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Objective
Provide a timely, rigorous and continuously updated summary of the evidence on the role of remdesivir in the treatment of patients with COVID-19.

Methods
Eligible studies were randomized trials evaluating the effect of remdesivir versus placebo or no treatment. We conducted searches in the special L·OVE (Living OVerview of Evidence) platform for COVID-19, a system that performs regular searches in databases, trial registries, preprint servers and websites relevant to COVID-19. All the searches covered the period until 25 August 2020. No date or language restrictions were applied. Two reviewers independently evaluated potentially eligible studies according to predefined selection criteria, and extracted data on study characteristics, methods, outcomes, and risk of bias, using a predesigned, standardized form. We performed meta-analyses using random-effect models and assessed overall certainty in evidence using the GRADE approach. A living, web-based version of this review will be openly available during the COVID-19 pandemic.

Results
Our search strategy yielded 574 references. Finally, we included three randomized trials evaluating remdesivir in addition to standard care versus standard care alone. The evidence is very uncertain about the effect of remdesivir on mortality (RR 0.7, 95% CI 0.46 to 1.05; very low certainty evidence) and the need for invasive mechanical ventilation (RR 0.69, 95% CI 0.39 to 1.24; very low certainty evidence). On the other hand, remdesivir likely results in a large increase in the incidence of adverse effects in patients with COVID-19 (RR 1.29, 95% CI 0.58 to 2.84; moderate certainty evidence).

Conclusions
The evidence is insufficient for the outcomes critical for making decisions on the role of remdesivir in the treatment of patients with COVID-19, so it is impossible to balance potential benefits, if there are any, with the adverse effects and costs.

PROSPERO registration number
CRD42020183384

Authors: Francisca Verdugo-Paiva[1,2], María Paz Acuña[3,4], Iván Solá[5,6,7], Gabriel Rada[1,2,8], COVID-19 L·OVE Working Group

Colaboradores:

Affiliation:
[1] Epistemonikos Foundation, Santiago, Chile
[2] UC Evidence Center, Cochrane Chile Associated Center, Pontificia Universidad Católica de Chile, Santiago, Chile
[3] Unidad de Infectología, Hospital Dr Sótero del Río, Santiago, Chile
[4] Unidad de Infectología, Hospital Clínico Dra Eloísa Díaz, La Florida, Santiago, Chile
[5] Biomedical Research Institute Sant Pau, Barcelona, Spain
[6] Iberoamerican Cochrane Centre, Barcelona, Spain
[7] CIBER Epidemiología y Salud Pública (CIBERESP)
[8] Internal Medicine Department, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile

E-mail: fverdugo@epistemonikos.org

Author address:
[1] Holanda 895
Providencia
Santiago, Chile

Citation: Verdugo-Paiva F, Acuña MP, Solá I, Rada G. Remdesivir for the treatment of COVID-19: a living systematic review. Medwave 2020;20(11):e8080 doi: 10.5867/medwave.2020.11.8080

Submission date: 28/8/2020

Acceptance date: 17/11/2020

Publication date: 9/12/2020

Origin: Not commissioned.

Type of review: Externally peer-reviewed by three reviewers, double-blind.

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1. World Health Organization. Director-General's remarks at the media briefing on 2019-nCoV on 11 February 2020. World Health Organization; 2020 [Accessed 2020 April 12]. [Internet] | Link |
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9. Siegel D, Hui HC, Doerffler E, Clarke MO, Chun K, Zhang L, et al. Discovery and Synthesis of a Phosphoramidate Prodrug of a Pyrrolo[2,1-f][triazin-4-amino] Adenine C-Nucleoside (GS-5734) for the Treatment of Ebola and Emerging Viruses. J Med Chem. 2017 Mar 9;60(5):1648-1661. | CrossRef | PubMed |
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12. US Food and Drug Administration. Coronavirus (COVID-19) Update: FDA Issues Emergency Use Authorization for Potential COVID-19 Treatment. FDA NEWS RELEASE. 2020
13. Herper M. Inside the NIH's controversial decision to stop its big remdesivir study. STAT. 2020.
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16. Verdugo F, Acuña MP, Solà I, Rada G. Remdesivir for the treatment of COVID-19: A living systematic review protocol. OSF. 2020. | CrossRef |
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19. Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019 Aug 28;366:l4898. | CrossRef | PubMed |
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23. Guyatt GH, Thorlund K, Oxman AD, Walter SD, Patrick D, Furukawa TA, et al. Preparing summary of findings tables and evidence profiles-continuous outcomes. J Clin Epidemiol. 2013 Feb;66(2):173-83. | CrossRef | PubMed |
24. Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, et al. Remdesivir for the Treatment of Covid-19 - Final Report. N Engl J Med. 2020 Nov 5;383(19):1813-1826. | CrossRef | PubMed |
25. 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. Lancet. 2020 May 16;395(10236):1569-1578. | CrossRef | PubMed |
26. Spinner CD, Gottlieb RL, Criner GJ, Arribas López JR, Cattelan AM, 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. JAMA. 2020 Sep 15;324(11):1048-1057. | CrossRef | PubMed |
27. Horby P, Lim WS, Emberson J, Mafham M, Bell J, Linsell L, et al. Effect of Dexamethasone in Hospitalized Patients with COVID-19: Preliminary Report. medRxiv. 2020.
28. Borah R, Brown AW, Capers PL, Kaiser KA. Analysis of the time and workers needed to conduct systematic reviews of medical interventions using data from the PROSPERO registry. BMJ Open. 2017 Feb 27;7(2):e012545. | CrossRef | PubMed |
29. Shojania KG, Sampson M, Ansari MT, Ji J, Doucette S, Moher D. How quickly do systematic reviews go out of date? A survival analysis. Ann Intern Med. 2007 Aug 21;147(4):224-33. | CrossRef | PubMed |
30. Coronavirus and the risks of 'speed science'. Reuters; 2020 [Accessed 2020 12 April]. [Internet] | Link |
31. Kelly SE, Moher D, Clifford TJ. Quality of conduct and reporting in rapid reviews: an exploration of compliance with PRISMA and AMSTAR guidelines. Syst Rev. 2016 May 10;5:79. | CrossRef | PubMed |
32. Elliott JH, Synnot A, Turner T, Simmonds M, Akl EA, McDonald S, et al. Introduction-the why, what, when, and how. J Clin Epidemiol. 2017 Nov;91:23-30. | CrossRef | PubMed |
33. Akl EA, Haddaway NR, Rada G, Lotfi T. Future of Evidence Ecosystem Series: Evidence synthesis 2.0: when systematic, scoping, rapid, living, and overviews of reviews come together. J Clin Epidemiol. 2020 Jul;123:162-165. | CrossRef | PubMed |

World Health Organization. Director-General's remarks at the media briefing on 2019-nCoV on 11 February 2020. World Health Organization; 2020 [Accessed 2020 April 12]. [Internet] | Link |

Hui DS, I Azhar E, Madani TA, Ntoumi F, Kock R, Dar O, et al. The continuing 2019-nCoV epidemic threat of novel coronaviruses to global health - The latest 2019 novel coronavirus outbreak in Wuhan, China. Int J Infect Dis. 2020 Feb;91:264-266. | CrossRef | PubMed |

Dong E, Du H, Gardner L. An interactive web-based dashboard to track COVID-19 in real time. Lancet Infect Dis. 2020 May;20(5):533-534. | CrossRef | PubMed |

Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020 Apr 30;382(18):1708-1720. | CrossRef | PubMed |

Tavakoli A, Vahdat K, Keshavarz M. Novel Coronavirus Disease 2019 (COVID-19): An Emerging Infectious Disease in the 21st Century. BPUMS. 2020;22(6):432-450. | CrossRef |

Li LQ, Huang T, Wang YQ, Wang ZP, Liang Y, Huang TB, COVID-19 patients' clinical characteristics, discharge rate, and fatality rate of meta-analysis. J Med Virol. 2020 Jun;92(6):577-583. | CrossRef | PubMed |

Global Covid-19 Case Fatality Rates. UK: Centre for Evidence-Based Medicine [Accessed 2020 12 April]. [Internet] | Link |

Rodriguez-Morales AJ, Cardona-Ospina JA, Gutiérrez-Ocampo E, Villamizar-Peña R, Holguin-Rivera Y, Escalera-Antezana JP, et al. Clinical, laboratory and imaging features of COVID-19: A systematic review and meta-analysis. Travel Med Infect Dis. 2020 Mar-Apr;34:101623. | CrossRef | PubMed |

Siegel D, Hui HC, Doerffler E, Clarke MO, Chun K, Zhang L, et al. Discovery and Synthesis of a Phosphoramidate Prodrug of a Pyrrolo[2,1-f][triazin-4-amino] Adenine C-Nucleoside (GS-5734) for the Treatment of Ebola and Emerging Viruses. J Med Chem. 2017 Mar 9;60(5):1648-1661. | CrossRef | PubMed |

Sheahan TP, Sims AC, Graham RL, Menachery VD, Gralinski LE, Case JB, et al. Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci Transl Med. 2017 Jun 28;9(396):eaal3653. | CrossRef | PubMed |

Williamson BN, Feldmann F, Schwarz B, Meade-White K, Porter DP, Schulz J, et al. Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2. Nature. 2020 Sep;585(7824):273-276. | CrossRef | PubMed |

US Food and Drug Administration. Coronavirus (COVID-19) Update: FDA Issues Emergency Use Authorization for Potential COVID-19 Treatment. FDA NEWS RELEASE. 2020

Herper M. Inside the NIH's controversial decision to stop its big remdesivir study. STAT. 2020.

Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol. 2009 Oct;62(10):1006-12. | CrossRef | PubMed |

Rada G, Verdugo-Paiva F, Ávila C, Morel-Marambio M, Bravo-Jeria R, Pesce F, et al. Evidence synthesis relevant to COVID-19: a protocol for multiple systematic reviews and overviews of systematic reviews. Medwave. 2020 Apr 1;20(3):e7868. | CrossRef | PubMed |

Verdugo F, Acuña MP, Solà I, Rada G. Remdesivir for the treatment of COVID-19: A living systematic review protocol. OSF. 2020. | CrossRef |

Github repository [Accessed 2020 3 April]. [Internet] | Link |

Methods for the special L·OVE of Coronavirus infection. Santiago: Epistemonikos Foundation [Accessed 2020 3 April]. [Internet] | Link |

Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019 Aug 28;366:l4898. | CrossRef | PubMed |

Review Manager (RevMan) [Software]. Version 5.3.5 Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.

Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008 Apr 26;336(7650):924-6. | CrossRef | PubMed |

Guyatt GH, Oxman AD, Santesso N, Helfand M, Vist G, Kunz R, et al. GRADE guidelines: 12. Preparing summary of findings tables-binary outcomes. J Clin Epidemiol. 2013 Feb;66(2):158-72. | CrossRef | PubMed |

Guyatt GH, Thorlund K, Oxman AD, Walter SD, Patrick D, Furukawa TA, et al. Preparing summary of findings tables and evidence profiles-continuous outcomes. J Clin Epidemiol. 2013 Feb;66(2):173-83. | CrossRef | PubMed |

Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, et al. Remdesivir for the Treatment of Covid-19 - Final Report. N Engl J Med. 2020 Nov 5;383(19):1813-1826. | CrossRef | PubMed |

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. Lancet. 2020 May 16;395(10236):1569-1578. | CrossRef | PubMed |

Spinner CD, Gottlieb RL, Criner GJ, Arribas López JR, Cattelan AM, 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. JAMA. 2020 Sep 15;324(11):1048-1057. | CrossRef | PubMed |

Horby P, Lim WS, Emberson J, Mafham M, Bell J, Linsell L, et al. Effect of Dexamethasone in Hospitalized Patients with COVID-19: Preliminary Report. medRxiv. 2020.

Borah R, Brown AW, Capers PL, Kaiser KA. Analysis of the time and workers needed to conduct systematic reviews of medical interventions using data from the PROSPERO registry. BMJ Open. 2017 Feb 27;7(2):e012545. | CrossRef | PubMed |

Shojania KG, Sampson M, Ansari MT, Ji J, Doucette S, Moher D. How quickly do systematic reviews go out of date? A survival analysis. Ann Intern Med. 2007 Aug 21;147(4):224-33. | CrossRef | PubMed |

Coronavirus and the risks of 'speed science'. Reuters; 2020 [Accessed 2020 12 April]. [Internet] | Link |

Kelly SE, Moher D, Clifford TJ. Quality of conduct and reporting in rapid reviews: an exploration of compliance with PRISMA and AMSTAR guidelines. Syst Rev. 2016 May 10;5:79. | CrossRef | PubMed |

Elliott JH, Synnot A, Turner T, Simmonds M, Akl EA, McDonald S, et al. Introduction-the why, what, when, and how. J Clin Epidemiol. 2017 Nov;91:23-30. | CrossRef | PubMed |

Akl EA, Haddaway NR, Rada G, Lotfi T. Future of Evidence Ecosystem Series: Evidence synthesis 2.0: when systematic, scoping, rapid, living, and overviews of reviews come together. J Clin Epidemiol. 2020 Jul;123:162-165. | CrossRef | PubMed |