Efficacy and safety of two neutralising monoclonal antibody therapies, sotrovimab and BRII-196 plus BRII-198, for adults hospitalised with COVID-19 (TICO): a randomised controlled trial

BACKGROUND: We aimed to assess the efficacy and safety of two neutralising monoclonal antibody therapies (sotrovimab [Vir Biotechnology and GlaxoSmithKline] and BRII-196 plus BRII-198 [Brii Biosciences]) for adults admitted to hospital for COVID-19 (hereafter referred to as hospitalised) with COVID-19. METHODS: In this multinational, double-blind, randomised, placebo-controlled, clinical trial (Therapeutics for Inpatients with COVID-19 [TICO]), adults (aged ≥18 years) hospitalised with COVID-19 at 43 hospitals in the USA, Denmark, Switzerland, and Poland were recruited. Patients were eligible if they had laboratory-confirmed SARS-CoV-2 infection and COVID-19 symptoms for up to 12 days. Using a web-based application, participants were randomly assigned (2:1:2:1), stratified by trial site pharmacy, to sotrovimab 500 mg, matching placebo for sotrovimab, BRII-196 1000 mg plus BRII-198 1000 mg, or matching placebo for BRII-196 plus BRII-198, in addition to standard of care. Each study product was administered as a single dose given intravenously over 60 min. The concurrent placebo groups were pooled for analyses. The primary outcome was time to sustained clinical recovery, defined as discharge from the hospital to home and remaining at home for 14 consecutive days, up to day 90 after randomisation. Interim futility analyses were based on two seven-category ordinal outcome scales on day 5 that measured pulmonary status and extrapulmonary complications of COVID-19. The safety outcome was a composite of death, serious adverse events, incident organ failure, and serious coinfection up to day 90 after randomisation. Efficacy and safety outcomes were assessed in the modified intention-to-treat population, defined as all patients randomly assigned to treatment who started the study infusion. This study is registered with ClinicalTrials.gov, NCT04501978. FINDINGS: Between Dec 16, 2020, and March 1, 2021, 546 patients were enrolled and randomly assigned to sotrovimab (n=184), BRII-196 plus BRII-198 (n=183), or placebo (n=179), of whom 536 received part or all of their assigned study drug (sotrovimab n=182, BRII-196 plus BRII-198 n=176, or placebo n=178; median age of 60 years [IQR 50-72], 228 [43%] patients were female and 308 [57%] were male). At this point, enrolment was halted on the basis of the interim futility analysis. At day 5, neither the sotrovimab group nor the BRII-196 plus BRII-198 group had significantly higher odds of more favourable outcomes than the placebo group on either the pulmonary scale (adjusted odds ratio sotrovimab 1·07 [95% CI 0·74-1·56]; BRII-196 plus BRII-198 0·98 [95% CI 0·67-1·43]) or the pulmonary-plus complications scale (sotrovimab 1·08 [0·74-1·58]; BRII-196 plus BRII-198 1·00 [0·68-1·46]). By day 90, sustained clinical recovery was seen in 151 (85%) patients in the placebo group compared with 160 (88%) in the sotrovimab group (adjusted rate ratio 1·12 [95% CI 0·91-1·37]) and 155 (88%) in the BRII-196 plus BRII-198 group (1·08 [0·88-1·32]). The composite safety outcome up to day 90 was met by 48 (27%) patients in the placebo group, 42 (23%) in the sotrovimab group, and 45 (26%) in the BRII-196 plus BRII-198 group. 13 (7%) patients in the placebo group, 14 (8%) in the sotrovimab group, and 15 (9%) in the BRII-196 plus BRII-198 group died up to day 90. INTERPRETATION: Neither sotrovimab nor BRII-196 plus BRII-198 showed efficacy for improving clinical outcomes among adults hospitalised with COVID-19. FUNDING: US National Institutes of Health and Operation Warp Speed

Exchange Reactions between Alkanethiolates and Alkaneselenols on Au{111}

When alkanethiolate self-assembled monolayers on Au{111} are exchanged with alkaneselenols from solution, replacement of thiolates by selenols is rapid and complete, and is well described by perimeter-dependent island growth kinetics. The monolayer structures change as selenolate coverage increases, from being epitaxial and consistent with the initial thiolate structure to being characteristic of selenolate monolayer structures. At room temperature and at positive sample bias in scanning tunneling microscopy, the selenolate-gold attachment is labile, and molecules exchange positions with neighboring thiolates. The scanning tunneling microscope probe can be used to induce these place-exchange reactions

Molecular Assembly and Electropolymerization of 3,4-Ethylenedioxythiophene on Au(111) Single Crystal Electrode as Probed by In Situ Electrochemical STM in 0.10 M HClO₄

We have used electrochemical scanning tunneling microscopy (EC-STM) to obtain molecular insights on the adlayer structures and electrochemical polymerization of 3,4-ethylenedioxythiophene (EDOT) on a bare Au(111) single crystal electrode in 0.1 M HClO4 solution. Cyclic voltammetric (CV) studies showed an increase in anodic current at 0.90 V with the oxidation of EDOT monomer occurring at E = 1.10 V (vs reversible hydrogen electrode). In situ STM revealed, for the first time, that EDOT molecules can spontaneously form organized adlayers on a bare Au(111) surface with 18 μM concentration of EDOT in aqueous solution. Molecularly resolved STM images of the EDOT adlayer showed two domains consisting of disordered and ordered structures with the formation of vacancy islands or “etch pits”. Several EDOT structures were observed at +0.60 V, namely, (4 × 7), (5 × √37), and (√7 × 3) with calculated coverages of 0.107, 0.114, and 0.111 ML, respectively. Electropolymerization was also carried out using in situ STM in 0.10 M HClO4 under potential control