Coronavirus (COVID-19) ACEi/ARB Investigation (CORONACION)

The CORONAvirus Disease 2019 Angiotensin Converting Enzyme Inhibitor/Angiotensin Receptor Blocker InvestigatiON (CORONACION) Randomized Clinical Trial

Coronavirus disease 2019 (COVID-19) is a pandemic infection caused by a virus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Because SARS-CoV-2 is known to require the angiotensin-converting enzyme 2 (ACE-2) receptor for uptake into the human body, there have been questions about whether medications that upregulate ACE-2 receptors might increase the risk of infection and subsequent complications. One such group of medications are anti-hypertensives that block the renin-angiotensin system, including both angiotensin converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB). Both ACEi and ARB are widely used for the treatment of hypertension. Early reports from China and Italy suggest that many of those who die from COVID-19 have a coexisting history of hypertension. Consequently, there have been questions raised as to whether these 2 types of blood pressure medication might increase the risk of death among patients with COVID-19. However, it is well known that the prevalence of hypertension increases linearly with age. Therefore, it is possible that the high prevalence of hypertension and ACEi/ARB use among persons who die from COVID-19 is simply confounded by age (older people are at risk of both a history of hypertension and dying from COVID-19). Whether these commonly prescribed blood pressure medications increase the risk of COVID-19 or not remains unanswered. Statements from professional cardiology societies on both sides of the Atlantic have called for urgent research into this question. Our study aims to randomize patients with primary (essential) hypertension who are already taking ACEi/ARB to either switch to an alternative BP medication or continue with the ACEi/ARB that they have already been prescribed. Adults with compelling indications for ACEi/ARB will not be enrolled.

Study Overview

• Status: Suspended
• Conditions: COVID-19; Hypertension
• Intervention / Treatment: Drug: Thiazide or Thiazide-like diuretics; Drug: Calcium Channel Blockers; Drug: ACE inhibitor; Drug: Angiotensin receptor blocker

• Study Type: Interventional
• Enrollment (Anticipated): 2414
• Phase: Phase 4

Contacts and Locations

Study Locations

• Ireland
  • Galway, Ireland, H91 YR71
    • University Hospital Galway

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 58 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Men and non-pregnant women aged 60 or over
• Known diagnosis of hypertension
• Current use of ACEi or ARB for the treatment of hypertension
• COVID-19 naïve (i.e. not known to be infected)
• English speaker

Exclusion Criteria:

• Known diabetic nephropathy
• Known heart failure with reduced ejection fraction
• Resistant hypertension (defined as blood pressure that remains above goal despite concurrent use of three anti-hypertensive agents of different classes, one of which should be a diuretic, or as blood pressure that is controlled with four or more medications)
• Contraindications or allergies to CCB or Thiazide
• Unconscious patients
• Current psychiatric in-patients
• Patients in an emergency medical setting
• Inability to consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Alternative anti-hypertensive medication; Switch to an alternative BP medication (specifically a Calcium channel blocker [CCB] or Thiazide/Thiazide-like diuretic at an equipotent blood pressure lowering dose). The choice of either CCB or Thiazide/Thiazide-like anti-hypertensive provided as alternative therapy will be at the discretion of the patient's treating physician.	Drug: Thiazide or Thiazide-like diuretics; Anti-hypertensive (Active Arm); Other Names: Hydrochlorothiazide, metolazone, chlorthalidone, chlorothiazide, bendroflumethiazide, indapamide; Drug: Calcium Channel Blockers; Anti-hypertensive (Active Arm); Other Names: Amlodipine, diltiazem, felodipine, nicardipine, nifedipine, nimodipine, nitrendipine, verapamil
Active Comparator: Continue ACEi/ARB antihypertensive; Continue with either the ACEi (Angiotensin Converting Enzyme Inhibitor) or the Angiotensin Receptor Blocker (ARB) that had already been prescribed for the treatment of hypertension.	Drug: ACE inhibitor; Anti-hypertensive (Control Arm); Other Names: Benazepril, captopril, enalapril, fosinopril, lisinopril, perindopril, quinapril, ramipril, trandolapril; Drug: Angiotensin receptor blocker; Anti-hypertensive (Control Arm); Other Names: Candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Covid-19 positive participants who die, require intubation in ICU, or require hospitalization for non-invasive ventilation (NIV)	Time from randomization to the first occurrence of any of the clinical events above	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Covid-19 positive participants who die	Time from randomization to the first occurrence of above	12 months
Number of Covid-19 positive participants who require intubation in intensive care unit (ICU)	Time from randomization to the first occurrence of above	12 months
Number of Covid-19 positive participants who require hospitalization for non-invasive ventilation (NIV)	Time from randomization to the first occurrence of above	12 months
Number of SARS-CoV-2 positive participants	Time from randomization to the first occurrence of above	12 months
Maximum troponin T value (ng/L) among Covid-19 positive participants who require acute hospitalization		12 months
24 hour mean systolic BP (mmHg) on ambulatory BP monitoring	Performed in a random sub-sample of the cohort (both study arms)	12 months
All-cause mortality	Time from randomization to the first occurrence of above	12 months

Collaborators and Investigators

• Sponsor: National University of Ireland, Galway, Ireland
• Investigators: Principal Investigator: John William McEvoy, MBBCh MHS, National University of Ireland, Galway, Ireland

Study record dates

Study Major Dates

• Study Start (Actual): April 30, 2020
• Primary Completion (Anticipated): July 31, 2021
• Study Completion (Anticipated): December 1, 2021

Study Registration Dates

• First Submitted: March 30, 2020
• First Submitted That Met QC Criteria: March 30, 2020
• First Posted (Actual): April 1, 2020

Study Record Updates

• Last Update Posted (Actual): June 30, 2020
• Last Update Submitted That Met QC Criteria: June 26, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Keywords: Cardiovascular Diseases; Hypertension; Coronavirus; COVID-19; Coronavirus Disease 2019; Blood Pressure; Diuretics; Novel Coronavirus; Intubation; Noninvasive Ventilation; Critical Care; Pandemic; Antihypertensive Agents; Renin-Angiotensin System; Angiotensin Receptor Antagonists; Calcium Channel Blockers; Angiotensin Converting Enzyme; Angiotensin Converting Enzyme 2; Angiotensin-Converting Enzyme Inhibitors; ACE-2
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Coronavirus Infections; Hypertension; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Vasodilator Agents; Enzyme Inhibitors; Protease Inhibitors; Protective Agents; Natriuretic Agents; Cardiotonic Agents; Membrane Transport Modulators; Calcium-Regulating Hormones and Agents; Reproductive Control Agents; Angiotensin II Type 1 Receptor Blockers; Tocolytic Agents; Sodium Chloride Symporter Inhibitors; Angiotensin II Type 2 Receptor Blockers; Amlodipine; Valsartan; Enalapril; Losartan; Olmesartan; Hydrochlorothiazide; Chlorthalidone; Nifedipine; Benazepril; Candesartan; Telmisartan; Diuretics; Verapamil; Trandolapril; Felodipine; Perindopril; Ramipril; Lisinopril; Captopril; Irbesartan; Diltiazem; Indapamide; Nicardipine; Bendroflumethiazide; Calcium Channel Blockers; Angiotensin-Converting Enzyme Inhibitors; Nimodipine; Nitrendipine; Angiotensin Receptor Antagonists; Eprosartan; Metolazone; Quinapril; Fosinopril; Chlorothiazide
• Other Study ID Numbers: C.A. 2348

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Sharing Time Frame: 12-24 months
• IPD Sharing Access Criteria: To be determined
• IPD Sharing Supporting Information Type: Study Protocol; Informed Consent Form (ICF); Clinical Study Report (CSR)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No