Rationale and design of the PRAETORIAN-COVID trial: A double-blind, placebo-controlled randomized clinical trial with valsartan for PRevention of Acute rEspiraTORy dIstress syndrome in hospitAlized patieNts with SARS-COV-2 Infection Disease

D H Frank Gommans, Joris Nas, Sara-Joan Pinto-Sietsma, Yvonne Koop, Regina E Konst, Frans Mensink, Goaris W A Aarts, Lara S F Konijnenberg, Kimberley Cortenbach, Dominique V M Verhaert, Jos Thannhauser, Jan-Quinten Mol, Maxim J P Rooijakkers, Jacqueline L Vos, Anouke van Rumund, Priya Vart, Robert-Jan Hassing, Jan-Hein Cornel, C Peter C de Jager, Michel M van den Heuvel, Hans G van der Hoeven, Annelies Verbon, Yigal M Pinto, Niels van Royen, Roland R J van Kimmenade, Event committee, Peter W de Leeuw, Michiel A van Agtmael, Paul Bresser, Data Safety Monitoring Board, Wiek H van Gilst, Anton Vonk-Noordergraaf, Jan G P Tijssen, Steering committee, Niels van Royen, C Peter C de Jager, Michel M van den Heuvel, Hans G van der Hoeven, Annelies Verbon, Yigal M Pinto, Roland R J van Kimmenade, D H Frank Gommans, Joris Nas, Sara-Joan Pinto-Sietsma, Yvonne Koop, Regina E Konst, Frans Mensink, Goaris W A Aarts, Lara S F Konijnenberg, Kimberley Cortenbach, Dominique V M Verhaert, Jos Thannhauser, Jan-Quinten Mol, Maxim J P Rooijakkers, Jacqueline L Vos, Anouke van Rumund, Priya Vart, Robert-Jan Hassing, Jan-Hein Cornel, C Peter C de Jager, Michel M van den Heuvel, Hans G van der Hoeven, Annelies Verbon, Yigal M Pinto, Niels van Royen, Roland R J van Kimmenade, Event committee, Peter W de Leeuw, Michiel A van Agtmael, Paul Bresser, Data Safety Monitoring Board, Wiek H van Gilst, Anton Vonk-Noordergraaf, Jan G P Tijssen, Steering committee, Niels van Royen, C Peter C de Jager, Michel M van den Heuvel, Hans G van der Hoeven, Annelies Verbon, Yigal M Pinto, Roland R J van Kimmenade

Abstract

There is much debate on the use of angiotensin receptor blockers (ARBs) in severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2)-infected patients. Although it has been suggested that ARBs might lead to a higher susceptibility and severity of SARS-CoV-2 infection, experimental data suggest that ARBs may reduce acute lung injury via blocking angiotensin-II-mediated pulmonary permeability, inflammation, and fibrosis. However, despite these hypotheses, specific studies on ARBs in SARS-CoV-2 patients are lacking. METHODS: The PRAETORIAN-COVID trial is a multicenter, double-blind, placebo-controlled 1:1 randomized clinical trial in adult hospitalized SARS-CoV-2-infected patients (n = 651). The primary aim is to investigate the effect of the ARB valsartan compared to placebo on the composite end point of admission to an intensive care unit, mechanical ventilation, or death within 14 days of randomization. The active-treatment arm will receive valsartan in a dosage titrated to blood pressure up to a maximum of 160 mg bid, and the placebo arm will receive matching placebo. Treatment duration will be 14 days, or until the occurrence of the primary end point or until hospital discharge, if either of these occurs within 14 days. The trial is registered at clinicaltrials.gov (NCT04335786, 2020). SUMMARY: The PRAETORIAN-COVID trial is a double-blind, placebo-controlled 1:1 randomized trial to assess the effect of valsartan compared to placebo on the occurrence of ICU admission, mechanical ventilation, and death in hospitalized SARS-CoV-2-infected patients. The results of this study might impact the treatment of SARS-CoV-2 patients globally.

Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1
Figure 1
Study rationale and hypothesis. Legend: The RAS is delicately balanced by counteracting enzymes ACE and ACE2, which regulate concentrations of the vasoconstrictor Ang-II and the vasodilator Ang-1-7. Increased ACE activity leads to higher Ang-II concentrations, whereas ACE2 breaks down Ang-II to Ang-1-7. The SARS-CoV-2 virus uses ACE2 as the cell entry site for internalization. It then decreases ACE2 and consequently increases Ang-II concentrations with deleterious effects such as increased vascular permeability, inflammation, and fibrosis. These pathways are thought to contribute to acute lung injury and ARDS. ARBs may attenuate acute lung injury in SARS-CoV-2 infectious disease by the following mechanisms. First and foremost, blockade of the AT1R may reduce the detrimental effects of Ang-II. Second, administration of ARBs may increase ACE2 expression, which may reduce the detrimental effects of Ang-II.
Figure 2
Figure 2
Study flowchart of the PRAETORIAN-COVID trial. Legend: The blue box comprises the primary end point analysis.

References

    1. Guan W.J., Ni Z.Y., Hu Y. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382:1708–1720.
    1. de Wit E., van Doremalen N., Falzarano D. SARS and MERS: recent insights into emerging coronaviruses. Nat Rev Microbiol. 2016;14(8):523–534.
    1. Zhou P., Yang X.L., Wang X.G. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579(7798):270–273.
    1. Hoffmann M., Kleine-Weber H., Schroeder S. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181(2):271–280.e8.
    1. Deshotels M.R., Xia H., Sriramula S. Angiotensin II mediates angiotensin converting enzyme type 2 internalization and degradation through an angiotensin II type I receptor-dependent mechanism. Hypertension. 2014;64(6):1368–1375.
    1. Li W., Moore M.J., Vasilieva N. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003;426(6965):450–454.
    1. Imai Y., Kuba K., Rao S. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature. 2005;436(7047):112–116.
    1. Kuba K., Imai Y., Rao S. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med. 2005;11(8):875–879.
    1. Fang L., Karakiulakis G., Roth M. 2020. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med.
    1. Sommerstein R, Gra¨ni C. Rapid response: re: preventing a covid-19 pandemic: ACE inhibitors as a potential risk factor for fatal Covid-19. BMJ 2020. https://
    1. Furuhashi M., Moniwa N., Mita T. Urinary angiotensin-converting enzyme 2 in hypertensive patients may be increased by olmesartan, an angiotensin II receptor blocker. Am J Hypertens. 2015;28(1):15–21.
    1. Klimas J., Olvedy M., Ochodnicka-Mackovicova K. Perinatally administered losartan augments renal ACE2 expression but not cardiac or renal Mas receptor in spontaneously hypertensive rats. J Cell Mol Med. 2015;19(8):1965–1974.
    1. Ishiyama Y., Gallagher P.E., Averill D.B. Upregulation of angiotensin-converting enzyme 2 after myocardial infarction by blockade of angiotensin II receptors. Hypertension. 2004;43(5):970–976.
    1. Bavishi C., Maddox T.M., Messerli F.H. Coronavirus disease 2019 (COVID-19) infection and renin angiotensin system blockers. JAMA Cardiol. 2020
    1. Patel A.B., Verma A. 2020. COVID-19 and angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: what is the evidence? JAMA.
    1. Vaduganathan M., Vardeny O., Pharm D. Renin-angiotensin-aldosterone system inhibitors in patients with Covid-19. N Engl J Med. 2020;382:1653–1659.
    1. Kuster G.M. SARS-CoV2: should inhibitors of the renin-angiotensin system be withdrawn in patients with COVID-19? European Heart Journal. 2020;0:1–3.
    1. Gurwitz D. Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics. Drug Dev Res. 2020:1–4.
    1. Battistoni A., Volpe M. 2020. Might renin-angiotensin system blockers play a role in the COVID-19 pandemic? Eur Heart J Cardiovasc Pharmacother.
    1. Danser A.H.J., Epstein M., Batlle D. Renin-angiotensin system blockers and the COVID-19 pandemic: at present there is no evidence to abandon renin-angiotensin system blockers. Hypertension. 2020;75:1382–1385.
    1. Chan A.W., Tetzlaff J.M., Altman D.G. SPIRIT 2013 statement: defining standard protocol items for clinical trials. Annals of internal medicine. 2013;158(3):200–207.
    1. Ciwit B.V. 2016. Castor electronic data capture. Amsterdam.
    1. Zhang P., Zhu L., Cai J. Association of inpatient use of angiotensin converting enzyme inhibitors and angiotensin ii receptor blockers with mortality among patients with hypertension hospitalized with COVID-19. Circulation Research. 2020
    1. Wan Y., Shang J., Graham R. Receptor recognition by the novel coronavirus from wuhan: an analysis based on decade-long structural studies of SARS coronavirus. J Virol. 2020;94(7)
    1. Van de Veerdonk F.L., Netea M.G., van Deuren M. Kinins and cytokines in COVID-19: a comprehensive pathophysiological approach. 2020.
    1. Li X.C., Zhang J., Zhuo J.L. The vasoprotective axes of the renin-angiotensin system: physiological relevance and therapeutic implications in cardiovascular, hypertensive and kidney diseases. Pharmacol Res. 2017;125(Pt A):21–38.
    1. Sun M.L., Yang J.M., Sun Y.P. Inhibitors of RAS might be a good choice for the therapy of COVID-19 pneumonia. Zhonghua Jie He He Hu Xi Za Zhi. 2020;43(3):219–222.
    1. Khan A., Benthin C., Zeno B. A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome. Crit Care. 2017;21(1):234.
    1. Campbell D.J., Zeitz C.J., Esler M.D. Evidence against a major role for angiotensin converting enzyme-related carboxypeptidase (ACE2) in angiotensin peptide metabolism in the human coronary circulation. J Hypertens. 2004;22(10):1971–1976.
    1. Rice G.I., Thomas D.A., Grant P.J. Evaluation of angiotensin-converting enzyme (ACE), its homologue ACE2 and neprilysin in angiotensin peptide metabolism. Biochem J. 2004;383(Pt 1):45–51.
    1. Vincent M.J., Bergeron E., Benjannet S. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol J. 2005;2:69.
    1. Xu Z., Shi L., Wang Y. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020;8:420–422.
    1. Abraham H.M., White C.M., White W.B. The comparative efficacy and safety of the angiotensin receptor blockers in the management of hypertension and other cardiovascular diseases. Drug Saf. 2015;38(1):33–54.
    1. Pfeffer M.A., Swedberg K., Granger C.B. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-overall programme. Lancet. 2003;362(9386):759–766.
    1. Zhou F., Yu T., Du R. 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.
    1. Richardson S., Hirsch J.S., Narasimhan M. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. JAMA. 2020;323(20):2052–2059.
    1. Remuzzi A., Remuzzi G. COVID-19 and Italy: what next? Lancet. 2020;395(10231):1225–1228.

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