Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Background: In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). Findings: Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001). Interpretation: In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

Background: Many patients with COVID-19 have been treated with plasma containing anti-SARS-CoV-2 antibodies. We aimed to evaluate the safety and efficacy of convalescent plasma therapy in patients admitted to hospital with COVID-19. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. The trial is underway at 177 NHS hospitals from across the UK. Eligible and consenting patients were randomly assigned (1:1) to receive either usual care alone (usual care group) or usual care plus high-titre convalescent plasma (convalescent plasma group). The primary outcome was 28-day mortality, analysed on an intention-to-treat basis. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings: Between May 28, 2020, and Jan 15, 2021, 11558 (71%) of 16287 patients enrolled in RECOVERY were eligible to receive convalescent plasma and were assigned to either the convalescent plasma group or the usual care group. There was no significant difference in 28-day mortality between the two groups: 1399 (24%) of 5795 patients in the convalescent plasma group and 1408 (24%) of 5763 patients in the usual care group died within 28 days (rate ratio 1·00, 95% CI 0·93–1·07; p=0·95). The 28-day mortality rate ratio was similar in all prespecified subgroups of patients, including in those patients without detectable SARS-CoV-2 antibodies at randomisation. Allocation to convalescent plasma had no significant effect on the proportion of patients discharged from hospital within 28 days (3832 [66%] patients in the convalescent plasma group vs 3822 [66%] patients in the usual care group; rate ratio 0·99, 95% CI 0·94–1·03; p=0·57). Among those not on invasive mechanical ventilation at randomisation, there was no significant difference in the proportion of patients meeting the composite endpoint of progression to invasive mechanical ventilation or death (1568 [29%] of 5493 patients in the convalescent plasma group vs 1568 [29%] of 5448 patients in the usual care group; rate ratio 0·99, 95% CI 0·93–1·05; p=0·79). Interpretation: In patients hospitalised with COVID-19, high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Galactosamine induced hepatitis induces a reduction in hepatocyte epidermal growth factor receptors.

The rapid regenerative response of the rat liver to partial hepatectomy is associated with a decline in liver epidermal growth factor receptor numbers which implies that ligand epidermal growth factor receptor interactions maybe important in initiating and/or modulating this process. The proliferative process in toxic hepatitis (where in contrast with partial hepatectomy the majority of hepatocytes have been exposed to damaging influences) has been less widely investigated. We studied the DNA synthetic response of rat livers to toxic injury induced by a 350 or 800 mg/kg ip injection of galactosamine and that caused by 70% hepatectomy, comparing the changes in epidermal growth factor receptor status. Both resulted in down regulation of epidermal growth factor receptors, suggesting similar ligand epidermal growth factor receptor binding occurs during the proliferative response after galactosamine administration and after partial hepatectomy. In vitro studies on isolated hepatocytes showed that epidermal growth factor receptor down regulation was not a direct effect of galactosamine on hepatocyte membranes

Effect of Invivo Administration of An Antibody to Epidermal Growth-Factor On the Rapid Increase in Dna-Synthesis Induced by Partial-Hepatectomy in the Rat

Recent reports indicate that transforming growth factor alpha (TGF-alpha) is produced within the fiver and acts as the natural ligand of the epidermal growth factor (EGF) receptor causing the EGF receptor down regulation and the hepatocyte proliferation observed after partial hepatectomy. The reported phenomenon that an antibody to EGF inhibits the regenerative response to partial hepatectomy was therefore re-investigated. The IgG fraction of an anti-rat EGF antibody was injected intravenously at the time of partial hepatectomy, and its effects on regenerative DNA synthesis were compared with those of non-immune IgG. Injection of IgG reduced the DNA synthetic response to partial hepatectomy, assessed 24 hours after resection by H-3-thymidine incorporation, but the effects of normal and anti-EGF IgG were not statistically different, despite the presence of excess anti-EGF IgG in the circulation throughout the experimental period. However, anti-EGF IgG could completely block the proliferative response of hepatocytes in culture to EGF. These results support the suggestion that EGF is not the major mediator of hepatocyte DNA synthesis in the early stages of liver regeneration