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

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ClinicalTrials.gov Identifier: NCT04338009
Recruitment Status : Enrolling by invitation
First Posted : April 8, 2020
Last Update Posted : April 24, 2020
Sponsor:
Collaborators:
Jordana B. Cohen, MD, MSCE
Thomas C. Hanff, MD, MPH
Vicente Corrales-Medina, MD, PhD
James Brian Byrd, MD
Roberto Viau Colindres
Information provided by (Responsible Party):
Julio A. Chirinos, University of Pennsylvania

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.

Condition or disease Intervention/treatment Phase
COVID-19 Other: Discontinuation of ARB/ACEI Other: Continuation of ARB/ACEI Not Applicable

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 152 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Treatment
Official Title: The Randomized Elimination or Prolongation of Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers in Coronavirus Disease 2019
Actual Study Start Date : March 31, 2020
Estimated Primary Completion Date : December 31, 2020
Estimated Study Completion Date : December 31, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Discontinuation arm
The randomized intervention will be the discontinuation of ACEI/ARBs
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.

Experimental: Continuation arm
The randomized intervention will be the continuation of ACEI/ARBs
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).




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. All-Cause Death [ Time Frame: Up to 28 days ]
  2. Length of Hospital Stay [ Time Frame: Up to 28 days ]
  3. Length of ICU Stay, invasive mechanical ventilation or extracorporeal membrane oxygenation [ Time Frame: Up to 28 days ]
  4. 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.


Other Outcome Measures:
  1. Intensive care unit admission or respiratory Failure Requiring Mechanical Ventilation. [ Time Frame: Up to 28 days ]
    Composite

  2. 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).

  3. 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.

  4. 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

  5. Change in serum creatinine between randomization and discharge (or time of death) [ Time Frame: Up to 28 days ]
    as above

  6. 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

  7. Proteinuria or Hematuria [ Time Frame: Up to 28 days ]
    Proteinuria or Hematuria detected on urinalysis



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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:

  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.

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): NCT04338009


Locations
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United States, Pennsylvania
University of Pennsylvania Health System
Philadelphia, Pennsylvania, United States, 19104
Sponsors and Collaborators
University of Pennsylvania
Jordana B. Cohen, MD, MSCE
Thomas C. Hanff, MD, MPH
Vicente Corrales-Medina, MD, PhD
James Brian Byrd, MD
Roberto Viau Colindres
Publications:
Forouzanfar MH, Liu P, Roth GA, Ng M, Biryukov S, Marczak L, Alexander L, Estep K, Hassen Abate K, Akinyemiju TF, Ali R, Alvis-Guzman N, Azzopardi P, Banerjee A, Bärnighausen T, Basu A, Bekele T, Bennett DA, Biadgilign S, Catalá-López F, Feigin VL, Fernandes JC, Fischer F, Gebru AA, Gona P, Gupta R, Hankey GJ, Jonas JB, Judd SE, Khang YH, Khosravi A, Kim YJ, Kimokoti RW, Kokubo Y, Kolte D, Lopez A, Lotufo PA, Malekzadeh R, Melaku YA, Mensah GA, Misganaw A, Mokdad AH, Moran AE, Nawaz H, Neal B, Ngalesoni FN, Ohkubo T, Pourmalek F, Rafay A, Rai RK, Rojas-Rueda D, Sampson UK, Santos IS, Sawhney M, Schutte AE, Sepanlou SG, Shifa GT, Shiue I, Tedla BA, Thrift AG, Tonelli M, Truelsen T, Tsilimparis N, Ukwaja KN, Uthman OA, Vasankari T, Venketasubramanian N, Vlassov VV, Vos T, Westerman R, Yan LL, Yano Y, Yonemoto N, Zaki ME, Murray CJ. Global Burden of Hypertension and Systolic Blood Pressure of at Least 110 to 115 mm Hg, 1990-2015. JAMA. 2017 Jan 10;317(2):165-182. doi: 10.1001/jama.2016.19043. Erratum in: JAMA. 2017 Feb 14;317(6):648.
Chow SC, Shao J, Wang H. Sample Size Calculations in Clinical Research. 2nd Edition ed. New York: Dekker; 2008.
PASS 16 Power Analysis and Sample Size Software. NCSS, LLC. Kaysville, Utah, USA, ncss.com/software/pass. 2018.
Therneau TM, Grambsch PM. Modeling Survival Data: Extending the Cox Model. In: Statistics for Biology and Health. New York, NY: Springer; 2001.
Little RJ. Modeling the drop-out mechanism in repeated-measures studies. Journal of the American Statistical Association. 1995;90:1112-1121.

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Responsible Party: Julio A. Chirinos, Associate Professor of Medicine at the Hospital of the University of Pennsylvania, University of Pennsylvania
ClinicalTrials.gov Identifier: NCT04338009    
Other Study ID Numbers: 842810
First Posted: April 8, 2020    Key Record Dates
Last Update Posted: April 24, 2020
Last Verified: April 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Not making it available

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Coronavirus Infections
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Virus Diseases
Angiotensin-Converting Enzyme Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action