Clinical trial NCT04606563: Host Response Mediators in Coronavirus (COVID-19) Infection - Is There a Protective Effect of Losartan and Other ARBs on Outcomes of Coronavirus Infection?
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?
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
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
Lead sponsor: University of British Columbia
Sponsor class: OTHER
Collaborators: name: Canadian Institutes of Health Research (CIHR)
First posted: 2020-10-28
Enrollment: 341
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Mortality
timeFrame: 28 days
Secondary outcomes:
measure: Hospital Mortality
timeFrame: up to 6 months
measure: ICU Admission
timeFrame: up to 6 months
measure: Days alive and free of vasopressors, ventilation, and renal replacement therapy
timeFrame: up to 14 days
measure: SOFA score
timeFrame: 28 days
measure: Acute cardiac injury
timeFrame: 6 months
measure: Severe adverse events
timeFrame: 6 months
measure: Mortality
timeFrame: at 1, 3 and 6 months
Other outcomes:
Locations:
city: Calgary
country: Canada
facility: University of Calgary - Foothills
state: Alberta
city: Nanaimo
country: Canada
facility: Royal Jubilee Hospital
state: British Columbia
city: Surrey
country: Canada
facility: Surrey Memorial Hospital
state: British Columbia
city: Vancouver
country: Canada
facility: St Paul's Hospital
state: British Columbia
city: Vancouver
country: Canada
facility: Vancouver General Hospital
state: British Columbia
city: Ottawa
country: Canada
facility: The Ottawa Hospital
state: Ontario
city: Saint Catharines
country: Canada
facility: Niagara Health
state: Ontario
city: Toronto
country: Canada
facility: St Michael's Hospital
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Hospital
state: Ontario
city: Laval
country: Canada
facility: CHU de Québec - Université Laval
state: Quebec
city: Montréal
country: Canada
facility: McGill University Health Center
state: Quebec
city: Sherbrooke
country: Canada
facility: Université de Sherbrooke
state: Quebec
city: Angers
country: France
facility: Centre Hospitalier Universitaire d'Angers
Study officials:
affiliation: University of British Columbia
name: James A Russell, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of British Columbia
name: Karen Tran, MD
role: PRINCIPAL_INVESTIGATOR
References: