed that the following values and preferences would berepresentative of those of typical well-informed patients:• Most patients would be reluctant to use a medication for which theevidence left high uncertainty regarding effects on the outcomes theyconsider important. Thiswasparticularly sowhen evidence suggestedtreatment effects, if they exist, are small and the possibility ofimportant harm remains.• In an alternative situation with larger benefits and less uncertaintyregarding both benefits and harms, more patients would be inclinedto choose the intervention.Although the GDG focused on an individual patient perspective, theyalso considered a population perspective in which feasibility,acceptability, equity, and cost are important considerations.Sources of evidenceTo create recommendations, the panel relied on evidence synthesisedin a living network meta-analysis led by MAGIC.5While the investigatorsresponsible for themeta-analyses rate the certainty of the evidence, thisis re-assessed independently by the guideline panel.Derivation of absolute effects for drug treatmentsThe control arm of the WHO SOLIDARITY trial, performed across a widevariety of countries and geographical regions, was identified by the GDGas generally representing the most relevant source of evidence forbaseline risk estimates for mortality and mechanical ventilation. Therationale for selecting theWHOSOLIDARITY trial was to reflect the overallprognosis of the global population for which the WHO guidelinethe bmj | BMJ 2020;370:m3379 | doi: 10.1136/bmj.m33792PRACTICEcopyright. on 16 June 2021 at The University of British Columbia Library. Protected byhttp://www.bmj.com/BMJ: first published as 10.1136/bmj.m3379 on 4 September 2020. Downloaded from recommendations are made. However, the SOLIDARITY trial only enrolspatients who are hospitalised with covid-19. Given ivermectin has beenproposed for use and is often studied in outpatients, on this occasion,the panel used the median of risk in the standard care arms of theincluded trials for baseline risk estimates for these outcomes. Whenapplying the evidence to a particular patient or setting, for anymedicationwith a convincing effect, clinicians should consider the individual’s riskof mortality and need for mechanical ventilation. In view of the studydesigns, the GDG determined that for other outcomes using the medianor mean of all patients randomised to usual care across the includedstudies would provide the most reliable estimate of baseline risk.Of note, baseline risks, and thus absolute effects, may vary significantlygeographically and over time. As such, users of this guidelinemay preferestimating absolute effects by using local event rates.Who do the recommendations apply to?This guideline applies to all patientswith covid-19. For somedrugs,such as corticosteroids, recommendations differ based on theseverity of covid-19disease. TheGDGelected touse theWHOseveritydefinitions basedon clinical indicators, adapted fromWHOcovid-19severity categorisation (see box 3).8These definitions avoid relianceonaccess tohealthcare to definepatient subgroups. The infographicillustrates these threedisease severity groups andkey characteristicsto apply in practice.Box 3: WHO definitions of disease severity for covid-19• Critical covid-19—Defined by the criteria for acute respiratory distresssyndrome (ARDS), sepsis, septic shock, or other conditions thatwouldnormally require the provision of life sustaining therapies such asmechanical ventilation (invasive or non-invasive) or vasopressortherapy.• Severe covid-19—Defined by any of:‐ Oxygen saturation <90% on room air*‐ Respiratory rate >30 breaths per minute in adults and children >5years old, ≥60 breaths/min in children <2 months old, ≥50 inchildren 2-11 months old, and ≥40 in children 1-5 years old‐ Signsof severe respiratory distress (accessorymuscle use, inabilityto complete full sentences, and, in children, very severe chest wallindrawing, grunting, central cyanosis, or presence of any othergeneral danger signs).• Non-severe covid-19—Defined as absence of any signs of severe orcritical covid-19.*The panel noted that the oxygen saturation threshold of 90% to definesevere covid-19was arbitrary and should be interpreted cautiously whendefiningdisease severity. For example, cliniciansmust use their judgmentto determine whether a low oxygen saturation is a sign of severity or isnormal for a given patient with chronic lung disease. Similarly, asaturation >90-94% is abnormal, and can be an early sign of severedisease, if the patient is on a downward trend. Generally, if there is anydoubt, the panel suggested erring on the side of considering the illnessas severe.The guidanceIvermectinIvermectin is relatively inexpensive and accessible, and somecountrieshavealreadywitnessed itswidespreaduse in the treatmentof covid-19; in other countries, there is increasing pressure to doso. Ivermectin is an antiparasitic agent that interferes with nerveandmuscle function of helminths throughbinding glutamate-gatedchloride channels.9We currently lack persuasive evidence of amechanism of action for ivermectin in covid-19; any observedclinical benefit would be unexplained.Evidenceunderpinning the recommendation comes from the linkedsystematic review and network meta-analysis.5 Compared withprevious drugs evaluated as part of this living guideline (see below),currently there are far fewer RCT data available for ivermectin. Theexisting data on ivermectin also have a substantially higher degreeof uncertainty, with included trials having enrolled substantiallyfewer patients with far fewer events, across multiple small trials.The evidence is outlined in box 4.Box 4: Ivermectin trial dataThe LNMA pooled data from 16 RCTs with 2407 participants.5 Of theincluded trials, 75%examinedpatientswith non-severe disease and25%included both severe and non-severe patients. A number of the includedtrials did not report on our outcomes of interest. Of the trials, 25% werepublished in peer-reviewed journals, 44% were available as preprintsand 31% were completed but unpublished (table 1). We excluded anumber of quasi-RCTs. None of the included RCTs enrolled children under15 or pregnant women but there is no rationale to suggest they wouldrespond differently.Although 16 RCTs contributed to the evidence summary informing thisdrug, only five directly compared ivermectin with standard care andreported mortality.10 -14Of these five RCTs, two were at high risk of bias,due to inadequate blinding.10 11 One of these two trials also startedenrolling and randomising patients before the protocol being publiclyposted, another factor that contributes to an increased risk of bias.10The potential impact of risk of bias is exemplified by subgroup analysesfor mortality based on trial risk of bias. As shown in the forest plot (fig1), the pooled estimate across all five RCTs that directly compareivermectin with standard care suggests a reduction in mortality withivermectin, but this effect is not apparent if we consider only the trialsat low risk of bias (which together contribute nearly two thirds of theevidence).Fig 1 | Forest plot showing direct comparison of ivermectin versus standard carefor mortality with subgroup analysis by risk of biasThis finding increases the degree of uncertainty regarding the true effectof ivermectin on mortality. Consistent with the direct evidence, a similarphenomenon is observedwith the indirect evidence comparing ivermectinwith standard care (via comparisons against hydroxychloroquine andlopinavir-ritonavir). The indirect evidence suggesting a reduction inmortality with ivermectin is driven almost entirely by one study which isat high risk of bias due to a lack of detailed description of blinding orrandomisation and the lack of a publicly available study protocol (figurenot shown).15In addition to concerns related to risk of bias, there are serious concernsrelated to imprecision for the outcome of mortality. According to GRADE,imprecision is evaluated based on both a confidence interval approachand an evaluation of information size (event number), ensuring there isadequate information on which to make informed judgments.16 In thiscase, despite confidence intervals that suggest benefit with ivermectin,3the bmj | BMJ 2020;370:m3379 | doi: 10.1136/bmj.m3379PRACTICEcopyright. on 16 June 2021 at The University of British Columbia Library. Protected byhttp://www.bmj.com/BMJ: first published as 10.1136/bmj.m3379 on 4 September 2020. Downloaded from the information size is very low. For mortality (and ignoring the concernsrelated to risk of bias discussed above), there were nine deaths acrossall 511 patients randomised to ivermectin (1.76%) and 22 deaths acrossall 404patients randomised to standard care (5.45%). This is an extremelysmall number of events on which to base conclusions, and far below theoptimal information size. Furthermore, the evidence informing thiscomparison is from multiple small trials, adding to the risk ofunrecognised imbalances in study arms. Given the strong likelihood thatchancemay be playing a role in the observed findings, the panel believedthere was very serious imprecision, further lowering the overall certaintyin findings.Understanding the recommendation on ivermectinWe recommend not to use ivermectin in patients with covid-19except in the context of a clinical trial, regardless of disease severityor duration of symptoms.Balance of benefit and harm—For most important outcomes, thepanel considered the evidence to be of very low certainty. Acombination of serious risk of bias and very serious imprecisioncontributed to very low certainty of evidence for mortality, despitea point estimate and confidence interval that appear to suggestbenefit with ivermectin (box 4). The picture was similar for otherimportant outcomes, including mechanical ventilation, hospitaladmission, duration of hospitalisation, and viral clearance. Thevery low certainty of evidence was a critical factor in therecommendation. Ivermectinmay have little or no effect on time toclinical improvement (low certainty evidence) and may increasethe risk of adverse effects leading to drug discontinuation (lowcertainty evidence). A recommendation to only use a drug in thesetting of a clinical trials is appropriate when there is very lowcertainty evidence and future research has a large potential forreducing uncertainty about the effects of the intervention and fordoing so at reasonable cost.Subgroup analyses indicated no effectmodification based on dose.We were unable to examine subgroups based on patient age orseverity of illness due to insufficient trial data. Therefore, weassumed similar effects in all subgroups.Values and preferences—The GDG inferred that almost allwell-informedpatientswouldnotwant to receive ivermectin, giventhe evidence left a veryhighdegree of uncertainty in effect on criticaloutcomes and there was a possibility of harms, such as adverseevents associated with treatment. The panel did not expect therewould bemuch variation amongpatients in values andpreferenceswhen it came to this intervention.Resource implications, feasibility, equity, andhuman rights—Althoughthe cost of ivermectinmay be low per patient, the GDGpanel raisedconcerns about diverting attention and resources away from carelikely to provide a benefit such as corticosteroids in patients withsevere covid-19 and other supportive care interventions. Also, useof ivermectin for covid-19 would divert supply away frompathologies forwhich it is clearly indicated, potentially contributingto drug shortages, especially for helminth control and eliminationprogrammes. If corticosteroids are used in the treatment of covid-19,empiric treatment with ivermectin may still be considered in areaswhere strongyloidiasis is endemic, albeit not for treatment ofcovid-19 itself.Hydroxychloroquine (published 17 December 2020)The recommendationaddressinghydroxychloroquinewas informedby results froma systematic reviewandnetworkmeta-analysis thatpooled data from 30 RCTs with 10 921 participants. Of note, none ofthe included RCTs enrolled children or adolescents under the ageof 19 years. Given this, the applicability of this recommendation tochildren is currently uncertain.Understanding the recommendation on hydroxychloroquineWe recommend against using hydroxychloroquine or chloroquinein addition to usual care for the treatment of patientswith covid-19,regardless of disease severity or duration of symptoms (strongrecommendation).Balance of benefit andharm—Hydroxychloroquine and chloroquineprobably do not reduce mortality or mechanical ventilation andmay not reduce duration of hospitalisation. The evidence does notexclude the potential for a small increased risk of death andmechanical ventilation with hydroxychloroquine. The effect onother less important outcomes—including time to symptomresolution, admission to hospital, and duration of mechanicalventilation—remains uncertain.Hydroxychloroquinemay increase the risk of diarrhoea andnauseaor vomiting, a finding consistentwith evidence from its use in otherconditions. Diarrhoea and vomiting may increase the risk ofhypovolaemia, hypotension, and acute kidney injury, especially insettings where healthcare resources are limited. Whether and towhat degree hydroxychloroquine increases the risk of cardiactoxicity, including life threatening arrhythmias, when used inpatients with covid-19 is uncertain.Subgroup analyses indicated no effect modification based onseverity of illness (comparingeither critical versus severe/non-severeor non-severe versus critical/severe) or age (comparing those aged<70 years versus those ≥70 years). Further, the cumulative dose andpredicted day 3 serum trough concentrations (lowest predictedblood concentration on day 3) did not modify the effect for anyoutcome. Therefore, we assumed similar effects in all subgroups.We also reviewed evidence comparing the use ofhydroxychloroquine plus azithromycin versus hydroxychloroquinealone. There was no evidence that the addition of azithromycinmodified the effect of hydroxychloroquine for any outcome (verylow certainty).Valuesandpreferences—Applying theagreedvaluesandpreferences(box 2), the GDG inferred that almost all well-informed patientswould not want to receive hydroxychloroquine given the evidencesuggesting there was probably no effect on mortality or need formechanical ventilation and that there was a risk of adverse eventsincludingdiarrhoea andnausea/vomiting. Thepanel did not expectthere would be much variation in values and preferences amongpatients when it came to this intervention.Resource implications, feasibility, equity, and humanrights—Hydroxychloroquine and chloroquine are relativelyinexpensive compared with other drugs used for covid-19 and arealreadywidely available, including in low income settings. Despitethis, the panel felt that almost all patients would choose not to usehydroxychloroquine or chloroquine because the harms outweighthe benefits. Although the cost may be low per patient, the GDGpanel raised concerns about diverting attention and resources awayfrom care likely to provide a benefit such as corticosteroids inpatients with severe covid-19 and other supportive careinterventions.Lopinavir-ritonavir (published 17 December 2020)The recommendation addressing lopinavir-ritonavir was informedby the samesystematic reviewandnetworkmeta-analysis, includingdata from seven RCTs with 7429 participants. None of the includedthe bmj | BMJ 2020;370:m3379 | doi: 10.1136/bmj.m33794PRACTICEcopyright. on 16 June 2021 at The University of British Columbia Library. Protected byhttp://www.bmj.com/BMJ: first published as 10.1136/bmj.m3379 on 4 September 2020. Downloaded from RCTs enrolled children or adolescents under the age of 19 years, sothe applicability of this recommendation to children is uncertain.Understanding the recommendation on lopinavir-ritonavirWe recommend against using lopinavir-ritonavir in addition tousual care for the treatment of patients with covid-19, regardless ofdisease severity and duration of symptoms (strongrecommendation).Balance of benefit and harm—The GDG panel found a lack ofevidence that lopinavir-ritonavir improved patient-importantoutcomes such as reduced mortality, need for mechanicalventilation, time to clinical improvement, and others. Formortalityand need for mechanical ventilation, this was based on moderatecertainty evidence; for the other outcomes, this was based on lowor very low certainty evidence.There was low certainty evidence that lopinavir-ritonavir mayincrease the risk of diarrhoea and nausea or vomiting, a findingconsistent with the indirect evidence evaluating its use in patientswith HIV infection. Diarrhoea and vomiting may increase the riskof hypovolaemia, hypotension, and acute kidney injury, especiallyin settings where healthcare resources are limited. There was anuncertain effect on viral clearance and acute kidney injury.Subgroupanalysis indicatednoeffectmodificationbasedonseverityof illness (comparing either critical versus severe/non-severe ornon-severe versus critical/severe) or age (comparing those aged<70 years versus those ≥70 years). As there was no evidence of astatistical subgroup effect, we did not formally evaluate credibility.Although the trials did not report subgroup effects by time fromsymptom onset, many of the trials enrolled patients early in thedisease course. The GDG panel therefore felt that the evidenceapplies to all patients with covid-19.Valuesandpreferences—Applying theagreedvaluesandpreferences(box 2), the GDG inferred that almost all well informed patientswouldnotwant to receive lopinavir-ritonavir given that the evidencesuggested there was probably no effect on mortality or need formechanical ventilation and there was a risk of adverse eventsincluding diarrhoea and nausea or vomiting. The panel did notexpect there would be much variation in values and preferencesbetween patients for this intervention.Resource implications, feasibility, equity, andhuman rights—Althoughthe cost of lopinavir-ritonavir is not as high as some otherinvestigational drugs for covid-19 and thedrug is generally availablein most healthcare settings, the GDG raised concerns aboutopportunity costs and the importance of not drawing attention andresources away from best supportive care or the use ofcorticosteroids in severe covid-19.Remdesivir (published 20 November 2020)The recommendation addressing remdesivir was informed by thesame systematic reviewandnetworkmeta-analysis, includingdatafrom fourRCTswith 7333 participants hospitalised for covid-19.5 17 -19Ofnote, none of the includedRCTs enrolled children or adolescentsunder the age of 19 years, and, although older peoplewere includedin the trials, their outcomes were not reported separately. Also,there is nopharmacokinetic or safetydataon remdesivir for children.Given this, the applicability of this recommendation to children iscurrently uncertain (see box 1 for links).Understanding the recommendation on remdesivirWe suggest against administering remdesivir in addition to usualcare for the treatment of patients hospitalised with covid-19,regardless of disease severity (weak or conditionalrecommendation).When moving from evidence to the conditional recommendationagainst the use of remdesivir for patients with covid-19, the panelemphasised the evidence of possibly no effect on mortality, needformechanical ventilation, time to clinical improvement, and otherpatient-important outcomes, albeit of low certainty; it also notedthe anticipated variability in patient values and preferences andother contextual factors, such as resource considerations,accessibility, feasibility and impact on health equity (see below).Balance of benefit and harm—The GDG panel found a lack ofevidence that remdesivir improved outcomes thatmatter to patientssuch as reduced mortality, need for mechanical ventilation, timeto clinical improvement, and others. However, the low certaintyevidence for these outcomes, especially mortality, does not provethat remdesivir is ineffective; rather, there is insufficient evidenceto confirm that it does improve patient-important outcomes.There was no evidence of increased risk of serious adverse eventsin patients receiving remdesivir, at least from the included trials.Further pharmacovigilance is required, because serious adverseevents are commonly underreported and rare events could bemissed, even in large RCTs.Data from the network meta-analysis indicated that a subgroup ofpeople with non-critical disease might benefit from remdesivir.However, the panel judged the credibility in this subgroup analysisto be insufficient tomake subgroup recommendations.18 Importantfactors influencing this decision included a lack of a priorihypothesised direction of subgroup effect by trial investigators,little or no previously existing supportive evidence for the subgroupfinding, and relatively arbitrary cut points used to examine thesubgroups of interest. The overall low certainty evidence for thebenefits and harms of remdesivir, driven by risk of bias andimprecision limitations, also contributed to the judgment (seeWHOguidance and MAGICapp linked from box 1 for full details). Thepanel highlighted that, despite the conditional recommendationagainst remdesivir, they support further enrolment into RCTsevaluating remdesivir, especially to provide higher certainty ofevidence for specific subgroups of patients. The panel had a priorirequested analyses of other important subgroups of patients,including children and older people, but there were no data toaddress these groups specifically.Valuesandpreferences—Applying theagreedvaluesandpreferences(box 2), the panel inferred that most patients would be reluctant touse remdesivir, given the evidence left high uncertainty regardingeffects on mortality and the other prioritised outcomes. This wasparticularly so as any beneficial effects of remdesivir, if they doexist, are likely to be small, and the possibility of important harmremains. The panel acknowledged, however, that values andpreferences are likely to vary, and there will be patients andclinicianswho choose to use remdesivir given that the evidence hasnot excluded the possibility of benefit.Resource implications, feasibility, equity, and human rights—Anoveltherapy typically requires higher certainty evidence of importantbenefits than is currently available for remdesivir, preferablysupported wherever possible by cost-effectiveness analysis. In theabsence of this information, the GDG raised concerns aboutopportunity costs and the importance of not drawing attention andresources away from best supportive care or the use ofcorticosteroids in severe covid-19. It was noted that, currently,remdesivir is administered only by the intravenous route and globalavailability is limited.5the bmj | BMJ 2020;370:m3379 | doi: 10.1136/bmj.m3379PRACTICEcopyright. on 16 June 2021 at The University of British Columbia Library. Protected byhttp://www.bmj.com/BMJ: first published as 10.1136/bmj.m3379 on 4 September 2020. Downloaded from Practical issues—Its use is contraindicated in those with liverdysfunction (ALT >5 times normal at baseline) or renal dysfunction(eGFR <30 mL/minute). To date, it can only be administeredintravenously, and it has relatively limited availability.Corticosteroids (published 4 September 2020)On 17 July 2020 the panel reviewed evidence from eight RCTs (7184patients)19 -23 evaluating systemic corticosteroids versus usual carein treatment of covid-19, seven of which reportedmortality data bysubgroup of illness severity. Mortality data from one trial,GLUCOCOVID,were not incorporated in the summary of finding formortality because the mortality outcome data were not availableby subgroup. The panel did not consider transdermal or inhaledadministration of corticosteroids, high dose or long-term regimens,or prophylaxis. The panel did not reach consensus onrecommendation 1, which required a vote. The secondrecommendation was made by consensus. The WHO guidelinepublication and MAGICapp provides details about the evidence,such as characteristics of trials, subgroup analyses performed, andunderlying panel discussions to inform recommendations (see box1 for link).Understanding the recommendations on corticosteroidsRecommendation1:Werecommendsystemic corticosteroids ratherthan no systemic corticosteroids for the treatment of patients withsevere and critical covid-19 (strong recommendation)Whodoes it apply to?This recommendation applies to patientswithsevere and critical covid-19. The panel judged that all or almost allfully informed patients with severe covid-19 would choose to takesystemic corticosteroids. The recommendation should apply topatients with severe and critical covid-19 even if they cannot behospitalised or receive oxygen because of resource limitations.The applicability of the recommendation is less clear for populationsthat were under-represented in the considered trials, such aschildren, patients with tuberculosis, and those who areimmunocompromised. In considering potential contraindicationsto short term systemic corticosteroids in such patients, cliniciansmust determine if they warrant depriving a patient of a potentiallylifesaving therapy. Clinicians should exercise caution in use ofcorticosteroids in patients with diabetes or underlyingimmunocompromise. The panelwas confident that clinicians usingthese guidelineswould be aware of additional potential side effectsand contraindications to systemic corticosteroid therapy, whichmay vary geographically in function of endemic microbiologicalflora.Balance of benefit and harm—Ultimately, the panel made itsrecommendation on the basis of the moderate certainty evidenceof a 28-daymortality reduction of 8.7% in the critically ill and 6.7%reduction in patients with severe covid-19 who were not criticallyill. Systemic corticosteroids comparedwithno corticosteroid therapyprobably reduce the risk of 28-daymortality in critically ill patientswith covid-19 (moderate certainty evidence; relative risk 0.80 (95%confidence interval 0.70 to 0.91); absolute effect estimate 87 fewerdeaths per 1000 patients (95%CI 124 fewer to 41 fewer)). In patientswith severe covid-19, systemic corticosteroids also probably reducethe risk of death (moderate certainty evidence; relative risk 0.80(0.70 to 0.92); absolute effect estimate 67 fewer deaths per 1000patients (100 fewer to 27 fewer)). The effects of systemiccorticosteroids on other outcomes are described in the summary offindings.Overall, the panel has high certainty that the adverse effects whenconsidered together are sufficiently limited in importance andfrequency and suggested that corticosteroids administered in thesedoses for 7-10 days are not associated with an increased risk ofadverse events, beyond likely increasing the incidence ofhyperglycaemia (moderate certainty evidence; absolute effectestimate 46 more per 1000 patients (23 more to 72 more)) andhypernatraemia (moderate certainty evidence; 26 more per 1000patients (13more to 41more)). In contrastwith newagents proposedfor covid-19, clinicians have a vast experience of systemiccorticosteroids, and the panel was reassured by their overall safetyprofile.Values and preferences—The panel took an individual patientperspective to values and preferences but, given the burden of thepandemic for healthcare systems globally, also placed a high valueon resource allocation and equity. The benefits of corticosteroidson mortality was deemed of critical importance to patients, withlittle or no anticipated variability in their preference to be offeredtreatment if severely ill from covid-19.Resource implications, feasibility, equity, andhuman rights—Systemiccorticosteroids are lowcost, easy to administer, and readily availableglobally.24 Dexamethasone and prednisolone are among the mostcommonly listed medicines in national essential medicines lists;listed by 95% of countries. Accordingly, systemic corticosteroidsare among a relatively small number of interventions for covid-19that have the potential to reduce inequities and improve equity inhealth. Those considerations influenced the strength of thisrecommendation.Acceptability—The ease of administration, the relatively shortduration of a course of systemic corticosteroid therapy, and thegenerally benign safety profile of systemic corticosteroidsadministered for up to 7-10 days led the panel to conclude that theacceptability of this intervention was high.Recommendation 2:We suggest not to use corticosteroids in thetreatment of patientswith non-severe covid-19 (weak or conditionalrecommendation)Whodoes it apply to?This recommendation applies to patientswithnon-severe disease regardless of their hospitalisation status. Thepanel noted that patients with non-severe covid-19 would notnormally require acute care in hospital or respiratory support, butin some jurisdictions thesepatientsmaybehospitalised for isolationpurposes only, in which case they should not be treated withsystemic corticosteroids. Several specific circumstances wereconsidered.• Systemic corticosteroids should not be stopped for patientswithnon-severe covid-19 who are already treated with systemiccorticosteroids for other reasons (such as patients with chronicobstructive pulmonary disease or chronic autoimmunedisease).• If the clinical condition of patients with non-severe covid-19worsens (that is, increase in respiratory rate, signs of respiratorydistress or hypoxaemia) they should receive systemiccorticosteroids (see recommendation 1).• Pregnancy: antenatal corticosteroid therapymaybeadministeredfor pregnant women at risk of preterm birth from 24 to 34weeks’gestationwhen there is no clinical evidence ofmaternal infectionandadequate childbirth andnewborn care are available. In caseswhere the woman presents with mild or moderate covid-19, theclinical benefits of antenatal corticosteroid might outweigh therisks of potential harm to the mother. In this situation, thebalance of benefits and harms for the woman and the pretermnewborn should be discussed with the woman to ensure aninformed decision, as this assessment may vary depending onthe bmj | BMJ 2020;370:m3379 | doi: 10.1136/bmj.m33796PRACTICEcopyright. on 16 June 2021 at The University of British Columbia Library. Protected byhttp://www.bmj.com/BMJ: first published as 10.1136/bmj.m3379 on 4 September 2020. Downloaded from the woman’s clinical condition, her wishes and those of herfamily, and available healthcare resources.• Endemic infections thatmayworsenwith corticosteroids shouldbe considered. For example, for Strongyloides stercoralishyperinfection associatedwith corticosteroid therapy, diagnosisor empiric treatment may be considered in endemic areas ifsteroids are used.Balance of benefit and harm—Systemic corticosteroidsmay increasethe risk of 28 day mortality (low certainty evidence; relative risk1.22 (95% CI 0.93 to 1.61); absolute effect estimate 39more per 1000patients (95%CI 12 fewer to 107more)). The certainty of the evidencefor this specific subgroup was downgraded due to seriousimprecision (that is, the evidence does not allow to rule out amortality reduction) and risk of bias due to lack of blinding. Theeffects of systemic corticosteroids on other outcomes are describedin the summary of findings (infographic and links to MAGICapp).Values and preferences—Theweak or conditional recommendationwas driven by likely variation in patient values and preferences.The panel judged that most individuals with non-severe illnesswould decline systemic corticosteroids. However, many may wantthem after shared decision making with their treating physician.Resource implications, feasibility, equity, and human rights—Tohelpguarantee access to systemic corticosteroids for patientswith severeand critical covid-19, it is reasonable to avoid their administrationto patients who, given the current evidence, do not seem to deriveany benefit from this interventionUncertainties, emerging evidence, and future researchThe guideline recommendations for covid-19 therapeuticsdemonstrate remaining uncertainties concerning treatment effectsfor all outcomes of importance to patients. There is also a need forbetter evidence onprognosis and values andpreferences of patientswith covid-19. Here we outline key uncertainties for ivermectinidentified by theGDG, adding to those for corticosteroids in the firstversion, remdesivir in the second version, andhydroxychloroquineand lopinavir-ritonavir in the third version of the living guideline.These uncertainties may inform future research—that is, theproduction of more relevant and reliable evidence to inform policyand practice. We also outline emerging evidence in the rapidlychanging landscape of trials for covid-19.IvermectinGiven the very low certainty in estimates formost critical outcomesof interest, the GDG felt that further high quality clinical trialsexamining this drugwouldbe essential before any recommendationfor use as part of clinical care. This includes further RCTs examiningboth inpatients and outpatients, patients with varying diseaseseverities, and using different ivermectin dosing regimens. Thefocus of these studies should be on outcomes important to patientssuch as mortality, quality of life, need for hospitalisation, need forinvasive mechanical ventilation and time to clinical or symptomimprovement. Also, a better characterisation of potential harmswith ivermectin in patients with covid-19 is important.Hydroxychloroquine and lopinavir-ritonavirAlthough someuncertainty remains, theGDGpanel felt that furtherresearchwasunlikely touncover a subgroupof patientswhowouldbenefit fromhydroxychloroquine or lopinavir-ritonavir on themostimportant outcomes (mortality, mechanical ventilation) given theconsistent results in trials across disease severity and location.RemdesivirRemaining uncertainties include effects on:• Critical outcomes of interest, particularly those that impactresource allocation, such as the need formechanical ventilation,duration of mechanical ventilation, and duration ofhospitalisation• Specific subgroups, such as different severities of illness,different time (days) since onset of illness, children and olderadults, pregnant women, duration of therapy• Long term outcomes (such as 1-year endpoint) examiningmortality or long term quality of life• Long term safety and rare but important side effects• Patient-reported outcomes such as symptom burden• Outcomeswhen used in combinationwith other agents such as,but not limited to, corticosteroids• Impact on viral shedding, viral clearance, patient infectivity.CorticosteroidsRemaining uncertainties include effects on:• Long term mortality and functional outcomes in covid-19survivors• Patients with non-severe covid-19 (that is, pneumonia withouthypoxaemia)• Whenused in combinationwith additional therapies for covid-19,such as novel immunomodulators. It will become increasinglyimportant to ascertain how these interact with systemiccorticosteroids. All investigational therapies for severe andcritical covid-19 (including remdesivir) should be comparedwithsystemic corticosteroids or evaluated in combination withsystemic corticosteroids versus systemic corticosteroids alone• Immunity and the risk of a subsequent infection, which mayaffect the risk of death after 28 days• By different steroid preparation, dosing, and optimal timing ofdrug initiation.Emerging evidenceThe unprecedented volume of planned and ongoing studies forcovid-19 interventions—over 3000RCTs as of 1March 2021—impliesthatmore reliable and relevant evidencewill emerge to informpolicyand practice.2 An overview of registered and ongoing trials forcovid-19 therapeutics is available from the InfectiousDiseasesDataObservatory, through their living systematic review of covid-19clinical trial registrations2 and WHO website https://www.covid-nma.com/dataviz/. Concerning ivermectin and covid-19,more than66 RCTs planning to enrol more than 12 000 participants (range24-2724) are registered or ongoing.2Although most of these studies are small and of variablemethodological quality, some large, international platform trials(such as RECOVERY, SOLIDARITY, and DISCOVERY) are betterequipped to provide robust evidence for several potential treatmentoptions. Such trials can also adapt their design, recruitmentstrategies, and selection of interventions based on new insights.How patients were involved in the creation of this articleThe guideline panel included four patients who have had covid-19. Theirperspectives were crucial in considering the values and preferences7the bmj | BMJ 2020;370:m3379 | doi: 10.1136/bmj.m3379PRACTICEcopyright. on 16 June 2021 at The University of British Columbia Library. Protected byhttp://www.bmj.com/BMJ: first published as 10.1136/bmj.m3379 on 4 September 2020. Downloaded from associated with ivermectin, hydroxychloroquine, lopinavir-ritonavir,remdesivir, and corticosteroids.AUTHOR AFFILIATIONS1Department of Health ResearchMethods, Evidence and Impact, McMaster University,Hamilton, Ontario, Canada2Department of Medicine, McMaster University, Hamilton, Ontario, Canada3Division of General Internal Medicine & Division of Clinical Epidemiology, UniversityHospitals of Geneva, Geneva, Switzerland4MAGIC Evidence Ecosystem Foundation, Oslo, Norway5Université de Sherbrooke, Centre de recherche due CHU de Sherbrooke, Quebec,Canada6World Health Organization, Geneva, Switzerland7Department of Medicine, University of Toronto, Toronto, Ontario, Canada8National Center for Infectious Diseases, Singapore9, London, UK10Ministry of Health and Population, Cairo, Egypt11Infection Division, Department of Pulmonology and Respiratory Medicine, Faculty ofMedicine Universitas Indonesia12Geneva University Hospital, Switzerland13University of California, San Francisco, USA14Department of Anesthesia and Intensive Care Medicine, Humanitas Clinical andResearch Center - IRCCS, Via Manzoni 56, 20089 Rozzano (MI), Italy15Adult Infectious Disease Centre, University Teaching Hospital, Lusaka, Zambia16Peking Union Medical College Hospital, Beijing, China17Division of EmergencyMedicine, Faculty ofMedicine and Health Sciences, StellenboschUniversity, Cape Town, South Africa18USA19Royal Melbourne Hospital and Epworth Healthcare, Melbourne , Australia20Ziauddin University, Karachi, Pakistan21St Thomas’ Hospital, London, UK22All India Institute of Medical Sciences, New Delhi, India23McMaster University (alumnus)24Pulmonary Division, Heart Institute (InCor)- HCFMUSP, Medical School, University ofSao Paulo, São Paulo, Brazil and Research Institute, Hospital do Coração (HCor), SãoPaulo, Brazil25SungkyunkwanUniversity School ofMedicine, SamsungMedical Center, Seoul, Republicof Korea26Department of Paediatrics and Emergency Medicine, University of British Columbia,Vancouver, Canada27Department of Anaesthesia and Critical Care, College of Health Sciences, MakerereUniversity, Kampala, Uganda28Zimbabwe29Emergency Medical Services, Faculty of Medicine, Tunis, Tunisia30Alcivar Hospital in Guayaquil, Ecuador31Sheikh Shakhbout Medical City, Abu Dhabi32Central Research Institute of Epidemiology of Rospotrebnadzor, Moscow, Russia33Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine,University of California Los Angeles, Los Angeles, California, USA34Aga Khan University, Karachi, Pakistan35National Institute of Tuberculosis and Respiratory Diseases, New Delhi, India36Guy’s and St Thomas’ NHS Foundation Trust, London, UK37St. George’s University Hospital, UK38Shanghai Public Health Clinical Center, Fudan University, Shanghai, China39University of Colombo, Sri Lanka40University of Sao Paulo, Brazil41Charité - Universitätsmedizin Berlin, Germany42University of Gent, Belgium43Faculty of Medicine Andres Bello University, Indisa Clinic, Santiago, Chile);44King’s College, London, UK45Department of Infectious Diseases, Hanoi Medical University, Hanoi, Vietnam46University of Stellenbosch, South Africa47Ministry of Health, Sri Lanka48Infectious Diseases Data Observatory (IDDO), Centre for Tropical Medicine and GlobalHealth, Nuffield Department of Medicine, University of Oxford, Oxford, UK49Evidence Based Social Science Research Centre, School of Public Health, LanzhouUniversity, Lanzhou, China and the Department of Social Medicine and HealthManagement, School of Public Health, Lanzhou University, Lanzhou, China50Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool,England51Royal Free London NHS Foundation Trust52Department of Health Economics and Health Management, Institute for Health andSociety, University of Oslo, Oslo, Norway*. Not panelmember; resource formethodology, systematic review, and content supportaRemdesivir, hydroxychloroquine, and lopinavir-ritonavir panel memberbCorticosteroid panel membercivermectin panel memberdco-senior authorFunding: No specific funding was provided for this guideline, with MAGIC providing pro-bonocontributions and support to WHO in the context of the COVID-19 pandemic.Competing interests: All guideline panel members have completed the WHO interest disclosure form.All authors have completed the BMJ Rapid Recommendations interest of disclosure form. The WHO,MAGIC and The BMJ judged that no panel member had any financial conflict of interest. Professionaland academic interests are minimised as much as possible, while maintaining necessary expertise onthe bmj | BMJ 2020;370:m3379 | doi: 10.1136/bmj.m33798PRACTICEcopyright. on 16 June 2021 at The University of British Columbia Library. Protected byhttp://www.bmj.com/BMJ: first published as 10.1136/bmj.m3379 on 4 September 2020. Downloaded from the panel tomake fully informed decisions. MAGIC and TheBMJ assessed declared interests from otherco-authors of this publication and found no relevant conflicts of interests.Provenance and peer review: This publication was commissioned by The BMJ in partnership withWHOand the MAGIC Evidence Ecosystem Foundation, in the context of the BMJ Rapid Recommendations.Pre-publication internal and external peer-review managed by WHO, and internal review at The BMJ.Post-publication review through rapid responses on bmj.com and through MAGICapp.We thank all the following collaborators who contributed to this endeavour, as detailed in the WHOguidance (see link in box 1)• World Health Organisation (WHO) Secretariat for Therapeutics and COVID-19• WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group• External reviewers for WHOWe also thank• The living systematic review and networkmeta-analysis team, led by investigators Dr Reed Siemienukand Romina Brignardello-Petersen at McMaster University, Canada• BMJ editorial team of Greg Cotton (technical editor), Navjoyt Ladher (head of education), and WillStahl-Timmins (data graphics designer) for their work on this living guideline publication in The BMJ• Brittany Maguire, Philippe Guerin, and Sumayyah Rashan for providing up to date data on ivermectintrials from the Infectious Diseases Data Observatory (IDDO) living systematic review for covid-19 clinicaltrial registration (https://www.iddo.org/research-themes/covid-19/live-systematic-clinical-trial-review)• Andrew Owen (University of Liverpool, UK) for contributions to subgroup analysis ofhydroxychloroquine by modelling expected serum concentrations over time1 Lamontagne F, Agoritsas T, Siemieniuk R, etal. A living WHO guideline on drugs to preventcovid-19. BMJ 2021;372:n526doi: 10.1136/bmj.n526. pmid: 336490772 Maguire BJ, Guérin PJ. A living systematic review protocol for COVID-19 clinical trial registrations.Wellcome Open Res 2020;5:60. doi: 10.12688/wellcomeopenres.15821.1 pmid: 322928263 Pan H, Peto R, Karim Q, etal. Repurposed antiviral drugs for COVID-19–interimWHOSOLIDARITYtrial results.MedRxiv 20204 Horby P, Lim WS, Emberson JR, etalRECOVERY Collaborative Group. Dexamethasone inhospitalized patients with Covid-19. N Engl J Med 2021;384:693-704.doi: 10.1056/NEJMoa2021436 pmid: 326785305 Siemieniuk RA, Bartoszko JJ, Ge L, etal. Drug treatments for covid-19: living systematic reviewand network meta-analysis. BMJ 2020;370:m2980. doi: 10.1136/bmj.m2980 pmid: 327321906 Pan H, Peto R, Henao-Restrepo AM, etalWHO Solidarity Trial Consortium. Repurposed antiviraldrugs for Covid-19 - Interim WHO Solidarity Trial Results. N Engl J Med 2021;384:497-511.doi: 10.1056/NEJMoa2023184 pmid: 332645567 World Health Organization. Handbook for guideline development. 2008.https://www.who.int/publications/guidelines/handbook_2nd_ed.pdf?ua=1.8 Qaseem A, Forland F, Macbeth F, Ollenschläger G, Phillips S, van der Wees PBoard of Trusteesof the Guidelines International Network. Guidelines International Network: toward internationalstandards for clinical practice guidelines. Ann Intern Med 2012;156:525-31.doi: 10.7326/0003-4819-156-7-201204030-00009 pmid: 224734379 World Health Organization. Clinical management of COVID-19: interim guidance. 2020.https://www.who.int/publications/i/item/clinical-management-of-covid-19.10 MSDBV. Stromectol® (ivermectin). 2009. https://www.accessdata.fda.gov/drugsatfda_docs/la-bel/2009/050742s026lbl.pdf.11 Kirti R, Roy R, Pattadar C, etal. Ivermectin as a potential treatment for mild tomoderate COVID-19– a double blind randomized placebo-controlled trial. MedRxiv 2021;12 Niaee MS, Gheibi N, Namdar P, etal. Ivermectin as an adjunct treatment for hospitalized adultCOVID-19 patients: a randomized multi-center clinical trial. Research Square 2020;13 Mohan A, Tiwari P, Suri T, etal. Ivermectin in mild and moderate COVID-19 (RIVET-COV): arandomized, placebo-controlled trial. Research Square 2021;14 López-Medina E, López P, Hurtado IC, etal. Effect of ivermectin on time to resolution of symptomsamong adults with mild covid-19: a randomized clinical trial. JAMA 2021.doi: 10.1001/jama.2021.3071 pmid: 3366210215 Gonzalez JLB, González Gámez M, Enciso EAM, etal. Efficacy and safety of ivermectin andhydroxychloroquine in patients with severe COVID-19. A randomized controlled trial. MedRxiv2021;16 Elgazzar A, Hany B, Youssef SA, etal. Efficacy and safety of ivermectin for treatment andprophylaxis of covid-19 pandemic. Research Square 2021;17 Beigel JH, Tomashek KM, Dodd LE, etalACTT-1 Study Group Members. Remdesivir for thetreatment of Covid-19 - final report. N Engl J Med 2020.doi: 10.1056/NEJMoa2007764 pmid: 3244544018 Spinner CD, Gottlieb RL, Criner GJ, etalGS-US-540-5774 Investigators. Effect of remdesivir vsstandard care on clinical status at 11 days in patients with moderate COVID-19. JAMA2020;324:1048-57. doi: 10.1001/jama.2020.16349 pmid: 3282193919 Wang Y, Zhang D, Du G, etal. Remdesivir in adults with severe COVID-19: a randomised,double-blind, placebo-controlled, multicentre trial. Lancet 2020;395:1569-78.doi: 10.1016/S0140-6736(20)31022-9 pmid: 3242358420 Schandelmaier S, Briel M, Varadhan R, etal. Development of the Instrument to assess theCredibility of Effect Modification Analyses (ICEMAN) in randomized controlled trials andmeta-analyses. CMAJ 2020;192:E901-6. doi: 10.1503/cmaj.200077 pmid: 3277860121 Horby P, Lim WS, Emberson JR, etalRECOVERY Collaborative Group. Dexamethasone inhospitalized patients with Covid-19 - preliminary report. N Engl J Med 2020;doi: 10.1056/NEJMoa2021436. pmid: 3267853022 Dequin PF, Heming N, Meziani F, etalCAPE COVID Trial Group and the CRICS-TriGGERSepNetwork. Effect of hydrocortisone on 21-day mortality or respiratory support among critically illpatients with COVID-19: a randomized clinical trial. JAMA 2020;324:1298-306.doi: 10.1001/jama.2020.16761 pmid: 3287668923 Angus DC, Derde L, Al-Beidh F, etalWriting Committee for the REMAP-CAP Investigators. Effectof hydrocortisone on mortality and organ support in patients with severe COVID-19: theREMAP-CAP COVID-19 corticosteroid domain randomized clinical trial. JAMA 2020;324:1317-29.doi: 10.1001/jama.2020.17022 pmid: 3287669724 Tomazini BM, Maia IS, Cavalcanti AB, etalCOALITION COVID-19 Brazil III Investigators. Effect ofdexamethasone on days alive and ventilator-free in patients with moderate or severe acuterespiratory distress syndrome and COVID-19: The CoDEX randomized clinical trial. JAMA2020;324:1307-16. doi: 10.1001/jama.2020.17021 pmid: 32876695Appendix 3. Table of registered ongoing trials for remdesivirAppendix 4. Table of registered ongoing trials for ivermectin9the bmj | BMJ 2020;370:m3379 | doi: 10.1136/bmj.m3379PRACTICEcopyright. on 16 June 2021 at The University of British Columbia Library. Protected byhttp://www.bmj.com/BMJ: first published as 10.1136/bmj.m3379 on 4 September 2020. Downloaded from Table 1 | Characteristics of included trials for ivermectinSeverity% MaleMean age (years)CountryNo of participantsRegistrationPublication statusStudyNon-severe46.042.0Bangladesh72NRPublishedAhmed, 2020Non-severe69.444.3Nigeria63ISRCTN40302986PreprintBabalola, 2021Non-severe84.840.5Pakistan100NCT04392713PreprintBukhari, 2021Non-severe50.026.0Spain24NCT04390022PublishedChaccour, 2020Non-severe62.041.8Pakistan50NRPublishedChachar, 2020Non-severe, severe70.357.1Egypt400NRPreprintElgazzar, 2020Non-severe, severe72.352.5India115CTRI/2020/08/027225PreprintKirti, 2021Non-severe55.640.9Argentina45NCT004381884PreprintKrolewiecki, 2020Non-severe58.839.6Bangladesh400NCT04523831Data from trialregistrationMahmud, 2020Non-severe88.835.3India157CTRI/2020/06/026001PreprintMohan, 2021RIVET-COVNon-severe, severe50.056.0Iran180IRCT20200408046987N1PreprintNiaee, 2020Non-severeNRNRLebanon~100ChiCTR2000033627Data from ameta-analysisRaad, 2020Non-severe, severeNRNRIran~103IRCT20111224008507N3Data frommeta-analysisRezai, 2021Non-severe80.939.5Israel94NCT04429711Data from authors(unpublished)Schwartz, 2021Non-severe40.537Colombia398NCT04405843Data from authors(unpublished)Lopez, 2021Severe62.253Mexico106NCT04391127PreprintGonzalez, 2021the bmj | BMJ 2020;370:m3379 | doi: 10.1136/bmj.m337910PRACTICEcopyright. on 16 June 2021 at The University of British Columbia Library. 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A living WHO guideline on drugs for covid-19
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