Use of Angiotensin-(1-7) in COVID-19

Randomized Clinical Trial Phase I/II for the Use of Angiotensin-(1-7) in the Treatment of Severe Infection by Sars-CoV-2

The renin-angiotensin system (RAS) has a relevant role in COVID-19, as the virus will enter host's cells via the angiotensin-converting enzyme 2 (ACE2); RAS disequilibrium might also play a key role in the modulation of the inflammatory response that characterizes the lung involvement. Angiotensin-(1-7) is a peptide that could be altered in COVID-19 patient and its supplementation may potentially helpful in this setting.

Study Overview

• Status: Completed
• Conditions: Respiratory Failure; Infection, Coronavirus
• Intervention / Treatment: Drug: Placebo; Drug: Angiotensin-(1-7)

Detailed Description

A novel Coronavirus (SARS-CoV-2) described in late 2019 in Wuhan, China, has led to a pandemic and to a specific coronavirus-related disease (COVID-19), which is mainly characterized by a respiratory involvement. While researching for a vaccine has been started, effective therapeutic solutions are urgently needed to face this threaten. The renin-angiotensin system (RAS) has a relevant role in COVID-19, as the virus will enter host's cells via the angiotensin-converting enzyme 2 (ACE2); RAS disequilibrium might also play a key role in the modulation of the inflammatory response that characterizes the lung involvement. Angiotensin-(1-7) is a peptide that could be altered in COVID-19 patient and it may potentially improve respiratory function in this setting. This a randomized, controlled, investigator-initiated Phase I/Phase II trial is conceived to test the safety and the efficacy of intravenous angiotensin-(1-7) infusion in COVID-19 patients with severe pneumonia admitted to the intensive care unit (ICU). The first phase of the study, with a limited number of patients (n=30) will serve to confirm the safety of the intravenous infusion of the drug by observing the incidence of the adverse events (phase I, open label). In a second phase of the study, conducted in a double-blind manner and including a larger cohort of patients (n=100, Phase II), patients will be randomly assigned to receive either an Angiotensin-(1-7) infusion or placebo. The primary endpoint of the study will be the number of supplemental oxygen-free days by day 28. Secondary outcomes will include length of hospital stay, ICU and hospital free days, ICU and hospital mortality, need for mechanical ventilation, weaning time from mechanical ventilation if intubated, secondary infections, vasopressor needs, changes in PaO2 / FiO2, incidence of deep vein thrombosis, changes in inflammatory markers, plasma levels of angiotensin II and angiotensin (1-7) and radiological findings.

• Study Type: Interventional
• Enrollment (Actual): 112
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Brazil
  • Minas Gerais
    • Belo Horizonte, Minas Gerais, Brazil, 30190-081
      • Hospital Eduardo de Menezes
    • Belo Horizonte, Minas Gerais, Brazil, 31270-910
      • Hospital Mater Dei

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 17 years to 81 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Admission to the Intensive Care Unit with severe pneumonia criteria (clinical signs of pneumonia + one of the following criteria: respiratory rate greater than 30/minute; signs of respiratory effort, SatO2 < 90% in room air);
• COVID-19 confirmed or highly suspicious (positive contact or suggestive image)

Exclusion Criteria:

• Diagnosed with cancer (at any stage);
• Hemodynamic instability (need for vasopressors);
• Pregnant women; Immunocompromised patients;
• Palliative Care;
• Inclusion in any other interventionist study;
• Heart failure as a predominant cause of acute respiratory failure;
• Decompensated liver cirrhosis;
• HIV +;
• Dialysis;
• Home / long-term oxygen therapy;
• Idiopathic pulmonary fibrosis

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; NaCl 0.9%
Experimental: Angiotensin-(1-7)	Drug: Angiotensin-(1-7); Intravenous supplementation of Angiotensin-(1-7)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
supplemental oxygen-free days (SOFDs)	28 - x, where x = number of days on which the patient is released from supplemental oxygen therapy after start	28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ventilator free days	composite outcome of mortality and necessity of mechanical ventilation	28 days
Hospital length of stay	Hospital length of stay	through study completion, on average 60 days
ICU free days	number of days free from intensive care unit	through study completion, on average 40 days
RAS effectors levels	Ang II and Ang-(1-7) circulating levels using mass spectrometry	Baseline, 3 and 24 hours after randomization and 72 hours after randomization
CT scan findings	CT scan evolutions compared to baseline including findings compatible with late pulmonary fibrosis.	through study completion, on average 30 days
Changes in inflammatory markers: C reactive protein	C-reactive protein levels daily measurements	through study completion, on average 30 days
Changes in clinical state: vasopressors usage	use of vasopressors during hospitalization	through study completion, on average 30 days
Chest X ray findings	Chest X-ray modifications until hospital discharge	through study completion, on average 30 days
Changes in inflammatory markers: chemokines	pro-inflammatory chemokine levels (IL-1/IL-6) at baseline day 3 and 7	Baseline, 3 and 24 hours after randomization and 72 hours after randomization
Changes in inflammatory markers: troponin	Troponin plasmatic levels	Baseline, 3 and 24 hours after randomization and 72 hours after randomization
Changes in thrombotic markers: D-Dimer	D-Dimer	Baseline, 3 and 24 hours after randomization and 72 hours after randomization
Changes in clinical state: secondary infections	Secondary infections recorded during hospitalization	through study completion, on average 30 days
Changes in clinical state: deep venous thrombosis	deep venous thrombosis recorded during hospitalization	through study completion, on average 30 days

Collaborators and Investigators

• Sponsor: Erasme University Hospital
• Collaborators: Federal University of Minas Gerais; Fonds Erasme pour la Recherche Médicale; Angitec
• Investigators: Principal Investigator: Robson AS Santos, Angitex; Principal Investigator: Ana Martins Valle, Federal University of Minas Gerais; Principal Investigator: Filippo Annoni, Hopital Erasme

Study record dates

Study Major Dates

• Study Start (Actual): August 5, 2020
• Primary Completion (Actual): November 1, 2021
• Study Completion (Actual): November 1, 2021

Study Registration Dates

• First Submitted: November 6, 2020
• First Submitted That Met QC Criteria: November 17, 2020
• First Posted (Actual): November 18, 2020

Study Record Updates

• Last Update Posted (Actual): November 9, 2021
• Last Update Submitted That Met QC Criteria: November 8, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Keywords: ARDS; renin angiotensin system; angiotensin-(1-7)
• Additional Relevant MeSH Terms: Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Diseases; Respiration Disorders; Coronavirus Infections; Infections; Respiratory Insufficiency; Antihypertensive Agents; Vasodilator Agents; Angiotensin I (1-7)
• Other Study ID Numbers: RBR-35734p

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No