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

NCT04606563 | Terminated Phase 3 DMC

• 1 other identifier: H20-01984
• Study Type: interventional
• Target: 341
• Locations: 2 countries
• Sites: 13

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.

Conditions

Covid19; SARS-CoV Infection

Keywords

ARBs; angiotensin II type 1 receptor blocker; ACEi; acute respiratory distress syndrome; COVID-19; coronavirus; multisite; Global; Canada; Acute kidney injury; acute cardiac injury; shock

Outcome Measures

Primary Outcomes (1)

• Mortality

  Survival status

  28 days

Secondary Outcomes (7)

• Hospital Mortality

  up to 6 months

• ICU Admission

  up to 6 months

• Days alive and free of vasopressors, ventilation, and renal replacement therapy

  up to 14 days

• SOFA score

  28 days

• Acute cardiac injury

  6 months

Study Arms (2)

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

EXPERIMENTAL

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.

Drug: Losartan; Drug: Valsartan; Drug: Azilsartan; Drug: Candesartan; Drug: Eprosartan; Drug: Irbesartan; Drug: Olmesartan; Drug: Telmisartan

Usual Care Control

NO INTERVENTION

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

Interventions

Losartan DRUG

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

Also known as: Cozaar

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

Valsartan DRUG

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

Also known as: Diovan

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

Azilsartan DRUG

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

Also known as: Edarbi

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

Candesartan DRUG

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

Also known as: Atacand

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

Eprosartan DRUG

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

Also known as: Teventen

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

Irbesartan DRUG

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

Also known as: Avapro

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

Olmesartan DRUG

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

Also known as: Olmetec

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

Telmisartan DRUG

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

Also known as: Micardis

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

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of British Columbia: lead
• Canadian Institutes of Health Research (CIHR): collaborator

Study Sites (13)

University of Calgary - Foothills

Calgary, Alberta, Canada

Location

Royal Jubilee Hospital

Nanaimo, British Columbia, Canada

Location

Surrey Memorial Hospital

Surrey, British Columbia, V3V 1Z2, Canada

Location

St Paul's Hospital

Vancouver, British Columbia, V6Z1Y6, Canada

Location

Vancouver General Hospital

Vancouver, British Columbia, Canada

Location

The Ottawa Hospital

Ottawa, Ontario, Canada

Location

Niagara Health

Saint Catharines, Ontario, Canada

Location

St Michael's Hospital

Toronto, Ontario, Canada

Location

Sunnybrook Hospital

Toronto, Ontario, Canada

Location

CHU de Québec - Université Laval

Laval, Quebec, Canada

Location

McGill University Health Center

Montreal, Quebec, Canada

Location

Université de Sherbrooke

Sherbrooke, Quebec, Canada

Location

Centre Hospitalier Universitaire d'Angers

Angers, France

Location

Related Publications (1)

• 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.

  PMID: 39325643 DERIVED

MeSH Terms

Conditions

COVID-19; Severe Acute Respiratory Syndrome; Respiratory Distress Syndrome; Coronavirus Infections; Acute Kidney Injury; Shock

Interventions

Losartan; Valsartan; azilsartan; candesartan; candesartan cilexetil; eprosartan; Irbesartan; olmesartan; Olmesartan Medoxomil; Telmisartan

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Respiration Disorders; Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Biphenyl Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Tetrazoles; Valine; Amino Acids, Branched-Chain; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Essential; Spiro Compounds; Polycyclic Compounds; Benzimidazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• James A Russell, MD

  University of British Columbia

  PRINCIPAL INVESTIGATOR

• Karen Tran, MD

  University of British Columbia

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: Our RCT uses blinded randomization and a usual care control.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Study Wide Principal Investigator

Study Record Dates

• First Submitted: October 27, 2020
• First Posted: October 28, 2020
• Study Start: October 9, 2020
• Primary Completion: April 22, 2022
• Study Completion: April 22, 2022
• Last Updated: February 16, 2023

Record last verified: 2023-02

Data Sharing

• IPD Sharing: Will not share

Locations

CA (12); FR (1)