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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Infection, Coronavirus, Respiratory Failure

Intervention / Treatment
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* Drug: Angiotensin-(1-7)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 17 Years
Maximum Age: 81 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* NaCl 0.9%<br>|
| Experimental: Angiotensin-(1-7)<br> | Drug: Angiotensin-(1-7)<br>* Intravenous supplementation of Angiotensin-(1-7)<br>|

What is the study measuring?
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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 |
| --- | --- | --- |
| Hospital length of stay | Hospital length of stay | through study completion, on average 60 days | 
| ventilator free days | composite outcome of mortality and necessity of mechanical ventilation | 28 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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angiotensin-(1-7), ARDS, renin angiotensin system