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: We aimed to evaluate the efficacy of sarilumab, an IL-6 receptor inhibitor, combined with SOC, in patients (pts) affected by severe COVID-19 pneumonia. Methods: Open-label, Phase III, randomized trial assessing clinical efficacy and safety of intravenous sarilumab in pts with severe COVID-19, at 5 clinical centers in Italy. We included hospitalized pts with SARS-CoV-2 infection and pneumonia, in severe or critical condition (excluding mechanically ventilated). Pts were randomized 2:1 to receive sarilumab 400 mg plus SOC (armA) or to continue SOC (armB). The primary endpoint was time to clinical improvement of 2 points on a 7-point category ordinal scale, ranging from 1 (discharged with resumption of normal activities) to 7 (death). Pts were stratified according to baseline disease severity (PaO2/FiO2 ratio < or ≥ 200 mmHg), C reactive protein (CRP < or ≥ 7 mg/dL) and lymphocytes count (< or ≥ 870/mmc). The key secondary endpoint was time to death. Adverse events (AE) were evaluated as safety outcomes. We used chi square test to compare proportions between arms, and Cox regression stratified by clinical center to estimate the hazard risk (HR) of primary endpoint. Results: Of 191 pts screened, 176 were assigned to armA (121) and B (55). A similar proportion of pts were treated with steroids (44 armA vs 26 armB, p=0.170) and remdesivir (22 armA vs 8 armB, p=0.552). 58/121 (48%) pts underwent to a second dose of sarilumab 12 hours after the first dose. At day 30, no significant differences in the primary endpoint were found between the arms (Figure1). After stratifying for inflammatory parameters, the probability of improvement seemed greater in armA than B, for the strata with CRP <7 mg/dL (88% [95% CI 77-96] vs 79% [63-91], HR 1.55 [0.9-2.6];log-rank p=0.049) and with lymphocytes <870/mmc (90% [79-96]) vs (73% [55-89], HR 1.53 [0.9-2.7];log-rank p=0.058). Figure2 for interaction tests between strata. There were no significant differences in death probability (armA 5% [2.3-10.9]) and armB 3.6% [0.9-13.8] HR 1.30 [0.41-4.15];log-rank p=0.79) and in the rates of AE (armA 32% [39/121] and armB 23% [14/55], p=0.195) and serious AE (armA 18% [22/121] and armB 11% [7/55], p=0.244). Conclusion: In our population, efficacy of sarilumab in pts with severe COVID-19 was not confirmed, even if some benefits were shown in those treated at an early stage of the disease with lower inflammatory burden. Further trials are needed for identifying targeted subgroups for maximizing benefit of this treatment.