Covid19, SARS-CoV Infection
Conditions
Keywords
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
Brief summary
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
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.
Interventions
DRUGLosartan
Oral losartan 25 mg, stepped up to 50 mg and then up to 100 mg peak dose, as tolerated.
DRUGValsartan
Oral Valsartan 40 mg, stepped up to 80 mg and then up to 160 mg peak dose, as tolerated.
DRUGAzilsartan
Oral Azilsartan 40 mg, and stepped up to 80 mg.
DRUGCandesartan
Oral Candesartan 8 mg, stepped up to 16 mg and then up to 32 mg peak dose, as tolerated.
DRUGEprosartan
Oral Eprosartan 400 mg, stepped up to 600 mg and then up to 800 mg peak dose, as tolerated.
DRUGIrbesartan
Oral Irbesartan 75 mg, stepped up to 150 mg and then up to 300 mg peak dose, as tolerated.
DRUGOlmesartan
Oral Olmesartan 10 mg, stepped up to 20 mg and then up to 40 mg peak dose, as tolerated.
DRUGTelmisartan
Oral Azilsartan 40 mg, and stepped up to 80 mg.
Sponsors
Canadian Institutes of Health Research (CIHR)
University of British Columbia
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
Our RCT uses blinded randomization and a usual care control.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mortality | 28 days | Survival status |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Survival and ICU support status |
| SOFA score | 28 days | Sequential Organ Failure Assessment (SOFA) score |
| Hospital Mortality | up to 6 months | Survival status |
| Severe adverse events | 6 months | Severe adverse effects of ARBs and mortality |
| Mortality | at 1, 3 and 6 months | Survival status |
| Acute cardiac injury | 6 months | Use of inotropic agents and increase(s) of of troponin and/or NT-proBNP from admission level |
Countries
Canada, France
Outcome results
None listed