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

  • STATUS
    Recruiting
  • End date
    Jun 30, 2021
  • participants needed
    1372
  • sponsor
    University of British Columbia
Updated on 25 January 2021

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.

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.

Details
Condition Severe Acute Respiratory Syndrome, COVID19
Treatment losartan
Clinical Study IdentifierNCT04606563
SponsorUniversity of British Columbia
Last Modified on25 January 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Is your age greater than or equal to 18 yrs?
Gender: Male or Female
Do you have any of these conditions: COVID19 or Severe Acute Respiratory Syndrome?
Do you have any of these conditions: Severe Acute Respiratory Syndrome or COVID19?
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
Clear my responses

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