We performed a randomized, double-blind, placebo-controlled trial between June 4, 2020 and October 25, 2020 (when the last patient completed follow-up), at clinical sites and geriatric units in Argentina. The trial was approved by the participating institutions and the Institutional Review Boards of Buenos Aires and was monitored by an independent data and security monitoring board. The authors who designed the test and wrote the manuscript are listed in Table S15. Supplementary Addendum, Is available at NEJM.org with the full text of this article. All authors compiled data and vouchers to ensure accuracy and completeness of data and adherence to testing Make a contract, Available at NEJM.org. Three of the authors analyzed the data. The last author wrote the first draft of the manuscript. Any person who is not an author contributed to the writing of the manuscript. No confidentiality agreements relating to data are between sponsors and authors or their institutions.
Patients who were 75 years of age or older, regardless of current co-current conditions, or between 65 and 74 years of age, had at least one coexistence condition identified and evaluated for eligibility Was. Co-existing conditions as defined in Table S1 include hypertension or diabetes for which the patient was currently receiving pharmacologic treatment, obesity, chronic kidney failure, heart disease, and COPD. By reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay at the time of screening for SARS-CoV-2, at least 48 hours in each sign or symptom in eligible patients, at least one of the two categories Was. : At least 37.5 ° C, unexplained sweating, or chills; And dry cough, indigestion, tiredness, myalgia, anorexia, sore throat, dysgepsia, anosmia, or rhinorrhea. Exclusion criteria included severe respiratory disease (primary end point), any disease listed in Table S5 or both.
Patients who agreed to the test with the RT-PCR assay (IAMPVID-19, Attila Bio System) to detect SARS-COV-2 provided consent to obtain samples of home seizures and nasopharyngeal and oropharyngeal secretions. Doing patients were obtained. Patients with detectable SARS-CoV-2 RNA were taken to test hospitals and invited to sign an informed-consent form. After July 22, 2020, legal guardians provided consent for patients who had cognitive impairment. Starting on July 27, 2020, as several geriatric institutions with the outbreak of SARS-CoV-2 were transformed into low-complex inaptic units for mildly ill residents infected with SARS-CoV-2, we tested Screened residents meeting the criteria and invited on-site testing.
Eligible patients who provided written informed consent were randomly administered a complex of 250 ml against a SARS-CoV-2 spike (S) protein (COVIDAR IgG, Instituto Leloir, Argentina) or 250 ml with a IgG titer greater than 1: 1000. Plasma was assigned to receive. Plesibo (0.9% normal saline). Convulsive plasma was arbitrarily defined as “high-titer” and contained antibody concentrations in the upper 28th percentile. A computer-generated randomization sequence was designed with a balanced allowed block design (block size 2) at the data center.
Convulsant plasma or placebo was administered less than 72 hours after the onset of symptoms, and infusions were given over a period of 1.5 to 2.0 hours. Both the convulsion plasma and placebo were concealed with opaque bags and tape to cover the confusion catheter. Patients were monitored for adverse events up to 12 hours after the intervention.
A total of 479 potential plasma donors with SARS-CoV-2 infection for at least 10 days and who had been asymptomatic for 3 days or more and had two negative RT-PCR tests17 Identification was done through hospital lists and an online campaign. Potential donors who provide written informed consent were screened at home and screened for SARS-CoV-2 S IgG, a titer in serum greater than 1: 1000. Each of the 135 candidates (28%) donated 750 ml of plasma (see Fig. S6) with sufficient titers.
24 hours after the infusion ended, a sample of venous blood (5 ml) was obtained from the patients. Serum samples were preserved at C20 ° C until the trial was completed. We assayed anti-S IgG SARS-CoV-2 using the COVIDAR IgG test. In addition, we assayed samples using the SARS-CoV-2 spike S1-RBD IgG enzyme-linked immunosorbent assay detection kit (GenScript) and the SARS-CoV-2 Surrogate Neutralization Test Kit (GenScript).
The clinical status of patients was tested daily for 15 days to evaluate for primary end-point events occurring in the hospital, in participating children’s institutions, or at home if patients were discharged. Was given (Figs. S7 and S8). Patients who had persistent symptoms, for whom medical care was approved, had a maximum of 25 days to follow until resolution of symptoms or an assessment of the incidence of secondary endpoint. Trial physicians used predefined questionnaires to collect clinical information. None of the patients received any experimental therapy for Kovid-19 other than conidient plasma. The data were recorded on paper forms and then double-entered into an electronic database.
The primary endpoint of the test was the development of severe respiratory disease, defined as a respiratory rate of 30 breaths per minute or more, oxygen saturation of less than 93% while the patient is breathing ambient air, or both. Was. Patients were assessed between 12 hours for this end point event, which was between day 15 of convulsion plasma or placebo violations and test participation.
Prespecified secondary clinical end points were fatal respiratory disease (defined as oxygen supplementation at a fraction of induced oxygen) [Fio2] 100%, lifeless or invasive ventilation, entry into an intensive care unit, or any combination of these), severe systemic disease (respiratory failure with a ratio of F to partial pressure of oxygen)I am2 ≤200 mm Hg, shock, multiple organ dysfunction syndrome, or any combination of these), and death associated with Kovid-19. Patients who did not resolve the disease were evaluated up to 25 days after trial participation for these end-point events. On July 22, 2020, we amended the protocol to include a fourth secondary end point, which included any of the three secondary end points alone or in combination, as described above.
The trial was initiated when the number of Kovid-19 cases in Buenos Aires was high. However, as the number of cases declined, it became apparent that it would take about 5 months to reach the enrollment target. As a result, after discussion with the data and safety monitoring board and enrollment of 76% of the target population, we decided that it would be logically impossible and morally questionable, given the daily costs of epidemics in life and disease, testing. To continue, and we stopped checking the results.
Given the complexity of implementing this intervention, a minimum clinically significant difference was determined to be a 50% relative decrease in the expected 50% of patients in the placebo group and 30% of patients in the convulsive plasma group whose primary endpoint was Will happen again. We estimated a total sample size of 210 patients (105 per test group) at a significance level of α = 0.05, providing tests with 80% power to detect between-time differences. We performed a two-sided z-test of ratios with continuity correction and a schematic interim analysis with the O-Bryan-Fleming spending function to determine test boundaries.
In the intention-to-treat analysis, endpoints were estimated from the time of randomization. Continuous variables are presented as means and standard deviations or median and interquartile ranges, appropriate and hierarchical variables are presented as percentages.
In the primary analysis strategy, we used Kaplan – Meier product range estimates to compare the time taken to reach the primary end point in the test groups. An estimate of relative risk and 95% confidence interval was also reported. A modified intention-to-treat analysis excluded patients who were disqualified between randomization and administration of plasma or placebo.
The protocol determined the evaluation of IgG safety correlations and a subgroup analysis that was suggested by the Data and Safety Monitoring Board and approved by the Institutional Review Boards on November 2, 2020. This analysis included evaluation of end-point events in patients. 75 years or older, regardless of co-conditions, and those between 65 and 74 years of age who had at least one co-condition.
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