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

Background: Empagliflozin has been proposed as a treatment for COVID-19 on the basis of its anti-inflammatory, metabolic and haemodynamic effects. Methods: In this randomised, controlled, open-label trial, several possible treatments are compared with usual care in patients hospitalised with COVID-19. Eligible and consenting adults were randomly allocated in a 1:1 ratio to either usual standard of care alone or usual standard of care plus empagliflozin 10mg once daily for 28 days or until discharge using web-based simple (unstratified) randomisation with allocation concealment. The primary outcome was 28-day mortality. On 3 March the independent data monitoring committee recommended that the investigators review the data and recruitment was consequently stopped on 7 March. The trial is registered with ISRCTN (50189673) and clinicaltrials.gov (NCT04381936). Findings: Between 8 July 2021 and 6 March 2023, 4271 patients were randomly allocated to receive either empagliflozin (2113 patients) or usual care alone (2158 patients). Overall, 289 (14%) patients allocated to empagliflozin and 307 (14%) patients allocated to usual care died within 28 days (rate ratio 0.96; 95% confidence interval [CI] 0.82-1.13; p=0.64). There was no evidence of significant differences in duration of hospitalisation (median 8 days vs. 8 days) or the proportion of patients discharged from hospital alive within 28 days (79% vs. 78%; rate ratio 1.03; 95% CI 0.96-1.10; p=0.44). Among those not on invasive mechanical ventilation at baseline, there was no evidence of a significant difference in the proportion meeting the composite endpoint of invasive mechanical ventilation or death (16% vs. 17%; risk ratio 0.95; 95% CI 0.84-1.08; p=0.44). Interpretation: In adults hospitalised with COVID-19, empagliflozin was not associated with reductions in 28-day mortality, duration of hospital stay, or risk of progressing to invasive mechanical ventilation or death.

Evaluation of S/F94 as a proxy for COVID-19 severity (preprint)

Optimising statistical power in early-stage trials and observational studies accelerates discovery and improves the reliability of results. Ideally, intermediate outcomes should be continuously distributed and lie on the causal pathway between an intervention and a definitive outcome such as mortality. In order to optimise power for an intermediate outcome in the RECOVERY trial, we devised and evaluated a modification to a simple, pragmatic measure of oxygenation function - the SaO2/FIO2 (S/F) ratio. We demonstrate that, because of the ceiling effect in oxyhaemoglobin saturation, S/F ceases to reflect pulmonary oxygenation function at high values of SaO2. Using synthetic and real data, we found that the correlation of S/F with a gold standard (PaO2/FIO2, P/F ratio) improved substantially when measurements with SaO2 > 0.94 are excluded(Spearman r, synthetic data: S/F: 0.31; S/F94: 0.85). We refer to this measure as S/F94. In order to test the underlying assumptions and validity of S/F94 as a predictor of a definitive outcome (mortality), we collected an observational dataset including over 39,000 hospitalised patients with COVID-19 in the ISARIC4C study. We first demonstrated that S/F94 is predictive of mortality in COVID-19. We then compared the sample sizes required for trials using different outcome measures (S/F94, the WHO ordinal scale, sustained improvement at day 28 and mortality at day 28) ensuring comparable effect sizes. The smallest sample size was needed when S/F94 on day 5 was used as an outcome measure. To facilitate future study design, we provide an online user interface to quantify realworld power for a range of outcomes and inclusion criteria, using a synthetic dataset retaining the population-level clinical associations in real data accrued in ISARIC4C https://isaric4c.net/endpoints. We demonstrated that S/F94 is superior to S/F as a measure of pulmonary oxygenation function and is an effective intermediate outcome measure in COVID-19. It is a simple and non-invasive measurement, representative of disease severity and provides greater statistical power to detect treatment differences than other intermediate endpoints.

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

Background: Dimethyl fumarate (DMF) is an anti-inflammatory drug that has been proposed as a treatment for patients hospitalised with COVID-19. Methods: This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple possible treatments in patients hospitalised for COVID-19. In this initial assessment of DMF, performed at 27 UK hospitals, eligible and consenting adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF 120mg twice daily for 2 days followed by 240mg twice daily for 8 days, or until discharge if sooner. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale, assessed using a proportional odds model. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. The trial is registered with ISRCTN (50189673) and clinicaltrials.gov (NCT04381936). Findings: Between 2 March 2021 and 18 November 2021, 713 patients were enrolled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients were receiving corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.85-1.46; p=0.42). There was no significant effect of DMF on any secondary outcome. As expected, DMF caused flushing and gastrointestinal symptoms, each in around 6% of patients, but no new adverse effects were identified. Interpretation: In adults hospitalised with COVID-19, DMF was not associated with an improvement in clinical outcomes.

An international observational study to assess the impact of the Omicron variant emergence on the clinical epidemiology of COVID-19 in hospitalised patients (preprint)

BackgroundWhilst timely clinical characterisation of infections caused by novel SARS-CoV-2 variants is necessary for evidence-based policy response, individual-level data on infecting variants are typically only available for a minority of patients and settings. MethodsHere, we propose an innovative approach to study changes in COVID-19 hospital presentation and outcomes after the Omicron variant emergence using publicly available population-level data on variant relative frequency to infer SARS-CoV-2 variants likely responsible for clinical cases. We apply this method to data collected by a large international clinical consortium before and after the emergence of the Omicron variant in different countries. ResultsOur analysis, that includes more than 100,000 patients from 28 countries, suggests that in many settings patients hospitalised with Omicron variant infection less often presented with commonly reported symptoms compared to patients infected with pre-Omicron variants. Patients with COVID-19 admitted to hospital after Omicron variant emergence had lower mortality compared to patients admitted during the period when Omicron variant was responsible for only a minority of infections (odds ratio in a mixed-effects logistic regression adjusted for likely confounders, 0.67 [95% confidence interval 0.61 - 0.75]). Qualitatively similar findings were observed in sensitivity analyses with different assumptions on population-level Omicron variant relative frequencies, and in analyses using available individual-level data on infecting variant for a subset of the study population. ConclusionsAlthough clinical studies with matching viral genomic information should remain a priority, our approach combining publicly available data on variant frequency and a multi-country clinical characterisation dataset with more than 100,000 records allowed analysis of data from a wide range of settings and novel insights on real-world heterogeneity of COVID-19 presentation and clinical outcome.

Baricitinib in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial and updated meta-analysis (preprint)

Background: We evaluated the use of baricitinib, a Janus kinase (JAK) 1/2 inhibitor, for the treatment of patients admitted to hospital because of COVID-19. Methods: This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple possible treatments in patients hospitalised for COVID-19. Eligible and consenting patients were randomly allocated (1:1) to either usual standard of care alone (usual care group) or usual care plus baricitinib 4 mg once daily by mouth for 10 days or until discharge if sooner (baricitinib group). The primary outcome was 28-day mortality assessed in the intention-to-treat population. A meta-analysis was conducted that included the results from the RECOVERY trial and all previous randomised controlled trials of baricitinib or other JAK inhibitor in patients hospitalised with COVID-19. Findings: Between 2 February 2021 and 29 December 2021, 8156 patients were randomly allocated to receive usual care plus baricitinib versus usual care alone. At randomisation, 95% of patients were receiving corticosteroids and 23% receiving tocilizumab (with planned use within the next 24 hours recorded for a further 9%). Overall, 513 (12%) of 4148 patients allocated to baricitinib versus 546 (14%) of 4008 patients allocated to usual care died within 28 days (age-adjusted rate ratio 0.87; 95% CI 0.77-0.98; p=0.026). This 13% proportional reduction in mortality was somewhat smaller than that seen in a meta-analysis of 8 previous trials of a JAK inhibitor (involving 3732 patients and 425 deaths) in which allocation to a JAK inhibitor was associated with a 43% proportional reduction in mortality (rate ratio 0.57; 95% CI 0.45-0.72). Including the results from RECOVERY into an updated meta-analysis of all 9 completed trials (involving 11,888 randomised patients and 1484 deaths) allocation to baricitinib or other JAK inhibitor was associated with a 20% proportional reduction in mortality (rate ratio 0.80; 95% CI 0.71-0.89; p<0.001). In RECOVERY, there was no significant excess in death or infection due to non-COVID-19 causes and no excess of thrombosis, or other safety outcomes. Interpretation: In patients hospitalised for COVID-19, baricitinib significantly reduced the risk of death but the size of benefit was somewhat smaller than that suggested by previous trials. The total randomised evidence to date suggests that JAK inhibitors (chiefly baricitinib) reduce mortality in patients hospitalised for COVID-19 by about one-fifth.

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

Background: REGEN-COV is a combination of 2 monoclonal antibodies (casirivimab and imdevimab) that bind to two different sites on the receptor binding domain of the SARS-CoV-2 spike protein. We aimed to evaluate the efficacy and safety of REGEN-COV in patients admitted to hospital with COVID-19. Methods: In this randomised, controlled, open-label platform trial, several possible treatments were compared with usual care in patients hospitalised with COVID-19. Eligible and consenting patients were randomly allocated (1:1) to either usual standard of care alone (usual care group) or usual care plus a single dose of REGEN-COV 8g (casirivimab 4g and imdevimab 4g) by intravenous infusion (REGEN-COV group). The primary outcome was 28-day mortality assessed first among patients without detectable antibodies to SARS-CoV-2 at randomisation (seronegative) and then in the overall population. Findings: Between 18 September 2020 and 22 May 2021, 9785 patients were randomly allocated to receive usual care plus REGEN-COV or usual care alone, including 3153 (32%) seronegative patients, 5272 (54%) seropositive patients and 1360 (14%) patients with unknown baseline antibody status. In the primary efficacy population of seronegative patients, 396 (24%) of 1633 patients allocated to REGEN-COV and 451 (30%) of 1520 patients allocated to usual care died within 28 days (rate ratio 0.80; 95% CI 0.70-0.91; p=0.0010). In an analysis involving all randomised patients (regardless of baseline antibody status), 944 (20%) of 4839 patients allocated to REGEN-COV and 1026 (21%) of 4946 patients allocated to usual care died within 28 days (rate ratio 0.94; 95% CI 0.86-1.03; p=0.17). The proportional effect of REGEN-COV on mortality differed significantly between seropositive and seronegative patients (p value for heterogeneity = 0.001). Interpretation: In patients hospitalised with COVID-19, the monoclonal antibody combination of casirivimab and imdevimab (REGEN-COV) reduced 28-day mortality among patients who were seronegative at baseline.

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

Background: Aspirin has been proposed as a treatment for COVID-19 on the basis of its antithrombotic properties. Methods: In this randomised, controlled, open-label trial, several possible treatments were compared with usual care in patients hospitalised with COVID-19. Eligible and consenting adults were randomly allocated in a 1:1 ratio to either usual standard of care alone or usual standard of care plus 150mg aspirin once daily until discharge using web-based simple (unstratified) randomisation with allocation concealment. The primary outcome was 28-day mortality. The trial is registered with ISRCTN (50189673) and clinicaltrials.gov (NCT04381936). Findings: Between 01 November 2020 and 21 March 2021, 7351 patients were randomly allocated to receive aspirin and 7541 patients to receive usual care alone. Overall, 1222 (17%) patients allocated to aspirin and 1299 (17%) patients allocated to usual care died within 28 days (rate ratio 0.96; 95% confidence interval [CI] 0.89-1.04; p=0.35). Consistent results were seen in all pre-specified subgroups of patients. Patients allocated to aspirin had a slightly shorter duration of hospitalisation (median 8 days vs. 9 days) and a higher proportion were discharged from hospital alive within 28 days (75% vs. 74%; rate ratio 1.06; 95% CI 1.02-1.10; p=0.0062). Among those not on invasive mechanical ventilation at baseline, there was no significant difference in the proportion meeting the composite endpoint of invasive mechanical ventilation or death (21% vs. 22%; risk ratio 0.96; 95% CI 0.90-1.03; p=0.23). Aspirin use was associated with an absolute reduction in thrombotic events of 0.6% (SE 0.4%) and an absolute increase in clinically significant bleeding of 0.6% (SE 0.2%). Interpretation: In patients hospitalised with COVID-19, aspirin was not associated with reductions in 28-day mortality or in the risk of progressing to invasive mechanical ventilation or death but was associated with a small increase in the rate of being discharged alive.

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

Background: Colchicine has been proposed as a treatment for COVID-19 on the basis of its anti-inflammatory actions. Methods: In this randomised, controlled, open-label trial, several possible treatments were compared with usual care in patients hospitalised with COVID-19. Eligible and consenting adults were randomly allocated in a 1:1 ratio to either usual standard of care alone or usual standard of care plus colchicine twice daily for 10 days or until discharge (or one of the other treatment arms) using web-based simple (unstratified) randomisation with allocation concealment. The primary outcome was 28-day mortality. The trial is registered with ISRCTN (50189673) and clinicaltrials.gov (NCT04381936). Findings: Between 27 November 2020 and 4 March 2021, 5610 patients were randomly allocated to receive colchicine and 5730 patients to receive usual care alone. Overall, 1173 (21%) patients allocated to colchicine and 1190 (21%) patients allocated to usual care died within 28 days (rate ratio 1.01; 95% confidence interval [CI] 0.93-1.10; p=0.77). Consistent results were seen in all pre-specified subgroups of patients. There was no significant difference in duration of hospitalisation (median 10 days vs. 10 days) or the proportion of patients discharged from hospital alive within 28 days (70% vs. 70%; rate ratio 0.98; 95% CI 0.94-1.03; p=0.44). Among those not on invasive mechanical ventilation at baseline, there was no significant difference in the proportion meeting the composite endpoint of invasive mechanical ventilation or death (25% vs. 25%; risk ratio 1.02; 95% CI 0.96-1.09; p=0.47). Interpretation: In adults hospitalised with COVID-19, colchicine was not associated with reductions in 28-day mortality, duration of hospital stay, or risk of progressing to invasive mechanical ventilation or death.

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

Background: Treatment of COVID-19 patients with plasma containing anti-SARS-CoV-2 antibodies may have a beneficial effect on clinical outcomes. We aimed to evaluate the safety and efficacy of convalescent plasma in patients admitted to hospital with COVID-19. Methods: In this randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) several possible treatments are being compared with usual care in patients hospitalised with COVID-19 in the UK. Eligible and consenting patients were randomly allocated to receive either usual care plus high titre convalescent plasma or usual care alone. The primary outcome was 28-day mortality. Findings: Between 28 May 2020 and 15 January 2021, 5795 patients were randomly allocated to receive convalescent plasma and 5763 to usual care alone. There was no significant difference in 28-day mortality between the two groups: 1398 (24%) of 5795 patients allocated convalescent plasma and 1408 (24%) of 5763 patients allocated usual care died within 28 days (rate ratio [RR] 1.00; 95% confidence interval [CI] 0.93 to 1.07; p=0.93). 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 (66% vs. 67%; rate ratio 0.98; 95% CI 0.94-1.03, p=0.50). Among those not on invasive mechanical ventilation at baseline, there was no significant difference in the proportion meeting the composite endpoint of progression to invasive mechanical ventilation or death (28% vs. 29%; rate ratio 0.99; 95% CI 0.93-1.05, p=0.79). Interpretation: Among patients hospitalised with COVID-19, high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes.

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

Findings: Between 23 April 2020 and 25 January 2021, 4116 adults were included in the assessment of tocilizumab, including 562 (14%) patients receiving invasive mechanical ventilation, 1686 (41%) receiving non-invasive respiratory support, and. 1868 (45%) receiving no respiratory support other than oxygen. Median CRP was 143 [IQR 107-205] mg/L and 3385 (82%) patients were receiving systemic corticosteroids at randomisation. Overall, 596 (29%) of the 2022 patients allocated tocilizumab and 694 (33%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0.86; 95% confidence interval [CI] 0.77-0.96; p=0.007). Consistent results were seen in all pre-specified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital alive within 28 days (54% vs. 47%; rate ratio 1.23; 95% CI 1.12-1.34; 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 (33% vs. 38%; risk ratio 0.85; 95% CI 0.78-0.93; p=0.0005). Interpretation: In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes regardless of the level of respiratory support received and in addition to the use of systemic corticosteroids.

Azithromycin in Hospitalised Patients with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial (preprint)

BackgroundAzithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatory actions. We evaluated the efficacy and safety of azithromycin in hospitalised patients with COVID-19. MethodsIn this randomised, controlled, open-label, adaptive platform trial, several possible treatments were compared with usual care in patients hospitalised with COVID-19 in the UK. Eligible and consenting patients were randomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once daily by mouth or intravenously for 10 days or until discharge (or one of the other treatment arms). Patients were twice as likely to be randomised to usual care as to any of the active treatment groups. The primary outcome was 28-day mortality. The trial is registered with ISRCTN (50189673) and clinicaltrials.gov (NCT04381936). FindingsBetween 7 April and 27 November 2020, 2582 patients were randomly allocated to receive azithromycin and 5182 patients to receive usual care alone. Overall, 496 (19%) patients allocated to azithromycin and 997 (19%) patients allocated to usual care died within 28 days (rate ratio 1{middle dot}00; 95% confidence interval [CI] 0{middle dot}90-1{middle dot}12; p=0{middle dot}99). Consistent results were seen in all pre-specified subgroups of patients. There was no difference in duration of hospitalisation (median 12 days vs. 13 days) or the proportion of patients discharged from hospital alive within 28 days (60% vs. 59%; rate ratio 1{middle dot}03; 95% CI 0{middle dot}97-1{middle dot}10; p=0{middle dot}29). Among those not on invasive mechanical ventilation at baseline, there was no difference in the proportion meeting the composite endpoint of invasive mechanical ventilation or death (21% vs. 22%; risk ratio 0{middle dot}97; 95% CI 0{middle dot}89-1{middle dot}07; p=0{middle dot}54). InterpretationIn patients hospitalised with COVID-19, azithromycin did not provide any clinical benefit. Azithromycin use in patients hospitalised with COVID-19 should be restricted to patients where there is a clear antimicrobial indication. FundingUK Research and Innovation (Medical Research Council) and National Institute of Health Research (Grant ref: MC_PC_19056).

Early clinical characteristics of Covid-19: scoping review (preprint)

ABSTRACT Background: The Coronavirus disease 2019 (covid-19) pandemic has spread rapidly across the globe. Accurate clinical characterisation studies are essential to informing research, diagnosis and clinical management efforts, particularly early in a pandemic. In this scoping review we identify the clinical characteristics of patients admitted to hospital in the early months of the pandemic, focusing on symptoms, laboratory and imaging findings, and clinical outcomes. Methods: A scoping review. MEDLINE, EMBASE and Global Health databases were searched studies published from January 1st 2020 to April 28th 2020. Studies which reported on at least 100 hospitalised patients with covid-19 of any age were included. Results: Of 1,249 studies identified through the search 78 studies were eligible for inclusion; one randomized control trial and 77 observational studies presenting data on 77,443 patients admitted with covid-19. Most studies were conducted in China (82%), 9% in the US and 10% in Europe and two studies were set in more than one country. No studies included patients from low and middle income countries. Coagulopathy was underrecognised as a complication in the early months of the pandemic. Use of corticosteroids varied widely, and the use of anticoagulants was reported in only one study. Fever, cough and dyspnoea are less common in older adults; gastrointestinal symptoms, as the only presenting feature may be underrecognised. The most common laboratory finding was lymphocytopenia. Inflammatory biomarkers were commonly elevated, including C-reactive protein and interleukin-6. Typical computed tomography findings include bilateral infiltrates however imaging may be normal in early disease. Data on clinical characteristics in children and vulnerable populations were limited. Conclusions: Clinical characterisation studies from early in the pandemic indicated that covid-19 is a multisystem disease, with biomarkers indicating inflammation and coagulopathy. However, early data collection on symptoms and clinical outcomes did not consistently reflect this wide spectrum. Corticosteroid use varied widely, and anticoagulants were rarely used. Clinicians should remain vigilant to the possibility of covid-19 in patients presenting without fever, cough and dyspnoea, particularly in older adults. Further characterisation studies in different at-risk populations is needed. Review registration: Available at https://osf.io/r2ch9 Keywords: Covid-19, clinical characteristics, symptoms, biochemical parameters, imaging, outcomes, pandemic research

Risk stratification of patients admitted to hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: development and validation of the 4C Mortality Score (preprint)

ObjectivesTo develop and validate a pragmatic risk score to predict mortality for patients admitted to hospital with covid-19. DesignProspective observational cohort study: ISARIC WHO CCP-UK study (ISARIC Coronavirus Clinical Characterisation Consortium [4C]). Model training was performed on a cohort of patients recruited between 6 February and 20 May 2020, with validation conducted on a second cohort of patients recruited between 21 May and 29 June 2020. Setting260 hospitals across England, Scotland, and Wales. ParticipantsAdult patients ([≥]18 years) admitted to hospital with covid-19 admitted at least four weeks before final data extraction. Main outcome measuresIn-hospital mortality. ResultsThere were 34 692 patients included in the derivation dataset (mortality rate 31.7%) and 22 454 in the validation dataset (mortality 31.5%). The final 4C Mortality Score included eight variables readily available at initial hospital assessment: age, sex, number of comorbidities, respiratory rate, peripheral oxygen saturation, level of consciousness, urea, and C-reactive protein (score range 0-21 points). The 4C risk stratification score demonstrated high discrimination for mortality (derivation cohort: AUROC 0.79; 95% CI 0.78 - 0.79; validation cohort 0.78, 0.77-0.79) with excellent calibration (slope = 1.0). Patients with a score [≥]15 (n = 2310, 17.4%) had a 67% mortality (i.e., positive predictive value 67%) compared with 1.0% mortality for those with a score [≤]3 (n = 918, 7%; negative predictive value 99%). Discriminatory performance was higher than 15 pre-existing risk stratification scores (AUROC range 0.60-0.76), with scores developed in other covid-19 cohorts often performing poorly (range 0.63-0.73). ConclusionsWe have developed and validated an easy-to-use risk stratification score based on commonly available parameters at hospital presentation. This outperformed existing scores, demonstrated utility to directly inform clinical decision making, and can be used to stratify inpatients with covid-19 into different management groups. The 4C Mortality Score may help clinicians identify patients with covid-19 at high risk of dying during current and subsequent waves of the pandemic. Study registrationISRCTN66726260

Clinical characteristics of children and young people hospitalised with covid-19 in the United Kingdom: prospective multicentre observational cohort study (preprint)

ObjectiveTo characterise the clinical features of children and young people admitted to hospital with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the UK, and explore factors associated with admission to critical care, mortality, and development of multisystem inflammatory syndrome in children and adolescents temporarily related to covid-19 (MIS-C). DesignProspective observational cohort study with rapid data gathering and near real time analysis. Setting260 acute care hospitals in England, Wales, and Scotland between 17th January and 5th June 2020, with a minimal follow-up time of two weeks (to 19th June 2020). Participants451 children and young people aged less than 19 years admitted to 116 hospitals and enrolled into the International Severe Acute Respiratory and emergency Infections Consortium (ISARIC) WHO Clinical Characterisation Protocol UK study with laboratory-confirmed SARS-CoV-2. Main Outcome MeasuresAdmission to critical care (high dependency or intensive care), in-hospital mortality, or meeting the WHO preliminary case definition for MIS-C. ResultsMedian age was 3.9 years [interquartile range (IQR) 0.3-12.9 years], 36% (162/451) were under 12 months old, and 57% (256/450) were male. 56% (224/401) were White, 12% (49/401) South Asian and 10% (40/401) Black. 43% (195/451) had at least one recorded comorbidity. A muco-enteric cluster of symptoms was identified, closely mirroring the WHO MIS-C criteria. 17% of children (72/431) were admitted to critical care. On multivariable analysis this was associated with age under one month odds ratio 5.05 (95% confidence interval 1.69 to 15.72, p=0.004), age 10 to 14 years OR 3.11 (1.21 to 8.55, p=0.022) and Black ethnicity OR 3.02 (1.30 to 6.84, p=0.008). Three young people died (0.7 %, 3/451) aged 16 to 19 years, all of whom had profound comorbidity. Twelve percent of children (36/303) met the WHO MIS-C criteria, with the first patient developing symptoms in mid-March. Those meeting MIS-C criteria were older, (median age 10.8 years ([IQR 8.4-14.1] vs 2.0 [0.2-12.6]), p<0.001) and more likely to be of non-White ethnicity (70% (23/33) vs 43% (101/237), p=0.005). Children with MIS-C were four times more likely to be admitted to critical care (61% (22/36) vs 15% (40/267, p<0.001). In addition to the WHO criteria, children with MIS-C were more likely to present with headache (45% (13/29) vs 11% (19/171), p<0.001), myalgia (39% (11/28) vs 7% (12/170), p<0.001), sore throat (37% (10/27) vs (13% (24/183, p = 0.004) and fatigue (57% (17/30) vs 31% (60/192), p =0.012) than children who did not and to have a platelet count of less than 150 x109/L (30% (10/33) vs 10% (24/232), p=0.004). ConclusionsOur data confirms less severe covid-19 in children and young people than in adults and we provide additional evidence for refining the MIS-C case definition. The identification of a muco-enteric symptom cluster also raises the suggestion that MIS-C is the severe end of a spectrum of disease. Study registrationISRCTN66726260

Features of 16,749 hospitalised UK patients with COVID-19 using the ISARIC WHO Clinical Characterisation Protocol (preprint)

Objective: To characterize the clinical features of patients with severe COVID-19 in the UK. Design: Prospective observational cohort study with rapid data gathering and near real-time analysis, using a pre-approved questionnaire adopted by the WHO. Setting: 166 UK hospitals between 6th February and 18th April 2020. Participants: 16,749 people with COVID-19. Interventions: No interventions were performed, but with consent samples were taken for research purposes. Many participants were co-enrolled in other interventional studies and clinical trials. Results: The median age was 72 years [IQR 57, 82; range 0, 104], the median duration of symptoms before admission was 4 days [IQR 1,8] and the median duration of hospital stay was 7 days [IQR 4,12]. The commonest comorbidities were chronic cardiac disease (29%), uncomplicated diabetes (19%), non-asthmatic chronic pulmonary disease (19%) and asthma (14%); 47% had no documented reported comorbidity. Increased age and comorbidities including obesity were associated with a higher probability of mortality. Distinct clusters of symptoms were found: 1. respiratory (cough, sputum, sore throat, runny nose, ear pain, wheeze, and chest pain); 2. systemic (myalgia, joint pain and fatigue); 3. enteric (abdominal pain, vomiting and diarrhoea). Overall, 49% of patients were discharged alive, 33% have died and 17% continued to receive care at date of reporting. 17% required admission to High Dependency or Intensive Care Units; of these, 31% were discharged alive, 45% died and 24% continued to receive care at the reporting date. Of those receiving mechanical ventilation, 20% were discharged alive, 53% died and 27% remained in hospital. Conclusions: We present the largest detailed description of COVID-19 in Europe, demonstrating the importance of pandemic preparedness and the need to maintain readiness to launch research studies in response to outbreaks. Trial documentation: Available at https://isaric4c.net/protocols . Ethical approval in England and Wales (13/SC/0149), and Scotland (20/SS/0028). ISRCTN (pending).

Evaluation of the Efficacy and Safety of Intravenous Remdesivir in Adult Patients with Severe Pneumonia caused by COVID-19 virus Infection: study protocol for a Phase 3 Randomized, Double-blind, Placebo-controlled, Multicentre trial (preprint)

Background: A novel coronavirus emerged in Wuhan, Hubei Province, China towards the end of 2019 (SARS-CoV-2 or COVID-19 virus). Large scale spread within China and internationally led the World Health Organisation to declare a Public Health Emergency of International Concern on 30th January 2020. The clinical manifestations of COVID-19 virus infection include asymptomatic infection, mild upper respiratory symptoms, severe viral pneumonia with respiratory failure and even death. There are no antivirals of proven clinical efficacy in coronavirus infections. Remdesivir (GS-5734), a nucleoside analogue, has inhibitory effects on animal and human highly pathogenic coronaviruses, including MERS-CoV and SARS-CoV, in in-vitro and in-vivo experiments. It is also inhibitory against the COVID-19 virus in-vitro. The aim of this study is to assess the efficacy and safety of remdesivir in adult patients with severe pneumonia caused by COVID-19 virus infection.Methods: The protocol is prepared in accordance with the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidelines. This is a phase 3, randomized, double-blind, placebo-controlled, multicentre trial. Adults (≥18 years) with laboratory confirmed COVID-19 virus infection, and severe pneumonia signs or symptoms, and radiologically confirmed severe pneumonia are randomly assigned in a 2:1 ratio to intravenous remdesivir or placebo for 10 days. The primary endpoint is time to clinical improvement (censored at Day 28), defined as the time (in days) from randomization of study treatment (remdesivir or placebo) until a decline of two categories on a six-category ordinal scale of clinical status (1 ꞊ discharged; 6 ꞊ death) or live discharge from hospital. One interim analysis for efficacy and futility will be conducted once half of the total number of events required had been observed.Discussion: This is the first randomized, placebo-controlled trial in 2019-nCoV. Enrolment began in sites in Wuhan, Hubei Province, China on 6th February 2020.Trial registration: ClinicalTrials.gov, NCT04257656, 6th February 2020.