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

Proceedings of the Ocean Drilling Program, Scientific Results. Vol. 193. Anatomy of an active felsic-hosted hydrothermal system, Eastern Manus Basin. Covering Leg 193 of the cruises of the drilling vessel "Joides Resolution", Apra Harbor, Guam, to Townsville, Australia, Sites 1188-1191, 7 November 2000 - 3 January 2001

In the Ocean Drilling Program's only foray to an active seafloor hydrothermal system hosted by felsic volcanic rocks at a convergent plate margin, deep penetrations were achieved at two contrasted sites within the PACMANUS field (Manus backarc basin, Papua New Guinea). Just 1.0 km apart, these sites are characterized, respectively, by diffuse low-temperature venting at the seabed (Site 1188, Snowcap site; 1650 meters below sea level [mbsl]) and focused high-temperature venting (Site 1189, Roman Ruins; 1700 mbsl). Shallow holes at a background location remote from known hydrothermal activity (Site 1190) and at a second high-temperature chimney field (Site 1191, Satanic Mills) failed to drill beyond unaltered felsic lavas which at Sites 1188 and 1189 form an impervious cap (as thick as 35 m) to an underlying, pervasively altered lava sequence with occasional volcaniclastic horizons. To the maximum depth drilled (387 meters below seafloor [mbsf]), alteration assemblages are characterized by clay minerals and ubiquitous disseminated pyrite. Hydrothermal K-feldspar at Site 1189 differentiates it from Site 1188 where, by contrast, several intervals of pyrophyllite-bearing acid sulfate alteration suggest input from magmatic volatiles. At both deeply penetrated sites the dominant silica phase in alteration assemblages changes downhole from opal-A at the transition from overlying unaltered lava to cristobalite and then to quartz. The boundary between the cristobalite and quartz domains is gradational between 60 and 110 mbsf in Hole 1188A under Snowcap but is sharper and shallower (~25 mbsf) in Hole 1189A on the fringes of the Roman Ruins field. Hole 1189B, higher on the Roman Ruins mound, intersected a "Stockwork Zone" with abundant quartz ± pyrite ± anhydrite veins and breccia infills, from base of casing (31 mbsf) to ~110 mbsf, below which an abrupt change occurred to a "Lower Sequence" with interleaved cristobalite- and quartz-bearing assemblages and common preservation of igneous plagioclase. Only two thin intervals of sulfide-rich mineralization were encountered, both below the Roman Ruins chimney field. Postcruise volcanic facies analyses based on logging data and cores with well-preserved fabrics, plus assessments of immobile element geochemistry for altered rocks referred against a local database for glassy lavas, establish that Pual Ridge is constructed from numerous lava flows averaging ~15 to 30 m thick and ranging from andesite to rhyodacite in composition, with dacites dominant. Investigations of alteration and mineralization support the concept of a single major hydrothermal event imposed at PACMANUS after accumulation of most of the Pual Ridge volcanic sequence. Different phases within this event, involving pronounced differences in fluid chemistry, created a variety of alteration styles yet to be fully unraveled. Much of the extensive subseafloor alteration may have been completed before uprise of high-temperature vent fluids that formed seabed chimneys. Prominent alteration-related geochemical differences between Sites 1188 and 1189 include enrichments in potassium, barium, and uranium at Site 1189. Altered wallrocks in the Stockwork Zone of Hole 1189B have lost silica, but Si is more generally conserved at precursor levels. Leaching during hydrothermal alteration did not contribute significant base or precious metals, or barium, to seabed chimney deposits. At both sites hydrothermal alteration involves volume expansion arising from grain-scale dilation imposed by excess pore fluid pressures. Progressive dilation with nonreplacive deposition of sulfides and gangue minerals in open spaces is a dominant process in the two occurrences of subseafloor semimassive sulfide encountered below Roman Ruins. Fluid inclusions in vein anhydrites provide conclusive evidence of phase separation ("boiling") within the PACMANUS hydrothermal system at temperatures exceeding 360°C, somewhat higher than alteration temperatures computed from oxygen isotope analyses of clay minerals but comparable with oxygen isotope temperature estimates for vein quartz. Strontium isotope characteristics of anhydrites from veins, breccia matrixes, and semimassive sulfides imply deposition from varied mixtures between seawater and high-temperature hydrothermal fluids. The latter are more radiogenic (87Sr/86Sr = 0.7050) than fresh lavas at Pual Ridge (basaltic andesite to rhyodacite; 87Sr/86Sr = 0.7036) and so include a component of very deeply circulated seawater. There is circumstantial evidence for a magmatic component in the high-temperature hydrothermal fluid. Hydrothermal alteration of the volcanic sequence at Pual Ridge may have been largely completed before the main mineralizing events. Excess fluid pressures during both alteration and subsequent mineralization suggest a "pressure cooker" model whereby the subseafloor hydrothermal system is largely confined by a cap of impervious volcanics that become sporadically breached by hydrofracturing or tectonic processes to allow seafloor venting and sulfide deposition. Fluid flow within the PACMANUS system, especially that related to seabed venting, is governed by fractures rather than high porosity and permeability of the subseafloor rocks. A vibrant microbial assemblage exists in the higher parts of the hydrothermal system (to ~130 mbsf). Below this the system appears sterile, but temperature limits for viability have not been established. Cultures at 60° and 90°C are dominated by Geobacillus sp. and Deinococcus sp., respectively. Whereas mineralized bacterial cells have been observed, subseafloor biomineralization appears not to play an important role at PACMANUS