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ESCMID COVID-19 Living guidelines: drug treatment and clinical management

Published:November 21, 2021DOI:https://doi.org/10.1016/j.cmi.2021.11.007

      Abstract

      Scope

      In January 2021, the ESCMID Executive Committee (EC) decided to launch a new initiative to develop ESCMID guidelines on several COVID19-related issues, including treatment of COVID-19.

      Methods

      An ESCMID COVID-19 guidelines task force was established by the ESCMID Executive Committee. A small group was established, half appointed by the chair, and the remaining selected with an open call. Each panel met virtually once a week. For all decisions, a simple majority vote was used. A long list of clinical questions using the PICO (population, intervention, comparison, outcome) format was developed at the beginning of the process. For each PICO, two panel members performed a literature search with a third panelist involved in case of inconsistent results. Voting was based on the GRADE approach.

      Questions addressed by the guideline and recommendations

      A synthesis of the available evidence and recommendations are provided for each of the 15 PICOs, which cover use of hydroxychloroquine, bamlanivimab alone or in combination with etesevimab, casirivimab combined with imdevimab, ivermectin, azithromycin and empirical antibiotics, colchicine, corticosteroids, convalescent plasma, favipiravir, remdesivir, tocilizumab, and interferon β-1a, as well as the utility of antifungal prophylaxis and enoxaparin. In general, the panel recommended against the use of hydroxychloroquine, ivermectin, azithromycin, colchicine, and interferon β-1a. Conditional recommendations were given for the use of monoclonal antibodies in high-risk outpatients with mild-moderate COVID-19, and remdesivir. There was insufficient evidence to make a recommendation for use of favipiravir and antifungal prophylaxis, and it was recommended that antibiotics should not be routinely prescribed in patients with COVID-19 unless bacterial coinfection or secondary infection is suspected or confirmed. Tocilizumab and corticosteroids was recommended for treatment of severe COVID-19 but not in outpatients with non-severe COVID-19.

      Scope

      The aim of the present guidance is to provide evidence-based recommendations for management of adults with coronavirus disease 2019 (COVID-19). More specifically, the goal is to aid clinicians managing patients with COVID-19 at various levels of severity including outpatients, hospitalized patients, and those admitted to intensive care unit (ICU). Considering the composition of the panel, mostly clinical microbiologists or infectious disease specialists with no pulmonology or intensive care background, we focus only on pharmacological treatment and do not give recommendations on oxygen supplement/support. Similarly, as no pediatricians were included in the panel, the recommendations are only for adult patients with COVID-19. Considering the current literature, no guidance was given for special populations such as the immunocompromised.

      Background

      The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a dramatic impact on healthcare systems, the global economy, and social life. The clinical spectrum of COVID-19 induced by SARS-CoV-2 is broad with the majority of infected individuals experiencing only mild or subclinical illness, especially in the early phase of disease [
      • Wu Z.
      • McGoogan J.M.
      Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72314 Cases From the Chinese Center for Disease Control and Prevention.
      ]. However, 14-30% of hospitalized patients with COVID-19 develop severe respiratory failure requiring intensive care [
      • Richardson S.
      • Hirsch J.S.
      • Narasimhan M.
      • Crawford J.M.
      • McGinn T.
      • Davidson K.W.
      • et al.
      Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area.
      ,
      • Grasselli G.
      • Pesenti A.
      • Cecconi M.
      Critical Care Utilization for the COVID-19 Outbreak in Lombardy, Italy: Early Experience and Forecast During an Emergency Response.
      ,
      • Huang C.
      • Wang Y.
      • Li X.
      • Ren L.
      • Zhao J.
      • Hu Y.
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      ]. Additionally, as the angiotensine-converterend enzyme 2 (ACE2) receptor is widely distributed in human organs and tissues, manifestations of COVID-19 involve many organs including the central nervous system, kidneys, myocardium, and gut.
      As of July 6, 2021, worldwide more than 184 million people have tested positive for SARS-CoV-2 and nearly 4 million have died of COVID-19. In light of this dramatic situation, the ongoing pandemic generated a historical effort involving many researchers worldwide and prompted an unprecedented number of clinical trials. According to ClinicalTrials.gov, as of March 10, 2021, nearly 5000 studies are investigating COVID-19.

       Motivations for guideline development

      ESCMID did not develop its own recommendations at the start of the pandemic for several reasons: clinical overload of most members, avoid duplication of ongoing efforts, heterogeneity of national recommendations, and lack of appropriate evidence. The latter is particularly relevant, since issuing guidance based on inappropriate evidence-base might do more harm than good. In January 2021, the ESCMID Executive Committee (EC) decided to launch a new initiative to develop ESCMID guidelines on several COVID19-related issues.

      Methods

      An ESCMID COVID-19 guidelines task force was established by the ESCMID EC. For each set of guidelines, a small group was established (10-15 panelists). Half were appointed by the chair, in agreement with the EC, and the remaining were selected with an open call carried out on January 2021 and advertised on all ESCMID channels. The ESCMID guidelines subcommittee evaluated the applications and issued a recommendation about inclusion/exclusion of each applicant. As for all ESCMID initiatives, balance in terms of gender, clinical specialty, and country was maintained.

       Project management

      Each panel met virtually once a week. For all decisions, a simple majority vote was used and a decision was made in case of ≥80% of agreement.
      . A long list of clinical questions using the PICO (population, intervention, comparison, outcome) format was developed at the beginning of the process. A maximum number of 15 PICOs was set and selected by vote (the 15 top-rated PICOs were chosen). Criteria for prioritization and vote were general interests by clinicians with clinical microbiology and infectious disease background and availability of evidence, especially for critical outcomes that included mortality or disease progression [ICU admission or need for mechanical ventilation or extracorporeal membrane oxygenation (ECMO)]. Additional PICOs will be developed at a further stage.

       Evidence review

      To avoid duplication of efforts, rather than performing a systematic review of the literature for each PICO, each panel reviewed whether evidence for each PICO was already available among the many ongoing initiatives [

      UNiversity M. COVID-END.

      ,

      library C. Coronavirus (COVID-19) [Available from: https://www.cochranelibrary.com/COVID-19#Special%20Collections.

      ,

      LOVE. Living Overview of evidence [Available from: https://app.iloveevidence.com/loves/5e6fdb9669c00e4ac072701d.

      ]. For each PICO and evidence synthesis, ADOLOPMENT criteria were used (Table 1). For each PICO, two panel members performed a literature search with a third panelist involved in case of inconsistent results. The results of the searches were presented to the panel during weekly meetings for discussion and voting (quality of evidence, evidence-to-decision criteria, need for update, etc.) based on the GRADE approach.
      Table 1ADOLOPMENT criteria used to determine the suitability of the existing evidence synthesis (need for updating the literature search and for revising the grading of the quality of the evidence).
      CriterionNew systematic review (a systematic review that does not qualify as major or minor update)Major update (first criterion applies and any of the following)Minor update (all criteria must apply)
      Prior review (for question)No credible available systematic review exists for the question
      A credible available review is one that has publicly available data, has been conducted in the past 4 months (or a different timescale if deemed appropriate by the drafting group), scores highly on the AMSTAR or another tool, has a reproducible search strategy, meta-analysis (that can be reproduced), existing accessible risk of bias evaluation of individual studies (that can be reproduced).
      A credible systematic review exists
      A credible available review is one that has publicly available data, has been conducted in the past 4 months (or a different timescale if deemed appropriate by the drafting group), scores highly on the AMSTAR or another tool, has a reproducible search strategy, meta-analysis (that can be reproduced), existing accessible risk of bias evaluation of individual studies (that can be reproduced).
      A credible systematic review exists
      A credible available review is one that has publicly available data, has been conducted in the past 4 months (or a different timescale if deemed appropriate by the drafting group), scores highly on the AMSTAR or another tool, has a reproducible search strategy, meta-analysis (that can be reproduced), existing accessible risk of bias evaluation of individual studies (that can be reproduced).
      Full text reviewed for the question of interestN/A>20<20
      New studiesN/A>5<5
      Evidence profile availableN/ANot availableAvailable
      Outcomes all addressedNot all important outcomes addressedAll important outcomes addressedAll important outcomes addressed
      Type of studiesSearch for observational studies
      a A credible available review is one that has publicly available data, has been conducted in the past 4 months (or a different timescale if deemed appropriate by the drafting group), scores highly on the AMSTAR or another tool, has a reproducible search strategy, meta-analysis (that can be reproduced), existing accessible risk of bias evaluation of individual studies (that can be reproduced).

       Definitions

      WHO severity criteria for COVID-19 were used []. Data from the European Center for Disease Prevention and Control (ECDC) was used to define risk factors and groups for severe COVID-19 [

      Control ECfDPa. Risk factors and risk groups 2021 [updated April 26, 2021.

      ].

      Questions addressed by guidelines and recommendations

      For each PICO question, the motivations for use, patient preferences and additional comments are presented in Supplementary Appendix 1. A summary of all recommendations is presented in Table 2.
      Table 2Summary of reccomendations and dosages
      Severity of disease/settingTreatment recommendedDosagesEuropean Medicine Agency

      Authorization
      https://www.ema.europa.eu/en/human-regulatory/overview/public-health-threats/coronavirus-disease-covid-19/treatments-vaccines/covid-19-treatments accessed October 20th 2021.
      Comments
      Mild COVID-19

      Outpatient setting
      AntiSpike monoclonal antibodies

      (conditional recommendation)
      • Bamlanivimab 700 mg + etesemivab 1400 mg
      • Casirivimab 1200mg + Imdevimab 1200 mg
      Rolling reviewOnly in patients with risk factors for disease progression
      Risk factors for disease progression to consider for mAb treatment in adult patients. • Body mass index ≥ 35. • Chronic kidney disease. • Diabetes. • Immunosupressive disease. • Age ≥ 65 years. • Age ≥ 55 years and at least one of the following. o Cardiovascular disease. o Hypertension. o Chronic obstructive pulmonary disease or other chronic respiratory conditions.
      Mild COVID-19

      Inpatient setting
      Casirivimab/imdevimab

      (conditional recommendation)
      Casirivimab 4 g plus imdevimab 4 gRolling review
      Remdesivir

      (conditional recommendation)
      200 mg IV loading dose, followed by 100 mg daily for 5 daysApproved
      Severe or Critical COVID-19Casirivimab/imdevimab

      (conditional recommendation)
      Casirivimab 4 g plus imdevimab 4 gRolling review
      Dexamethasone

      (strong recommendation)
      6 mg PO or IV daily for 10 days or until dischargeApprovedrecommended in patients receiving oxygen supplement
      Tocilizumab

      (Strong recommendation)
      8 mg per kg of actual body weight (up to a maximum of 800 mg), as an intravenous infusion over a period of 1 hour. A second dose may be repeated 12 to 24 hours laterApproved
      Remdesivir

      (conditional recommendation)
      200 mg IV loading dose, followed by 100 mg daily for 5 daysApprovedNot recommended in patients requiring high-flow oxygen supplementation
      b Risk factors for disease progression to consider for mAb treatment in adult patients. • Body mass index ≥ 35. • Chronic kidney disease. • Diabetes. • Immunosupressive disease. • Age ≥ 65 years. • Age ≥ 55 years and at least one of the following. o Cardiovascular disease. o Hypertension. o Chronic obstructive pulmonary disease or other chronic respiratory conditions.

      What is the effect of hydroxychloroquine treatment on mortality or disease progression in patients with mild COVID-19 compared with no treatment?

       Narrative synthesis of evidence

      Twenty-three randomized trials in >10,000 patients have assessed the effect of hydroxychloroquine (HCQ) on COVID-19 compared with standard of care (SOC). For the present assessment, 19 trials were included (Table 3). HCQ had no impact on death (risk ratio [RR] 1.06, 95% confidence interval [CI] 0.97–1.16) or need for mechanical ventilation (RR 1.08, 95% CI 0.91 to 1.28). The majority of patients were included in the RECOVERY and SOLIDARITY trials. RECOVERY is an investigator-initiated platform trial at 176 hospitals in the UK. Within this, 1561 patients were randomized to receive HCQ and 3155 to SOC. No difference in 28-day mortality was observed between HCQ and SOC (RR 1.09; 95% CI, 0.97–1.23; p=0.15) [
      • Horby P.
      • Mafham M.
      • Linsell L.
      • Bell J.L.
      • Staplin N.
      • Emberson J.R.
      • et al.
      Effect of Hydroxychloroquine in Hospitalized Patients with Covid-19.
      ]. In SOLIDARITY, hospitalized patients with COVID-19 were randomized to remdesivir (n=2750), HCQ (n=954), lopinavir (n=1411), interferon β-1a (n=2063), or SOC (n=4088). The primary outcome was 28-day mortality and occurred in 104 of 947 patients receiving HCQ and in 84 of 906 controls (RR 1.19; 95% CI 0.89–1.59; p=0.23) [
      • Pan H.
      • Peto R.
      • Henao-Restrepo A.M.
      • Preziosi M.P.
      • Sathiyamoorthy V.
      • Abdool Karim Q.
      • et al.
      Repurposed Antiviral Drugs for Covid-19 - Interim WHO Solidarity Trial Results.
      ]. HCQ was not effective in smaller randomized controlled trials (RCTs) in hospitalized patients [
      • Ader F.
      • Peiffer-Smadja N.
      • Poissy J.
      • Bouscambert-Duchamp M.
      • Belhadi D.
      • Diallo A.
      • et al.
      An open-label randomized controlled trial of the effect of lopinavir/ritonavir, lopinavir/ritonavir plus IFN-beta-1a and hydroxychloroquine in hospitalized patients with COVID-19.
      ,
      • Ulrich R.J.
      • Troxel A.B.
      • Carmody E.
      • Eapen J.
      • Backer M.
      • DeHovitz J.A.
      • et al.
      Treating COVID-19 With Hydroxychloroquine (TEACH): A Multicenter, Double-Blind Randomized Controlled Trial in Hospitalized Patients.
      ,
      • Abd-Elsalam S.
      • Esmail E.S.
      • Khalaf M.
      • Abdo E.F.
      • Medhat M.A.
      • Abd El Ghafar M.S.
      • et al.
      Hydroxychloroquine in the Treatment of COVID-19: A Multicenter Randomized Controlled Study.
      ], hospitalized patients with severe [

      Hernandez-Cardenas C, Thirion-Romero I, Rivera-Martinez NE, Meza-Meneses PE, Remigio-Luna A, Perez-Padilla R. HYDROXYCHLOROQUINE FOR THE TREATMENT OF SEVERE RESPIRATORY INFECTION BY COVID-19: A RANDOMIZED CONTROLLED TRIA..

      ,

      Beltran Gonzalez JL, González Gámez M, Mendoza Enciso EA, Esparza Maldonado RJ, Hernández Palacios D, al. e. Efficacy and safety of ivermectin and hydroxychloroquine in patients with severe COVID-19. A randomized controlled trial.

      ,
      • Rea-Neto A.
      • Bernardelli R.S.
      • Camara B.M.D.
      • Reese F.B.
      • Queiroga M.V.O.
      • Oliveira M.C.
      An open-label randomized controlled trial evaluating the efficacy of chloroquine/hydroxychloroquine in severe COVID-19 patients.
      ] or mild-moderate disease [
      • Dubee V.
      • Roy P.M.
      • Vielle B.
      • Parot-Schinkel E.
      • Blanchet O.
      • Darsonval A.
      • et al.
      Hydroxychloroquine in mild-to-moderate coronavirus disease 2019: a placebo-controlled double blind trial.
      ,
      • Cavalcanti A.B.
      • Zampieri F.G.
      • Rosa R.G.
      • Azevedo L.C.P.
      • Veiga V.C.
      • Avezum A.
      • et al.
      Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19.
      ,

      Chen L, Zhang Z, Fu J, Feng Z, Zhang S, Han Q, et al. Efficacy and safety of chloroquine or hydroxychloroquine in moderate type of COVID-19: a prospective open-label randomized controlled study [Available from: https://www.medrxiv.org/content/10.1101/2020.06.19.20136093v1.

      ,
      • Tang W.
      • Cao Z.
      • Han M.
      • Wang Z.
      • Chen J.
      • Sun W.
      • et al.
      Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial.
      ,
      • Chen J.
      • Liu D.
      • Liu L.
      • Liu P.
      • Xu Q.
      • Xia L.
      • et al.
      [A pilot study of hydroxychloroquine in treatment of patients with moderate COVID-19].
      ,
      • Chen C.P.
      • Lin Y.C.
      • Chen T.C.
      • Tseng T.Y.
      • Wong H.L.
      • Kuo C.Y.
      • et al.
      A multicenter, randomized, open-label, controlled trial to evaluate the efficacy and tolerability of hydroxychloroquine and a retrospective study in adult patients with mild to moderate coronavirus disease 2019 (COVID-19).
      ,

      Omrani AS, Pathan SA, Thomas SA, Harris TRE, Coyle PV, Thomas CE, et al. Randomized double-blinded placebo-controlled trial of hydroxychloroquine with or without azithromycin for virologic cure of non-severe Covid-19. EClinicalMedicine. 2020;29100645.

      ], or outpatients [
      • Johnston C.
      • Brown E.R.
      • Stewart J.
      • Karita H.C.S.
      • Kissinger P.J.
      • Dwyer J.
      • et al.
      Hydroxychloroquine with or without azithromycin for treatment of early SARS-CoV-2 infection among high-risk outpatient adults: A randomized clinical trial.
      ,
      • Skipper C.P.
      • Pastick K.A.
      • Engen N.W.
      • Bangdiwala A.S.
      • Abassi M.
      • Lofgren S.M.
      • et al.
      Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19 : A Randomized Trial.
      ,
      • Mitja O.
      • Corbacho-Monne M.
      • Ubals M.
      • Tebe C.
      • Penafiel J.
      • Tobias A.
      • et al.
      Hydroxychloroquine for Early Treatment of Adults with Mild Covid-19: A Randomized-Controlled Trial.
      ]. Lastly, HCQ has not been associated with a faster decline of viral load or higher virological cure compared to SOC in hospitalized patients [
      • Dubee V.
      • Roy P.M.
      • Vielle B.
      • Parot-Schinkel E.
      • Blanchet O.
      • Darsonval A.
      • et al.
      Hydroxychloroquine in mild-to-moderate coronavirus disease 2019: a placebo-controlled double blind trial.
      ,
      • Tang W.
      • Cao Z.
      • Han M.
      • Wang Z.
      • Chen J.
      • Sun W.
      • et al.
      Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial.
      ,

      Omrani AS, Pathan SA, Thomas SA, Harris TRE, Coyle PV, Thomas CE, et al. Randomized double-blinded placebo-controlled trial of hydroxychloroquine with or without azithromycin for virologic cure of non-severe Covid-19. EClinicalMedicine. 2020;29100645.

      ,
      • Mitja O.
      • Corbacho-Monne M.
      • Ubals M.
      • Tebe C.
      • Penafiel J.
      • Tobias A.
      • et al.
      Hydroxychloroquine for Early Treatment of Adults with Mild Covid-19: A Randomized-Controlled Trial.
      ,
      • Lyngbakken M.N.
      • Berdal J.E.
      • Eskesen A.
      • Kvale D.
      • Olsen I.C.
      • Rueegg C.S.
      • et al.
      A pragmatic randomized controlled trial reports lack of efficacy of hydroxychloroquine on coronavirus disease 2019 viral kinetics.
      ].
      Table 3Grade evidence profile PICO1: Hydroxychloroquine for COVID-19
      Hydroxychloroquine for COVID-19

      People: Patients with COVID-19

      Settings: Inpatients (15 studies) Outpatient (5 studies)

      Intervention: Hydroxychloroquine

      Comparison: No treatment
      OutcomesAbsolute EffectRelative effect (95% CI)Number of studiesCertainty of the evidence (GRADE)
      Without HydroxychloroquineWith Hydroxychloroquine
      All-cause mortality168

      per 1000
      178

      per 1000
      RR 1.06

      (0.97to 1.16)
      19 [
      • Pan H.
      • Peto R.
      • Henao-Restrepo A.M.
      • Preziosi M.P.
      • Sathiyamoorthy V.
      • Abdool Karim Q.
      • et al.
      Repurposed Antiviral Drugs for Covid-19 - Interim WHO Solidarity Trial Results.
      ,
      • Ader F.
      • Peiffer-Smadja N.
      • Poissy J.
      • Bouscambert-Duchamp M.
      • Belhadi D.
      • Diallo A.
      • et al.
      An open-label randomized controlled trial of the effect of lopinavir/ritonavir, lopinavir/ritonavir plus IFN-beta-1a and hydroxychloroquine in hospitalized patients with COVID-19.
      ,
      • Ulrich R.J.
      • Troxel A.B.
      • Carmody E.
      • Eapen J.
      • Backer M.
      • DeHovitz J.A.
      • et al.
      Treating COVID-19 With Hydroxychloroquine (TEACH): A Multicenter, Double-Blind Randomized Controlled Trial in Hospitalized Patients.
      ,
      • Abd-Elsalam S.
      • Esmail E.S.
      • Khalaf M.
      • Abdo E.F.
      • Medhat M.A.
      • Abd El Ghafar M.S.
      • et al.
      Hydroxychloroquine in the Treatment of COVID-19: A Multicenter Randomized Controlled Study.
      ,

      Hernandez-Cardenas C, Thirion-Romero I, Rivera-Martinez NE, Meza-Meneses PE, Remigio-Luna A, Perez-Padilla R. HYDROXYCHLOROQUINE FOR THE TREATMENT OF SEVERE RESPIRATORY INFECTION BY COVID-19: A RANDOMIZED CONTROLLED TRIA..

      ,
      • Rea-Neto A.
      • Bernardelli R.S.
      • Camara B.M.D.
      • Reese F.B.
      • Queiroga M.V.O.
      • Oliveira M.C.
      An open-label randomized controlled trial evaluating the efficacy of chloroquine/hydroxychloroquine in severe COVID-19 patients.
      ,
      • Dubee V.
      • Roy P.M.
      • Vielle B.
      • Parot-Schinkel E.
      • Blanchet O.
      • Darsonval A.
      • et al.
      Hydroxychloroquine in mild-to-moderate coronavirus disease 2019: a placebo-controlled double blind trial.
      ,
      • Cavalcanti A.B.
      • Zampieri F.G.
      • Rosa R.G.
      • Azevedo L.C.P.
      • Veiga V.C.
      • Avezum A.
      • et al.
      Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19.
      ,

      Chen L, Zhang Z, Fu J, Feng Z, Zhang S, Han Q, et al. Efficacy and safety of chloroquine or hydroxychloroquine in moderate type of COVID-19: a prospective open-label randomized controlled study [Available from: https://www.medrxiv.org/content/10.1101/2020.06.19.20136093v1.

      ,
      • Chen J.
      • Liu D.
      • Liu L.
      • Liu P.
      • Xu Q.
      • Xia L.
      • et al.
      [A pilot study of hydroxychloroquine in treatment of patients with moderate COVID-19].
      ,

      Omrani AS, Pathan SA, Thomas SA, Harris TRE, Coyle PV, Thomas CE, et al. Randomized double-blinded placebo-controlled trial of hydroxychloroquine with or without azithromycin for virologic cure of non-severe Covid-19. EClinicalMedicine. 2020;29100645.

      ,
      • Johnston C.
      • Brown E.R.
      • Stewart J.
      • Karita H.C.S.
      • Kissinger P.J.
      • Dwyer J.
      • et al.
      Hydroxychloroquine with or without azithromycin for treatment of early SARS-CoV-2 infection among high-risk outpatient adults: A randomized clinical trial.
      ,
      • Skipper C.P.
      • Pastick K.A.
      • Engen N.W.
      • Bangdiwala A.S.
      • Abassi M.
      • Lofgren S.M.
      • et al.
      Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19 : A Randomized Trial.
      ,
      • Mitja O.
      • Corbacho-Monne M.
      • Ubals M.
      • Tebe C.
      • Penafiel J.
      • Tobias A.
      • et al.
      Hydroxychloroquine for Early Treatment of Adults with Mild Covid-19: A Randomized-Controlled Trial.
      ,
      • Amaravadi R.K.
      • Giles L.
      • Carberry M.
      • Hyman M.C.
      • Frank I.
      • Nasta S.D.
      • et al.
      Hydroxychloroquine for SARS-CoV-2 positive patients quarantined at home: The first interim analysis of a remotely conducted randomized clinical trial.
      ,
      • Gonzalez J.L.B.
      • González Gámez M.
      • Enciso E.A.M.
      • Maldonado R.J.E.
      • Hernández Palacios D.
      • Dueñas Campos S.
      • et al.
      Efficacy and safety of Ivermectin and Hydroxychloroquine in patients with severe COVID-19. A randomized controlled trial.
      ,
      • Group R.C.
      • Horby P.
      • Mafham M.
      • Linsell L.
      • Bell J.L.
      • Staplin N.
      • et al.
      Effect of Hydroxychloroquine in Hospitalized Patients with Covid-19.
      ,
      • Reis G.
      • Moreira Silva E.
      • Medeiros Silva D.C.
      • Thabane L.
      • Singh G.
      • Park J.J.H.
      • et al.
      Effect of Early Treatment With Hydroxychloroquine or Lopinavir and Ritonavir on Risk of Hospitalization Among Patients With COVID-19: The TOGETHER Randomized Clinical Trial.
      ,
      • Self W.H.
      • Semler M.W.
      • Leither L.M.
      • Casey J.D.
      • Angus D.C.
      • Brower R.G.
      • et al.
      Effect of Hydroxychloroquine on Clinical Status at 14 Days in Hospitalized Patients With COVID-19: A Randomized Clinical Trial.
      ]

      (10,382 patients)
      ⊕⊕⊕⊕

      High
      Difference: 10 more per 1000

      (95% CI: -5 to 27)
      Invasive mechanical ventilation or ECMO85

      per 1000
      92

      per 1000
      RR 1.08

      (0.91 to 1.28)
      8 [
      • Ulrich R.J.
      • Troxel A.B.
      • Carmody E.
      • Eapen J.
      • Backer M.
      • DeHovitz J.A.
      • et al.
      Treating COVID-19 With Hydroxychloroquine (TEACH): A Multicenter, Double-Blind Randomized Controlled Trial in Hospitalized Patients.
      ,
      • Abd-Elsalam S.
      • Esmail E.S.
      • Khalaf M.
      • Abdo E.F.
      • Medhat M.A.
      • Abd El Ghafar M.S.
      • et al.
      Hydroxychloroquine in the Treatment of COVID-19: A Multicenter Randomized Controlled Study.
      ,
      • Rea-Neto A.
      • Bernardelli R.S.
      • Camara B.M.D.
      • Reese F.B.
      • Queiroga M.V.O.
      • Oliveira M.C.
      An open-label randomized controlled trial evaluating the efficacy of chloroquine/hydroxychloroquine in severe COVID-19 patients.
      ,
      • Dubee V.
      • Roy P.M.
      • Vielle B.
      • Parot-Schinkel E.
      • Blanchet O.
      • Darsonval A.
      • et al.
      Hydroxychloroquine in mild-to-moderate coronavirus disease 2019: a placebo-controlled double blind trial.
      ,
      • Cavalcanti A.B.
      • Zampieri F.G.
      • Rosa R.G.
      • Azevedo L.C.P.
      • Veiga V.C.
      • Avezum A.
      • et al.
      Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19.
      ,
      • Mitja O.
      • Corbacho-Monne M.
      • Ubals M.
      • Tebe C.
      • Penafiel J.
      • Tobias A.
      • et al.
      Hydroxychloroquine for Early Treatment of Adults with Mild Covid-19: A Randomized-Controlled Trial.
      ,
      • Group R.C.
      • Horby P.
      • Mafham M.
      • Linsell L.
      • Bell J.L.
      • Staplin N.
      • et al.
      Effect of Hydroxychloroquine in Hospitalized Patients with Covid-19.
      ,
      • Self W.H.
      • Semler M.W.
      • Leither L.M.
      • Casey J.D.
      • Angus D.C.
      • Brower R.G.
      • et al.
      Effect of Hydroxychloroquine on Clinical Status at 14 Days in Hospitalized Patients With COVID-19: A Randomized Clinical Trial.
      ]

      (5701 patients)
      ⊕⊕⊕⊕

      High
      Difference: 7 more per 1000

      (95% CI: -8 to 24)
      Hospitalization

      (end of follow-up)
      55

      per 1000
      37

      per 1000
      RR 0.68

      (0.41to 1.13)
      5 [
      • Johnston C.
      • Brown E.R.
      • Stewart J.
      • Karita H.C.S.
      • Kissinger P.J.
      • Dwyer J.
      • et al.
      Hydroxychloroquine with or without azithromycin for treatment of early SARS-CoV-2 infection among high-risk outpatient adults: A randomized clinical trial.
      ,
      • Skipper C.P.
      • Pastick K.A.
      • Engen N.W.
      • Bangdiwala A.S.
      • Abassi M.
      • Lofgren S.M.
      • et al.
      Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19 : A Randomized Trial.
      ,
      • Mitja O.
      • Corbacho-Monne M.
      • Ubals M.
      • Tebe C.
      • Penafiel J.
      • Tobias A.
      • et al.
      Hydroxychloroquine for Early Treatment of Adults with Mild Covid-19: A Randomized-Controlled Trial.
      ,
      • Amaravadi R.K.
      • Giles L.
      • Carberry M.
      • Hyman M.C.
      • Frank I.
      • Nasta S.D.
      • et al.
      Hydroxychloroquine for SARS-CoV-2 positive patients quarantined at home: The first interim analysis of a remotely conducted randomized clinical trial.
      ,
      • Reis G.
      • Moreira Silva E.
      • Medeiros Silva D.C.
      • Thabane L.
      • Singh G.
      • Park J.J.H.
      • et al.
      Effect of Early Treatment With Hydroxychloroquine or Lopinavir and Ritonavir on Risk of Hospitalization Among Patients With COVID-19: The TOGETHER Randomized Clinical Trial.
      ]

      (1345 patients)
      ⊕⊕⊖⊖

      Low

      (serious imprecision and serious risk of bias)
      Difference: 18 fewer per 1000

      (95% CI: -32 to 7)
      Clinical deterioration

      (within 28 days of treatment begin)
      89

      per 1000
      72

      per 1000
      RR 0.81

      (0.35 to 1.89)
      1 [
      • Dubee V.
      • Roy P.M.
      • Vielle B.
      • Parot-Schinkel E.
      • Blanchet O.
      • Darsonval A.
      • et al.
      Hydroxychloroquine in mild-to-moderate coronavirus disease 2019: a placebo-controlled double blind trial.
      ]

      (247 patients)
      ⊕⊕⊖⊖

      Low

      (very serious imprecision)
      Difference: 17 fewer per 1000

      (95% CI: -58 to 79)
      Clinical Improvement (within 28 days of treatment begin)756

      per 1000
      794

      per 1000
      RR 1.05

      (0.91 to 1.2)
      1 [
      • Dubee V.
      • Roy P.M.
      • Vielle B.
      • Parot-Schinkel E.
      • Blanchet O.
      • Darsonval A.
      • et al.
      Hydroxychloroquine in mild-to-moderate coronavirus disease 2019: a placebo-controlled double blind trial.
      ]

      (247 patients)
      ⊕⊕⊖⊖

      Low

      (very serious imprecision)
      Difference: 38 more per 1000

      (95% CI: -68 to 151)
      Discharge for hospital

      (within 28 days of treatment begin)
      694

      per 1000
      680

      per 1000
      RR 0.98

      (0.96 to 1.01)
      5 [
      • Pan H.
      • Peto R.
      • Henao-Restrepo A.M.
      • Preziosi M.P.
      • Sathiyamoorthy V.
      • Abdool Karim Q.
      • et al.
      Repurposed Antiviral Drugs for Covid-19 - Interim WHO Solidarity Trial Results.
      ,
      • Dubee V.
      • Roy P.M.
      • Vielle B.
      • Parot-Schinkel E.
      • Blanchet O.
      • Darsonval A.
      • et al.
      Hydroxychloroquine in mild-to-moderate coronavirus disease 2019: a placebo-controlled double blind trial.
      ,
      • Gonzalez J.L.B.
      • González Gámez M.
      • Enciso E.A.M.
      • Maldonado R.J.E.
      • Hernández Palacios D.
      • Dueñas Campos S.
      • et al.
      Efficacy and safety of Ivermectin and Hydroxychloroquine in patients with severe COVID-19. A randomized controlled trial.
      ,
      • Group R.C.
      • Horby P.
      • Mafham M.
      • Linsell L.
      • Bell J.L.
      • Staplin N.
      • et al.
      Effect of Hydroxychloroquine in Hospitalized Patients with Covid-19.
      ,
      • Self W.H.
      • Semler M.W.
      • Leither L.M.
      • Casey J.D.
      • Angus D.C.
      • Brower R.G.
      • et al.
      Effect of Hydroxychloroquine on Clinical Status at 14 Days in Hospitalized Patients With COVID-19: A Randomized Clinical Trial.
      ]

      (7365 patients)
      ⊕⊕⊕⊕

      High
      Difference: 14 fewer per 1000

      (95% CI: -28 to 7
      Adverse events

      (end of follow-up)
      322

      per 1000
      538

      per 1000
      RR 1.67

      (1.21 to 2.3)
      11 [
      • Ader F.
      • Peiffer-Smadja N.
      • Poissy J.
      • Bouscambert-Duchamp M.
      • Belhadi D.
      • Diallo A.
      • et al.
      An open-label randomized controlled trial of the effect of lopinavir/ritonavir, lopinavir/ritonavir plus IFN-beta-1a and hydroxychloroquine in hospitalized patients with COVID-19.
      ,
      • Ulrich R.J.
      • Troxel A.B.
      • Carmody E.
      • Eapen J.
      • Backer M.
      • DeHovitz J.A.
      • et al.
      Treating COVID-19 With Hydroxychloroquine (TEACH): A Multicenter, Double-Blind Randomized Controlled Trial in Hospitalized Patients.
      ,
      • Dubee V.
      • Roy P.M.
      • Vielle B.
      • Parot-Schinkel E.
      • Blanchet O.
      • Darsonval A.
      • et al.
      Hydroxychloroquine in mild-to-moderate coronavirus disease 2019: a placebo-controlled double blind trial.
      ,
      • Cavalcanti A.B.
      • Zampieri F.G.
      • Rosa R.G.
      • Azevedo L.C.P.
      • Veiga V.C.
      • Avezum A.
      • et al.
      Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19.
      ,

      Chen L, Zhang Z, Fu J, Feng Z, Zhang S, Han Q, et al. Efficacy and safety of chloroquine or hydroxychloroquine in moderate type of COVID-19: a prospective open-label randomized controlled study [Available from: https://www.medrxiv.org/content/10.1101/2020.06.19.20136093v1.

      ,
      • Tang W.
      • Cao Z.
      • Han M.
      • Wang Z.
      • Chen J.
      • Sun W.
      • et al.
      Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial.
      ,
      • Chen J.
      • Liu D.
      • Liu L.
      • Liu P.
      • Xu Q.
      • Xia L.
      • et al.
      [A pilot study of hydroxychloroquine in treatment of patients with moderate COVID-19].
      ,
      • Skipper C.P.
      • Pastick K.A.
      • Engen N.W.
      • Bangdiwala A.S.
      • Abassi M.
      • Lofgren S.M.
      • et al.
      Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19 : A Randomized Trial.
      ,
      • Mitja O.
      • Corbacho-Monne M.
      • Ubals M.
      • Tebe C.
      • Penafiel J.
      • Tobias A.
      • et al.
      Hydroxychloroquine for Early Treatment of Adults with Mild Covid-19: A Randomized-Controlled Trial.
      ,
      • Amaravadi R.K.
      • Giles L.
      • Carberry M.
      • Hyman M.C.
      • Frank I.
      • Nasta S.D.
      • et al.
      Hydroxychloroquine for SARS-CoV-2 positive patients quarantined at home: The first interim analysis of a remotely conducted randomized clinical trial.
      ,
      • Chen Z.
      • Hu J.
      • Zhang Z.
      • Jiang S.
      • Han S.
      • Yan D.
      • et al.
      Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial.
      ]

      (2077 patients)
      ⊕⊕⊕⊖

      Moderate

      (serious risk of bias)
      Difference: 216 more per 1000

      (95% CI: 68 to 419)
      Serious adverse events

      (end of follow-up)
      68

      per 1000
      74

      per 1000
      RR 1.09

      (0.86 to 1.37)
      11 [
      • Ader F.
      • Peiffer-Smadja N.
      • Poissy J.
      • Bouscambert-Duchamp M.
      • Belhadi D.
      • Diallo A.
      • et al.
      An open-label randomized controlled trial of the effect of lopinavir/ritonavir, lopinavir/ritonavir plus IFN-beta-1a and hydroxychloroquine in hospitalized patients with COVID-19.
      ,
      • Dubee V.
      • Roy P.M.
      • Vielle B.
      • Parot-Schinkel E.
      • Blanchet O.
      • Darsonval A.
      • et al.
      Hydroxychloroquine in mild-to-moderate coronavirus disease 2019: a placebo-controlled double blind trial.
      ,
      • Cavalcanti A.B.
      • Zampieri F.G.
      • Rosa R.G.
      • Azevedo L.C.P.
      • Veiga V.C.
      • Avezum A.
      • et al.
      Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19.
      ,
      • Tang W.
      • Cao Z.
      • Han M.
      • Wang Z.
      • Chen J.
      • Sun W.
      • et al.
      Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial.
      ,
      • Chen J.
      • Liu D.
      • Liu L.
      • Liu P.
      • Xu Q.
      • Xia L.
      • et al.
      [A pilot study of hydroxychloroquine in treatment of patients with moderate COVID-19].
      ,

      Omrani AS, Pathan SA, Thomas SA, Harris TRE, Coyle PV, Thomas CE, et al. Randomized double-blinded placebo-controlled trial of hydroxychloroquine with or without azithromycin for virologic cure of non-severe Covid-19. EClinicalMedicine. 2020;29100645.

      ,
      • Skipper C.P.
      • Pastick K.A.
      • Engen N.W.
      • Bangdiwala A.S.
      • Abassi M.
      • Lofgren S.M.
      • et al.
      Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19 : A Randomized Trial.
      ,
      • Mitja O.
      • Corbacho-Monne M.
      • Ubals M.
      • Tebe C.
      • Penafiel J.
      • Tobias A.
      • et al.
      Hydroxychloroquine for Early Treatment of Adults with Mild Covid-19: A Randomized-Controlled Trial.
      ,
      • Lyngbakken M.N.
      • Berdal J.E.
      • Eskesen A.
      • Kvale D.
      • Olsen I.C.
      • Rueegg C.S.
      • et al.
      A pragmatic randomized controlled trial reports lack of efficacy of hydroxychloroquine on coronavirus disease 2019 viral kinetics.
      ,
      • Reis G.
      • Moreira Silva E.
      • Medeiros Silva D.C.
      • Thabane L.
      • Singh G.
      • Park J.J.H.
      • et al.
      Effect of Early Treatment With Hydroxychloroquine or Lopinavir and Ritonavir on Risk of Hospitalization Among Patients With COVID-19: The TOGETHER Randomized Clinical Trial.
      ,
      • Chen Z.
      • Hu J.
      • Zhang Z.
      • Jiang S.
      • Han S.
      • Yan D.
      • et al.
      Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial.
      ]

      (2721 patients)
      ⊕⊕⊕⊖

      Moderate

      (Serious risk of bias)
      Difference: 6 more per 1000

      (95% CI: -10 to 25)
      95% CI: 95% Confidence interval; RR: Risk ratio.
      References: [
      • Pan H.
      • Peto R.
      • Henao-Restrepo A.M.
      • Preziosi M.P.
      • Sathiyamoorthy V.
      • Abdool Karim Q.
      • et al.
      Repurposed Antiviral Drugs for Covid-19 - Interim WHO Solidarity Trial Results.
      ,
      • Ader F.
      • Peiffer-Smadja N.
      • Poissy J.
      • Bouscambert-Duchamp M.
      • Belhadi D.
      • Diallo A.
      • et al.
      An open-label randomized controlled trial of the effect of lopinavir/ritonavir, lopinavir/ritonavir plus IFN-beta-1a and hydroxychloroquine in hospitalized patients with COVID-19.
      ,
      • Ulrich R.J.
      • Troxel A.B.
      • Carmody E.
      • Eapen J.
      • Backer M.
      • DeHovitz J.A.
      • et al.
      Treating COVID-19 With Hydroxychloroquine (TEACH): A Multicenter, Double-Blind Randomized Controlled Trial in Hospitalized Patients.
      ,
      • Abd-Elsalam S.
      • Esmail E.S.
      • Khalaf M.
      • Abdo E.F.
      • Medhat M.A.
      • Abd El Ghafar M.S.
      • et al.
      Hydroxychloroquine in the Treatment of COVID-19: A Multicenter Randomized Controlled Study.
      ,

      Hernandez-Cardenas C, Thirion-Romero I, Rivera-Martinez NE, Meza-Meneses PE, Remigio-Luna A, Perez-Padilla R. HYDROXYCHLOROQUINE FOR THE TREATMENT OF SEVERE RESPIRATORY INFECTION BY COVID-19: A RANDOMIZED CONTROLLED TRIA..

      ,
      • Rea-Neto A.
      • Bernardelli R.S.
      • Camara B.M.D.
      • Reese F.B.
      • Queiroga M.V.O.
      • Oliveira M.C.
      An open-label randomized controlled trial evaluating the efficacy of chloroquine/hydroxychloroquine in severe COVID-19 patients.
      ,
      • Dubee V.
      • Roy P.M.
      • Vielle B.
      • Parot-Schinkel E.
      • Blanchet O.
      • Darsonval A.
      • et al.
      Hydroxychloroquine in mild-to-moderate coronavirus disease 2019: a placebo-controlled double blind trial.
      ,
      • Cavalcanti A.B.
      • Zampieri F.G.
      • Rosa R.G.
      • Azevedo L.C.P.
      • Veiga V.C.
      • Avezum A.
      • et al.
      Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19.
      ,

      Chen L, Zhang Z, Fu J, Feng Z, Zhang S, Han Q, et al. Efficacy and safety of chloroquine or hydroxychloroquine in moderate type of COVID-19: a prospective open-label randomized controlled study [Available from: https://www.medrxiv.org/content/10.1101/2020.06.19.20136093v1.

      ,
      • Tang W.
      • Cao Z.
      • Han M.
      • Wang Z.
      • Chen J.
      • Sun W.
      • et al.
      Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial.
      ,
      • Chen J.
      • Liu D.
      • Liu L.
      • Liu P.
      • Xu Q.
      • Xia L.
      • et al.
      [A pilot study of hydroxychloroquine in treatment of patients with moderate COVID-19].
      ,
      • Chen C.P.
      • Lin Y.C.
      • Chen T.C.
      • Tseng T.Y.
      • Wong H.L.
      • Kuo C.Y.
      • et al.
      A multicenter, randomized, open-label, controlled trial to evaluate the efficacy and tolerability of hydroxychloroquine and a retrospective study in adult patients with mild to moderate coronavirus disease 2019 (COVID-19).
      ,

      Omrani AS, Pathan SA, Thomas SA, Harris TRE, Coyle PV, Thomas CE, et al. Randomized double-blinded placebo-controlled trial of hydroxychloroquine with or without azithromycin for virologic cure of non-severe Covid-19. EClinicalMedicine. 2020;29100645.

      ,
      • Johnston C.
      • Brown E.R.
      • Stewart J.
      • Karita H.C.S.
      • Kissinger P.J.
      • Dwyer J.
      • et al.
      Hydroxychloroquine with or without azithromycin for treatment of early SARS-CoV-2 infection among high-risk outpatient adults: A randomized clinical trial.
      ,
      • Skipper C.P.
      • Pastick K.A.
      • Engen N.W.
      • Bangdiwala A.S.
      • Abassi M.
      • Lofgren S.M.
      • et al.
      Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19 : A Randomized Trial.
      ,
      • Mitja O.
      • Corbacho-Monne M.
      • Ubals M.
      • Tebe C.
      • Penafiel J.
      • Tobias A.
      • et al.
      Hydroxychloroquine for Early Treatment of Adults with Mild Covid-19: A Randomized-Controlled Trial.
      ,
      • Lyngbakken M.N.
      • Berdal J.E.
      • Eskesen A.
      • Kvale D.
      • Olsen I.C.
      • Rueegg C.S.
      • et al.
      A pragmatic randomized controlled trial reports lack of efficacy of hydroxychloroquine on coronavirus disease 2019 viral kinetics.
      ,
      • Amaravadi R.K.
      • Giles L.
      • Carberry M.
      • Hyman M.C.
      • Frank I.
      • Nasta S.D.
      • et al.
      Hydroxychloroquine for SARS-CoV-2 positive patients quarantined at home: The first interim analysis of a remotely conducted randomized clinical trial.
      ,
      • Gonzalez J.L.B.
      • González Gámez M.
      • Enciso E.A.M.
      • Maldonado R.J.E.
      • Hernández Palacios D.
      • Dueñas Campos S.
      • et al.
      Efficacy and safety of Ivermectin and Hydroxychloroquine in patients with severe COVID-19. A randomized controlled trial.
      ,
      • Group R.C.
      • Horby P.
      • Mafham M.
      • Linsell L.
      • Bell J.L.
      • Staplin N.
      • et al.
      Effect of Hydroxychloroquine in Hospitalized Patients with Covid-19.
      ,
      • Reis G.
      • Moreira Silva E.
      • Medeiros Silva D.C.
      • Thabane L.
      • Singh G.
      • Park J.J.H.
      • et al.
      Effect of Early Treatment With Hydroxychloroquine or Lopinavir and Ritonavir on Risk of Hospitalization Among Patients With COVID-19: The TOGETHER Randomized Clinical Trial.
      ,
      • Self W.H.
      • Semler M.W.
      • Leither L.M.
      • Casey J.D.
      • Angus D.C.
      • Brower R.G.
      • et al.
      Effect of Hydroxychloroquine on Clinical Status at 14 Days in Hospitalized Patients With COVID-19: A Randomized Clinical Trial.
      ,
      • Chen Z.
      • Hu J.
      • Zhang Z.
      • Jiang S.
      • Han S.
      • Yan D.
      • et al.
      Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial.
      ].
      Evidence adopted: Australian National COVID-19 Evidence Taskforce (https://app.magicapp.org/#/guideline/5446/section/78675).
      Evidence Search date: April 23 - June 11.

       Safety

      Concerns for safety and potential harm have been raised in observational trials and RCTs evaluating patients receiving HCQ. RECOVERY reported that those receiving HCQ experienced longer in-hospital stay, lower probability of being discharged alive within the 28-day study period (RR 0.92; 95% CI 0.85–0.99), and higher chance to receive mechanical ventilation (30.7% vs. 26.9%; RR 1.14; 95% CI 1.03–1.27). A trend towards greater harm with HCQ was also seen in SOLIDARITY and other RCTs [
      • Pan H.
      • Peto R.
      • Henao-Restrepo A.M.
      • Preziosi M.P.
      • Sathiyamoorthy V.
      • Abdool Karim Q.
      • et al.
      Repurposed Antiviral Drugs for Covid-19 - Interim WHO Solidarity Trial Results.
      ].

       Recommendation

      Strong recommendation against use of HCQ for COVID-19 [quality of evidence (QoE): high for critical outcomes].

      What is the effect of bamlanivimab alone or in combination with etesevimab in reducing the risk of disease progression or mortality in patients with mild COVID-19 compared with no treatment?

       Narrative synthesis of evidence

      Bamlanivimab and etesevimab are recombinant neutralizing human IgG1κ monoclonal antibodies (mAb) directed against the spike protein of SARS-CoV-2. They were evaluated in BLAZE-1, a randomized, double-blind, placebo-controlled, multipart phase 2/3 trial enrolling outpatients with COVID-19. In the first dataset of BLAZE-1, bamlanivimab showed a trend towards decreased viral load vs. placebo with a significant difference for the 2800 mg dose. [
      • Chen P.
      • Nirula A.
      • Heller B.
      • Gottlieb R.L.
      • Boscia J.
      • Morris J.
      • et al.
      SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19.
      ]. The second dataset of the BLAZE-1 trial analyzed patients randomized to receive a single infusion of bamlanivimab at different dosages, combined bamlanivimab and etesevimab, or placebo. Compared with placebo, a significant decrease in viral load was observed only for combination treatment [log -0.57 (95% CI, -1.00–-0.14; p= 0.01)]. The percentages of patients with COVID-19–related hospitalizations or emergency department visits was 5.8% (n=9) for placebo, 1.0% (n=1) for 700 mg, 1.9% (n=2) for 2800 mg, 2.0% (n=2) for 7000 mg, and 0.9% (n=1) for combination treatment [
      • Gottlieb R.L.
      • Nirula A.
      • Chen P.
      • Boscia J.
      • Heller B.
      • Morris J.
      • et al.
      Effect of Bamlanivimab as Monotherapy or in Combination With Etesevimab on Viral Load in Patients With Mild to Moderate COVID-19: A Randomized Clinical Trial.
      ].
      On March 10, 2021, via press release, a new analysis on 769 high-risk patients with mild to moderate COVID-19 receiving bamlanivimab plus etesevimab (n=511) or placebo (n=258) was presented. There were four hospitalizations in patients taking bamlanivimab and etesevimab compared to 15 for placebo (risk reduction 87%; p<0.0001) [

      Eli Lilly, Company. Lilly's bamlanivimab and etesevimab together reduced hospitalizations and death in Phase 3 trial for early COVID-19 [updated March 10, 2021. Available from: https://investor.lilly.com/news-releases/news-release-details/lillys-bamlanivimab-and-etesevimab-together-reduced.

      ].
      Overall, in high-risk outpatients bamlanivimab alone (RR 0.26; 95% CI 0.09–0.75; Table 4) or combined with etesevimab (RR 0.30; 95% CI 0.16–0.59; Table 5) is associated with reduced hospitalization. Bamlanivimab plus etesevimab is also associated with reduction in 29-day mortality (RR 0.05; 95%CI 0.00–0.80) in the same population (Table 5).
      Table 4Grade evidence profile PICO2: Bamlanivimab for COVID-19
      People: Patients with COVID-19

      Settings: Outpatients

      Intervention: bamlanivimab

      Comparison: No treatment
      OutcomesAbsolute Effect*Relative effect (95% CI)Number of studiesCertainty of the evidence (GRADE)
      With bamlanivimabWithout bamlanivimab
      Hospitalization

      (within 29 days from treatment)
      5/309 (1.6%)9/143 (6.3%)RR 0.26

      (0.09 to 0.75)
      1 [
      • Chen P.
      • Nirula A.
      • Heller B.
      • Gottlieb R.L.
      • Boscia J.
      • Morris J.
      • et al.
      SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19.
      ]

      (452 patients)
      ⊕⊕⊖⊖

      Low

      (very serious imprecision)
      Difference: 47 fewer per 1000

      (95% CI:-57 to -16)
      Serious adverse events

      (end of follow-up)
      0/309 (0%)

      per 1000
      1/143 (0.7%)

      per 1000
      RR 0.15

      (0.01 to 3.78)
      1 [
      • Chen P.
      • Nirula A.
      • Heller B.
      • Gottlieb R.L.
      • Boscia J.
      • Morris J.
      • et al.
      SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19.
      ]

      (452 patient)
      ⊕⊕⊖⊖

      Low

      (very serious imprecision)
      Difference: 6 fewer per 1000

      (95% CI: -7to 19)
      95% CI: 95% Confidence interval; RR: Risk ratio.
      References: [
      • Chen P.
      • Nirula A.
      • Heller B.
      • Gottlieb R.L.
      • Boscia J.
      • Morris J.
      • et al.
      SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19.
      ].
      Evidence adopted: Infectious Disease Society of America (IDSA) guidelines available at https://www.idsociety.org/practice-guideline/COVID-19-guideline-treatment-and-management/.
      Evidence Search date: April 23 - June 11.
      Table 5Grade evidence profile PICO2: Bamlanivimab in combination with etesevimab for COVID-19
      People: Patients with COVID-19

      Settings: Outpatients

      Intervention: bamlanivimab/etesevimab

      Comparison: No treatment
      OutcomesAbsolute EffectRelative effect (95% CI)Number of studiesCertainty of the evidence (GRADE)
      With bamlanivimab/etesevimabWithoutbamlanivimab/etesevimab
      All-cause mortality

      (within 29 days from treatment)
      0/518 (0%)10/517 (1.9%)RR 0.05

      (0.00 to 0.80)
      1 [

      Dougan M, Nirula A, Azizad M, Mocherla B, Gottlieb RL, Chen P, et al. Bamlanivimab plus Etesevimab in Mild or Moderate Covid-19. N Engl J Med. 2021.

      ]

      (1035 patients)
      ⊕⊕⊖⊖

      Low

      (due to serius imprecision)
      Difference: 19 fewer per 1000

      (95% CI: -31 to -7)
      Hospitalization

      (within 29 days from treatment)
      11/518 (2.1%)36/517 (7.0%)RR 0.30

      (0.16 to 0.59)
      1 [

      Dougan M, Nirula A, Azizad M, Mocherla B, Gottlieb RL, Chen P, et al. Bamlanivimab plus Etesevimab in Mild or Moderate Covid-19. N Engl J Med. 2021.

      ]

      (1035 patients)
      ⊕⊕⊖⊖

      Low

      (due to serius imprecision)
      Difference: 49 fewer per 1000

      (95% CI:-58 to -29)
      Serious adverse events

      (end of follow-up)
      7/518 (1.4%)5/517 (1%)RR 1.40

      (0.45 to 4.37)
      1 [

      Dougan M, Nirula A, Azizad M, Mocherla B, Gottlieb RL, Chen P, et al. Bamlanivimab plus Etesevimab in Mild or Moderate Covid-19. N Engl J Med. 2021.

      ]

      (1035 patients)
      ⊕⊕⊖⊖

      Low

      (serious imprecision)
      Difference: 4 more per 1000

      (95% CI: -5 to +33)
      95% CI: 95% Confidence interval; RR: Risk ratio.
      References: [

      Dougan M, Nirula A, Azizad M, Mocherla B, Gottlieb RL, Chen P, et al. Bamlanivimab plus Etesevimab in Mild or Moderate Covid-19. N Engl J Med. 2021.

      ].
      Evidence adopted: Infectious Disease Society of America (IDSA) guidelines available at https://www.idsociety.org/practice-guideline/COVID-19-guideline-treatment-and-management/.
      Evidence Search date: April 23 - June 11.
      Bamlanivimab was effective in preventing severe disease among residents and staff of long-term care facilities (BLAZE-2 trial) [

      Cohen MS, Nirula A, Mulligan M, R.L G, Novak R, Marovich M, et al. Bamlanivimab prevents COVID-19 morbidity and mortality in nursing-home settin. Conference on retroviruses and Opportunistic infection (CROI); June 3-November 3, 2021 Virtual.

      ], but not in recovery of hospitalized patients [
      • Lundgren J.D.
      • Grund B.
      • Barkauskas C.E.
      • Holland T.L.
      • Gottlieb R.L.
      • Sandkovsky U.
      • et al.
      A Neutralizing Monoclonal Antibody for Hospitalized Patients with Covid-19.
      ].
      In vitro studies suggest that bamlanivimab plus etesevimab retains in vitro susceptibility to the B.1.1.7 (Alpha – UK variant), but has markedly reduced activity against the P1 (Gamma, Brazilian) and B.1.351 (Beta, South African) variants. Lastly, the SARS-CoV-2 variant B.1.617 (Delta, Indian) seems to be resistant to bamlanivimab, but its activity may be restored when combined with etesevimab.

       Safety

      Infusion-related adverse events were reported in 14% of patients in one study. Overall, adverse events were not higher vs. placebo in all studies [
      • Chen P.
      • Nirula A.
      • Heller B.
      • Gottlieb R.L.
      • Boscia J.
      • Morris J.
      • et al.
      SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19.
      ,
      • Gottlieb R.L.
      • Nirula A.
      • Chen P.
      • Boscia J.
      • Heller B.
      • Morris J.
      • et al.
      Effect of Bamlanivimab as Monotherapy or in Combination With Etesevimab on Viral Load in Patients With Mild to Moderate COVID-19: A Randomized Clinical Trial.
      ,

      Eli Lilly, Company. Lilly's bamlanivimab and etesevimab together reduced hospitalizations and death in Phase 3 trial for early COVID-19 [updated March 10, 2021. Available from: https://investor.lilly.com/news-releases/news-release-details/lillys-bamlanivimab-and-etesevimab-together-reduced.

      ].

       Recommendation

      Weak recommendation against use of bamlanivimab alone (QoE: very low).
      Conditional recommendation for use of bamlanivimab plus etesevimab in high-risk outpatients with mild to moderate COVID-19 (QoE: moderate).

      What is the effect of casirivimab combined with imdevimab in reducing the risk of disease progression or mortality in patients with mild COVID-19 compared with no treatment?

       Narrative synthesis of evidence

      Casirivimab and imdevimab were assessed in a phase 1-3 trial in which patients were randomized to placebo, 2.4 g of combination therapy (casirivimab 1200 mg and imdevimab 1200 mg), or 8.0 g of combination therapy (4.0 g casirivimab and 4.0 g imdevimab). The combination of casirivimab and imdevimab was significantly associated with reduction of viral load [
      • Weinreich D.M.
      • Sivapalasingam S.
      • Norton T.
      • Ali S.
      • Gao H.
      • Bhore R.
      • et al.
      REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with Covid-19.
      ], COVID-19–related hospitalization, and all-cause death vs. placebo (71.3% reduction; 1.3% vs. 4.6%; p<0.0001) [
      • Weinreich D.M.
      • Sivapalasingam S.
      • Norton T.
      • Ali S.
      • Gao H.
      • Bhore R.
      • et al.
      REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with Covid-19.
      ]. A significant effect was also seen in patients with baseline positive serum anti-SARS-CoV-2 antibodies [
      • Weinreich D.M.
      • Sivapalasingam S.
      • Norton T.
      • Ali S.
      • Gao H.
      • Bhore R.
      • et al.
      REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with Covid-19.
      ]. Casirivimab combined with imdevimab was associated with a lower rate of hospitalization (RR 0.27; 95% CI 0.11–0.65; Table 6).
      Table 6Grade evidence profile PICO3: Casirivimab combined with imdevimab for COVID-19
      People: Patients with COVID-19

      Settings: Outpatients

      Intervention: casirivimab (1200 mg) combined with imdevimab (1200 mg)

      Comparison: No treatment
      OutcomesAbsolute EffectRelative effect (95% CI)Number of studiesCertainty of the evidence (GRADE)
      With casirivimab combined with imdevimabWithout casirivimab combined with imdevimab
      All-cause mortality

      (within 29 days from treatment)
      1/736 (0.1%)1/748 (0.4%)RR 1.02

      (0.06 to 16.20)
      1 [
      • Weinreich D.M.
      • Sivapalasingam S.
      • Norton T.
      • Ali S.
      • Gao H.
      • Bhore R.
      • et al.
      REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with Covid-19.
      ]

      (1484 patients)
      ⊕⊕⊖⊖

      Low

      due to very serious imprecision)
      Difference: 0 fewer per 1000

      (95% CI: -4 to 4)
      Hospitalization

      (within 29 days from treatment)
      6/736 (1.9%)23/748 (4.3%)RR 0.27

      (0.11 to 0.65)
      1 [
      • Weinreich D.M.
      • Sivapalasingam S.
      • Norton T.
      • Ali S.
      • Gao H.
      • Bhore R.
      • et al.
      REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with Covid-19.
      ]

      (1484 patients)
      ⊕⊕⊕⊖

      Moderate (Due to serious imprecision)
      Difference: 22 fewer per 1000

      (95% CI:-27 to -11)
      Serious adverse events

      (end of follow-up)
      50/3688 (1.2%)74/1843 (4%)RR 0.34

      (0.24 to 0.48)
      1 [
      • Weinreich D.M.
      • Sivapalasingam S.
      • Norton T.
      • Ali S.
      • Gao H.
      • Bhore R.
      • et al.
      REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with Covid-19.
      ]

      (5531 patients)
      ⊕⊕⊕⊖

      Moderate

      (Due to serious imprecision
      Difference: 27 fewer per 1000

      (95% CI: -31 to -21)
      95% CI: 95% Confidence interval; RR: Risk ratio.
      References: [
      • Weinreich D.M.
      • Sivapalasingam S.
      • Norton T.
      • Ali S.
      • Gao H.
      • Bhore R.
      • et al.
      REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with Covid-19.
      ].
      Evidence adopted: Infectious Disease Society of America (IDSA) guidelines available at https://www.idsociety.org/practice-guideline/COVID-19-guideline-treatment-and-management/.
      Evidence Search date: April 23 - June 11.

       Hospitalized patients

      The combination of casirivimab (4.0 g) plus imdevimab (4.0 g) was assessed in RECOVERY and was associated with lower 28-day mortality among anti-SARS-CoV-2 Ab seronegative patients at baseline (RR 0.80; 95% CI 0.70–0.91; p=0.0010) [

      Group RC. Casirivimab and imdevimab in patients admitted to 3 hospital with COVID-19 (RECOVERY): a randomised, 4 controlled, open-label, platform trial. medRxiv preprint. 2021.

      ].

       Safety

      The rate of adverse events was similar between patients receiving casirivimab plus imdevimab or placebo, while the combination showed fewer serious adverse events [
      • Weinreich D.M.
      • Sivapalasingam S.
      • Norton T.
      • Ali S.
      • Gao H.
      • Bhore R.
      • et al.
      REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with Covid-19.
      ,

      Group RC. Casirivimab and imdevimab in patients admitted to 3 hospital with COVID-19 (RECOVERY): a randomised, 4 controlled, open-label, platform trial. medRxiv preprint. 2021.

      ].

       Recommendation

      Conditional recommendation for use of combination casirivimab plus imdevimab in high-risk outpatients with mild-moderate COVID-19 (QoE: moderate for hospitalization; low for 29-day mortality).

      What is the effect of ivermectin in reducing the risk of disease progression or mortality in patients with mild COVID-19 compared with no treatment?

       Narrative synthesis of evidence

      Ivermectin has been evaluated in 18 RCTs using different dosing regimens and number of doses (1 to 5). Ten studies primarily had a virological outcome, i.e. virological reduction or clearance [
      • Mohan A.
      • Tiwari P.
      • Suri T.
      Ivermectin in mild and moderate COVID-19 (RIVET-COV): a randomized, placebo-controlled trial.
      ,
      • Shah Bukhari K.H.
      • Asghar A.
      • Perveen N.
      Efficacy of ivermectin in COVID-19 patients with mild to moderate disease.
      ,
      • Biber A.
      • Mandelboim M.
      • Harmelin G.
      Favorable outcome on viral load and culture viability using ivermectin in early treatment of non-hospitalized patients with mild COVID-19 - a double-blind, randomized placebo-controlled trial.
      ,
      • Ahmed S.
      • Karim M.M.
      • Ross A.G.
      • Hossain M.S.
      • Clemens J.D.
      • Sumiya M.K.
      • et al.
      A five-day course of ivermectin for the treatment of COVID-19 may reduce the duration of illness.
      ,
      • Babalola O.E.
      • Bode C.O.
      • Ajayi A.A.
      • Alakaloko F.M.
      • Akase I.E.
      • Otrofanowei E.
      • et al.
      Ivermectin shows clinical benefits in mild to moderate COVID19: A randomised controlled double-blind, dose-response study in Lagos.
      ,
      • Chaccour C.
      • Casellas A.
      • Blanco-Di Matteo A.
      • Pineda I.
      • Fernandez-Montero A.
      • Ruiz-Castillo P.
      • et al.
      The effect of early treatment with ivermectin on viral load, symptoms and humoral response in patients with non-severe COVID-19: A pilot, double-blind, placebo-controlled, randomized clinical trial.
      ,
      • Krolewiecki A.
      • Lifschitz A.
      • Moragas M.
      • Travacio M.
      • Valentini R.
      • Alonso D.F.
      • et al.
      Antiviral effect of high-dose ivermectin in adults with COVID-19: A proof-of-concept randomized trial.
      ,
      • Pott-Junior H.
      • Bastos Paoliello M.M.
      • Miguel A.Q.C.
      • da Cunha A.F.
      • de Melo Freire C.C.
      • Neves F.F.
      • et al.
      Use of ivermectin in the treatment of Covid-19: A pilot trial.
      ,
      • Ravikirti Roy R.
      • Pattadar C.
      • Raj R.
      • Agarwal N.
      • Biswas B.
      • et al.
      Evaluation of Ivermectin as a Potential Treatment for Mild to Moderate COVID-19: A Double-Blind Randomized Placebo Controlled Trial in Eastern India.
      ,
      • Samaha A.A.
      • Mouawia H.
      • Fawaz M.
      • Hassan H.
      • Salami A.
      • Bazzal A.A.
      • et al.
      Effects of a Single Dose of Ivermectin on Viral and Clinical Outcomes in Asymptomatic SARS-CoV-2 Infected Subjects: A Pilot Clinical Trial in Lebanon.
      ], while most reported secondary clinical outcomes like mechanical ventilation and death. Overall, 11 studies showed a positive effect of ivermectin while 7 did not (Table 7), with the largest reporting no effects [
      • Lopez-Medina E.
      • Lopez P.
      • Hurtado I.C.
      • Davalos D.M.
      • Ramirez O.
      • Martinez E.
      • et al.
      Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19: A Randomized Clinical Trial.
      ,
      • Vallejos J.
      • Zoni R.
      • Bangher M.
      • Villamandos S.
      • Bobadilla A.
      • Plano F.
      • et al.
      Ivermectin to prevent hospitalizations in patients with COVID-19 (IVERCOR-COVID19) a randomized, double-blind, placebo-controlled trial.
      ]. The committee was thus uncertain whether ivermectin increased or decreased the chance of need for mechanical ventilation or death.
      Table 7GRADE evidence profile for PICO 4: Ivermectin for COVID-19.
      Ivermectin vs Standard care
      People:Adult patients with COVID-19

      Setting: Inpatients (10 studies), Outpatients (7 studies)

      Intervention: Ivermectin

      Comparison: Standard Care (15 studies), HCQ (1 study), Lopinavir/ritonavir (1 study)
      OutcomesAbsolute EffectRelative effect (95% CI)Number of studiesCertainty of the evidence (GRADE)
      Without Ivermectin (Standard Care)With Ivermectin
      All-cause mortality

      Within 28 days of commencing treatment
      53

      per 1000
      22

      per 1000
      RR 0.41

      (0.19 to 0.92)
      6 [

      Beltran Gonzalez JL, González Gámez M, Mendoza Enciso EA, Esparza Maldonado RJ, Hernández Palacios D, al. e. Efficacy and safety of ivermectin and hydroxychloroquine in patients with severe COVID-19. A randomized controlled trial.

      ,
      • Ravikirti Roy R.
      • Pattadar C.
      • Raj R.
      • Agarwal N.
      • Biswas B.
      • et al.
      Evaluation of Ivermectin as a Potential Treatment for Mild to Moderate COVID-19: A Double-Blind Randomized Placebo Controlled Trial in Eastern India.
      ,
      • Lopez-Medina E.
      • Lopez P.
      • Hurtado I.C.
      • Davalos D.M.
      • Ramirez O.
      • Martinez E.
      • et al.
      Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19: A Randomized Clinical Trial.
      ,
      • Abd-Elsalam S.
      • Noor R.A.
      • Badawi R.
      • Khalaf M.
      • Esmail E.S.
      • Soliman S.
      • et al.
      Clinical study evaluating the efficacy of ivermectin in COVID-19 treatment: A randomized controlled study.
      ,

      Mohan A, Tiwari P, Suri T. Ivermectin in mild and moderate COVID-19 (RIVET-COV): a randomized, placebo-controlled trial. PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-191648/v1]. 2021.

      ,

      Niaee MS, Gheibi N, Namdar Pea. Ivermectin as an adjunct treatment for hospitalized adult COVID-19 patients: A randomized multi-center clinical trial, 24 November 2020, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-109670/v1]. 2020.

      ]

      (1079

      patients)
      ⊕⊕⊖⊖

      Low

      (serious risk of bias and serious imprecision
      Difference: 31 fewer per 1000

      (95% CI: 43 fewer to 4 more)
      Mechanical ventilation

      Within 28 days of commencing treatment
      40

      per 1000
      30

      per 1000
      RR 0.75

      (0.23 to 2.43)
      4 [,
      • Abd-Elsalam S.
      • Noor R.A.
      • Badawi R.
      • Khalaf M.
      • Esmail E.S.
      • Soliman S.
      • et al.
      Clinical study evaluating the efficacy of ivermectin in COVID-19 treatment: A randomized controlled study.
      ,

      Mohan A, Tiwari P, Suri T. Ivermectin in mild and moderate COVID-19 (RIVET-COV): a randomized, placebo-controlled trial. PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-191648/v1]. 2021.

      ]

      (497

      patients)
      ⊕⊕⊖⊖

      Low

      (very serious imprecsion)
      Difference: 4 fewer per 1000

      (95% CI: 31 fewer to 57 more)
      Serious adverse events

      End of treatment
      7

      per 1000
      8

      per 1000
      RR 1.12

      (0.21 to 5.88)
      6 [
      • Chaccour C.
      • Casellas A.
      • Blanco-Di Matteo A.
      • Pineda I.
      • Fernandez-Montero A.
      • Ruiz-Castillo P.
      • et al.
      The effect of early treatment with ivermectin on viral load, symptoms and humoral response in patients with non-severe COVID-19: A pilot, double-blind, placebo-controlled, randomized clinical trial.
      ,
      • Krolewiecki A.
      • Lifschitz A.
      • Moragas M.
      • Travacio M.
      • Valentini R.
      • Alonso D.F.
      • et al.
      Antiviral effect of high-dose ivermectin in adults with COVID-19: A proof-of-concept randomized trial.
      ,
      • Pott-Junior H.
      • Bastos Paoliello M.M.
      • Miguel A.Q.C.
      • da Cunha A.F.
      • de Melo Freire C.C.
      • Neves F.F.
      • et al.
      Use of ivermectin in the treatment of Covid-19: A pilot trial.
      ,
      • Lopez-Medina E.
      • Lopez P.
      • Hurtado I.C.
      • Davalos D.M.
      • Ramirez O.
      • Martinez E.
      • et al.
      Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19: A Randomized Clinical Trial.
      ,
      • Shah Bukhari K.H.
      • Asghar A.
      • Perveen N.
      • Hayat A.
      • Mangat S.A.
      • Butt K.R.
      • et al.
      Efficacy of Ivermectin in COVID-19 Patients with Mild to Moderate Disease.
      ,
      • Shahbaznejad L.
      • Davoudi A.
      • Eslami G.
      • Markowitz J.S.
      • Navaeifar M.R.
      • Hosseinzadeh F.
      • et al.
      Effects of Ivermectin in Patients With COVID-19: A Multicenter, Double-Blind, Randomized, Controlled Clinical Trial.
      ]

      (644

      patients)
      ⊕⊕⊖⊖

      Low

      (Very Serious imprecision,)
      Difference: 25 more per 1000

      (95% CI: 19 fewer to 89 more)
      Adverse events

      End of treatment
      497

      per 1000
      472

      per 1000
      RR 0.95

      (0.86 to 1.05)
      7 [
      • Chaccour C.
      • Casellas A.
      • Blanco-Di Matteo A.
      • Pineda I.
      • Fernandez-Montero A.
      • Ruiz-Castillo P.
      • et al.
      The effect of early treatment with ivermectin on viral load, symptoms and humoral response in patients with non-severe COVID-19: A pilot, double-blind, placebo-controlled, randomized clinical trial.
      ,
      • Krolewiecki A.
      • Lifschitz A.
      • Moragas M.
      • Travacio M.
      • Valentini R.
      • Alonso D.F.
      • et al.
      Antiviral effect of high-dose ivermectin in adults with COVID-19: A proof-of-concept randomized trial.
      ,
      • Pott-Junior H.
      • Bastos Paoliello M.M.
      • Miguel A.Q.C.
      • da Cunha A.F.
      • de Melo Freire C.C.
      • Neves F.F.
      • et al.
      Use of ivermectin in the treatment of Covid-19: A pilot trial.
      ,
      • Lopez-Medina E.
      • Lopez P.
      • Hurtado I.C.
      • Davalos D.M.
      • Ramirez O.
      • Martinez E.
      • et al.
      Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19: A Randomized Clinical Trial.
      ,
      • Shah Bukhari K.H.
      • Asghar A.
      • Perveen N.
      • Hayat A.
      • Mangat S.A.
      • Butt K.R.
      • et al.
      Efficacy of Ivermectin in COVID-19 Patients with Mild to Moderate Disease.
      ,
      • Shahbaznejad L.
      • Davoudi A.
      • Eslami G.
      • Markowitz J.S.
      • Navaeifar M.R.
      • Hosseinzadeh F.
      • et al.
      Effects of Ivermectin in Patients With COVID-19: A Multicenter, Double-Blind, Randomized, Controlled Clinical Trial.
      ]

      (805

      patients)
      ⊕⊕⊖⊖

      Low

      (Serious imprecision, serious risk of bias)
      Difference: 25 fewer per 1000

      (95% CI: 70 fewer to 25 more)
      ICU admission

      End of follow-up
      115

      per 1000
      61

      per 1000
      RR 0.53

      (0.11 to 2.51)
      2 [
      • Pott-Junior H.
      • Bastos Paoliello M.M.
      • Miguel A.Q.C.
      • da Cunha A.F.
      • de Melo Freire C.C.
      • Neves F.F.
      • et al.
      Use of ivermectin in the treatment of Covid-19: A pilot trial.
      ,
      • Ravikirti Roy R.
      • Pattadar C.
      • Raj R.
      • Agarwal N.
      • Biswas B.
      • et al.
      Evaluation of Ivermectin as a Potential Treatment for Mild to Moderate COVID-19: A Double-Blind Randomized Placebo Controlled Trial in Eastern India.
      ]

      (143

      patients)
      ⊕⊕⊖⊖

      Low

      (Serious imprecision, serious risk of bias)
      Difference: 54 fewer per 1000

      (95% CI: 102 fewer to 174 more)
      Discharge from hospital

      Within 28 days of commencing treatment
      868

      per 1000
      920

      per 1000
      RR 1.06

      (0.99 to 1.12)
      4 [

      Beltran Gonzalez JL, González Gámez M, Mendoza Enciso EA, Esparza Maldonado RJ, Hernández Palacios D, al. e. Efficacy and safety of ivermectin and hydroxychloroquine in patients with severe COVID-19. A randomized controlled trial.

      ,
      • Krolewiecki A.
      • Lifschitz A.
      • Moragas M.
      • Travacio M.
      • Valentini R.
      • Alonso D.F.
      • et al.
      Antiviral effect of high-dose ivermectin in adults with COVID-19: A proof-of-concept randomized trial.
      ,

      Mohan A, Tiwari P, Suri T. Ivermectin in mild and moderate COVID-19 (RIVET-COV): a randomized, placebo-controlled trial. PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-191648/v1]. 2021.

      ,
      • Kishoria N.
      • Mathur S.L.
      • Parmar V.
      Ivermectin as adjuvant to hydroxychloroquine in patients resistant to standard treatment for SARS-CoV-2: Results of an open-label randomized clinical study.
      ]

      (342

      patients)
      ⊕⊕⊖⊖

      Low

      (Serious imprecision, serious risk of bias)
      Difference: 52 more per 1000

      (95% CI: 9 fewer to 104 more)
      95% CI: 95% Confidence interval; RR: Risk ratio.
      References: [

      Beltran Gonzalez JL, González Gámez M, Mendoza Enciso EA, Esparza Maldonado RJ, Hernández Palacios D, al. e. Efficacy and safety of ivermectin and hydroxychloroquine in patients with severe COVID-19. A randomized controlled trial.

      ,
      • Biber A.
      • Mandelboim M.
      • Harmelin G.
      Favorable outcome on viral load and culture viability using ivermectin in early treatment of non-hospitalized patients with mild COVID-19 - a double-blind, randomized placebo-controlled trial.
      ,
      • Ahmed S.
      • Karim M.M.
      • Ross A.G.
      • Hossain M.S.
      • Clemens J.D.
      • Sumiya M.K.
      • et al.
      A five-day course of ivermectin for the treatment of COVID-19 may reduce the duration of illness.
      ,
      • Chaccour C.
      • Casellas A.
      • Blanco-Di Matteo A.
      • Pineda I.
      • Fernandez-Montero A.
      • Ruiz-Castillo P.
      • et al.
      The effect of early treatment with ivermectin on viral load, symptoms and humoral response in patients with non-severe COVID-19: A pilot, double-blind, placebo-controlled, randomized clinical trial.
      ,
      • Krolewiecki A.
      • Lifschitz A.
      • Moragas M.
      • Travacio M.
      • Valentini R.
      • Alonso D.F.
      • et al.
      Antiviral effect of high-dose ivermectin in adults with COVID-19: A proof-of-concept randomized trial.
      ,
      • Pott-Junior H.
      • Bastos Paoliello M.M.
      • Miguel A.Q.C.
      • da Cunha A.F.
      • de Melo Freire C.C.
      • Neves F.F.
      • et al.
      Use of ivermectin in the treatment of Covid-19: A pilot trial.
      ,
      • Ravikirti Roy R.
      • Pattadar C.
      • Raj R.
      • Agarwal N.
      • Biswas B.
      • et al.
      Evaluation of Ivermectin as a Potential Treatment for Mild to Moderate COVID-19: A Double-Blind Randomized Placebo Controlled Trial in Eastern India.
      ,
      • Samaha A.A.
      • Mouawia H.
      • Fawaz M.
      • Hassan H.
      • Salami A.
      • Bazzal A.A.
      • et al.
      Effects of a Single Dose of Ivermectin on Viral and Clinical Outcomes in Asymptomatic SARS-CoV-2 Infected Subjects: A Pilot Clinical Trial in Lebanon.
      ,
      • Lopez-Medina E.
      • Lopez P.
      • Hurtado I.C.
      • Davalos D.M.
      • Ramirez O.
      • Martinez E.
      • et al.
      Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19: A Randomized Clinical Trial.
      ,
      • Abd-Elsalam S.
      • Noor R.A.
      • Badawi R.
      • Khalaf M.
      • Esmail E.S.
      • Soliman S.
      • et al.
      Clinical study evaluating the efficacy of ivermectin in COVID-19 treatment: A randomized controlled study.
      ,

      Mohan A, Tiwari P, Suri T. Ivermectin in mild and moderate COVID-19 (RIVET-COV): a randomized, placebo-controlled trial. PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-191648/v1]. 2021.

      ,

      Niaee MS, Gheibi N, Namdar Pea. Ivermectin as an adjunct treatment for hospitalized adult COVID-19 patients: A randomized multi-center clinical trial, 24 November 2020, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-109670/v1]. 2020.

      ,
      • Shah Bukhari K.H.
      • Asghar A.
      • Perveen N.
      • Hayat A.
      • Mangat S.A.
      • Butt K.R.
      • et al.
      Efficacy of Ivermectin in COVID-19 Patients with Mild to Moderate Disease.
      ,
      • Shahbaznejad L.
      • Davoudi A.
      • Eslami G.
      • Markowitz J.S.
      • Navaeifar M.R.
      • Hosseinzadeh F.
      • et al.
      Effects of Ivermectin in Patients With COVID-19: A Multicenter, Double-Blind, Randomized, Controlled Clinical Trial.
      ,
      • Kishoria N.
      • Mathur S.L.
      • Parmar V.
      Ivermectin as adjuvant to hydroxychloroquine in patients resistant to standard treatment for SARS-CoV-2: Results of an open-label randomized clinical study.
      ,
      • Podder C.S.
      • Chowdhury N.
      • Sina M.I.
      • Haque W.M.M.U.
      Outcome of ivermectin treated mild to moderate COVID-19 cases: a single-centre, open-label, randomised controlled study.
      ].
      Evidence adopted Australian guidelines for the clinical care of people with COVID-19, Available at: https://app.magicapp.org/#/guideline/5446/section/78706.
      Evidence Search date: April 23 - June 11.

       Safety

      While no serious adverse events were recorded (Table 7), there was uncertainty with regards to adverse events and gastrointestinal effects were frequently reported in some studies. Common side effects associated with ivermectin included diarrhea, nausea, and dizziness.

       Recommendation

      Strong recommendation against use of ivermectin to treat COVID-19 (QoE: low).

      What is the effect of azithromycin on disease progression in patients with COVID-19 compared to no treatment?

       Narrative synthesis of evidence

      Azithromycin was assessed in four randomized trials (1 in outpatients and 3 in hospitalized patients). In our analysis, it had no effect on 28-day mortality [RR 1.01; 95% CI 0.92–1.10), risk of disease progression (RR 0.94; 95% CI 0.79–1.14 for mechanical ventilation or ECMO; Table 8), or need for supplemental oxygen [RR 0.84; 95% CI 0.38–1.85). Azithromycin was assessed within the RECOVERY trial which allocated 2582 hospitalized patients to azithromycin and 5181 to SOC; 28-day mortality was similar between groups (RR 0.97, 95% CI 0.87–1.07; p=0.50) [
      Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.
      ].
      Table 8Grade evidence profile PICO5: Azithromycin for COVID-19
      Azithromycin vs Standard care
      People:Adult patients with COVID-19 (pregnant patients excluded)

      Setting: hospital (4 studies), outpatients (1 study) [
      • Group P.T.C.
      Azithromycin for community treatment of suspected COVID-19 in people at increased risk of an adverse clinical course in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial.
      ], 3 Countries (Iran, Brazil, UK)

      Intervention: Azithromycin (500 mg o.d.), 3 to 10 days.

      Comparison: Standard Care

      Patients in both intervention and comparator arms also receiving HCQ in 2 studies [
      • Cavalcanti A.B.
      • Zampieri F.G.
      • Rosa R.G.
      • Azevedo L.C.P.
      • Veiga V.C.
      • Avezum A.
      • et al.
      Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19.
      ,
      • Furtado R.H.M.
      • Berwanger O.
      • Fonseca H.A.
      • Correa T.D.
      • Ferraz L.R.
      • Lapa M.G.
      • et al.
      Azithromycin in addition to standard of care versus standard of care alone in the treatment of patients admitted to the hospital with severe COVID-19 in Brazil (COALITION II): a randomised clinical trial.
      ] and HCQ+ LPV/r in 1 study [
      • Sekhavati E.
      • Jafari F.
      • SeyedAlinaghi S.
      • Jamalimoghadamsiahkali S.
      • Sadr S.
      • Tabarestani M.
      • et al.
      Safety and effectiveness of azithromycin in patients with COVID-19: An open-label randomised trial.
      ].
      OutcomesAbsolute Effect*Relative effect (95% CI)Number of studiesCertainty of the evidence (GRADE)
      Without Azithromycin (Standard Care)With Azithromycin
      All-cause mortality

      Within 28 days of commencing treatment
      172

      per 1000
      174

      per 1000
      RR 1.01

      (0.92 to 1.10)
      4 [
      • Furtado R.H.M.
      • Berwanger O.
      • Fonseca H.A.
      • Correa T.D.
      • Ferraz L.R.
      • Lapa M.G.
      • et al.
      Azithromycin in addition to standard of care versus standard of care alone in the treatment of patients admitted to the hospital with severe COVID-19 in Brazil (COALITION II): a randomised clinical trial.
      ,
      • Sekhavati E.
      • Jafari F.
      • SeyedAlinaghi S.
      • Jamalimoghadamsiahkali S.
      • Sadr S.
      • Tabarestani M.
      • et al.
      Safety and effectiveness of azithromycin in patients with COVID-19: An open-label randomised trial.
      ,
      • Group P.T.C.
      Azithromycin for community treatment of suspected COVID-19 in people at increased risk of an adverse clinical course in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial.
      ,
      • Group R.C.
      Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.
      ]

      (9595

      patients)
      ⊕⊕⊕⊕

      High
      Difference: 2 more per 1000

      (95% CI: 14 fewer to 17 more)
      Supplemental oxygen

      Within 28 days of commencing treatment
      24

      per 1000
      20

      per 1000
      RR 0.84

      (0.38 to 1.85)
      1 [
      • Group P.T.C.
      Azithromycin for community treatment of suspected COVID-19 in people at increased risk of an adverse clinical course in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial.
      ]

      (1122

      patients)
      ⊕⊕⊖⊖

      Low

      (Very serious imprecision; only data from one study, due to few events)
      Difference: 4 fewer per 1000

      (95% CI: 15 fewer to 20 more)
      Clinical recovery

      Within 28 days of commencing treatment
      658

      per 1000
      632

      per 1000
      RR 0.96

      (0.88 to 1.05)
      1 [
      • Group P.T.C.
      Azithromycin for community treatment of suspected COVID-19 in people at increased risk of an adverse clinical course in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial.
      ]

      (1129

      patients)
      ⊕⊕⊖⊖

      Low

      (Very serious imprecision; wide confidence intervals, only data from one study)
      Difference: 26 fewer per 1000

      (95% CI: 79 fewer to 33 more)
      Mechanical ventilation or ECMO

      Within 28 days of commencing treatment
      60

      per 1000
      56

      per 1000
      RR 0.94

      (0.79 to 1.14)
      2 [
      • Group P.T.C.
      Azithromycin for community treatment of suspected COVID-19 in people at increased risk of an adverse clinical course in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial.
      ,
      • Group R.C.
      Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.
      ]

      (8433

      patients)
      ⊕⊕⊕⊕

      High
      Difference: 4 fewer per 1000

      (95% CI: 13 fewer to 8 more)
      Serious adverse events

      End of treatment
      194

      per 1000
      219

      per 1000
      RR 1.13

      (0.90 to 1.42)
      2 [
      • Cavalcanti A.B.
      • Zampieri F.G.
      • Rosa R.G.
      • Azevedo L.C.P.
      • Veiga V.C.
      • Avezum A.
      • et al.
      Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19.
      ,
      • Furtado R.H.M.
      • Berwanger O.
      • Fonseca H.A.
      • Correa T.D.
      • Ferraz L.R.
      • Lapa M.G.
      • et al.
      Azithromycin in addition to standard of care versus standard of care alone in the treatment of patients admitted to the hospital with severe COVID-19 in Brazil (COALITION II): a randomised clinical trial.
      ]

      (877

      patients)
      ⊕⊕⊕⊖

      Moderate

      (serious imprecision; wide confidence intervals)
      Difference: 25 more per 1000

      (95% CI: 19 fewer to 89 more)
      Adverse events

      End of treatment
      337

      per 1000
      394

      per 1000
      RR 1.17

      (0.91 to 1.50)
      1 [
      • Cavalcanti A.B.
      • Zampieri F.G.
      • Rosa R.G.
      • Azevedo L.C.P.
      • Veiga V.C.
      • Avezum A.
      • et al.
      Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19.
      ]

      (438

      patients)
      ⊕⊕⊖⊖

      Low

      (Very serious imprecision; wide confidence intervals, only data from one study)
      Difference: 57 more per 1000

      (95% CI: 30 fewer to 169 more)
      ICU admission

      End of follow-up
      18

      per 1000
      9

      per 1000
      RR 0.48

      (0.17 to 1.35)
      2 [
      • Group P.T.C.
      Azithromycin for community treatment of suspected COVID-19 in people at increased risk of an adverse clinical course in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial.
      ]

      (1231

      patients)
      ⊕⊕⊖⊖

      Low

      (Very serious imprecision, due to few events)
      Difference: 9 fewer per 1000

      (95% CI: 15 fewer to 6 more)
      Discharge from hospital

      Within 28 days of commencing treatment
      586

      per 1000
      539

      per 1000
      RR 0.92

      (0.72 to 1.19)
      2 [
      • Furtado R.H.M.
      • Berwanger O.
      • Fonseca H.A.
      • Correa T.D.
      • Ferraz L.R.
      • Lapa M.G.
      • et al.
      Azithromycin in addition to standard of care versus standard of care alone in the treatment of patients admitted to the hospital with severe COVID-19 in Brazil (COALITION II): a randomised clinical trial.
      ,
      • Group R.C.
      Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.
      ]

      (8162

      patients)
      ⊕⊕⊕⊖

      Moderate

      (serious imprecision; wide confidence intervals)
      Difference: 47 fewer per 1000

      (95% CI: 170 fewer to 111 more)
      Duration of hospital stay MeanDifference: 0.41 lower (MD)

      (95% CI: 2.42lowerto 1.59 higher)
      -2 [
      • Cavalcanti A.B.
      • Zampieri F.G.
      • Rosa R.G.
      • Azevedo L.C.P.
      • Veiga V.C.
      • Avezum A.
      • et al.
      Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19.
      ,
      • Sekhavati E.
      • Jafari F.
      • SeyedAlinaghi S.
      • Jamalimoghadamsiahkali S.
      • Sadr S.
      • Tabarestani M.
      • et al.
      Safety and effectiveness of azithromycin in patients with COVID-19: An open-label randomised trial.
      ]

      (442

      patients)
      ⊕⊕⊖⊖

      Low

      (serious inconsistency and imprecision; wide confidence intervals)
      Duration of hospital stay

      Median
      1312-1 [
      • Group R.C.
      Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.
      ]

      (7764 patients)
      ⊕⊕⊕⊖

      Moderate

      (serious imprecision; only data from1 study)
      95% CI: 95% Confidence interval; RR: Risk ratio.
      References: [
      • Cavalcanti A.B.
      • Zampieri F.G.
      • Rosa R.G.
      • Azevedo L.C.P.
      • Veiga V.C.
      • Avezum A.
      • et al.
      Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19.
      ,
      • Furtado R.H.M.
      • Berwanger O.
      • Fonseca H.A.
      • Correa T.D.
      • Ferraz L.R.
      • Lapa M.G.
      • et al.
      Azithromycin in addition to standard of care versus standard of care alone in the treatment of patients admitted to the hospital with severe COVID-19 in Brazil (COALITION II): a randomised clinical trial.
      ,
      • Sekhavati E.
      • Jafari F.
      • SeyedAlinaghi S.
      • Jamalimoghadamsiahkali S.
      • Sadr S.
      • Tabarestani M.
      • et al.
      Safety and effectiveness of azithromycin in patients with COVID-19: An open-label randomised trial.
      ,
      • Group P.T.C.
      Azithromycin for community treatment of suspected COVID-19 in people at increased risk of an adverse clinical course in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial.
      ,
      • Group R.C.
      Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.
      ].
      Evidence adopted Australian guidelines for the clinical care of people with COVID-19, Available at: https://app.magicapp.org/#/guideline/5446/section/78706.
      Evidence Search date: April 23 - June 11.
      COALITION and COALITION II were open-label randomized trials assessing HCQ, HCQ plus azithromycin, azithromycin, and SOC [
      • Cavalcanti A.B.
      • Zampieri F.G.
      • Rosa R.G.
      • Azevedo L.C.P.
      • Veiga V.C.
      • Avezum A.
      • et al.
      Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19.
      ,
      • Furtado R.H.M.
      • Berwanger O.
      • Fonseca H.A.
      • Correa T.D.
      • Ferraz L.R.
      • Lapa M.G.
      • et al.
      Azithromycin in addition to standard of care versus standard of care alone in the treatment of patients admitted to the hospital with severe COVID-19 in Brazil (COALITION II): a randomised clinical trial.
      ]. The primary endpoint (clinical status at day 15 assessed by 7-grade ordinal scale) was not affected by any of the study drugs in either trial [
      • Cavalcanti A.B.
      • Zampieri F.G.
      • Rosa R.G.
      • Azevedo L.C.P.
      • Veiga V.C.
      • Avezum A.
      • et al.
      Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19.
      ,
      • Furtado R.H.M.
      • Berwanger O.
      • Fonseca H.A.
      • Correa T.D.
      • Ferraz L.R.
      • Lapa M.G.
      • et al.
      Azithromycin in addition to standard of care versus standard of care alone in the treatment of patients admitted to the hospital with severe COVID-19 in Brazil (COALITION II): a randomised clinical trial.
      ]. Azithromycin was not associated with better outcomes in hospitalized patients [
      • Sekhavati E.
      • Jafari F.
      • SeyedAlinaghi S.
      • Jamalimoghadamsiahkali S.
      • Sadr S.
      • Tabarestani M.
      • et al.
      Safety and effectiveness of azithromycin in patients with COVID-19: An open-label randomised trial.
      ] or outpatients [
      Azithromycin for community treatment of suspected COVID-19 in people at increased risk of an adverse clinical course in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial.
      ].

       Safety

      Rates of adverse events and severe adverse events were similar in patients receiving azithromycin or SOC [
      Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.
      ,
      • Furtado R.H.M.
      • Berwanger O.
      • Fonseca H.A.
      • Correa T.D.
      • Ferraz L.R.
      • Lapa M.G.
      • et al.
      Azithromycin in addition to standard of care versus standard of care alone in the treatment of patients admitted to the hospital with severe COVID-19 in Brazil (COALITION II): a randomised clinical trial.
      ,
      Azithromycin for community treatment of suspected COVID-19 in people at increased risk of an adverse clinical course in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial.
      ]. In the only study that assessed azithromycin and HCQ, adverse events and prolongation of the QTc interval were more frequent in patients receiving HCQ or HCQ plus azithromycin compared to controls [
      • Cavalcanti A.B.
      • Zampieri F.G.
      • Rosa R.G.
      • Azevedo L.C.P.
      • Veiga V.C.
      • Avezum A.
      • et al.
      Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19.
      ].

       Recommendation

      Strong recommendation against use of azithromycin for COVID-19 (QoE: high for 28-day mortality, low for disease progression)

      What is the effect of colchicine treatment on mortality or disease progression in patients with mild COVID-19 compared with no treatment?

       Narrative synthesis of evidence

      More than 30 trials have assessed the role of colchicine in COVID-19. Five were considered to define the current position statement. Overall, colchicine had no impact on mortality (RR 1.00; 95% CI 0.93–1.07) or need for mechanical ventilation [RR 1.01; 95% CI 0.91–1.13; Table 9).
      Table 9Grade evidence profile PICO6: Colchicine for COVID-19
      People:Adult patients with COVID-19 (pregnant patients excluded)

      Setting: Hospital

      Intervention: Colchicine

      Comparison: Standard Care
      OutcomesAbsolute EffectRelative effect (95% CI)Number of studiesCertainty of the evidence (GRADE)
      Without Colchicine (Standard Care)With Colchicine
      All cause mortality

      within 21-28 days of treatment administration
      149 per 1000149 per 1000RR 1.00 (0.93 - 1.07)4 [
      • Tardif J.C.
      • Bouabdallaoui N.
      • L'Allier P.L.
      • Gaudet D.
      • Shah B.
      • Pillinger M.H.
      • et al.
      Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial.
      ,
      • Deftereos S.G.
      • Giannopoulos G.
      • Vrachatis D.A.
      • Siasos G.D.
      • Giotaki S.G.
      • Gargalianos P.
      • et al.
      Effect of Colchicine vs Standard Care on Cardiac and Inflammatory Biomarkers and Clinical Outcomes in Patients Hospitalized With Coronavirus Disease 2019: The GRECCO-19 Randomized Clinical Trial.
      ,
      • Lopes M.I.
      • Bonjorno L.P.
      • Giannini M.C.
      • Amaral N.B.
      • Menezes P.I.
      • Dib S.M.
      • et al.
      Beneficial effects of colchicine for moderate to severe COVID-19: a randomised, double-blinded, placebo-controlled clinical trial.
      ,
      • Group R.C.
      • Horby P.W.
      • Campbell M.
      • Spata E.
      • Emberson J.R.
      • Staplin N.
      • et al.
      Colchicine in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.
      ]

      (15968

      patients)
      ⊕⊕⊕⊕

      High
      0 fewer per 1000

      (CI 95% 10 fewer - 10 more)
      Disease progression

      Increase of 2 grades on 7-grade scale; 21 days after commencing treatment
      140

      per 1000
      18

      per 1000
      RR 0.13 (0.02 - 1.02)1 [
      • Deftereos S.G.
      • Giannopoulos G.
      • Vrachatis D.A.
      • Siasos G.D.
      • Giotaki S.G.
      • Gargalianos P.
      • et al.
      Effect of Colchicine vs Standard Care on Cardiac and Inflammatory Biomarkers and Clinical Outcomes in Patients Hospitalized With Coronavirus Disease 2019: The GRECCO-19 Randomized Clinical Trial.
      ]

      (105

      patients)
      ⊕⊕⊖⊖

      Low

      (Very serious imprecision; only data from one study, due to few events)
      Difference: 4

      122 fewer per 1000

      (95% CI: 187 fewer to 3 more)
      Invasive mechanical ventilation

      within 21-28 days of treatment administration
      80

      per 1000
      81

      per 1000
      RR 1.01 (0.91 - 1.13)3 [
      • Tardif J.C.
      • Bouabdallaoui N.
      • L'Allier P.L.
      • Gaudet D.
      • Shah B.
      • Pillinger M.H.
      • et al.
      Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial.
      ,
      • Deftereos S.G.
      • Giannopoulos G.
      • Vrachatis D.A.
      • Siasos G.D.
      • Giotaki S.G.
      • Gargalianos P.
      • et al.
      Effect of Colchicine vs Standard Care on Cardiac and Inflammatory Biomarkers and Clinical Outcomes in Patients Hospitalized With Coronavirus Disease 2019: The GRECCO-19 Randomized Clinical Trial.
      ,
      • Group R.C.
      • Horby P.W.
      • Campbell M.
      • Spata E.
      • Emberson J.R.
      • Staplin N.
      • et al.
      Colchicine in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.
      ]

      (15404 patients)
      ⊕⊕⊕⊕

      High
      Difference:

      1 more per 1000 (CI 95% 7 fewer - 10 more)
      Serious adverse events

      End of treatment
      61

      per 1000
      48

      per 1000
      RR 0.78

      (0.61 to 1.00)
      2 [
      • Tardif J.C.
      • Bouabdallaoui N.
      • L'Allier P.L.
      • Gaudet D.
      • Shah B.
      • Pillinger M.H.
      • et al.
      Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial.
      ,
      • Deftereos S.G.
      • Giannopoulos G.
      • Vrachatis D.A.
      • Siasos G.D.
      • Giotaki S.G.
      • Gargalianos P.
      • et al.
      Effect of Colchicine vs Standard Care on Cardiac and Inflammatory Biomarkers and Clinical Outcomes in Patients Hospitalized With Coronavirus Disease 2019: The GRECCO-19 Randomized Clinical Trial.
      ]

      (4517

      patients)
      ⊕⊕⊕⊖

      Moderate

      (serious imprecision; wide confidence intervals)
      Difference: 13 more per 1000

      (95% CI: 24 fewer to 0 more)
      Adverse events

      End of treatment
      158

      per 1000
      305

      per 1000
      RR 1.93

      (1.18 to 3.16)
      2 [
      • Tardif J.C.
      • Bouabdallaoui N.
      • L'Allier P.L.
      • Gaudet D.
      • Shah B.
      • Pillinger M.H.
      • et al.
      Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial.
      ,
      • Deftereos S.G.
      • Giannopoulos G.
      • Vrachatis D.A.
      • Siasos G.D.
      • Giotaki S.G.
      • Gargalianos P.
      • et al.
      Effect of Colchicine vs Standard Care on Cardiac and Inflammatory Biomarkers and Clinical Outcomes in Patients Hospitalized With Coronavirus Disease 2019: The GRECCO-19 Randomized Clinical Trial.
      ]

      (4517

      patients)
      ⊕⊕⊕⊖

      Moderate

      (serious imprecision; wide confidence intervals)
      Difference: 147 more per 1000

      (95% CI: 28 more to 341 more)
      95% CI: 95% Confidence interval; RR: Risk ratio.
      References: [
      • Tardif J.C.
      • Bouabdallaoui N.
      • L'Allier P.L.
      • Gaudet D.
      • Shah B.
      • Pillinger M.H.
      • et al.
      Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial.
      ,
      • Deftereos S.G.
      • Giannopoulos G.
      • Vrachatis D.A.
      • Siasos G.D.
      • Giotaki S.G.
      • Gargalianos P.
      • et al.
      Effect of Colchicine vs Standard Care on Cardiac and Inflammatory Biomarkers and Clinical Outcomes in Patients Hospitalized With Coronavirus Disease 2019: The GRECCO-19 Randomized Clinical Trial.
      ,
      • Lopes M.I.
      • Bonjorno L.P.
      • Giannini M.C.
      • Amaral N.B.
      • Menezes P.I.
      • Dib S.M.
      • et al.
      Beneficial effects of colchicine for moderate to severe COVID-19: a randomised, double-blinded, placebo-controlled clinical trial.
      ,
      • Group R.C.
      • Horby P.W.
      • Campbell M.
      • Spata E.
      • Emberson J.R.
      • Staplin N.
      • et al.
      Colchicine in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.
      ,

      Salehzadeh F, Pourfarzi F, Ataei Sea. The Impact of Colchicine on The COVID-19 Patients; A Clinical Trial Study, 21 September 2020, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-69374/v1].

      ].
      Evidence adopted Australian guidelines for the clinical care of people with COVID-19, Available at: https://app.magicapp.org/#/guideline/5446/section/78673.
      Evidence Search date: April 23 - May 25.
      COLCORONA compared colchicine to placebo in 4488 outpatients with COVID-19. The primary composite endpoint – death or hospitalization for COVID19 – occurred in 4.7% and 5.8% of patients receiving colchicine and placebo, respectively (OR 0.79; 95% CI 0.61–1.03; p=0.08). Rates of hospitalization and mechanical ventilation and mortality were similar between two groups [
      • Tardif J.C.
      • Bouabdallaoui N.
      • L'Allier P.L.
      • Gaudet D.
      • Shah B.
      • Pillinger M.H.
      • et al.
      Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial.
      ]. Colchicine showed promising results in small preliminary RCTs [
      • Deftereos S.G.
      • Giannopoulos G.
      • Vrachatis D.A.
      • Siasos G.D.
      • Giotaki S.G.
      • Gargalianos P.
      • et al.
      Effect of Colchicine vs Standard Care on Cardiac and Inflammatory Biomarkers and Clinical Outcomes in Patients Hospitalized With Coronavirus Disease 2019: The GRECCO-19 Randomized Clinical Trial.
      ,
      • Lopes M.I.
      • Bonjorno L.P.
      • Giannini M.C.
      • Amaral N.B.
      • Menezes P.I.
      • Dib S.M.
      • et al.
      Beneficial effects of colchicine for moderate to severe COVID-19: a randomised, double-blinded, placebo-controlled clinical trial.
      ]. However, recent unrefereed results of RECOVERY comparing 28-day mortality in patients receiving colchicine (n=5160) or SOC (n=5730) showed no benefit (RR 1.01; 95% CI 0.93–1.10; p=0.77); this finding was similar in all pre-specified subgroups and in those with SARS-CoV-2 infection confirmed by molecular analysis [

      RECOVERY Collaborative Group PWH, Mark Campbell , Enti Spata , Jonathan R Emberson , Natalie Staplin , Guilherme Pessoa-Amorim , Leon Peto , Martin Wiselka , Laura Wiffen , Simon Tiberi , Ben Caplin , Caroline Wroe , Christopher Green , Paul Hine , Benjamin Prudon , Tina George , Andrew Wight , J Kenneth Baillie , Buddha Basnyat , Maya H Buch , Lucy C Chappell , Jeremy N Day , Saul N Faust , Raph L Hamers , Thomas Jaki , Edmund Juszczak , Katie Jeffery , Wei Shen Lim , Alan Montgomery , Andrew Mumford , Kathryn Rowan , Guy Thwaites , Marion Mafham , Richard Haynes , Martin J Landray. Colchicine in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. 2021.

      ].

       Safety

      Colchicine has known bone marrow toxicity and several dose-dependent gastrointestinal adverse effects [
      • Alabed S.
      • Cabello J.B.
      • Irving G.J.
      • Qintar M.
      • Burls A.
      Colchicine for pericarditis.
      ]. In COLCORONA, the rate of serious adverse events was 4.9% and 6.3% (p=0.05) and drug-related adverse events were 24.2% and 15.5% (p<0.0001) in the intervention and placebo groups, respectively. Gastrointestinal adverse events were significantly increased with colchicine (23.9% vs 14.8%, p<0.0001) as was diarrhea (13.7% vs 7.3%, p<0.0001) [
      • Tardif J.C.
      • Bouabdallaoui N.
      • L'Allier P.L.
      • Gaudet D.
      • Shah B.
      • Pillinger M.H.
      • et al.
      Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial.
      ]. In the GRECCO trial, no serious adverse events were reported, while adverse events were similar in the two groups with the exception of diarrhea which was mainly seen with colchicine (45.5% vs 18%; p=0.003) [
      • Deftereos S.G.
      • Giannopoulos G.
      • Vrachatis D.A.
      • Siasos G.D.
      • Giotaki S.G.
      • Gargalianos P.
      • et al.
      Effect of Colchicine vs Standard Care on Cardiac and Inflammatory Biomarkers and Clinical Outcomes in Patients Hospitalized With Coronavirus Disease 2019: The GRECCO-19 Randomized Clinical Trial.
      ].

       Recommendation

      Strong recommendation against use of colchicine for COVID-19 (QoE: high).

      What is the effect of corticosteroid treatment on mortality in patients with mild COVID-19 compared with no treatment?

       Narrative synthesis of evidence

      The evidence involved 5789 patients from 9 RCTs [
      • Group R.C.
      • Horby P.
      • Lim W.S.
      • Emberson J.R.
      • Mafham M.
      • Bell J.L.
      • et al.
      Dexamethasone in Hospitalized Patients with Covid-19.
      ,
      • Dequin P.F.
      • Heming N.
      • Meziani F.
      • Plantefeve G.
      • Voiriot G.
      • Badie J.
      • et al.
      Effect of Hydrocortisone on 21-Day Mortality or Respiratory Support Among Critically Ill Patients With COVID-19: A Randomized Clinical Trial.
      ,

      Du B, Weng LI. Glucocorticoid therapy for COVID-19 critically ill patients with severe acute respiratory failure 2021 [Available from: https://www.clinicaltrials.gov/ct2/show/study/NCT04244591.

      ,
      • Jeronimo C.M.P.
      • Farias M.E.L.
      • Val F.F.A.
      • Sampaio V.S.
      • Alexandre M.A.A.
      • Melo G.C.
      • et al.
      Methylprednisolone as Adjunctive Therapy for Patients Hospitalized With Coronavirus Disease 2019 (COVID-19; Metcovid): A Randomized, Double-blind, Phase IIb, Placebo-controlled Trial.
      ,
      • Angus D.C.
      • Derde L.
      • Al-Beidh F.
      • Annane D.
      • Arabi Y.
      • Beane A.
      • et al.
      Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.
      ,
      • Tomazini B.M.
      • Maia I.S.
      • Cavalcanti A.B.
      • Berwanger O.
      • Rosa R.G.
      • Veiga V.C.
      • et al.
      Effect of Dexamethasone on Days Alive and Ventilator-Free in Patients With Moderate or Severe Acute Respiratory Distress Syndrome and COVID-19: The CoDEX Randomized Clinical Trial.
      ,
      • Munch M.W.
      • Meyhoff T.S.
      • Helleberg M.
      • Kjaer M.N.
      • Granholm A.
      • Hjortso C.J.S.
      • et al.
      Low-dose hydrocortisone in patients with COVID-19 and severe hypoxia: the COVID STEROID randomised, placebo-controlled trial.
      ,
      • Villar J.
      • Ferrando C.
      • Martinez D.
      • Ambros A.
      • Munoz T.
      • Soler J.A.
      • et al.
      Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial.
      ,
      • Edalatifard M.
      • Akhtari M.
      • Salehi M.
      • Naderi Z.
      • Jamshidi A.
      • Mostafaei S.
      • et al.
      Intravenous methylprednisolone pulse as a treatment for hospitalised severe COVID-19 patients: results from a randomised controlled clinical trial.
      ]. The RR for mortality was significantly lower in patients who received corticosteroids compared to SOC [RR 0.83; 95% CI 0.73–0.99). Corticosteroid treatment was also associated with reduced need for mechanical ventilation [RR 0.88; 95% CI 0.79–0.97; Table 10).
      Table 10Grade evidence profile of PICO 7: corticosteroids for adult patients with COIVD-19 requiring oxygen supplement
      Corticosteroids for severe COVID-19 i.e. patients requiring oxygen including mechanically ventilated patients
      People: Patients with COVID-19

      Settings: Inpatients

      Intervention: Corticosteroids

      Comparison: No treatment
      OutcomesAbsolute EffectRelative effect (95% CI)Number of studiesCertainty of the evidence (GRADE)
      Without CorticosteroidsWith Corticosteroids
      All-cause mortality (adults requiring oxygen)316

      per 1000
      265

      per 1000
      RR 0.84

      (0.73 to 0.98)
      9 [
      • Group R.C.
      • Horby P.
      • Lim W.S.
      • Emberson J.R.
      • Mafham M.
      • Bell J.L.
      • et al.
      Dexamethasone in Hospitalized Patients with Covid-19.
      ,
      • Dequin P.F.
      • Heming N.
      • Meziani F.
      • Plantefeve G.
      • Voiriot G.
      • Badie J.
      • et al.
      Effect of Hydrocortisone on 21-Day Mortality or Respiratory Support Among Critically Ill Patients With COVID-19: A Randomized Clinical Trial.
      ,

      Du B, Weng LI. Glucocorticoid therapy for COVID-19 critically ill patients with severe acute respiratory failure 2021 [Available from: https://www.clinicaltrials.gov/ct2/show/study/NCT04244591.

      ,
      • Jeronimo C.M.P.
      • Farias M.E.L.
      • Val F.F.A.
      • Sampaio V.S.
      • Alexandre M.A.A.
      • Melo G.C.
      • et al.
      Methylprednisolone as Adjunctive Therapy for Patients Hospitalized With Coronavirus Disease 2019 (COVID-19; Metcovid): A Randomized, Double-blind, Phase IIb, Placebo-controlled Trial.
      ,
      • Angus D.C.
      • Derde L.
      • Al-Beidh F.
      • Annane D.
      • Arabi Y.
      • Beane A.
      • et al.
      Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.
      ,
      • Tomazini B.M.
      • Maia I.S.
      • Cavalcanti A.B.
      • Berwanger O.
      • Rosa R.G.
      • Veiga V.C.
      • et al.
      Effect of Dexamethasone on Days Alive and Ventilator-Free in Patients With Moderate or Severe Acute Respiratory Distress Syndrome and COVID-19: The CoDEX Randomized Clinical Trial.
      ,
      • Villar J.
      • Ferrando C.
      • Martinez D.
      • Ambros A.
      • Munoz T.
      • Soler J.A.
      • et al.
      Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial.
      ,
      • Edalatifard M.
      • Akhtari M.
      • Salehi M.
      • Naderi Z.
      • Jamshidi A.
      • Mostafaei S.
      • et al.
      Intravenous methylprednisolone pulse as a treatment for hospitalised severe COVID-19 patients: results from a randomised controlled clinical trial.
      ,
      • Petersen M.W.
      • Meyhoff T.S.
      • Helleberg M.
      • Kjaer M.N.
      • Granholm A.
      • Hjortso C.J.S.
      • et al.
      Low-dose hydrocortisone in patients with COVID-19 and severe hypoxia (COVID STEROID) trial-Protocol and statistical analysis plan.
      ,

      World Health Organization : Corticosteroids for COVID-19, Living Guidance. 2 September 2020. Available at: https://apps.who.int/iris/handle/10665/334125.

      ]

      (5789 patients)
      ⊕⊕⊕⊖

      Moderate

      (due to serious inconsistency)
      Difference: 51 fewer per 1000

      (95% CI: 85 fewer – 6 fewer)
      Invasive mechanical ventilation or death (adults requiring oxygen)320

      per 1000
      282

      per 1000
      RR 0.88

      (0.79 to 0.97)
      1 [
      • Group R.C.
      • Horby P.
      • Lim W.S.
      • Emberson J.R.
      • Mafham M.
      • Bell J.L.
      • et al.
      Dexamethasone in Hospitalized Patients with Covid-19.
      ]

      (3883 patients)
      ⊕⊕⊕⊖

      Moderate

      due to serious inconsistency
      Difference: 38 fewer per 1000

      (95% CI: 67 fewer – 10 fewer)
      Serious adverse events (adults requiring oxygen)234

      per 1000
      187

      per 1000
      RR 0.80

      (0.53 to 1.19)
      6 [
      • Dequin P.F.
      • Heming N.
      • Meziani F.
      • Plantefeve G.
      • Voiriot G.
      • Badie J.
      • et al.
      Effect of Hydrocortisone on 21-Day Mortality or Respiratory Support Among Critically Ill Patients With COVID-19: A Randomized Clinical Trial.
      ,

      Du B, Weng LI. Glucocorticoid therapy for COVID-19 critically ill patients with severe acute respiratory failure 2021 [Available from: https://www.clinicaltrials.gov/ct2/show/study/NCT04244591.

      ,
      • Angus D.C.
      • Derde L.
      • Al-Beidh F.
      • Annane D.
      • Arabi Y.
      • Beane A.
      • et al.
      Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.
      ,
      • Tomazini B.M.
      • Maia I.S.
      • Cavalcanti A.B.
      • Berwanger O.
      • Rosa R.G.
      • Veiga V.C.
      • et al.
      Effect of Dexamethasone on Days Alive and Ventilator-Free in Patients With Moderate or Severe Acute Respiratory Distress Syndrome and COVID-19: The CoDEX Randomized Clinical Trial.
      ,
      • Villar J.
      • Ferrando C.
      • Martinez D.
      • Ambros A.
      • Munoz T.
      • Soler J.A.
      • et al.
      Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial.
      ,
      • Petersen M.W.
      • Meyhoff T.S.
      • Helleberg M.
      • Kjaer M.N.
      • Granholm A.
      • Hjortso C.J.S.
      • et al.
      Low-dose hydrocortisone in patients with COVID-19 and severe hypoxia (COVID STEROID) trial-Protocol and statistical analysis plan.
      ]

      (696 patients)
      ⊕⊕⊕⊖

      Moderate

      (due to serious inconsistency)
      Difference: 47 more per 1000

      (95% CI: 110 fewer – 44 more)
      Superinfection

      (end of treatment)
      186

      per 1000
      188

      per 1000
      RR 1.01

      (0.90 to 1.13)
      32 [

      World Health Organization : Corticosteroids for COVID-19, Living Guidance. 2 September 2020. Available at: https://apps.who.int/iris/handle/10665/334125.

      ]

      (6027 patients)
      ⊕⊕⊖⊖

      Low

      (Due to serious indirectness and imprecision)
      Difference: 2 more per 1000

      (95% CI: 19 fewer – 24 more)
      Hyperglycemia

      (end of treatment)
      286

      Per 1000
      332

      Per 1000
      RR 1.16 (1.08-1.25)24 [

      World Health Organization : Corticosteroids for COVID-19, Living Guidance. 2 September 2020. Available at: https://apps.who.int/iris/handle/10665/334125.

      ]
      ⊕⊕⊕⊖

      Moderate

      (due to serious indirectness)
      Difference: 46 more per 1000

      (95% CI 23 more -72 more)
      Discharge from hospital

      (within 28 days of treatment begin, adults requiring oxygen)
      582

      per 1000
      640

      per 1000
      RR 1.10

      (1.06 to 1.15)
      2 [
      • Group R.C.
      • Horby P.
      • Lim W.S.
      • Emberson J.R.
      • Mafham M.
      • Bell J.L.
      • et al.
      Dexamethasone in Hospitalized Patients with Covid-19.
      ,
      • Edalatifard M.
      • Akhtari M.
      • Salehi M.
      • Naderi Z.
      • Jamshidi A.
      • Mostafaei S.
      • et al.
      Intravenous methylprednisolone pulse as a treatment for hospitalised severe COVID-19 patients: results from a randomised controlled clinical trial.
      ]

      (4952 patients)
      ⊕⊕⊕⊖

      Moderate

      (due to serious inconsistency
      Difference: 58 more per 1000

      (95% CI: 35 more to 87 more)
      95% CI: 95% Confidence interval; RR: Risk ratio.
      References: [
      • Group R.C.
      • Horby P.
      • Lim W.S.
      • Emberson J.R.
      • Mafham M.
      • Bell J.L.
      • et al.
      Dexamethasone in Hospitalized Patients with Covid-19.
      ,
      • Dequin P.F.
      • Heming N.
      • Meziani F.
      • Plantefeve G.
      • Voiriot G.
      • Badie J.
      • et al.
      Effect of Hydrocortisone on 21-Day Mortality or Respiratory Support Among Critically Ill Patients With COVID-19: A Randomized Clinical Trial.
      ,

      Du B, Weng LI. Glucocorticoid therapy for COVID-19 critically ill patients with severe acute respiratory failure 2021 [Available from: https://www.clinicaltrials.gov/ct2/show/study/NCT04244591.

      ,
      • Jeronimo C.M.P.
      • Farias M.E.L.
      • Val F.F.A.
      • Sampaio V.S.
      • Alexandre M.A.A.
      • Melo G.C.
      • et al.
      Methylprednisolone as Adjunctive Therapy for Patients Hospitalized With Coronavirus Disease 2019 (COVID-19; Metcovid): A Randomized, Double-blind, Phase IIb, Placebo-controlled Trial.
      ,
      • Angus D.C.
      • Derde L.
      • Al-Beidh F.
      • Annane D.
      • Arabi Y.
      • Beane A.
      • et al.
      Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.
      ,
      • Tomazini B.M.
      • Maia I.S.
      • Cavalcanti A.B.
      • Berwanger O.
      • Rosa R.G.
      • Veiga V.C.
      • et al.
      Effect of Dexamethasone on Days Alive and Ventilator-Free in Patients With Moderate or Severe Acute Respiratory Distress Syndrome and COVID-19: The CoDEX Randomized Clinical Trial.
      ,
      • Villar J.
      • Ferrando C.
      • Martinez D.
      • Ambros A.
      • Munoz T.
      • Soler J.A.
      • et al.
      Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial.
      ,
      • Edalatifard M.
      • Akhtari M.
      • Salehi M.
      • Naderi Z.
      • Jamshidi A.
      • Mostafaei S.
      • et al.
      Intravenous methylprednisolone pulse as a treatment for hospitalised severe COVID-19 patients: results from a randomised controlled clinical trial.
      ,
      • Petersen M.W.
      • Meyhoff T.S.
      • Helleberg M.
      • Kjaer M.N.
      • Granholm A.
      • Hjortso C.J.S.
      • et al.
      Low-dose hydrocortisone in patients with COVID-19 and severe hypoxia (COVID STEROID) trial-Protocol and statistical analysis plan.
      ,

      World Health Organization : Corticosteroids for COVID-19, Living Guidance. 2 September 2020. Available at: https://apps.who.int/iris/handle/10665/334125.

      ].
      Evidence adopted: Australian guidelines for the clinical care of people with COVID-19, Available at: https://app.magicapp.org/#/guideline/5477/section/80465.
      Evidence Search date: April 23 - May 11.
      The results of meta-analyses are largely influenced by the RECOVERY trial which enrolled 83% of patients [
      • Group R.C.
      • Horby P.
      • Lim W.S.
      • Emberson J.R.
      • Mafham M.
      • Bell J.L.
      • et al.
      Dexamethasone in Hospitalized Patients with Covid-19.
      ]. In RECOVERY, corticosteroid (dexamethasone) provided greater mortality benefits in patients requiring invasive mechanical ventilation (29.3% vs 41.4%) or oxygen support without invasive mechanical ventilation (23.3% vs 26.2%) at randomization [
      • Group R.C.
      • Horby P.
      • Lim W.S.
      • Emberson J.R.
      • Mafham M.
      • Bell J.L.
      • et al.
      Dexamethasone in Hospitalized Patients with Covid-19.
      ]. Of the remaining 7 studies (5-11), despite lower mortality with corticosteroid treatment in several trials, some failed to detect significant differences, and some were terminated early based on the results of RECOVERY. In patients who did not require oxygen, corticosteroids likely increased mortality (RR 1.27; 95% CI 1.00–1.61; 1535 patients in one study) and the composite of invasive mechanical ventilation or death [
      • Group R.C.
      • Horby P.
      • Lim W.S.
      • Emberson J.R.
      • Mafham M.
      • Bell J.L.
      • et al.
      Dexamethasone in Hospitalized Patients with Covid-19.
      ] (Table 11).
      Table 11GRADE evidence profile PICO7: Corticosteroid for COVID-19 in the subgroup of hospitalized patients not requiring supplemental oxygen
      Corticosteroids for mild COVID-19 i.e. patients not requiring oxygen
      People: Patients with COVID-19

      Settings: Inpatients

      Intervention: Corticosteroids

      Comparison: No treatment
      OutcomesAbsolute EffectRelative effect (95% CI)Number of studiesCertainty of the evidence (GRADE)
      Without CorticosteroidsWith Corticosteroids
      All-cause mortality140

      per 1000
      178

      per 1000
      RR 1.27

      (1.00 to 1.61)
      1 [
      • Group R.C.
      • Horby P.
      • Lim W.S.
      • Emberson J.R.
      • Mafham M.
      • Bell J.L.
      • et al.
      Dexamethasone in Hospitalized Patients with Covid-19.
      ]

      (1535 patients)
      ⊕⊕⊕⊖

      Moderate

      (serious imprecision)
      Difference: 38 more per 1000

      (95% CI: 0 more to85 more)
      Invasive mechanical ventilation or death155

      per 1000
      194

      per 1000
      RR 1.25

      (1.0 to 1.57
      1 [
      • Group R.C.
      • Horby P.
      • Lim W.S.
      • Emberson J.R.
      • Mafham M.
      • Bell J.L.
      • et al.
      Dexamethasone in Hospitalized Patients with Covid-19.
      ]

      (1535 patients)
      ⊕⊕⊕⊖

      Moderate

      (serious imprecision)
      Difference: 39 more per 1000

      (95% CI: 0 more to88 more)
      Discharge for hospital

      (within 28 days of treatment begin)
      804

      per 1000
      772

      per 1000
      RR 0.96

      (0.9 to 1.01)
      1 [
      • Group R.C.
      • Horby P.
      • Lim W.S.
      • Emberson J.R.
      • Mafham M.
      • Bell J.L.
      • et al.
      Dexamethasone in Hospitalized Patients with Covid-19.
      ]

      (1535 patients)
      ⊕⊕⊕⊖

      Moderate

      (serious imprecision)
      Difference: 32 fewer per 1000

      (95% CI: 80 fewer to 8 more)
      95% CI: 95% Confidence interval; RR: Risk ratio.
      References: [
      • Group R.C.
      • Horby P.
      • Lim W.S.
      • Emberson J.R.
      • Mafham M.
      • Bell J.L.
      • et al.
      Dexamethasone in Hospitalized Patients with Covid-19.
      ].
      Evidence adopted: Australian guidelines for the clinical care of people with COVID-19, Available at: https://app.magicapp.org/#/guideline/5477/section/80465.
      Evidence Search date: April 23 - May 11.

       Safety

      There was no significant difference between corticosteroid and SOC considering severe adverse events and superinfections. However, corticosteroids are associated with an increase in hyperglycemia. Indirect evidence of corticosteroid use in patients with similar indications has shown no difference in the incidence of gastrointestinal bleeding, superinfections, neuromuscular weakness, or neuropsychiatric effects (Table 10).

       Recommendation

      Strong recommendation for systemic corticosteroids for treatment of patients with severe and critical COVID-19 (QoE: moderate).
      Strong recommendation against the use corticosteroids to treat patients with non-severe COVID-19 (QoE: moderate).

      What is the effect of empirical antibiotic treatment on mortality in patients with severe COVID-19 compared to no treatment?

       Narrative synthesis of evidence

      Several RCTs have not found any effect of azithromycin compared with SOC [
      Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.
      ,
      • Furtado R.H.M.
      • Berwanger O.
      • Fonseca H.A.
      • Correa T.D.
      • Ferraz L.R.
      • Lapa M.G.
      • et al.
      Azithromycin in addition to standard of care versus standard of care alone in the treatment of patients admitted to the hospital with severe COVID-19 in Brazil (COALITION II): a randomised clinical trial.
      ,
      Azithromycin for community treatment of suspected COVID-19 in people at increased risk of an adverse clinical course in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial.
      ]. In the absence of RCTs assessing antibiotic use in patients with COVID-19 complicated with bacterial coinfections or secondary infections, general principles of antimicrobial stewardship should be applied [
      • Huttner B.D.
      • Catho G.
      • Pano-Pardo J.R.
      • Pulcini C.
      • Schouten J.
      COVID-19: don't neglect antimicrobial stewardship principles.
      ]. Given the low rate of bacterial coinfections, only patients with clinical or radiological suspicion of an associated bacterial infection should receive empirical antibiotics when COVID-19 is diagnosed or when hospitalization is needed.

       Recommendation

      Insufficient evidence to make a proper recommendation. Antibiotics should not be routinely prescribed in patients with COVID-19 unless bacterial coinfection or secondary infection is suspected or confirmed.

      What is the effect of convalescent plasma on mortality in patients with severe COVID-19 compared with no treatment?

       Narrative synthesis of evidence

      Nine RCTs comparing convalescent plasma with SOC in >12,800 patients with COVID-19 were considered [
      • Cadegiani F.A.
      • Goren A.
      • Wambier C.G.
      • McCoy J.
      Early COVID-19 therapy with azithromycin plus nitazoxanide, ivermectin or hydroxychloroquine in outpatient settings significantly improved COVID-19 outcomes compared to known outcomes in untreated patients.
      ,
      • Agarwal A.
      • Mukherjee A.
      • Kumar G.
      • Chatterjee P.
      • Bhatnagar T.
      • Malhotra P.
      Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial).
      ,
      • AlQahtani M.
      • Abdulrahman A.
      • Almadani A.
      • Alali S.Y.
      • Al Zamrooni A.M.
      • Hejab A.H.
      • et al.
      Randomized controlled trial of convalescent plasma therapy against standard therapy in patients with severe COVID-19 disease.
      ,

      Avendaño-Solà C, Ramos-Martínez A, Muñez-Rubio E, Ruiz-Antorán B, Malo de Molina R, Torres F, et al. Convalescent Plasma for COVID-19: A multicenter, randomized clinical trial 2020 [Available from: https://www.medrxiv.org/content/10.1101/2020.08.26.20182444v3.

      ,
      • Gharbharan A.
      • Jordans C.C.E.
      • GeurtsvanKessel C.
      • den Hollander J.G.
      • Karim F.
      • Mollema F.P.N.
      • et al.
      Effects of potent neutralizing antibodies from convalescent plasma in patients hospitalized for severe SARS-CoV-2 infection.
      ,
      • Wang D.
      • Ju X.L.
      • Xie F.
      • Lu Y.
      • Li F.Y.
      • Huang H.H.
      • et al.
      [Clinical analysis of 31 cases of 2019 novel coronavirus infection in children from six provinces (autonomous region) of northern China].
      ,
      • Libster R.
      • Perez Marc G.
      • Wappner D.
      • Coviello S.
      • Bianchi A.
      • Braem V.
      • et al.
      Early High-Titer Plasma Therapy to Prevent Severe Covid-19 in Older Adults.
      ,
      • Rasheed A.M.
      • Fatak D.F.
      • Hashim H.A.
      • Maulood M.F.
      • Kabah K.K.
      • Almusawi Y.A.
      • et al.
      The therapeutic potential of convalescent plasma therapy on treating critically-ill COVID-19 patients residing in respiratory care units in hospitals in Baghdad, Iraq.
      ,
      • Simonovich V.A.
      • Burgos Pratx L.D.
      • Scibona P.
      • Beruto M.V.
      • Vallone M.G.
      • Vazquez C.
      • et al.
      A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia.
      ]. Convalescent plasma did not confer a benefit compared with SOC in 28-day mortality (RR 0.93; 95% CI 0.79–1.10), need for mechanical ventilation (RR 0.98; 95% CI 0.89–1.08), or ICU admission (RR 0.75; 95% CI 0.36–1.59; Table 12). Within RECOVERY, 5795 patients received convalescent plasma and 5763 SOC; 28-day mortality was similar between groups (24% vs. 24%; RR 1.00; 95% CI 0.93–1.07; p=0.95) [
      • Cadegiani F.A.
      • Goren A.
      • Wambier C.G.
      • McCoy J.
      Early COVID-19 therapy with azithromycin plus nitazoxanide, ivermectin or hydroxychloroquine in outpatient settings significantly improved COVID-19 outcomes compared to known outcomes in untreated patients.
      ].
      Table 12GRADE evidence profile for PICO 9: convalescent plasma for COVID-19
      People:Adult patients with COVID-19 (pregnant patients excluded)

      Setting: hospitalized patients (8 studies), outpatients (1 study)

      Intervention: Convalescent plasma

      Comparison: Standard Care
      OutcomesAbsolute EffectRelative effect (95% CI)Number of studiesCertainty of the evidence (GRADE)
      Without Convalescent Plasma (Standard Care)With Convalescent Plasma
      All-cause mortality

      Within 28 days of commencing treatment
      235

      per 1000
      219

      per 1000
      RR 0.93

      (0.79 to 1.10)
      9 [
      • Agarwal A.
      • Mukherjee A.
      • Kumar G.
      • Chatterjee P.
      • Bhatnagar T.
      • Malhotra P.
      Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial).
      ,
      • AlQahtani M.
      • Abdulrahman A.
      • Almadani A.
      • Alali S.Y.
      • Al Zamrooni A.M.
      • Hejab A.H.
      • et al.
      Randomized controlled trial of convalescent plasma therapy against standard therapy in patients with severe COVID-19 disease.
      ,

      Avendaño-Solà C, Ramos-Martínez A, Muñez-Rubio E, Ruiz-Antorán B, Malo de Molina R, Torres F, et al. Convalescent Plasma for COVID-19: A multicenter, randomized clinical trial 2020 [Available from: https://www.medrxiv.org/content/10.1101/2020.08.26.20182444v3.

      ,
      • Gharbharan A.
      • Jordans C.C.E.
      • GeurtsvanKessel C.
      • den Hollander J.G.
      • Karim F.
      • Mollema F.P.N.
      • et al.
      Effects of potent neutralizing antibodies from convalescent plasma in patients hospitalized for severe SARS-CoV-2 infection.
      ,
      • Libster R.
      • Perez Marc G.
      • Wappner D.
      • Coviello S.
      • Bianchi A.
      • Braem V.
      • et al.
      Early High-Titer Plasma Therapy to Prevent Severe Covid-19 in Older Adults.
      ,
      • Rasheed A.M.
      • Fatak D.F.
      • Hashim H.A.
      • Maulood M.F.
      • Kabah K.K.
      • Almusawi Y.A.
      • et al.
      The therapeutic potential of convalescent plasma therapy on treating critically-ill COVID-19 patients residing in respiratory care units in hospitals in Baghdad, Iraq.
      ,
      • Simonovich V.A.
      • Burgos Pratx L.D.
      • Scibona P.
      • Beruto M.V.
      • Vallone M.G.
      • Vazquez C.
      • et al.
      A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia.
      ,
      • Group R.C.
      Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial.
      ,
      • Li L.
      • Zhang W.
      • Hu Y.
      • Tong X.
      • Zheng S.
      • Yang J.
      • et al.
      Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life-threatening COVID-19: A Randomized Clinical Trial.
      ].

      (12872

      patients)
      ⊕⊕⊕⊖

      Moderate

      (due to serious imprecision)
      Difference: 16 fewer per 1000

      (95% CI: 49 fewer to 24 more)
      Invasive mechanical ventilation

      Within 28 days of commencing treatment
      124

      per 1000
      122

      per 1000
      RR 0.98

      (0.89 to 1.08)
      4 [
      • Agarwal A.
      • Mukherjee A.
      • Kumar G.
      • Chatterjee P.
      • Bhatnagar T.
      • Malhotra P.
      Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial).
      ,
      • Libster R.
      • Perez Marc G.
      • Wappner D.
      • Coviello S.
      • Bianchi A.
      • Braem V.
      • et al.
      Early High-Titer Plasma Therapy to Prevent Severe Covid-19 in Older Adults.
      ,
      • Simonovich V.A.
      • Burgos Pratx L.D.
      • Scibona P.
      • Beruto M.V.
      • Vallone M.G.
      • Vazquez C.
      • et al.
      A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia.
      ,
      • Group R.C.
      Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial.
      ]

      (11898

      patients)
      ⊕⊕⊕⊕

      High
      Difference: 2 fewer per 1000

      (95% CI: 14 fewer to 10 more)
      Serious Adverse events

      Within 28 days of commencing treatment
      176

      per 1000
      218

      per 1000
      RR 1.24

      (0.81 to 1.90)
      2 [

      Avendaño-Solà C, Ramos-Martínez A, Muñez-Rubio E, Ruiz-Antorán B, Malo de Molina R, Torres F, et al. Convalescent Plasma for COVID-19: A multicenter, randomized clinical trial 2020 [Available from: https://www.medrxiv.org/content/10.1101/2020.08.26.20182444v3.

      ,
      • Simonovich V.A.
      • Burgos Pratx L.D.
      • Scibona P.
      • Beruto M.V.
      • Vallone M.G.
      • Vazquez C.
      • et al.
      A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia.
      ]

      (414

      patients)
      ⊕⊕⊖⊖

      Low

      (Very serious imprecision; wide confidence intervals, only data from one study)
      Difference: 42 more per 1000

      (95% CI: 33 fewer to 158 more)
      Adverse events

      Within 28 days of commencing treatment
      537

      per 1000
      789

      per 1000
      RR 1.47

      (0.38 to 5.74)
      2 [
      • AlQahtani M.
      • Abdulrahman A.
      • Almadani A.
      • Alali S.Y.
      • Al Zamrooni A.M.
      • Hejab A.H.
      • et al.
      Randomized controlled trial of convalescent plasma therapy against standard therapy in patients with severe COVID-19 disease.
      ,
      • Simonovich V.A.
      • Burgos Pratx L.D.
      • Scibona P.
      • Beruto M.V.
      • Vallone M.G.
      • Vazquez C.
      • et al.
      A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia.
      ]

      (370

      patients)
      ⊕⊕⊖⊖

      Low

      (risk of bias; serious imprecision; wide confidence intervals, only data from 2 study)
      Difference: 252 more per 1000

      (95% CI: 333 fewer to 2545 more)
      ICU admission

      End of follow-up
      373

      per 1000
      280

      per 1000
      RR 0.75

      (0.36 to 1.59)
      2 [
      • Libster R.
      • Perez Marc G.
      • Wappner D.
      • Coviello S.
      • Bianchi A.
      • Braem V.
      • et al.
      Early High-Titer Plasma Therapy to Prevent Severe Covid-19 in Older Adults.
      ,
      • Simonovich V.A.
      • Burgos Pratx L.D.
      • Scibona P.
      • Beruto M.V.
      • Vallone M.G.
      • Vazquez C.
      • et al.
      A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia.
      ]

      (493

      patients)
      ⊕⊕⊖⊖

      Low

      (Risk of bias serious imprecision, due to few events)
      Difference: 93 fewer per 1000

      (95% CI: 239 fewer to 220 more)
      Clinical deterioration (progression to severe/critical)

      Within 28 days of commencing treatment
      74

      per 1000
      53

      per 1000
      RR 0.71

      (0.18 to 2.78)
      2 [
      • Agarwal A.
      • Mukherjee A.
      • Kumar G.
      • Chatterjee P.
      • Bhatnagar T.
      • Malhotra P.
      Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial).
      ,

      Avendaño-Solà C, Ramos-Martínez A, Muñez-Rubio E, Ruiz-Antorán B, Malo de Molina R, Torres F, et al. Convalescent Plasma for COVID-19: A multicenter, randomized clinical trial 2020 [Available from: https://www.medrxiv.org/content/10.1101/2020.08.26.20182444v3.

      ]

      (545

      patients)
      ⊕⊕⊖⊖

      Low

      (Risk of bias serious imprecision, wide confidence intervals)
      Difference: 21 fewer per 1000

      (95% CI: 61 fewer to 132 more)
      95% CI: 95% Confidence interval; RR: Risk ratio.
      References: [
      • Agarwal A.
      • Mukherjee A.
      • Kumar G.
      • Chatterjee P.
      • Bhatnagar T.
      • Malhotra P.
      Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial).
      ,
      • AlQahtani M.
      • Abdulrahman A.
      • Almadani A.
      • Alali S.Y.
      • Al Zamrooni A.M.
      • Hejab A.H.
      • et al.
      Randomized controlled trial of convalescent plasma therapy against standard therapy in patients with severe COVID-19 disease.
      ,

      Avendaño-Solà C, Ramos-Martínez A, Muñez-Rubio E, Ruiz-Antorán B, Malo de Molina R, Torres F, et al. Convalescent Plasma for COVID-19: A multicenter, randomized clinical trial 2020 [Available from: https://www.medrxiv.org/content/10.1101/2020.08.26.20182444v3.

      ,
      • Gharbharan A.
      • Jordans C.C.E.
      • GeurtsvanKessel C.
      • den Hollander J.G.
      • Karim F.
      • Mollema F.P.N.
      • et al.
      Effects of potent neutralizing antibodies from convalescent plasma in patients hospitalized for severe SARS-CoV-2 infection.
      ,
      • Libster R.
      • Perez Marc G.
      • Wappner D.
      • Coviello S.
      • Bianchi A.
      • Braem V.
      • et al.
      Early High-Titer Plasma Therapy to Prevent Severe Covid-19 in Older Adults.
      ,
      • Rasheed A.M.
      • Fatak D.F.
      • Hashim H.A.
      • Maulood M.F.
      • Kabah K.K.
      • Almusawi Y.A.
      • et al.
      The therapeutic potential of convalescent plasma therapy on treating critically-ill COVID-19 patients residing in respiratory care units in hospitals in Baghdad, Iraq.
      ,
      • Simonovich V.A.
      • Burgos Pratx L.D.
      • Scibona P.
      • Beruto M.V.
      • Vallone M.G.
      • Vazquez C.
      • et al.
      A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia.
      ,
      • Group R.C.
      Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial.
      ,
      • Li L.
      • Zhang W.
      • Hu Y.
      • Tong X.
      • Zheng S.
      • Yang J.
      • et al.
      Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life-threatening COVID-19: A Randomized Clinical Trial.
      ].
      Evidence adopted: Australian guidelines for the clinical care of people with COVID-19, Available at: https://app.magicapp.org/#/guideline/5477/section/80436.
      Evidence Search date: April 23 - May 11.
      PLACID was a multicenter open-label RCT at 39 centers in India enrolling 464 hospitalized adults with moderate-severe COVID-19 [
      • Agarwal A.
      • Mukherjee A.
      • Kumar G.
      • Chatterjee P.
      • Bhatnagar T.
      • Malhotra P.
      Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial).
      ]. The primary outcome of progression to critical disease or all-cause mortality at 28 days after enrolment was similar between groups (risk difference 0.008; 95% CI -0.062–0.078) (RR 1.04; 95% CI 0.71–1.54).
      PlasmAr was a double-blind, placebo-controlled, multicenter trial involving 12 sites in Argentina enrolling patients with severe COVID-19 pneumonia randomized to receive convalescent plasma (n=228) or placebo (n=105). The primary outcome (clinical status 30 days after intervention) was similar between groups (OR 0.83; 95% CI 0.52–1.35; p=0.46) [
      • Simonovich V.A.
      • Burgos Pratx L.D.
      • Scibona P.
      • Beruto M.V.
      • Vallone M.G.
      • Vazquez C.
      • et al.
      A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia.
      ].
      Other smaller RCTs found no significant differences in outcomes in patients with moderate-severe [

      Avendaño-Solà C, Ramos-Martínez A, Muñez-Rubio E, Ruiz-Antorán B, Malo de Molina R, Torres F, et al. Convalescent Plasma for COVID-19: A multicenter, randomized clinical trial 2020 [Available from: https://www.medrxiv.org/content/10.1101/2020.08.26.20182444v3.

      ] or severe-critical COVID-19 [
      • AlQahtani M.
      • Abdulrahman A.
      • Almadani A.
      • Alali S.Y.
      • Al Zamrooni A.M.
      • Hejab A.H.
      • et al.
      Randomized controlled trial of convalescent plasma therapy against standard therapy in patients with severe COVID-19 disease.
      ,

      Avendaño-Solà C, Ramos-Martínez A, Muñez-Rubio E, Ruiz-Antorán B, Malo de Molina R, Torres F, et al. Convalescent Plasma for COVID-19: A multicenter, randomized clinical trial 2020 [Available from: https://www.medrxiv.org/content/10.1101/2020.08.26.20182444v3.

      ,
      • Rasheed A.M.
      • Fatak D.F.
      • Hashim H.A.
      • Maulood M.F.
      • Kabah K.K.
      • Almusawi Y.A.
      • et al.
      The therapeutic potential of convalescent plasma therapy on treating critically-ill COVID-19 patients residing in respiratory care units in hospitals in Baghdad, Iraq.
      ]. Only one study showed a benefit for convalescent plasma administered in older adult patients within 72 hours after onset of mild COVID-19 symptoms. Progression to severe COVID-19 occurred in 13 of 80 (16%) patients receiving plasma and in 25 of 80 (31%) receiving placebo (RR 0.52; 95% CI 0.29–0.94; p=0.03).

       Safety

      In general, adverse events were not increased compared to controls [
      • Cadegiani F.A.
      • Goren A.
      • Wambier C.G.
      • McCoy J.
      Early COVID-19 therapy with azithromycin plus nitazoxanide, ivermectin or hydroxychloroquine in outpatient settings significantly improved COVID-19 outcomes compared to known outcomes in untreated patients.
      ,
      • Agarwal A.
      • Mukherjee A.
      • Kumar G.
      • Chatterjee P.
      • Bhatnagar T.
      • Malhotra P.
      Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial).
      ,
      • Gharbharan A.
      • Jordans C.C.E.
      • GeurtsvanKessel C.
      • den Hollander J.G.
      • Karim F.
      • Mollema F.P.N.
      • et al.
      Effects of potent neutralizing antibodies from convalescent plasma in patients hospitalized for severe SARS-CoV-2 infection.
      ,
      • Libster R.
      • Perez Marc G.
      • Wappner D.
      • Coviello S.
      • Bianchi A.
      • Braem V.
      • et al.
      Early High-Titer Plasma Therapy to Prevent Severe Covid-19 in Older Adults.
      ]. Some studies reported higher rates of serious adverse events [
      • Simonovich V.A.
      • Burgos Pratx L.D.
      • Scibona P.
      • Beruto M.V.
      • Vallone M.G.
      • Vazquez C.
      • et al.
      A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia.
      ] or a small number of infusion-related adverse events [
      • Wang D.
      • Ju X.L.
      • Xie F.
      • Lu Y.
      • Li F.Y.
      • Huang H.H.
      • et al.
      [Clinical analysis of 31 cases of 2019 novel coronavirus infection in children from six provinces (autonomous region) of northern China].
      ,
      • Rasheed A.M.
      • Fatak D.F.
      • Hashim H.A.
      • Maulood M.F.
      • Kabah K.K.
      • Almusawi Y.A.
      • et al.
      The therapeutic potential of convalescent plasma therapy on treating critically-ill COVID-19 patients residing in respiratory care units in hospitals in Baghdad, Iraq.
      ,
      • Simonovich V.A.
      • Burgos Pratx L.D.
      • Scibona P.
      • Beruto M.V.
      • Vallone M.G.
      • Vazquez C.
      • et al.
      A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia.
      ].

       Recommendation

      Strong recommendation against use of convalescent plasma for COVID-19 (QoE: moderate for mortality, high for mechanical ventilation).

      What is the effect of remdesivir on mortality or mechanical ventilation in patients with severe COVID-19 compared to no treatment?

       Narrative synthesis of evidence

      Our analysis showed that remdesivir probably decreases death slightly in hospitalized patients who do not require ventilation [RR 0.76; 95% CI 0.57–1.02) with uncertain effects on patients undergoing ventilation [RR 1.2; 95% CI 0.98–1.78). Additionally, remdesivir may decrease the need for invasive mechanical ventilation or ECMO (RR 0.57; 95% CI 0.42–0.79; Table 13).
      Table 13GRADE evidence profile for PICO 10: remdesivir for severe COVID-19
      Remdesivir for COVID-19
      People: Patients with severe COVID-19

      Settings: Inpatients

      Intervention:Remdesivir

      Comparison:No treatment
      OutcomesAbsolute EffectRelative effect (95% CI)Number of studiesCertainty of the evidence (GRADE)
      Without RemdesivirWith Remdesivir
      All-cause mortality (hospital, no ventilation)90

      per 1000
      68

      per 1000
      RR 0.76

      (0.57 to 1.02)
      5 [
      • Pan H.
      • Peto R.
      • Henao-Restrepo A.M.
      • Preziosi M.P.
      • Sathiyamoorthy V.
      • Abdool Karim Q.
      • et al.
      Repurposed Antiviral Drugs for Covid-19 - Interim WHO Solidarity Trial Results.
      ,
      • Wang Y.
      • Zhang D.
      • Du G.
      • Du R.
      • Zhao J.
      • Jin Y.
      • et al.
      Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial.
      ,
      • Beigel J.H.
      • Tomashek K.M.
      • Dodd L.E.
      • Mehta A.K.
      • Zingman B.S.
      • Kalil A.C.
      • et al.
      Remdesivir for the Treatment of Covid-19 - Final Report.
      ,
      • Spinner C.D.
      • Gottlieb R.L.
      • Criner G.J.
      • Arribas Lopez J.R.
      • Cattelan A.M.
      • Soriano Viladomiu A.
      • et al.
      Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19: A Randomized Clinical Trial.
      ,
      • Goldman J.D.
      • Lye D.C.B.
      • Hui D.S.
      • Marks K.M.
      • Bruno R.
      • Montejano R.
      • et al.
      Remdesivir for 5 or 10 Days in Patients with Severe Covid-19.
      ,
      • Mahajan L.
      • Singh A.P.
      • Gifty
      Clinical outcomes of using remdesivir in patients with moderate to severe COVID-19: A prospective randomised study.
      ]

      (6,400 patients)
      ⊕⊕⊕⊖

      Moderate

      (Due to serious imprecision)
      Difference: 22 fewer per 1000

      (95% CI: 39 fewer to 2 more)
      All-cause mortality (ventilation)248

      per 1000
      298

      per 1000
      RR 1.2

      (0.98 to 1.47)
      3 [
      • Pan H.
      • Peto R.
      • Henao-Restrepo A.M.
      • Preziosi M.P.
      • Sathiyamoorthy V.
      • Abdool Karim Q.
      • et al.
      Repurposed Antiviral Drugs for Covid-19 - Interim WHO Solidarity Trial Results.
      ,
      • Wang Y.
      • Zhang D.
      • Du G.
      • Du R.
      • Zhao J.
      • Jin Y.
      • et al.
      Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial.
      ,
      • Beigel J.H.
      • Tomashek K.M.
      • Dodd L.E.
      • Mehta A.K.
      • Zingman B.S.
      • Kalil A.C.
      • et al.
      Remdesivir for the Treatment of Covid-19 - Final Report.
      ]

      (1,004 patients)
      ⊕⊕⊕⊖

      Moderate

      (Due to serious imprecision)
      Difference: 50 more per 1000

      (95% CI: 5 fewer to 117 more)
      Respiratory failure or ARDS143

      per 1000
      113

      per 1000
      RR 0.79

      (0.35 to 1.78)
      2 [
      • Wang Y.
      • Zhang D.
      • Du G.
      • Du R.
      • Zhao J.
      • Jin Y.
      • et al.
      Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial.
      ,
      • Beigel J.H.
      • Tomashek K.M.
      • Dodd L.E.
      • Mehta A.K.
      • Zingman B.S.
      • Kalil A.C.
      • et al.
      Remdesivir for the Treatment of Covid-19 - Final Report.
      ]

      (1,296 patients)
      ⊕⊕⊖⊖

      Low

      (Due to serious risk of bias and serious inconsistency)
      Difference: 30 fewer per 1000

      (95% CI: 93 fewer to 112 more)
      Invasive mechanical ventilation or ECMO (within 28 days of treatment start)225

      per 1000
      128

      per 1000
      RR 0.57

      (0.42 to 0.79)
      1 [
      • Beigel J.H.
      • Tomashek K.M.
      • Dodd L.E.
      • Mehta A.K.
      • Zingman B.S.
      • Kalil A.C.
      • et al.
      Remdesivir for the Treatment of Covid-19 - Final Report.
      ]

      (766 patients)
      ⊕⊕⊖⊖

      Low

      (Due to serious risk of bias and serious inconsistency)
      Difference: 97 fewer per 1000

      (95% CI: 131 fewer-to 47 fewer)
      Patients requiring ventilation (within 28 days of treatment start)114

      per 1000
      119

      per 1000
      RR 1.04

      (0.89 to 1.21)
      2 [
      • Wang Y.
      • Zhang D.
      • Du G.
      • Du R.
      • Zhao J.
      • Jin Y.
      • et al.
      Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial.
      ,
      • Mahajan L.
      • Singh A.P.
      • Gifty
      Clinical outcomes of using remdesivir in patients with moderate to severe COVID-19: A prospective randomised study.