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Trial record 6 of 10 for:    Losartan | ( Map: Canada )

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

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ClinicalTrials.gov Identifier: NCT04606563
Recruitment Status : Recruiting
First Posted : October 28, 2020
Last Update Posted : October 28, 2020
Sponsor:
Collaborator:
Canadian Institutes of Health Research (CIHR)
Information provided by (Responsible Party):
Jim Russell, University of British Columbia

Brief Summary:

SARS-CoV-2 is a member of a class of viruses: angiotensin converting enzyme 2 (ACE2)-binding viruses that we call "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 ARB, losartan, limits lung injury in murine influenza H7N9 and decreases viral titre and RNA.

We have 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 (ARB, losartan) to decrease the mortality of hospitalized COVID-19 patient.


Condition or disease Intervention/treatment Phase
Covid19 SARS-CoV Infection Drug: Losartan Phase 3

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[29]. 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[30], 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 losartan can decrease mortality in hospitalized COVID-19 patients.

HYPOTHESIS:

Primary - Losartan (25 to 50 to 100 mg daily) decreases mortality and is safe in hospitalized COVID-19 infected adults compared to standard of care.

Secondary - ACE pathway proteins (aka RAS components) (ATI, AT1-7, ATII, ACE and ACE2 levels), cytokines and metabolomics/proteomics predict mortality and efficacy of losartan in hospitalized COVID-19 adults

RESEARCH DESIGN: We will assess losartan (25-50-100 mg daily) vs. usual care for safety and efficacy in decreasing organ dysfunction and mortality of hospitalized adults with COVID-19. Dr. Srinivas Murthy, a co-investigator herein and PI of the SOLIDARITY RCT in Canada (CATCO), Dr. John Marshall, co-investigator herein and PI of REMAPCAP, and Dr. Russell have coordinated alignment by allowing co-enrollment.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1372 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Masking Description: Our RCT uses blinded randomization and a usual care control.
Primary Purpose: Treatment
Official Title: Host Response Mediators in Coronavirus (COVID-19) Infection - Is There a Protective Effect of Losartan on Outcomes of Coronavirus Infection?
Actual Study Start Date : October 9, 2020
Estimated Primary Completion Date : June 30, 2021
Estimated Study Completion Date : June 30, 2021


Arm Intervention/treatment
Experimental: Losartan
Patients will initially receive 25 mg oral losartan, increased to 50 mg after 24 hours and then increased to a max dose of 100 mg 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 25 or 50 mg.
Drug: Losartan
Oral losartan 25 mg, stepped up to 50 mg and then up to 100 mg peak dose, as tolerated.

No Intervention: 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



Primary Outcome Measures :
  1. Mortality [ Time Frame: 28 days ]

Secondary Outcome Measures :
  1. Hospital Mortality [ Time Frame: up to 6 months ]
  2. ICU Admission [ Time Frame: up to 6 months ]
    Location within hospital (ICU or wards)

  3. days alive and free of vasopressors, ventilation, and renal replacement therapy [ Time Frame: up to 14 days ]
  4. SOFA score [ Time Frame: 28 days ]
    Sequential Organ Failure Assessment (SOFA) score

  5. Acute cardiac injury [ Time Frame: 6 months ]
    Use of inotropic agents and increase(s) of of troponin and/or NT-proBNP from admission level

  6. Severe adverse events [ Time Frame: 6 months ]
    Severe adverse effects of ARBs and mortality

  7. Mortality [ Time Frame: at 1, 3 and 6 months ]


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • First Hospitalization for acute COVID-19
  • Adults 18 years of age or greater
  • Laboratory-proven COVID-19 within 24 hours of 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 ARB/ACEi within 7 days of presentation
  • Pregnant or breastfeeding
  • Have a known allergy to losartan 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04606563


Contacts
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Contact: Puneet Mann 604-682-2344 ext 64734 pmann7@providencehealth.bc.ca
Contact: Lynda Lazosky 604-682-2344 ext 68191 llazosky@providencehealth.bc.ca

Locations
Show Show 19 study locations
Sponsors and Collaborators
University of British Columbia
Canadian Institutes of Health Research (CIHR)
Investigators
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Principal Investigator: James A Russell, MD University of British Columbia
Principal Investigator: Karen Tran, MD University of British Columbia
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Responsible Party: Jim Russell, Study Wide Principal Investigator, University of British Columbia
ClinicalTrials.gov Identifier: NCT04606563    
Other Study ID Numbers: H20-01984
First Posted: October 28, 2020    Key Record Dates
Last Update Posted: October 28, 2020
Last Verified: October 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Jim Russell, University of British Columbia:
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
Additional relevant MeSH terms:
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Infection
Communicable Diseases
Coronavirus Infections
Severe Acute Respiratory Syndrome
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Virus Diseases
Respiratory Tract Infections
Respiratory Tract Diseases
Losartan
Anti-Arrhythmia Agents
Antihypertensive Agents
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action