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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04338009
Recruitment Status : Completed
First Posted : April 8, 2020
Results First Posted : April 9, 2021
Last Update Posted : April 9, 2021
Sponsor:
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
Information provided by (Responsible Party):
Julio A. Chirinos, University of Pennsylvania

Tracking Information
First Submitted Date  ICMJE April 1, 2020
First Posted Date  ICMJE April 8, 2020
Results First Submitted Date  ICMJE January 28, 2021
Results First Posted Date  ICMJE April 9, 2021
Last Update Posted Date April 9, 2021
Actual Study Start Date  ICMJE March 31, 2020
Actual Primary Completion Date August 20, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 7, 2021)
Hierarchical Composite Endpoint [ Time Frame: Up to 28 days ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: April 7, 2020)
Hierarchical Composite Endpoint [ Time Frame: Up to 28 days ]
The primary endpoint of the trial will be a global rank score that ranks 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.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 7, 2021)
  • All-Cause Death [ Time Frame: Up to 28 days ]
  • Length of Hospital Stay [ Time Frame: Up to 28 days ]
    This outcome measurement looked at the median length of hospitalization.
  • Length of ICU Stay, Invasive Mechanical Ventilation or Extracorporeal Membrane Oxygenation [ Time Frame: Up to 28 days ]
  • AUC SOFA [ Time Frame: Up to 28 days ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: April 7, 2020)
  • All-Cause Death [ Time Frame: Up to 28 days ]
  • Length of Hospital Stay [ Time Frame: Up to 28 days ]
  • Length of ICU Stay, Invasive Mechanical Ventilation or Extracorporeal Membrane Oxygenation [ Time Frame: Up to 28 days ]
  • AUC SOFA [ Time Frame: Up to 28 days ]
    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.
Current Other Pre-specified Outcome Measures
 (submitted: April 7, 2021)
  • Intensive Care Unit Admission or Respiratory Failure Requiring Mechanical Ventilation. [ Time Frame: Up to 28 days ]
    Need to be transferred to an intensive care unit or to supported by a breathing machine
  • Hypotension Requiring Vasopressors, Inotropes or Mechanical Hemodynamic Support [ Time Frame: Up to 28 days ]
    Hypotension Requiring Vasopressors, inotropes or mechanical hemodynamic support (ventricular assist device or intra-aortic balloon pump).
Original Other Pre-specified Outcome Measures
 (submitted: April 7, 2020)
  • Intensive Care Unit Admission or Respiratory Failure Requiring Mechanical Ventilation. [ Time Frame: Up to 28 days ]
    Composite
  • Hypotension Requiring Vasopressors, Inotropes or Mechanical Hemodynamic Support [ Time Frame: Up to 28 days ]
    Hypotension Requiring Vasopressors, inotropes or mechanical hemodynamic support (ventricular assist device or intra-aortic balloon pump).
  • Number of 28-Day Ventilator-Free Days. [ Time Frame: Up to 28 days ]
    Number of days in 28-day period feee of invasive or non-invasive mechanical ventilation.
  • Maximal change in NT-proBNP from baseline [ Time Frame: 28 days from enrollment ]
    Difference between NT-proBNP at the time of randomization and the maximum value
  • Change in serum creatinine between randomization and discharge (or time of death) [ Time Frame: Up to 28 days ]
    as above
  • Acute kidney injury during hospitalization [ Time Frame: Up to 28 days ]
    defined as Kidney Disease Improving Global Outcomes Stage 2 or higher or initiation of renal replacement therapy
  • Proteinuria or Hematuria [ Time Frame: Up to 28 days ]
    Proteinuria or Hematuria detected on urinalysis
 
Descriptive Information
Brief Title  ICMJE Elimination or Prolongation of ACE Inhibitors and ARB in Coronavirus Disease 2019
Official Title  ICMJE The Randomized Elimination or Prolongation of Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers in Coronavirus Disease 2019
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Treatment
Condition  ICMJE COVID-19
Intervention  ICMJE
  • Other: Discontinuation of ARB/ACEI
    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.
  • Other: Continuation of ARB/ACEI
    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).
Study Arms  ICMJE
  • Experimental: Discontinuation arm
    The randomized intervention will be the discontinuation of ACEI/ARBs
    Intervention: Other: Discontinuation of ARB/ACEI
  • Experimental: Continuation arm
    The randomized intervention will be the continuation of ACEI/ARBs
    Intervention: Other: Continuation of ARB/ACEI
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 7, 2020)
152
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE August 20, 2020
Actual Primary Completion Date August 20, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04338009
Other Study ID Numbers  ICMJE 842810
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description: Not making it available
Responsible Party Julio A. Chirinos, University of Pennsylvania
Study Sponsor  ICMJE University of Pennsylvania
Collaborators  ICMJE
  • 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
Investigators  ICMJE Not Provided
PRS Account University of Pennsylvania
Verification Date April 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP