Votre navigateur ne supporte pas le javascript Wallonia & Brussels against COVID-19 - Maya Hites, Associate Professor


Maya Hites, Associate Professor

" "a. Background Coronavirus disease 2019 (COVID-19) is a respiratory tract infection caused by a new coronavirus SARS CoV-2, responsible for the current pandemic, causing a lot of morbidity and mortality. Most people with COVID-19 develop mild respiratory illness (stage I). However, in a sub-group of patients (+/- 15%) there are increasing respiratory symptoms and persistent fever (stage II). Patients may develop acute lung injury (hypoxia, and bilateral opacities on chest computed tomography (CT-scan)), requiring hospitalisation. A further 5% of patients develop stage III disease, requiring admission to the intensive care unit (ICU) due to acute respiratory distress syndrome (ARDS), sepsis and septic shock, and multi-organ failure. As patients progress from stage I to stage III, there are increasing signs of systemic hyper-inflammatory response, reflected by high levels of cytokines, C-reactive protein (CRP), ferritin, and lymphopenia. Different viral, bacterial, and fungal infections can cause cytokine storm syndromes. An increase in cytokines TNF, IL-1α, IL-8, and MCP-1 are observed, followed by a more sustained increase in IL-6. Interactions of IL-6 and its' receptor enhance the activity of IL-6 on target cells to further aggravate inflammation. These cytokines cause increases in ferritin and CRP, but are also involved in causing acute lung injury. A counter inflammatory response is also produced. Interleukin-10 is a marker of this response that is associated with downregulation of neutrophil and monocyte function in the systemic circulation, and down regulation of HLA-DR on monocytes. When there is a lack of balance between pro and inflammatory response, the outcome may contribute toward a cytokine storm and progression of acute lung injury to clinical ARDS. In a recent retrospective, multicentric study from China on 150 confirmed COVID-19 cases, predictors of fatality were elevated ferritin and IL-6, suggesting that mortality might be due to virally driven hyper-inflammation. In another study on 69 patients with severe COVID-19, elevated IL-6 levels were significantly related to severity of clinical manifestations, and decrease in IL-6 was linked to treatment effectiveness. Preliminary data on 21 patients in an open label study report a favorable evolution of tocilizumab (IL-6 receptor blockade) treated patients. Furthermore, IL-1 is also an important mediator in acute lung injury and sometimes increased in severe COVID-19 patients. The justification of this study is to prevent the cytokine release syndrome and progression from early hypoxic respiratory failure and mild acute lung injury to ARDS. The hypothesis of the intervention is that IL-6 and/or IL-1 are important mediators of the cytokine release syndrome that has an important impact on acute lung injury and development of secondary cytopenias post COVID-19, and thus affect the clinical outcome of patients. b. Objective of the Study The primary objective of the intervention is to study if the blockade of IL-6 +/- IL-1 to block the cytokine storm and acute lung injury affects the rate of clinical improvement. The primary endpoint of this study is the clinical status after 15 days of treatment. c. Study Design This is a prospective, randomized, factorial design, interventional study. Inclusion criteria are consenting patients who were diagnosed with PCR-Confirmed COVID-19 within the last 2 weeks, and presenting hypoxia and signs of a cytokine storm syndrome. Exclusion criteria are those who have a clinical fraility score ≥ 3, an active bacterial or fungal infection, are unlikely to survive beyond 48 hours, mechanically ventilated for more than 24 hours, a neutrophil count below 1500 cells/microliter, a platelet count below 50,000/microliter, and serum transaminase levels > 5 times the upper normal limit. Other exclusion criteria are patients already enrolled in another investigational drug study, patients who have a known history of serious allergic reactions to any of the study medications, patients on high dose systemic steroids for a COVID-19 unrelated disorder, patients on immunosuppressive or immunomodulatory drugs, patients on current anti-IL-1 or anti-IL-6 treatment, signs of active tuberculosis, and those who present bowel perforation or diverticulitis. Finally, pregnant or breatfeeding females are also excluded. Three hundred and forty-two patients will be recruited and randomized to 6 arms: usual care, Anakinra, Siltuximab, Siltuximab + Tocilizumab or Tocilizumab + Anakinra. These 3 pharmacological substances are already on the market for other clinical indications. 1. Tocilizumab: is a humanised anti-IL-6 antibody approved for the treatment of rheumatoidarthritis, juvenile idiopathic arthritis, and giant cell arteritis. It is also licensed for the induction of the rapid reversal of cytokine release syndrome (CRS). The drug prevents IL-6 from binding to soluble and cell associated IL-6 receptors, thus inhibiting signaling. 2. Siltuximab: is a chimeric antibody neutralizing IL-6. It has already been used in the treatment of metastatic kidney cell tumors, prostate cancer, and the multicentric form of Castelman's disease. 3. Anakinra: is a Il-1 receptor antagonist approved in the EU for treatment of Rheumatoid arthritis, cropyrin-associated periodic syndromes (CAPS, NOMID), and Still's disease Randomization will be performed by REDCap. The treatment will be given on Day 1 for tocilizumab and siltuximab. However the anakinra treatment will be given on a daily basis sub-cutaneously until 28 days or hospital discharge (whichever is first). Daily clinical assesment of severity will be performed, with blood tests, measurements of oxygen saturation in relation to Fi02, arterial blood gas measurement, chest X-rays, or CT-Scans. Patients will be followed up with a 12-20 weeks clinical follow up visit. d. Statistical considerations The study was powered to detect the 2 main effects of the 2 x 2 factorial design, assuming that there is no interaction between the different treatments. The first effect relates to the IL-6 blockers compared to usual care: 2 to 1 randomization. To achieve at least 80% power to detect an improvement in median time to improvement from 12 to 8 days, at a 2 sided significance level of 5%, 215 clinical improvements are needed. With an accrual period of 24 days and a follow-up period for the last patient of 28 days, 333 patients are needed to observe 215 events, assuming that 30% of patients are not susceptible to clinical improvement. The second main effect relates to comparison of the IL-1 bloquer to standard of care (1 :2). To achieve at least 80% power to detect an improvement in median time to clinical improvement from 12 to 8 days at a two-sided significance level of 5%, 215 clinical improvements are needed. With an accrual period of 24 days and a follow up period for the last patient of 28 days, 342 patients to observe at least 215 events are needed, assuming 30% of patients are not susceptible to clinical improvement." "
Funding: Special Projects COVID-19 ULB
Publication References: 1. Marty FM, Vidal-Puigserver J, Clark C, Gupta SK, Merino E, Garot D, Chapman MJ, Jacobs F, Rodriguez-Noriega E, Husa P, Shortino D, Watson HA, Yates PJ, Peppercorn AF. Intravenous zanamivir or oral oseltamivir for hospitalized patients with influenza: an international, randomized, double-blind, double-dummy, phase-3 trial. Lancet Respir. Med. 2017. 5(2): 135-46. 2. Mitha E, Krivan G, Jacobs F, Nagler A, Alrabaa S, Mykietiuk A, Kenwright A, et al. Safety, resistance, and efficacy results from a phase IIIb study of conventional- and double dose oseltamivir regimens for treatment of influenza in immunocompromised patients. Infect Dis Ther. 2019. 8(4): 613-26. 3. Persson EK, Verstraete K, Heyndrickx I, Gevaert E, Aegerter H, Percier JM, Deswarte K, Verschueren KHG, Dansercoer A, Gras D, Chanez P, Bachert C, Gonçalves A, Van Gorp H, De Haard H, Blanchetot C, Saunders M, Hammad H, Savvides SN, Lambrecht BN. Protein crystaliization promotes type 2 immunity and is reversible by antibiody treatment. Science. 2019. 364(6442): eaaw4295. Doi: 10.1126/science.aaw4295. 4. Naessens T, Schepens B, Smet M, Pollard C, Van Hoecke L, De Beuckelaer A, Willart M, Lambrecht B, De Koker S; Saelens Grooten J. GM-CSF treatment prevents respiratory syncytial virus-induced pulmonary exacerbation responses in postallergic mice by stimulating alveolar macrophage maturation. J Allergy Clin Immunol. 2016. 137(3): 700-9.e9. doi: 10.1016/j.jaci.2015.09.031 5. Taccone FS, Laterre PF, Spapen H, Dugernier T, Delattre I, Layeux B, De Backer D, Wittebole X, Wallemacq P, Vincent JL, Jacobs F. Crit Care. 2010. 14(2): R53. Doi: 10.1186/cc8945.
Contact: Maya Hites, M.D, PhD Clinic of Infectious Diseases CUB-Erasme Route de Lennik, 808 1070 BXL Tel: +32.2.555.5779 e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.
Comment: The Erasme team is not the promotor of this study. However, iti is a multi-centric, national study. It is important to collaborate to help identify as quickly as possible some effective treatment options for COVID-19.

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Brussels & Wallonia against COVID19