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

Trials. 2021 Jan 20;22(1):71. doi: 10.1186/s13063-021-05027-9.

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.

Keywords: ACE2; Bradykinin; C1 esterase inhibitor; Icatibant; Pneumonia.

Publication types

  • Clinical Trial Protocol

MeSH terms

  • Adult
  • Angiotensin-Converting Enzyme 2 / metabolism
  • Bradykinin / administration & dosage
  • Bradykinin / adverse effects
  • Bradykinin / analogs & derivatives*
  • Bradykinin / antagonists & inhibitors
  • Bradykinin / immunology
  • Bradykinin / metabolism
  • Bradykinin B2 Receptor Antagonists / administration & dosage
  • Bradykinin B2 Receptor Antagonists / adverse effects
  • Brazil
  • COVID-19 / complications
  • COVID-19 / drug therapy*
  • COVID-19 / immunology
  • COVID-19 / virology
  • Clinical Trials, Phase II as Topic
  • Complement C1 Inhibitor Protein / administration & dosage*
  • Complement C1 Inhibitor Protein / adverse effects
  • Drug Administration Schedule
  • Drug Therapy, Combination / adverse effects
  • Drug Therapy, Combination / methods
  • Humans
  • Injections, Intravenous
  • Injections, Subcutaneous
  • Kallikreins / antagonists & inhibitors
  • Kallikreins / metabolism
  • Randomized Controlled Trials as Topic
  • Respiratory Insufficiency / drug therapy*
  • Respiratory Insufficiency / immunology
  • Respiratory Insufficiency / virology
  • SARS-CoV-2 / isolation & purification
  • SARS-CoV-2 / pathogenicity
  • Severity of Illness Index
  • Treatment Outcome

Substances

  • Bradykinin B2 Receptor Antagonists
  • Complement C1 Inhibitor Protein
  • icatibant
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2
  • Kallikreins
  • Bradykinin

Supplementary concepts

  • COVID-19 drug treatment