Angiotensin-(1–7) infusion in COVID-19 patients admitted to the ICU: a seamless phase 1–2 randomized clinical trial

Autor: Ana Luiza Valle Martins, Filippo Annoni, Filipe Alex da Silva, Lucas Bolais-Ramos, Gisele Capanema de Oliveira, Renata Cunha Ribeiro, Mirella Monique Lana Diniz, Thuanny Granato Fonseca Silva, Beatriz Dias Pinheiro, Natália Abdo Rodrigues, Alana Helen dos Santos Matos, Daisy Motta-Santos, Maria José Campagnole-Santos, Thiago Verano-Braga, Fabio Silvio Taccone, Robson Augusto Souza Santos
Jazyk: angličtina
Rok vydání: 2024
Předmět:
Zdroj: Annals of Intensive Care, Vol 14, Iss 1, Pp 1-10 (2024)
Druh dokumentu: article
ISSN: 2110-5820
DOI: 10.1186/s13613-024-01369-0
Popis: Abstract Background The coronavirus-related disease (COVID-19) is mainly characterized by a respiratory involvement. The renin-angiotensin system (RAS) has a relevant role in the pathogenesis of COVID-19, as the virus enters host’s cells via the angiotensin-converting enzyme 2 (ACE2). Methods This investigator-initiated, seamless phase 1–2 randomized clinical trial was conceived to test the safety and efficacy of continuous short-term (up to 7 days) intravenous administration of Angiotensin-(1–7) in COVID-19 patients admitted to two intensive care units (ICU). 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 h (Phase 1; open label trial) or given at 10 mcg/Kg day and continued for a maximum of 7 days or until ICU discharge (Phase 2; double-blind randomized controlled trial). The rate of serious adverse events (SAEs) served as the primary outcome of the study for Phase 1, and the number of oxygen free days (OFDs) by day 28 for Phase 2. Results Between August 2020 and July 2021, when the study was prematurely stopped due to low recruitment rate, 28 patients were included in Phase 1 and 79 patients in Phase 2. Of those, 78 were included in the intention to treat analysis, and the primary outcome was available for 77 patients. During Phase 1, one SAE (i.e., bradycardia) was considered possibly related to the infusion, justifying its discontinuation. In Phase 2, OFDs did not differ between groups (median 19 [0–21] vs. 14 [0–18] days; p = 0.15). When patients from both phases were analyzed in a pooled intention to treat approach (Phase 1–2 trial), OFDs were significantly higher in treated patients, when compared to controls (19 [0–21] vs. 14 [0–18] days; absolute difference −5 days, 95% CI [0–7] p = 0.04). Conclusions The main findings of our study indicate that continuous intravenous infusion of Angiotensin-(1–7) at 10 mcg/Kg day in COVID-19 patients admitted to the ICU with severe pneumonia is safe. In Phase II intention to treat analysis, there was no significant difference in OFD between groups. Trial Registration ClinicalTrials.gov Identifier: NCT04633772—Registro Brasileiro de Ensaios Clínicos, UTN number: U1111-1255-7167.
Databáze: Directory of Open Access Journals
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