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

Sponsor

University of British Columbia (Other)

Overall Status

Recruiting

CT.gov ID

NCT04606563

Collaborator

Canadian Institutes of Health Research (CIHR) (Other)

1,372

Enrollment

Locations

Arms

8.7

Anticipated Duration (Months)

72.2

Patients Per Site

8.3

Patients Per Site Per Month

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
Covid19 SARS-CoV Infection	Drug: Losartan	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

Study Type:

Interventional

Anticipated Enrollment :

1372 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Masking Description:

Our RCT uses blinded randomization and a usual care control.

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Oct 9, 2020

Anticipated Primary Completion Date :

Jun 30, 2021

Anticipated Study Completion Date :

Jun 30, 2021

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

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

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

First Hospitalization for acute COVID-19
Adults 18 years of age or greater
Laboratory-proven COVID-19 within 24 hours of 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 ARB/ACEi within 7 days of presentation
Pregnant or breastfeeding
Have a known allergy to losartan 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

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