We performed this randomized, double-blind, placebo-controlled, phase 3 trial to evaluate the safety and efficacy of tokilizumab in hospitalized patients with Kovid-19 pneumonia who were not receiving mechanical ventilation. Global test sites that recorded high-risk and minority populations were included to increase understanding of the clinical profile of tokizulam in these patients and to allow access to underscore and minority populations, which are commonly used in clinical trials Do not represent in Details of site selection are given in the methods section. Supplementary Addendum, Is available at NEJM.org with the full text of this article.
Patients who were 18 years of age or older (there was no upper age limit) and who were hospitalized with Kovid-19 pneumonia who were confirmed by polymerase-chain-reaction tests and for radiographic imaging enrollment Were eligible. Blood oxygen saturation in patients was less than 94% when inhaling ambient air, but was excluded if they were consistently receiving positive airway pressure, bilewell positive airway pressure, or mechanical ventilation. Patients received standard care according to local practice, which may include antiviral treatment, systemic glucocorticoids (recommended dose, ≤1 mg per kilogram of body weight of methylpredisolone or equivalent), and limited use of supportive care. If it is prescribed by the treating physician, or if they show signs of active tuberculosis or suspected active bacterial, fungal or viral infections (other than SARS-CoV-2 infection), then death from the disease within 24 hours Patients were excluded. Or well-controlled human immunodeficiency virus infection). Patients with coexistence status were not excluded until the investigator determined that safe participation in the trial would be preferred.
The legally authorized representative of each patient or patient provided written or orally informed consent. Declaration of good clinical practice and Helsinki or local regulations, whichever cost the maximum patient safety, were tested according to the International Conference on Harmonization E6 Guidelines. This test was approved by all testing sites through the Central Trial Institutional Review Board, Western Institutional Review Board or a local institutional review board; In addition, testing was approved at some sites by local ethics committees. Institutional Review Boards or Ethical Committees approved Make a contract (Available at NEJM.org in each part). The sponsor designed the test, conducted it according to protocol, collected data, and analyzed it; A contract research organization, paid by the sponsor, manages and supervises the test under the direction and supervision of the sponsor. All authors pledge for the accuracy and completeness of the data and for the integrity of the test for the protocol. All drafts of the manuscript were prepared by the authors with editorial and sponsor-funded assistance.
Using permissive-block randomization and an interactive voice- or web-response system, we randomized patients to a 2: 1 ratio, standard care, as well as one or two doses of either intravenous tocilizumab (8 kg per kg) Body weight) assigned to receive. , Maximum 800 mg per dose) or placebo. Randomization was stratified by country (United States, Mexico, Kenya, South Africa, Peru or Brazil) and age (age60 or> 60 years). Details of trial blinding are given in Supplementary Addendum. If a patient’s clinical signs or symptoms have worsened or have not improved (ie, if the patient had a persistent fever or worsening condition as assessed with the use of a seven-grade ordinal scale), So an additional infusion can be administered 8 to 24 hours later.
Efficacy was evaluated for 28 days, and patients were followed up for a total of 60 days. Patients who were discharged before 28 days were considered to have completed the test and followed weekly until the 28th day, who were protected for 60 days.
The primary efficacy outcome is mechanical ventilation (aggressive mechanical ventilation or extraspial membrane oxygenation) or death by day 28. In addition to the evaluation of primary efficacy outcome, the results of the primary efficacy analysis were evaluated according to age, race, or ethnic group. , Geographic area, glucocorticoid use, antiviral use, and number of tocilizumab or placebo supplements received.
The major secondary efficacy assessed over the 28-day period was the time of hospital discharge or readiness for discharge as assessed with the use of a seven-grade ordinal scale (with ranges from 1 to 7 and higher ranges. Give a bad signal. Condition) (Table S1 in Supplementary Addendum); Time to at least two-grade improvement in clinical status relative to baseline on a seven-category ordinal scale (for patients in Category 2 at baseline, those with Category 1 clinical status were considered thresholds) ; Time of clinical failure (time of death, mechanical ventilation, entry into an intensive care unit) [ICU] [or, in patients who were already in the ICU at trial enrollment, worsening by two categories from baseline on the seven-category ordinal scale], Or return [whichever occurred first]); And death.
The occurrence and severity of adverse events were evaluated. These events were determined according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0.
The modified intention-to-treat population included all patients who underwent randomization and received either tocilizumab or placebo. We estimated that assignments of 379 patients with 2: 1 would provide at least 80% power, detecting an intergroup difference of 15 percentage points in the primary outcome with the use of the log-rank test For, assume a cumulative incidence rate. (Death or mechanical ventilation) in 25% of the tocizumab group and 40% in the placebo group. Efficacy analysis was performed in a population with modifiable intention to treat patients grouped according to treatment assignment. The analyzes were stratified according to age group (> 60 or> 60 years).
The primary outcome was estimated with the Kaplan – Maier method, and the cumulative incidence curves were compared between the two groups with a stratified log-rank test. The stratified Cox proportional-hazards model was used to estimate hazard ratios (for tocilizumab compared to placebo) and 95% confidence intervals. In this analysis, data on patients who survived and did not receive mechanical ventilation on or before date 28 were censored on the last follow-up date or day 28, whichever occurred first.
Primary and key secondary outcomes were evaluated in a hierarchical manner to control the overall test-wide type I error rate at the 5% significance level. If the primary outcome reached a two-party 5% level of significance, the major secondary outcomes were tested in the following predetermined order: time to discharge or readiness of hospital discharge, time to improve clinical status, clinical Time to failure, and death.
Time-to-event secondary results were compared between the two groups with the use of the Kaplan – Meier approach. Death at the 28 days was censored in an analysis of readiness and timing of hospital discharge or improvement in clinical status. Data on patients who discontinued testing before hospital discharge or readiness for discharge or improvement in clinical status were censored on the date of the last serialization assessment. In the analysis of time to clinical failure, data on patients who did not have clinical failure before or on day 28 were censored on the last contact date or day 28, whichever occurred first. The Cochran – Mantel – Hensel test with adjustment for age was used to assess intra-group differences in mortality for up to 28 days. The 95% confidence interval was not adjusted for plurality and cannot be used to assess effects. An analysis of the sensitivity of the time of discharge to hospital and improvement in clinical status, treated as an increased risk, was performed with death. Information about source data validation and subgroup analysis is given. Supplementary Addendum.
Safety was assessed in all patients who received either tocilizumab or placebo; The patients were grouped according to the actual agent received. An interim security review was conducted by the Internal Monitoring Committee.
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