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

Sponsor

Erasme University Hospital (Other)

Overall Status

Completed

CT.gov ID

NCT04633772

Collaborator

Federal University of Minas Gerais (Other), Angitec (Other), Fonds Erasme pour la Recherche Medicale (Other)

112

Enrollment

Locations

Arms

14.9

Actual Duration (Months)

Patients Per Site

3.8

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Infection, Coronavirus Respiratory Failure	Drug: Angiotensin-(1-7) Drug: Placebo	Phase 1/Phase 2

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 Design

Study Type:

Interventional

Actual Enrollment :

112 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Aug 5, 2020

Actual Primary Completion Date :

Nov 1, 2021

Actual Study Completion Date :

Nov 1, 2021

Arms and Interventions

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)

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)

Outcome Measures

Primary Outcome Measures

supplemental oxygen-free days (SOFDs) [28 days]
28 - x, where x = number of days on which the patient is released from supplemental oxygen therapy after start

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

17 Years to 81 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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)