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

Respiratory Failure Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04633772
• Other study ID #: RBR-35734p
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: August 5, 2020
• Est. completion date: November 1, 2021

Study information

• Verified date: November 2021
• Source: Erasme University Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 112
• Est. completion date: November 1, 2021
• Est. primary completion date: November 1, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 17 Years to 81 Years

Eligibility

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

Related Conditions & MeSH terms

• Coronavirus Infections
• Infection, Coronavirus
• Infections
• Respiratory Failure
• Respiratory Insufficiency

Intervention

Drug:
• Angiotensin-(1-7)
Intravenous supplementation of Angiotensin-(1-7)
• Placebo
NaCl 0.9%

Locations

Country	Name	City	State
Brazil	Hospital Eduardo de Menezes	Belo Horizonte	Minas Gerais
Brazil	Hospital Mater Dei	Belo Horizonte	Minas Gerais

Sponsors (4)

Lead Sponsor	Collaborator
Erasme University Hospital	Angitec, Federal University of Minas Gerais, Fonds Erasme pour la Recherche Medicale

Country where clinical trial is conducted

Brazil, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Hospital length of stay	Hospital length of stay	through study completion, on average 60 days
Secondary	ventilator free days	composite outcome of mortality and necessity of mechanical ventilation	28 days
Secondary	ICU free days	number of days free from intensive care unit	through study completion, on average 40 days
Secondary	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
Secondary	CT scan findings	CT scan evolutions compared to baseline including findings compatible with late pulmonary fibrosis.	through study completion, on average 30 days
Secondary	Changes in inflammatory markers: C reactive protein	C-reactive protein levels daily measurements	through study completion, on average 30 days
Secondary	Changes in clinical state: vasopressors usage	use of vasopressors during hospitalization	through study completion, on average 30 days
Secondary	Chest X ray findings	Chest X-ray modifications until hospital discharge	through study completion, on average 30 days
Secondary	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
Secondary	Changes in inflammatory markers: troponin	Troponin plasmatic levels	Baseline, 3 and 24 hours after randomization and 72 hours after randomization
Secondary	Changes in thrombotic markers: D-Dimer	D-Dimer	Baseline, 3 and 24 hours after randomization and 72 hours after randomization
Secondary	Changes in clinical state: secondary infections	Secondary infections recorded during hospitalization	through study completion, on average 30 days
Secondary	Changes in clinical state: deep venous thrombosis	deep venous thrombosis recorded during hospitalization	through study completion, on average 30 days