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

NCT04332666 | Unknown Phase 2 DMC

• 1 other identifier: P2020/201
• Study Type: interventional
• Target: 60
• Locations: 0 countries
• Sites: N/A

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.

Conditions

Coronavirus; Respiratory Failure; Coronavirus Sars-Associated as Cause of Disease Classified Elsewhere; SARS-CoV-2

Outcome Measures

Primary Outcomes (1)

• ventilator free days

  composite outcome of mortality and necessity of mechanical ventilation

  28 days

Secondary Outcomes (8)

• ICU free days

  trough study completion, on average 40 days

• Hospital length of stay

  through study completion, on average 60 days

• Time to wean from mechanical ventilation

  through study completion, on average 14 days

• PaO2/FiO2 changes during drug administration

  48 hours

• Deep vein thrombosis incidence

  through study completion, on average 30 days

Other Outcomes (1)

• Rate of serious adverse events

  study drug administration/day 28 or ICU discharge or death

Study Arms (2)

Placebo

PLACEBO COMPARATOR

Standard of care treatment

Drug: Placebos

Study drug

EXPERIMENTAL

Angiotensin-(1-7) infusion (venous) of 0.2 mcg/Kg/h for 48h

Drug: Angiotensin 1-7

Interventions

Angiotensin 1-7 DRUG

endogenous peptide dilution: angiotensin-(1-7) 0.5 mg / L NaCl 0.9%

Study drug

Placebos DRUG

infusion of NaCl 0.9% without diluted peptide in it

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Erasme University Hospital: lead
• Fonds Erasme pour la Recherche Médicale: collaborator

MeSH Terms

Conditions

Coronavirus Infections; Respiratory Insufficiency

Interventions

angiotensin I (1-7)

Condition Hierarchy (Ancestors)

Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiration Disorders; Respiratory Tract Diseases

Study Officials

• Filippo Annoni, MD

  Erasme University Hospital

  PRINCIPAL INVESTIGATOR

• Robson AS Santos, MD,PhD

  Minas Gerais University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

filippo annoni, MD

CONTACT

0032(0)483141483; filippo.annoni@erasme.ulb.ac.be

Fabio S Taccone, PD,PhD

CONTACT

fabio.tacconei@erasme.ulb.ac.be

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: March 27, 2020
• First Posted: April 3, 2020
• Study Start: December 30, 2021
• Primary Completion: December 30, 2022
• Study Completion: June 15, 2023
• Last Updated: August 2, 2021

Record last verified: 2020-08

Data Sharing

• IPD Sharing: Will not share