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    Clinical Trial Results:
    Amantadine for COVID-19: A randomized, placebo controlled, double-blinded, clinical trial

    Summary
    EudraCT number
    2021-001177-22
    Trial protocol
    DK  
    Global end of trial date
    28 Apr 2022

    Results information
    Results version number
    v1(current)
    This version publication date
    25 Apr 2024
    First version publication date
    25 Apr 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    02032021
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Department of Biomedical Sciences, Lab. for Molecular Pharmacology University of Copenhagen
    Sponsor organisation address
    Blegdamsvej 3B, Copenhagen, Denmark, 2200
    Public contact
    Department of Infectious diseases, Copenhagen University Hospital, Hvidovre, +45 38623514, Nina.Weis@regionh.dk
    Scientific contact
    Department of Infectious diseases, Copenhagen University Hospital, Hvidovre, +45 38623514, Nina.Weis@regionh.dk
    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
    01 Feb 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Apr 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Apr 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The aim of the study is to investigate if early preemptive therapy with amantadine in non-hospitalized high-risk individuals with symptomatic COVID-19 disease can prevent disease progression.
    Protection of trial subjects
    Amantadine is an approved therapy with a well-defined risk profile and has been used in clinical praxis for years. In this trial, amantadine was given for a short period of time (5 days). Consequently, the treatment was considered safe. Persons with a known increased risk of adverse reactions to the drug due to allergy, disease, or medications were excluded from the study. Unblinding could happen at any point if necessary, to ensure the health of the study participant. An interim analysis was performed to ensure a continuous evaluation of the outcome and safety of the study. This included identifying factors that could be considered harmful to the study participant and, as such, make the continuation of the study unethical. The personal data was stored in a secure web application for managing online databases REDCap designed for non-commercial clinical research. Only personnel associated with the research project (sponsor, investigators, sub-investigators, and research personnel) had encoded access to the eCRFs via personal user ID and password.
    Background therapy
    None
    Evidence for comparator
    -
    Actual start date of recruitment
    09 Jun 2021
    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
    Denmark: 242
    Worldwide total number of subjects
    242
    EEA total number of subjects
    242
    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)
    215
    From 65 to 84 years
    27
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Information on potential study participants with a positive SARS-CoV-2 test was disclosed by the medical doctors at the Departments of Microbiology in the Capital Region and Region Zealand and Statens Serum Institut to the study investigators for the purpose of recruitment. Potential study participants received an invitation letter.

    Pre-assignment
    Screening details
    Basic screening was performed by a phone interview. Potential participants were asked about pregnancy, medication, comorbidity and if relevant body weight.

    Period 1
    Period 1 title
    Baseline (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    Unblinded personnel at the regional pharmacy used Sealed Envelope for patient randomization into one of two arms (ratio 1:1). The randomization list was be generated centrally in random blocks. Blinded personnel did not have access to the randomization key. Pharmacy staff delivered sealed envelopes containing treatment allocation to blinded study personnel to use for emergency unblinding. All investigators, outcome assessors, and study participants were blinded to the treatment allocation.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    -
    Arm type
    Placebo

    Investigational medicinal product name
    Lactose monohydrate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Enteral use
    Dosage and administration details
    1 capsule twice daily for 5 days

    Arm title
    Amantadine
    Arm description
    -
    Arm type
    Active comparator

    Investigational medicinal product name
    Amantadine
    Investigational medicinal product code
    N04BB
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Enteral use
    Dosage and administration details
    100mg twice daily for five days

    Number of subjects in period 1
    Placebo Amantadine
    Started
    121
    121
    Completed
    121
    121

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    -

    Reporting group title
    Amantadine
    Reporting group description
    -

    Reporting group values
    Placebo Amantadine Total
    Number of subjects
    121 121 242
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    50.5 (43.5 to 56.9) 50.9 (45.1 to 58.3) -
    Gender categorical
    Units: Subjects
        Female
    57 53 110
        Male
    62 63 125
        Missing
    2 5 7
    Subject analysis sets

    Subject analysis set title
    Final analysis
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Final analysis

    Subject analysis sets values
    Final analysis
    Number of subjects
    242
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    51 (45 to 58)
    Gender categorical
    Units: Subjects
        Female
    110
        Male
    125
        Missing
    7

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    -

    Reporting group title
    Amantadine
    Reporting group description
    -

    Subject analysis set title
    Final analysis
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Final analysis

    Primary: Clinical status day 14

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    End point title
    Clinical status day 14
    End point description
    The primary outcome was 14th-day symptom status severity. The primary endpoint was assessed on an ordinal scale (levels I-VIII) with a proportional odds model.
    End point type
    Primary
    End point timeframe
    14 days
    End point values
    Placebo Amantadine Final analysis
    Number of subjects analysed
    121
    121
    242
    Units: 242
        No limitations to activities
    94
    82
    176
        Limitations to activities
    25
    37
    62
        Hospitalized no oxygen therapy
    0
    0
    0
        Oxygen by mask or nasal prongs
    0
    0
    0
        Non-invasive ventilation or high flow oxygen
    0
    0
    0
        Intubation and mechanical ventilation
    0
    0
    0
        Ventilation + additional organ support -pressors,
    0
    0
    0
        Death
    0
    0
    0
    Statistical analysis title
    proportional odds model
    Statistical analysis description
    proportional odds model adjusting for age, sex, CCI and vaccination.
    Comparison groups
    Placebo v Amantadine
    Number of subjects included in analysis
    242
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.051
    Method
    proportional odds model
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1
         upper limit
    3.3

    Secondary: Searous adverse Events

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    End point title
    Searous adverse Events
    End point description
    Median number of serous adverse events within 90 days of randomization.
    End point type
    Secondary
    End point timeframe
    90 days
    End point values
    Placebo Amantadine Final analysis
    Number of subjects analysed
    121
    121
    121
    Units: 1000
        median (inter-quartile range (Q1-Q3))
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
    No statistical analyses for this end point

    Secondary: Hospitalization

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    End point title
    Hospitalization
    End point description
    Number of hospitalizations within 90 days.
    End point type
    Secondary
    End point timeframe
    90 days
    End point values
    Placebo Amantadine Final analysis
    Number of subjects analysed
    121
    121
    242
    Units: Events
    3
    5
    8
    No statistical analyses for this end point

    Secondary: Mortality

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    End point title
    Mortality
    End point description
    Number of deaths within 90 days of randomization.
    End point type
    Secondary
    End point timeframe
    90 days
    End point values
    Placebo Amantadine Final analysis
    Number of subjects analysed
    121
    121
    242
    Units: Events
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Within 90 days of randomization.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    No dictionary used
    Dictionary version
    1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    -

    Reporting group title
    Amantadine
    Reporting group description
    -

    Serious adverse events
    Placebo Amantadine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 121 (2.48%)
    5 / 121 (4.13%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    General disorders and administration site conditions
    Headache
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory distress
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 121 (0.83%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    kidney stone
         subjects affected / exposed
    1 / 121 (0.83%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Adjustment disorder with anxiety
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Hip arthroplasty
    Additional description: Planned
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Placebo Amantadine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    115 / 121 (95.04%)
    120 / 121 (99.17%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Benign tumor
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 121 (0.83%)
         occurrences all number
    0
    1
    Cardiac disorders
    Chest pain
         subjects affected / exposed
    3 / 121 (2.48%)
    4 / 121 (3.31%)
         occurrences all number
    3
    6
    Palpitations
         subjects affected / exposed
    1 / 121 (0.83%)
    2 / 121 (1.65%)
         occurrences all number
    1
    3
    Nervous system disorders
    loss of sense of smell
         subjects affected / exposed
    67 / 121 (55.37%)
    72 / 121 (59.50%)
         occurrences all number
    72
    75
    No sense of taste
         subjects affected / exposed
    62 / 121 (51.24%)
    68 / 121 (56.20%)
         occurrences all number
    63
    70
    General disorders and administration site conditions
    general discomfort
         subjects affected / exposed
    40 / 121 (33.06%)
    54 / 121 (44.63%)
         occurrences all number
    46
    63
    Fever
         subjects affected / exposed
    34 / 121 (28.10%)
    34 / 121 (28.10%)
         occurrences all number
    37
    37
    Sore throat
         subjects affected / exposed
    58 / 121 (47.93%)
    60 / 121 (49.59%)
         occurrences all number
    63
    70
    Headache
         subjects affected / exposed
    86 / 121 (71.07%)
    93 / 121 (76.86%)
         occurrences all number
    90
    99
    Runny nose
         subjects affected / exposed
    16 / 121 (13.22%)
    19 / 121 (15.70%)
         occurrences all number
    16
    19
    Sleeplessness
         subjects affected / exposed
    2 / 121 (1.65%)
    3 / 121 (2.48%)
         occurrences all number
    2
    3
    Fatigue
         subjects affected / exposed
    95 / 121 (78.51%)
    107 / 121 (88.43%)
         occurrences all number
    107
    125
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    5 / 121 (4.13%)
    9 / 121 (7.44%)
         occurrences all number
    6
    10
    Eye disorders
    Blurred vision
         subjects affected / exposed
    8 / 121 (6.61%)
    15 / 121 (12.40%)
         occurrences all number
    8
    17
    Red eyes
         subjects affected / exposed
    4 / 121 (3.31%)
    6 / 121 (4.96%)
         occurrences all number
    4
    6
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    40 / 121 (33.06%)
    29 / 121 (23.97%)
         occurrences all number
    44
    33
    Nausea
         subjects affected / exposed
    57 / 121 (47.11%)
    68 / 121 (56.20%)
         occurrences all number
    86
    94
    Stomach pain
         subjects affected / exposed
    25 / 121 (20.66%)
    27 / 121 (22.31%)
         occurrences all number
    27
    29
    Dry mouth
         subjects affected / exposed
    4 / 121 (3.31%)
    4 / 121 (3.31%)
         occurrences all number
    4
    4
    Reproductive system and breast disorders
    vaginal bleeding
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 121 (0.00%)
         occurrences all number
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    100 / 121 (82.64%)
    101 / 121 (83.47%)
         occurrences all number
    107
    101
    Laboured breathing
         subjects affected / exposed
    45 / 121 (37.19%)
    43 / 121 (35.54%)
         occurrences all number
    47
    46
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    11 / 121 (9.09%)
    16 / 121 (13.22%)
         occurrences all number
    11
    18
    Itch
         subjects affected / exposed
    22 / 121 (18.18%)
    16 / 121 (13.22%)
         occurrences all number
    23
    17
    Edema
         subjects affected / exposed
    8 / 121 (6.61%)
    8 / 121 (6.61%)
         occurrences all number
    10
    9
    Psychiatric disorders
    Mental disorder
    Additional description: Nervousness, anxiety, lack of concentration
         subjects affected / exposed
    39 / 121 (32.23%)
    46 / 121 (38.02%)
         occurrences all number
    66
    81
    Musculoskeletal and connective tissue disorders
    Muscle pain
         subjects affected / exposed
    53 / 121 (43.80%)
    60 / 121 (49.59%)
         occurrences all number
    63
    69

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Jul 2021
    Inclusion criteria changed from Population at risk of developing severe COVID-19, defined as either: ○ Age ≥ 50 years ○ Age ≥ 18 years and at least one of the following comorbidities: Chronic heart disease without heart failure or proarrhythmic conditions or ventricular arrythmias, diabetes, chronic lung disease, hypertension, chronic kidney disease GFR<60 ml/minute, BMI ≥30 kg/m2. To Population at risk of developing severe COVID-19, defined as either: ○ Age ≥ 40 years ○ Age ≥ 18 years and at least one of the following comorbidities: Chronic heart disease without heart failure or proarrhythmic conditions or ventricular arrythmias, diabetes, chronic lung disease, hypertension, chronic kidney disease GFR<60 ml/minute, BMI ≥30 kg/m2.

    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
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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