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

Terminated
COVID19
SARS-CoV Infection

Drug: Losartan

Oral losartan 25 mg, stepped up to 50 mg and then up to 100 mg peak dose, as tolerated.
Other Name: Cozaar

Drug: Valsartan

Oral Valsartan 40 mg, stepped up to 80 mg and then up to 160 mg peak dose, as tolerated.
Other Name: Diovan

Drug: Azilsartan

Oral Azilsartan 40 mg, and stepped up to 80 mg.
Other Name: Edarbi

Drug: Candesartan

Oral Candesartan 8 mg, stepped up to 16 mg and then up to 32 mg peak dose, as tolerated.
Other Name: Atacand

Drug: Eprosartan

Oral Eprosartan 400 mg, stepped up to 600 mg and then up to 800 mg peak dose, as tolerated.
Other Name: Teventen

Drug: Irbesartan

Oral Irbesartan 75 mg, stepped up to 150 mg and then up to 300 mg peak dose, as tolerated.
Other Name: Avapro

Drug: Olmesartan

Oral Olmesartan 10 mg, stepped up to 20 mg and then up to 40 mg peak dose, as tolerated.
Other Name: Olmetec

Drug: Telmisartan

Oral Azilsartan 40 mg, and stepped up to 80 mg.
Other Name: Micardis

Eligibility Criteria

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

Eligibility Gender
All
Eligibility Age
Minimum: 18 Years ~ Maximum: N/A
Countries
Canada
France
Locations

University of Calgary - Foothills
Calgary, Alberta, Canada

Royal Jubilee Hospital
Nanaimo, British Columbia, Canada

Surrey Memorial Hospital
Surrey, British Columbia, Canada

St Paul's Hospital
Vancouver, British Columbia, Canada

Vancouver General Hospital
Vancouver, British Columbia, Canada

The Ottawa Hospital
Ottawa, Ontario, Canada

Niagara Health
Saint Catharines, Ontario, Canada

St Michael's Hospital
Toronto, Ontario, Canada

Sunnybrook Hospital
Toronto, Ontario, Canada

CHU de Québec - Université Laval
Laval, Quebec, Canada

McGill University Health Center
Montréal, Quebec, Canada

Université de Sherbrooke
Sherbrooke, Quebec, Canada

Centre Hospitalier Universitaire d'Angers
Angers, France

Canadian Institutes of Health Research (CIHR)
NCT Number
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
MeSH Terms
Infections
Communicable Diseases
COVID-19
Coronavirus Infections
Severe Acute Respiratory Syndrome
Losartan
Valsartan
Telmisartan
Candesartan
Olmesartan
Irbesartan
Eprosartan
Azilsartan medoxomil