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)

Pierre Malchair, Aurema Otero, Jordi Giol, Xavier Solanich, Thiago Carnaval, Alonso Fernández-Nistal, Ana Sánchez-Gabriel, Carmen Montoto, Ramon Lleonart, Sebastián Videla, ICAT-COVID team, Arnau Antoli, Marta Benjumeda, Tania Bernal, Laura Calatayud, Xavier Corbella, Anna Ferrer, Vanesa Garcia, Mercè Gasa, Carlota Gudiol, Pilar Hereu, Javier Jacob, Hector Jofre, Ferran Llopis, Leire Matellan, Natalia Pallarés, Raul Rigo, Gemma Rocamora, Freddy Rodríguez, Alexander Rombauts, José Carlos Ruibal, Joan Sabater, Carmen Serrano, Ana Suárez-Lledó, Cristian Tebé, Jesús Villoria, Alvaro Zarauza, Pierre Malchair, Aurema Otero, Jordi Giol, Xavier Solanich, Thiago Carnaval, Alonso Fernández-Nistal, Ana Sánchez-Gabriel, Carmen Montoto, Ramon Lleonart, Sebastián Videla, ICAT-COVID team, Arnau Antoli, Marta Benjumeda, Tania Bernal, Laura Calatayud, Xavier Corbella, Anna Ferrer, Vanesa Garcia, Mercè Gasa, Carlota Gudiol, Pilar Hereu, Javier Jacob, Hector Jofre, Ferran Llopis, Leire Matellan, Natalia Pallarés, Raul Rigo, Gemma Rocamora, Freddy Rodríguez, Alexander Rombauts, José Carlos Ruibal, Joan Sabater, Carmen Serrano, Ana Suárez-Lledó, Cristian Tebé, Jesús Villoria, Alvaro Zarauza

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.

Keywords: ACE2; ARDS; Bradykinin; COVID-19; Icatibant; SARS; SARS-CoV-2.

Conflict of interest statement

AF-N, AS-G and CM are employees of Takeda. The other authors declare that they have no competing interests.

© 2022. The Author(s).

References

    1. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. China Novel Coronavirus Investigating and Research Team. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. 2020;382:727–733. doi: 10.1056/NEJMoa2001017.
    1. . WHO Coronavirus (COVID-19) Dashboard. (accessed February 3th, 2022).
    1. Sidiqqi HK, Mehra MR. COVID-19 illness in native and immunosupressed states: a clinical- therapeutic staging proposal. J Heart Lung Transplant. 2020;39(5):405–407. doi: 10.1016/j.healun.2020.03.012.
    1. Cicardi M, Banerji A, Bracho F, Malbrán A, Rosenkranz B, Riedl M, Bork K, Lumry W, Aberer W, Bier H, Bas M, Greve J, Hoffmann TK, Farkas H, Reshef A, Ritchie B, Yang W, Grabbe J, Kivity S, Kreuz W, Levy RJ, Luger T, Obtulowicz K, Schmid-Grendelmeier P, Bull C, Sitkauskiene B, Smith WB, Toubi E, Werner S, Anné S, Björkander J, Bouillet L, Cillari E, Hurewitz D, Jacobson KW, Katelaris CH, Maurer M, Merk H, Bernstein JA, Feighery C, Floccard B, Gleich G, Hébert J, Kaatz M, Keith P, Kirkpatrick CH, Langton D, Martin L, Pichler C, Resnick D, Wombolt D, Romero DSF, Zanichelli A, Arcoleo F, Knolle J, Kravec I, Dong L, Zimmermann J, Rosen K, Fan WT. Icatibant, a new bradykinin-receptor antagonist in hereditary angioedema. N Engl J Med. 2010;363(6):532–541. doi: 10.1056/NEJMoa0906393.
    1. Icatibant (Firazyr®). Summary of product characteristics (Ficha técnica, Febrero 2019). (accessed July 5th, 2021).
    1. Busse PJ, Christiansen SC. Hereditary angioedema. N Engl J Med. 2020;382(12):1136–1148. doi: 10.1056/NEJMra1808012.
    1. Zanichelli A, Maurer M, Aberer W, Caballero T, Longhurst HJ, Bouillet L, Fabien V, Andresen I, the IOS Study Group Long-term safety of Icatibant treatment of patients with angioedema in real- world clinical practice. Allergy Eur J Allergy Clin Immunol. 2017;72(6):994–998. doi: 10.1111/all.13103.
    1. Bygum A, Caballero T, Grumach AS, Longhurst HJ, Bouillet L, Aberer W, et al. Elderly versus younger patients with hereditary angioedema type I/II: patient characteristics and safety analysis from the Icatibant Outcome Survey. Clin Transl Allergy. 2019;9(1):37. doi: 10.1186/s13601-019-0272-9.
    1. Bova M, Guilarte M, Sala-Cunill A, Borrelli P, Rizzelli GM, Zanichelli A. Treatment of ACEI-related angioedema with Icatibant: a case series. Intern Emerg. 2015;10(3):345–350. doi: 10.1007/s11739-015-1205-9.
    1. Hess R, Wujak L, Hesse C, Sewald K, Jonigk D, Warnecke G, Fieguth HG, Maat S, Maas C, Bonella F, Preissner K, Weiss B, Schaefer L, Kuebler W, Markart P, Wygrecka M. Coagulation factor XII regulates inflammatory responses in human lungs. Thromb Haemost. 2017;117(10):1896–1909. doi: 10.1160/TH16-12-0904.
    1. Van De Veerdonk FL, Netea MG, van Deuren M, van der Meer JWM, de Mast Q, Brüggemann RJ, et al. Kinins and cytokines in COVID-19: a comprehensive pathophysiological approach. 10.20944/preprints202004.0023.v1.
    1. Tolouian R, Vahed SZ, Ghiyasvand S, Tolouian A, Ardalan M. COVID-19 interactions with angiotensin-converting enzyme 2 (ACE2) and the kinin system; looking at a potential treatment. J Ren Inj Prev. 2020;9:19. doi: 10.34172/jrip.2020.19.
    1. Yang G, Tan Z, Zhou L, Yang M, Peng L, Liu J, Cai J, Yang R, Han J, Huang Y, He S. Effects of angiotensin II receptor blockers and ACE (angiotensin-converting enzyme) inhibitors on virus infection, inflammatory status, and clinical outcomes in patients with COVID-19 and hypertension: a single-center retrospective study. Hypertension. 2020;76(1):51–58. doi: 10.1161/HYPERTENSIONAHA.120.15143.
    1. COVID-19 guidelines. Pharmacological treatment of SARS-CoV-2 infection. Catalan Health Service. Available in: (ca|en) (accessed January 18th, 2022)
    1. l. World Health Organization 2020. Available in: (accessed July 5th, 2021).
    1. National Early Warning Score (NEWS) 2, available in: (accessed July 5th, 2021).
    1. Liu X, Wang X. Potential inhibitors against 2019-nCoV coronavirus M protease from clinically approved medicines. J Genet Genomics. 2020;47(2):119–121. doi: 10.1016/j.jgg.2020.02.001.
    1. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, Zhao Y, Li Y, Wang X, Peng Z. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. 2020;323(11):1061–1069. doi: 10.1001/jama.2020.1585.
    1. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054–1062. doi: 10.1016/S0140-6736(20)30566-3.
    1. van de Veerdonk FL, Kouijzer IJE, de Nooijer AH, van der Hoeven HG, Maas C, Netea MG, et al. Outcomes associated with use of a kinin B2 receptor antagonist among patients with COVID-19. JAMA Netw Open. 2020;3:e2017708. doi: 10.1001/jamanetworkopen.2020.17708.
    1. Mansour E, Bueno FF, de Lima-Júnior JC, Palma A, Monfort-Pires M, Bombassaro B, Araujo EP, Bernardes AF, Ulaf RG, Nunes TA, Ribeiro LC, Falcão ALE, Santos TM, Trabasso P, Dertkigil RP, Dertkigil SS, Maia RP, Benaglia T, Moretti ML, Velloso LA. 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;22(1):71. doi: 10.1186/s13063-021-05027-9.
    1. Leach JK, Spencer K, Mascelli M, McCauley TG. Pharmacokinetics of single and repeat doses of icatibant. Clin Pharmacol Drug Dev. 2015;4(2):105–111. doi: 10.1002/cpdd.138.

Source: PubMed

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