Efficacy and safety of baricitinib or ravulizumab in adult patients with severe COVID-19 (TACTIC-R): a randomised, parallel-arm, open-label, phase 4 trial

Background From early in the COVID-19 pandemic, evidence suggested a role for cytokine dysregulation and complement activation in severe disease. In the TACTIC-R trial, we evaluated the efficacy and safety of baricitinib, an inhibitor of Janus kinase 1 (JAK1) and JAK2, and ravulizumab, a monoclonal inhibitor of complement C5 activation, as an adjunct to standard of care for the treatment of adult patients hospitalised with COVID-19. Methods TACTIC-R was a phase 4, randomised, parallel-arm, open-label platform trial that was undertaken in the UK with urgent public health designation to assess the potential of repurposing immunosuppressants for the treatment of severe COVID-19, stratified by a risk score. Adult participants (aged ≥18 years) were enrolled from 22 hospitals across the UK. Patients with a risk score indicating a 40% risk of admission to an intensive care unit or death were randomly assigned 1:1:1 to standard of care alone, standard of care with baricitinib, or standard of care with ravulizumab. The composite primary outcome was the time from randomisation to incidence (up to and including day 14) of the first event of death, invasive mechanical ventilation, extracorporeal membrane oxygenation, cardiovascular organ support, or renal failure. The primary interim analysis was triggered when 125 patient datasets were available up to day 14 in each study group and we included in the analysis all participants who were randomly assigned. The trial was registered on ClinicalTrials.gov (NCT04390464). Findings Between May 8, 2020, and May 7, 2021, 417 participants were recruited and randomly assigned to standard of care alone (145 patients), baricitinib (137 patients), or ravulizumab (135 patients). Only 54 (39%) of 137 patients in the baricitinib group received the maximum 14-day course, whereas 132 (98%) of 135 patients in the ravulizumab group received the intended dose. The trial was stopped after the primary interim analysis on grounds of futility. The estimated hazard ratio (HR) for reaching the composite primary endpoint was 1·11 (95% CI 0·62–1·99) for patients on baricitinib compared with standard of care alone, and 1·53 (0·88–2·67) for ravulizumab compared with standard of care alone. 45 serious adverse events (21 deaths) were reported in the standard-of-care group, 57 (24 deaths) in the baricitinib group, and 60 (18 deaths) in the ravulizumab group. Interpretation Neither baricitinib nor ravulizumab, as administered in this study, was effective in reducing disease severity in patients selected for severe COVID-19. Safety was similar between treatments and standard of care. The short period of dosing with baricitinib might explain the discrepancy between our findings and those of other trials. The therapeutic potential of targeting complement C5 activation product C5a, rather than the cleavage of C5, warrants further evaluation

Piperazinyl fragment improves anticancer activity of Triapine

<div><p>A new class of TSCs containing piperazine (piperazinylogs) of Triapine, was designed to fulfill the di-substitution pattern at the TSCs N4 position, which is a crucial prerequisite for the high activity of the previously obtained TSC compounds–DpC and Dp44mT. We tested the important physicochemical characteristics of the novel compounds L¹-L¹². The studied ligands are neutral at physiological pH, which allows them to permeate cell membranes and bind cellular Fe pools more readily than less lipid-soluble ligands, e.g. DFO. The selectivity and anti-cancer activity of the novel TSCs were examined in a variety of cancer cell types. In general, the novel compounds demonstrated the greatest promise as anti-cancer agents with both a potent and selective anti-proliferative activity. We investigated the mechanism of action more deeply, and revealed that studied compounds inhibit the cell cycle (G1/S phase). Additionally we detected apoptosis, which is dependent on cell line’s specific genetic profile. Accordingly, structure-activity relationship studies suggest that the combination of the piperazine ring with Triapine allows potent and selective anticancer chelators that warrant further <i>in vivo</i> examination to be identified. Significantly, this study proved the importance of the di-substitution pattern of the amine N4 function.</p></div

Piperazinyl fragment improves anticancer activity of Triapine - Fig 3

<p>(a) Absorption spectrophotometric titration vs. pH of the free L² ligand; (b) electronic spectra of the protonated species of L²; (c) concentration distribution curves for the L² species. (I = 0.1 M (KCl) in 80% (w/w) MeOH/H₂O; T = 25.0°C; [L²] = 5x10^-5M; pH 1.6–11.02).</p

Protonation constants (log<i>β</i> ^H) of the L¹-L¹² ligands in the MeOH/H₂O mixed solution^a.

<p>Protonation constants (log<i>β</i> ^H) of the L¹-L¹² ligands in the MeOH/H₂O mixed solution<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0188767#t001fn001" target="_blank">^a</a>.</p

Anti-proliferative activity (IC₅₀ values) of the novel Triapine analogs compared to Triapine in several tumor cell-types and normal human dermal fibroblast (NHDF) cells.

<p>Individual IC50 values IC50 < 1μM, IC50 1–10 μM, IC50 > 10 μM are coded by red, yellow and grey, respectively.</p

Design strategy for novel TSCs (L¹-L¹²).

<p>All designed ligands are based on the Triapine skeleton, which is present in the active analogs Dp44mT, DpC and 1b, 1d that have been described as highly active analogs [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0188767#pone.0188767.ref021" target="_blank">21</a>].</p

Evaluation of the induction of apoptosis in the HCT116 p53^+/+, U-251 and MCF-7 cells 48 h after treatment with L⁹.

<p>The histograms show the percentage of early and late apoptosis for one of three independent experiments (<b>A</b>). The table shows the mean ± SD percentage of live, early and late apoptotic cells from three independent experiments (<b>B</b>). Data were analyzed using one-way ANOVA with Bonferroni’s post-hoc test: *p<0.05, **p<0.01, ***p<0.001 compared to the control (<b>C</b>).</p

Electronic absorption spectra of the Cu(II) and Fe(III)-L²; L⁴; L⁸ system recorded at various metal to ligand ratios.

<p>I = 0.1 M (KCl) in 80% (w/w) MeOH/H₂O; T = 25.0°C; [L] = 5x10^-5M.</p