key: cord-1032902-gmm3ysfz
authors: Lescure, F.-X.; Honda, H.; Fowler, R. A.; Sloane Lazar, J.; Shi, G.; Wung, P.; Patel, N.; Hagino, O.
title: Sarilumab treatment of hospitalised patients with severe or critical COVID-19: a multinational, randomised, adaptive, phase 3, double-blind, placebo-controlled trial
date: 2021-02-03
journal: nan
DOI: 10.1101/2021.02.01.21250769
sha: 1484426a278d4ff4c01a650d59bd01681697b96f
doc_id: 1032902
cord_uid: gmm3ysfz

Background: Elevated 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. Methods: This 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). Findings: Between 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 (12.0 [9.0-15.0] days) and sarilumab groups (200 mg: 10.0 [9.0-12.0] days, p=0.96, log-rank test; 400 mg: 10.0 [9.0-13.0] days, p=0.34) or in proportions of patients alive (placebo, 91.7%; sarilumab 200 mg, 89.9%, p=0.63; sarilumab 400 mg, 91.9%, p=0.85). At day 29, there were numerical, nonsignificant survival differences between sarilumab 400 mg (88%) and placebo (79%; difference +9%, 95% CI -7.7 to 25.5, p=0.25) for critical patients. There were no unexpected safety signals. Interpretation: This 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. Funding: Sanofi and Regeneron Pharmaceuticals, Inc.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in December 2019 and the associated coronavirus disease (COVID-19) 1 has resulted in ≥47 million confirmed infections and ≥1ꞏ2 million deaths worldwide as of November 4, 2020.

COVID-19-associated pneumonia can rapidly progress to acute respiratory distress syndrome (ARDS), estimated to affect 5-20% of patients with COVID-19. [2] [3] [4] [5] In some patients, COVID-19 may cause damage to additional organs, including heart, brain, kidney, and liver. 6 In the first several months of the pandemic, there were no treatments with proven efficacy for patients with severe or critical COVID-19; therefore, carefully designed randomised, controlled trials of novel or repurposed medications were, and still are, warranted.

Literature to date supports an association of proinflammatory cytokines with acute, lifethreatening respiratory injury observed in patients with COVID-19. 7 Among these cytokines, interleukin (IL)-6 appears to play a prominent role in the pathogenesis of COVID-19-related ARDS. 8 Results of a meta-analysis of laboratory findings indicate that 53% of patients with COVID-19 have increased IL-6 levels. 9 A meta-analysis of 23 clinical trials involving 3400 patients showed that patients with severe COVID-19 had higher levels of IL-6 than those with mild disease, and even higher levels were observed in patients who died. 10 Two additional meta-analyses 11, 12 and a large, prospective cohort study of patients hospitalised with COVID-19 13 also demonstrated an association between elevated IL-6 and COVID-19related mortality. Many of these findings were first published during the early months of the pandemic, suggesting that inhibition of IL-6 signaling may have value as a treatment to manage inflammatory manifestations of COVID-19 pneumonia.

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The copyright holder for this preprint this version posted February 3, 2021. ; https://doi.org/10.1101/2021.02.01.21250769 doi: medRxiv preprint Sarilumab is a human monoclonal antibody that inhibits the binding of IL-6 to its α receptor and is approved for treatment of adults with moderate to severely active rheumatoid arthritis. 14,15 Because sarilumab inhibits both soluble and membrane-bound forms of IL-6 receptors, 14,16 potentially suppressing proinflammatory signaling by both pulmonary epithelial and immune cells, 8 we hypothesised it could reduce the severity of pulmonary complications of COVID-19, including respiratory failure. Here, we report results of a 60day, randomised, placebo-controlled trial of sarilumab in hospitalised patients with severe to critical COVID-19.

This study was an adaptive, phase 2/3, multicentre, randomised, double-blinded trial. Because of the uncertainties of assessing treatment efficacy in COVID-19 pneumonia at the time of study design, the initial protocol allowed adaptations such as modification of the provisional phase 3 endpoints, sample size re-estimation before entering phase 3, or closing a dose group while the study remained blinded. Patients were assessed daily while hospitalised until discharge, or death, with a final follow-up on day 60. The trial was monitored by an external independent data monitoring committee (IDMC) with ongoing access to unblinded clinical data. The protocol was approved by the institutional review boards at each participating hospital and by national ethics committees, as required by local and national regulations. The study was carried out in accordance with the International

Association's Declaration of Helsinki and its amendments. 17 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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This study enrolled patients aged 18 years or older at the time of signing informed consent who had been hospitalised for laboratory-confirmed SARS-CoV-2 infection in any specimen within 2 weeks prior to randomisation and with evidence of pneumonia by chest imaging or chest auscultation and no alternative explanation for current clinical presentation. Patients also had to meet criteria for severe disease (defined as administration of supplemental oxygen by nasal cannula, simple face mask, or another similar device) or critical disease (defined as need for supplemental oxygen delivered by nonrebreather mask or high-flow nasal cannula, use of invasive or noninvasive ventilation, or treatment in an intensive care unit). Before participating in the trial, informed consent was obtained from all patients or their legally authorised/appointed representatives, as specified by local law and in compliance with or exceeding ethics committee requirements.

Patients were excluded from the study if they had at least one of the following: in the investigator's opinion, a low probability of surviving 48 hours or remaining at the investigational site beyond 48 hours, or dysfunction of ≥2 organ systems or need for extracorporeal life support or renal replacement therapy at screening; absolute neutrophil count <2000/mm 3 ; aspartate aminotransferase or alanine aminotransferase (ALT) exceeding 5-fold upper limit of normal (ULN) at screening; platelets <50,000/mm 3 at screening; known active, incompletely treated, suspected or known extrapulmonary tuberculosis; prior or concurrent use of immunosuppressants at screening, including, but not limited to, IL-6 inhibitors or Janus kinase inhibitors within 30 days of baseline; anti-CD20 agents without evidence of B-cell recovery to baseline levels or IL-1 receptor antagonist (anakinra) within 1

week of baseline; abatacept within 8 weeks of baseline; tumor necrosis factor α inhibitors within 2-8 weeks of baseline; alkylating agents, including cyclophosphamide, within 6 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted February 3, 2021. ; https://doi.org/10.1101/2021.02.01.21250769 doi: medRxiv preprint 6 months of baseline; cyclosporine, azathioprine, mycophenolate mofetil, leflunomide, or methotrexate within 4 weeks of baseline; or intravenous (IV) immunoglobulin within 5 months of baseline; use of systemic chronic (eg, oral) corticosteroids for a condition not related to COVID-19 at doses higher than prednisone 10 mg/day or equivalent at screening; or suspected or known active systemic bacterial or fungal infections within 4 weeks of screening.

Eligible patients were randomised (2:2:1) to IV sarilumab 400 mg, sarilumab 200 mg, or placebo according to a central randomisation scheme using permuted blocks of 5 and implemented through an interactive response technology (IRT). Randomisation was stratified by severity of illness (severe or critical) and use of systemic corticosteroids (yes or no).

Patients and investigators remained blinded to patients' assigned intervention throughout the course of the study. An unblinded pharmacist was responsible for the preparation and dispensation of all study interventions.

Sarilumab 400 mg, sarilumab 200 mg, or placebo were prepared according to instructions provided in the pharmacy manual. After confirming the randomisation number accessed via IRT, the hospital pharmacist added the contents of prefilled syringes (PFS) of sarilumab 200 mg solution for subcutaneous injection supplied by the sponsor into a specified volume of locally sourced 0ꞏ9% NaCl solution for IV infusion (two syringes for the 400-mg dose, one syringe for the 200-mg dose, and 0ꞏ9% NaCl solution for the placebo dose) to produce an IV bag containing a colourless solution to be administered by blinded hospital staff as a single IV infusion. Patients could have the IV infusion stopped for a safety-related issue, in which . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted February 3, 2021. ; https://doi.org/10.1101/2021.02.01.21250769 doi: medRxiv preprint case they did not continue with dosing. An option for a second dose existed (within the assigned treatment arm) within 24-48 hours of the first dose, based on the investigator's benefit-risk assessment (Amended protocol 02; April 8, 2020).

Efficacy assessments included a daily assessment of clinical status until discharge, body temperature (day 1-3: four times a day; day 4-29: twice a day), oxygen administration (day . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The original phase 2 primary endpoint was the time to resolution of fever for at least 48 hours without antipyretics or until discharge (original protocol; March 18, 2020). However, the unanticipated rapid rate of enrolment made the plan to use the phase 2 analysis to select phase 3 efficacy endpoints unfeasible. As a result, the primary and key secondary endpoints for phase 3, as described above, were adopted a priori in the Amended protocol 04 (April 8, 2020).

Other secondary efficacy endpoints included differences in time-to-event endpoints by treatment (eg, time to improvement of ≥1 point on the 7-point scale, fever resolution, or discharge from hospital), score changes at specific time points (eg, proportion with 1-point improvement/worsening), and event durations (eg, mechanical ventilation, hospitalisation).

Safety was assessed by investigator reports of adverse events (AEs), serious AEs, AEs of special interest (infusion-related reactions; hypersensitivity reactions; absolute neutrophil count <500/mm 3 with or without concurrent invasive infection; increase in ALT of at least 3fold ULN or in excess of 3-fold ULN and at least 2-fold over the baseline level; invasive bacterial or fungal infections of clinical significance with confirmed diagnosis based on the investigator's assessment with appropriate diagnostic workups and consultations;

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The copyright holder for this preprint this version posted February 3, 2021. ; https://doi.org/10.1101/2021.02.01.21250769 doi: medRxiv preprint symptomatic overdose), 19 and clinical laboratory parameters including lymphocyte count, neutrophil count, and ALT on days 1, 4, 7, 15, 21, and 29 (if still hospitalised).

This study addressed the null hypothesis of no difference in time to ≥2-point improvement on the 7-point scale between a sarilumab dose group and placebo. In sample size determination, approximately 400 patients, randomised 2:2:1, were estimated to provide ≥90% power for pairwise comparison between each sarilumab dose (approximately 160 patients each) and

placebo (approximately 80 patients) using a log-rank test of superiority at a two-sided significance level of 0ꞏ05. Assumptions included accrual duration of 3 months, each patient being followed up for ≥29 days, and proportions of patients with 2-point improvement at day 15 being 45% for placebo and 70% for sarilumab.

The modified intention-to-treat (mITT) and safety populations included all randomised patients treated with study medication. Primary analysis was planned at day 29 and final analysis at day 60. Analysis of the primary endpoint (mITT) involved a stratified log-rank test with treatment as a fixed factor. Estimation of treatment effect was provided as hazard ratio (HR), generated using a stratified Cox proportional hazards model with treatment as a covariate. Patients without improvement were censored at the last observation time point; patients who took rescue medication in the study without prior improvement were censored at rescue medication start date. Patients who died were deemed no improvement starting from death date. The proportional hazards assumption was assessed by visual inspection of the plot of log(-log(survival)) versus log(survival time) to determine whether curves were parallel among treatments. Analysis of the key secondary endpoint (mITT) involved a Cochran-Mantel-Haenszel test, with estimation of treatment effect reported as the difference in . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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The study sponsor designed the study and was responsible for data collection, data analysis, and data interpretation. All authors, including those affiliated with the study sponsor, contributed to writing the manuscript, and reviewed and approved the manuscript. The authors had full access to all data in the study and had final responsibility for the decision to submit for publication. This trial is registered with EudraCT (2020-001162-12), ClinicalTrials.gov (NCT04327388), and WHO (U1111-1249-6021).

In total, four amendments were made to the original protocol. Amended protocol 01 (March 26, 2020) implemented clarifications to the original version. Amended protocol 02 (April 8, 2020) implemented changes from phase 2 primary and key secondary endpoints to the phase 3 primary and key secondary endpoints and added an option for a second dose. Amended protocol 03 (April 29, 2020) added an interim analysis when approximately 50% of the total planned number of patients reached day 15, for review by the IDMC and unblinded representatives of sponsor's senior management, who were not involved in study conduct; clarified the extent to which the sponsor could adapt the study following review of an interim . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted February 3, 2021. report; and removed the use of vasopressors as an exclusion criterion. Amended protocol 04 (June 11, 2020) closed enrolment into the 200-mg arm following senior management review of interim results and subsequent confirmation by IDMC review, which favoured the 400-mg arm.

The first patient was screened on March 28, 2020, and the last patient was randomised on July 3, 2020. Last patient -last visit was on September 2, 2020. The study was conducted at 45 sites in Argentina, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Russia, and Spain (table S1). Of 431 patients who were screened, 420 were randomised and 416 received treatment (placebo, n=84; sarilumab 200 mg, n=159; sarilumab 400 mg, n=173) (figure 1).

Baseline demographic, clinical, and laboratory characteristics were overall similar among the treatment groups, with exceptions including sex distribution, ferritin concentration, and proportions of patients with fever and obesity (table 1). Median age was 59ꞏ0 years (interquartile range [IQR] 50ꞏ0-68ꞏ0 years) and 37% of participants were women. According to investigator-reported severity, 61% had severe disease and 39% had critical disease. Two (0ꞏ5%) patients randomised into the severe disease stratum were recorded in the eCRF as having multisystem organ dysfunction because they required renal replacement therapy.

Fever was reported in 52% of patients. Median duration of hospitalisation before dosing was 3ꞏ0 days (IQR 2ꞏ0-4ꞏ0 days). Use of systemic corticosteroids (including dexamethasone), antiviral medications, antibacterial medications (including azithromycin), and hydroxychloroquine/chloroquine prior to, prior to and during, and after first infusion of study medication did not differ substantially across treatment arms (table S2) .

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The copyright holder for this preprint this version posted February 3, 2021. ; https://doi.org/10.1101/2021.02.01.21250769 doi: medRxiv preprint For the primary endpoint of time to improvement of ≥2 points on a 7-point clinical assessment scale, no significant difference was observed between sarilumab doses and placebo up to day 29 (figure 2). Although the between-group differences were not significant, median time to improvement was 2 days longer in the placebo group compared with the sarilumab groups (12 days vs 10 days) (table 2). In addition, no significant differences were observed in the proportions of patients alive at day 29 (placebo, 91ꞏ7%; sarilumab 200 mg, 89ꞏ9%; sarilumab 400 mg, 91ꞏ9%) (table 2).

The proportions of patients discharged due to recovery by day 29 were 83ꞏ3% (placebo), 79ꞏ2% (sarilumab 200 mg), and 79ꞏ2% (sarilumab 400 mg) and the percentages of patients alive at day 60 were 89ꞏ3%, 89ꞏ3%, and 89ꞏ6%, respectively (table S3) . Additional secondary endpoints related to fever, oxygenation, and hospital status are presented in the supplementary materials (table S3) .

Prespecified analysis of day 29 data showed a numerical but nonsignificant difference in survival between sarilumab 400 mg (88%) and placebo (79%; difference +9%, 95% CI −7ꞏ7 to 25ꞏ5, p=0ꞏ25) for the sickest patients in this trial, those with critical disease (table 2) .

In patients with either severe or critical disease, differences between sarilumab 400 mg and placebo on the 7-point clinical status scale were larger during the first 2 weeks of treatment than during the second 2 weeks (figure 2). The time-concentration plot of sarilumab concentration following IV infusion showed an initially rapid decline over the first 4 days and a slower decline from day 7 onward, with nearly complete elimination by day 21 even among patients who received two doses of 400 mg within the first 48 hours (figure S2A).

. CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. curves up to day 60 also suggest more rapid improvement and earlier discharge due to improvement in the sarilumab arms than the placebo arm among the patients with severe . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted February 3, 2021. ; https://doi.org/10.1101/2021.02.01.21250769 doi: medRxiv preprint disease; and higher probability of survival among sarilumab-treated patients than placebotreated in the critically ill group (table 2, figure S1 ). . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted February 3, 2021. ; https://doi.org/10.1101/2021.02.01.21250769 doi: medRxiv preprint 17 Despite these limitations, survival at day 29 was possibly higher by 9% in the sarilumab arms than in the placebo arm for patients who required noninvasive or invasive mechanical ventilation or ECMO at baseline. Therefore, we think the results of this study do not exclude the possibility of a benefit from targeted immunomodulation in hospitalised patients with COVID-19 pneumonia with critical illness and suggest that subsequent randomised trials of targeted immunomodulatory therapies in this disease focus on critically ill patients and are adequately powered to assess survival as a primary endpoint.

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The copyright holder for this preprint this version posted February 3, 2021. ; https://doi.org/10.1101/2021.02.01.21250769 doi: medRxiv preprint Contributors F-XL, JSL, GS, and OH had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. JSL, GS, PW, and OH provided input on the trial design. F-XL, HH, and RF were responsible for acquisition and interpretation of data. F-XL and OH drafted the manuscript. F-XL, HH, RF, NP, and OH critically revised the manuscript. GS contributed to statistical analysis. F-XL, HH, RF, JSL, and PW contributed to conducting the trial. All authors reviewed and approved the final version of the manuscript.

F-XL has received lecture fees from Merck Sharp & Dohme and Gilead Science. HH has nothing to disclose of relevance to this study. RF has no financial conflicts to disclose. JSL, GS, PW, NP, and OH are employees of Sanofi and may hold stock and/or stock options in the company.

Qualified researchers may request access to patient-level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and data set specifications. Patient-level data will be anonymised and study documents will be redacted to protect the privacy of trial participants.

Further details on Sanofi's data-sharing criteria, eligible studies, and process for requesting access can be found at: https://www.clinicalstudydatarequest.com.

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Eli Lilly and Company. Baricitinib in combination with remdesivir reduces time to recovery in hospitalized patients with COVID-19 in NIAID-sponsored ACTT-2 trial. 2020.

https://investor.lilly.com/node/43706/pdf (accessed Oct 20 2020).

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The copyright holder for this preprint this version posted February 3, 2021. ; https://doi.org/10.1101/2021.02.01.21250769 doi: medRxiv preprint ECMO=extracorporeal membrane oxygenation.

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It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted February 3, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted February 3, 2021. .

It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted February 3, 2021. .

It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted February 3, 2021. 

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The copyright holder for this preprint this version posted February 3, 2021. *Analyses for "All patients" were stratified by severity of illness (severe, critical) and use of systemic corticosteroids as entered in IRT. †For analyses of severe and critical disease the category was based on severity entered by the investigator in the eCRF and the stratification factor for disease severity was removed from the model. ‡Severe disease was defined by supplemental oxygen administration by nasal cannula, simple face mask, or another similar device. §Critical disease was defined by one of the following criteria: supplemental oxygen delivered by nonrebreather mask or high-flow nasal cannula, use of invasive or noninvasive ventilation, or treatment in an ICU. ¶Patients without improvement were censored at the last observation time point; patients who took rescue medication in the study without prior improvement were censored at rescue medication start date; patients who died were categorised as no improvement, starting from death date.

.

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The copyright holder for this preprint this version posted February 3, 2021. **p value based on log-rank test. † †Cox proportional hazard model. Hazard ratio >1 indicates greater chance of improvement for sarilumab as compared to placebo. ‡ ‡One death in the sarilumab 200-mg group was included in the "All patients" summary but not in either the "severe" or "critical" categories, as the patient had multiorgan failure. § §Based on asymptomatic confidence limits. ¶ ¶p value based on Cochran-Mantel-Haenszel test.

eCRF=electronic clinical research form. ICU=intensive care unit. IRT=interactive response technology. mITT=modified intention-to-treat.

.

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A novel coronavirus from patients with pneumonia in China

Critical care utilization for the COVID-19

early experience and forecast during an emergency response

Clinical characteristics of coronavirus disease 2019 in China

Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the

Chinese Center for Disease Control and Prevention

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

Multiple organ dysfunction in SARS-CoV-2: MODS-CoV-2

Cytokine levels in critically ill patients with COVID-19 and other conditions

COVID-19: a new virus, but a familiar receptor and cytokine release syndrome

Laboratory findings of COVID-19: a systematic review and meta-analysis

Predictors of mortality in hospitalized COVID-19 patients: a systematic review and meta-analysis

Association of inflammatory markers with the severity of COVID-19: a meta-analysis

Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort study

15. sanofi-aventis groupe. KEVZARA ® (sarilumab) Summary of Product Characteristics

Profile of sarilumab and its potential in the treatment of rheumatoid arthritis

WMA Declaration of Helsinki -Ethical Principles for

The authors and Sanofi thank the patients for their participation in the trial, as well as the investigators. Special thanks to Meng Zhang, Christine Xu, and Evelyne Dombrecht of Sanofi for their expertise, dedication, and leadership of a remarkable team, and to the

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