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

Rationale for the study The cellular entry of the SARS-CoV-2 can result in a functional reduction of ACE2 activity and this could lead to an increased activity of the Ang II/AT1 axis and decreased levels Ang-(1-7)/MasR expression that could contribute to the severity of the disease. The administration of Ang-(1-7) could reestablish this equilibrium, contributing to decrease pulmonary inflammation e thus decreasing the symptoms of the disease.

Eligible patients and the next of kin (whenever possible) should be informed about the rationale and the aims of the study and potential risks of drug infusion. Local ethical regulations should be otherwise followed. Due to the eligibility criteria and the urgency setting, a delayed written consent may be obtained after randomization from the next of kin and/or the patient (i.e. after ICU discharge).

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. Randomization should occur within 24 hours since orotracheal intubation and drug infusion initiated within 4 hours from randomization.

Trial will be conducted in adherence to the current Helsinki Declaration and the standard of good clinical practice. Screening of patients will only start after approval of the ethical committees (EC) in the trial sites. No deviation of the protocol will be implemented without the prior review and approval of the ECs.

Study Treatment Ang-(1-7) is a pre-constitute intravenous lyophilized formulation containing 0.5 mg/ ampoule and will be administered to patients via a dedicated central venous line at the initial dose of 0.1 mcg/Kg/h (equivalent to 2.5 mcg/Kg/day). After the first hour of infusion, if no decrease in mean arterial pressure (decrease superior to 30% or need to increase vasopressors ≥ 50% of an initial dosage to maintain a MAP ≥ 65mmHg), the infusion rate will be increased to 0.2 mcg/Kg/h (equivalent to 5 mcg/Kg/day). The infusion will be continued for up to 48 hours and then stopped. To this end, the substance solution, prepackaged, will be diluted in 1000ml of NaCl 0.9% and then infused using an infusion pump at corresponding speed. The placebo substance, made up of the vehicle alone, will also be intravenously administrated using the same procedure as that for the substance containing the active principle.