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

• ClinicalTrials.gov Identifier: NCT04633772
• Recruitment Status: Completed
• First Posted: November 18, 2020
• Last Update Posted: November 9, 2021
• Sponsor: Erasme University Hospital
• Collaborators: Federal University of Minas Gerais; Angitec; Fonds Erasme pour la Recherche Medicale
• Information provided by (Responsible Party): Erasme University Hospital

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 (Clinical Trial)
• 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: August 5, 2020
• Actual Primary Completion Date: November 1, 2021
• Actual Study Completion Date: November 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)

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 17 Years to 81 Years (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

Brazil

Hospital Eduardo de Menezes

Belo Horizonte, Minas Gerais, Brazil, 30190-081

Hospital Mater Dei

Belo Horizonte, Minas Gerais, Brazil, 31270-910

Sponsors and Collaborators

Erasme University Hospital

Federal University of Minas Gerais

Angitec

Fonds Erasme pour la Recherche Medicale

Investigators

• Principal Investigator: Robson AS Santos; Angitex
• Principal Investigator: Ana Martins Valle; Federal University of Minas Gerais
• Principal Investigator: Filippo Annoni; Hôpital Erasme

More Information

• Responsible Party: Erasme University Hospital
• ClinicalTrials.gov Identifier: NCT04633772
• Other Study ID Numbers: RBR-35734p
• First Posted: November 18, 2020
• Last Update Posted: November 9, 2021
• Last Verified: November 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Erasme University Hospital:

angiotensin-(1-7); ARDS; renin angiotensin system

Additional relevant MeSH terms:

Infections; Coronavirus Infections; Respiratory Insufficiency; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Respiration Disorders; Respiratory Tract Diseases; Angiotensin I (1-7); Antihypertensive Agents; Vasodilator Agents