REGN-COV2, a neutralizing antibody cocktail, in outpatients with Covid-19

Experience design

We are conducting an operationally seamless (continuous enrollment) multicenter, randomized, double-blind, placebo-controlled, phase 1–3 clinical trial involving asymptomatic non-hospitalized patients with Covid-19. The interim analysis we describe here included the first 275 patients enrolled during the phase 1-2 portion of the trial and was performed to evaluate the safety and efficacy of REGN-COV2, to gain an understanding of the natural history of Covid-19 in the outpatient setting, and to refine endpoints for subsequent analyses. The trial continues to recruit more than 275 patients whose data is described in this report; It is planned to report the results of the predetermined major and minor endpoints upon completion of the experiment. The data cut-off for this interim analysis was September 4, 2020.

In the phase 1-2 portion of the trial described here, all patients were randomly assigned (1:1:1) to receive placebo, REGN-COV2 at a dose of 2.4 g (low dose), or REGN-COV2 at a dose of 8.0 g (high dose). ) (Figure S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org). Both the component antibodies to REGN-COV2 – casirivimab (REGN10933) and imdevimab (REGN10987) – are administered in equal doses in the cocktail.

Details of the random stratification are provided in the Supplementary Appendix. The phase 1 portion of the trial included additional pharmacokinetic analyzes but was identical to the phase 2 portion. The number of patients in the current analysis was pooled from both phases.

Patients

To be eligible to participate, patients must be 18 years of age or older and not be a hospital resident. All patients had to have had confirmed SARS-CoV-2 infection, with a positive SARS-CoV-2 test result not received more than 72 hours prior to randomization and symptom onset no more than 7 days prior to randomization. The full list of inclusion and exclusion criteria is provided in the Supplementary Appendix. The protocol is available at NEJM.org.

An anti-SARS-CoV-2 antibody test was performed in all patients. Because these results were not available in randomization, patients were randomized regardless of their baseline serostatus, and analyzes were pre-selected to assess efficacy first in the subgroup of patients whose serum antibodies were negative—that is, those patients whose result was They tested negative for all three of the following antibodies: the IgA anti-S1 domain of the spike protein, the IgG anti-S1 domain of the spike protein, and the IgG anti-nucleocapsid protein. Patients who were positive for any of these antibodies were classified as positive serum antibodies. Few patients could not be evaluated or had borderline findings (status of serum antibodies not known); Analyzes including these patients were performed but are not reported here.

Interventions and assessments

At baseline (day 1), REGN-COV2 (high-dose or low-dose) or saline placebo was administered intravenously in 250 mL normal saline over 1 hour. The schedule of assessments is described in the protocol, along with a summary of protocol modifications. Quantitative virological analysis, assay for SARS-CoV-2 serum antibodies, and measurement of the two components of REGN-COV2 in serum are described in the Supplementary Appendix.

endpoints

Multiple pre-selected end points were assigned to the phase 1-2 portion of the experiment (see Supplementary Appendix and Statistical Analysis Plan, provided with the protocol). However, due to the lack of prior information that would allow us to correctly identify endpoints, and because some Regeneron Pharmaceuticals employees (who had no role in conducting the trial) had access to unblinded early data from the trial as described in the protocol, No formal hypothesis testing was performed.

The major viral endpoint defined previously in the statistical analysis plan was defined as the time-weighted mean change in viral load (in log10 copies per milliliter) from baseline (day 1) through day 7, as measured by a quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) assay of nasopharyngeal swab samples obtained from antibody-negative patients in the blood. The change in viral load from baseline to different days during the experiment was a pre-defined additional viral endpoint, and the change in absolute viral load (measured in copies per milliliter) was a subsequent viral endpoint.

The pre-specified primary clinical endpoint was the percentage of patients who had at least one Covid-19-related medical visit attended medically up to day 29 in both the serum antibody-negative subgroup and the total experimental population. Medically supervised visits can include telemedicine visits, in-person doctor visits, urgent care or emergency department visits, and hospitalization.

To assess safety, we collected data on adverse events that occurred or worsened during the observation period (grade 3 and 4; stage 1 only), serious adverse events that occurred or worsened during the observation period (stages 1 and 2), and after significant adverse events Special (stages 1 and 2): Hypersensitivity of grade 2 or higher or infusion-related reactions. Pharmacokinetic variables included serum concentrations of cacervimab and imdivimab over time.

Trial Observation

Regeneron designed the trial. data collection with trial investigators; and data analysis. Regeneron and the authors ensure the accuracy and completeness of the data, and Regeneron emphasizes the accuracy of the experiment with the protocol. The authors provided critical notes and final approval of the manuscript for submission. No unauthorized person contributed to the manuscript. All investigators have confidential agreements with Regeneron.

The investigators, site staff, and Regeneron staff who were involved in data collection and analysis were unaware of the treatment group assignments. An independent data and safety oversight committee periodically monitored the unblinded data to make recommendations about trial modification and termination. The independent panel and, separately, Regeneron physicians who were familiar with the treatment group assignments and were not involved in conducting the trial performed interim reviews of the data in order to adapt the trial design.

The trial was conducted in accordance with the principles of the Declaration of Helsinki, the International Coordinating Council Good Clinical Practice Guidelines, and applicable regulatory requirements. The trials were supervised and documented by the local Institutional Review Board or Ethics Committee at each study center. One center was found to have violations of good clinical practice guidelines (not related to data collection on efficacy or safety end points) and was withdrawn from the trial after the analyzes were completed. All patients provided written informed consent prior to participating in the trial.

statistical analysis

The statistical analysis plan for the presented analysis was completed before the database was locked and de-blinded. The full analysis set included the first 275 patients with Covid-19 symptoms who were randomized into the combined phase 1-2 parts of the trial. A sample of 275 patients (72 in stage 1 and 203 in stage 2) was considered sufficient to assess virological efficacy, clinical trends, and safety for the purpose of informing subsequent analyses. Because patients could score if they tested positive for SARS-CoV-2 72 hours before randomization, patients who tested negative by qualitative RT-PCR at baseline (lower detection limit, 714 copies per milliliter). [2.85 log10 copies per milliliter]) from the analyzes of viral endpoints in a modified full analysis set. Because of the a priori hypothesis that patients whose immune system was already clearing the virus were unlikely to benefit from additional antibody therapy, analyzes were pre-selected in the statistical analysis plan to focus on the antibody-negative subgroup in the blood. All patients who received REGN-COV2 or placebo were included in the safety group.

The time-weighted mean change from baseline (day 1) to day 7 was calculated for each patient as the area under the concentration-time curve, using a linear trapezoidal rule for change from baseline divided by the observational period. This end point was analyzed with a combined analysis of variance model with treatment group, risk factor, baseline serum antibody status as fixed effects and base viral load and treatment group-individually base viral load as covariates. The confidence intervals in this report have not been adjusted for plurality. Statistical analyzes were performed using SAS software, version 9.4 or higher (SAS Institute). Additional statistical and pharmacological methods of analysis are described in the Supplementary Appendix.

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