Controlled evaLuation of Angiotensin Receptor Blockers for COVID-19 respIraTorY Disease

Study Overview
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Brief Summary
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The Controlled evaLuation of Angiotensin Receptor Blockers for COVID-19 respIraTorY disease (CLARITY) study is a pragmatic prospective, open-label, randomised controlled trial. CLARITY aims to examine the effectiveness of angiotensin II receptor blockers (ARBs) on improving the outcomes of people who tested positive for COVID-19 disease.

Official Title
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Controlled evaLuation of Angiotensin Receptor Blockers for COVID-19 respIraTorY Disease

Conditions
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Coronavirus Disease 2019, COVID-19

Intervention / Treatment
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* Drug: Angiotensin Receptor Blockers
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Potential participants must satisfy all of the following: Laboratory-confirmed* diagnosis of Severe Acute Respiratory Syndrome-Coronavirus-2 infection within 10 days prior to randomisation Age ≥ 18 years a) Systolic Blood Pressure (SBP) ≥ 120 mmHg OR b) SBP ≥ 115 mmHg and currently treated with a non-Renin Angiotensin Aldosterone System inhibitor Blood Pressure (BP) lowering agent that can be ceased Participant and treating clinician are willing and able to perform trial procedures. Either Intended for hospital admission for management of COVID-19, or (In Australia Only) Intended for management at home with one or more of the following criteria: Age≥60 years Body Mass Index ≥30kg/m2 (derived from the patient's self-report of their height and weight where these are not measured directly) Diagnosis of diabetes defined as HbA1c ≥7% and/or the consumption of glucose lowering medication History of cardiovascular disease History of chronic respiratory illness Currently treated with immunosuppression Exclusion Criteria: Currently treated with an angiotensin-converting enzyme inhibitor, Angiotensin Receptor Blocker or aldosterone antagonist, aliskiren, or angiotensin receptor-neprilysin inhibitors (ARNi) Serum potassium > 5.2 mmol/L or no potassium testing within the last 3 months For those intended for hospital admission, an estimated Glomerular Filtration Rate (eGFR) <30ml/min/1.73m2 or no eGFR testing within the last 3 months, or For those intended for management at home (Australia only), an eGFR <45ml/min/1.73m2 or no eGFR testing within the last 3 months Known symptomatic postural hypotension Known biliary obstruction, known severe hepatic impairment (Child-Pugh-Turcotte score 10-15) - see Table below Intolerance of ARB Pregnancy or risk of pregnancy, defined as; (In Australia only) Women younger than 51 years who have not had a negative pregnancy test during the past 3 days and/or who do not agree to use adequate contraception (In India Only) Women who are pregnant Women who are currently breastfeeding Individuals who are not able to take medications by mouth at enrolment, or who are not expected to be able to take medications by mouth during the first 48 hours after randomisation

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
Interventional Model Description: CLARITY is a randomised control trial of two parallel groups; Standard Care + Angiotensin Receptor Blocker (ARB) Standard Care Participants will be randomised in a 1:1 ratio. Randomisation will be stratified according to country and whether the participant is planned for hospital admission or home-based care.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard Care + Angiotensin Receptor Blocker (ARB)<br>Participants will receive an Angiotensin Receptor Blocker on top of the standard care provided by their institution. | Drug: Angiotensin Receptor Blockers<br>* Angiotensin Receptor Blockers (ARBs) have been in clinical use for more than 30 years for their cardiac and renal protective effects. ARBs mechanism of action is through selective inhibition of angiotensin-II (Ang-II) by competitive antagonism of the angiotensin receptor. ARBs displace ang-II from the angiotensin I receptor and produce their protective effects by reducing the downstream effects of ang-II induced vasoconstriction, aldosterone release, catecholamine release, arginine vasopressin release, water intake, and hypertrophic response The virus causing COVID-19, SARS-CoV-2, binds to the extracellular portion of Angiotensin-Converting-Enzyme-2 (ACE2) expressed on type II alveolar cells in the lungs which is followed by internalization of ACE2 before downregulating membrane ACE2 expression. Both these components appear to require angiotensin receptor Type 1 (AT1R), and ARBs, which block the actions of AT1R, would reduce the severity of COVID-19 and reduce the duration of symptoms<br>* Other names: Valsartan;|
| Placebo Comparator: Standard Care + Placebo<br>Participants will receive a placebo on top of the standard care provided by their institution. | Other: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 7-Point National Institute of Health Clinical Health Score | To determine whether the addition of the intervention, compared to standard care, changes the clinical health score of a participant on the following scale; Not hospitalized, no limitations on activities. Not hospitalized, limitation on activities; Hospitalized, not requiring supplemental oxygen; Hospitalized, requiring supplemental oxygen; Hospitalized, on non-invasive ventilation or high flow oxygen devices; Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); Death; | 14 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 7-Point National Institute of Health Clinical Health Score | To determine whether the addition of the intervention, compared to standard care, changes the clinical health score of a participant on the following scale; Not hospitalized, no limitations on activities. Not hospitalized, limitation on activities; Hospitalized, not requiring supplemental oxygen; Hospitalized, requiring supplemental oxygen; Hospitalized, on non-invasive ventilation or high flow oxygen devices; Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); Death; | 28 Days | 
| Mortality | To determine whether the addition of the intervention, compared to standard care, changes the risk of all cause mortality | 28 Days | 
| Mortality | To determine whether the addition of the intervention, compared to standard care, changes the risk of all cause mortality | 90 Days | 
| Intensive Care Unit Admission | To determine whether the addition of the intervention, compared to standard care, changes the count of all cause Intensive Care Unit admission | 28 Days | 
| Intensive Care Unit Admission | To determine whether the addition of the intervention, compared to standard care, changes the count of all cause Intensive Care Unit admission | 90 Days | 
| Intensive Care Unit Number of Days | To determine whether the addition of the intervention, compared to standard care, changes the number of days total, of intensive care unit admission | 90 Days | 
| Respiratory Failure | To determine whether the addition of the intervention, compared to standard care, changes the incidence of respiratory failure | 28 Days | 
| Dialysis Requirement | To determine whether the addition of the intervention, compared to standard care, changes the requirements for dialysis | 28 Days | 
| Hospitalisation Days | To determine whether the addition of the intervention, compared to standard care, changes the number of hospitalisation days | 28 Days | 
| Hospitalisation Days | To determine whether the addition of the intervention, compared to standard care, changes the number of hospitalisation days | 90 Days | 
| Ventilator-Free Days | To determine whether the addition of the intervention, compared to standard care, changes need for ventilation | 28 Days | 
| Dialysis Days | To determine whether the addition of the intervention, compared to standard care, changes need for dialysis | 28 Days | 
| Acute Kidney Injury | To determine whether the addition of the intervention, compared to standard care, changes risk of acute kidney injury, based on the Kidney Disease: Improving Global Outcomes definition | 28 Days | 
| Hypotension Requiring Vasopressors | To determine whether the addition of the intervention, compared to standard care, changes risk of hypotension requiring vasopressors | 28 Days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Angiotensin Receptor Blocker (ARB), Angiotensin Converting Enzyme 2 (ACE2), Coronavirus Disease 2019 (COVID-19), Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-Cov-2)