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
Eli Mansour,
Flávia F. Bueno,
José C. de Lima-Júnior,
Andre Palma,
Milena Monfort-Pires,
Bruna Bombassaro,
Eliana P. Araujo,
Ana Flavia Bernardes,
Raisa G. Ulaf,
Thyago A. Nunes,
Luciana C. Ribeiro,
Antônio Luís E. Falcão,
Thiago Martins Santos,
Plinio Trabasso,
Rachel P. Dertkigil,
Sergio S. Dertkigil,
Rafael P. Maia,
Tatiana Benaglia,
Maria Luiza Moretti,
Licio A. Velloso
Affiliations
Eli Mansour
Department of Internal Medicine, School of Medical Sciences, University of Campinas
Flávia F. Bueno
Obesity and Comorbidities Research Center, University of Campinas
José C. de Lima-Júnior
Obesity and Comorbidities Research Center, University of Campinas
Andre Palma
Department of Internal Medicine, School of Medical Sciences, University of Campinas
Milena Monfort-Pires
Obesity and Comorbidities Research Center, University of Campinas
Bruna Bombassaro
Obesity and Comorbidities Research Center, University of Campinas
Eliana P. Araujo
Obesity and Comorbidities Research Center, University of Campinas
Ana Flavia Bernardes
Department of Internal Medicine, School of Medical Sciences, University of Campinas
Raisa G. Ulaf
Department of Internal Medicine, School of Medical Sciences, University of Campinas
Thyago A. Nunes
Department of Internal Medicine, School of Medical Sciences, University of Campinas
Luciana C. Ribeiro
Department of Internal Medicine, School of Medical Sciences, University of Campinas
Antônio Luís E. Falcão
Department of Surgery, School of Medical Sciences, University of Campinas
Thiago Martins Santos
Department of Internal Medicine, School of Medical Sciences, University of Campinas
Plinio Trabasso
Department of Internal Medicine, School of Medical Sciences, University of Campinas
Rachel P. Dertkigil
Department of Radiology, School of Medical Sciences, University of Campinas
Sergio S. Dertkigil
Department of Radiology, School of Medical Sciences, University of Campinas
Rafael P. Maia
Department of Statistics, Institute of Mathematics, Statistics, and Scientific Computation, University of Campinas
Tatiana Benaglia
Department of Statistics, Institute of Mathematics, Statistics, and Scientific Computation, University of Campinas
Maria Luiza Moretti
Department of Internal Medicine, School of Medical Sciences, University of Campinas
Licio A. Velloso
Department of Internal Medicine, School of Medical Sciences, University of Campinas
Abstract 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. Trial registration Brazilian Clinical Trials Registry Universal Trial Number (UTN) U1111-1250-1843. Registered on May/5/2020.
