The COVID-RASi Trial (COVID-19)

Study Overview
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Brief Summary
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The COVID-RASi study is an international randomized clinical trial that will evaluate the potential benefit of angiotensin modulators on clinical outcomes, in COVID-19 patients. The purpose of this study is to determine if renin-angiotensin system inhibitors (RASi), with angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB), has a beneficial effect in patients with COVID-19 infections, by reducing ICU admission, ventilator requirement or death. We would also like to determine if there are differences between ACEi and ARB therapeutic treatments. With the increasing potential of long COVID symptoms, at the 1 year follow up, a primary endpoint will be the quality of life of study participants, as assessed by ongoing symptoms and/or the standardized questionnaires.

Detailed Description
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The goal is to determine if RASi with ACEi or ARB, has a beneficial effect in patients with COVID-19 infections, by reducing hospitalizations, ICU admission, ventilator requirement or death. This is a multi-centre study, conducted in major centres treating COVID-19 patients in-hospital and in various outpatient settings. Patients admitted to hospital or outpatients that test positive for COVID-19 and meet the inclusion/exclusion criteria will be eligible to participate in this study. All study participants will not be on RASi (ACEi/ARB) treatment at the time of consent. Participants will be randomized to initiation of ACEi vs ARB treatment vs no RASi treatment as part of care for COVID-19 in a 1:1:1 ratio. The patient will be followed by their physician according to usual clinical care. Sites will complete research-related follow-ups at 24 hours, 7 and 28 days to asssess patient's clinical status, side effects and the achievement of clinical endpoints by telephone interviews. Phone call follow ups will also be conducted at 6 months and 12 months after enrollment in the study.

Official Title
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Evaluation of the Potential Benefit of Renin-angiotensin System Inhibitors (RASi, ACEi/ARB) in High-risk Patients With COVID-19. The COVID-RASi Trial

Conditions
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COVID-19, Cardiovascular Diseases

Intervention / Treatment
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* Drug: Angiotensin converting enzyme inhibitor
* Drug: Angiotensin II Receptor Blockers


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient with COVID-19 diagnosis with laboratory confirmation within the last 30 days AND Age 40 years old or greater if outpatient OR age 18 years old or greater if inpatient (admitted to the hospital) at time of recruitment Exclusion Criteria: Contraindication to ARB or ACEi, including severe aortic stenosis and angioedema Patients who are currently on active treatment with ARB/ACEi Known bilateral renal artery stenosis Systolic BP ≤90 mmHg eGFR<30 ml/min, if not receiving dialysis treatment K>5.5 mmol/L on screening laboratory testing Recent history of dizziness, vertigo, related to hypotension or orthostatic hypotension, that can lead to contraindication to ACEI/ARBs Acute respiratory distress syndrome requiring invasive ventilation

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: No Treatment (Standard of Care)<br>Participants will be treated as per standardized care pathway according to province/state and institutional guidelines. Physicians will be reminded not to start ACEi or ARB throughout admission or to outpatients until active study participation is complete at 28 days post symptoms. | |
| Experimental: ACEi treatment<br>The physician will initiate any ACE inhibitor and dose at their discretion. | Drug: Angiotensin converting enzyme inhibitor<br>* The study recommends physicians to select an ACEi with proven benefit in cardiovascular diseases such as perindopril, ramipril or enalapril. Lab values will be obtained during baseline. The patient will be followed by the physician clinically, with recommended laboratory testing in one week, including renal function, potassium assessment, and dose adjustments as appropriate.<br>|
| Experimental: ARB treatment<br>The physician will initiate any ARB and dose at their discretion. | Drug: Angiotensin II Receptor Blockers<br>* The study recommends physicians to select evidence-based ARBs such as candesartan or valsartan or losartan. Lab values will be obtained during baseline. The patient will be followed by the physician clinically, with recommended laboratory testing in one week, and dose adjustments as appropriate.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Death | Within first 28 days post randomization | 28 days | 
| Mechanical ventilation | Within first 28 days post randomization | 28 days | 
| ICU admission | Within first 28 days post randomization | 28 days | 
| Major Adverse Cardiac Events (MACE) | Within first 28 days post randomization | 28 days | 
| Hospitalizations | Within first 28 days post randomization | 28 days | 
| Quality of life of study participants | Assessed by ongoing symptoms and standardized questionnaires, scale to assess overall health 1-100, 100 is the best, higher score means better outcome | 1 year | 
| Quality of life of study participants | Assessed by ongoing symptoms and standardized questionnaires- scale to assess overall health 1-100, 100 is the best, higher score means better outcome | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Days alive and out of hospital |  | 30 days | 
| Days alive and out of hospital |  | 180 days | 
| Cardiovascular mortality |  | 1 year | 
| All cause hospitalization |  | 1 year | 
| Percent of patients require intensive care |  | 1 year | 
| Percent of patients requiring ventilation |  | 1 year | 
| Percent of patients requiring dialysis |  | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cardiovascular risk factors, corona virus, COVID-19, severe acute respiratory syndrome coronavirus 2 (SARS-COV-2), Angiotensin-converting enzyme inhibitors, ACEi, Renin-angiotensin system inhibitors, RASi, Angiotensin receptor blockers, ARB