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

Covid19 Clinical Trial

— ARBs CORONA II  

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?

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04606563
• Other study ID #: H20-01984
• Status: Terminated
• Phase: Phase 3
• Start date: October 9, 2020
• Est. completion date: April 22, 2022

Study information

• Verified date: February 2023
• Source: University of British Columbia
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 341
• Est. completion date: April 22, 2022
• Est. primary completion date: April 22, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Communicable Diseases
• Coronavirus Infections
• COVID-19
• Covid19
• Infections
• SARS-CoV Infection
• Severe Acute Respiratory Syndrome

Intervention

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

Locations

Country	Name	City	State
Canada	University of Calgary - Foothills	Calgary	Alberta
Canada	CHU de Québec - Université Laval	Laval	Quebec
Canada	McGill University Health Center	Montréal	Quebec
Canada	Royal Jubilee Hospital	Nanaimo	British Columbia
Canada	The Ottawa Hospital	Ottawa	Ontario
Canada	Niagara Health	Saint Catharines	Ontario
Canada	Université de Sherbrooke	Sherbrooke	Quebec
Canada	Surrey Memorial Hospital	Surrey	British Columbia
Canada	St Michael's Hospital	Toronto	Ontario
Canada	Sunnybrook Hospital	Toronto	Ontario
Canada	St Paul's Hospital	Vancouver	British Columbia
Canada	Vancouver General Hospital	Vancouver	British Columbia
France	Centre Hospitalier Universitaire d'Angers	Angers

Sponsors (2)

Lead Sponsor	Collaborator
University of British Columbia	Canadian Institutes of Health Research (CIHR)

Countries where clinical trial is conducted

Canada,  France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Mortality	Survival status	28 days
Secondary	Hospital Mortality	Survival status	up to 6 months
Secondary	ICU Admission	Location within hospital (ICU or wards)	up to 6 months
Secondary	Days alive and free of vasopressors, ventilation, and renal replacement therapy	Survival and ICU support status	up to 14 days
Secondary	SOFA score	Sequential Organ Failure Assessment (SOFA) score	28 days
Secondary	Acute cardiac injury	Use of inotropic agents and increase(s) of of troponin and/or NT-proBNP from admission level	6 months
Secondary	Severe adverse events	Severe adverse effects of ARBs and mortality	6 months
Secondary	Mortality	Survival status	at 1, 3 and 6 months