A multicenter, open-label, randomized, proof-of-concept phase II clinical trial to assess the efficacy and safety of icatibant in patients infected with SARS-CoV-2 (COVID-19) and admitted to hospital units without invasive mechanical ventilation: study protocol (ICAT-COVID)
Authors: Malchair Pierre , Otero Aurema , Giol Jordi , Solanich Xavier , Carnaval Thiago , Fernández-Nistal Alonso , Sánchez-Gabriel Ana , Montoto Carmen , Lleonart Ramon , Videla Sebastián ,   on behalf of the ICAT-COVID team, Antoli Arnau , Benjumeda Marta , Bernal Tania , Calatayud Laura , Corbella Xavier , Ferrer Anna , Garcia Vanesa , Gasa Mercè , Gudiol Carlota , Hereu Pilar , Jacob Javier , Jofre Hector , Llopis Ferran , Matellan Leire , Pallarés Natalia , Rigo Raul , Rocamora Gemma , Rodríguez Freddy , Rombauts Alexander , Ruibal José Carlos , Sabater Joan , Serrano Carmen , Suárez-Lledó Ana , Tebé Cristian , Villoria Jesús , Zarauza Alvaro 
Published: April 2022

Abstract
Background
COVID-19 has quickly become a global pandemic with a substantial number of deaths and is a considerable burden for healthcare systems worldwide. Although most cases are paucisymptomatic and limited to the viral infection-related symptoms, some patients evolve to a second phase, with an impaired inflammatory response (cytokine storm) that may lead to acute respiratory distress syndrome and death. This is thought to be caused by increased bradykinin synthesis.

Methods
ICAT-COVID is a multicenter, randomized, open-label, proof-of-concept phase II clinical trial assessing the clinical efficacy and safety of adding icatibant to the standard of care in patients hospitalized with COVID-19 without invasive mechanical ventilation. Patients hospitalized with a confirmed COVID-19 pneumonia diagnosis (RT-PCR or antigen test ≤ 10 days prior to randomization, and radiographic evidence of pulmonary infiltrates), rated “4” or “5” on the WHO’s clinical status scale, are eligible. Patients will be randomized on a 1:1 ratio to either standard of care-plus-icatibant (experimental group) or to standard of care alone (control group). The experimental group will receive 30 mg of icatibant subcutaneously 3 times a day for 3 days (for a total of 9 doses). The expected sample size is 120 patients (60 per group) from 2 sites in Spain. Primary outcomes are the efficacy and safety of Icatibant. The main efficacy outcome is the number of patients reaching grades “2” or “1” on the WHO scale within 10 days of starting treatment. Secondary outcomes include “long-term efficacy”: number of patients discharged who do not present COVID-19-related relapse or comorbidity up until 28 days after discharge, and mortality.

Discussion
Icatibant, a bradykinin type 2 receptor antagonist with proven effectiveness and safety against hereditary angioedema attacks, may be beneficial for COVID-19 patients by inhibiting bradykinin’s action on endothelial cells and by inhibiting the SARS-CoV-2 M protease. Our working hypothesis is that treatment with standard of care-plus-icatibant is effective and safe to treat patients infected with SARS-CoV-2 admitted to hospital for pneumonia without invasive mechanical ventilation.

Trial registration
EudraCT 2020-002166-13. ClinicalTrials.gov NCT04978051