Clinical trial NCT04633772: Use of Angiotensin-(1-7) in COVID-19
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Infection, Coronavirus
Respiratory Failure
Keywords: angiotensin-(1-7)
ARDS
renin angiotensin system
Lead sponsor: Erasme University Hospital
Sponsor class: OTHER
Collaborators: name: Federal University of Minas Gerais
name: Angitec
name: Fonds Erasme pour la Recherche Medicale
First posted: 2020-11-18
Enrollment: 112
Sex: ALL
Minimum age (years): 17
Maximum age (years): 81
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: supplemental oxygen-free days (SOFDs)
timeFrame: 28 days
Secondary outcomes:
measure: Hospital length of stay
timeFrame: through study completion, on average 60 days
measure: ventilator free days
timeFrame: 28 days
measure: ICU free days
timeFrame: through study completion, on average 40 days
measure: RAS effectors levels
timeFrame: Baseline, 3 and 24 hours after randomization and 72 hours after randomization
measure: CT scan findings
timeFrame: through study completion, on average 30 days
measure: Changes in inflammatory markers: C reactive protein
timeFrame: through study completion, on average 30 days
measure: Changes in clinical state: vasopressors usage
timeFrame: through study completion, on average 30 days
measure: Chest X ray findings
timeFrame: through study completion, on average 30 days
measure: Changes in inflammatory markers: chemokines
timeFrame: Baseline, 3 and 24 hours after randomization and 72 hours after randomization
measure: Changes in inflammatory markers: troponin
timeFrame: Baseline, 3 and 24 hours after randomization and 72 hours after randomization
measure: Changes in thrombotic markers: D-Dimer
timeFrame: Baseline, 3 and 24 hours after randomization and 72 hours after randomization
measure: Changes in clinical state: secondary infections
timeFrame: through study completion, on average 30 days
measure: Changes in clinical state: deep venous thrombosis
timeFrame: through study completion, on average 30 days
Other outcomes:
Locations:
city: Belo Horizonte
country: Brazil
facility: Hospital Eduardo de Menezes
state: Minas Gerais
city: Belo Horizonte
country: Brazil
facility: Hospital Mater Dei
state: Minas Gerais
Study officials:
affiliation: Angitex
name: Robson AS Santos
role: PRINCIPAL_INVESTIGATOR
affiliation: Federal University of Minas Gerais
name: Ana Martins Valle
role: PRINCIPAL_INVESTIGATOR
affiliation: Hôpital Erasme
name: Filippo Annoni
role: PRINCIPAL_INVESTIGATOR
References: