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Effects of Discontinuing Renin-angiotensin System Inhibitors in Patients With and Without COVID-19 (RASCOVID-19)

Primary Purpose

Covid-19

Status
Completed
Phase
Not Applicable
Locations
Denmark
Study Type
Interventional
Intervention
Discontinuation of ACEi/ARB
Continuation of ACEi/ARB
Sponsored by
University Hospital, Gentofte, Copenhagen
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Covid-19 focused on measuring COVID-19, RAS, Renin-angiotensin system, Angiotensin II receptor blocker, Angiotensin converting enzyme inhibitor, ARB, ACEi

Eligibility Criteria

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

Group A and B

Inclusion Criteria:

  1. Verified COVID-19
  2. Hospital admitted
  3. Daily administration of RAS-inhibiting therapy
  4. Age 18 years and above
  5. Informed consent

Exclusion Criteria:

  1. Diagnosed with systolic heart failure (heart failure with reduced ejection fraction)
  2. Severe kidney disease; defined by estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m2
  3. Severe hypertension; defined by systolic pressure >175 mm Hg and/or diastolic pressure >105 mm Hg
  4. Hypotension; defined by systolic pressure <100 mm Hg and/or diastolic pressure <60 mm Hg
  5. Non-compliance of RAS-inhibiting therapy; defined as an estimated adherence <80% assessed by a questionnaire in combination with checking the Danish electronic medication system "FMK" (obligatory for clinicians in Denmark to ensure the Danish electronic medication system "FMK" is correct and up-to-date) for redeemed prescriptions in the last six months; in borderline cases, the participant is assumed compatible
  6. Pregnancy or breastfeeding

  7. Contra indications for receiving ACE inhibitors or ARBs:

    1. Severe liver disease
    2. Hypersensitivity or allergic reactions to the therapy
    3. Angioneurotic edema during previous treatments
    4. Family history of or previous idiopathic angioneurotic edema
    5. Treatment with sacubitril/valsartan or aliskiren

Group C and D:

Inclusion Criteria:

  1. Daily administration of RAS-inhibiting therapy
  2. Age 18 years and above
  3. Informed consent

Exclusion Criteria:

  1. Diagnosed with systolic heart failure (heart failure with reduced ejection fraction)
  2. Severe kidney disease; defined by estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m2
  3. Severe hypertension; defined by systolic pressure >175 mm Hg and/or diastolic pressure >105 mm Hg
  4. Hypotension; defined by systolic pressure <100 mm Hg and/or diastolic pressure <60 mm Hg
  5. Non-compliance of RAS-inhibiting therapy; defined as an estimated adherence <80% assessed by a questionnaire in combination with checking the Danish electronic medication system "FMK" (obligatory for clinicians in Denmark to ensure the Danish electronic medication system "FMK" is correct and up-to-date) for redeemed prescriptions in the last six months; in borderline cases, the participant is assumed compatible
  6. Pregnancy or breastfeeding

  7. Contra indications for receiving ACE inhibitors or ARBs:

    1. Severe liver disease
    2. Hypersensitivity or allergic reactions to the therapy
    3. Angioneurotic edema during previous treatments
    4. Family history of or previous idiopathic angioneurotic edema
    5. Treatment with sacubitril/valsartan or aliskiren

Sites / Locations

  • Department of Medicine, Gentofte Hospital, University of Copenhagen
  • Department of Medicine, Herlev Hospital, University of Copenhagen

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

A: COVID+ Continuation

B: Covid+ Discontinuation

C: COVID% Continuation

D: COVID% DIscontinuation

Arm Description

The enrolled patients will continue their prescribed ACEi/ARB in the same dose. The clinicians will be encouraged to continue the medication throughout the hospital admission but it will be permissable for the clinician to stop treatment if necessary e.g. due to hypotension.

The enrolled patients will discontinue their prescribed ACEi/ARB. If hypertensive treatment is necessary during hospital admission the clinicians will first be encouraged to start non-ACEi/non-ARB treatment; however, if needed it will be possible to start ACEi/ARB again during hospital admission. After study completion (30 days from randomization) the patients will be reminded to seek their generel practitioner to reinitiate ACEi/ARB treatment.

The enrolled patients will continue their prescribed ACEi/ARB in the same dose.

The enrolled patients will discontinue their prescribed ACEi/ARB. If hypertensive treatment is necessary during the study period clinicians will first be encouraged to start non-ACEi/non-ARB treatment; however, if needed it will be possible to start ACEi/ARB again during the study period. After study completion (30 days from randomization) the patients will be reminded to seek their generel practitioner to reinitiate ACEi/ARB treatment.

Outcomes

Primary Outcome Measures

Days alive and out of hospital within 14 days after recruitment (group A vs. group B).
The primary endpoint is days alive and out of hospital within 14 days after recruitment on which a patient satisfies categories 0, 1 or 2 on the eight-category ordinal scale. WHO defined Ordinal Scale for Clinical Improvement: 0. Not hospitalized, no clinical or virological evidence of infection Not hospitalized, no limitations of activities Not hospitalized, limitation of activities Hospitalized, no oxygen therapy Hospitalized, oxygen by mask or nasal prongs Hospitalized, non-invasive ventilation or high-flow oxygen Hospitalized, intubation and mechanical ventilation Hospitalized, ventilation and additional organ support - pressors, rapid response team (RRT), extracorporeal membrane oxygenation (ECMO) Death

Secondary Outcome Measures

Key-secondary composite endpoint: Occurrence of worsening of COVID-19 (group A vs. group B)
The key-secondary composite endpoint is the occurrence of worsening of COVID-19 (group A vs. group B) as assessed by when a patient satisfies category 6, 7 or 8 on the ordinal scale within the trial period.
Occurrence and time to occurrence of each of the components of the key-secondary composite endpoint (group A vs. group B)
Occurrence and time to occurrence of each of the components of the key-secondary composite endpoint
Kidney function assessed by plasma creatinine (group A vs. group B)
Kidney function assessed by plasma creatinine
Duration of index hospitalisation (group A vs. group B)
Duration of index hospitalisation
30-day mortality (group A vs. group B)
30-day mortality
Number of days alive during the intervention period (group A vs. group B)
Number of days alive during the intervention period
Number of participants not yet discharged at day 30 (group A vs. group B)
Number of participants not yet discharged at day 30
Number of readmissions after 30 days. (group A vs. group B)
Number of readmissions after 30 days.
Kidney function as assessed by eGFR (group A vs. group B)
Kidney function as assessed by eGFR

Full Information

First Posted
April 14, 2020
Last Updated
January 17, 2023
Sponsor
University Hospital, Gentofte, Copenhagen
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1. Study Identification

Unique Protocol Identification Number
NCT04351581
Brief Title
Effects of Discontinuing Renin-angiotensin System Inhibitors in Patients With and Without COVID-19
Acronym
RASCOVID-19
Official Title
Effects of Discontinuing Renin-angiotensin System Inhibitors in Patients With and Without COVID-19
Study Type
Interventional

2. Study Status

Record Verification Date
January 2023
Overall Recruitment Status
Completed
Study Start Date
May 18, 2020 (Actual)
Primary Completion Date
December 22, 2022 (Actual)
Study Completion Date
December 22, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University Hospital, Gentofte, Copenhagen

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
Recent data from some of the earliest and worst affected countries of COVID-19 suggest a major overrepresentation of hypertension and diabetes among COVID-19-related deaths and among patients experiencing severe courses of the disease. The vast majority of patients with hypertension and/or diabetes are taking drugs targeting the renin-angiotensin system (RAS) because of their blood pressure-lowering and/or kidney-protective effects. Importantly, the virus causing COVID-19, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to the transmembrane protein angiotensin converting enzyme 2 (ACE2) - an important component of RAS - for host cell entry and subsequent viral replication. ACE2 is normally considered to be an enzyme that limits airway inflammation via effects in RAS and increased ACE2 activity seems to alleviate acute respiratory distress syndrome (ARDS). Importantly, evidence from human studies as well as rodent studies suggests that the inhibition of RAS by angiotensin converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB) leads to upregulation of ACE2, and treatment with ARB leads to attenuation of SARS-CoV-induced ARDS. This is of interest, as the vast majority of deaths from COVID-19 are due to ARDS and expression of ACE2 has previously been shown to be reduced by the binding of SARS-CoV to ACE2. Thus, ACE inhibitors and ARBs have been suggested to alleviate the COVID-19 pulmonary manifestations. In contrast to these notions, concern has been raised that ACE2 upregulation (by RAS-inhibiting drugs) will multiply the cellular access points for viral entry and might increase the risk of severe progression of COVID-19. The multiplied viral entry points could perhaps explain the alarmingly high morbidity and mortality among COVID-19 patients with diabetes and/or hypertension. Thus, a delineation of the role of RAS for the course of COVID-19 is of crucial importance for the management of COVID-19 patients. Aim: This randomised clinical trial will investigate whether to continue or discontinue treatment with ACE inhibitors or ARBs in hospitalised patients with COVID-19.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Covid-19
Keywords
COVID-19, RAS, Renin-angiotensin system, Angiotensin II receptor blocker, Angiotensin converting enzyme inhibitor, ARB, ACEi

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
Outcomes Assessor
Allocation
Randomized
Enrollment
78 (Actual)

8. Arms, Groups, and Interventions

Arm Title
A: COVID+ Continuation
Arm Type
Experimental
Arm Description
The enrolled patients will continue their prescribed ACEi/ARB in the same dose. The clinicians will be encouraged to continue the medication throughout the hospital admission but it will be permissable for the clinician to stop treatment if necessary e.g. due to hypotension.
Arm Title
B: Covid+ Discontinuation
Arm Type
Experimental
Arm Description
The enrolled patients will discontinue their prescribed ACEi/ARB. If hypertensive treatment is necessary during hospital admission the clinicians will first be encouraged to start non-ACEi/non-ARB treatment; however, if needed it will be possible to start ACEi/ARB again during hospital admission. After study completion (30 days from randomization) the patients will be reminded to seek their generel practitioner to reinitiate ACEi/ARB treatment.
Arm Title
C: COVID% Continuation
Arm Type
Experimental
Arm Description
The enrolled patients will continue their prescribed ACEi/ARB in the same dose.
Arm Title
D: COVID% DIscontinuation
Arm Type
Experimental
Arm Description
The enrolled patients will discontinue their prescribed ACEi/ARB. If hypertensive treatment is necessary during the study period clinicians will first be encouraged to start non-ACEi/non-ARB treatment; however, if needed it will be possible to start ACEi/ARB again during the study period. After study completion (30 days from randomization) the patients will be reminded to seek their generel practitioner to reinitiate ACEi/ARB treatment.
Intervention Type
Other
Intervention Name(s)
Discontinuation of ACEi/ARB
Intervention Description
Discontinuation of ACEi/ARB
Intervention Type
Other
Intervention Name(s)
Continuation of ACEi/ARB
Intervention Description
Continuation of ACEi/ARB
Primary Outcome Measure Information:
Title
Days alive and out of hospital within 14 days after recruitment (group A vs. group B).
Description
The primary endpoint is days alive and out of hospital within 14 days after recruitment on which a patient satisfies categories 0, 1 or 2 on the eight-category ordinal scale. WHO defined Ordinal Scale for Clinical Improvement: 0. Not hospitalized, no clinical or virological evidence of infection Not hospitalized, no limitations of activities Not hospitalized, limitation of activities Hospitalized, no oxygen therapy Hospitalized, oxygen by mask or nasal prongs Hospitalized, non-invasive ventilation or high-flow oxygen Hospitalized, intubation and mechanical ventilation Hospitalized, ventilation and additional organ support - pressors, rapid response team (RRT), extracorporeal membrane oxygenation (ECMO) Death
Time Frame
14 days
Secondary Outcome Measure Information:
Title
Key-secondary composite endpoint: Occurrence of worsening of COVID-19 (group A vs. group B)
Description
The key-secondary composite endpoint is the occurrence of worsening of COVID-19 (group A vs. group B) as assessed by when a patient satisfies category 6, 7 or 8 on the ordinal scale within the trial period.
Time Frame
30 days
Title
Occurrence and time to occurrence of each of the components of the key-secondary composite endpoint (group A vs. group B)
Description
Occurrence and time to occurrence of each of the components of the key-secondary composite endpoint
Time Frame
30 days
Title
Kidney function assessed by plasma creatinine (group A vs. group B)
Description
Kidney function assessed by plasma creatinine
Time Frame
30 days
Title
Duration of index hospitalisation (group A vs. group B)
Description
Duration of index hospitalisation
Time Frame
30 days
Title
30-day mortality (group A vs. group B)
Description
30-day mortality
Time Frame
30 days
Title
Number of days alive during the intervention period (group A vs. group B)
Description
Number of days alive during the intervention period
Time Frame
30 days
Title
Number of participants not yet discharged at day 30 (group A vs. group B)
Description
Number of participants not yet discharged at day 30
Time Frame
30 days
Title
Number of readmissions after 30 days. (group A vs. group B)
Description
Number of readmissions after 30 days.
Time Frame
30 days
Title
Kidney function as assessed by eGFR (group A vs. group B)
Description
Kidney function as assessed by eGFR
Time Frame
30 days
Other Pre-specified Outcome Measures:
Title
Support for clinical findings via relevant blood markers
Description
To support the clinical findings, blood samples will be analysed for ACE, ACE2, aldosterone, angiotensin II and renin, and expression of ACE, interferon signatures and T cell exhaustion markers.
Time Frame
30 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Group A and B Inclusion Criteria: Verified COVID-19 Hospital admitted Daily administration of RAS-inhibiting therapy Age 18 years and above Informed consent Exclusion Criteria: Diagnosed with systolic heart failure (heart failure with reduced ejection fraction) Severe kidney disease; defined by estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m2 Severe hypertension; defined by systolic pressure >175 mm Hg and/or diastolic pressure >105 mm Hg Hypotension; defined by systolic pressure <100 mm Hg and/or diastolic pressure <60 mm Hg Non-compliance of RAS-inhibiting therapy; defined as an estimated adherence <80% assessed by a questionnaire in combination with checking the Danish electronic medication system "FMK" (obligatory for clinicians in Denmark to ensure the Danish electronic medication system "FMK" is correct and up-to-date) for redeemed prescriptions in the last six months; in borderline cases, the participant is assumed compatible Pregnancy or breastfeeding Contra indications for receiving ACE inhibitors or ARBs: Severe liver disease Hypersensitivity or allergic reactions to the therapy Angioneurotic edema during previous treatments Family history of or previous idiopathic angioneurotic edema Treatment with sacubitril/valsartan or aliskiren Group C and D: Inclusion Criteria: Daily administration of RAS-inhibiting therapy Age 18 years and above Informed consent Exclusion Criteria: Diagnosed with systolic heart failure (heart failure with reduced ejection fraction) Severe kidney disease; defined by estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m2 Severe hypertension; defined by systolic pressure >175 mm Hg and/or diastolic pressure >105 mm Hg Hypotension; defined by systolic pressure <100 mm Hg and/or diastolic pressure <60 mm Hg Non-compliance of RAS-inhibiting therapy; defined as an estimated adherence <80% assessed by a questionnaire in combination with checking the Danish electronic medication system "FMK" (obligatory for clinicians in Denmark to ensure the Danish electronic medication system "FMK" is correct and up-to-date) for redeemed prescriptions in the last six months; in borderline cases, the participant is assumed compatible Pregnancy or breastfeeding Contra indications for receiving ACE inhibitors or ARBs: Severe liver disease Hypersensitivity or allergic reactions to the therapy Angioneurotic edema during previous treatments Family history of or previous idiopathic angioneurotic edema Treatment with sacubitril/valsartan or aliskiren
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Filip K Knop, MD, PhD
Organizational Affiliation
Center for Clinical Metabolic Research, Gentofte Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Department of Medicine, Gentofte Hospital, University of Copenhagen
City
Hellerup
State/Province
Capital Region Of Denmark
ZIP/Postal Code
2900
Country
Denmark
Facility Name
Department of Medicine, Herlev Hospital, University of Copenhagen
City
Herlev
State/Province
Capital Region Of Denmark
ZIP/Postal Code
2730
Country
Denmark

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
32125455
Citation
Zhang H, Penninger JM, Li Y, Zhong N, Slutsky AS. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Med. 2020 Apr;46(4):586-590. doi: 10.1007/s00134-020-05985-9. Epub 2020 Mar 3. No abstract available.
Results Reference
background
PubMed Identifier
16001071
Citation
Imai Y, Kuba K, Rao S, Huan Y, Guo F, Guan B, Yang P, Sarao R, Wada T, Leong-Poi H, Crackower MA, Fukamizu A, Hui CC, Hein L, Uhlig S, Slutsky AS, Jiang C, Penninger JM. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature. 2005 Jul 7;436(7047):112-6. doi: 10.1038/nature03712.
Results Reference
background
PubMed Identifier
24842388
Citation
Furuhashi M, Moniwa N, Mita T, Fuseya T, Ishimura S, Ohno K, Shibata S, Tanaka M, Watanabe Y, Akasaka H, Ohnishi H, Yoshida H, Takizawa H, Saitoh S, Ura N, Shimamoto K, Miura T. Urinary angiotensin-converting enzyme 2 in hypertensive patients may be increased by olmesartan, an angiotensin II receptor blocker. Am J Hypertens. 2015 Jan;28(1):15-21. doi: 10.1093/ajh/hpu086. Epub 2014 May 18.
Results Reference
background
PubMed Identifier
25534429
Citation
Vuille-dit-Bille RN, Camargo SM, Emmenegger L, Sasse T, Kummer E, Jando J, Hamie QM, Meier CF, Hunziker S, Forras-Kaufmann Z, Kuyumcu S, Fox M, Schwizer W, Fried M, Lindenmeyer M, Gotze O, Verrey F. Human intestine luminal ACE2 and amino acid transporter expression increased by ACE-inhibitors. Amino Acids. 2015 Apr;47(4):693-705. doi: 10.1007/s00726-014-1889-6. Epub 2014 Dec 23.
Results Reference
background

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Effects of Discontinuing Renin-angiotensin System Inhibitors in Patients With and Without COVID-19

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