NCT04606563

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

• Status: Terminated
• Phase: Phase 3
• Study type: Interventional
• Enrollment: 341 (actual)
• Sponsor: University of British Columbia · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

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.

Conditions

• Covid19
• SARS-CoV Infection

Interventions

Type	Name	Description
DRUG	Losartan	Oral losartan 25 mg, stepped up to 50 mg and then up to 100 mg peak dose, as tolerated.
DRUG	Valsartan	Oral Valsartan 40 mg, stepped up to 80 mg and then up to 160 mg peak dose, as tolerated.
DRUG	Azilsartan	Oral Azilsartan 40 mg, and stepped up to 80 mg.
DRUG	Candesartan	Oral Candesartan 8 mg, stepped up to 16 mg and then up to 32 mg peak dose, as tolerated.
DRUG	Eprosartan	Oral Eprosartan 400 mg, stepped up to 600 mg and then up to 800 mg peak dose, as tolerated.
DRUG	Irbesartan	Oral Irbesartan 75 mg, stepped up to 150 mg and then up to 300 mg peak dose, as tolerated.
DRUG	Olmesartan	Oral Olmesartan 10 mg, stepped up to 20 mg and then up to 40 mg peak dose, as tolerated.
DRUG	Telmisartan	Oral Azilsartan 40 mg, and stepped up to 80 mg.

Timeline

• Start date: 2020-10-09
• Primary completion: 2022-04-22
• Completion: 2022-04-22
• First posted: 2020-10-28
• Last updated: 2023-02-16

Locations

13 sites across 2 countries: Canada, France