Efficacy and safety of Ixekizumab vs. low-dose IL-2 vs. Colchicine vs. standard of care in the treatment of patients hospitalized with moderate-to-critical COVID-19: A pilot randomized clinical trial (STRUCK: Survival Trial Using Cytokine Inhibitors)

Abstract

Background: Cases of coronavirus disease 2019 (COVID-19) requiring hospitalization continue to appear in vulnerable populations, highlighting the importance of novel treatments. The hyperinflammatory response underlies the severity of the disease, and targeting this pathway may be useful. Herein, we tested whether immunomodulation focusing on interleukin (IL)-6, IL-17, and IL-2, could improve the clinical outcomes of patients admitted with COVID-19. Methods: This multicenter, open-label, prospective, randomized controlled trial was conducted in Brazil. Sixty hospitalized patients with moderate-to-critical COVID-19 received in addition to standard of care (SOC): IL-17 inhibitor (ixekizumab 80 mg SC/week) 1 dose every 4 weeks; low-dose IL-2 (1.5 million IU per day) for 7 days or until discharge; or indirect IL-6 inhibitor (colchicine) orally (0.5 mg) every 8 hours for 3 days, followed by 4 weeks at 0.5 mg 2x/day; or SOC alone. The primary outcome was accessed in the “per protocol” population as the proportion of patients with clinical improvement, defined as a decrease greater or equal to two points on the World Health Organization’s (WHO) seven-category ordinal scale by day 28. Results: All treatments were safe, and the efficacy outcomes did not differ significantly from those of SOC. Interestingly, in the colchicine group, all participants had an improvement of greater or equal to two points on the WHO seven-category ordinal scale and no deaths or patient deterioration were observed. Conclusions: Ixekizumab, colchicine, and IL-2 were demonstrated to be safe but ineffective for COVID-19 treatment. These results must be interpreted cautiously because of the limited sample size.

The Impact of Cytokines on Coagulation Profile in COVID-19 Patients: Controlled for Socio-Demographic, Clinical, and Laboratory Parameters

“…Similar clinical circumstances exist for dexamethasone’s effect on COVID-19 mortality, which may also be brought on by eosinophil apoptosis [ 55 ]. A recent study found that the IL-17 inhibitor ixekizumab, the indirect IL-6 inhibitor colchicine, and IL-2 to be safe but ineffective for treating COVID-19 [ 56 ]. Surprisingly, the anti-IL-17 drugs netacimab and secukinumab reduce the risk of pulmonary embolism in patients with severe COVID-19, indicating that IL-17 may be a major factor causing this complication of COVID-19, given its documented prothrombotic and procoagulant effects [ 57 , 58 ].…”

SARS-CoV-2 infection induces a long-lived pro-inflammatory transcriptional profile

“…To mitigate the potential variability introduced by chronic immune activation in COVID-19 patients, it is critical to consider that the putative administration of low-dose IL-2 in COVID-19 patients should be restricted to the convalescent phase of the disease, long after the acute inflammation has been resolved, to avoid unwanted hyperactivation of the immune response during the acute phase of the disease. To date, there have been very few pilot studies investigating the use of low-dose IL-2 in COVID-19 patients, and these have been limited to the treatment of patients with acute disease, which may explain the reported lack of clear therapeutic benefit for these patients [ 34 , 35 ]. Further work will therefore be necessary to support the potential clinical application of low-dose IL-2 in convalescent COVID-19 patients, including the retrospective analysis of the incidence of PASC in cohorts of patients treated with low-dose IL-2.…”

CCR5/CXCR3 antagonist TAK-779 prevents diffuse alveolar damage of the lung in the murine model of the acute respiratory distress syndrome

“…Tocilizumab proved its clinical effectiveness in patients during the coronavirus pandemic ( Io et al, 2021 ). One more approach of the treatment is using colchicine, an indirect IL-6 inhibitor, which is also applied in the treatment of coronary heart disease ( Bonifácio et al, 2023 ). Colchicine suppresses the recruitment of neutrophils, inhibits cytoskeleton metabolism, and opposes SARS-CoV-2 functionality in human cells ( Kasiri et al, 2023 ).…”