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

Abstract

The pandemic of the new severe acute respiratory syndrome virus (SARS-CoV-2) has been confirmed in morethan 330,000 people being responsible for more than 14,000 deaths worldwide (World Health Organization -official data of March 23, 2020). Current treatment for severe cases it is based on respiratory support, use of avariety of antibiotics with eventual extracorporeal oxygenation; however, the results are still unsatisfactory. Researchers have shown that the virus binds to Angiotensin-Converting Enzyme 2 (ECA2) to access the cells. This enzyme is essential in the inactivation of Angiotensin II (ANGII) and of bradykinin. The accumulation ofbradykinin in the lungs is a common effect after using ACE inhibitors with consequent increased cough. In studieswith animal models, the inactivation of ACE2 leads to severe pneumonitis after administration oflipopolysaccharides (LPS) and inhibition of bradykinin completely restores lung function and structure. Such aspneumonia is the most intense condition and a marker of disease progression, our hypothesis is that the increasein bradykinin is the main link between SARS-CoV-2 infection and the inhibition of ACE2 resulting in a severerespiratory syndrome. OBJECTIVE: To evaluate the effectiveness of two pharmacological inhibitors of bradykinin, the C1 esterase / kallikrein inhibitor (Berinert®, CSL Behring GmbH) and the bradykinin receptor 2 inhibitors, icatibant (Firazyr®, Shire) in severe patients hospitalized for SARS-CoV-2. METHODOLOGY: This is a clinical trialrandomized open study to be carried out at the Hospital de Clínicas, Universidade Estadual Campinas, Brazil. Onehundred and eighty patients will be divided in a 1: 1: 1 ratio to receive: i, the basic support established bypublished clinical trials, which include support from oxygen, invasive and non-invasive mechanical ventilation, useof antibiotics, use of vasopressors and renal support therapy; or, ii, Berinert, 20 U / Kg intravenously, one doseon the day of inclusion in the study and a dose on the fourth day; patients in this group will receive the samebasic support procedure offered to the control group; iii, Firazyr, 30 mg route subcutaneous 8/8 h for four days;patients in this group will receive the same procedure basic support offered to the control group. The primaryoutcomes are, recovery complete with hospital discharge or death; monitoring will be done for 28 days. Thecriteria of inclusion 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; saturation oxygen in room 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), HIVinfection, cancer, hereditary angioedema, other immunodeficiencies, ischemic disease myocardial infarction, previous thromboembolic disease. All study patients and / or your relatives will be informed about the researchobjectives and risks and should read and sign the Free and Informed Consent Form. (AU)