key: cord-0692477-w2cvmjsa authors: Qaseem, Amir; Yost, Jennifer; Etxeandia-Ikobaltzeta, Itziar; Abraham, George M.; Jokela, Janet A.; Forciea, Mary Ann; Miller, Matthew C.; Humphrey, Linda L. title: Should Remdesivir Be Used for the Treatment of Patients With COVID-19? Rapid, Living Practice Points From the American College of Physicians (Version 1) date: 2020-10-05 journal: Ann Intern Med DOI: 10.7326/m20-5831 sha: fb946c82c888aefbd414981b4b6e1c324ea8c7bb doc_id: 692477 cord_uid: w2cvmjsa These rapid and living practice points from the American College of Physicians address the effectiveness and harms of remdesivir treatment in patients with COVID-19. Remdesivir, a broad-spectrum antiviral agent administered intravenously, was developed and studied as a potential treatment for Ebola virus disease and Marburg virus infection (1) (2) (3) . In vitro and in vivo preclinical studies found antiviral activity for remdesivir against corona-like viruses, including Middle East respiratory syndrome coronavirus (4 -6) , severe acute respiratory syndrome coronavirus (SARS-CoV-1) (5), the circulating human coronaviruses HCoV-OC42 and HCoV-229E (7) , and SARS-CoV-2 (8) . Currently, the effectiveness of remdesivir is being tested as a treatment for patients infected with SARS-CoV-2 (COVID- 19) and has been authorized for emergency use for treating COVID-19, by the U.S. Food and Drug Administration (9) in the United States, and in other countries (10 -13). The American College of Physicians (ACP) Scientific Medical Policy Committee (SMPC) based these rapid and living practice points ( Table 1 ) on a systematic evidence review conducted by the U.S. Department of Veterans Affairs (VA) Evidence Synthesis Program in Minneapolis, Minnesota (14) (Appendix, available at Annals.org). This version of the practice points, based on a search completed on 3 June 2020 and updated through 31 August 2020, was approved by the ACP's Executive Committee of Board of Regents on behalf of the Board of Regents on 14 August 2020 and submitted to Annals of Internal Med-icine on 13 August 2020. Because many studies are planned or under way, literature surveillance is ongoing, with updates currently planned for every 2 months through December 2021. The target audience for these practice points includes clinicians and the public. The target patient population includes all nonpregnant patients with COVID-19. Critical and important outcomes were determined by the evidence review team in collaboration with methodological and content experts. The magnitude of the effect (such as little or no, slight, modest, or large) for critical and important outcomes was determined by applying thresholds prespecified by the evidence review team ( Table 2) . Table 3 presents clinical considerations, the Figure and Tables 4 and 5 summarize current evidence, and Table 6 identifies additional evidence gaps. Appendix Tables 1 and 2 (available at Annals.org) present the data estimates supporting the practice points. Table 4 summarizes the current evidence on the use of remdesivir in patients with moderate COVID- 19 . Overall, the current evidence points toward a net benefit for remdesivir in patients with moderate COVID-19 and suggests that a shorter treatment period (5 days) is as effective as a longer one (10 days), with no increase in harms (16). Low-certainty evidence shows that the 5-day course may be superior for mortality, recovery, and clinical improvement; however, low-certainty evidence also shows improvement for several outcomes when comparing the 10-day course to placebo. Thus, the SMPC believes that it is reasonable to consider extending treatment to 10 days for patients whose condition does not improve during the initial 5 days. Because the overall certainty of evidence is low across the comparisons, the SMPC has flagged course duration as a particular area of interest for further discussion and close monitoring. Evidence from 1 randomized controlled trial (RCT) (16) compared a 5-or 10-day course of remdesivir with standard care, although "standard care" was not defined. Among outcomes rated as critical, remdesivir (5or 10-day course) may reduce mortality slightly and result in slightly fewer serious adverse events compared with standard care (low certainty). Evidence also showed a modest increase in recovery and clinical improvement with a 5-day course, and slight increases in recovery and clinical improvement with a 10-day course, compared with standard care (low certainty). A 5-day course may also reduce time to recovery slightly (low certainty), but evidence is insufficient to make any conclusions about a 10-day course. Both courses of remdesivir (5-and 10-day) may slightly reduce the need for invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) (low certainty). However, the occurrence of any adverse events may increase with a 5-day course (slight effect) and with a 10-day course (modest effect) compared with standard care (low certainty). Evidence comparing a 5-versus 10-day course of remdesivir (16) showed that a 5-day course may reduce mortality slightly and may increase recovery (modest effect) and clinical improvement (slight effect) compared with a 10-day course (low certainty). However, evidence showed little to no difference between the 2 courses in reducing the need for invasive mechanical ventilation or ECMO (low certainty), and evidence is insufficient to show a difference in time to recovery. Evidence for potential harms showed that a 5-day course may result in fewer adverse events (any) compared with a 10-day course (modest effect), although the shorter course may not result in fewer serious adverse events (low certainty). No evidence was found for any effect on other critical outcomes (hospital length of stay) or important outcomes (time to clinical improvement, nonserious adverse events) with either course in patients with moderate COVID-19. No evidence was identified as to whether outcomes vary by symptom duration in patients with moderate COVID-19. Table 5 summarizes the current evidence on the use of remdesivir in patients with severe COVID-19 (15, 17, 18) . • Use remdesivir* for 5 days as a treatment for patients with severe † COVID-19 who do not require mechanical ventilation or extracorporeal membrane oxygenation (ECMO). • Consider extending the use of remdesivir* to 10 days in patients with severe † COVID-19 requiring mechanical ventilation or ECMO within a 5-day course. COVID-19 = coronavirus disease 2019. * Remdesivir is not recommended for patients with an alanine aminotransferase level ≥5 times the upper limit of normal or an estimated glomerular filtration rate <30 mL/min/1.73 m 2 (see further details in Table 3 ). † Within the evidence reviewed, severe COVID-19 is defined as hospitalized patients meeting ≥1 of the following criteria: radiographic infiltrates on imaging or clinical assessment, an oxygen saturation level ≤94% on room air, tachypnea (respiratory rate >24 breaths per minute without supplemental oxygen), or the need for supplemental oxygen or mechanical ventilation; moderate COVID-19 is defined as hospitalized patients with radiographic evidence of pulmonary infiltrates and oxygen saturation >94% on room air; and mild COVID-19 was not defined (14) . Use of Remdesivir to Treat COVID-19 Overall, the current evidence points toward a net benefit for a 10-day course of remdesivir in patients with severe COVID-19 (including those requiring mechanical ventilation or ECMO at baseline) compared with placebo (15, 18) . No evidence was found comparing a 5-day course of remdesivir with placebo or standard care in patients with severe COVID-19. In the absence of this direct evidence, the SMPC looked at the indirect evidence that a 5-day course is as effective as a 10-day course of remdesivir with the same, or probably fewer, potential harms in patients with severe COVID-19 not requiring mechanical ventilation or ECMO at baseline (17). In addition, the compliance data showed that a 10day course (10 doses) was used in 40.8% of patients with severe COVID-19 (including those requiring mechanical ventilation or ECMO at baseline), and 38.1% received Table 3 • Remdesivir is currently administered only by IV infusion, generally in hospital settings. • 5-d course in adults is 200 mg IV on day 1 followed by 100 mg/d for a total of 5 d (5 doses). • 10-d course in adults is 200 mg IV on day 1 followed by 100 mg/d for a total of 10 d (10 doses). • The practice points do not apply to pregnant women, because they were excluded from the studies included in the evidence review. • A greater percentage of patients with severe COVID-19 (not requiring mechanical ventilation or ECMO) treated within 10 d of symptom onset vs. after 10 d of symptom onset with a 5-or 10-d course of remdesivir were discharged from the hospital (17). • The effectiveness of a 10-d course of remdesivir in reducing time to recovery in patients with severe COVID-19 may not vary by age, sex, or race (15) . • Not enough information was reported in the studies included in the evidence review to determine what other treatment interventions, including experimental or off-label medications, were given in parallel to remdesivir. • Currently, the cost of a 5-d course of remdesivir in the United States varies from $2340 (Indian Health Services and VA) to $3120 ($520/vial) (U.S. insurers, including Medicare and Medicaid). The cost for persons without insurance is currently $390/vial (14, 19) . • The FDA recommends that clinicians assess kidney and hepatic function at baseline and during treatment (8) . The FDA recomends the following: ⅙ Not using remdesivir in patients with an eGFR <30 mL/min/1.73 m 2 . ⅙ Discontinuing the use of remdesivir if ALT levels increase to ≥5 times the upper limit of normal or any ALT elevation is accompanied by signs or symptoms of liver inflammation, or increasing conjugated bilirubin levels, alkaline phosphatase levels, or INR. • The FDA reports that hypersensitivity reactions, including infusion-related and anaphylactic reactions have been observed during and after remdesivir administration (9) . Additional adverse events include endocrine and metabolic (hyperglycemia, increased serum glucose), hepatic (increased serum ALT and AST levels), and renal (renal toxicity) events (9, 20) . The evidence search and assessment were conducted by the U.S. Department of Veterans Affairs Evidence Synthesis Program, Minneapolis, Minnesota (14) . Current search for evidence, completed on 3 June 2020, aimed to identify RCTs evaluating remdesivir for treatment of patients with COVID-19. COVID-19 = coronavirus disease 2019; ECMO = extracorporeal membrane oxygenation; RCT = randomized controlled trial. * Patients requiring mechanical ventilation or ECMO were excluded from 1 RCT (17); therefore, despite a few patients (3.3%) developing a requirement for invasive mechanical ventilation between screening and the beginning of the treatment, this study is analyzed as being representative of patients with severe disease not requiring mechanical ventilation or ECMO at baseline. † Within the evidence reviewed, severe COVID-19 is defined as hospitalized patients meeting 1 or more of the following criteria: radiographic infiltrates on imaging, an oxygen saturation level ≤94% on room air, tachypnea (respiratory rate >24 breaths per minute without supplemental oxygen), or need for supplemental oxygen or mechanical ventilation; moderate COVID-19 is defined as hospitalized patients with radiographic infiltrates and oxygen saturation greater than 94% on room air; and mild COVID-19 was not defined (14). ‡ Most (88.7%) of the participants enrolled in 1 RCT (16) had severe disease, so this study is analyzed as being representative of patients with severe disease. Use of Remdesivir to Treat COVID-19 CLINICAL GUIDELINE fewer than 10 doses because they recovered and were discharged from the hospital (15) . However, for a subgroup of patients with severe COVID-19 receiving mechanical ventilation or ECMO at day 5, extending treatment to 10 days may be beneficial compared with discontinuing treatment on day 5 (17). Evidence from 2 RCTs (15, 18) showed that among outcomes rated as critical, a 10-day course of remdesivir compared with placebo may slightly reduce mortality (low certainty) and probably increases recovery by a large effect (moderate certainty), and that there are probably fewer serious adverse events (modest effect, moderate certainty). Evidence from 1 RCT showed that a 10-day course may not reduce hospital length of stay (low certainty) (18) . Low-certainty evidence also showed improvement with a 10-day course compared with placebo for the following important outcomes: time to recovery (large effect), clinical improvement (modest effect), time to clinical improvement (slight effect), the need for mechanical ventilation or ECMO (slight effect), and nonserious adverse events (slight effect). Evidence was insufficient regarding differences in any adverse events. For a 10-day course of remdesivir compared with placebo, the outcomes of mortality (18) , time to recovery (15) , and time to clinical improvement (18) did not vary by symptom duration (≤10 days vs. >10 days), and time to recovery also did not vary by baseline oxygenation or ventilation requirements (15) . No evidence was found on whether other outcomes vary by symptom duration. Evidence from 1 RCT (17) that compared a 5-day course with a 10-day course of remdesivir showed that the 5-day course may reduce mortality slightly versus the 10-day course in patients with severe COVID-19 who did not require mechanical ventilation or ECMO at baseline (17). However, a post hoc analysis suggested that a 5-versus a 10-day course might result in a large increase in mortality among the most critical patients of those with severe COVID-19 (those receiving mechanical ventilation or ECMO at day 5) (17). Treatment beyond 5 days did not improve mortality among patients who were receiving noninvasive positive pressure ventilation or high-flow oxygen, those receiving low-flow oxygen, or those breathing ambient air. This finding suggests that extending treatment to 10 days for patients receiving mechanical ventilation or ECMO at day 5 may be beneficial (17). Compared with a 10-day course, a 5-day course shows a modest increase in recovery, a slight decrease in the time to recovery, and a modest reduction in the need for mechanical ventilation or ECMO (low certainty). Evidence for potential harms showed that a 5-day course of remdesivir results in fewer serious adverse events (large effect, low certainty) and a fewer number of any adverse events (slight effect, low certainty) compared with a 10-day course. Low COVID-19 = coronavirus disease 2019; ECMO = extracorporeal membrane oxygenation; NA = not applicable; RCT = randomized controlled trial. * Within the evidence reviewed, severe COVID-19 is defined as hospitalized patients meeting ≥1 of the following criteria: radiographic infiltrates on imaging, an oxygen saturation level ≤94% on room air, tachypnea (respiratory rate >24 breaths per minute without supplemental oxygen), or need for supplemental oxygen or mechanical ventilation; moderate COVID-19 is defined as hospitalized patients with radiographic infiltrates and oxygen saturation >94% on room air; and mild COVID-19 was not defined (14) . † Certainty of evidence: insufficient, confidence is inadequate to assess the likelihood of benefit (benefit minus harm) of an intervention or its impact on a health outcome; low, confidence in the effect is limited because the true effect may be substantially different from the estimated effect; moderate, confidence in the effect is moderate because the true effect is probably close to the estimated effect, but a sizable possibility exists that it is substantially different; high, confidence that the true effect is close to the estimated effect. ‡ Recovery is defined as discharge from the hospital or hospitalization for infection control purposes only in 1 RCT (15, 18) and discharge from the hospital or hospitalized but not requiring supplemental oxygen or ongoing medical care in 3 RCTs (17). § Serious adverse events reported in studies included in the evidence review (15) (16) (17) were acute coronary syndrome, acute kidney injury, acute respiratory distress syndrome, acute respiratory failure, increased aminotransferase levels, atrial fibrillation, bronchitis, cardiac arrest, cardiopulmonary failure, increased D-dimer, deep venous thrombosis, diabetic ketoacidosis, dyspnea, endotracheal intubation, decreased glomerular filtration rate, hemorrhage of lower digestive tract, hypotension, hypoxia, ileus, lung abscess, mechanical ventilation, multiple organ dysfunction syndrome, respiratory distress, respiratory failure, pneumothorax, pulmonary embolism, pulmonary failure, recurrence of COVID-19, septic shock, sepsis, shock, tachycardia, thrombocytopenia, and viral pneumonia. Nonserious adverse events reported in studies included in the evidence review (16) were acidosis, acute kidney injury, alkalosis, increased aspartate aminotransferase, anemia, atrial fibrillation, decreased blood albumin, increased blood bilirubin, increased blood glucose, increased blood creatinine, deep venous thrombosis, delirium, dyspnea, decreased glomerular filtration rate, decreased hemoglobin, hyperglycemia, hypertension, hypoalbuminemia, hypotension, hypoxia, decreased lymphocyte count, lymphopenia, pneumonia, increased prothrombin time, pyrexia, respiratory distress, increased aminotransferase levels, and decreased urine creatinine clearance. Any adverse events reported in studies included in the evidence review (15, 17) were acute kidney injury, acute respiratory failure, increased alanine aminotransferase, anemia, increased aspartate aminotransferase, increased blood glucose, increased blood lipids, increased blood urea nitrogen, constipation, hyperlipidemia, hypoalbuminemia, hypokalemia, hypotension, insomnia, nausea, increased neutrophil count, rash, respiratory failure, increased serum potassium, reduced serum sodium, thrombocytopenia, increased total bilirubin, vomiting, and increased leukocyte count. ͉͉ Clinical improvement is defined as a 2-point reduction in patients' hospitalization status on a 6-point ordinal scale (1 = live discharge to 6 = death) or live discharge from the hospital, whichever came first (18) , and as an improvement of at least 2 points from baseline on a 7-point ordinal scale (1 = death to 7 = discharged from hospital) (17). Disclosures: All financial and intellectual disclosures of interest were declared and potential conflicts were discussed and managed. Dr. Obley participated in discussion of the practice points but was recused from authorship and voting due to a moderate-level conflict of interest (author of supporting systematic review). A record of disclosures of interest and management of conflicts of is kept for each SMPC meeting and conference call and can be viewed at https://www.acponline .org/about-acp/who-we-are/leadership/boards-committees -councils/scientific-medical-policy-committee/disclosure-of -interests-and-conflict-of-interest-management-summary-for -scientific-medical-policy. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms .do?msNum=M20-5831. * Within the evidence reviewed, severe COVID-19 is defined as hospitalized patients meeting ≥1 of the following criteria: radiographic infiltrates on imaging, an oxygen saturation level ≤94% on room air, tachypnea (respiratory rate >24 breaths per minute without supplemental oxygen), or the need for supplemental oxygen or mechanical ventilation; moderate COVID-19 is defined as hospitalized patients with radiographic infiltrates and oxygen saturation >94% on room air; and mild COVID-19 was not defined (14) . † Certainty of evidence: insufficient, confidence is inadequate to assess the likelihood of benefit (benefit minus harm) of an intervention or its impact on a health outcome; low, confidence in the effect is limited because the true effect may be substantially different from the estimated effect; moderate, confidence in the effect is moderate because the true effect is probably close to the estimated effect, but a sizable possibility exists that it is substantially different; high, confidence that the true effect is close to the estimated effect. ‡ Most (88.7%) of the participants enrolled in 1 RCT (15, 18) had severe disease, so this study is analyzed as being representative of patients with severe disease. § Determined from a subgroup analysis; the certainty of evidence was not assessed for this comparison. ͉͉ Recovery is defined as discharge from the hospital or hospitalization for infection control purposes only in 1 RCT (15, 18) and as discharge from the hospital or hospitalized but not requiring supplemental oxygen or ongoing medical care in 3 RCTs (17, 18). ¶ Serious adverse events reported in studies included in the evidence review (15) (16) (17) were acute coronary syndrome, acute kidney injury, acute respiratory distress syndrome, acute respiratory failure, increased aminotransferase levels, atrial fibrillation, bronchitis, cardiac arrest, cardiopulmonary failure, increased D-dimer, deep venous thrombosis, diabetic ketoacidosis, dyspnea, endotracheal intubation, decreased glomerular filtration rate, hemorrhage of lower digestive tract, hypotension, hypoxia, ileus, lung abscess, mechanical ventilation, multiple organ dysfunction syndrome, respiratory distress, respiratory failure, pneumothorax, pulmonary embolism, pulmonary failure, recurrence of COVID-19, septic shock, sepsis, shock, tachycardia, thrombocytopenia, and viral pneumonia. Nonserious adverse events reported in studies included in the evidence review (16) were acidosis, acute kidney injury, alkalosis, increased aspartate aminotransferase, anemia, atrial fibrillation, decreased blood albumin, increased blood bilirubin, increased blood glucose, increased blood creatinine, deep venous thrombosis, delirium, dyspnea, decreased glomerular filtration rate, decreased hemoglobin, hyperglycemia, hypertension, hypoalbuminemia, hypotension, hypoxia, decreased lymphocyte count, lymphopenia, pneumonia, increased prothrombin time, pyrexia, respiratory distress, increased aminotransferase levels, and decreased urine creatinine clearance. Any adverse events reported in studies included in the evidence review (15, 17) were acute kidney injury, acute respiratory failure, increased alanine aminotransferase, anemia, increased aspartate aminotransferase, increased blood glucose, increased blood lipids, increased blood urea nitrogen, constipation, hyperlipidemia, hypoalbuminemia, hypokalemia, hypotension, insomnia, nausea, increased neutrophil count, rash, respiratory failure, increased serum potassium, reduced serum sodium, thrombocytopenia, increased total bilirubin, vomiting, and increased leukocyte count. ** Clinical improvement is defined as a 2-point reduction in patients' hospitalization status on a 6-point ordinal scale (1 = live discharge to 6 = death) or live discharge from the hospital, whichever came first (18) , and as an improvement of at least 2 points from baseline on a 7-point ordinal scale (1 = death to 7 = discharged from hospital) (17). ‡ ‡ Patients requiring mechanical ventilation or ECMO were excluded from 1 RCT (17), so despite a few patients (3.3%) developing a requirement for invasive mechanical ventilation between screening and the beginning of the treatment, this study is analyzed as being representative of patients with severe disease not requiring mechanical ventilation or ECMO at baseline. The SMPC, in collaboration with staff from ACP's Department of Clinical Policy, developed these practice points on the basis of a rapid and living systematic evidence review conducted by the VA Evidence Synthesis Program, Minneapolis, Minnesota (14) . The SMPC comprises 11 internal medicine physicians representing various clinical areas of expertise and 1 public (nonclinician) member, and includes members with expertise in epidemiology, evidence synthesis, health policy, and guideline development. In addition to contributing clinical, scientific, and methodological expertise, Clinical Policy staff provided administrative support and liaised among the SMPC, the evidence review funding entity and evidence team, and the journal. Clinical Policy staff and the SMPC reviewed and prioritized potential topic suggestions from ACP members, SMPC members, and ACP governance. A committee subgroup, including the SMPC chair, worked with staff to draft the key questions and led the development of the practice points. Clinical Policy staff worked with the subgroup and an independent evidence review team to refine the key questions and determine appropriate evidence synthesis methods for each key question. Via conference calls and e-mail, Clinical Policy staff worked with the committee subgroup to draft the practice points on the basis of the results of the rapid and living systematic evidence review. The full SMPC reviewed and approved the final practice points. Before journal submission, ACP's Executive Committee of the Board of Regents also reviewed and approved the practice points on behalf of the ACP Board of Regents. The evidence review team will continually update the evidence review. The ACP will update the practice points based on the evidence review by using the same process as the first version described above. Updates are currently planned for every 2 months through December 2021. The SMPC will continuously assess the priority of the topic and the overall state of evidence, including the anticipated rate of new evidence, and may choose to modify the update intervals accordingly (any modifications will be described in an Update Alert). Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys Coronavirus susceptibility to the antiviral remdesivir (GS-5734) is mediated by the viral polymerase and the proofreading exoribonuclease. mBio Ebola viral dynamics in nonhuman primates provides insights into virus immunopathogenesis and antiviral strategies Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV Intracellular metabolism of nucleoside/ nucleotide analogues: a bottleneck to reach active drugs on HIV reverse transcriptase Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection Broad spectrum antiviral remdesivir inhibits human endemic and zoonotic deltacoronaviruses with a highly divergent RNA dependent RNA polymerase Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro India approves emergency use of remdesivir to treat Covid-19 patients Japan approves remdesivir for COVID-19 despite uncertainties UK authorises anti-viral drug remdesivir. Accessed at www.bbc.com/news/health-52805828 on 26 May 2020. 13. Reuters Staff. Singapore approves remdesivir drug for emergency COVID-19 treatment Rapid Response: COVID-19: Remdesivir for Hospitalized Adults. Evidence Synthesis Program, Health Services Research and Development Service, Office of Research and Development, Department of Veterans Affairs GS-US-540-5774 Investigators. Effect of remdesivir vs standard care on clinical status at 11 days in patients with moderate COVID-19: a randomized clinical trial Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial United States: Investigational agent; refer to Prescribing and Access Restrictions): Drug information. Accessed at www.uptodate.com/contents/remdesivir-united-states-investigational -agent-refer-to-prescribing-and-access-restrictions-drug-information Use of Remdesivir to Treat COVID-19 (14). † Statistically significant findings are in bold. ‡ Certainty of evidence: insufficient, confidence is inadequate to assess the likelihood of benefit (benefit minus harm) of an intervention or its impact on a health outcome; low, confidence in the effect is limited because the true effect may be substantially different from the estimated effect; moderate, confidence in the effect is moderate because the true effect is probably close to the estimated effect, but a sizable possibility exists that it is substantially different; high, confidence that the true effect is close to the estimated effect. § Recovery is defined as discharge from the hospital or hospitalization for infection control purposes only in 1 RCT (15, 18) and as discharge from the hospital or hospitalized but not requiring supplemental oxygen or ongoing medical care in 3 RCTs (17, 18). ͉͉ Serious adverse events reported in studies included in the evidence review (15) (16) (17) were acute coronary syndrome, acute kidney injury, acute respiratory distress syndrome, acute respiratory failure, increased aminotransferase levels, atrial fibrillation, bronchitis, cardiac arrest, cardiopulmonary failure, increased D-dimer, deep venous thrombosis, diabetic ketoacidosis, dyspnea, endotracheal intubation, decreased glomerular filtration rate, hemorrhage of lower digestive tract, hypotension, hypoxia, ileus, lung abscess, mechanical ventilation, multiple organ dysfunction syndrome, respiratory distress, respiratory failure, pneumothorax, pulmonary embolism, pulmonary failure, recurrence of COVID-19, septic shock, sepsis, shock, tachycardia, thrombocytopenia, and viral pneumonia. Nonserious adverse events reported in studies included in the evidence review (16) were acidosis, acute kidney injury, alkalosis, increased aspartate aminotransferase, anemia, atrial fibrillation, decreased blood albumin, increased blood bilirubin, increased blood glucose, increased blood creatinine, deep venous thrombosis, delirium, dyspnea, decreased glomerular filtration rate, decreased hemoglobin, hyperglycemia, hypertension, hypoalbuminemia, hypotension, hypoxia, decreased lymphocyte count, lymphopenia, pneumonia, increased prothrombin time, pyrexia, respiratory distress, increased aminotransferase levels, and decreased urine creatinine clearance. Any adverse events reported in studies included in the evidence review (15, 17) were acute kidney injury, acute respiratory failure, increased alanine aminotransferase, anemia, increased aspartate aminotransferase, increased blood glucose, increased blood lipids, increased blood urea nitrogen, constipation, hyperlipidemia, hypoalbuminemia, hypokalemia, hypotension, insomnia, nausea, increased neutrophil count, rash, respiratory failure, increased serum potassium, reduced serum sodium, thrombocytopenia, increased total bilirubin, vomiting, and increased leukocyte count. ¶ Clinical improvement is defined as a 2-point reduction in patients' hospitalization status on a 6-point ordinal scale (1 = live discharge to 6 = death) or live discharge from the hospital, whichever came first (18) , and as an improvement of at least 2 points from baseline on a 7-point ordinal scale (1 = death to 7 = discharged from hospital) (17). (16) were acidosis, acute kidney injury, alkalosis, increased aspartate aminotransferase, anemia, atrial fibrillation, decreased blood albumin, increased blood bilirubin, increased blood glucose, increased blood creatinine, deep venous thrombosis, delirium, dyspnea, decreased glomerular filtration rate, decreased hemoglobin, hyperglycemia, hypertension, hypoalbuminemia, hypotension, hypoxia, decreased lymphocyte count, lymphopenia, pneumonia, increased prothrombin time, pyrexia, respiratory distress, increased aminotransferase levels, and decreased urine creatinine clearance. Any adverse events reported in studies included in the evidence review (15, 17) were acute kidney injury, acute respiratory failure, increased alanine aminotransferase, anemia, increased aspartate aminotransferase, increased blood glucose, increased blood lipids, increased blood urea nitrogen, constipation, hyperlipidemia, hypoalbuminemia, hypokalemia, hypotension, insomnia, nausea, increased neutrophil count, rash, respiratory failure, increased serum potassium, reduced serum sodium, thrombocytopenia, increased total bilirubin, vomiting, and increased leukocyte count. † † Clinical improvement is defined as a 2-point reduction in patients' hospitalization status on a 6-point ordinal scale (1 = live discharge to 6 = death) or live discharge from the hospital, whichever came first (18) , and as an improvement of at least 2 points from baseline on a 7-point ordinal scale (1 = death to 7 = discharged from hospital) (17). ‡ ‡ Patients requiring mechanical ventilation or ECMO were excluded from 1 RCT (17), so despite a few patients (3.3%) developing a requirement for invasive mechanical ventilation between screening and the beginning of the treatment, this study is analyzed as being representative of patients with severe disease not requiring mechanical ventilation or ECMO at baseline.