Infection, Coronavirus, Respiratory Failure
Conditions
Keywords
angiotensin-(1-7), ARDS, renin angiotensin system
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.
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.
Interventions
Intravenous supplementation of Angiotensin-(1-7)
DRUGPlacebo
NaCl 0.9%
Sponsors
Federal University of Minas Gerais
Angitec
Fonds Erasme pour la Recherche Medicale
Erasme University Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
17 Years to 81 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| Hospital length of stay | through study completion, on average 60 days | Hospital length of stay |
| 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 |
| Chest X ray findings | through study completion, on average 30 days | Chest X-ray modifications until hospital discharge |
Countries
Brazil
Outcome results
None listed