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| Name | Class |
|---|---|
| Jordana B. Cohen, MD, MSCE | UNKNOWN |
| Hanff, Thomas C., M.D., MPH | INDIV |
| University of Arizona | OTHER |
| Hospital Nacional Carlos Alberto Seguin Escobedo - EsSalud |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Discontinuation arm | Experimental | The randomized intervention will be the discontinuation of ACEI/ARBs |
|
| Continuation arm | Experimental | The randomized intervention will be the continuation of ACEI/ARBs |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Discontinuation of ARB/ACEI | Other | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Up to 28 days |
| Measure | Description | Time Frame |
|---|---|---|
| All-Cause Death | Up to 28 days | |
| Length of Hospital Stay | This outcome measurement looked at the median length of hospitalization. | Up to 28 days |
| Measure | Description | Time Frame |
|---|---|---|
| Intensive Care Unit Admission or Respiratory Failure Requiring Mechanical Ventilation. | Need to be transferred to an intensive care unit or to supported by a breathing machine | Up to 28 days |
| Hypotension Requiring Vasopressors, Inotropes or Mechanical Hemodynamic Support |
Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Pennsylvania Health System | Philadelphia | Pennsylvania | 19104 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 32091533 | Background | Wu Z, McGoogan JM. Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention. JAMA. 2020 Apr 7;323(13):1239-1242. doi: 10.1001/jama.2020.2648. No abstract available. | |
| 32171076 | Background |
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| ID | Title | Description |
|---|---|---|
| FG000 | Discontinuation Arm | The randomized intervention will be the discontinuation of ACEI/ARBs 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. |
| FG001 | Continuation Arm | The randomized intervention will be the continuation of ACEI/ARBs 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). |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Discontinuation Arm | The randomized intervention will be the discontinuation of ACEI/ARBs 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Customized | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | Posted | Median | Inter-Quartile Range | score on a scale (range 1 to 152) | Up to 28 days |
|
until hospital discharge or up to 28 days if participant were discharged prior to this time point
The research team kept a log of all adverse events in the trial. A medically-qualified investigator assessed all AEs.
The definition of adverse events and Serious Adverse Events (SAE) is presented in detail in the study protocol, available in this clinicaltrials.gov record (protocol sections 5.2 and 5.3)
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Discontinuation Arm | The randomized intervention will be the discontinuation of ACEI/ARBs 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Delirium or encephalopathy | Investigations | Systematic Assessment |
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Limitations of the study include (1) small sample size; (2) we did not control participant ACEI or ARB dosing or other medication exposures during the trial; (3) Although outcome adjudicators were masked to the randomly assigned groups when determining clinical endpoints, providers caring for the patients were aware of the group the patient was assigned to. It is possible that the open-label nature of the study might have introduced information bias or influenced provider behavior.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Jordana Cohen | University of Pennsylvania | 215-662-4000 | jco@pennmedicine.upenn.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Apr 1, 2020 | Apr 2, 2021 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D000086382 | COVID-19 |
| ID | Term |
|---|---|
| D011024 | Pneumonia, Viral |
| D011014 | Pneumonia |
| D012141 | Respiratory Tract Infections |
| D007239 | Infections |
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| OTHER |
| Hospital Nacional Edgardo Rebagliati Martins | OTHER |
| Hospital Español de Mendoza | OTHER |
| Stanford University | OTHER |
| Ottawa Hospital Research Institute | OTHER |
| Hospital Civil de Guadalajara | OTHER |
| Universidad Catolica Argentina | OTHER |
| Caja Nacional de Salud | OTHER |
| Departamento de Medicina, Hospital Alberto Barton Thompson, Callao, Peru | OTHER |
| Karolinska Institutet | OTHER |
| University of Miami | OTHER |
| Division of Cardiology, Department of Medicine, Hospital Español, Buenos Aires, Argentina | OTHER |
| University of Michigan | OTHER |
| Jesse Chittams, MS | UNKNOWN |
| Duke University | OTHER |
| Vasquez, Charles R., M.D. | INDIV |
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|
| Continuation of ARB/ACEI | Other | 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). |
|
| Length of ICU Stay, Invasive Mechanical Ventilation or Extracorporeal Membrane Oxygenation | Up to 28 days |
| 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. | Up to 28 days |
Hypotension Requiring Vasopressors, inotropes or mechanical hemodynamic support (ventricular assist device or intra-aortic balloon pump). |
| Up to 28 days |
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| 33422263 | Derived | Cohen JB, Hanff TC, William P, Sweitzer N, Rosado-Santander NR, Medina C, Rodriguez-Mori JE, Renna N, Chang TI, Corrales-Medina V, Andrade-Villanueva JF, Barbagelata A, Cristodulo-Cortez R, Diaz-Cucho OA, Spaak J, Alfonso CE, Valdivia-Vega R, Villavicencio-Carranza M, Ayala-Garcia RJ, Castro-Callirgos CA, Gonzalez-Hernandez LA, Bernales-Salas EF, Coacalla-Guerra JC, Salinas-Herrera CD, Nicolosi L, Basconcel M, Byrd JB, Sharkoski T, Bendezu-Huasasquiche LE, Chittams J, Edmonston DL, Vasquez CR, Chirinos JA. Continuation versus discontinuation of renin-angiotensin system inhibitors in patients admitted to hospital with COVID-19: a prospective, randomised, open-label trial. Lancet Respir Med. 2021 Mar;9(3):275-284. doi: 10.1016/S2213-2600(20)30558-0. Epub 2021 Jan 7. |
| BG001 | Continuation Arm | The randomized intervention will be the continuation of ACEI/ARBs 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). |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Hypertension | Count of Participants | Participants |
|
| Diabetes | Count of Participants | Participants |
|
| Dyslipidemia | Count of Participants | Participants |
|
| Pre-existing cardiac disease | Count of Participants | Participants |
|
| Ischemic heart disease | Count of Participants | Participants |
|
| Heart Failure | Count of Participants | Participants |
|
| Atrial fibrillation | Count of Participants | Participants |
|
| Previous PE or DVT | PE: pulmonary embolism DVT: deep vein thrombosis | Count of Participants | Participants |
|
| Obstructive sleep apnea | Count of Participants | Participants |
|
| Chronic pulmonary disease | Count of Participants | Participants |
|
| Current Smoker | Count of Participants | Participants |
|
| Illicit drug use | Count of Participants | Participants |
|
| Dyspnoea | Count of Participants | Participants |
|
| Cough | Count of Participants | Participants |
|
| Multifocal infiltrates on chest x-ray or CT | Count of Participants | Participants |
|
| Oxygen saturation | Taken with pulse oximeter, usually affixed onto right index finger. Measures the amount of oxygen in a subject's blood. A higher percentage is preferred. | Mean | Standard Deviation | % of oxygen in blood |
|
| Oxygen supplementation | Refers to the number of subjects requiring supplemental oxygen (given to maintain adequate levels of blood oxygenation). | Number | number of subjects requiring extra O2 |
|
| Systolic BP | Mean | Standard Deviation | mmHg |
|
| Diastolic BP | Mean | Standard Deviation | mmHg |
|
| Heart rate | Mean | Standard Deviation | bpm |
|
| BMI | Mean | Standard Deviation | kg/m^2 |
|
| eGFR | Mean | Standard Deviation | mL/min/1.73m^2 |
|
| K Serum | K: potassium measured from subject's serum Normal levels range from 3.5-5.0 mmol/L | Mean | Standard Deviation | mmol/L |
|
| Leukocyte count | Mean | Standard Deviation | 10^9 cells/L |
|
| Platelets | Mean | Standard Deviation | 10^3 cells/microL |
|
| C reactive protein | Mean | Standard Deviation | mg/dL |
|
| Days from admission to randomization | Mean | Standard Deviation | days |
|
| Days from symptom onset to randomization | Mean | Standard Deviation | days |
|
| OG001 | Continuation Arm | The randomized intervention will be the continuation of ACEI/ARBs 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). |
|
|
| Secondary | All-Cause Death | Posted | Count of Participants | Participants | Up to 28 days |
|
|
|
| Secondary | Length of Hospital Stay | This outcome measurement looked at the median length of hospitalization. | Posted | Median | Inter-Quartile Range | days | Up to 28 days |
|
|
|
| Secondary | Length of ICU Stay, Invasive Mechanical Ventilation or Extracorporeal Membrane Oxygenation | Posted | Median | Inter-Quartile Range | days | Up to 28 days |
|
|
|
| Secondary | 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. | Posted | Median | Inter-Quartile Range | units on a scale (SOFA x days) | Up to 28 days |
|
|
|
| Other Pre-specified | Intensive Care Unit Admission or Respiratory Failure Requiring Mechanical Ventilation. | Need to be transferred to an intensive care unit or to supported by a breathing machine | Posted | Count of Participants | Participants | Up to 28 days |
|
|
|
| Other Pre-specified | Hypotension Requiring Vasopressors, Inotropes or Mechanical Hemodynamic Support | Hypotension Requiring Vasopressors, inotropes or mechanical hemodynamic support (ventricular assist device or intra-aortic balloon pump). | Posted | Count of Participants | Participants | Up to 28 days |
|
|
|
| 10 |
| 77 |
| 28 |
| 77 |
| 0 |
| 77 |
| EG001 | Continuation Arm | The randomized intervention will be the continuation of ACEI/ARBs 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). | 11 | 75 | 29 | 75 | 0 | 75 |
| New or worsening congestive heart failure | Cardiac disorders | Systematic Assessment |
|
| Myocarditis | Cardiac disorders | Systematic Assessment |
|
| Acute myocardial infarction | Cardiac disorders | Systematic Assessment |
|
| Pulmonary embolism or deep vein thrombosis | Vascular disorders | Systematic Assessment |
|
| Acute arrhythmia | Cardiac disorders | Systematic Assessment |
|
| Acute kidney injury, defined as >2-fold increase in creatinine | Renal and urinary disorders | Systematic Assessment |
|
| Acute kidney injury requiring renal replacement therapy | Renal and urinary disorders | Systematic Assessment |
|
| Hypotension requiring hemodynamic support | Vascular disorders | Systematic Assessment |
|
| Invasive mechanical ventilation | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Worsening dyspnoea or acute respiratory distress syndrome | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| ICU transfer | General disorders | Systematic Assessment |
|
| All-cause death | General disorders | Systematic Assessment |
|
Not provided
| D014777 |
| Virus Diseases |
| D018352 | Coronavirus Infections |
| D003333 | Coronaviridae Infections |
| D030341 | Nidovirales Infections |
| D012327 | RNA Virus Infections |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |