key: cord-0783245-sax7qc85
authors: Rosas, I.; Bräu, N.; Waters, M.; Go, R. C.; Hunter, B. D.; Bhagani, S.; Skiest, D.; Aziz, M. S.; Cooper, N.; Douglas, I. S.; Savic, S.; Youngstein, T.; Del Sorbo, L.; Cubillo Gracian, A.; De La Zerda, D. J.; Ustianowski, A.; Bao, M.; Dimonaco, S.; Graham, E.; Matharu, B.; Spotswood, H.; Tsai, L.; Malhotra, A.
title: Tocilizumab in Hospitalized Patients With COVID-19 Pneumonia
date: 2020-09-01
journal: nan
DOI: 10.1101/2020.08.27.20183442
sha: 0c9eed4210c16bcde59b7ad5a1fff729aa712d17
doc_id: 783245
cord_uid: sax7qc85

BACKGROUND COVID-19 is associated with immune dysregulation and hyperinflammation. Tocilizumab is an anti-interleukin-6 receptor antibody. METHODS Patients hospitalized with severe COVID-19 pneumonia receiving standard care were randomized (2:1) to double-blinded intravenous tocilizumab 8 mg/kg or placebo. The primary outcome measure was clinical status on a 7-category ordinal scale at day 28 (1, discharged/ready for discharge; 7, death). RESULTS Overall, 452 patients were randomized; the modified-intention-to-treat population included 294 tocilizumab-treated and 144 placebo-treated patients. Clinical status at day 28 was not statistically significantly improved for tocilizumab versus placebo (P=0.36). Median (95% CI) ordinal scale values at day 28: 1.0 (1.0 to 1.0) for tocilizumab and 2.0 (1.0 to 4.0) for placebo (odds ratio, 1.19 [0.81 to 1.76]). There was no difference in mortality at day 28 between tocilizumab (19.7%) and placebo (19.4%) (difference, 0.3% [95% CI, -7.6 to 8.2]; nominal P=0.94). Median time to hospital discharge was 8 days shorter with tocilizumab than placebo (20.0 and 28.0, respectively; nominal P=0.037; hazard ratio 1.35 [95% CI 1.02 to 1.79]). Median duration of ICU stay was 5.8 days shorter with tocilizumab than placebo (9.8 and 15.5, respectively; nominal P=0.045). In the safety population, serious adverse events occurred in 34.9% of 295 patients in the tocilizumab arm and 38.5% of 143 in the placebo arm. CONCLUSIONS In this randomized placebo-controlled trial in hospitalized COVID-19 pneumonia patients, tocilizumab did not improve clinical status or mortality. Potential benefits in time to hospital discharge and duration of ICU stay are being investigated in ongoing clinical trials.

Coronavirus disease 2019 (COVID-19) has rapidly developed into a global health threat since emerging in China in late 2019. 1 Severe COVID-19 pneumonia, occurring in approximately 15% of patients infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is associated with high mortality rates and places extensive burden on intensive care units to provide mechanical ventilation and other advanced forms of life support. 2, 3 Similar to Middle Eastern Respiratory Syndrome and SARS-CoV-1, 4 an initial phase of with high viral replication precedes a second disease phase that may be driven by the host immune response. This can lead to rapid increase in proinflammatory cytokines, an uncontrolled inflammatory response, acute respiratory distress syndrome (ARDS), and multiple organ failure. 4, 5 Interleukin-6 levels correlate with COVID-19 severity, 6, 7 suggesting that, in this setting, immune dysregulation and ARDS might be influenced by interleukin-6. 5, 8 Accumulation of lymphocytes and inflammatory monocytes, endotheliitis, apoptosis, thrombosis, and angiogenesis in the pulmonary vasculature of patients with suggests that vascular inflammation and dysfunction contribute to the pathophysiology of severe COVID-19 pneumonia. 9,10 Interleukin-6 promotes endothelial dysfunction and development of vascular permeability and might play a role in the vascular dysfunction of this disease. 11 The potential role of interleukin-6 in COVID-19 pneumonia 5, 8 provides rationale for investigation of interleukin-6 signaling inhibitors. Tocilizumab is a monoclonal antiinterleukin-6 receptor-alpha blocking antibody used to treat certain inflammatory diseases. 12 Improvements in patients with severe COVID-19 pneumonia who received tocilizumab were observed in case reports [13] [14] [15] and supported by retrospective observational cohort studies that showed rapid reduction in fever, reduced need for oxygen support and mechanical ventilation, and improvement in lung manifestations. [16] [17] [18] [19] [20] [21] . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity.

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The copyright holder for this this version posted September 1, 2020. . https://doi.org/10.1101/2020.08.27.20183442 doi: medRxiv preprint This is the first global, randomized, double-blind, placebo-controlled trial to investigate whether tocilizumab has clinical benefit in hospitalized patients with severe COVID-19 pneumonia.

COVACTA is a global, multicenter, randomized, double-blind, placebo-controlled, phase 3 trial investigating the efficacy and safety of tocilizumab in patients with severe COVID-19 pneumonia (ClinicalTrials.gov, NCT04320615). Patients 18 years or older with severe COVID-19 pneumonia confirmed by positive polymerase chain reaction test in any body fluid and evidenced by bilateral chest infiltrates on chest x-ray or computed tomography were enrolled. Eligible patients had blood oxygen saturation ≤93% or partial pressure of oxygen/fraction of inspired oxygen <300 mm/Hg. Patients were excluded if the treating physician determined that death was imminent and inevitable within 24 hours or if they had active tuberculosis or bacterial, fungal, or viral infection other than SARS-CoV-2. Standard care per local practice (antiviral treatment, low-dose steroids, convalescent plasma, supportive care) was permitted; however, concomitant treatment with another investigational agent (except antivirals) or any immunomodulatory agent was prohibited. Informed consent was obtained for all enrolled patients. The study was conducted in accordance with the International Council for Harmonization E6 guideline for good clinical practice and the Declaration of Helsinki or local regulations, whichever afforded greater patient protection.

The protocol was reviewed by institutional review boards or ethics committees.

Eligible patients were randomized (2:1) to receive intravenous tocilizumab (8 mg/kg infusion, maximum 800 mg) or placebo plus standard care using an interactive voice or web-based . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity.

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The copyright holder for this this version posted September 1, 2020. . https://doi.org/10.1101/2020.08.27.20183442 doi: medRxiv preprint response system and permuted-block randomization. Randomization was stratified by geographic region (North America, Europe) and mechanical ventilation (yes, no). If clinical signs or symptoms did not improve or worsened (defined as sustained fever or worsened ordinal scale clinical status), a second infusion could be administered 8 to 24 hours after the first. The primary analysis was performed at day 28, and the final study visit occurred at day 60.

The primary efficacy outcome was clinical status assessed on a 7-category ordinal scale (1, discharged is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted September 1, 2020. . https://doi.org/10.1101/2020.08.27.20183442 doi: medRxiv preprint were recorded according to Medical Dictionary for Regulatory Activities system organ class and preferred term.

Efficacy was assessed in the modified-intention-to-treat (mITT) population (any randomized patients who received study medication) for the primary and secondary endpoints according to treatment assigned at randomization. Analyses were stratified by region and mechanical ventilation status at randomization except for some subgroup analyses, as specified. The primary endpoint compared distribution of the ordinal scale of clinical status between treatment groups using a nonparametric van Elteren test. The ratio of the odds of being in a better clinical status category for tocilizumab versus placebo was determined using a proportional odds model to give odds ratios and 95% CIs. Data from the last available postbaseline assessment on the ordinal scale were used for patients who withdrew before day 28, and all deaths and hospital discharges were carried forward. Differences in mortality were analyzed using the Cochran-Mantel-Haenszel test, differences in the number of ventilatorfree days were assessed using the van Elteren test, and time-to-event secondary endpoints were assessed using a log-rank test with Kaplan-Meier plots produced (deaths were rightcensored for all time-to-event endpoints assessing improvement). Cumulative incidence plots were generated using the nonparametric Aalen-Johansen estimator, where death is a competing risk. Safety was assessed in the safety-evaluable population (all patients who received any study medication) according to treatment first received. An estimated mITT population sample size of 450 patients randomized to tocilizumab or placebo was determined to give 90% power for the primary endpoint using the van Elteren test and an assumed distribution of the ordinal scale (Appendix 2). If significance was met, mortality at day 28 would be tested at the 5% level, but no other adjustment for multiplicity was planned. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

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Overall, 479 patients from 9 countries (Canada, Denmark, France, Germany, Italy, Netherlands, Spain, United Kingdom, United States) were screened, 452 patients were randomized, and 438 received study treatment ( Figure 1 ). The mITT population included 294 patients randomized to tocilizumab and 144 to placebo. The safety population included 295 and 143 patients, respectively, because 1 patient randomized to placebo received tocilizumab.

Overall, 224 of 301 patients (74.4%) randomized to tocilizumab and 108 of 151 patients (71.5%) randomized to placebo completed the 28-day follow-up. Excluding those who died, 20 patients (6.6%) from the tocilizumab arm and 14 (9.3%) from the placebo arm discontinued before day 28; none discontinued because of safety reasons.

Baseline demographics and disease characteristics were generally balanced between treatment arms. Approximately 70% of patients in each arm were men; 176 patients (59.9%) were white and 40 (13.6%) were black in the tocilizumab arm compared with 76 (52.8%) and 26 (18.1%), respectively, in the placebo arm. Mean age was 60.9 ±14.6 years in the tocilizumab arm and 60.6 ±13.7 years in the placebo arm. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted September 1, 2020. Figure S1 ). Missing data were minimal for the primary endpoint of clinical status for the mITT population (3.7% tocilizumab, 2.1% placebo).

All P values for secondary endpoints are nominal because the primary endpoint was not met. Figure 2B ).

Median duration of ICU stay was 9.8 days in the tocilizumab arm and 15.5 days in the placebo arm (difference, -5.8 days [95% CI -15.0 to 2.9]; van Elteren P=0.05) ( Table 2) .

Cumulative incidences of time to improvement in clinical status, time to hospital discharge/ready for discharge, and mortality are shown in Figure S3 . is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

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In the safety population, adverse events were reported in 77.3% of 295 patients in the tocilizumab arm and 81.1% of 143 patients in the placebo arm through day 28 (Table 3) (Table S1 ).

COVACTA, the first randomized, double-blind, placebo-controlled trial of tocilizumab in COVID-19 pneumonia, included patients from 9 countries. The primary endpoint was not met; there was no significant difference between tocilizumab plus standard care and placebo plus standard care in clinical status assessed using a 7-category ordinal scale at day 28, and no mortality benefit was demonstrated. However, tocilizumab appeared to be safe, and potentially clinically meaningful benefits were identified in time to hospital discharge/ready for discharge and duration of ICU stay. Among patients not mechanically ventilated at randomization, fewer treatment failures (progression to mechanical ventilation, ICU admission, or death) occurred in tocilizumab-treated than placebo-treated patients. Because the primary endpoint of the study was not met, these findings require validation in additional studies. Adverse events, including those of special interest for tocilizumab (bleeding events, is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted September 1, 2020. . https://doi.org/10.1101/2020.08.27.20183442 doi: medRxiv preprint hepatic events, cardiac events), were generally balanced between tocilizumab and placebo, and incidences of infections or serious infections were lower in the tocilizumab arm.

The design and conduct of clinical trials in patients with COVID-19 present unique challenges and limitations. The COVACTA study population was intentionally chosen to be heterogeneous with regard to patient characteristics, previous/concurrent treatments, and disease severity to allow assessment of potential benefit across a broad range of patients and to reflect real-world practice in the expanding pandemic. Despite this heterogeneity, the proportion of patients discharged or ready for discharge by day 28 was higher in the tocilizumab arm than the placebo arm across the baseline ordinal scale of clinical status categories, whereas no consistent pattern was observed for mortality. The lack of standardized treatment across study sites and countries is an important limitation of this study considering potential interactions with antivirals and steroids. More patients in the placebo arm than the tocilizumab arm received concomitant steroids, which might have created bias toward lower mortality in the placebo arm 22 ; however, this imbalance is unlikely to have obscured a significant treatment effect because the mortality rate was similar between treatment arms regardless of steroid use and was higher in patients who received steroids in both treatment arms than in those who did not (Table S2 ). Since our study was initiated, standard care treatment and understanding of the natural history of COVID-19 and its associated complications have evolved substantially. Based on current knowledge, optimal endpoints for clinical trials and effective treatments are likely to be different for different stages of disease. Future trials should be more narrowly focused or much larger to allow for further stratification based on disease severity and other baseline characteristics.

Results of this study must be interpreted in the context of therapies for severe COVID-19. Among treatments for patients hospitalized with COVID-19 investigated in randomized controlled trials, dexamethasone reduced mortality in patients receiving is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted September 1, 2020. . https://doi.org/10.1101/2020.08.27.20183442 doi: medRxiv preprint mechanical ventilation or supplemental oxygen at randomization, but not in patients not receiving respiratory support. 22 Remdesivir shortened time to recovery, but there was no statistically significant difference in 14-day mortality. 23 Clinical trials investigating potential treatments-including other antivirals, anti-inflammatories, other targeted immunomodulators (sarilumab, anakinra, baricitinib, canakinumab), anticoagulants, and antifibrotics (tyrosine kinase inhibitors)-are underway, 24 but the urgent need for effective treatments remains. In the absence of a more effective therapy, treatments such as tocilizumab, which this study suggests might hasten recovery and decrease the need for intensive care without increasing the risk for infections, serious infections, or other adverse events, might be clinically useful, even without a demonstrated mortality benefit.

Additional studies are ongoing and might expand the findings of COVACTA and address outstanding scientifically and medically relevant questions regarding the risk/benefit profile of tocilizumab in COVID-19 in more narrowly defined patient populations and in conjunction with current treatments. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

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The copyright holder for this this version posted September 1, 2020. * Includes a patient who died on study day 1 (baseline ordinal category 7) but who was in category 6 on day 1 before death. † Values below the lower limit of quantitation of 3.12 ng/L were set at this value. ‡ At randomization (for stratification). § Counted from recorded intubation start date to the day before study day 1 (inclusive). The earliest start date was used if multiple procedures were recorded. Patients first intubated on study day 1 were assigned zero days on mechanical ventilation before baseline. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted September 1, 2020. . https://doi.org/10.1101/2020.08.27.20183442 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted September 1, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted September 1, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted September 1, 2020. . https://doi.org/10.1101/2020.08.27.20183442 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted September 1, 2020. . https://doi.org/10.1101/2020.08.27.20183442 doi: medRxiv preprint † Defined as all events that occurred during or within 24 hours of the infusion and were not assessed as "unrelated to study treatment" by the investigator, regardless of whether they were clinically consistent with hypersensitivity. ‡ Alanine aminotransferase or aspartate aminotransferase levels >3× upper limit of normal with either bilirubin level >2× upper limit of normal. § Reported by Medical Dictionary for Regulatory Activities preferred term.

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The copyright holder for this this version posted September 1, 2020. . https://doi.org/10.1101/2020.08.27.20183442 doi: medRxiv preprint *One patient randomly assigned to the placebo arm was treated with tocilizumab; this patient was included in the tocilizumab group for the safety population and in the placebo group for the mITT population.

mITT population, modified-intention-to-treat population, which included all randomized patients who received study treatment. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

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The copyright holder for this this version posted September 1, 2020. . https://doi.org/10.1101/2020.08.27.20183442 doi: medRxiv preprint 7-category ordinal scale: 1, discharged or ready for discharge; 2, non-ICU hospital ward, not requiring supplemental oxygen; 3, non-ICU hospital ward requiring supplemental oxygen; 4, ICU or non-ICU hospital ward, requiring noninvasive ventilation or high-flow oxygen; 5, ICU, requiring intubation and mechanical ventilation; 6, ICU, requiring ECMO or mechanical ventilation and additional organ support; 7, death.

(A, B) Data are plotted as one minus the Kaplan-Meier estimator. Patients who discontinued or were lost to follow-up for any reason before the event were censored at their last ordinal scale assessment.

Patients who died were censored at day 28. (C) Death or hospital discharge were carried forward, including deaths that occurred after withdrawal. Any remaining missing data were imputed using the last postbaseline observation carried forward method. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted September 1, 2020. . https://doi.org/10.1101/2020.08.27.20183442 doi: medRxiv preprint Category 6 includes a patient who died on study day 1 (ordinal category 7) but was in category 6 on day 1 before receiving study treatment; this patient was not included in the calculation of medians. NE, not evaluable.

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The copyright holder for this this version posted September 1, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted September 1, 2020. Under these assumptions, the total modified intention-to-treat sample size of 450 patients with a 2:1 randomization of tocilizumab to placebo provides approximately 90% power to detect a difference in distribution of the ordinal scale at week 28 between the treatment arms using a 2-sided van Elteren test at the 5% significance level. The sample size also provides 90% power to detect a ratio of 2 (tocilizumab to placebo) for the odds of being in a category or a better category under the assumptions of the expected probability distribution of patients in the placebo arm using a proportional odds model with a 2-sided P value at the 5% significance level. Assuming proportional odds and the assumed distribution in the placebo arm, the smallest odds ratio that could be statistically significant would be approximately 1.5.

Finally, the sample size provides approximately 90% power to detect a 10% absolute difference in mortality rate assuming a mortality rate of 15% in the placebo arm. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

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The copyright holder for this this version posted September 1, 2020. . https://doi.org/10.1101/2020.08.27.20183442 doi: medRxiv preprint 7-category ordinal scale: 1, discharged or ready for discharge; 2, non-ICU hospital ward, not requiring supplemental oxygen; 3, non-ICU hospital ward requiring supplemental oxygen; 4, ICU or non-ICU hospital ward, requiring noninvasive ventilation or high-flow oxygen; 5, ICU, requiring intubation and mechanical ventilation; 6, ICU requiring extracorporeal membrane oxygenation or mechanical ventilation and additional organ support; 7, death. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

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The copyright holder for this this version posted September 1, 2020. . https://doi.org/10.1101/2020.08.27.20183442 doi: medRxiv preprint 7-category ordinal scale: 1, discharged or ready for discharge; 2, non-ICU hospital ward, not requiring supplemental oxygen; 3, non-ICU hospital ward, requiring supplemental oxygen; 4, ICU or non-ICU hospital ward, requiring noninvasive ventilation or high-flow oxygen; 5, ICU, requiring intubation and mechanical ventilation; 6, ICU, requiring extracorporeal membrane oxygenation or mechanical ventilation and additional organ support; 7, death.

Death or hospital discharge were carried forward, including deaths that occurred after withdrawal. Any remaining missing data were imputed using the last postbaseline observation carried forward method.

Category 6 includes a patient who died on study day 1 (ordinal category 7) but was in category 6 on day 1 before receiving study treatment; this patient was not included in the calculation of medians. NE, not evaluable. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted September 1, 2020. . https://doi.org/10.1101/2020.08.27.20183442 doi: medRxiv preprint Figure S3 . Cumulative incidence function plot of (A) time to improvement in clinical status on the 7-category ordinal scale, (B) time to hospital discharge/ready for discharge, and (C) mortality to day 28.

Time to improvement in clinical status was defined as days from first dose of study drug to the time of at least a 2-category improvement in clinical status on the 7-category ordinal scale. Time to hospital discharge (or ready for discharge) was defined as days from the first dose of study drug to hospital discharge (or ready for discharge), defined as normal body temperature and respiratory rate and stable oxygen saturation on ambient air or ≤2 L supplemental oxygen. Patients who discontinued or who were lost to follow-up before improvement in clinical status or before ready for discharge criteria were met were censored at their last ordinal scale assessment. Cumulative incidence plots were produced using the nonparametric Aalen-Johansen estimator. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted September 1, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted September 1, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted September 1, 2020. . https://doi.org/10.1101/2020.08.27.20183442 doi: medRxiv preprint 7-category ordinal scale: 1, discharged or ready for discharge; 2, non-ICU hospital ward, not requiring supplemental oxygen; 3, non-ICU hospital ward, requiring supplemental oxygen; 4, ICU or non-ICU hospital ward, requiring noninvasive ventilation or high-flow oxygen; 5, ICU, requiring intubation and mechanical ventilation; 6, ICU, requiring extracorporeal membrane oxygenation or mechanical ventilation and additional organ support; 7, death.

Last postbaseline observation carried forward was used for imputation of missing data for day 28 analyses; observed data were used for over time analyses other than deaths and hospital discharge, which were imputed using last postbaseline observation carried forward. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

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The copyright holder for this this version posted September 1, 2020. . https://doi.org/10.1101/2020.08.27.20183442 doi: medRxiv preprint † Defined as all events that occurred during or within 24 hours of the infusion and were not assessed as "unrelated to study treatment" by the investigator, regardless of whether or not they were clinically consistent with hypersensitivity. ‡ Alanine aminotransferase or aspartate aminotransferase levels >3× upper limit of normal with either bilirubin levels >2× upper limit of normal. § Reported by Medical Dictionary for Regulatory Activities preferred term.

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The copyright holder for this this version posted September 1, 2020. . https://doi.org/10.1101/2020.08.27.20183442 doi: medRxiv preprint 7-category ordinal scale: 1, discharged or ready for discharge; 2, non-ICU hospital ward, not requiring supplemental oxygen; 3, non-ICU hospital ward, requiring supplemental oxygen; 4, ICU or non-ICU hospital ward, requiring noninvasive ventilation or high-flow oxygen; 5, ICU, requiring intubation and mechanical ventilation; 6, ICU, requiring extracorporeal membrane oxygenation or mechanical ventilation and additional organ support; 7, death.

Death or hospital discharge were carried forward, including deaths after withdrawal with any remaining missing data imputed using the last postbaseline observation carried forward method.

Steroids included corticosteroids except topical, inhaled, or dermatologic applications.

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World Health Organization. Coronavirus disease (COVID-19) pandemic

Clinical characteristics of coronavirus disease 2019 in China

Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study

Immunology of COVID-19: current state of the science

Complex immune dysregulation in COVID-19 patients with severe respiratory failure

Elevated interleukin-6 and severe COVID-19: a metaanalysis

Endothelial cell infection and endotheliitis in COVID-19

Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19

The vascular endothelium: the cornerstone of organ dysfunction in severe SARS-CoV-2 infection

A review of recent advances using tocilizumab in the treatment of rheumatic diseases

Favorable changes of CT findings in a patient with COVID-19 pneumonia after treatment with tocilizumab

Tocilizumab, an anti-IL6 receptor antibody, to treat Covid-19-related respiratory failure: a case report

First case of COVID-19 in a patient with multiple myeloma successfully treated with tocilizumab