Trial Design and Oversight
We conducted 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 institutional review boards of the participating institutions and the state of Buenos Aires and was supervised by an independent data and safety monitoring board. The authors who designed the trial and wrote the manuscript are listed in Table S15 in the Supplementary Appendix, available with the full text of this article at NEJM.org. All the authors compiled the data and vouch for the accuracy and completeness of the data and the adherence of the trial to the protocol, available at NEJM.org. Three of the authors analyzed the data. The last author wrote the first draft of the manuscript. No one who is not an author contributed to the writing of the manuscript. No confidentiality agreements related to the data are in place between the sponsors and the authors or their institutions.
Trial Patients
Patients who were 75 years of age or older, irrespective of current coexisting conditions, or between 65 and 74 years of age with at least one coexisting condition were identified and assessed for eligibility. Coexisting conditions, which are defined in Table S1, included hypertension or diabetes for which the patient was currently receiving pharmacologic treatment, obesity, chronic renal failure, cardiovascular disease, and COPD. At the time of screening for SARS-CoV-2 by reverse-transcriptase–polymerase-chain-reaction (RT-PCR) assay, eligible patients had had at least one of each sign or symptom in the following two categories for less than 48 hours: a temperature of at least 37.5°C, unexplained sweating, or chills; and dry cough, dyspnea, fatigue, myalgia, anorexia, sore throat, dysgeusia, anosmia, or rhinorrhea. Exclusion criteria included severe respiratory disease (the primary end point), any disease listed in Table S5, or both.
Patients who provided consent to undergo screening received home visits, and samples of nasopharyngeal and oropharyngeal secretions were obtained for testing with an RT-PCR assay (iAMP COVID-19, Atila BioSystems) to detect SARS-CoV-2. Patients with detectable SARS-CoV-2 RNA were transported to trial hospitals and invited to sign the informed-consent form. After July 22, 2020, legal guardians provided consent for patients who had cognitive impairment. Starting on July 27, 2020, since several geriatric institutions with SARS-CoV-2 outbreaks were transformed into low-complexity inpatient units for mildly ill residents infected with SARS-CoV-2, we screened and invited residents who met the trial criteria to participate in the trial on-site.
Randomization and Intervention
Eligible patients who provided written informed consent were randomly assigned to receive either 250 ml of convalescent plasma with an IgG titer greater than 1:1000 against SARS-CoV-2 spike (S) protein (COVIDAR IgG, Instituto Leloir, Argentina) or 250 ml of placebo (0.9% normal saline). The convalescent plasma was arbitrarily defined as “high-titer” and included antibody concentrations in the upper 28th percentile. A computer-generated randomization sequence with a balanced permuted block design (block size 2) was prepared at the data center.
Convalescent plasma or placebo was administered less than 72 hours after the onset of symptoms, and the infusions were given over a period of 1.5 to 2.0 hours. Both the convalescent plasma and placebo were concealed with opaque bags and tape to cover the infusion catheter. Patients were monitored for adverse events until 12 hours after the intervention.
A total of 479 potential plasma donors who had had SARS-CoV-2 infection for a minimum of 10 days and who had been asymptomatic for 3 days or longer and had two negative RT-PCR tests17 were identified through hospital lists and an online campaign. Potential donors who provided written informed consent were visited at home and screened for SARS-CoV-2 S IgG at a titer greater than 1:1000 in serum. Each of the 135 candidates (28%) with adequate titers donated 750 ml of plasma (see Fig. S6).
Clinical and Laboratory Monitoring
A total of 24 hours after the end of the infusion, a sample of venous blood (5 ml) was obtained from the patients. Serum samples were preserved at −20°C until completion of the trial. 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 virus neutralization test kit (GenScript).
The patients’ clinical status was monitored daily by trial physicians until day 15 to assess for primary end-point events that occurred in the hospital, in participating geriatric institutions, or at home if the patients had been discharged (Figs. S7 and S8). Patients who had persistent symptoms for which medical care was warranted were followed until the resolution of symptoms or for a maximum of 25 days to assess for secondary end-point events. The trial physicians used predesigned questionnaires to collect clinical information. None of the patients received any experimental therapy for Covid-19 besides convalescent plasma. Data were recorded on paper forms and then double-entered into an electronic database.
Trial End Points
The primary end point of the trial was the development of severe respiratory disease, defined as a respiratory rate of 30 breaths per minute or more, an oxygen saturation of less than 93% while the patient was breathing ambient air, or both. Patients were assessed for this end-point event between 12 hours after the infusion of convalescent plasma or placebo and day 15 of trial participation.
Prespecified secondary clinical end points were life-threatening respiratory disease (defined as oxygen supplementation at a fraction of inspired oxygen [Fio2] of 100%, noninvasive or invasive ventilation, admission to an intensive care unit, or any combination of these), critical systemic illness (respiratory failure with a ratio of the partial pressure of oxygen to Fio2 ≤200 mm Hg, shock, multiple organ dysfunction syndrome, or any combination of these), and death associated with Covid-19. Patients in whom the illness had not resolved were assessed for these end-point events until day 25 of trial participation. On July 22, 2020, we amended the protocol to include a fourth secondary end point that included any of the three secondary end points described above, alone or in combination.
Early Trial Termination
The trial was initiated when the number of cases of Covid-19 in Buenos Aires was high. However, as the number of cases decreased, it became clear that it would take approximately 5 months to reach the enrollment goal. Consequently, after discussions with the data and safety monitoring board and enrollment of 76% of the target population, we decided that it would be logistically impossible and ethically questionable, given the daily cost of the pandemic in lives and illness, to continue the trial, and we stopped to examine the results.
Statistical Analysis
Given the complexity of implementing this intervention, the minimal clinically important difference was set at a 40% relative reduction for an expected 50% of the patients in the placebo group and 30% of the patients in the convalescent plasma group who would have a primary end-point event. We estimated that a total sample size of 210 patients (105 per trial group) would provide the trial with 80% power to detect a between-group difference, at a significance level of α=0.05. We used a two-sided z-test of proportions with continuity correction and one planned interim analysis with the O’Brien–Fleming spending function to determine the test boundaries.
In the intention-to-treat analysis, the end points were assessed from the time of randomization. Continuous variables are presented as means and standard deviations or medians and interquartile ranges, as appropriate, and categorical variables are presented as percentages.
In the primary analysis strategy, we used the Kaplan–Meier product limit estimates to compare the time to reach the primary end point in the trial groups. An estimate of the relative risk and 95% confidence interval was also reported. A modified intention-to-treat analysis excluded patients who became ineligible between randomization and the administration of convalescent plasma or placebo.
The protocol prespecified an evaluation of IgG protection correlates 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 an evaluation of end-point events in patients who were 75 years of age or older, irrespective of coexisting conditions, and in those between 65 and 74 years of age who had at least one coexisting condition.
Health - Latest - Google News
January 07, 2021 at 05:01AM
https://ift.tt/2LuLCkB
Early High-Titer Plasma Therapy to Prevent Severe Covid-19 in Older Adults - nejm.org
Health - Latest - Google News
https://ift.tt/2zrj9Ud
Bagikan Berita Ini
0 Response to "Early High-Titer Plasma Therapy to Prevent Severe Covid-19 in Older Adults - nejm.org"
Post a Comment