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

NCT ID: NCT04606563

Last Updated: 2023-02-16

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 341 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-10-09
• Study Completion Date: 2022-04-22

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.

Conditions

Covid19; SARS-CoV Infection

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

ARBs (Losartan, Valsartan, Azilsartan, Candesartan, Eprosartan, Irbesartan, Olmesartan, Telmisartan)

Patients will initially receive initial dose of oral ARBs, increased to higher dose after 24 hours and then increased to a max dose 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 initial or higher dose.

Group Type: EXPERIMENTAL

Losartan

Intervention Type: DRUG

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

Valsartan

Intervention Type: DRUG

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

Azilsartan

Intervention Type: DRUG

Oral Azilsartan 40 mg, and stepped up to 80 mg.

Candesartan

Intervention Type: DRUG

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

Eprosartan

Intervention Type: DRUG

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

Irbesartan

Intervention Type: DRUG

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

Olmesartan

Intervention Type: DRUG

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

Telmisartan

Intervention Type: DRUG

Oral Azilsartan 40 mg, and stepped up to 80 mg.

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

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

Losartan

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

Intervention Type: DRUG

Valsartan

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

Intervention Type: DRUG

Azilsartan

Oral Azilsartan 40 mg, and stepped up to 80 mg.

Intervention Type: DRUG

Candesartan

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

Intervention Type: DRUG

Eprosartan

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

Intervention Type: DRUG

Irbesartan

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

Intervention Type: DRUG

Olmesartan

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

Intervention Type: DRUG

Telmisartan

Oral Azilsartan 40 mg, and stepped up to 80 mg.

Intervention Type: DRUG

Other Intervention Names

Cozaar; Diovan; Edarbi; Atacand; Teventen; Avapro; Olmetec; 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Canadian Institutes of Health Research (CIHR)

OTHER_GOV

Sponsor Role: collaborator

University of British Columbia

OTHER

Sponsor Role: lead

Responsible Party

Jim Russell

Study Wide Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

James A Russell, MD

Role: PRINCIPAL_INVESTIGATOR

University of British Columbia

Karen Tran, MD

Role: PRINCIPAL_INVESTIGATOR

University of British Columbia

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

St. 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

Montreal, Quebec, Canada

Université de Sherbrooke

Sherbrooke, Quebec, Canada

Centre Hospitalier Universitaire d'Angers

Angers, , France

Countries

Canada; France

References

Tran KC, Asfar P, Cheng M, Demiselle J, Singer J, Lee T, Sweet D, Boyd J, Walley K, Haljan G, Sharif O, Geri G, Auchabie J, Quenot JP, Lee TC, Tsang J, Meziani F, Lamontagne F, Dubee V, Lasocki S, Ovakim D, Wood G, Turgeon A, Cohen Y, Lebas E, Goudelin M, Forrest D, Teale A, Mira JP, Fowler R, Daneman N, Adhikari NKJ, Gousseff M, Leroy P, Plantefeve G, Rispal P, Courtois R, Winston B, Reynolds S, Birks P, Bienvenu B, Tadie JM, Talarmin JP, Ansart S, Russell JA; ARBs CORONA II Team. Effects of Losartan on Patients Hospitalized for Acute COVID-19: A Randomized Controlled Trial. Clin Infect Dis. 2024 Sep 26;79(3):615-625. doi: 10.1093/cid/ciae306.

Reference Type: DERIVED

PMID: 39325643 (View on PubMed)

Other Identifiers

H20-01984

Identifier Type: -

Identifier Source: org_study_id