Angiotensin-(1,7) Treatment in COVID-19: the ATCO Trial (ATCO)
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ClinicalTrials.gov Identifier: NCT04332666 |
Recruitment Status :
Not yet recruiting
First Posted : April 3, 2020
Last Update Posted : August 2, 2021
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Background: 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 is downregulated in COVID-19 patient and it may potentially improve respiratory function in this setting.
Methods/Design: The Investigators describe herein the methodology of a randomized, controlled, adaptive Phase II/Phase III trial to test the safety, efficacy and clinical impact of the infusion of angiotensin-(1-7) in COVID-19 patients with respiratory failure requiring mechanical ventilation. A first phase of the study, including a limited number of patients (n=20), will serve to confirm the safety of the study drug, by observing the number of the severe adverse events. In a second phase, the enrollment will continue to investigate the primary endpoint of the study (i.e. number of days where the patient is alive and not on mechanical ventilation up to day 28) to evaluate the efficacy and the clinical impact of this drug. Secondary outcomes will include the hospital length of stay, ICU length of stay, ICU and hospital mortality, time to weaning from mechanical ventilation, reintubation rate, secondary infections, needs for vasopressors, PaO2/FiO2 changes, incidence of deep vein thrombosis, changes in inflammatory markers, angiotensins plasmatic levels and changes in radiological findings. The estimated sample size to demonstrate a reduction in the primary outcome from a median of 14 to 11 days is 56 patients, 60 including a dropout rate of 3% (i.e. 30 per group), but a preplanned recalculation of the study sample size is previewed after the enrollment of 30 patients.
Expected outcomes/Discussion: This controlled trial will assess the efficacy, safety and clinical impact of the Angiotensin-(1-7) infusion in a cohort of COVID-19 patients requiring mechanical ventilation. The results of this trial may provide useful information for the management of this disease.
Condition or disease | Intervention/treatment | Phase |
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Coronavirus Respiratory Failure Coronavirus Sars-Associated as Cause of Disease Classified Elsewhere SARS-CoV-2 | Drug: Angiotensin 1-7 Drug: Placebos | Phase 2 Phase 3 |

Study Type : | Interventional (Clinical Trial) |
Estimated Enrollment : | 60 participants |
Allocation: | Randomized |
Intervention Model: | Parallel Assignment |
Intervention Model Description: | Randomized, controlled, investigator initiated, phase II/phase III seamless, adaptive, single blinded, interventional trial to evaluate the efficacy, safety and clinical impact of intravenous Ang-(1-7) infusion compared to standard treatment in ICU patients with severe respiratory failure associated with COVID-19. This study will be conducted initially in one center (Erasme Hospital, Belgium), but other sites will be allowed to join if: Number of expected patients with COVID related ARF ≥ 10, experience in treatment of ARDS patients (> 25/year), including prone positioning ,availability of the equipment required to provide the blood sample processing and storage. We planned a first phase of the study where 30 patients will be randomly receiving Ang-(1-7) or placebo to confirm the safety. The Final power calculation will be reassessed after 30 included patients (i.e. 15 in each arm), in line with a preplanned expected total number of patients needed of 60. |
Masking: | Triple (Participant, Investigator, Outcomes Assessor) |
Masking Description: | Randomization will be performed using sealed envelopes with a ratio of 1:1 including information on treatment assignment and a five-digit number, which will be open by the person responsible for drug constitution. Each vial or syringe will be then labeled with the randomly allocated number it will be assigned to the nursing personnel. The doctors and nurses administering the drugs, as well as the local investigators and research personnel who collected data, were unaware of the treatment assignments. |
Primary Purpose: | Treatment |
Official Title: | Angiotensin-(1,7) Treatment in COVID-19: the ATCO Trial |
Estimated Study Start Date : | December 30, 2021 |
Estimated Primary Completion Date : | December 30, 2022 |
Estimated Study Completion Date : | June 15, 2023 |

Arm | Intervention/treatment |
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Placebo Comparator: Placebo
Standard of care treatment
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Drug: Placebos
infusion of NaCl 0.9% without diluted peptide in it |
Experimental: Study drug
Angiotensin-(1-7) infusion (venous) of 0.2 mcg/Kg/h for 48h
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Drug: Angiotensin 1-7
endogenous peptide dilution: angiotensin-(1-7) 0.5 mg / L NaCl 0.9% |
- ventilator free days [ Time Frame: 28 days ]composite outcome of mortality and necessity of mechanical ventilation
- ICU free days [ Time Frame: trough study completion, on average 40 days ]number of days free from intensive care unit
- Hospital length of stay [ Time Frame: through study completion, on average 60 days ]Hospital length of stay
- Time to wean from mechanical ventilation [ Time Frame: through study completion, on average 14 days ]Time to wean from mechanical ventilation
- PaO2/FiO2 changes during drug administration [ Time Frame: 48 hours ]PaO2/FiO2 changes during drug administration
- Deep vein thrombosis incidence [ Time Frame: through study completion, on average 30 days ]US confirmed deep vein thrombosis
- Changes in inflammatory markers [ Time Frame: at randomization, 48 hours after randomization and 72 hours after randomization ]including IL-1, IL-2, IL-6, IL-7, IL-8, IL-10, TNF-alpha, interferon gamma
- RAS effectors levels [ Time Frame: at randomization, 48 hours after randomization and 72 hours after randomization ]Ang II and Ang-(1-7) plasmatic levels
- Radiological findings [ Time Frame: through study completion, on average 30 days ]Chest x-ray or CT scan changes
- Rate of serious adverse events [ Time Frame: study drug administration/day 28 or ICU discharge or death ]phase 2b = principal safety outcome; phase 3 = secondary outcome

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Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Age > 18 years old
- Expected ICU stay of > 48 hours
- Bilateral Viral Pneumonia
- Orotracheal intubation from less than 24 hours
- Confirmed or highly suspected COVID-19
Exclusion Criteria:
- Patients with cancer (all stages) diagnosis
- Severe hemodynamic instability (need of vasopressors >1 mcg/Kg/min to maintain a MAP > 65 mmHg)
- Pregnant women
- Immunocompromised patients
- Limitations of care
- Inclusion in any other interventional trial

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04332666
Contact: filippo annoni, MD | 0032(0)483141483 | filippo.annoni@erasme.ulb.ac.be | |
Contact: Fabio S Taccone, PD,PhD | fabio.tacconei@erasme.ulb.ac.be |
Principal Investigator: | Filippo Annoni, MD | Erasme hospital | |
Principal Investigator: | Robson AS Santos, MD,PhD | Minas Gerais University |
Responsible Party: | Erasme University Hospital |
ClinicalTrials.gov Identifier: | NCT04332666 |
Other Study ID Numbers: |
P2020/201 |
First Posted: | April 3, 2020 Key Record Dates |
Last Update Posted: | August 2, 2021 |
Last Verified: | August 2020 |
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 |
Coronavirus Infections Severe Acute Respiratory Syndrome Respiratory Insufficiency Coronaviridae Infections Nidovirales Infections RNA Virus Infections Virus Diseases |
Infections Respiration Disorders Respiratory Tract Diseases Respiratory Tract Infections Angiotensin I (1-7) Antihypertensive Agents Vasodilator Agents |