Evaluation of the efficacy and safety of icatibant and C1 esterase/kallikrein inhibitor in severe COVID-19: study protocol for a three-armed randomized controlled trial

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Mansour, Eli ^[1] ; Bueno, Flavia F. ^[2] ; de Lima-Junior, Jose C. ^[2] ; Palma, Andre ^[1] ; Monfort-Pires, Milena ^[2] ; Bombassaro, Bruna ^[2] ; Araujo, Eliana P. ^{[3, 2]} ; Bernardes, Ana Flavia ^[1] ; Ulaf, Raisa G. ^[1] ; Nunes, Thyago A. ^[1] ; Ribeiro, Luciana C. ^[1] ; Falcao, Antonio Luis E. ^[4] ; Santos, Thiago Martins ^[1] ; Trabasso, Plinio ^[1] ; Dertkigil, Rachel P. ^[5] ; Dertkigil, Sergio S. ^[5] ; Maia, Rafael P. ^[6] ; Benaglia, Tatiana ^[6] ; Moretti, Maria Luiza ^[1] ; Velloso, Licio A. ^{[1, 2]}

Afiliação do(s) autor(es)

^[1] Univ Estadual Campinas, Sch Med Sci, Dept Internal Med, Campinas, SP - Brazil

^[2] Univ Estadual Campinas, Obes & Comorbid Res Ctr, Campinas, SP - Brazil

^[3] Univ Estadual Campinas, Sch Nursing, Campinas, SP - Brazil

^[4] Univ Estadual Campinas, Sch Med Sci, Dept Surg, Campinas, SP - Brazil

^[5] Univ Estadual Campinas, Sch Med Sci, Dept Radiol, Campinas, SP - Brazil

^[6] Univ Estadual Campinas, Inst Math Stat & Sci Computat, Dept Stat, Campinas, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Trials; v. 22, n. 1 JAN 20 2021.
• Citações Web of Science: 0

Resumo

Background: SARS-CoV-2, the virus that causes COVID-19, enters the cells through a mechanism dependent on its binding to angiotensin-converting enzyme 2 (ACE2), a protein highly expressed in the lungs. The putative viral-induced inhibition of ACE2 could result in the defective degradation of bradykinin, a potent inflammatory substance. We hypothesize that increased bradykinin in the lungs is an important mechanism driving the development of pneumonia and respiratory failure in COVID-19. Methods: This is a phase II, single-center, three-armed parallel-group, open-label, active control superiority randomized clinical trial. One hundred eighty eligible patients will be randomly assigned in a 1:1:1 ratio to receive either the inhibitor of C1e/kallikrein 20 U/kg intravenously on day 1 and day 4 plus standard care; or icatibant 30 mg subcutaneously, three doses/day for 4 days plus standard care; or standard care alone, as recommended in the clinical trials published to date, which includes supplemental oxygen, non-invasive and invasive ventilation, antibiotic agents, anti-inflammatory agents, prophylactic antithrombotic therapy, vasopressor support, and renal replacement therapy. Discussion: Accumulation of bradykinin in the lungs is a common side effect of ACE inhibitors leading to cough. In animal models, the inactivation of ACE2 leads to severe acute pneumonitis in response to lipopolysaccharide (LPS), and the inhibition of bradykinin almost completely restores the lung structure. We believe that inhibition of bradykinin in severe COVID-19 patients could reduce the lung inflammatory response, impacting positively on the severity of disease and mortality rates. (AU)

• Processo FAPESP: 13/07607-8 - CMPO - Centro Multidisciplinar de Pesquisa em Obesidade e Doenças Associadas
• Beneficiário: Licio Augusto Velloso
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 20/04522-5 - Ensaio clínico de inibição de bradicinina em adultos hospitalizados com COVID-19 grave
• Beneficiário: Licio Augusto Velloso
• Modalidade de apoio: Auxílio à Pesquisa - Regular