The McGill RAAS-COVID-19 Trial

Study Overview
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Brief Summary
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Coronavirus disease (COVID-19) related pneumonia significantly impact patients with underlying cardiovascular (CV) conditions. Animal studies suggest that drugs commonly used to treated CV diseases may increase the ability of COVID-19 to infect cells. The RAAS-COVID-19 trial aims to assess whether temporarily holding these CV drugs in patients who are admitted with COVID-19, versus continuing them, in patients admitted with COVID-19 can impact short term outcomes.

Detailed Description
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Open-label, pragmatic, randomized, study of approximately 40 adults. The following groups of participants will be considered: i) within 48 hours of diagnosis of COVID-19; ii) who have received a diagnosis of COVID-19 from another facility and are within 48 hours of transfer to a study recruitment site (Royal Victoria Hospital, Montreal General Hospital, and Jewish General Hospital [all in Montreal, Quebec, Canada]). Participants will be randomized 1:1 to an upfront temporary discontinuation) of RAAS inhibition for the duration of the hospitalization (and to consider re-initiate after day 7 of admission or on discharge) versus a strategy continuation of RAAS inhibition. Re-initiation of held RAAS inhibition will be based on treating team's clinical judgement. The RAAS-COVID-19 RCT will evaluate whether an upfront strategy of temporary discontinuation of RAAS inhibition compared to the continuation of RAAS inhibition among patients admitted with established COVID-19 infection and on chronic RAAS inhibition therapy impacts short term clinical outcomes and biomarkers.

Official Title
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Management of Renin-Angiotensin-Aldosterone System Blockade in Patients Admitted in Hospital With Confirmed Coronavirus Disease (COVID-19) Infection: The McGill RAAS-COVID-19 Randomized Controlled Trial

Conditions
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COVID-19, Cardiovascular Diseases

Intervention / Treatment
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* Other: Temporarily holding the RAAS inhibitor [intervention]
* Other: RAAS inhibitor [continued standard of care]


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years old. Hospitalization with a Covid-19 infection Chronically treated with RAAS blockers (ACE inhibitors or ARBs on the last prescription prior to admission with a treatment duration ≥ 1 month Diagnosis of COVID-19 confirmed by the presence of SARS-CoV-2 on any biological sample Participants are within 48 hours of diagnosis of COVID-19 or have received a diagnosis of COVID-19 from another facility and are within 48 hours of transfer to a study recruitment site Exclusion Criteria: Shock requiring vasoactive agents. Requiring invasive mechanical ventilation. History of malignant hypertension Use of five or more antihypertensive drugs. History of heart failure with reduced ejection fraction History of hospitalization for acute heart failure in past 3 months History of hospitalization for hemorrhagic stroke in the past 3 months. History of CKD with an eGFR <45 ml/min/1.73m2 History of COPD GOLD III/IV History of end-stage dementia History of active liver cirrhosis RAAS blockers therapy previously stopped > 48h. Anticipated discharge in less than 24 hours. History of current active cancer receiving chemotherapy Inability to obtain informed consent.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Open-label, randomized, study of approximately 40 adults. The following groups of participants will be considered: i) within 48 hours of diagnosis of COVID-19; ii) who have received a diagnosis of COVID-19 from another facility and are within 48 hours of transfer to a study recruitment site (Royal Victoria Hospital, Montreal General Hospital, and Jewish General Hospital [all in Montreal, Quebec, Canada])). Participants will be randomized 1:1 to an upfront temporary discontinuation) of RAAS inhibition for the duration of the hospitalization (and to consider re-initiate on discharge) versus a strategy continuation of RAAS inhibition.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention<br>Temporarily holding the RAAS inhibitor. Among participants who will be randomized to the intervention arm, a possible guideline-directed alternative to anti-hypertensive medication alternatives will be provided to the treating physician team. | Other: Temporarily holding the RAAS inhibitor [intervention]<br>* Temporarily holding the RAAS inhibitor. Among participants who will be randomized to the intervention arm, a possible guideline-directed alternative to anti-hypertensive medication alternatives will be provided to the treating physician team.<br>|
| Other: Continuation of standard of care<br>No intervention, Continuation RAAS inhibitor [continued standard of care]. | Other: RAAS inhibitor [continued standard of care]<br>* No intervention, Continuation RAAS inhibitor [continued standard of care].<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Global rank score | The primary end point is a global rank score which is applied to all participants. The global rank sum is based on the following endpoints (and corresponding score): Death (7); Transfer to ICU for Invasive ventilation (6); Transfer to ICU for other indication (5); Non-fatal MACE (Any of the following - MI, Stroke, Acute HF, new onset Afib) (4); Length of stay > 4 days (3); Development of acute kidney injury (>40% decline in eGFR or doubling of serum Cr) (2); Urgent intravenous treatment for high blood pressure/hypertensive crisis (2); >30% Increase in baseline high sensitivity troponin (1); >30% increase in baseline BNP (1); Increase in baseline CRP to 48 hours >30%(1); Lymphocyte count drop >30% (1). The primary endpoint will be assessed from baseline to day 7 (or day of discharge if occurs before day 7). Participants will receive a weighted score depending on the events experienced. The global rank sum score will then be averaged and compared between treatment arms. | Baseline - day 7 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Renin, Angiotensin, Aldosterone, coronavirus, Cardiovascular Diseases, COVID-19