key: cord-264462-4vfk99f5 authors: Piscoya, A.; Ng-Sueng, L. F.; Parra del Riego, A.; Cerna-Viacava, R.; Pasupuleti, V.; Roman, Y. M.; Thota, P.; White, C. M.; Hernandez, A. V. title: Efficacy and harms of remdesivir for the treatment of COVID-19: a systematic review and meta-analysis date: 2020-05-27 journal: nan DOI: 10.1101/2020.05.26.20109595 sha: doc_id: 264462 cord_uid: 4vfk99f5 Background: We evaluated the efficacy and safety of remdesivir for the treatment of COVID-19. Methods: Systematic review in five engines, pre-print webpages and RCT registries until May 22, 2020 for randomized controlled trials (RCTs) and observational studies evaluating remdesivir on confirmed, COVID-19 adults with pneumonia and/or respiratory insufficiency. Primary outcomes were all-cause mortality, clinical improvement or recovery, need for invasive ventilation, and serious adverse events (SAE). Secondary outcomes included length of hospital stay, progression of pneumonia, and adverse events (AE). Inverse variance random effects meta-analyses were performed. Results: Two placebo-controlled RCTs (n=1300) and two case series (n=88) were included. All studies used remdesivir 200mg IV the first day and 100mg IV for 9 more days, and followed up until 28 days. Wang et al. RCT was stopped early due to AEs; ACTT-1 was preliminary reported at 15-day follow up. Time to clinical improvement was not decreased in Wang et al. RCT, but median time to recovery was decreased by 4 days in ACTT-1. Remdesivir did not decrease all-cause mortality (RR 0.71, 95%CI 0.39 to 1.28) and need for invasive ventilation at 14 days (RR 0.57, 95%CI 0.23 to 1.42), but had fewer SAEs (RR 0.77, 95%CI 0.63 to 0.94). AEs were similar between remdesivir and placebo arms. Risk of bias ranged from some concerns to high risk in RCTs. Interpretation: There is paucity of adequately powered and fully reported RCTs evaluating effects of remdesivir in adult, hospitalized COVID-19 patients. Remdesivir should not be recommended for the treatment of severe COVID-19. Coronavirus Disease 2019 (COVID- 19) , has caused millions of infections and hundreds of thousands of deaths worldwide. 1 COVID-19 has more severe manifestations in older populations with chronic diseases such as obesity, hypertension, diabetes, and chronic kidney disease. 2 In the absence of an effective vaccine, medication to reduce the severity of COVID-19 manifestations is desperately needed. While many drugs are under investigation, no drugs have demonstrated efficacy in randomized controlled trials (RCTs) with a reasonable safety profile. 3 The nucleotide analogue, remdesivir, inhibits RNA polymerase limiting viral replication. 4, 5 It was originally developed to treat Ebola but promising in vitro effects were not translated into acceptable clinical efficacy. Remdesivir has shown antiviral effects on coronaviruses in vitro and a recent study in monkeys infected with COVID-19 showed that remdesivir significantly reduced pulmonary damage when administered early. 4, 6 On May 1 st 2020, the Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for remdesivir in severe, hospitalized COVID-19 patients; valid for one year. 7 Giving this promising designation, we systematically evaluated the human studies assessing the efficacy and safety of remdesivir for the treatment of COVID-19. We performed a systematic review of RCTs and observational studies (cohort studies, case series) evaluating the effects of remdesivir in adult hospitalized COVID-19 confirmed patients. A comprehensive literature search was conducted in PubMed, Web of Science, Scopus, Embase and the Cochrane Library. The search was broadened for preprints at medRxiv.org, and for records of ongoing remdesivir RCTs at www.ClinicalTrials.gov, www.who.int/ictrp/about/en/, and www.clinicaltrialsregister.eu/. A special twitter search was performed using the advanced search setting. Databases were searched on May 5 th , 2020 and updated on May 22 nd , 2020. Search strategies were adjusted for each engine using the following combination of keywords: remdesivir AND (COVID-19 OR coronavirus OR coronavirus disease OR coronavirus disease-19 OR severe acute respiratory syndrome OR SARS-CoV-2) with no limitations for time or language. The PubMed strategy is included in the Supplement. Included studies specified remdesivir dosage and duration with at least one efficacy or harm outcome. We excluded studies All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 27, 2020 Assessment of risk of bias was performed independently by two investigators (VP, AVH) using the Cochrane RoB 2.0 tool 8 for RCTs, and ROBINS-I tool 9 for cohort studies with a third All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 27, 2020. . https://doi.org/10.1101/2020.05.26.20109595 doi: medRxiv preprint reviewer (AP) resolving discrepancies when needed. Case series lack a control group and cannot evaluate efficacy or harmful effects so risk of bias cannot be conducted. We reported our systematic review according to 2009 PRISMA guidelines. 10 Effects of remdesivir on outcomes from individual studies were reported as hazard ratio (HR) or absolute risk difference (ARD) and their 95 confidence intervals (CIs) for dichotomous outcomes and mean differences (MD) and their 95%CIs for continuous outcomes. Inverse variance random effect meta-analyses were performed when outcome data was available for at least two studies judged to be homogeneous about study characteristics. Between study variance tau 2 was calculated with the Paule-Mandel method. Effects of meta-analyses were reported as RRs and their 95%CIs, and heterogeneity of effects among studies was quantified with the I 2 statistic (an I 2 >60% means high heterogeneity of effects). Because this was a systematic review of published studies, no patients were involved in setting the research question or the outcome measures; thus, no ethics approval was required. We identified 612 records in our searches. After removing duplicates, 553 articles were screened for eligibility by reviewing titles and abstracts. Among the records screened, 544 were excluded and nine full-text articles were further assessed for eligibility ( Figure 1 ). Review of full text articles led to the exclusion of five articles due to: duplicated data (n=3), remdesivir efficacy or safety was not the main aim of study (n=1), and no outcomes for patients receiving remdesivir (n=1). Two RCTs (n=1300) and two case series (n=88) were included in the final analysis. 11, 12, 13, 14 One remdesivir RCT planned to be performed in China for patients with mild and moderate COVID-19 (NCT04252664) was suspended on April 15 th 2020 because no eligible patients could be enrolled to the study. 15 Characteristics of four included studies are shown in Table 1 . All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. remdesivir 200 mg on day one, followed by 100mg IV once-daily for nine more days vs. placebo in adults with RT-PCR confirmed SARS-CoV-2 infection, pneumonia, and respiratory insufficiency in Wuhan, China (Table 1) . 11 The primary outcome was the time to clinical improvement within 28 days after randomization or discharged alive from the hospital, whichever came first. Clinical improvement was defined as a decline of two points using a 6point ordinal severity scale (Table 1 ). This scale was modified from a 7-point ordinal severity scale used by the lopinavir/ritonavir RCT by Cao et al, 16 which has been used in previous influenza studies by Wang. et Due to higher occurrence of AEs leading to drug discontinuation vs. placebo (12% vs 5%), the trial was stopped early, with 236 recruited patients and a statistical power of 56%. Authors mentioned that they followed specific termination criteria, but the criteria are not available in the protocol. 19 Some imbalances existed at enrollment between arms, including more patients with hypertension, diabetes, or coronary artery disease in the remdesivir arm. Also, more patients in the control group than in the remdesivir arm had been symptomatic for ≤ 10 days at the time of starting remdesivir or placebo treatment. The multicenter Beigel et al. ACTT-1 RCT (NCT04280705) evaluated remdesivir 200 mg IV on day 1, followed by a 100mg IV once-daily for nine more days vs. placebo in adults with RT-PCR confirmed SARS-CoV-2 infection, pneumonia, and respiratory insufficiency (Table 1) . 12, 20 According to historical changes made to the trial at clinicaltrials.gov, on February 20 th 2020, its primary outcome was the percentage of subjects reporting each severity rating on the aforementioned 7-point ordinal scale from Cao et al at 15 days. 16 On March 20 th 2020, the primary outcome was changed to a new 8-point ordinal severity scale, in which a subdivision was made on hospitalized patients (i.e. 5=hospitalized, not requiring supplemental oxygenrequiring ongoing medical care, and 6=hospitalized, not requiring supplemental oxygen -no longer requires ongoing medical care) ( Table 1) . 16 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 27, 2020. . https://doi.org/10.1101/2020.05.26.20109595 doi: medRxiv preprint On March 22 nd 2020, blinded statisticians recommended changing again the outcome to time to recovery, which was defined as the first day during the 28 days after enrollment on which a patient satisfied category 1, 2 or 3 in the 8-point category scale. 12 This trial was stopped on April 29 th 2020, given that its safety monitoring board decided to release preliminary results, pointing out that the primary efficacy endpoint had been achieved. 21 At that moment, 1063 had been recruited, and 482 recoveries (exceeding the number needed for the trial) and 81 deaths had been entered to the database. 12 No substantial imbalances in baseline characteristics were observed between the remdesivir group and the placebo group. The case series by Grein et al 13 was conducted on a multinational basis. All 53 patients received remdesivir 200 mg IV on day one, followed by a 100mg IV once-daily for nine more days as compassionate use in RT-PCR confirmed COVID-19 patients, with oxygen saturation <94%, and a follow up of 28 days. Clinical improvement (live discharge from the hospital, a decrease of at least two points from baseline on the modified 6-point ordinal severity scale) 18 and key clinical events (changes in oxygen support, AEs, discharge, deaths) were recorded. In this study, the mean age was 64 (48 to 71) years and 75% were male. About 60% patients had hypertension, diabetes, hyperlipidemia and asthma and most of patients were either on low flow oxygen support or invasive ventilation (i.e. categories 3 and 5 from the 6-point scale). patients, with oxygen saturation <94% or mechanically ventilated or NEWS2 score ≥ 4. 14 Patients received a loading IV dose of 200 mg of remdesivir on day one and then 100 mg IV daily dose through day two to ten to assess changes on patient hospitalization status on day 10 and 28. They used the 7-point ordinal severity scale used by Cao et al. 16 In this study, the median age was 63 (51 to 69) years with 74% male, and 9% had diabetes, 34% hypertension, 9% obesity and 3% cancer. Eighteen patients were in the ICU and 17 patients in an infectious disease ward. We merged the 6-point severity scale used in Wang et al. and the 8-point severity scale used in Beigel et al. into 5 ordinal categories (outpatient; hospitalized, non-oxygen user; hospitalized, oxygen user non-invasive; hospitalized, invasive ventilation; and death). There was no reduction All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 0.63 to 0.94) ( Figure S1 ). In ACCT-1, SAE were present in 21.1% vs. 27% in remdesivir and placebo, respectively. The most common SAEs were acute respiratory failure, hypotension, viral pneumonia and acute kidney injury, more frequent in the placebo arm. Grein et al. reported 23% of SAE, most commonly multiple organ failure, septic shock, kidney injury and hypotension with an 8% drug discontinuation rate. 13 There was no effect of remdesivir in hospitalization without oxygen or with oxygen support/noninvasive ventilation in both RCTs ( Figures S2 and S3 ). There was a higher proportion of discharged patients with remdesivir ( Figure S4 ), and there was no different in treatment discontinuation ( Figure S5 ). There was no difference in AEs in the two RCTs (RR 0.94, 95%CI 0.81 to 1.10) ( Figure S6 ). No effect of remdesivir was found on specific AEs such as anemia, elevated liver enzymes, hyperbilirubinemia, hypoalbuminemia, deep vein thrombosis, pulmonary embolism or renal impairment (Figures S7 to S13). Antinori et al. reported that 23% of AE led to drug discontinuation but with no further description. 14 Grein et al reported 60% for AE and the most prevalent were elevated liver enzymes (23%), diarrhea (9%) and rash (8%). 13 Antinori et al. reported elevated liver enzymes in 43% of patients, followed by acute kidney injury (23%) and elevated bilirubin levels (20%). 14 None of the studies documented radiological progression or viral clearance at follow up. The risk of bias of each of the 2 RCTs are shown in Figure S14 (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. In adult, hospitalized, RT-PCR confirmed COVID-19 patients with respiratory insufficiency or pneumonia, there was scarce data on efficacy and safety associated with the use of 10-day remdesivir regimens. RCTs used a common treatment regimen and a true placebo control. There were substantial differences between the two case series in the magnitude of their outcomes. There were some differences in the scales used to assess outcomes across studies as shown in 12, 13 These scales were strongly correlated, and that allowed us to formally group those scale categories in five in order to perform our metaanalyses. According to the Emergency Use Authorization (EUA) by the FDA on May 1 st 2020 32 , it was reasonable to believe that remdesivir may be effective in treating COVID-19, and that, when used under the conditions described in the EUA, the known and potential benefits of remdesivir outweigh the known and potential risks of such products. This EUA allows to use remdesivir under the control of the US government, to treat adults and children with suspected or laboratory All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. ≤ 94% on room air, requiring supplemental oxygen, MV, or ECMO, in an in-hospital setting intravenously, and in doses described in the authorized Fact Sheet. 7 We need the 29-day follow up analyses of the ACTT in order to reach more definitive conclusions. Patients may ask specifically for remdesivir therapy because of the EUA and feel a failure to do so a substandard practice. Similarly, there is a risk that the benefits and harms of remdesivir will remain unknown if other remdesivir RCTs vs. placebo are stopped and substituted with trials where remdesivir becomes the standard of care and other experimental drugs are added onto remdesivir versus remdesivir alone. Our systematic review has several strengths. We ran a recent and extensive systematic search in several engines and websites, and we did not restrict by language. We found commonalities across studies: all studies were in adult, hospitalized patients with severe COVID-19, in particular with pneumonia and respiratory insufficiency. All four studies evaluated the same dose and duration of remdesivir (200 mg IV the first day and then 100mg IV qd for nine more days), and the two RCTs were compared to placebo. We also systematically searched for worldwide ongoing RCTs and ongoing systematic reviews in PROSPERO that can be found in Table 3 . Some limitations can be highlighted. First, the number of RCTs was scarce, and the reporting of the ACTT-1 is based on 15-day outcomes of the totality of recruited patients. Second, Wang et al. RCT was stopped early for presence of higher proportion of adverse events leading to drug discontinuation in an unplanned interim analysis 11 .Third, our meta-analyses for primary outcomes and secondary outcomes were based only on two RCTs; however, we used outcomes similar time points of follow up and re-categorized heterogeneous ordinal outcome scales into five categories. Finally, all studies included patients within 10 to 15 days of when symptoms began. Remdesivir antiviral activity should be the highest during the first few days of active viral multiplication, as supported by a study performed in monkeys where early administration of remdesivir prevent progression to pneumonia after SARS-CoV-2 innoculation. 6 There is paucity of adequately powered and fully reported RCTs evaluating efficacy and harms of remdesivir use in adult, hospitalized, severely-ill COVID-19 patients. One RCT was stopped early without a clear description of the reasons and the largest ACTT-1 altered their primary All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 27, 2020. . https://doi.org/10.1101/2020.05.26.20109595 doi: medRxiv preprint 1 5 Tables Table 1 . Description of characteristics of included studies Grein et al. 13 Antinori et al 14 (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. supportive care or other therapeutic methods All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 27, 2020. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 27, 2020. . https://doi.org/10.1101/2020.05.26.20109595 doi: medRxiv preprint Figure 1 3 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 27, 2020. . https://doi.org/10.1101/2020.05.26.20109595 doi: medRxiv preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 27, 2020. . https://doi.org/10.1101/2020.05.26.20109595 doi: medRxiv preprint COVID-19 Coronavirus Pandemic OpenSAFELY: factors associated with COVID-19 related hospital deaths in the linked electronic health records of 17 million adult NHS patients World Health Organization. International Clinical Trials Registry Platform (ICTRP) Current knowledge about the antivirals Remdesivir (GS-5734) and GS-441524 as therapeutic options for coronaviruses. 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