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Elimination or Prolongation of ACE Inhibitors and ARB in Coronavirus Disease 2019 (REPLACECOVID)

Primary Purpose

COVID-19

Status
Completed
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Discontinuation of ARB/ACEI
Continuation of ARB/ACEI
Sponsored by
University of Pennsylvania
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for COVID-19

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Age 18 years or older
  2. Hospitalization with a suspected diagnosis of COVID-19, based on: (a) A compatible clinical presentation with a positive laboratory test for SARS-CoV-2, or (b) Considered by the primary team to be a Person Under Investigation due to undergo testing for COVID-19 in addition to compatible pulmonary infiltrates on chest x-ray (mutilobar, intersticial or ground glass opacities).
  3. Use of ACEI or ARB as an outpatient prior to hospital admission.

Exclusion Criteria:

  1. Systolic blood pressure <100 mmHg.
  2. Systolic blood pressure > 180 mmHg or >160 if unable to substitute ACEIs/ARBs for another antihypertensive class, per the investigator's discretion.
  3. Diastolic blood pressure > 110 mmHg
  4. Known history of heart failure with reduced ejection fraction (EF <40%) on their most recent echo and/or clinical heart failure with unknown EF (i.e. no echo in approximately the past year).
  5. Serum K>5.0 mEq/L on admission.
  6. Known pregnancy or breastfeeding.
  7. eGFR <30 mL/min/1.73m2
  8. >50% increase in creatinine (to a creatinine >1.5 mg/dl) compared to most recent creatinine in the past six months, if available
  9. Urine protein-to-creatitine ratio > 3 g/g or proteinuria > 3 g/24-hours within the past year
  10. Ongoing treatment with aliskiren or sacubitril-valsartan.
  11. Inability to obtain informed consent from patient.
  12. Inability to read and write or lack of access to a smart phone, computer or tablet device at the time of evaluation.

Sites / Locations

  • University of Pennsylvania Health System

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Discontinuation arm

Continuation arm

Arm Description

The randomized intervention will be the discontinuation of ACEI/ARBs

The randomized intervention will be the continuation of ACEI/ARBs

Outcomes

Primary Outcome Measures

Hierarchical Composite Endpoint
The primary endpoint of the trial will be a global rank based on patient outcomes according to four factors: (1) time to death, (2) the number of days supported by invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO), (3) the number of days supported by renal replacement therapy or pressor/inotropic therapy, and (4) a modified sequential Organ Failure Assessment (SOFA) score. The modified SOFA score will include the cardiac, respiratory, renal and coagulation domains of the SOFA score. How to interpret the rank?: patients are ranked from worst to best outcomes, such that patients with bad outcomes are ranked at the top and patients who have the best outcomes are ranked at the bottom.

Secondary Outcome Measures

All-Cause Death
Length of Hospital Stay
This outcome measurement looked at the median length of hospitalization.
Length of ICU Stay, Invasive Mechanical Ventilation or Extracorporeal Membrane Oxygenation
AUC SOFA
The Area Under the Curve of the modified SOFA (AUC SOFA) from daily measurements, weighted to account for the shorter observation period among patients who die in-hospital. How to interpret the AUC SOFA?: a higher area indicates more severe disease and/or longer hospitalization.The range is 0.1 to 377.3.

Full Information

First Posted
April 1, 2020
Last Updated
April 7, 2021
Sponsor
University of Pennsylvania
Collaborators
Jordana B. Cohen, MD, MSCE, Thomas C. Hanff, MD, MPH, University of Arizona, Department of Medicine, Hospital Nacional Carlos Alberto Seguín Escobedo, Arequipa, Peru, Department of Nephrology, Hospital Nacional Edgardo Rebagliati Martins, Lima, Peru, Hypertension Unit, Department of Pathology, Hospital Español de Mendoza, National University of Cuyo, IMBECU-CONICET, Mendoza, Argentina, Division of Nephrology, Stanford University School of Medicine, Stanford, CA, USA, Division of Infectious Diseases, University of Ottawa and The Ottawa Hospital Research Institute, Ottawa, ON, Canada, Unidad de VIH, Hospital Civil de Guadalajara and Universidad de Guadalajara, Guadalajara, Mexico, Universidad Católica de Buenos Aires, Buenos Aires, Argentina, Departamento de Medicina Interna, Hospital Obrero number 3 Caja Nacional de Salud, Santa Cruz de la Sierra, Bolivia, Departamento de Medicina, Hospital Alberto Barton Thompson, Callao, Peru, Department of Clinical Sciences, Danderyd University Hospital, Karolinska Institutet, Stockholm, Sweden, Division of Cardiology, University of Miami Miller School of Medicine, Miami, FL, USA, Departamento de Emergencia, Hospital Nacional Edgardo Rebagliati Martins, Lima, Peru, Division of Cardiology, Department of Medicine, Hospital Español, Buenos Aires, Argentina, Division of Cardiovascular Medicine, University of Michigan Medical School, Ann Arbor, MI, USA, Jesse Chittams, MS, Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC, USA, Charles R Vasquez, MD
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1. Study Identification

Unique Protocol Identification Number
NCT04338009
Brief Title
Elimination or Prolongation of ACE Inhibitors and ARB in Coronavirus Disease 2019
Acronym
REPLACECOVID
Official Title
The Randomized Elimination or Prolongation of Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers in Coronavirus Disease 2019
Study Type
Interventional

2. Study Status

Record Verification Date
April 2021
Overall Recruitment Status
Completed
Study Start Date
March 31, 2020 (Actual)
Primary Completion Date
August 20, 2020 (Actual)
Study Completion Date
August 20, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Pennsylvania
Collaborators
Jordana B. Cohen, MD, MSCE, Thomas C. Hanff, MD, MPH, University of Arizona, Department of Medicine, Hospital Nacional Carlos Alberto Seguín Escobedo, Arequipa, Peru, Department of Nephrology, Hospital Nacional Edgardo Rebagliati Martins, Lima, Peru, Hypertension Unit, Department of Pathology, Hospital Español de Mendoza, National University of Cuyo, IMBECU-CONICET, Mendoza, Argentina, Division of Nephrology, Stanford University School of Medicine, Stanford, CA, USA, Division of Infectious Diseases, University of Ottawa and The Ottawa Hospital Research Institute, Ottawa, ON, Canada, Unidad de VIH, Hospital Civil de Guadalajara and Universidad de Guadalajara, Guadalajara, Mexico, Universidad Católica de Buenos Aires, Buenos Aires, Argentina, Departamento de Medicina Interna, Hospital Obrero number 3 Caja Nacional de Salud, Santa Cruz de la Sierra, Bolivia, Departamento de Medicina, Hospital Alberto Barton Thompson, Callao, Peru, Department of Clinical Sciences, Danderyd University Hospital, Karolinska Institutet, Stockholm, Sweden, Division of Cardiology, University of Miami Miller School of Medicine, Miami, FL, USA, Departamento de Emergencia, Hospital Nacional Edgardo Rebagliati Martins, Lima, Peru, Division of Cardiology, Department of Medicine, Hospital Español, Buenos Aires, Argentina, Division of Cardiovascular Medicine, University of Michigan Medical School, Ann Arbor, MI, USA, Jesse Chittams, MS, Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC, USA, Charles R Vasquez, MD

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19), is associated with a high incidence of acute respiratory distress syndrome (ARDS) and death. Hypertension and cardiovascular disease are risk factors for death in COVID-19. Angiotensin converting enzyme 2 (ACE2), an important component of the renin-angiotensin system, serves as the binding site of SARS-CoV-2 and facilitates host cell entry in the lungs. In experimental models, angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have been shown to increase ACE2 expression in several organs, potentially promoting viral cell invasion, although these findings are not consistent across studies. Alternatively, ACEIs and ARBs may actually improve mechanisms of host defense or hyperinflammation, ultimately reducing organ injury. Finally, ACEIs and ARBs may have direct renal, pulmonary and cardiac protective benefits in the setting of COVID-19. Therefore, it is unclear if ACEIs and ARBs may be beneficial or harmful in patients with COVID-19. Given the high prevalence of hypertension, cardiovascular and renal disease in the world, the high prevalence of ACEIs or ARBs in these conditions, and the clinical equipoise regarding the continuation vs. discontinuation of ACEIs/ARBs in the setting of COVID, a randomized trial is urgently needed. The aim of this trial is to assess the clinical impact of continuation vs. discontinuation of ACE inhibitors and angiotensin receptor blockers on outcomes in patients hospitalized with COVID-19.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
COVID-19

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
Participant
Allocation
Randomized
Enrollment
152 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Discontinuation arm
Arm Type
Experimental
Arm Description
The randomized intervention will be the discontinuation of ACEI/ARBs
Arm Title
Continuation arm
Arm Type
Experimental
Arm Description
The randomized intervention will be the continuation of ACEI/ARBs
Intervention Type
Other
Intervention Name(s)
Discontinuation of ARB/ACEI
Intervention Description
The randomized intervention will be the discontinuation of ACEI/ARBs. In all participants randomized to discontinuation, treating clinicians will be reminded about the medication discontinuation upon discharge and will be prompted to consider re-initiation of the medication at that time if appropriate, per the clinician's discretion.
Intervention Type
Other
Intervention Name(s)
Continuation of ARB/ACEI
Intervention Description
The randomized intervention will be the continuation of ACEI/ARBs at the doses previously prescribed for patients during their routine care. Clinicians will be encouraged to continue the randomized treatment but will be allowed to change the dose of ACEI/ARB or discontinue these medications if any compelling clinical reasons are identified (such as hypotension, hyperkalemia, acute kidney injury).
Primary Outcome Measure Information:
Title
Hierarchical Composite Endpoint
Description
The primary endpoint of the trial will be a global rank based on patient outcomes according to four factors: (1) time to death, (2) the number of days supported by invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO), (3) the number of days supported by renal replacement therapy or pressor/inotropic therapy, and (4) a modified sequential Organ Failure Assessment (SOFA) score. The modified SOFA score will include the cardiac, respiratory, renal and coagulation domains of the SOFA score. How to interpret the rank?: patients are ranked from worst to best outcomes, such that patients with bad outcomes are ranked at the top and patients who have the best outcomes are ranked at the bottom.
Time Frame
Up to 28 days
Secondary Outcome Measure Information:
Title
All-Cause Death
Time Frame
Up to 28 days
Title
Length of Hospital Stay
Description
This outcome measurement looked at the median length of hospitalization.
Time Frame
Up to 28 days
Title
Length of ICU Stay, Invasive Mechanical Ventilation or Extracorporeal Membrane Oxygenation
Time Frame
Up to 28 days
Title
AUC SOFA
Description
The Area Under the Curve of the modified SOFA (AUC SOFA) from daily measurements, weighted to account for the shorter observation period among patients who die in-hospital. How to interpret the AUC SOFA?: a higher area indicates more severe disease and/or longer hospitalization.The range is 0.1 to 377.3.
Time Frame
Up to 28 days
Other Pre-specified Outcome Measures:
Title
Intensive Care Unit Admission or Respiratory Failure Requiring Mechanical Ventilation.
Description
Need to be transferred to an intensive care unit or to supported by a breathing machine
Time Frame
Up to 28 days
Title
Hypotension Requiring Vasopressors, Inotropes or Mechanical Hemodynamic Support
Description
Hypotension Requiring Vasopressors, inotropes or mechanical hemodynamic support (ventricular assist device or intra-aortic balloon pump).
Time Frame
Up to 28 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age 18 years or older Hospitalization with a suspected diagnosis of COVID-19, based on: (a) A compatible clinical presentation with a positive laboratory test for SARS-CoV-2, or (b) Considered by the primary team to be a Person Under Investigation due to undergo testing for COVID-19 in addition to compatible pulmonary infiltrates on chest x-ray (mutilobar, intersticial or ground glass opacities). Use of ACEI or ARB as an outpatient prior to hospital admission. Exclusion Criteria: Systolic blood pressure <100 mmHg. Systolic blood pressure > 180 mmHg or >160 if unable to substitute ACEIs/ARBs for another antihypertensive class, per the investigator's discretion. Diastolic blood pressure > 110 mmHg Known history of heart failure with reduced ejection fraction (EF <40%) on their most recent echo and/or clinical heart failure with unknown EF (i.e. no echo in approximately the past year). Serum K>5.0 mEq/L on admission. Known pregnancy or breastfeeding. eGFR <30 mL/min/1.73m2 >50% increase in creatinine (to a creatinine >1.5 mg/dl) compared to most recent creatinine in the past six months, if available Urine protein-to-creatitine ratio > 3 g/g or proteinuria > 3 g/24-hours within the past year Ongoing treatment with aliskiren or sacubitril-valsartan. Inability to obtain informed consent from patient. Inability to read and write or lack of access to a smart phone, computer or tablet device at the time of evaluation.
Facility Information:
Facility Name
University of Pennsylvania Health System
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
Not making it available
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Elimination or Prolongation of ACE Inhibitors and ARB in Coronavirus Disease 2019

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