Host Response Mediators in Coronavirus (COVID-19) Infection - Is There a Protective Effect of Losartan and Other ARBs on Outcomes of Coronavirus Infection?

Study Overview
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Brief Summary
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SARS-CoV-2 is a member of a class of viruses: angiotensin converting enzyme 2 (ACE2)-binding viruses that study calls ABVs. The World Health Organization (WHO) and others are performing randomized controlled trials (RCTs) of vaccines and novel antivirals to address SARS-CoV-2 directly. However, the critical illness complications of COVID-19 are caused in part by SARS-CoV-2's binding and inhibiting ACE2 and the consequent host response. ACE 2 is the receptor for H1N1, H5N1, and SARS-CoV-2. After binding ACE2, SARS-CoV-2 is endocytosed, and surface ACE2 is down-regulated, increasing angiotensin II (ATII a potent vasoconstrictor) in COVID-19. The original ARBs limits lung injury in murine influenza H7N9 and decreases viral titre and RNA. Study has a unique opportunity to complement vaccine and anti-viral RCTs with an RCT modulating the host response using an angiotensin II type 1 receptor blocker (ARBs) to decrease the mortality of hospitalized COVID-19 patient.

Detailed Description
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PURPOSE: There is clinical equipoise around the safety and efficacy of ARBs in COVID-19, but there are few RCTs of ARBs in COVID-19. Guo and colleagues' meta-analysis showed that ARBs/ACE inhibitor use was associated with decreased mortality. Our structured literature review (Cheng et al., submitted) shows that SARS-CoV-2 and other viruses that bind ACE2 cause acute cardiac injury in nearly 50% of cases. Safety concerns of ARBs in COVID-19 arise because ARBs increase cardiac ACE2, potentially increasing SARS-CoV-2 cellular uptake and worsening outcomes. On the other hand, ARBs block the effects of excess angiotensin II and could be beneficial. Our proposed ARBs CORONA II Phase 3 RCT will establish whether ARBs can decrease mortality in hospitalized COVID-19 patients. HYPOTHESIS: Primary - ARBs (losartan, valsartan, azilsartan, candesartan, eprosartan, irbesartan, olmesartan, telmisartan) decreases mortality and are safe in hospitalized COVID-19 infected adults compared to standard of care. Secondary - ACE pathway proteins (ATI, AT1-7, ATII, ACE and ACE2 levels), cytokines and metabolomics/proteomics predict mortality and efficacy of ARBs in hospitalized COVID19 adults. RESEARCH DESIGN: Study will assess ARBs (losartan, valsartan, azilsartan, candesartan, eprosartan, irbesartan, olmesartan, telmisartan) (see 6.3 Intervention for more) vs. usual care for safety and efficacy in decreasing organ dysfunction and mortality of hospitalized adults with COVID-19. Dr. Srinivas Murthy and Dr Rob Fowler, co-investigators herein and PIs of the CATCO RCT in Canada, Dr. John Marshall, co-investigator herein and PI of REMAPCAP, and Dr. Russell have coordinated alignment by allowing co-enrollment and harmonization of data and sample collection and primary endpoints.

Official Title
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Host Response Mediators in Coronavirus (COVID-19) Infection - Is There a Protective Effect of Losartan and Other ARBs on Outcomes of Coronavirus Infection?

Conditions
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Covid19, SARS-CoV Infection

Intervention / Treatment
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* Drug: Losartan
* Drug: Valsartan
* Drug: Azilsartan
* Drug: Candesartan
* Drug: Eprosartan
* Drug: Irbesartan
* Drug: Olmesartan
* Drug: Telmisartan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Hospitalized Must be first admission of COVID-19, not re-admission Primary reason for hospitalization or prolonged hospitalization is because of acute COVID-19 diagnosis Adults 18 years of age or greater Laboratory-proven COVID-19 within 14 days prior to hospital admission Exclusion Criteria: Hypotension (SAP < 100 mmHg or DAP < 50 mmHg or MAP < 65 mmHg) Hyperkalemia (> 5.5 mmol/l) Acute kidney injury (urine output < 0.5 ml/kg/hr and new creatinine > 200 mmol/l, or increase > 100 mmol/l, or GFR < 30 ml/min) Use of aliskiren in patients with diabetes mellitus (type 1 or type 2) or moderate-severe renal impairment (GFR less than 60mL/min) Use of ARB/ACEi within 7 days of presentation Pregnant or breastfeeding Have a known allergy to ARBs or any component of the drug product Have written legal document to withhold life-sustaining (patients not wishing to receive Cardiopulmonary Resuscitation (CPR) can participate if other medical treatments will be given) Have signed a Do No Resuscitate (DNR) Form

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 |
| --- | --- |
| Experimental: ARBs (Losartan, Valsartan, Azilsartan, Candesartan, Eprosartan, Irbesartan, Olmesartan, Telmisartan)<br>Patients will initially receive initial dose of oral ARBs, increased to higher dose after 24 hours and then increased to a max dose after another 24 hours, dependent on tolerance. Patient will remain at dose for duration of hospital (max of 3 months if still hospitalized). Tolerance is defined as having no severe adverse events 24 hours after the first dose. Investigators and/or attending physicians discretion may dictate that dose will not be increased, at which point dose will stay at initial or higher dose. | Drug: Losartan<br>* Oral losartan 25 mg, stepped up to 50 mg and then up to 100 mg peak dose, as tolerated.<br>* Other names: Cozaar;Drug: Valsartan<br>* Oral Valsartan 40 mg, stepped up to 80 mg and then up to 160 mg peak dose, as tolerated.<br>* Other names: Diovan;Drug: Azilsartan<br>* Oral Azilsartan 40 mg, and stepped up to 80 mg.<br>* Other names: Edarbi;Drug: Candesartan<br>* Oral Candesartan 8 mg, stepped up to 16 mg and then up to 32 mg peak dose, as tolerated.<br>* Other names: Atacand;Drug: Eprosartan<br>* Oral Eprosartan 400 mg, stepped up to 600 mg and then up to 800 mg peak dose, as tolerated.<br>* Other names: Teventen;Drug: Irbesartan<br>* Oral Irbesartan 75 mg, stepped up to 150 mg and then up to 300 mg peak dose, as tolerated.<br>* Other names: Avapro;Drug: Olmesartan<br>* Oral Olmesartan 10 mg, stepped up to 20 mg and then up to 40 mg peak dose, as tolerated.<br>* Other names: Olmetec;Drug: Telmisartan<br>* Oral Azilsartan 40 mg, and stepped up to 80 mg.<br>* Other names: Micardis;|
| No Intervention: Usual Care Control<br>Usual care for duration of hospitalization for up to 3 months if still hospitalized. Due to the lack of clinical guidance from this emergent disease, this may vary dependent on Institution and/or country | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality | Survival status | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hospital Mortality | Survival status | up to 6 months | 
| ICU Admission | Location within hospital (ICU or wards) | up to 6 months | 
| Days alive and free of vasopressors, ventilation, and renal replacement therapy | Survival and ICU support status | up to 14 days | 
| SOFA score | Sequential Organ Failure Assessment (SOFA) score | 28 days | 
| Acute cardiac injury | Use of inotropic agents and increase(s) of of troponin and/or NT-proBNP from admission level | 6 months | 
| Severe adverse events | Severe adverse effects of ARBs and mortality | 6 months | 
| Mortality | Survival status | at 1, 3 and 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ARBs, angiotensin II type 1 receptor blocker, ACEi, acute respiratory distress syndrome, COVID-19, coronavirus, multisite, Global, Canada, Acute kidney injury, acute cardiac injury, shock