ARBs CORONA II: Host Response Mediators in Coronavirus (COVID-19) Infection - Is There a Protective Effect of Losartan on Outcomes of Coronavirus Infection?
Study Details
Study Description
Brief Summary
SARS-CoV-2 is a member of a class of viruses: angiotensin converting enzyme 2 (ACE2)-binding viruses that we call "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 ARB, losartan, limits lung injury in murine influenza H7N9 and decreases viral titre and RNA.
We have 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 (ARB, losartan) to decrease the mortality of hospitalized COVID-19 patient.
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
Phase 3 |
Detailed Description
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[29]. 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[30], 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 losartan can decrease mortality in hospitalized COVID-19 patients.
HYPOTHESIS:
Primary - Losartan (25 to 50 to 100 mg daily) decreases mortality and is safe in hospitalized COVID-19 infected adults compared to standard of care.
Secondary - ACE pathway proteins (aka RAS components) (ATI, AT1-7, ATII, ACE and ACE2 levels), cytokines and metabolomics/proteomics predict mortality and efficacy of losartan in hospitalized COVID-19 adults
RESEARCH DESIGN: We will assess losartan (25-50-100 mg daily) vs. usual care for safety and efficacy in decreasing organ dysfunction and mortality of hospitalized adults with COVID-19. Dr. Srinivas Murthy, a co-investigator herein and PI of the SOLIDARITY RCT in Canada (CATCO), Dr. John Marshall, co-investigator herein and PI of REMAPCAP, and Dr. Russell have coordinated alignment by allowing co-enrollment.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Experimental: Losartan Patients will initially receive 25 mg oral losartan, increased to 50 mg after 24 hours and then increased to a max dose of 100 mg 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 25 or 50 mg. |
Drug: Losartan
Oral losartan 25 mg, stepped up to 50 mg and then up to 100 mg peak dose, as tolerated.
|
No Intervention: Usual Care Control 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 |
Outcome Measures
Primary Outcome Measures
- Mortality [28 days]
Secondary Outcome Measures
- Hospital Mortality [up to 6 months]
- ICU Admission [up to 6 months]
Location within hospital (ICU or wards)
- days alive and free of vasopressors, ventilation, and renal replacement therapy [up to 14 days]
- SOFA score [28 days]
Sequential Organ Failure Assessment (SOFA) score
- Acute cardiac injury [6 months]
Use of inotropic agents and increase(s) of of troponin and/or NT-proBNP from admission level
- Severe adverse events [6 months]
Severe adverse effects of ARBs and mortality
- Mortality [at 1, 3 and 6 months]
Eligibility Criteria
Criteria
Inclusion Criteria:
-
First Hospitalization for acute COVID-19
-
Adults 18 years of age or greater
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Laboratory-proven COVID-19 within 24 hours of hospital admission
Exclusion Criteria:
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Hypotension (SAP < 100 mmHg or DAP < 50 mmHg or MAP < 65 mmHg)
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Hyperkalemia (> 5.5 mmol/l)
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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)
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Use of ARB/ACEi within 7 days of presentation
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Pregnant or breastfeeding
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Have a known allergy to losartan or any component of the drug product
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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)
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Have signed a Do No Resuscitate (DNR) Form
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | University of Nebraska | Omaha | Nebraska | United States | 68198 |
2 | Brown University | Providence | Rhode Island | United States | 02912 |
3 | Vanderbilt University | Nashville | Tennessee | United States | 37235 |
4 | St. Luc University Hospital | Brussels | Belgium | ||
5 | Clinique Saint-Pierre | Ottignies | Belgium | ||
6 | University of Calgary - Foothills | Calgary | Alberta | Canada | |
7 | Royal Columbian Hospital | New Westminster | British Columbia | Canada | |
8 | Surrey Memorial Hospital | Surrey | British Columbia | Canada | V3V 1Z2 |
9 | St Paul's Hospital | Vancouver | British Columbia | Canada | V6Z1Y6 |
10 | Vancouver General Hospital | Vancouver | British Columbia | Canada | |
11 | Queens University | Kingston | Ontario | Canada | |
12 | The Ottawa Hospital | Ottawa | Ontario | Canada | |
13 | St Michael's Hospital | Toronto | Ontario | Canada | |
14 | Sunnybrook Hospital | Toronto | Ontario | Canada | |
15 | McGill University Health Center | Montréal | Quebec | Canada | |
16 | Université de Sherbrooke | Sherbrooke | Quebec | Canada | |
17 | Centre Hospitalier Universitaire d'Angers | Angers | France | ||
18 | Chiba University | Chiba | Japan | ||
19 | Hospital Clínico San Carlos | Madrid | Spain |
Sponsors and Collaborators
- University of British Columbia
- Canadian Institutes of Health Research (CIHR)
Investigators
- Principal Investigator: James A Russell, MD, University of British Columbia
- Principal Investigator: Karen Tran, MD, University of British Columbia
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- H20-01984