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    Clinical Trial Results:
    Stopping ACE-inhibitors in COVID-19 - a randomized, controlled clinical trial

    Summary
    EudraCT number
    		 2020-001206-35
    Trial protocol
    		 AT   DE  
    Global end of trial date
    31 Dec 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Jan 2023
    First version publication date
    29 Jan 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ACEI-COVID-19
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04353596
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Medical University Innsbruck
    Sponsor organisation address
    Christoph-Probst-Platz 1, Innrain 52, Innsbruck, Austria, 6020
    Public contact
    Univ.-Prof. Dr. Axel Bauer, University Hospital for Internal Medicine III, Anichstrasse 35, 6020 Innsbruck, +43 51250425621, kks-regulatory@i-med.ac.at
    Scientific contact
    Univ.-Prof. Dr. Axel Bauer, University Hospital for Internal Medicine III, Anichstrasse 35, 6020 Innsbruck, +43 51250425621, kks-regulatory@i-med.ac.at
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    31 Dec 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Dec 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Dec 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Patients with coronary artery disease, arterial hypertension or diabetes are often treated with angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB). Treatment with ACEI and ARB may be of great relevance for the course of COVID-19: Similar to SARS-CoV (epidemic 2002-2003), the novel SARS-CoV2 is also absorbed into human cells via angiotensin converting enzyme 2 (ACE2). Treatment with ACEI and ARB leads to a significant upregulation of the SARS-CoV2 receptor ACE2. An increased expression of ACE2 in turn correlates with a higher intake of SARS-CoV2 and possibly promotes a faster spread of the virus in the organism of infected patients. The primary aim of the study is to test whether discontinuing chronic ACEI or ARB therapy in patients with proven SARS-CoV2 infection leads to a more favorable course of the disease of COVID-19 than the continuation of the ACEI or ARB therapy.
    Protection of trial subjects
    After randomisation, the treating physicians were asked to follow the respective treatment strategy. Treating physicians could stop or initiate ACEI or ARB therapy at any time for clinical indications. Participants discharged from hospital were contacted daily by telephone by the local study teams to obtain clinical and medical information.
    Background therapy
    		 Patients received treatment due to their medical history.
    Evidence for comparator
    		 Patients were randomly assigned 1:1 to discontinuation or continuation of RAS inhibition for 30 days.
    Actual start date of recruitment
    09 Apr 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 127
    Country: Number of subjects enrolled
    Germany: 89
    Worldwide total number of subjects
    216
    EEA total number of subjects
    216
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    50
    From 65 to 84 years
    148
    85 years and over
    18

    Subject disposition

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    Recruitment
    Recruitment details
    		 The Stopping ACE-inhibitors in Covid-19 (ACEI-COVID) trial was a prospective, parallel group, randomised, controlled, open-label study done at 35 centres, including 19 university clinics and 16 large referral hospitals, in Austria and Germany.

    Pre-assignment
    Screening details
    		 Eligible patients were aged 18 years or older, had had a recent symptomatic SARS-CoV-2 infection confirmed by a positive RT-PCR test result within the last 5 days and were on chronic treatment with ACEIs or ARBs for at least 1 month. Admission to hospital was no requirement for study inclusion.

    Period 1
    Period 1 title
    Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Discontinuation group
    Arm description
    		 Patients were randomly assigned to discontinuation of RAS inhibition for 30 days. If participants were randomly assigned to a discontinuation strategy, a substitution with an alternative substance class was at the discretion of the treating physician.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Continuation group
    Arm description
    		 Patients were randomly assigned to continuation of RAS inhibition for 30 days.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    ACE Inhibitor
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Depends on medical history of patient.

    Investigational medicinal product name
    Angiotensin II Rezeptor Blocker
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Depends on medical history of patient.

    Number of subjects in period 1
    		Discontinuation group Continuation group
    Started
    109
    107
    Completed
    74
    64
    Not completed
    35
    43
         Adverse event, serious fatal
    8
    12
         Consent withdrawn by subject
    6
    2
         No evidence of recent SARS-CoV-2 infection
    1
    3
         Did not complete follow-up
    15
    18
         Lost to follow-up
    1
    4
         Never received intervention per protocol
    4
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Discontinuation group
    Reporting group description
    		 Patients were randomly assigned to discontinuation of RAS inhibition for 30 days. If participants were randomly assigned to a discontinuation strategy, a substitution with an alternative substance class was at the discretion of the treating physician.

    Reporting group title
    Continuation group
    Reporting group description
    		 Patients were randomly assigned to continuation of RAS inhibition for 30 days.

    Reporting group values
    		 Discontinuation group Continuation group Total
    Number of subjects
    		 109 107 216
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 27 23 50
        From 65-84 years
    		 73 75 148
        85 years and over
    		 9 9 18
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 71.80 (38 to 93) 73.42 (51 to 93) -
    Gender categorical
    Units: Subjects
        Female
    		 41 39 80
        Male
    		 68 68 136

    End points

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    End points reporting groups
    Reporting group title
    Discontinuation group
    Reporting group description
    		 Patients were randomly assigned to discontinuation of RAS inhibition for 30 days. If participants were randomly assigned to a discontinuation strategy, a substitution with an alternative substance class was at the discretion of the treating physician.

    Reporting group title
    Continuation group
    Reporting group description
    		 Patients were randomly assigned to continuation of RAS inhibition for 30 days.

    Primary: Maximum median (IQR) SOFA score

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    End point title
    		 Maximum median (IQR) SOFA score
    End point description
    The primary outcome measure was the composite of the maximum sequential organ failure assessment (SOFA) score and death within 30 days.The score is calculated from six different components, each of which reflects the status of an organ system, including respiratory function, cardiovascular integrity, liver function, coagulation, renal function and neurological status. The score can range from 0 (best) to 24 (worst).
    End point type
    Primary
    End point timeframe
    20.04.20202-20.01.2021
    End point values
    		 Discontinuation group Continuation group
    Number of subjects analysed
    104
    100
    Units: number
        median (inter-quartile range (Q1-Q3))
    0.00 (0.00 to 2.00)
    0.00 (0.00 to 3.00)
    Statistical analysis title
    		 Maximum median (IQR) SOFA score
    Comparison groups
    Discontinuation group v Continuation group
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.12
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [1] - The primary endpoint of our study, the maximum median (IQR) SOFA score, did not significantly differ between treatment groups.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    20.04.2020-20.01.2021
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    5.0
    Reporting groups
    Reporting group title
    Intervention
    Reporting group description
    		 Patients were randomly assigned to discontinuation of RAS inhibition for 30 days. If participants were randomly assigned to a discontinuation strategy, a substitution with an alternative substance class was at the discretion of the treating physician.

    Reporting group title
    Control
    Reporting group description
    		 Patients were randomly assigned to continuation of RAS inhibition for 30 days.

    Serious adverse events
    		 Intervention Control
    Total subjects affected by serious adverse events
         subjects affected / exposed
    28 / 109 (25.69%)
    31 / 107 (28.97%)
         number of deaths (all causes)
    8
    12
         number of deaths resulting from adverse events
    0
    0
    General disorders and administration site conditions
    General deterioration
         subjects affected / exposed
    3 / 109 (2.75%)
    5 / 107 (4.67%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 8
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Respiratory, thoracic and mediastinal disorders
    Respiratory deterioration
         subjects affected / exposed
    14 / 109 (12.84%)
    10 / 107 (9.35%)
         occurrences causally related to treatment / all
    0 / 24
    0 / 24
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory exhaustion
         subjects affected / exposed
    1 / 109 (0.92%)
    4 / 107 (3.74%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 109 (0.00%)
    2 / 107 (1.87%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 109 (1.83%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Intervention Control
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    66 / 109 (60.55%)
    65 / 107 (60.75%)
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    66 / 109 (60.55%)
    65 / 107 (60.75%)
         occurrences all number
    131
    131
    Fever
         subjects affected / exposed
    42 / 109 (38.53%)
    39 / 107 (36.45%)
         occurrences all number
    81
    81
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    9 / 109 (8.26%)
    3 / 107 (2.80%)
         occurrences all number
    12
    12
    Diarrhoea
         subjects affected / exposed
    15 / 109 (13.76%)
    15 / 107 (14.02%)
         occurrences all number
    30
    30
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    38 / 109 (34.86%)
    43 / 107 (40.19%)
         occurrences all number
    81
    81
    Cough
         subjects affected / exposed
    53 / 109 (48.62%)
    54 / 107 (50.47%)
         occurrences all number
    107
    107
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    24 / 109 (22.02%)
    36 / 107 (33.64%)
         occurrences all number
    60
    60

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/34126053
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