Angiotensin-(1,7) Treatment in COVID-19: the ATCO Trial : 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.Patient's management Management of any underlying comorbidity will be at discretion of the attending physicians; the use of international guidelines for the monitoring and the adequate therapeutic interventions are recommended in all patients.In particular, patients ventilation should be managed according to ATS/ESICM/SCCM 2017 consensus for the ventilation in ARDS patients which suggest low tidal volume ventilation (4-8 mL/Kg predicted body weight) associated with low plateau pressure (<30 cmH2O), high positive end-expiratory pressure (PEEP) associated with recruitment maneuvers and prone positioning for periods longer than 12h in severe ARDS patients. Arterial gas analysis assessment should be performed at maximum intervals of six hours or more often according to the attending physician beliefs. Maintenance fluid should be chosen among balanced crystalloids and the quantity will be decided by the attending physician. Glucose management, nutrition protocols, decision to administer neuromuscular blockade, prone positioning, ECMO, nitric oxide or any other adjunctive therapies will be continued according to center current clinical practice and will be recorded in the CRF file.Weaning procedure Regarding the weaning from mechanical ventilation, in order to standardize and reduce bias we will comply with the following procedures based on ARDS Network protocol (ARDSnet).Each day the patients enrolled will be assessed by the medical staff for the following weaning criteria:FiO2 ≤ 0.40 and PEEP ≤ 8 cmH2O OR FiO2 < 0.50 and PEEP < 5 cmH2OPEEP and FiO2 ≤ values of previous day.No neuromuscular blocking agentsPatient has acceptable spontaneous breathing efforts (It will be allowed to decrease the respiratory rate on the ventilator up to 50% for 5 min to detect inspiratory effort)Systolic BP ≥ 90 mmHgIf all the above conditions will be met, medical staff will start a spontaneous breathing test (SBT) for up to 120 minutes using one of the following methods and maintaining a: FiO2 ≤ 0.5:T-piece TubePressure Support Ventilation ≤ 5 cmH2O with PEEP ≤ 5 cmH2OCPAP with PEEP ≤ 5 cmH2OTracheal Collar maskTo test the tolerance at such measures the medical staff will evaluate the following goals for a minimum of 30 minutes up to 120 minutes:SpO2 ≥ 90% and / or PaO2 ≥ 60 mm HgMean spontaneous tidal volume ≥ 4 ml/kg PBW (if measured)Respiratory Rate ≤ 35 / minpH ≥ 7.30 (if measured)No respiratory distress (defined as 2 or more of the following):Heart rate ≥ 120% of the rate (≤ 5 min at > 120% may be tolerated)Marked use of accessory musclesAbdominal paradoxDiaphoresisMarked subjective dyspneaIf all these goals will be met, the medical staff will consider extubation, otherwise the patient will be treated with the pre-weaning settings.Data Collection Data collection on admission will include: demographic characteristics, comorbidities, including use of antihypertensive medications, source of admission, primary and secondary diagnosis, delay since symptoms begin, APACHE II Score (the worst values within the first 24 hours), SOFA score on admission, Chest X-ray and Thoracic CT scan results if available, EKG trace, PaO2/FiO2 on admission. Daily data collection during ICU stay will include: continuous hemodynamic monitoring, including invasive arterial pressure monitoring and continuous EKG; SaO2 and PaO2/FiO2 every 2 hours; blood samples including Hb, glucose and several other chemical variables will be collected at least once per day at 8 am (or the first value of the day); ventilatory parameters and arterial gas analysis will be also collected every six hours; SOFA score; presence of any other documented infection (site, pathogen, treatment); presence of septic shock; daily diuresis and daily total fluid infusion, urine analysis including main electrolytes (sodium, potassium, chloride, calcium) and osmolarity every morning. The occurrence of serious adverse events (see specific paragraph in the text). Duration of ICU stay, duration of mechanical ventilation, need for tracheostomy. In case of death, reasons for withdrawal of care will be recorded. All the data will be recorded using the specific CRF forms, divided into a core section and a daily section and will be uploaded to a web-centralized protected database.Statistical AnalysisFirst phase (Phase IIb) = 15 vs 15 patients Second phase (Phase III) = expected 30 vs 30 patients in total (recalculation of sample size after 15 vs. 15 patients included)The primary outcome of this study is the number of ventilator free days at day 28.Considering an expected median duration of mechanical ventilation in COVID-19 related respiratory insufficiency patients of 14 days, to provide an absolute reduction of 22,5% with an alpha error of 0.05 and to provide a power to detect the effect of 80% and a dropout rate of 3%, 60 patients will need to be included in the primary analysis, 30 in each group.Pre-planned Stratified group analysis will be performed for the following group of patients:History of hypertension vs. no history of hypertensionTreatment with ACEi, ARB or DRI drugs vs no treatmentAge (<65 vs. ≥ 65 years)PaO2/FiO2 values at randomization (<100 vs ≥ 100)Confirmed vs highly suspected COVID-19Data Safety Management Members of the Data Safety Monitoring Committee (DSMC) are individuals free of conflicts of interest for this protocol; DSMC will analyze the safety of the study and their membership within the DSMC will be for the duration of this clinical trial. Serious Adverse Events (SAEs) will be recorded at the participating site on the specific CRF and their occurrence will be monitored by the DSMC at the different interim analysis. Formal meeting will be held for each interim analysis to review the data related to the primary outcome, the safety findings as well as the quality of the trial conduct. To enhance the integrity of the trial, the DSMC will have access to the different results aggregated by treatment group and remain unaware of the treatment assignment (the groups will be encoded as A and B). A report including data on recruitment and baseline characteristics and pooled data on eligibility violations will be prepared by the statistician for each DSMC meeting. Only the independent statistician will have access to the whole d....

Medienart:	Klinische Studie

Erscheinungsjahr:	2021
Erschienen:	2021

Enthalten in:	ClinicalTrials.gov - (2021) vom: 02. Aug. Zur Gesamtaufnahme - year:2021

Sprache:	Englisch

Links:	Volltext [kostenfrei]

Themen:	610 Coronavirus Infections Medical Condition: Coronavirus, Respiratory Failure, Coronavirus Sars-Associated as Cause of Disease Classified Elsewhere, SARS-CoV-2 Phase: Phase 2, Phase 3 Recruitment Status: Not yet recruiting Respiratory Insufficiency Severe Acute Respiratory Syndrome Study Type: Interventional

Anmerkungen:	Source: Link to the current ClinicalTrials.gov record., First posted: April 3, 2020, Last downloaded: ClinicalTrials.gov processed this data on August 09, 2021, Last updated: August 11, 2021

Study ID:	NCT04332666 P2020/201
Veröffentlichungen zur Studie:

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PPN (Katalog-ID):	CTG003349101