Trial design and randomization
In this trial, 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 measured adults (≥18) entered. age) with severe Covid-19 pneumonia, as confirmed by positive polymerase chain reaction (PCR) testing of any body fluid and evidenced by bilateral chest infiltrations 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 unavoidable within 24 hours or if they had active tuberculosis or another bacterial, fungal or viral infection other than SARS-CoV-2. Standard practice according to local practice (antiviral treatment, low dose glucocorticoids, recovery plasma and supportive care) were provided. However, concomitant treatment with another investigating agent (other than antivirals) or any immunomodulatory agent is prohibited. Written informed consent was obtained from all the patients, or if the written consent could not be granted, the legally authorized representative of the patient could give oral consent with appropriate documentation by the examiner.
Eligible patients were randomly assigned to 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 through an interactive voice or web-based response system and random blocking with permute. Randomization was stratified by geographic region (North America or Europe) and the use of mechanical ventilation (yes or no). If clinical signs or symptoms do not improve or worsen (defined as persistent fever or poor clinical status on an ordinal scale), a second infusion of tocilizumab or placebo may be administered 8 to 24 hours after the first dose. The primary analysis was performed on day 28, and the final trial visit took place on day 60. Additional details regarding the design of the experiment are provided in the protocol document (which includes the statistical analysis plan), which is available at NEJM with the full text of this article. .org.
Evaluations
For the evaluation of patients in this trial, the baseline was defined as the last observation before administration of tocilizumab or placebo on day 1. The clinical status of the patients was assessed on an ordinal scale according to the following categories: 1, discharged or ready for dismissal; 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 non-invasive ventilation or high flow oxygen; 5, ICU hospitalization with intubation and mechanical ventilation; 6, ICU hospitalization with out-of-body membrane oxygenation or mechanical ventilation and additional organ support; and 7, death. Clinical status was recorded at baseline and daily during hospitalization.
Patients were also evaluated according to the level of clinical severity on National Early Warning Score 2, which is a standardized assessment for identifying acutely ill patients based on respiratory 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 a greater clinical risk.
Outcome measures
The primary efficacy outcome was clinical status on day 28, as assessed on the seven-category ordinal scale. Key outcomes for secondary efficacy were clinical status on day 14 on the ordinal scale, mortality on day 28, number of ventilator-free days on day 28, time to at least two categories on the ordinal scale from baseline, and time to discharge from hospital. or readiness for dismissal; the latter is defined as a normal body temperature and respiratory rate and stable oxygen saturation while the air inhales or 2 liters or less of supplemental oxygen. Other secondary outcomes were the time to clinical failure, which was defined as death, cessation of participation in the trial during hospitalization, initiation of mechanical ventilation, or ICU transfer or a deterioration of clinical status in one category at patients who received mechanical ventilation or in the ICU at baseline; the onset of mechanical ventilation among patients who did not receive random ventilation; the incidence of ICU transfer among patients who were not on the baseline in an ICU; and the duration of the ICU stay. Adverse events were recorded according to the system organ class and the preferred terms in the Medical dictionary for regulatory activities, version 23.0.
Trial supervision
The trial was conducted in accordance with the guidelines for good clinical practice of the International Council for Harmonization E6 and the principles of the Declaration of Helsinki or local regulations, which also provide the protection of patients. The protocol has been reviewed by the institutional review board or ethics committee in each area.
The first draft of the manuscript was written by the penultimate author, with written support from 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 enrolled at their trial site. All the authors made the decision to submit the manuscript for publication and declare for the completeness and accuracy of the data and for compliance with the trial with the protocol.
Statistical analysis
We performed efficacy assessments of the primary and secondary outcomes in the modified population for the purpose of treatment, which included all patients who underwent 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 difference between groups in the primary outcome (clinical status on day 28), assuming a distribution on the ordinal scale that corresponds to a odds ratio of 2.0. If significance was met, we tested mortality at day 5 at the 5% level using a hierarchical approach, but no other adjustment for multiple comparisons was planned. The statistical analysis plan specified up to three interim efficiency analyzes, but this was not performed due to rapid entry.
The analyzes were stratified according to randomization according to regional and mechanical ventilation status, except for some subgroup analyzes, as prescribed. For the primary outcome of clinical status on day 28, we compared the distribution on the ordinal scale using a non-parametric Parental Test. We used a proportional odds model to calculate the 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-attribution approach was used to handle missing data and was implemented through bootstrapping. This approach assumed that data were randomly missing within strata and experimental group. (Details regarding these methods are provided in the Methods section of the supplementary appendix, available at NEJM.org.)
We used the Cochran – Mantle – Haenszel test to analyze differences in mortality and incidence of mechanical ventilation and ICU transmission, that of Parental test to determine differences in the number of fan-free days, and a log-rank test and Kaplan – Meier erven to assess secondary outcomes in time-to-event analyzes. Death data were censored on day 28 for all time-to-event analyzes involving clinical improvement. Patients who died on day 28 are considered no ventilator-free days.24 It is assumed that patients who died on day 28 before discharge or discontinued participation in the trial suspect that they require mechanical ventilation or ICU transfer for the respective occurrence analyzes. Cumulative occurrence plots were generated using the non-parametric Aalen – Johansen estimator, in which death is a competitive risk, and additional cause-specific Cox regression was performed.
Safety was assessed in the population including all patients who received a dose of tocilizumab or placebo, according to the first-time trial. Patients who incorrectly received tocilizumab or placebo were included in the safety analysis.