ABSTRACT
BACKGROUND: Bebtelovimab is a potent, fully human IgG1 monoclonal antibody (mAb) targeting the S-protein of SARS-CoV-2, with broad neutralizing activity to all currently known SARS-CoV-2 variants of concern, including omicron variant lineages. Specialized developmental approaches accelerated the initiation of a clinical trial designed to evaluate the efficacy and safety of bebtelovimab alone (BEB) or together with bamlanivimab (BAM) and etesevimab (ETE) delivered via slow intravenous push for the treatment of mild-to-moderate COVID-19. METHODS: This portion of the phase 2, BLAZE-4 trial (J2X-MC-PYAH; NCT04634409) enrolled 714 patients (between May and July 2021) with mild-to-moderate COVID-19 within 3 days ([≤]3 days) of laboratory diagnosis of SARS-CoV-2 infection. Patients at low risk for severe COVID-19 were randomized 1:1:1 (double-blinded) to placebo, BEB 175 mg, or BEB 175 mg+BAM 700 mg+ETE 1400 mg (BEB+BAM+ETE). Patients at high risk for progression to severe COVID-19 were randomized 2:1 (open-label) to BEB or BEB+BAM+ETE, and a subsequent treatment arm enrolled patients to BEB+BAM+ETE using Centers for Disease Control and Prevention (CDC) updated criteria for High-risk. All treatments were administered intravenously over [≥]30 seconds (open-label BEB) or [≥]6.5 minutes (all other treatment arms). For the placebo-controlled patients (termed Low-risk), the primary endpoint was the proportion of patients with persistently high viral load (PHVL) (log viral load >5.27) on Day 7. For the open-label patients (termed High-risk), the primary endpoint was safety. In nonclinical studies, SARS-CoV-2 isolates were tested using an endpoint neutralization assay to measure BEB's inhibitory concentration greater than 99% (IC99). RESULTS: Baseline viral sequencing data were available from 611 patients; 90.2% (n=551) aligned with a variant of interest or concern (WHO designation), with the majority infected with delta (49.8%) or alpha (28.6%) variants. Among the Low-risk patients, PHVL occurred in 19.8% of patients treated with placebo, as compared to 12.7% (p=0.132) of patients treated with BEB+BAM+ETE and 12.0% (p=0.097) of patients treated with BEB, a 36% and 40% relative risk reduction, respectively. Viral load-area under the curve analysis from baseline to Day 11 showed statistically signficant reductions for patients treated with BEB (p=0.006) and BEB+BAM+ETE (p=0.043) compared to patients who received placebo. Time to sustained symptom resolution was reduced by a median of 2 days for patients treated with BEB (6 days; p=0.003) and 1 day for patients treated with BEB+BAM+ETE (7 days; p=0.289) compared to placebo (8 days). The incidence of COVID-19-related hospitalization or all-cause deaths by day 29 were similar across treatment arms, as expected given the patients' risk status (the Low risk cohorts had a Low risk of hospitalization, and High risk cohorts received only active therapy without placebo). Overall, safety results were consistent with previous studies investigating mAbs targeting SARS-CoV-2. The proportion of patients with treatment emergent adverse events (AEs) were 9.7% in Low-risk (n=37/380) and 14.7% in High-risk (n=48/326) patients treated with BEB or BEB+BAM+ETE; majority of AEs were considered mild or moderate in severity. Serious AEs were reported in 2.1% of High-risk patients (n=7/326), including one death (a cerebrovascular accident); 1 serious AE was reported among Low-risk patients. In an in vitro neutralization assay, BEB neutralized the omicron isolate (BA.1) with <2.44ng/ml estimated IC99. CONCLUSIONS: In patients with mild-to-moderate COVID-19, treatment with BEB or BEB+BAM+ETE was associated with greater viral clearance, a reduction in time to sustained symptom resolution, and safety results consistent with mAbs that target SARS-CoV-2. Integration of clinical findings with in vitro neutralization of emerging viral variants offered a pragmatic framework for investigating the efficacy of a new antiviral mAb agent, as demonstrated by bebtelovimab.
Subject(s)
Death , COVID-19ABSTRACT
Purpose: Many commonly used mask designs are secured by elastic straps looping around the posterior auricular region. This constant pressure and friction against the skin may contribute to increased wearer pain, irritation, and discomfort. The purpose of this work is to report a modified 3D printed mask extender to alleviate discomfort and increase mask wearability by relieving posterior auricular pressure from isolation masks.Methods : Our institutional review board designated this project as non-human research and exempt. As part of resourcing 3D printing laboratories along with individual 3D printers to provide resources to healthcare workers, mask extenders were printed to relieve posterior auricular pressure from individuals wearing isolation masks. The authors modifed an existing mask extender, increasing its length with accompanying peripheral rungs for isolation mask securement. 3D printing was performed with Ultimaker S5 (Ultimaker B.V.; Geldermalsen, Netherlands) and CR-10 (Creality3D; Shenzhen, China) 3D printers using polylactic acid filaments. The author’s modified extended mask extenders were printed and freely delivered to healthcare workers (physicians, nurses, technologists, and other personnel) at the authors’ institution. Results: The final mask extender design was printed with the two 3D printers with a maximum 7 straps printed simultaneously on each 3D printer. Mean print times ranges from 105 minutes for the Ultimaker S5 printer and 150 minutes for the CR-10. 475 mask extenders were delivered to healthcare workers at the authors’ institution, with the demand far exceeding the available supply. Conclusion: We offer a modification of a 3D printed mask extender design that decreases discomfort and increases the wearability of isolation mask designs with ear loops thought to relieve posterior auricular skin pressure and ability to control strap tension. The design is simple, produced with inexpensive material (polylactic acid), and have been well-received by healthcare providers at our institution