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

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.

Increased complement activation is a distinctive feature of severe SARS-CoV-2 infection

“…A specific interest in COVID-19 stems from features of endothelial injury and hypercoagulability, given the cross-talk between the complement and coagulation systems (18). This observation has resulted in multiple phase II and III clinical trials targeting various components of the complement system (27)(28)(29)(30)(31). However, many cytokines that have been implicated in COVID-19, are also elevated in other forms of acute infection, including those leading to respiratory failure (6,32).…”

“…Accordingly, multiple studies have demonstrated elevation of C5a and sC5b-9 in patients with COVID-19 (15,23,24), as well as deposition of activated complement proteins in injured tissues and organs (25,26). As a result, these studies have created a precedent for targeting the complement system in multiple ongoing phase II and phase III clinical trials employing complement inhibitors in COVID-19 (27)(28)(29)(30).…”

Increased complement activation is a distinctive feature of severe SARS-CoV-2 infection

“…A specific interest in COVID-19 stems from features of endothelial injury and hypercoagulability, given the cross-talk between the complement and coagulation systems (Perico et al ., 2020). This observation has resulted in multiple phase II and III clinical trials targeting various components of the complement system (Declercq et al ., 2020; Mastellos et al ., 2020; Smith et al ., 2020; Vlaar et al ., 2020; Mansour et al ., 2021). However, many cytokines that have been implicated in COVID-19, are also elevated in other forms of acute infection, including those leading to respiratory failure (Mudd et al ., 2020; Bain et al ., 2021).…”

“…Accordingly, multiple studies have demonstrated elevation of C5a and sC5b-9 in patients with COVID-19 (Carvelli et al ., 2020; Cugno et al ., 2020; Holter et al ., 2020), as well as deposition of activated complement proteins in injured tissues and organs (Magro et al ., 2020; Macor et al ., 2021). As a result, these studies have created a precedent for targeting the complement system in multiple ongoing phase II and phase III clinical trials employing complement inhibitors in COVID-19 (Declercq et al ., 2020; Mastellos et al ., 2020; Smith et al ., 2020; Vlaar et al ., 2020; Mansour et al ., 2021).…”

Severe COVID-19 Infection Associated with Endothelial Dysfunction Induces Multiple Organ Dysfunction: A Review of Therapeutic Interventions

“…Interestingly, three out of 10 patients (30%) using icatibant did need to go back on oxygen again, which may be due to icatibant's short-acting effect (half-life of 2 h) [143]. Recently, an RCT to evaluate the efficacy and safety of icatibant, a C1 esterase/kallikrein inhibitor, in severe COVID-19 has been launched [144] and this study may lead to a more rigorous association between COVID-19 infection and bradykinin systems.…”