Trial Design and Randomization
In this trial, which was conducted at 62 hospitals in nine countries in Europe and North America (Canada, Denmark, France, Germany, Italy, the Netherlands, Spain, the United Kingdom, and the United States), we enrolled adults (≥18 years of age) with severe Covid-19 pneumonia, as confirmed by positive polymerase-chain-reaction (PCR) assay of any body fluid and evidenced by bilateral chest infiltrates on chest radiography or computed tomography. Eligible patients had a blood oxygen saturation of 93% or less or a ratio of the partial pressure of oxygen to the fraction of inspired oxygen of less than 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 a bacterial, fungal, or viral infection other than SARS-CoV-2. Standard care according to local practice (antiviral treatment, low-dose glucocorticoids, convalescent plasma, and supportive care) was provided. However, concomitant treatment with another investigational agent (except antiviral drugs) or any immunomodulatory agent was prohibited. Written informed consent was obtained from all the patients or, if written consent could not be provided, the patient’s legally authorized representative could provide oral consent with appropriate documentation by the investigator.
Eligible patients were randomly assigned in a 2:1 ratio to receive a single intravenous infusion of tocilizumab (at a dose of 8 mg per kilogram of body weight, with a maximum dose of 800 mg) or placebo plus standard care by means of an interactive voice or Web-based response system and permuted-block randomization. Randomization was stratified according to geographic region (North America or Europe) and the use of mechanical ventilation (yes or no). If clinical signs or symptoms did not improve or worsened (defined as sustained fever or worsened clinical status on an ordinal scale), a second infusion of tocilizumab or placebo could be administered 8 to 24 hours after the first dose. The primary analysis was performed at day 28, and the final trial visit occurred at day 60. Additional details regarding the trial design are provided in the protocol document (which includes the statistical analysis plan), available with the full text of this article at NEJM.org.
Evaluations
For the evaluation of patients in this trial, baseline was defined as the last observation before the administration of tocilizumab or placebo on day 1. The patients’ clinical status was assessed on an ordinal scale according to the following categories: 1, discharged or ready for discharge; 2, hospitalization in a non–intensive care unit (ICU) without supplemental oxygen; 3, non–ICU hospitalization with supplemental oxygen; 4, ICU or non–ICU hospitalization with noninvasive ventilation or high-flow oxygen; 5, ICU hospitalization with intubation and mechanical ventilation; 6, ICU hospitalization with extracorporeal membrane oxygenation or mechanical ventilation and additional organ support; and 7, death. Clinical status was recorded at baseline and every day during hospitalization.
Patients were also evaluated according to the level of clinical severity on the National Early Warning Score 2, which is a standardized assessment for identifying acutely ill patients on the basis of respiration rate, oxygen saturation, systolic blood pressure, pulse rate, level of consciousness, and temperature; values on this instrument range from 0 to 20, with higher scores indicating greater clinical risk.
Outcome Measures
The primary efficacy outcome was clinical status at day 28, as assessed on the seven-category ordinal scale. Key secondary efficacy outcomes were clinical status at day 14 on the ordinal scale, mortality at day 28, number of ventilator-free days by day 28, the time to improvement from baseline by at least two categories on the ordinal scale, and the time to hospital discharge or readiness for discharge; the latter was defined as a normal body temperature and respiratory rate and stable oxygen saturation while breathing ambient air or 2 liters or less of supplemental oxygen. Other secondary outcomes were the time until clinical failure, which was defined as death, discontinuation from trial participation during hospitalization, initiation of mechanical ventilation, or ICU transfer or a 1-category worsening of clinical status in patients who were receiving mechanical ventilation or who were in the ICU at baseline; the initiation of mechanical ventilation among patients who were not receiving mechanical ventilation at randomization; the incidence of ICU transfer among patients who were not in an ICU at baseline; and the duration of ICU stay. Adverse events were recorded according to the system organ class and preferred terms in the Medical Dictionary for Regulatory Activities, version 23.0.
Trial Oversight
The trial was conducted in accordance with the Good Clinical Practice guidelines of the International Council for Harmonisation E6 and the principles of the Declaration of Helsinki or local regulations, whichever afforded greater patient protection. The protocol was reviewed by the institutional review board or ethics committee at each site.
The first draft of the manuscript was written by the penultimate author, with writing support provided by ApotheCom and funded by the sponsor, F. Hoffmann–La Roche. The data were analyzed by the sponsor. The authors had access to all the data for the patients who were enrolled at their trial site. All the authors made the decision to submit the manuscript for publication and vouch for the completeness and accuracy of the data and for the adherence of the trial to the protocol.
Statistical Analysis
We performed efficacy assessments of the primary and secondary outcomes in the modified intention-to-treat population, which included all the patients who had undergone randomization and received a dose of tocilizumab or placebo. We calculated that a sample size of 450 patients would provide a power of 90% to determine a between-group difference in the primary outcome (clinical status at day 28), assuming a distribution on the ordinal scale that corresponded to an odds ratio of 2.0. If significance was met, we tested mortality at day 28 at the 5% level using a hierarchical approach, but no other adjustment for multiple comparisons was planned. In the statistical analysis plan, up to three interim efficacy analyses were specified but were not performed because of rapid enrollment.
The analyses were stratified according to region and mechanical-ventilation status at randomization, except for some subgroup analyses, as prespecified. For the primary outcome of clinical status at day 28, we compared the distribution on the ordinal scale using a nonparametric van Elteren test. We used a proportional-odds model to calculate odds ratios and 95% confidence intervals to determine the odds of being in a better clinical-status category in the tocilizumab group than in the placebo group. A multiple-imputation approach was used to handle missing data and was implemented by means of bootstrapping. This approach assumed that data were missing at random within strata and trial group. (Details regarding these methods are provided in the Methods section in the Supplementary Appendix, available at NEJM.org.)
We used the Cochran–Mantel–Haenszel test to analyze differences in mortality and incidence of mechanical ventilation and ICU transfer, the van Elteren test to assess differences in the number of ventilator-free days, and a log-rank test and Kaplan–Meier plots to assess secondary outcomes in time-to-event analyses. Data regarding deaths were censored at day 28 for all time-to-event analyses involving clinical improvement. Patients who had died by day 28 were considered to have had no ventilator-free days.24 Patients who had died or discontinued participation in the trial before discharge by day 28 were assumed to have required mechanical ventilation or ICU transfer for the respective incidence analyses. Cumulative incidence plots were generated with the use of the nonparametric Aalen–Johansen estimator, in which death is a competing risk, and additional cause-specific Cox regression was performed.
Safety was assessed in the population that included all the patients who had received a dose of tocilizumab or placebo, according to the trial agent that was first received. Patients who received either tocilizumab or placebo in error were included in the safety analysis.
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