Clinical trial NCT04510623: Host Response Mediators in Coronavirus (COVID-19) Infection
Official title: Host Response Mediators in Coronavirus (COVID-19) Infection - Is There a Protective Effect of Angiotensin II Type 1 Receptor Blockers (ARBs) on Outcomes of Coronavirus Infection?
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: COVID-19
SARS-CoV2
Keywords: ARBs
angiotensin II type 1 receptor blocker
ACEi
acute respiratory distress syndrome
COVID-19
coronavirus
Multisite
Canada
Observational
acute kidney injury
shock
Lead sponsor: University of British Columbia
Sponsor class: OTHER
Collaborators: name: Canadian Institutes of Health Research (CIHR)
name: British Columbia Centre for Disease Control
name: McGill University Health Centre/Research Institute of the McGill University Health Centre
name: University of Toronto
name: University of Ottawa
name: University of Calgary
name: University of Alberta
name: University of Victoria
name: Wuhan University
name: Peking Union Medical College
name: University of Pennsylvania
First posted: 2020-08-12
Enrollment: 500
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: OTHER
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Adult hospitalized patients with confirmed COVID-19

Brief summary: The coronavirus (COVID-19) pandemic continues to grow exponentially. Angiotensin II levels are increased in human influenza and are associated with influenza viral load, disease progression and mortality. Preliminary data shows angiotensin II receptor blockers (ARBs) limits lung injury in murine influenza H7N9, as well as viral titre and RNA. ARBs could limit viral titre and organ injury in COVID-19. We will therefore collect clinical chart data and test angiotensin II levels of patients who are admitted to ICU with COVID-19 to determine whether there is a correlation between taking ARBs and clinical outcomes in these patients.

Other blood biomarkers and clinical risk factors for COVID-19 have come to light in recent weeks. We include these in our observational analysis to help generate an understanding of COVID-19 presentation and blood biomarker characterization of disease.

Detailed description: Purpose: To determine whether angiotensin II receptor blockers (ARBs) decrease severity or mortality in hospitalized COVID-19 infected adults.

Main Hypothesis: Modulation of ACE2 by ARBs decreases the need for hospitalization, severity (need for ventilation, vasopressors, extracorporeal membrane oxygenation or renal replacement therapy) or mortality of hospitalized COVID-19 infected adults.

Secondary Hypotheses:

* Plasma angiotensin I and II and other biomarker levels are associated with effectiveness of ARBs in hospitalized COVID-19 adults
* Modulation of ACE2 by angiotensin type I receptor blockers is associated with decreased rate of hospitalization for COVID-19
* In patients already on ARBs when they are hospitalized continuing ARBs is associated with decreased World Health Organization (WHO) COVID-19 ordinal outcome scale

Justification: The COVID-19 epidemic continues to grow exponentially affecting over 71,429 individuals with 1775 deaths (February 17, 2020), mostly in China but also in other countries. The population mortality rate is 2% (lower than SARS (10%) and MERS (36%) but is 10% in hospitalized and 24% in ICU-admitted COVID-19 patients in China. Recent data from China (not yet public domain) suggest ICU mortality is higher (J. Marshall personal communication). Interventions to date include quarantine, isolation and usual clinical care. There are no proven antiviral or host modulating interventions for COVID-19. Notably, critically ill COVID-19 patients have similar mortality rates as sepsis and acute respiratory distress syndrome. Cohort studies have shown that patients already on angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) have lower sepsis mortality. Angiotensin II worsens lung injury in influenza models because ACE2 is downregulated in H1N1, H5N1, H7N9, and SARS viral infections leading to increased angiotensin II. Angiotensin II levels are increased in human influenza and are associated with influenza viral load, disease progression and mortality. Preliminary data shows ARBs limits lung injury in murine influenza H7N9, as well as viral titre and RNA. ARBs could limit viral titre and organ injury in COVID-19.

Research Design:

Prospective clinical chart review: we will collect clinical data on the participant throughout their hospital stay. Includes collection of baseline characteristics such as age, sex, heart rate, respiratory rate, temperature, blood pressure, SaO2, respiratory (PaO2/FiO2), renal (creatinine) and hepatic (bilirubin) function, use of oxygen, vasopressors, ventilation and RRT. They will be followed daily throughout their hospital stay, until death or discharge. Using left over clinical blood collected upon admission to hospital, plasma angiotensin I and II and other biomarker levels will be measured in our research laboratories.

Eligibility criteria: Inclusion Criteria:

* Individuals over 18 years of age who have confirmed COVID-19 infection (according to local hospital or provincial laboratories clinically approved laboratory testing for COVID-19).

Exclusion Criteria:

* None

Primary outcomes:
measure: COVID-19 WHO ordinal scale
timeFrame: 14 days
Secondary outcomes:
measure: Organ Dysfunction
timeFrame: 14 days
measure: 28-day mortality
timeFrame: 29 days or less (may be discharged from critical care before day 28)
measure: Hospital/ICU length of stay
timeFrame: 29 days or less (may be discharged before day 28)
measure: ICU admission
timeFrame: 29 days or less (may be discharged from critical care before day 28)
Other outcomes:
Locations:
city: Calgary
country: Canada
facility: University of Calgary - Foothills
state: Alberta
city: Edmonton
country: Canada
facility: Stollery Children's Hospital
state: Alberta
city: Edmonton
country: Canada
facility: University of Alberta
state: Alberta
city: Surrey
country: Canada
facility: Surrey Memorial Hospital
state: British Columbia
city: Vancouver
country: Canada
facility: St Pauls Hospital
state: British Columbia
city: Vancouver
country: Canada
facility: Vancouver General Hospital
state: British Columbia
city: Brampton
country: Canada
facility: William Osler Health System
state: Ontario
city: Kingston
country: Canada
facility: Queens University
state: Ontario
city: North York
country: Canada
facility: Humber River Hospital
state: Ontario
city: Toronto
country: Canada
facility: Mount Sinai Hospital
state: Ontario
city: Toronto
country: Canada
facility: St Michael's Hospital
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Hospital
state: Ontario
city: Montréal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: Montréal
country: Canada
facility: McGill University Health Center
state: Quebec
city: Sherbrooke
country: Canada
facility: Université de Sherbrooke
state: Quebec
Study officials:
affiliation: St Paul's Hospital, Center for Heart and Lung Innovation
name: James A Russell, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Lee T, Cheng MP, Vinh DC, Lee TC, Tran KC, Winston BW, Sweet D, Boyd JH, Walley KR, Haljan G, McGeer A, Lamontagne F, Fowler R, Maslove D, Singer J, Patrick DM, Marshall JC, Burns KD, Murthy S, Mann PK, Hernandez G, Donohoe K, Rocheleau G, Russell JA; ARBs CORONA I study investigators. Organ dysfunction and death in patients admitted to hospital with COVID-19 in pandemic waves 1 to 3 in British Columbia, Ontario and Quebec, Canada: a cohort study. CMAJ Open. 2022 Apr 19;10(2):E379-E389. doi: 10.9778/cmajo.20210216. Print 2022 Apr-Jun.
citation: Russell JA, Marshall JC, Slutsky A, Murthy S, Sweet D, Lee T, Singer J, Patrick DM, Du B, Peng Z, Cheng M, Burns KD, Harhay MO. Study protocol for a multicentre, prospective cohort study of the association of angiotensin II type 1 receptor blockers on outcomes of coronavirus infection. BMJ Open. 2020 Dec 7;10(12):e040768. doi: 10.1136/bmjopen-2020-040768.