Clinical trial for bradykinin inhibition in hospitalized adults with COVID-19 grave

Abstract

The pandemic of the new severe acute respiratory syndrome virus (SARS-CoV-2) has already been confirmed in more than 330 thousand people, being responsible for more than 14 thousand deaths worldwide (World Health Organization - official data of 23 March 2020). The current treatment for severe cases is based on respiratory support, use of a variety of antibiotics with possible extracorporeal oxygenation; however, the results are still unsatisfactory. Researchers have shown that the virus binds to Angiotensin-Converting Enzyme 2 (ECA2) to gain access to cells. This enzyme is essential in the inactivation of Angiotensin II (ANGII) and bradykinin. The accumulation of bradykinin in the lungs is a common effect after the use of ACE inhibitors with a consequent increase in cough. In studies with animal models, inactivation of ACE2 leads to severe pneumonitis after administration of lipopolysaccharides (LPS) and the inhibition of bradykinin completely restores lung function and structure. As pneumonia is the most intense condition and a marker of disease progression, our hypothesis is that the increase in bradykinin is the main link between SARS-CoV-2 infection and ACE2 inhibition resulting in a severe respiratory syndrome. OBJECTIVE: To evaluate the efficacy of two pharmacological inhibitors of bradykinin, the C1 esterase/kallikrein inhibitor (Berinert®, CSL Behring GmbH) and the bradykinin receptor 2 inhibitor, icatibant (Firazyr®, Shire) in critically ill patients hospitalized for SARS -CoV-2. METHODOLOGY: This is an open randomized clinical trial to be carried out at Hospital de Clínicas, Universidade Estadual de Campinas, Brazil. One hundred and eighty patients will be divided in a 1: 1: 1 ratio to receive: i, the basic support established by clinical trials already published, which include oxygen support, invasive and non-invasive mechanical ventilation, use of antibiotics, use of vasopressors and therapy renal support; or, ii, Berinert, 20 U/Kg intravenously, one dose on the day of inclusion in the study and one dose on the fourth day; patients in this group will receive the same basic support procedure offered to the control group; iii, Firazyr, 30 mg subcutaneously 8/8 h for four days; patients in this group will receive the same basic support procedure offered to the control group. The primary outcomes are complete recovery with hospital discharge or death; monitoring will be done for 28 days. The inclusion criteria will be: men and women aged 18 years or older with positive RT-PCR for SARS-CoV-2; pneumonia confirmed by computed tomography (CT) of the chest; oxygen saturation in ambient air of 94% or less. Exclusion criteria: Pregnant or lactating women; patients with severe liver disease (alanine aminotransferase and/or aspartate aminotransferase> 5x above normal); severe nephropathy (kidney transplant or dialysis), HIV infection, cancer, hereditary angioedema, other immunodeficiencies, past myocardial ischemic disease, past thromboembolic disease. All study patients and/or their relatives will be informed about the objectives and risks of the research and should read and sign the Informed Consent Form. (AU)