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Angiotensin-(1,7) Treatment in COVID-19: the ATCO Trial (ATCO)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04332666
Recruitment Status : Not yet recruiting
First Posted : April 3, 2020
Last Update Posted : April 6, 2020
Sponsor:
Collaborator:
Fonds Erasme pour la Recherche Médicale
Information provided by (Responsible Party):
Erasme University Hospital

Brief Summary:

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
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

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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 : March 31, 2020
Estimated Primary Completion Date : May 30, 2020
Estimated Study Completion Date : June 15, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Placebo Comparator: Placebo
Standard of care treatment
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
Drug: Angiotensin 1-7
endogenous peptide dilution: angiotensin-(1-7) 0.5 mg / L NaCl 0.9%




Primary Outcome Measures :
  1. ventilator free days [ Time Frame: 28 days ]
    composite outcome of mortality and necessity of mechanical ventilation


Secondary Outcome Measures :
  1. ICU free days [ Time Frame: trough study completion, on average 40 days ]
    number of days free from intensive care unit

  2. Hospital length of stay [ Time Frame: through study completion, on average 60 days ]
    Hospital length of stay

  3. Time to wean from mechanical ventilation [ Time Frame: through study completion, on average 14 days ]
    Time to wean from mechanical ventilation

  4. PaO2/FiO2 changes during drug administration [ Time Frame: 48 hours ]
    PaO2/FiO2 changes during drug administration

  5. Deep vein thrombosis incidence [ Time Frame: through study completion, on average 30 days ]
    US confirmed deep vein thrombosis

  6. 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

  7. RAS effectors levels [ Time Frame: at randomization, 48 hours after randomization and 72 hours after randomization ]
    Ang II and Ang-(1-7) plasmatic levels

  8. Radiological findings [ Time Frame: through study completion, on average 30 days ]
    Chest x-ray or CT scan changes


Other Outcome Measures:
  1. 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



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

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


Contacts
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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

Sponsors and Collaborators
Erasme University Hospital
Fonds Erasme pour la Recherche Médicale
Investigators
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Principal Investigator: Filippo Annoni, MD Erasme hospital
Principal Investigator: Robson AS Santos, MD,PhD Minas Gerais University
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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: April 6, 2020
Last Verified: March 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Coronavirus Infections
Severe Acute Respiratory Syndrome
Respiratory Insufficiency
Respiration Disorders
Respiratory Tract Diseases
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Virus Diseases
Respiratory Tract Infections
Angiotensin I (1-7)
Antihypertensive Agents
Vasodilator Agents