Research Remdesivir for the treatment of COVID-19: a living systematic review Francisca Verdugo-Paivaa,b,*, , María Paz Acuñac,d, , Iván Soláe,f,g, , Gabriel Radaa,b,h, , COVID-19 L·OVE Working Group a Epistemonikos Foundation, Santiago, Chile b UC Evidence Center, Cochrane Chile Associated Center, Pontificia Universidad Católica de Chile, Santiago, Chile c Unidad de Infectología, Hospital Dr Sótero del Río, Santiago, Chile d Unidad de Infectología, Hospital Clínico Dra Eloísa Díaz, La Florida, Santiago, Chile e Biomedical Research Institute Sant Pau, Barcelona, Spain f Iberoamerican Cochrane Centre, Barcelona, Spain g CIBER Epidemiología y Salud Pública (CIBERESP) h Internal Medicine Department, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile * Corresponding author fverdugo@epistemonikos.org Abstract Objective Citation Verdugo-Paiva F, Acuña MP, Solá I, Rada G, COVID-19 L·OVE Working Group. Remdesivir for the Provide a timely, rigorous and continuously updated summary of the treatment of COVID-19: a living systematic evidence on the role of remdesivir in the treatment of patients with review. Medwave 2020;20(11):e8080 COVID-19. Methods Doi 10.5867/medwave.2020.11.8080 Eligible studies were randomized trials evaluating the effect of Submission date 28/8/2020 remdesivir versus placebo or no treatment. We conducted searches in the special L·OVE (Living OVerview of Evidence) platform for Acceptance date 17/11/2020 COVID-19, a system that performs regular searches in databases, trial Publication date 09/12/2020 registries, preprint servers and websites relevant to COVID-19. All the searches covered the period until 25 August 2020. No date or Origin Not commissioned. language restrictions were applied. Two reviewers independently evaluated potentially eligible studies according to predefined selection Type of review Externally peer-reviewed by three criteria, and extracted data on study characteristics, methods, reviewers, double-blind. outcomes, and risk of bias, using a predesigned, standardized form. We performed meta-analyses using random-effect models and Keywords COVID-19, Coronavirus disease, Severe Acute assessed overall certainty in evidence using the GRADE approach. A Respiratory Syndrome Coronavirus 2, SARS-CoV-2 living, web-based version of this review will be openly available Coronavirus Infections, Systematic Review, Remdesivir, during the COVID-19 pandemic. Antivirals 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. 1 / 11 Main messages • The evidence is very uncertain about the effects of remdesivir on mortality and the need for invasive mechanical ventilation in patients with COVID-19. • Remdesivir likely results in a large increase in the incidence of adverse effects leading to discontinuation. • Remdesivir may result in little to no difference in the duration of hospitalization. • Multiple ongoing trials should shed light on the actual role of remdesivir in patients with COVID-19. Remdesivir for the treatment of COVID-19 Patients Confirmed COVID-19 Intervention Remdesivir ± standard treatment (as defined by the studies) Comparison Placebo or no treatment ± standard treatment (as defined by the studies) Relative effect Absolut effect* Certainty of (95% CI) Outcomes WITHOUT WITH Difference evidence Key messages -- Remdesivir Remdesivir (CI 95%) (GRADE) Patients/ studies The evidence is very RR 0.7 25 less uncertain about the All-cause (0.46 to 1.05) 85 60 ⊕○○○ (46 less to 4 effect of remdesivir on mortality 1879 patients in 3 per 1000 per 1000 Very low (1) more) mortality in patients studies [24,25,26] with COVID-19 The evidence is very uncertain about the RR 0.69 Invasive 36 less effect of remdesivir on (0.39 to 1.24) 116 80 ⊕○○○ mechanical (71 less to 28 the need for invasive 1659 patients in 3 study per 1000 per 1000 Very low (2) ventilation more) mechanical ventilation [24,25,26] in patients with COVID-19 Adverse RR 1.29 Remdesivir likely results effects 19 more (0.58 to 2.84) 67 86 ⊕⊕⊕○ in a large increase in the leading to (28 less to 123 1296 patients in 2 study per 1000 per 1000 Moderate (3) incidence of adverse discontinuati more) [24,25] effects on This outcome was not Time to viral -- Not reported -- -- (4) measured or reported by clearance the included studies MD 1 Remdesivir may result in 1 day less Length of (-2.86 to 4.86) ⊕⊕○○ little to no difference in 24 days 23 days (6 days less to hospital stay 236 patients in 1 study Low (5) the duration of 3 days more) [25] hospitalization RR 0.74 Serious 58 less Remdesivir likely (0.62 to 0.9) 224 166 ⊕⊕⊕○ adverse (85 less to 22 reduces the number of 1880 patients in 3 study per 1000 per 1000 Moderate (7) effects more) serious adverse effects [24,25,26] CI: confidence interval; RR: Risk ratio; MD: Mean difference; GRADE: Grading of Recommendations Assessment, Development and Evaluation. *Other trial reported length of hospital stay, but data was not usable in meta-analysis 1 - The certainty of the evidence is based in the following judgments: Risk of bias: downgraded in one level since the overall risk of bias for studies was evaluated as 'high' and 'some concerns'; Inconsistency: downgraded in one level for inconsistency since the studies show contradictory results; Indirectness: no concerns; Imprecision: downgraded in one level for imprecision since each end of the confidence interval would lead to different conclusions; Publication bias: no concerns. 2- The certainty of the evidence is based in the following judgments: Risk of bias: downgraded in one level since the overall risk of bias for studies was evaluated as 'high' and 'some concerns'; Inconsistency: no concerns; Indirectness: no concerns; Imprecision: downgraded in two levels for imprecision since each end of the confidence interval would lead to widely different conclusions; Publication bias: no concerns. 2 / 11 3- The certainty of the evidence is based in the following judgments: Risk of bias: downgraded in one level since the overall risk of bias for studies was evaluated as 'high' and 'some concerns'; Inconsistency: no concerns; Indirectness: no concerns; Imprecision: no concerns; Publication bias: no concerns. 4- The certainty of the evidence cannot be estimated since the studies did not report this outcome. It is highly likely that the outcome was measured in the studies. 5- The certainty of the evidence is based in the following judgments: Risk of bias: downgraded in one level since the overall risk of bias for studies was evaluated as 'high' and 'some concerns'; Inconsistency: no concerns; Indirectness: no concerns; Imprecision: downgraded in one level for imprecision, since each end of the confidence interval would lead to different conclusions; Publication bias: no concerns. 6- The certainty of the evidence cannot be estimated since the studies did not report this outcome. It is highly likely that the outcome was measured in the studies. 7- The certainty of the evidence is based in the following judgments: Risk of bias: downgraded in one level since the overall risk of bias for studies was evaluated as 'high' and 'some concerns'; Inconsistency: no concerns; Indirectness: no concerns; Imprecision: no concerns; Publication bias: no concerns. Introduction A protocol stating the shared objectives and methodology of multiple evidence syntheses (systematic reviews and overviews of COVID-19 is an infection caused by the SARS-CoV-2 coronavirus1. systematic reviews) to be conducted in parallel for different It was first identified in Wuhan, China, on 31 December 2019 2; questions relevant to COVID-19 was published elsewhere15. The seven months later, more than fifteen million cases of contagion had review was registered in PROSPERO with the number been identified across 188 countries 3. On 11 March 2020, the WHO CRD42020183384, and a full protocol was made available 16. characterized the COVID-19 outbreak as a pandemic1. Search strategies While the majority of cases result in mild symptoms, some might progress to pneumonia, acute respiratory distress syndrome, and Electronic searches death4-6. The case fatality rate reported across countries, settings and We used the search strategies already developed in the L·OVE age groups is highly variable, but it ranges from about 0.5% to 10%7. (Living OVerview of Evidence) platform, a system that maps the In hospitalized patients, it has been reported to be higher than 10% evidence to different research questions. The full methods to in some centers8. maintain L·OVE are described in the website, but the process to One of the strategies underway to identify effective interventions for devise the search strategies can be briefly described as: COVID-19 is repurposing drugs that have been used for the ● Identification of terms relevant to the population and treatment of other diseases. Remdesivir is among these intervention components of the search strategy, applying investigational medications. It is a directly acting antiviral agent, Word2vec technology17 to the corpus of documents available in initially developed for the treatment of Ebola virus during the 2014 Epistemonikos Database. outbreak in Western Africa9. Remdesivir displays antiviral activity ● Discussion of terms with content and methods experts to against many RNA viruses, including SARS-CoV-2, in both in vitro10 identify relevant, irrelevant and missing terms. and animal studies11. ● Creation of a sensitive boolean strategy encompassing all the Following the publication of the ACTT-1, a trial conducted by the relevant terms. National Institute of Allergy and Infectious Diseases (NIAID), the ● Iterative analysis of articles missed by the boolean strategy, and US Food and Drug Administration issued an emergency use refinement of the strategy accordingly. authorization of remdesivir for the treatment of COVID-1912. All the information in the L·OVE platform comes from a repository However, the results of ACTT-1 were questioned immediately, developed and maintained by Epistemonikos Foundation through particularly for the decision to stop it early for benefit 13. On the other the screening of different sources relevant to COVID-19. At the hand, the decision of the United States government to buy virtually time of releasing this article, this repository included more than 66 all stocks of the drug generated an urgent need for independent, 989 articles relevant to the Coronavirus disease, coming from the transparent information about the effects of remdesivir on COVID- following databases, trial registries, preprint servers and websites 19. relevant to COVID-19: Epistemonikos database, Pubmed, EMBASE, ICTRP Search Portal, Clinicaltrials.gov, ISRCTN Using innovative and agile processes, taking advantage of registry, Chinese Clinical Trial Registry, IRCT - Iranian Registry of technological tools, and resorting to the collective effort of several Clinical Trials, EU Clinical Trials Register: Clinical trials for covid- research groups, this living systematic review aims to provide a 19, NIPH Clinical Trials Search (Japan) - Japan Primary Registries timely, rigorous and continuously updated summary of the evidence Network (JPRN) (JapicCTI, JMACCT CTR, jRCT, UMIN CTR), available on the effects of remdesivir in patients with COVID-19. UMIN-CTR - UMIN Clinical Trials Registry, JRCT - Japan Registry of Clinical Trials, JAPIC Clinical Trials Information, Clinical Methods Research Information Service (CRiS), Republic of Korea, ANZCTR This manuscript complies with the 'Preferred Reporting Items for - Australian New Zealand Clinical Trials Registry, ReBec - Brazilian Systematic reviews and Meta-Analyses' (PRISMA) guidelines for Clinical Trials Registry, CTRI - Clinical Trials Registry - India, DRKS reporting systematic reviews and meta-analyses14 (see Appendix 1 - - German Clinical Trials Register, LBCTR - Lebanese Clinical Trials PRISMA Checklist). Registry, TCTR - Thai Clinical Trials Registry, NTR - The Netherlands National Trial Register,PACTR - Pan African Clinical 3 / 11 Trial Registry, REPEC - Peruvian Clinical Trial Registry,SLCTR - Sri and abstracts yielded against the inclusion criteria (Appendix 2). We Lanka Clinical Trials Registry, medRxiv Preprints, bioRxiv Preprints, obtained the full reports for all titles that appeared to meet the SSRN Preprints, WHO COVID-19 database. inclusion criteria or required further analysis and then decided about their inclusion. The last version of the methods, the total number of sources screened, and a living flow diagram and report of the project is We recorded the reasons for excluding trials in any stage of the updated regularly on the website18. search and outlined the study selection process in a PRISMA flow diagram that we adapted for the purpose of this project. The repository is continuously updated18, and the information is transmitted in real time to the L·OVE platform; however, it was last Extraction and management of data checked for this review the day before release on 25 August 2020. Using standardized forms, two reviewers independently extracted The searches covered the period from the inception date of each the following data from each included trial: study design, setting, database, and no study design, publication status, or language participant characteristics (including disease severity and age) and restriction was applied. study eligibility criteria; details about the administered intervention The following strategy was used to retrieve from the repository the and comparison, including dose, duration and timing (i.e. the time articles potentially eligible for this review: coronavir* OR after diagnosis); the outcomes assessed and the time they were coronovirus* OR betacoronavir* OR "beta-coronavirus" OR "beta- measured; the source of funding of the study and the conflicts of coronaviruses" OR "corona virus" OR "virus corona" OR "corono interest disclosed by the investigators; the risk of bias assessment for virus" OR "virus corono" OR hcov* OR covid* OR "2019-ncov" each individual study. We resolved disagreements by discussion, with OR cv19* OR "cv-19" OR "cv 19" OR "n-cov" OR ncov* OR one arbiter adjudicating unresolved disagreements. (wuhan* and (virus OR viruses OR viral)) OR sars* OR sari OR Risk of bias assessment "severe acute respiratory syndrome" OR mers* OR "middle east respiratory syndrome" OR "middle-east respiratory syndrome" OR The risk of bias for each randomized trial was assessed by using the "2019-ncov-related" OR "cv-19-related" OR "n-cov-related" AND 'risk of bias' tool (RoB 2.0: a revised tool to assess risk of bias in (remdesivir* OR "GS-5734" OR "GS 5734" OR GS5734*) randomized trials)19, considering the following domains of bias for each outcome result of all reported outcomes and time points: bias Other sources due to (1) the randomization process, (2) deviations from intended In order to identify articles that might have been missed in the interventions (effects of assignment to interventions at baseline), (3) electronic searches, we proceeded as follows: missing outcome data, (4) measurement of the outcome, and (5) selection of reported results. ● Screened the reference lists of other systematic reviews. ● Scanned the reference lists of selected guidelines, narrative Discrepancies between review authors were resolved by discussion reviews, and other documents. to reach a consensus. If necessary, a third review author was consulted to achieve a decision. Eligibility criteria Measures of treatment effect We included randomized controlled trials evaluating patients infected with SARS-CoV-2 of any severity. The intervention of For dichotomous outcomes, we expressed the estimate of the interest was remdesivir at any dosage, duration, timing or route of treatment effect of an intervention as risk ratios (RR) along with 95% administration. The comparison of interest was a placebo confidence intervals (CI). (remdesivir plus standard of care versus placebo plus standard of For continuous outcomes, we used the mean difference and care) or no treatment (remdesivir plus standard of care versus standard deviation to summarize the data along with a 95% standard of care). confidence interval. For continuous outcomes reported using Our primary outcome of interest was all-cause mortality at longest different scales, the treatment effect was expressed as a standardized follow-up. Secondary outcomes were invasive mechanical mean difference with 95% confidence interval. ventilation and adverse effects leading to discontinuation. We also Strategy for data synthesis extracted information on the following outcomes: time to viral clearance, length of hospital stay, and serious adverse effects. The results of the search and the selection of the studies is presented in the corresponding flow chart, according to recommendations of We did not consider the outcomes as an inclusion criterion during the PRISMA statement14. For any outcomes where it was not the selection process. Any article meeting all the criteria except for possible to calculate an effect estimate, a narrative synthesis is the outcome criterion was preliminarily included and assessed in full presented, describing the studies in terms of the direction and the text. size of effects, and any available measure of precision. Selection of studies For any outcomes where data were available from more than one The results of the searches in the individual sources were de- trial, we conducted a formal quantitative synthesis (meta-analysis) duplicated by an algorithm that compares unique identifiers for studies clinically homogeneous using RevMan 520 and using the (database ID, DOI, trial registry ID), and citation details (i.e. author inverse variance method with the random-effects model. We names, journal, year of publication, volume, number, pages, article assessed inconsistency by visual inspection of the forest plots and title, and article abstract). Then, the information matching the search using the I² index. strategy was sent in real-time to the classification tab in the L·OVE platform where at least two authors independently screened the titles 4 / 11 Subgroup and sensitivity analysis Results As few trials were found, we did not perform sensitivity or subgroup Results of the search analysis. We conducted searches using L·OVE (Living OVerview of Assessment of certainty of the evidence Evidence) platform for COVID-19, a system that maps PICO The certainty of the evidence for all outcomes was judged using the questions to a repository, maintained through regular searches in 27 Grading of Recommendations Assessment, Development and databases, preprint servers, trial registries and websites relevant to Evaluation working group methodology (GRADE Working COVID-19. All the searches covered the period until 25 August Group)21, across the domains of risk of bias, consistency, directness, 2020. No date or language restrictions were applied. precision and reporting bias. For the main comparisons and The search in the L·OVE platform yielded 574 records after removal outcomes, we prepared a Summary of Findings (SoF) tables 22,23. of duplicates. We considered 489 as potentially eligible and obtained Living evidence synthesis and evaluated their full texts. We finally included three randomized trials (11 references)24-26. An artificial intelligence algorithm deployed in the Coronavirus/COVID-19 topic of the L·OVE platform provides The reasons for excluding studies at the time of full-text review were instant notification of articles with a high likelihood of being eligible. the following: not a primary study in humans (398 records); wrong The authors review them, decide upon inclusion, and update the study design (51 records), wrong comparison (three records) and living web version of the review accordingly. wrong population (one record). We also identified 16 ongoing randomized trials. This review is part of a larger project set up to produce multiple parallel systematic reviews relevant to COVID-1915. The complete study selection process is summarized in the PRISMA flow chart (Figure 1) and the full list of included, excluded and ongoing trials is presented in Appendix 3. Figure 1 - PRISMA Flowchart (prepared by the authors from the study data). Description of the included studies that one of the following criteria were also fulfilled: SpO2 94% on room air. Tables 1 and 2 summarize the Table 1. Inclusion criteria of the studies. Age Setting Confirmation Clinical or severity parameters Radiological findings as method criteria ACTT-124 Adults Hospital RT-PCR One of several criteria (SpO2 94% on room air at screening) Mandatory (any radiographic children evidence of pulmonary infiltrates) All trials administered the same doses of remdesivir plus standard Two trials reported that the standard of care was determined by the care24-26. One trial included two intervention arms of remdesivir trial site hospital24. The other one only reported that concomitant (five-day and ten-day course of remdesivir)26. None of the trials use of lopinavir/ritonavir, interferons, and corticoids were provides further details regarding the standard care treatment permitted25. delivered. Table 2. Characteristics of the intervention. Intervention Dose Duration Standard care ACTT-124 Remdesivir 200 mg in 10 days All patients received supportive care according to the standard of care for the trial site hospital. day 1, If a hospital had a written policy or guideline for use of other treatments for Covid-19, patients followed by could receive those treatments. In the absence of a written policy or guideline, other 100 mg qd experimental treatment or off-label use of marketed medications intended as specific treatment for Covid-19 were prohibited from day 1 through day 29 (though such medications could have been used before enrollment in this trial). CAP-China Remdesivir 200 mg in 10 days No standard treatment was reported. Patients were permitted concomitant use of lopinavir– remdesivir day 1, ritonavir, interferons, and corticosteroids 225 followed by 100 mg qd SIMPLE 226 Remdesivir 200 mg in 5/10 days Treatment with standard of care according to local guidelines. The original protocol allowed use day 1, of other agents with presumptive activity against SARS-CoV-2 if such use was local standard followed by care. This exception was disallowed in a subsequent amendment. 100 mg qd In total, trials included 1 896 hospitalized patients 24-26. One trial was participants regarding age, gender, and chronic disease were similar conducted in China25, and the other two were multicenter trials between studies, but the number of patients requiring supplemental conducted in several countries 24,26. All trials included patients with oxygen or mechanical ventilation varied substantially between radiologically confirmed pneumonia25,26. Baseline characteristics of trials24,25. 6 / 11 Table 3. Baseline characteristics of the participants. ACTT-124 CAP-China remdesivir 225 SIMPLE 226 Number randomized 1063 237 596 Geographic location United States, Europe and China; inpatient setting United States, Europe and Asia; inpatient and setting Asia; inpatient setting setting Mean age (years) 58.9 65 57 Females (%) 35.7 41 38.8 Time from 9 10 9 onset to treatment (days) Pneumonia (%) 100 100 100 Supplemental oxygen 39.6 83 15.1 or NIRS (%) Receiving 25.6 0.3 Not reported mechanical ventilation (%) Underlying chronic 49.6% hypertension, 37% Hypertension: 72 (46%) vs 30 (38%); Diabetes:40 (25%) Cardiovascular disease: 56%, diseases obesity, 29.7% diabetes vs 16 (21%); Coronary heart disease: 15 (9%) vs 2 (3%) hypertension: 42%, Diabetes 40%, (%) Asthma: 14% Risk of bias in the included studies 2 trial overall risk of bias was "some concern" for all outcomes, because of problems in the randomization process 25. SIMPLE 2 We judge that the overall risk of bias was "high" for all outcomes overall risk of bias was some concern for all outcomes due to regarding the ACTT-1 trial24. The study was judged to raise "some deviations from intended interventions 26. Table 4 summarizes the concerns'' in deviations from the intended intervention domain and risk of bias assessments and details of each assessment are presented "high" in bias due to missing outcome data. CAP-China remdesivir in Appendix 3. Table 4. Risk of bias in the included studies assessed by ROB-2 tool. Risk of bias Risk of bias due Risk of bias Risk of bias in Risk of bias in Overall risk of arising from to deviations due to missing the the selection of bias the from the outcome data measurement the reported randomizatio intended of the outcome result n process intervention ACTT-124 Low Some concerns High Low Low High CAP-China Some concerns Low Low Low Low Some concerns remdesivir 225 SIMPLE 226 Low Some concerns Low Low Low Some concerns Efficacy of remdesivir in the treatment of patients with Primary outcome COVID-19 All-cause mortality The main results are summarized in the Summary of Findings table, All studies reported this outcome24-26 and the evidence is very uncertain presented at the beginning of the manuscript. about the effect of remdesivir on mortality (RR 0.7, 95% CI 0.46 to 1.05; very low certainty evidence). Figure 2. Relative risk for all-cause mortality for remdesivir versus standard care (prepared by the authors from the study data). 7 / 11 Secondary outcomes ical ventilation (RR 0.69, 95% CI 0.39 to 1.24; very low certainty evidence). Invasive mechanical ventilation All studies reported this outcome 24-26 and the evidence is very uncertain about the effect of remdesivir on the need for invasive mechan- Figure 3. The relative risk for invasive mechanical ventilation for remdesivir versus standard care (prepared by the authors from the study data). Adverse effects leading to discontinuation in a large increase in the incidence of adverse effects (RR 1.29, 95% CI 0.58 to 2.84; moderate certainty evidence). Two trials reported this outcome24,25 and remdesivir likely results Figure 4. The relative risk for adverse effects leading to discontinuation for remdesivir versus standard care (prepared by the authors from the study data). Time to viral clearance significant differences between the remdesivir and standard care groups in duration of hospitalization25. Quantitative synthesis This outcome was not measured or reported by the included studies. showed that remdesivir might result in little to no difference in the Length of hospital stay duration of hospitalization (MD 1, 95% CI -2.86 to 4.86; low certainty evidence). Two studies reported this outcome25,26, but only one was usable for meta analysis25. SIMPLE 2 trial reported that there were no Figure 5. The relative risk for the length of hospital stay for remdesivir versus standard care (prepared by the authors from the study data). Other outcomes the number of serious adverse effects (RR 0.74, 95% CI 0.62 to 0.9; moderate certainty evidence). Serious adverse effects All studies reported this outcome24-26 and remdesivir likely reduces 8 / 11 Figure 6. Relative risk for serious adverse effects for remdesivir versus standard care (prepared by the authors from the study data). Discussion might prove more successful in providing the scientific community and other interested parties with evidence that is actionable, rapidly We conducted a systematic review and identified three randomized and efficiently produced, up to date, and of the highest quality 33. trials that reported data on the effect of remdesivir in patients with COVID-1924-26. Even though remdesivir appears to be safe, the This review is part of a larger project set up to put such an approach evidence is very uncertain about the impact on the outcomes critical into practice. The project aims to produce multiple parallel living for decision-making in moderate and severe patients—the more systematic reviews relevant to COVID-19 following the higher relevant clinical scenario for this drug, such as mortality and need of standards of quality in evidence synthesis production15. We believe mechanical ventilation. that our methods are well suited to handle the abundance of evidence that is to come, including evidence on the role of It is unfortunate not knowing yet if one of the pharmaceutical lopinavir/ritonavir for COVID-19. interventions that have sparked more interest is effective or not. One of the limitations comes from the lack of precision of the result for During the COVID-19 pandemic, we will maintain the search and the main outcomes. The early termination of the ACTT-1 trial can selection of evidence for this review continuously updated, as well be seen as a missed opportunity in this regard 25. In addition, all the as an update when conclusions change or whenever there are trials concluded enrollment before the release of the RECOVERY substantial updates. Our systematic review aims to provide a high- trial, which showed a mortality reduction with dexamethasone 27. It quality, up-to-date synthesis of the evidence that is useful for is not clear if this factor would modify the effect, if any, of clinicians and other decision-makers. remdesivir. Notes By now, clinicians and other decision-makers are in a difficult Authorship contributions position. The pressure to act is high, particularly after the US Food All the review authors drafted and revised the manuscript, conducted article and Drug Administration issued an emergency use authorization of screening and data collection, and drafted and revised the review. remdesivir for the treatment of COVID-1912. We anticipate that the The COVID-19 L·OVE Working Group was created by Epistemonikos range of recommendations from different organizations should and a number of expert teams in order to provide decision-makers with the range between a suggestion against its use and a weak best evidence related to COVID-19. Up-to-date information about the recommendation for its use in severe cases, especially in settings group and its member organizations is available here: without resource constraints. epistemonikos.cl/working-group There are at least 46 ongoing trials that we expect will provide data Acknowledgments The members of the COVID-19 L·OVE Working Group and in the near future. Making sense of this information is not going to Epistemonikos Foundation have made it possible to build the systems and be an easy task. Systematic reviews are considered the gold standard compile the information needed by this project. Epistemonikos is a to make sense of multiple trials addressing a similar scientific collaborative effort, based on the ongoing volunteer work of over a question, but the traditional model for conducting reviews has thousand contributors since 2012. several limitations, including high demand for time and resources28 Competing interest and rapid obsolescence29. Amid the COVID-19 crisis, researchers All authors declare no financial relationships with any organization that should make their best effort to answer the urgent needs of health might have a real or perceived interest in this work. There are no other decision-makers without giving up scientific accuracy. Information relationships or activities that might have influenced the submitted work. is being produced at a vertiginous speed30, so alternative models are needed. Funding This This project was not commissioned by any organization and did not One potential solution to these shortfalls is rapid reviews, a form of receive external funding. knowledge synthesis that streamlines or omits specific methods of a Epistemonikos Foundation is providing training, support and tools at no traditional systematic review in order to move faster. Unfortunately, cost for all the members of the COVID-19 L·OVE Working Group. in many cases, this speed comes at the cost of quality 31. Furthermore, Ethics they do not solve the issue of obsolescence. Living systematic As researchers will not access information that could lead to the reviews do address that issue32. They are continually updated by identification of an individual participant, obtaining ethical approval was incorporating relevant new evidence as it becomes available, at a waived. substantial effort. So, an approach combining these two models 9 / 11 Data sharing 15. Rada G, Verdugo-Paiva F, Ávila C, Morel-Marambio M, Bravo-Jeria All data related to the project will be available. Epistemonikos Foundation R, Pesce F, et al. Evidence synthesis relevant to COVID-19: a protocol will grant access to data. for multiple systematic reviews and overviews of systematic reviews. Medwave. 2020 Apr 1;20(3):e7868. | CrossRef | PubMed | PROSPERO registration 16. Verdugo F, Acuña MP, Solà I, Rada G. Remdesivir for the treatment CRD42020183384 of COVID-19: A living systematic review protocol. OSF. 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