Infection, CoronavirusPhase 1/2NCT04633772
Use of Angiotensin-(1-7) in COVID-19
A Phase 1/2 study testing Angiotensin-(1-7) in people with Infection, Coronavirus and Respiratory Failure, run by Erasme University Hospital at 2 sites in Brazil.
Trial 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. Read more about this study
- Who is it for?
- Ages 17 to 81 years
- Conditions the study is for
- Infection, Coronavirus, Respiratory Failure
- What is being tested?
- Angiotensin-(1-7)
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 112 participants
- Where
- 2 sitesBrazil
- Study dates
- 5 Aug 2020to 1 Nov 2021
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 17 to 81 years
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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)
- Heart failure as a predominant cause of acute respiratory failure;
- Decompensated liver cirrhosis;
- HIV +;
- Dialysis;
- Home / long-term oxygen therapy;
- Idiopathic pulmonary fibrosis
Who cannot join
- Diagnosed with cancer (at any stage);
- Hemodynamic instability (need for vasopressors);
- Pregnant women; Immunocompromised patients;
- Palliative Care;
Trial locations and contacts
2 sites in 1 country.
Brazil2 sites
Hospital Eduardo de Menezes
Belo Horizonte, Minas Gerais, 30190-081
Hospital Mater Dei
Belo Horizonte, Minas Gerais, 31270-910
About this study
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
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.
Read the 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.
- Conditions
- Infection, Coronavirus, Respiratory Failure
- Being tested
- Angiotensin-(1-7), Placebo
- Keywords
- angiotensin-(1-7), ARDS, renin angiotensin system
- Medical subject headings
- Coronavirus Infections, Respiratory Insufficiency
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Angiotensin-(1-7)Drug
Intravenous supplementation of Angiotensin-(1-7)
PlaceboDrug
NaCl 0.9%
| Study group | Role | What they receive |
|---|---|---|
| Placebo | Placebo comparator | Not described Receives: Drug: Placebo |
| Angiotensin-(1-7) | Experimental | Not described Receives: Drug: Angiotensin-(1-7) |
What is being measured
The primary outcome is the main question the study is designed to answer.
supplemental oxygen-free days (SOFDs)
28 - x, where x = number of days on which the patient is released from supplemental oxygen therapy after start
Measured: 28 days
Secondary outcomes (13)
Hospital length of stay
Hospital length of stay
Measured: through study completion, on average 60 days
ventilator free days
composite outcome of mortality and necessity of mechanical ventilation
Measured: 28 days
ICU free days
number of days free from intensive care unit
Measured: through study completion, on average 40 days
RAS effectors levels
Ang II and Ang-(1-7) circulating levels using mass spectrometry
Measured: 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.
Measured: through study completion, on average 30 days
Changes in inflammatory markers: C reactive protein
C-reactive protein levels daily measurements
Measured: through study completion, on average 30 days
Changes in clinical state: vasopressors usage
use of vasopressors during hospitalization
Measured: through study completion, on average 30 days
Chest X ray findings
Chest X-ray modifications until hospital discharge
Measured: 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
Measured: Baseline, 3 and 24 hours after randomization and 72 hours after randomization
Changes in inflammatory markers: troponin
Troponin plasmatic levels
Measured: Baseline, 3 and 24 hours after randomization and 72 hours after randomization
Changes in thrombotic markers: D-Dimer
D-Dimer
Measured: Baseline, 3 and 24 hours after randomization and 72 hours after randomization
Changes in clinical state: secondary infections
Secondary infections recorded during hospitalization
Measured: through study completion, on average 30 days
Changes in clinical state: deep venous thrombosis
deep venous thrombosis recorded during hospitalization
Measured: through study completion, on average 30 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Nov 2020
- Study start5 Aug 2020
- Primary completion1 Nov 2021
- Study completion1 Nov 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Infection, CoronavirusStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 112 participants (actual)
Sponsor and investigators
- Lead sponsor
- Erasme University Hospital
- Sponsor type
- University, hospital or other
- Collaborators
- Federal University of Minas Gerais, Angitec, Fonds Erasme pour la Recherche Medicale
- Responsible party
- Sponsor
- Investigators
- Robson AS Santos, Principal investigator, AngitexAna Martins Valle, Principal investigator, Federal University of Minas GeraisFilippo Annoni, Principal investigator, Erasme University Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04633772
- Sponsor's protocol ID
- RBR-35734p
- Status last verified
- Nov 2021
- First submitted
- 6 Nov 2020
- Last updated
- 9 Nov 2021
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Martins ALV, Annoni F, da Silva FA, Bolais-Ramos L, de Oliveira GC, Ribeiro RC, Diniz MML, Silva TGF, Pinheiro BD, Rodrigues NA, Dos Santos Matos AH, Motta-Santos D, Campagnole-Santos MJ, Verano-Braga T, Taccone FS, Santos RAS. Angiotensin-(1-7) infusion in COVID-19 patients admitted to the ICU: a seamless phase 1-2 randomized clinical trial. Ann Intensive Care. 2024 Sep 4;14(1):139. doi: 10.1186/s13613-024-01369-0.
PubMed 39231898
Study at a glance
From the registry record, last updated by the sponsor on 9 Nov 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT04633772
- Acronym / sponsor ID
- RBR-35734p
- Conditions
- Infection, Coronavirus, Respiratory Failure
- Keywords
- angiotensin-(1-7), ARDS, renin angiotensin system
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 112 participants (actual)
- Lead sponsor
- Erasme University HospitalUniversity, hospital or other
- Collaborators
- Federal University of Minas Gerais, Angitec, Fonds Erasme pour la Recherche Medicale
- Study start
- 5 Aug 2020 (actual)
- Primary completion
- 1 Nov 2021 (actual)
- Study completion
- 1 Nov 2021 (actual)
- First posted
- 18 Nov 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Placebo | Placebo comparator | Drug: Placebo |
| Angiotensin-(1-7) | Experimental | Drug: Angiotensin-(1-7) |
Who may qualify
- Ages
- 17 to 81 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (8 listed)
- 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)
- Heart failure as a predominant cause of acute respiratory failure;
- Decompensated liver cirrhosis;
- HIV +;
Key exclusion criteria (4 listed)
- Diagnosed with cancer (at any stage);
- Hemodynamic instability (need for vasopressors);
- Pregnant women; Immunocompromised patients;
- Palliative Care;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Angiotensin-(1-7)Intravenous supplementation of Angiotensin-(1-7) | Drug | Angiotensin-(1-7) |
| PlaceboNaCl 0.9% | Drug | Placebo |
Primary outcome
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
13 secondary outcomes
Hospital length of stay
Time frame: through study completion, on average 60 days
ventilator free days
Time frame: 28 days
ICU free days
Time frame: through study completion, on average 40 days
RAS effectors levels
Time frame: Baseline, 3 and 24 hours after randomization and 72 hours after randomization
CT scan findings
Time frame: through study completion, on average 30 days
Changes in inflammatory markers: C reactive protein
Time frame: through study completion, on average 30 days
Changes in clinical state: vasopressors usage
Time frame: through study completion, on average 30 days
Chest X ray findings
Time frame: through study completion, on average 30 days
Changes in inflammatory markers: chemokines
Time frame: Baseline, 3 and 24 hours after randomization and 72 hours after randomization
Changes in inflammatory markers: troponin
Time frame: Baseline, 3 and 24 hours after randomization and 72 hours after randomization
Changes in thrombotic markers: D-Dimer
Time frame: Baseline, 3 and 24 hours after randomization and 72 hours after randomization
Changes in clinical state: secondary infections
Time frame: through study completion, on average 30 days
Changes in clinical state: deep venous thrombosis
Time frame: through study completion, on average 30 days
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Nov 2021.
- Derived from this study: PubMed 39231898Martins ALV, Annoni F, da Silva FA, Bolais-Ramos L, de Oliveira GC, Ribeiro RC, Diniz MML, Silva TGF, Pinheiro BD, Rodrigues NA, Dos Santos Matos AH, Motta-Santos D, Campagnole-Santos MJ, Verano-Braga T, Taccone FS, Santos RAS. Angiotensin-(1-7) infusion in COVID-19 patients admitted to the ICU: a seamless phase 1-2 randomized clinical trial. Ann Intensive Care. 2024 Sep 4;14(1):139. doi: 10.1186/s13613-024-01369-0.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Robson AS Santos principal investigator
Angitex
Ana Martins Valle principal investigator
Federal University of Minas Gerais
Filippo Annoni principal investigator
Erasme University Hospital
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Angiotensin-(1-7) in people with Infection, Coronavirus and Respiratory Failure, run by Erasme University Hospital at 2 sites in Brazil.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 9 Nov 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Brazil. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
supplemental oxygen-free days (SOFDs) (time frame: 28 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04633772, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Nov 2021; AzTrials last refreshed its copy on 7 Nov 2026.