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BackgroundElevated proinflammatory cytokines have been associated with 2019 coronavirus disease (COVID-19) severity. We assessed efficacy and safety of sarilumab, an interleukin-6 receptor inhibitor, in severe (requiring supplemental oxygen by nasal canula or face mask) or critical (requiring greater supplemental oxygen, mechanical ventilation, or extracorporeal support) COVID-19. MethodsThis was a 60-day, randomised, double-blind, placebo-controlled, multinational trial in patients hospitalised with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and pneumonia, who required oxygen supplementation or intensive care. Patients were randomised 2:2:1 to intravenous sarilumab 400 mg, sarilumab 200 mg, or placebo. The primary endpoint was time to [≥]2-point clinical improvement (7-point scale; range: 1 [death] to 7 [not hospitalised]). The key secondary endpoint was proportion of patients alive at day 29. Safety outcomes included adverse events and laboratory assessments. This trial is registered with ClinicalTrials.gov (NCT04327388). FindingsBetween March 28 and July 3, 2020, 420 patients were randomised; 416 received treatment (placebo, n=84; sarilumab 200 mg, n=159; sarilumab 400 mg, n=173). At day 29, there were no significant differences in median (95% CI) time to [≥]2-point improvement between placebo (12{middle dot}0 [9{middle dot}0-15{middle dot}0] days) and sarilumab groups (200 mg: 10{middle dot}0 [9{middle dot}0-12{middle dot}0] days, p=0.96, log-rank test; 400 mg: 10{middle dot}0 [9{middle dot}0-13{middle dot}0] days, p=0.34) or in proportions of patients alive (placebo, 91{middle dot}7%; sarilumab 200 mg, 89{middle dot}9%, p=0{middle dot}63; sarilumab 400 mg, 91{middle dot}9%, p=0{middle dot}85). At day 29, there were numerical, nonsignificant survival differences between sarilumab 400 mg (88%) and placebo (79%; difference +9%, 95% CI -7{middle dot}7 to 25{middle dot}5, p=0{middle dot}25) for critical patients. There were no unexpected safety signals. InterpretationThis trial did not demonstrate efficacy of sarilumab in patients hospitalised with COVID-19 and receiving supplemental oxygen. Adequately powered trials of targeted immunomodulatory therapies assessing survival as a primary endpoint are suggested in patients with critical COVID-19. FundingSanofi and Regeneron Pharmaceuticals, Inc.
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<b>Background: </b>At present clinical reasoning skills are not systematically taught in Japanese medical universities. We developed a prototypic preliminary module for clinical tutors to introduce clinical reasoning to Japanese medical students. We hypothesized that tutored medical students would outperform self-study students.<br><b>Method: </b>Using the web-based Sequential Question and Answer test that rewarded history and differential diagnosis as proxies for clinical reasoning, we compared the pre and posttest scores of 12 randomized fifth grade tutored students at two universities during four tutor-led 1.5-hour web-based seminars using a structured syllabus to 12 randomized self-study students.<br><b>Results: </b>The tutored and self-study groups’ pretest scores were statistically similar at about 40 out of 100 weighted correct points. The tutored students’ posttest scores were 62 points, significantly greater (p = 0.007) than the pretest mean 42 points, compared to the self-study students’ posttest scores of 52 points, significantly greater (p = 0.012) than pretest mean 40 points. The difference between the two posttest groups was of borderline statistical significance (p = 0.08).<br><b>Conclusions: </b>We successfully assessed a prototypic module for tutors to introduce clinical reasoning to Japanese medical students. The tutored students achieved higher scores than the self-study students. Further research is needed to exploit the potential of our modular clinical reasoning system.
