key: cord-0807012-shbjksrw authors: Pimentel, Juan; Laurie, Cassandra; Cockcroft, Anne; Andersson, Neil title: Clinical studies assessing the efficacy, effectiveness and safety of remdesivir in management of COVID‐19: A scoping review date: 2020-12-15 journal: Br J Clin Pharmacol DOI: 10.1111/bcp.14677 sha: ab64d45da85484eaf826a57794cc1998c0a12255 doc_id: 807012 cord_uid: shbjksrw AIMS: Remdesivir is 1 of the repurposed drugs under investigation to treat patients with COVID‐19. Clinicians and decision‐makers need a summary of the most recent evidence. This scoping review maps the evidence on the efficacy, effectiveness and safety of remdesivir for patients with COVID‐19, up to 14 September 2020. METHODS: Our scoping review searched Pubmed, Embase (Ovid), Scopus and 17 primary trial registries for empirical publications or active registered clinical trials for data on the efficacy, effectiveness, or safety of remdesivir for COVID‐19 or SARS‐CoV‐2. We conducted a narrative synthesis of the included publications. RESULTS: Seventeen empirical studies and 23 clinical trial registrations (n = 40) accumulated 46 508 participants. We found 4 published randomized–controlled trials accumulating 2293 patients. Two trials reported shorter median recovery time and better clinical status among patients who received remdesivir compared with the control groups. Observational studies report an association between remdesivir treatment and decreased mortality, as well as increased survival. The most common adverse reaction was hepatic impairment, although the trials reported a similar proportion of adverse events in the intervention and control groups. CONCLUSION: Remdesivir might shorten the time to clinical improvement among hospitalized adults with severe COVID‐19. Trial data report a similar proportion of adverse events in treated and control groups. The results of the 23 registered active trials, including more than 30 000 participants, will shed light on the efficacy and safety of the antiviral. The findings of the remaining clinical trials expected to report results in 2020 will allow a quantitative synthesis of available evidence. SARS-CoV and MERS-CoV. 7, 8 Remdesivir is intracellularly metabolized into an adenosine analogue that combines with nascent viral RNA chains producing pre-mature termination of RNA transcription. 9 Several clinical studies report compassionate use of remdesivir to treat patients with COVID-19. [10] [11] [12] Beigel et al. 13 oxygen saturation ≤94% on room air to receive the drug. 14 On 7 May, the government of Japan approved remdesivir for treatment of patients with COVID-19. 15 On 25 June, the European Medicines Agency granted a conditional market authorization for the drug to treat patients from age 12 years with COVID-19 pneumonia who require supplemental oxygen. 16 Real-time dissemination of reliable information is key to guiding front-line clinicians managing patients, epidemiologists, epidemic modellers and decision-makers working to control the COVID-19 pandemic and to address public panic. 17 Two systematic reviews have explored the efficacy, effectiveness and safety of remdesivir for patients with COVID-19. 18, 19 This, however, is the first scoping review assessing the efficacy, effectiveness and safety of remdesivir in management of COVID-19. Compared with systematic reviews, scoping reviews typically address broader research questions, seeking to examine the extent, range and nature of the research activity on a research area. 2 This approach allows identification of research gaps in the existing literature, which is critical to inform ongoing research in a rapidly evolving landscape such as COVID-19 research. 3 Our scoping review aimed to map the extent and nature of the evidence on the efficacy, effectiveness, and safety of remdesivir for patients with COVID-19, up to 14 September 2020. Our inclusion criteria were as follows: (i) empirical publications (case series, observational and experimental studies) or active randomized controlled trial registrations; (ii) the objective of the study was to investigate efficacy, effectiveness or safety of remdesivir; (iii) the disease was COVID-19; and (iv) the language was English, Spanish, French, Italian or Portuguese. We excluded publications that did not fulfil all inclusion criteria, such as single case reports. We searched in Pubmed, Embase (Ovid), and Scopus, using Boolean operators, truncators, and search terms according to each database. Clinical Trials Registry (SLCTR). These trial registries meet criteria for quality and validity, content, unique identification, accessibility, technical capacity and administration, as well as the criteria of the International Committee of Medical Journal Editors. 24 Two independent reviewers (C.L. and J.P.) performed the initial title and abstract screening using the open-source systematic review application Rayyan. 25 They resolved discrepancies by discussion and consensus. They retrieved the full-text format of the included documents, removed duplicates using Endnote X8.2, and performed the final selection of studies using an eligibility format based on the inclusion criteria. Charting the included studies is a "technique for synthesizing and interpreting qualitative data by sifting, categorizing, and sorting material according to key issues and themes." 20 Through regular meetings, we developed and adjusted the data charting form based on the variables that would answer our research question. We piloted the form with 5% of the studies and registries. The data extraction form is available in Supporting information 2. We extracted the following data from eligible studies: authors; type of study (case series, observational, experimental); aim; sample size; inclusion criteria; remdesivir scheme; primary outcome; main findings; and reported adverse events. In the case of the clinical trial registries, we extracted the trial identifier, recruitment status, trial design, country, sample size, intervention and control details, primary outcome, date registered or start date, and anticipated end date. We generated a narrative synthesis of the main results and created tables to display an overview of the included studies. In this article, we adhered to the PRISMA extension for reporting scoping reviews (PRISMA-ScR) 26 (Appendix 2). Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, and are permanently archived in the Concise Guide to PHARMACOLOGY 2019/20. 27 We included 17 empirical studies. which accumulated 8696 patients and 23 clinical trial registrations, which will accumulate at least 37 812 participants. (Figure 1 and Appendix 3). Among the empirical studies, we found 2 completed randomized-controlled trials (RCTs), 28,29 a preliminary report of an RCT, 13 an RCT that was prematurely stopped, 30 Shih et al. 32 reanalysed the data from Wang et al. 30 using a "more powerful and clinically meaningful method," focusing their analysis on patients whose condition was not critically severe. The authors reported a response rate of 85% among those in the intervention group who were in the moderately severe category at baseline, and 70% for the placebo group on day 28 (odds ratio [OR] = 2.38, P = .0012). They suggested that remdesivir should be provided to hospitalized patients as early as possible. Goldman et al. 28 Spinner et al. 29 published the first trial exploring the efficacy of 5 or 10 days of remdesivir treatment against standard care on the clinical status of adults with moderate pneumonia (oxygen saturation >94% on room air). The authors found a statistically significant difference among patients randomized to a 5-day course of the antiviral compared with standard care, but concluded that "the difference was of uncertain clinical importance." Additionally, patients in the 10-day group did not show a significant difference compared with standard care at day 11 of treatment. Nausea, hypokalaemia and headache were more frequent in the treated group compared with standard care. Table 1 shows the characteristics of the trials included in our study. At the time of reporting, there are 13 trials registered in the USA, 7 in Europe, and 1 each in Iran, UK and Japan. The trials include 37 812 participants. One registered trial (ISRCTN83971151) did not specify the sample size but is planning to recruit "several thousand" participants. The biggest trial (NCT04501978) is a multicentre trial in US sites, planning to recruit 10 000 participants. Eleven trials will include more than 1 country, with 1 trial (ISRCTN83971151) including 23 countries. Five trials will evaluate remdesivir exclusively, and 11 will include additional arms evaluating chloroquine, hydroxychloroquine, lopinavir plus ritonavir, and/or interferon. One trial, however, recently discontinued the additional arms (NCT04315948). Other drugs being tested, typically in combination with remdesivir, include merimepodib, tocilizumab, baricitinib, cenicriviroc, icatibant, razuprotafib, apremilast, LY3819253, methylprednisolone, losartan, convalescent serum, azithromycin, doxycycline, clindamycin, and primaquine (n = 6). One study will explore inhaled remdesivir (NCT04539262). Nine trials explicitly stated an arm would include remdesivir and standard care. The remaining trials did not specify patients would receive standard care. Regarding the control group, 9 trials will use standard care for COVID-19, 4 trials will use a placebo drug (either aerosolized, intravenous or tablet form), 1 trial will use standard care and placebo, and for the remaining 9 studies, the comparator arm is another drug. For the primary outcome, 10 trials will evaluate patient mortality, A panel of international experts reporting in July 2020 44 The preliminary evidence of positive results of remdesivir treatment for patients with COVID-19 raises a concern that available doses will not be enough to cover a global demand. 46 The USA recently purchased almost all supplies of this antiviral available worldwide. 47 Two observational studies are consistent with an association between remdesivir treatment and decreased mortality. 40 The Compared with available reviews, 44 NA Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally using a flow diagram. Characteristics of sources of evidence WHO Director-General's opening remarks at the media briefing on COVID-19 Quarantine alone or in combination with other public health measures to control COVID-19: a rapid review. 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[mp = title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword coronavirus disease 2019 or severe acute respiratory syndrome coronavirus 2).sh,dj OR "SARS2" OR "SARS-CoV-2" OR "SARS-CoV-19" OR "COVID-19" OR ("severe acute respiratory" AND "pneumonia outbreak*") OR PRISMA Extension for Scoping Reviews (PRISMA-ScR): Checklist and Explanation Remdesivir for 5 or 10 Days in Patients with Severe Covid-19 Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19 Remdesivir for the Treatment of Covid-19 -Preliminary Report Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial Remdesivir for Severe COVID-19 versus a Cohort Receiving Standard of Care Remdesivir is Effective for Moderately Severe Patients: A Re-Analysis of the First Double-Blind, Placebo-Controlled, Randomized Trial on Remdesivir for Treatment of Severe COVID-19 Patients Conducted in Wuhan City Clinical Experience with Use of Remdesivir in the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2: a Case Series Case report study of the first five COVID-19 patients treated with remdesivir in France Compassionate use of remdesivir for treatment of severe coronavirus disease 2019 in pregnant women at a United States academic center Liver injury in remdesivirtreated COVID-19 patients Early experience with remdesivir in SARS-CoV-2 pneumonia. Infection Use of remdesivir for pregnant patients with severe novel coronavirus disease Hepatic Disorders With the Use of Remdesivir for Coronavirus Utilization of COVID-19 treatments and clinical outcomes among patients with cancer: A COVID-19 and Cancer Consortium (CCC19) cohort study. Cancer Discov Compassionate Use of Remdesivir for Patients with Severe Covid-19 Effectiveness of remdesivir in patients with COVID-19 under mechanical ventilation in an Italian ICU Compassionate remdesivir treatment of severe Covid-19 pneumonia in intensive care unit (ICU) and Non-ICU patients: Clinical outcome and differences in post_treatment hospitalisation status Genevieve Gore provided advice for conducting the systematic literature search. No competing financial interests exist. *We used the terms ("remdesivir*" OR "GS 5734" OR "GS5734" OR "compound 4b" OR "D11472")