Angiotensin 1-7 in severe COVID-19 patients: a phase 1 clinical trial

Background The coronavirus-related disease (COVID-19) is mainly characterized by a respiratory involvement, with few available therapeutics for critically cases. The renin-angiotensin system (RAS) has a relevant role in the pathogenesis of COVID-19, as the virus enter host’s cells via the angiotensin-converting enzyme 2 (ACE2) and RAS disequilibrium promote inflammation and fibrosis. Exogenous angiotensin-(1-7) might modulate RAS in COVID-19 patients; however, no data on its safety are available in this setting. Methods This investigator-initiated, open label, phase I clinical trial was conducted to test the safety of intravenous administration of Angiotensin-(1-7) in severe COVID-19 patients admitted in two intensive care units (ICU) in Belo Horizonte, Brazil. In addition to standard of care, intravenous administration of Angiotensin-(1-7) was started at 5 mcg/Kg*day and increased to 10 mcg/Kg*day after 24 hours and continued for a maximum of 7 days or until ICU discharge. The rate of serious adverse events (SAEs) served as the primary outcome of the study. Results Between August and December 2020, 28 patients were included (mean age of 55.8±12.0 years). All but one patient underwent dose escalation after 24 hours and 8 (28.5%) received the treatment until day 7. No significant differences in mean blood pressure and heart rate were observed before and after the initiation of the drug. During the period of intervention, 5/28 (17.8%) patients required vasopressors, 4 at low dose norepinephrine (i.e. <0.05 mcg/kg*min), while one patient required higher doses because of septic shock. One patient presented with sinus bradycardia, which was considered possibly related to the study drug and resolved after discontinuation. Six patients (21.4%) died before ICU discharge. Conclusions Intravenous infusion of Angiotensin-(1-7) up to 10 mcg/Kg*day was safe in severe COVID-19 patients and could represent a potential therapeutic strategy in this setting. Trial Registration Registro Brasileiro de Ensaios Clínicos, UTN code: U1111-1255-7167, registered on 08/05/2020; [ClinicalTrials.gov][1] Identifier: [NCT04633772][2]; retrospectively registered on November 18 2020 ### Competing Interest Statement The authors of the trial declared to have no conflict of interest. Prof Robson is the CEO of the company Angitec, which provided economic and logistic support without any monetary or contractual compensation. ### Clinical Trial Registro Brasileiro de Ensaios Clinicos, UTN code: U1111-1255-7167, registered on 08/05/2020; [ClinicalTrials.gov][1] Identifier: [NCT04633772][2] ### Funding Statement The study was conducted with the support of the Universite Libre de Bruxelles (ULB) grant for COVID-19 (Research Number 5C06G000010), Fundacao de Amparo a Pesquisa do Estado de Minas Gerais (Fapemig), Angitec (Brazilian Start-up). Dr Annoni received research grant from Fonds Erasme pour la Recherche Medicale. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the ethic committee of the Federal University of Minas Gerais (CAAE: 34080720.0.1001.5149) and was carried out in accordance with the declaration of Helsinki after the approval of the CONEP (national council of ethics in research). Written informed consent was obtained from a legal representative or the patient, depending on the circumstances, before inclusion. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The data that support the findings of this study are available from the corresponding author, [R.A.S.S.], upon reasonable request. * ACE : angiotensin converting enzyme ACE2 : angiotensin converting enzyme 2 ACEi : ACE inhibitors ARBs : angiotensin II receptor blockers, or sartans Ang I : angiotensin I Ang-(1-7) : angiotensin-(1-7) Ang II : angiotensin II ICU : intensive care unit OFDs : oxygen-free days RAS : renin angiotensin system SAEs : serious adverse events DSMC : data safety monitoring committee [1]: http://ClinicalTrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04633772&atom=%2Fmedrxiv%2Fearly%2F2022%2F09%2F15%2F2022.09.15.22279897.atom