Early Remdesivir to prevent progression to severe Covid-19 in outpatients
Early Remdesivir to prevent progression to severe Covid-19 in outpatients

Early Remdesivir to prevent progression to severe Covid-19 in outpatients

Patients

Eligible patients were 12 years of age or older and had at least one pre-existing risk factor for progression to severe Covid-19 or were 60 years of age or older, whether or not they had other risk factors. Risk factors included hypertension, cardiovascular or cerebrovascular disease, diabetes mellitus, obesity (a body mass index [BMI; the weight in kilograms divided by the square of the height in meters] at ≥30), immune compromise, chronic mild or moderate kidney disease, chronic liver disease, chronic lung disease, current cancer or sickle cell disease. Eligible patients had at least one ongoing symptom consistent with Covid-19, with onset of the first symptom within 7 days before randomization (considering that hospitalization typically occurs at or after 7 days of symptoms).13.14 Eligible patients had SARS-CoV-2 infection confirmed by a molecular diagnostic assay within 4 days prior to screening (corresponding to the period characterized by the highest viral load).15

Patients were not eligible if they received or were expected to receive supplemental oxygen or hospital treatment at the time of screening. Patients were also not eligible if they had previously been hospitalized for Covid-19, had previously received treatment for Covid-19 (including experimental drugs), or had received a SARS-CoV-2 vaccine. Full details are given in protocol and the Statistical Analysis Plan (available in full text of this article at NEJM.org).

Sample design and supervision

From September 18, 2020 to April 8, 2021, patients were enrolled in 64 locations in the United States, Spain, Denmark, and the United Kingdom. Experimental sites included outpatient infusion facilities and skilled nursing facilities, and some participants received infusions at home. Patients were randomly assigned to a 1: 1 ratio to receive intravenous remdesivir (200 mg on day 1 followed by 100 mg on days 2 and 3) or placebo. Randomization was stratified by residency at a qualified care center (yes or no), age (<60 years or ≥60 years), and country (US or outside the US). All patients and experimental staff were unaware of the tasks of the experimental group. Before undergoing experimental procedures, patients gave written informed consent. Consent and consent from the parent or guardian was obtained if the patients were younger than 18 years of age.

The trial was approved by the institutional evaluation committee or ethics committee at each trial site and was conducted in accordance with the Helsinki Declaration, Guidelines for Good Clinical Practice and local regulations. The experiment was designed and performed by the sponsor (Gilead Sciences) in collaboration with the main investigators and in accordance with the protocol and the amendments. The sponsor collected the data, monitored the conduct of the experiment and performed the statistical analyzes. A preliminary analysis to be carried out by the Data and Security Monitoring Board was planned when 50% registration had been reached. The manuscript was prepared by an author employed by Gilead Sciences, with input from all authors. All authors had data confidentiality agreements with the sponsor. All authors are responsible for the accuracy and completeness of the data and for the fidelity of the experiment to the protocol.

Test assessments

Assessments included physical examinations, adverse event reporting, blood tests, and collection of nasopharyngeal swabs to quantify SARS-CoV-2 viral load using reverse transcriptase-polymerase-chain-reaction (RT-PCR) assay at predetermined intervals. The electronic Covid-19-adapted Influenza Patient-Reported Outcome (FLU-PRO) Plus Questionnaire (Evidera-PPD) was used to assess patient-reported symptoms. Patients completed the first questionnaire before the first infusion on day 1 and then daily until day 14. The symptom questionnaire was not available until 21 October 2020 (1 month after the start of enrollment). The full schedule of trial procedures is set out in the protocol.

End points

The primary endpoint was a composition of hospitalization related to Covid-19 (as determined by on-site investigators unaware of experimental group assignments and defined as ≥24 hours of acute treatment) or death by any cause before day 28. The primary endpoint was originally a composition of hospitalization of any cause or death of any cause before day 14 and was amended on 14 January 2021 in response to comments from the Food and Drug Administration; experimental glare was maintained. The primary safety endpoint was any unwanted incident.

Secondary endpoints included the composition of Covid-19-related doctor visits or deaths of any cause within days 14 and 28, Covid-19-related hospitalization on days 14 and 28, the time-weighted mean change in nasopharyngeal SARS-CoV-2 viral load from baseline to day 7, and the time to relief of baseline Covid-19 symptoms (with relief defined as mild or absent symptoms) compared to those reported on the baseline FLU-PRO Plus questionnaire completed prior to the first infusion. Post hoc analyzes of hospitalization for any cause before day 28 and time for relief of covid-19 symptoms at baseline were also performed as reported on the FLU-PRO Plus questionnaire completed on the day of the first infusion, either before or after the infusion. .

Statistical analysis

Assuming that 9.3% of patients would die or have a Covid-19-related hospitalization, and 5% would drop out of the trial, we determined that a sample of 1264 patients would give the trial more than 90% power to detect a hazard ratio for Covid-19-related hospitalization or death of any cause of 0.55 for comparison with stradesivir with placebo, with a bilateral significance level of 0.05. All patients who underwent randomization and received at least one infusion were included in the analyzes (the full analysis set). Demographic characteristics, baseline measurements, adverse events, and laboratory abnormalities were summarized descriptively.

Hazard ratios, rate ratios and two-sided 95% confidence intervals for the primary and secondary endpoints were calculated using a Cox proportional hazard model adjusted for the stratification factors of residence in a qualified care center (yes or no), age (<60 years or ≥60 years) and country (US or outside the US). The p-value for the primary power endpoint was calculated using the same method. The percentage of patients admitted with Covid-19 on day 28 was estimated using a Kaplan-Meier assay. The time to relief of baseline Covid-19 symptoms in the pre-specified and post hoc analyzes was estimated using the Kaplan-Meier product threshold method. The time-weighted mean change in viral load from baseline to day 7 was assessed using analysis-of-covariance, with baseline viral load as a covariate. The width of all calculated confidence intervals was not adjusted for multiplicity.

On April 6, 2021, an orderly closure of trial enrollment was announced by the sponsor due to administrative reasons related to a decrease in the incidence of SARS-CoV-2 infections, ethical concerns regarding the allocation of patients to placebo in connection with increased access to emergency treatment-authorized treatments such as monoclonal antibodies and increasing vaccination rates among high-risk individuals. The last patient was enrolled on April 8, 2021. Of the 1264 patients who were expected to enroll, 562 (44.5%) had undergone randomization and had begun the experimental regimen when enrollment was stopped. The Data and Security Monitoring Board was informed that the trial had been stopped and no interim analyzes were carried out before the trial was terminated. Double glare was maintained until the completion of the data.

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