Martins Ana Luiza Valle, Annoni Filippo, da Silva Filipe Alex, Bolais-Ramos Lucas, de Oliveira Gisele Capanema, Ribeiro Renata Cunha, Diniz Mirella Monique Lana, Silva Thuanny Granato Fonseca, Pinheiro Beatriz Dias, Rodrigues Natália Abdo, Dos Santos Matos Alana Helen, Motta-Santos Daisy, Campagnole-Santos Maria José, Verano-Braga Thiago, Taccone Fabio Silvio, Santos Robson Augusto Souza
National Institute of Science and Technology in Nanobiopharmaceutics (INCT-Nanobiofar), Laboratory of Hypertension, Institute of Biological Sciences, Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais Av. Antonio Carlos, 6627-ICB-UFMG, Belo Horizonte, 31270-901, Brazil.
Department of Intensive Care Erasme Hospital, University Hospital of Brussels (HUB), Lennik Road 808, 1070, Brussels, Belgium.
Ann Intensive Care. 2024 Sep 4;14(1):139. doi: 10.1186/s13613-024-01369-0.
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).
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.
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).
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.
冠状病毒相关疾病（COVID-19）主要以呼吸系统受累为特征。肾素-血管紧张素系统（RAS）在COVID-19的发病机制中起相关作用，因为该病毒通过血管紧张素转换酶2（ACE2）进入宿主细胞。
这项由研究者发起的1-2期无缝随机临床试验旨在测试在两家重症监护病房（ICU）收治的COVID-19患者中连续短期（最长7天）静脉注射血管紧张素-（1-7）的安全性和有效性。除标准治疗外，血管紧张素-（1-7）的静脉注射起始剂量为5微克/千克/天，24小时后增至10微克/千克/天（第1阶段；开放标签试验），或给予10微克/千克/天并持续最长7天或直至ICU出院（第2阶段；双盲随机对照试验）。严重不良事件（SAE）发生率作为第1阶段研究的主要结局，第2阶段则为第28天的无吸氧天数（OFD）。
在2020年8月至2021年7月期间，由于招募率低该研究提前终止，第1阶段纳入28例患者，第2阶段纳入79例患者。其中，78例纳入意向性分析，77例患者可获得主要结局数据。在第1阶段，1例SAE（即心动过缓）被认为可能与输注有关，因此停止了输注。在第2阶段，两组间的OFD无差异（中位数分别为19 [0-21]天和14 [0-18]天；p = 0.15）。当对两个阶段的患者进行汇总意向性分析（1-2期试验）时，与对照组相比，治疗组患者的OFD显著更高（19 [0-21]天对14 [0-18]天；绝对差异-5天，95%CI [0-7]，p = 0.04）。
我们研究的主要发现表明，在入住ICU且患有重症肺炎的COVID-19患者中，每天10微克/千克静脉持续输注血管紧张素-（1-7）是安全的。在第II阶段意向性分析中，两组间的OFD无显著差异。试验注册ClinicalTrials.gov标识符：NCT04633772 - 巴西临床试验注册中心，UTN编号：U1111-1255-7167。
