ABSTRACT
Background: Antivirals and monoclonal antibodies (mAbs) were approved for early treatment of COVID-19 based on data from trials conducted in unvaccinated people before the Omicron era. The comparative effectiveness of different treatments is unknown. We present the results of the interim analysis of MONET trial (EudraCT: 2021-004188-28). Method(s): In this ongoing multicenter, open-label, phase 4 trial, we randomly assigned, in a 1:1:1 ratio, non-hospitalized patients with early symptomatic Covid-19 (<=5 days after symptoms onset) and >=1 risk factor for disease progression, to receive 500 mg of intravenous sotrovimab (SOT) or 600 mg of intramuscular tixagevimab/cilgavimab (TIX/CIL) or oral 5-days course of NMV/r 300/100 mg BID. Primary outcome was hospitalization or death for any cause within 29 days after randomization, reported as cumulative incidence per 100 (95% CI), and P-value calculated by Fisher's exact test. Inflammatory marker (CRP, d-dimer, and neutrophils-to-lymphocytes ratio) and antibody level (serum anti-S IgG and anti-N IgG) analysed by mixed linear regression with random intercept and P-values for time trend calculated by ANOVA-style test with Bonferroni correction. Result(s): Prespecified interim analysis, including 400 patients (SOT =133, TIX/ CIL=130, NMV/r=137) enrolled from Mar 4 to Nov 16, 2022 (Fig.1A). Overall, 5 pts (3/5 immunosuppressed) had disease progression leading to hospitalization [1.25% (95% CI 0.4%-2.89%)], 1 in SOT (0.75%, 95% CI 0.01%-4.1%), 4 in TIX/CIL (3.08%, 95% CI 0.84%-7.69%) and none in NMV/r arm (P=0.030). No deaths or ICU admissions were observed. Among the hospitalized pts, 3 were infected with BA.2 (1 SOT, 2 TIX/CIL), one with BA.4/5, and one BQ.1.1 (both TIX/ CIL). No serious adverse events and no kidney or liver toxicity were reported. Temporal trend of inflammation markers was similar in the three arms, and their estimates are shown in Fig.1B. Kinetics of antibody was reported in Fig.1C. The plot shows a rapid increase of anti-S in both mAb arm and a linear increase of IgG in the NMV/r arm. Anti-N IgG kinetics was similar in the three arms. Conclusion(s): By these data the overall cumulative risk of clinical failure in mild Covid-19 occurring in the Omicron era is low. The hypothesis that differences in clinical progression among the three arms could be related to different activity against the Omicron subvariant observed in vitro should be further investigated. Type of treatment does not seem to influence the development of the natural antibody response.
ABSTRACT
Background: Early treatment for preventing severe outcome of COVID-19 in high-risk not-hospitalized patients (pts) by monoclonal antibodies or antivirals represented a high-priority approach. Real-world evidence (RWE) from observational studies could give information on clinical effectiveness and predictors of treatment failure. Method(s): Single-center observational study on SARS-CoV-2 pts, not requiring hospital admission but having high-risk of severe outcome from COVID-19. All were selected for early treatment with monoclonal antibodies or antivirals from March 2021 to November 2022. Participants were classified according to whether they were hospitalized due to severe COVID-19 or died by day 30 from starting treatment in the outpatient setting (baseline). We conducted a logistic regression analysis with this binary endpoint and 4 main exposures of interest measured at baseline: i) age ( >75 years old) ii) vaccination status iii) VoC, and iv) immunosuppression or having received immunosuppressive therapy. We built a separate model for each of these exposures, which included a specific set of potential confounders. Result(s): 3,491 pts, female 48.6%, median age 67 yrs (IQR 55-77), fully vaccinated 83.7%;previous infection 4.6%;CVD 52.2%;cancer 24.6%;immunodeficiency 40.6%. Prevalence of SARS-CoV-2 VoC: delta 8.7%, BA.1 16.9%, BA.2 6.8%, BA.4/5 12.2, BQ 0.1%, other 3.0% (Tab.1A). Treatment exposure was BAM/ETE 569 (16.5%), CAS/IMD 262 (7.6%), SOT 935 (27.1%), TIX/CIL 79 (2.3%), NMV/r 555 (16.1%), MLP 684 (19.8%), RDV 356 (10.3%). Primary endpoint occurred in 80/3,491 pts with a day-30 incident risk of 2.3% (95%CI 1.8-2.9). Tab.1B shows the unadjusted and adjusted odds ratios (OR) of hospitalization due to COVID-19 or death by day 30. After controlling for potential confounders, higher risk was observed for the unvaccinated (OR 1.95;95%CI 1.03-3.71) and for those affected by immunodeficiency [1.73;1.04-2.89). Having delta as reference variant, an increased risk was observed for BA.2 [2.08;1.00-2.34]. No evidence for a difference was seen by age or other comorbidities. Conclusion(s): In this RWE study, largely represented by vaccinated people and prevalently observed in the Omicron era, the estimated risk of clinical failure of early treatment was slightly higher than that recorded in the experimental arms of randomized studies. The analysis confirms that among those eligible for early treatment, the unvaccinated and those with severe immunodeficiency are at higher risk of developing severe COVID-19. Table 1 -A. Main characteristics of 3,491 not-hospitalized people with mildto-moderate COVID-19 at high risk of severe disease observed between March 2021 to November 2022 according to reaching (n=80) or not reaching (3,411) primary clinical endpoint. B. Odds ratios (OR) of having a COVID-19-related hospitalization or death by different exposure factors.