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    Clinical Trial Results:
    Trial of beta blocker therapy (atenolol) vs. angiotensin II receptor blocker therapy (losartan) in individuals with Marfan syndrome

    Summary
    EudraCT number
    2006-003991-37
    Trial protocol
    BE  
    Global end of trial date
    13 Feb 2013

    Results information
    Results version number
    v1(current)
    This version publication date
    15 Aug 2021
    First version publication date
    15 Aug 2021
    Other versions
    Summary report(s)
    Statement

    Trial information

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    Trial identification
    Sponsor protocol code
    AGO/2006/009
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00429364
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    New England Research Institutes
    Sponsor organisation address
    480 Pleasant, St, Watertown, MA 02472, United States,
    Public contact
    HIRUZ CTU, Ghent University Hospital, HIRUZ CTU, Ghent University Hospital, +32 93320500, hiruz.ctu@uzgent.be
    Scientific contact
    HIRUZ CTU, Ghent University Hospital, HIRUZ CTU, Ghent University Hospital, +32 93320500, hiruz.ctu@uzgent.be
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    27 Feb 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Feb 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the effect of beta blockers therapy to that of angiotension II receptor blocker therapy on the rates of aortic growth and progression of aortic regurgitation.
    Protection of trial subjects
    ethics review and approval, informed consent, supportive care and routine monitoring
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    31 Jan 2007
    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
    Belgium: 37
    Country: Number of subjects enrolled
    United States: 571
    Worldwide total number of subjects
    608
    EEA total number of subjects
    37
    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)
    608
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    All children and young adults (6 months to 25 years old) diagnosed with Marfan Syndrome, according to Ghent criteria and aortic root Z-score greater than 3.0

    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Single blind
    Roles blinded
    Assessor [1]

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    atenolol
    Arm description
    Participants with Marfan’s syndrome and ≥3 maximum aortic root z-score received 0.5 - 4.0 mg/kg/day Atenolol (not to exceed a total dose of 250 mg), with a goal of a 20% or greater decrease in the mean heart rate.
    Arm type
    Experimental

    Investigational medicinal product name
    atenolol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for oral suspension, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    commercially available atenolol tablets, 25mg, 50mg and 100mg will be used in this trial. The 25mg tablet will be cut in half to provide 12.5mg doses. For young children and older patients who cannot or prefer not to take tablets, a 2mg/mL suspension will be used.

    Arm title
    Losartan
    Arm description
    Participants with Marfan’s syndrome and ≥3 maximum aortic root z-score received 0.4 - 1.4 mg/kg/day Losartan (not to exceed a total dose of 100 mg).
    Arm type
    Experimental

    Investigational medicinal product name
    losartan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Clinical images (unmarked, plain white versions) of COZAAR (losartan Potassium Tablets), 12.5 mg, 25 mg and 50mg will be used in this trial. For young children and older patients who cannot or prefer not to take tablets, a 2.5 mg /mL suspension will be used.

    Notes
    [1] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: It will not be possible to mask all of the subjects or their care providers to the study drug assignment. Valid treatment comparisons can be made without masking, as long as care is taken to avoid treatment-related biases in outcome assessment. This will be achieved because the physicians at the echocardiography core laboratory evaluating the primary end point and many secondary end points will be masked to treatment assignment. In addition, every effort will be made to prevent the study subject
    Number of subjects in period 1
    atenolol Losartan
    Started
    303
    305
    Completed
    303
    305

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    atenolol
    Reporting group description
    Participants with Marfan’s syndrome and ≥3 maximum aortic root z-score received 0.5 - 4.0 mg/kg/day Atenolol (not to exceed a total dose of 250 mg), with a goal of a 20% or greater decrease in the mean heart rate.

    Reporting group title
    Losartan
    Reporting group description
    Participants with Marfan’s syndrome and ≥3 maximum aortic root z-score received 0.4 - 1.4 mg/kg/day Losartan (not to exceed a total dose of 100 mg).

    Reporting group values
    atenolol Losartan Total
    Number of subjects
    303 305 608
    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
        arithmetic mean (standard deviation)
    11.5 ± 6.5 11.0 ± 6.2 -
    Gender categorical
    Units: Subjects
        Female
    123 119 242
        Male
    180 186 366
    Race/ethnicity
    Units: Subjects
        white
    266 260 526
        black
    21 25 46
        asian
    6 10 16
        other
    10 10 20
    Presence of causal FBN1 mutation
    Units: Subjects
        yes
    93 88 181
        no
    9 15 24
        unknown
    201 202 403
    Family history of Marfan
    Units: Subjects
        yes
    180 181 361
        no
    115 109 224
        unknown
    8 15 23
    Maximum aortic-root diameter z-score
    Data are based on readings at a central echocardiographic laboratory. Echocardiographic data were missing for one participant in the losartan group because of an unreadable echocardiogram
    Units: Subjects
        ≥z-score of 4.5
    106 114 220
        <z-score of 4.5
    197 191 388
    Had medical history of cardiac surgery
    Units: Subjects
        yes
    6 6 12
        no
    297 299 596
    Had medical history of cardiovascular disorder
    Cardiovascular disorder was defined by exercise intolerance, syncope; arrhythmia, hypertension, or hypotension requiring therapy; chest pain, shortness of breath; or other cardiovascular conditions.
    Units: Subjects
        yes
    39 36 75
        no
    264 269 533
    Prior use of beta-blocker
    Units: Subjects
        yes
    173 171 344
        no
    130 134 264
    Had medical history of endocrine disorder
    Endocrine disorder was defined by either the use of hormone therapy to limit growth, delayed puberty.
    Units: Subjects
        yes
    7 0 7
        no
    296 305 601
    Had medical history of neurodevelopmental disorder
    Neurodevelopmental disorder was defined as attention deficit-hyperactivity disorder requiring therapy, developmental delay requiring therapy, learning disability requiring services, or other neurodevelopmental conditions.
    Units: Subjects
        yes
    56 61 117
        no
    247 244 491
    Had medical history of psychiatric disorder
    Psychiatric disorder was defined as depression requiring therapy, anxiety, or other psychiatric conditions.
    Units: Subjects
        yes
    23 16 39
        no
    280 289 569
    Maximum aortic-root diameter
    Data are based on readings at a central echocardiographic laboratory. Echocardiographic data were missing for one participant in the losartan group because of an unreadable echocardiogram.
    Units: cm
        arithmetic mean (standard deviation)
    3.4 ± 0.7 3.4 ± 0.7 -
    Maximum aortic-root diameter z-score
    Data are based on readings at a central echocardiographic laboratory. Echocardiographic data were missing for one participant in the losartan group because of an unreadable echocardiogram.
    Units: Z-score
        median (inter-quartile range (Q1-Q3))
    4.0 (3.5 to 4.8) 4.0 (3.3 to 5.0) -

    End points

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    End points reporting groups
    Reporting group title
    atenolol
    Reporting group description
    Participants with Marfan’s syndrome and ≥3 maximum aortic root z-score received 0.5 - 4.0 mg/kg/day Atenolol (not to exceed a total dose of 250 mg), with a goal of a 20% or greater decrease in the mean heart rate.

    Reporting group title
    Losartan
    Reporting group description
    Participants with Marfan’s syndrome and ≥3 maximum aortic root z-score received 0.4 - 1.4 mg/kg/day Losartan (not to exceed a total dose of 100 mg).

    Primary: Annual Rate of Change in Aortic Root (Sinuses of Valsalva) Body-surface-area-adjusted Z-score

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    End point title
    Annual Rate of Change in Aortic Root (Sinuses of Valsalva) Body-surface-area-adjusted Z-score
    End point description
    The rate of aortic root enlargement, expressed as the annual change in the maximum aortic-root-diameter z score indexed to body-surface area over a 3-year period following randomization
    End point type
    Primary
    End point timeframe
    Up to 3 years following randomization.
    End point values
    atenolol Losartan
    Number of subjects analysed
    303
    305
    Units: z-score/year
        least squares mean (standard error)
    -0.139 ± 0.013
    -0.107 ± 0.013
    Statistical analysis title
    linear regression mixed-effect model
    Statistical analysis description
    P values are based on a linear regression mixed-effect model comparing slopes under compound symmetry, with adjustment for baseline.
    Comparison groups
    atenolol v Losartan
    Number of subjects included in analysis
    608
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.08
    Method
    Mixed models analysis
    Confidence interval

    Secondary: Annual Rate of Change in Aortic Root (Sinuses of Valsalva) Absolute Dimension

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    End point title
    Annual Rate of Change in Aortic Root (Sinuses of Valsalva) Absolute Dimension
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 3 years following randomization.
    End point values
    atenolol Losartan
    Number of subjects analysed
    303
    305
    Units: cm/year
        least squares mean (standard error)
    0.069 ± 0.004
    0.075 ± 0.004
    No statistical analyses for this end point

    Secondary: Annual Rate of Change in Ascending-aorta-diameter Z Score, Adjusted by Body-surface-area.

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    End point title
    Annual Rate of Change in Ascending-aorta-diameter Z Score, Adjusted by Body-surface-area.
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 3 years following randomization.
    End point values
    atenolol Losartan
    Number of subjects analysed
    296
    303
    Units: z-score/year
        least squares mean (standard error)
    -0.140 ± 0.013
    -0.114 ± 0.013
    No statistical analyses for this end point

    Secondary: Annual Rate of Change in the Absolute Diameter of the Ascending Aorta

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    End point title
    Annual Rate of Change in the Absolute Diameter of the Ascending Aorta
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 3 years following randomization.
    End point values
    atenolol Losartan
    Number of subjects analysed
    296
    303
    Units: cm/year
        least squares mean (standard error)
    0.039 ± 0.004
    0.044 ± 0.004
    No statistical analyses for this end point

    Secondary: Annual Rate of Change in Aortic-annulus-diameter Z Score, Adjusted by Body-surface Area

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    End point title
    Annual Rate of Change in Aortic-annulus-diameter Z Score, Adjusted by Body-surface Area
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 3 years following randomization
    End point values
    atenolol Losartan
    Number of subjects analysed
    302
    304
    Units: z-score/year
        least squares mean (standard error)
    -0.279 ± 0.018
    -0.175 ± 0.018
    No statistical analyses for this end point

    Secondary: Annual Rate of Change in the Absolute Diameter of the Aortic Annulus

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    End point title
    Annual Rate of Change in the Absolute Diameter of the Aortic Annulus
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 3 years following randomization
    End point values
    atenolol Losartan
    Number of subjects analysed
    302
    304
    Units: cm/year
        least squares mean (standard error)
    0.015 ± 0.003
    0.030 ± 0.003
    No statistical analyses for this end point

    Secondary: Annual Rate of Change in Total Aortic Proximal Regurgitant Jet Area Indexed to Body-surface-area

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    End point title
    Annual Rate of Change in Total Aortic Proximal Regurgitant Jet Area Indexed to Body-surface-area
    End point description
    End point type
    Secondary
    End point timeframe
    up to 3 years following ramdomization
    End point values
    atenolol Losartan
    Number of subjects analysed
    301
    303
    Units: (mm^2/m^2)/year
        least squares mean (standard error)
    0.005 ± 0.003
    0.001 ± 0.003
    No statistical analyses for this end point

    Secondary: Annual Rate of Change in Weight

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    End point title
    Annual Rate of Change in Weight
    End point description
    End point type
    Secondary
    End point timeframe
    up to 3 years following randomization
    End point values
    atenolol Losartan
    Number of subjects analysed
    303
    305
    Units: kg/year
        least squares mean (standard error)
    0.239 ± 0.153
    0.229 ± 0.154
    No statistical analyses for this end point

    Secondary: Annual Rate of Change in Weight-for-age Z-score

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    End point title
    Annual Rate of Change in Weight-for-age Z-score
    End point description
    End point type
    Secondary
    End point timeframe
    up to 3 years following randomization
    End point values
    atenolol Losartan
    Number of subjects analysed
    270
    278
    Units: z-score/year
        least squares mean (standard error)
    0.011 ± 0.013
    0.019 ± 0.013
    No statistical analyses for this end point

    Secondary: Annual Rate of Change in Weight-for-height Z-score

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    End point title
    Annual Rate of Change in Weight-for-height Z-score
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 3 years following randomization.
    End point values
    atenolol Losartan
    Number of subjects analysed
    58
    61
    Units: z-score/year
        least squares mean (standard error)
    -0.001 ± 0.072
    -0.157 ± 0.076
    No statistical analyses for this end point

    Secondary: Annual Rate of Change in Height

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    End point title
    Annual Rate of Change in Height
    End point description
    End point type
    Secondary
    End point timeframe
    up to 3 years following randomization
    End point values
    atenolol Losartan
    Number of subjects analysed
    303
    305
    Units: cm/year
        least squares mean (standard error)
    0.822 ± 0.204
    0.935 ± 0.202
    No statistical analyses for this end point

    Secondary: Annual Rate of Change in Height-for-age Z-score

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    End point title
    Annual Rate of Change in Height-for-age Z-score
    End point description
    End point type
    Secondary
    End point timeframe
    up to 3 years following randomization
    End point values
    atenolol Losartan
    Number of subjects analysed
    269
    272
    Units: z-score/year
        least squares mean (standard error)
    0.046 ± 0.013
    0.019 ± 0.013
    No statistical analyses for this end point

    Secondary: Annual Rate of Change in Body Mass Index

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    End point title
    Annual Rate of Change in Body Mass Index
    End point description
    End point type
    Secondary
    End point timeframe
    up to 3 years following randomization
    End point values
    atenolol Losartan
    Number of subjects analysed
    283
    295
    Units: kg/m^2 per year
        least squares mean (standard error)
    0.063 ± 0.044
    0.076 ± 0.044
    No statistical analyses for this end point

    Secondary: Annual Rate of Change in Body Mass Index for Age Z-score

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    End point title
    Annual Rate of Change in Body Mass Index for Age Z-score
    End point description
    End point type
    Secondary
    End point timeframe
    up to 3 years following randomization
    End point values
    atenolol Losartan
    Number of subjects analysed
    250
    263
    Units: z-score/year
        least squares mean (standard error)
    0.007 ± 0.022
    0.021 ± 0.022
    No statistical analyses for this end point

    Secondary: Annual Rate of Change in Arm Span to Height Ratio

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    End point title
    Annual Rate of Change in Arm Span to Height Ratio
    End point description
    End point type
    Secondary
    End point timeframe
    up to 3 years following randomization
    End point values
    atenolol Losartan
    Number of subjects analysed
    301
    303
    Units: 1/year
        least squares mean (standard error)
    0.001 ± 0.001
    0.001 ± 0.001
    No statistical analyses for this end point

    Secondary: Annual Rate of Change in Upper to Lower Segment Ratio

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    End point title
    Annual Rate of Change in Upper to Lower Segment Ratio
    End point description
    End point type
    Secondary
    End point timeframe
    up to 3 years following randomization
    End point values
    atenolol Losartan
    Number of subjects analysed
    301
    301
    Units: 1/year
        least squares mean (standard error)
    -0.014 ± 0.002
    -0.015 ± 0.002
    No statistical analyses for this end point

    Secondary: Number of Participants With Aortic Dissection.

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    End point title
    Number of Participants With Aortic Dissection.
    End point description
    End point type
    Secondary
    End point timeframe
    up to 3 years following randomization
    End point values
    atenolol Losartan
    Number of subjects analysed
    303
    305
    Units: participants
    0
    2
    No statistical analyses for this end point

    Secondary: Event Rate of Aortic Dissection

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    End point title
    Event Rate of Aortic Dissection
    End point description
    End point type
    Secondary
    End point timeframe
    up to 3 years following randomization
    End point values
    atenolol Losartan
    Number of subjects analysed
    303
    305
    Units: percentage of participants
        number (confidence interval 95%)
    0 (0 to 0)
    0.7 (0.2 to 2.7)
    No statistical analyses for this end point

    Secondary: Number of Participants With Aortic-root Surgery

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    End point title
    Number of Participants With Aortic-root Surgery
    End point description
    End point type
    Secondary
    End point timeframe
    up to 3 years following randomization
    End point values
    atenolol Losartan
    Number of subjects analysed
    303
    305
    Units: participants
    10
    18
    No statistical analyses for this end point

    Secondary: Event Rate of Aortic-Root Surgery

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    End point title
    Event Rate of Aortic-Root Surgery
    End point description
    End point type
    Secondary
    End point timeframe
    up to 3 years following randomization
    End point values
    atenolol Losartan
    Number of subjects analysed
    303
    305
    Units: percentage of participants
        number (confidence interval 95%)
    3.4 (1.9 to 6.3)
    6.0 (3.8 to 9.4)
    No statistical analyses for this end point

    Secondary: Number of Death

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    End point title
    Number of Death
    End point description
    End point type
    Secondary
    End point timeframe
    up to 3 years following randomization
    End point values
    atenolol Losartan
    Number of subjects analysed
    303
    305
    Units: participants
    0
    1
    No statistical analyses for this end point

    Secondary: Event Rate of Death

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    End point title
    Event Rate of Death
    End point description
    End point type
    Secondary
    End point timeframe
    up to 3 years following randomization
    End point values
    atenolol Losartan
    Number of subjects analysed
    303
    305
    Units: percentage of participants
        number (confidence interval 95%)
    0 (0 to 0)
    0.3 (0 to 2.4)
    No statistical analyses for this end point

    Secondary: Number of Participants With the Composite Adverse Clinical Outcomes, Including Aortic Dissection, Aortic-root Surgery and Death

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    End point title
    Number of Participants With the Composite Adverse Clinical Outcomes, Including Aortic Dissection, Aortic-root Surgery and Death
    End point description
    End point type
    Secondary
    End point timeframe
    up to 3 years following randomization
    End point values
    atenolol Losartan
    Number of subjects analysed
    303
    305
    Units: participants
    10
    19
    No statistical analyses for this end point

    Secondary: Event Rate of the Composite Adverse Clinical Outcomes, Including Aortic Dissection, Aortic-root Surgery and Death

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    End point title
    Event Rate of the Composite Adverse Clinical Outcomes, Including Aortic Dissection, Aortic-root Surgery and Death
    End point description
    End point type
    Secondary
    End point timeframe
    up to 3 years following randomization
    End point values
    atenolol Losartan
    Number of subjects analysed
    303
    305
    Units: percentage of participants
        number (confidence interval 95%)
    3.4 (1.9 to 6.3)
    6.4 (4.1 to 9.8)
    No statistical analyses for this end point

    Secondary: adverse drug reactions reported at the baseline visit

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    End point title
    adverse drug reactions reported at the baseline visit
    End point description
    End point type
    Secondary
    End point timeframe
    at baseline
    End point values
    atenolol Losartan
    Number of subjects analysed
    303
    305
    Units: partipants
        headache, any severity
    112
    114
        headache, bothersom
    10
    10
        fatigue, any severity
    84
    105
        fatigue, bothersome
    0
    0
        mood alterations, any severity
    54
    49
        mood alterations, bothersome
    7
    3
        behavior changes, any severity
    21
    23
        behavior changes, bothersome
    2
    1
        insomnia, any seveity
    60
    61
        insomnia, bothersome
    2
    2
        nightmares, any severity
    52
    53
        nightmares, bothersome
    2
    3
        dizziness with standing, any severity
    60
    58
        dizziness with standing, bothersome
    0
    2
        dizziness - other, any severity
    25
    27
        dizziness - other, bothersome
    0
    1
        fainting with loss of consiousness any severity
    5
    9
        fainting with loss of consiousness, bothersome
    5
    9
        palpitations, any severity
    60
    53
        palpitations, bothersome
    0
    0
        chest pain, any severity
    54
    58
        chest pain, bothersome
    1
    5
        dyspnea, any severity
    43
    38
        dyspnea, bothersome
    3
    0
        wheezing, any severity
    15
    14
        wheezing, bothersome
    2
    1
        upper respiratory/nasal congestion, any severity
    106
    117
        upper respiratory/nasal congestion, bothersome
    0
    2
        cough, any severity
    47
    59
        cough, bothersome
    1
    0
        dysgeusia, any severity
    10
    3
        dysgeusia, bothersome
    0
    0
        stomach pain/indigestion, any severity
    47
    61
        stomach pain/indigestion, bothersome
    0
    1
        nausea, any severity
    30
    35
        nausea, bothersome
    1
    0
        vomiting, any severity
    23
    23
        vomiting, bothersome
    0
    0
        diarrhea, any severity
    35
    43
        diarrhea, bothersome
    1
    1
        constipation, any severity
    44
    35
        constipation, bothersome
    0
    0
        vascular (hands, feet), any severity
    35
    34
        vascular (hands, feet) bothersome
    0
    1
        muscle pain or cramps, any severity
    59
    58
        muscle pain or cramps, bothersome
    2
    4
        back pain, any severity
    60
    67
        back pain, bothersome
    3
    2
        periorbital edema, any severity
    13
    15
        periorbital edema, bothersome
    0
    0
        pedal edema, any severity
    2
    3
        pedal edema, bothersome
    0
    0
        other, any severity
    21
    16
        other, bothersome
    3
    1
    No statistical analyses for this end point

    Secondary: Adverse Drug Reactions Reported During Routine Follow-up Surveillance

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    End point title
    Adverse Drug Reactions Reported During Routine Follow-up Surveillance
    End point description
    End point type
    Secondary
    End point timeframe
    From 6 months to 3 years following randomization
    End point values
    atenolol Losartan
    Number of subjects analysed
    291
    297
    Units: participants
        headache, any severity
    202
    208
        headache, bothersome
    27
    20
        fatigue, any severity
    152
    153
        fatigue, bothersome
    7
    5
        mood alterations, any severity
    89
    86
        mood alterations, bothersome
    13
    13
        behavior changes, any severity
    51
    46
        behaviour changes, bothersome
    5
    8
        insomnia, any severity
    108
    107
        insomnia, bothersome
    6
    4
        nightmares, any severity
    100
    94
        nightmares, bothersome
    7
    4
        dizziness with standing, any severity
    119
    105
        dizziness with standing, bothersome
    6
    0
        dizziness - other, any severity
    60
    61
        dizziness - other, bothersome
    2
    0
        fainting with loss of consciousness, any severity
    21
    16
        fainting with loss of consciousness, bothersome
    21
    16
        palpitations, any severity
    86
    101
        palpitations, bothersome
    0
    0
        chest pain, any severity
    114
    106
        chest pain, bothersome
    14
    1
        dyspnea, any severity
    75
    72
        dyspnea, bothersome
    1
    3
        wheezing, any severity
    36
    32
        wheezing, bothersome
    2
    5
        upper respiratory/nasal congestion, any severity
    188
    186
        upper respiratory/nasal cangestion, bothersome
    3
    3
        cough, any severity
    117
    113
        cough, bothersome
    1
    1
        dysgeusia, any severity
    29
    16
        dysgeusia, bothersome
    0
    0
        stomach pain/indigestion, any severity
    119
    121
        stomach pain/indigestion, bothersome
    2
    8
        nausea, any severity
    99
    78
        nausea, bothersome
    0
    0
        vomiting, any severity
    81
    75
        vomiting, bothersome
    1
    2
        diarrhea, any severity
    94
    90
        diarrhea, bothersome
    1
    3
        constipation, any severity
    77
    66
        constipation, bothersome
    1
    0
        vascular (hands, feet) any severity
    73
    66
        vascular (hands, feet), bothersome
    0
    0
        muscle pain or cramps, any severity
    148
    124
        muscle pain or cramps, bothersome
    6
    7
        back pain, any severity
    137
    134
        back pain, bothersome
    5
    8
        periorbital edema, any severity
    22
    27
        periorbital edema, bothersome
    0
    1
        pedal edema, any severity
    6
    5
        pedal edema, bothersome
    0
    0
        other, any severity
    105
    108
        other, bothersome
    10
    12
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years.
    Adverse event reporting additional description
    Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    6.0
    Reporting groups
    Reporting group title
    atenolol
    Reporting group description
    Participants with Marfan’s syndrome and ≥3 maximum aortic root z-score received 0.5 - 4.0 mg/kg/day Atenolol (not to exceed a total dose of 250 mg), with a goal of a 20% or greater decrease in the mean heart rate.

    Reporting group title
    Losartan
    Reporting group description
    Participants with Marfan’s syndrome and ≥3 maximum aortic root z-score received 0.4 - 1.4 mg/kg/day Losartan (not to exceed a total dose of 100 mg).

    Serious adverse events
    atenolol Losartan
    Total subjects affected by serious adverse events
         subjects affected / exposed
    27 / 303 (8.91%)
    33 / 305 (10.82%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Thrombosis
         subjects affected / exposed
    1 / 303 (0.33%)
    1 / 305 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    aortic root enlargement
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cardiac general-other: mitral valve replacement
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Autoimmune disorder NOS
         subjects affected / exposed
    1 / 303 (0.33%)
    1 / 305 (0.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity NOS
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Serum sickness
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Pregnancy
         subjects affected / exposed
    1 / 303 (0.33%)
    2 / 305 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 303 (0.33%)
    2 / 305 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 303 (0.33%)
    2 / 305 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    2 / 303 (0.66%)
    0 / 305 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    3 / 303 (0.99%)
    1 / 305 (0.33%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    psychosis aggravated
         subjects affected / exposed
    1 / 303 (0.33%)
    1 / 305 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine haemorrhage
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Haematoma
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    vascular: vessel injury-artery, other NOS
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Weight decreased
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 303 (0.00%)
    2 / 305 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pericarditis NOS
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 303 (0.33%)
    1 / 305 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    valvular heart disease NOS
         subjects affected / exposed
    0 / 303 (0.00%)
    3 / 305 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Blood/bone marrow(sickle cell crisis)
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         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
    Pneumonia
         subjects affected / exposed
    4 / 303 (1.32%)
    1 / 305 (0.33%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pneumonitis NOS
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pneumothorax NOS
         subjects affected / exposed
    3 / 303 (0.99%)
    5 / 305 (1.64%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pulmonary/upper respiratory - other
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    cerebral abscess
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    convulsions NOS
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Retinal detachment
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    abdominal pain NOS
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    diarrhoea NOS
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pancreatitis NOS
         subjects affected / exposed
    1 / 303 (0.33%)
    1 / 305 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urethral obstruction
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    culture wound negative
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         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
    Scoliosis
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    3 / 303 (0.99%)
    0 / 305 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pyrexia
         subjects affected / exposed
    1 / 303 (0.33%)
    1 / 305 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection NOS
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue infection NOS
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    urinary tract infection NOS
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    wound - snake bite
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    atenolol Losartan
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    135 / 303 (44.55%)
    121 / 305 (39.67%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    Hypertension
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    Hypotension
         subjects affected / exposed
    0 / 303 (0.00%)
    3 / 305 (0.98%)
         occurrences all number
    0
    3
    Raynaud's phenomenon
         subjects affected / exposed
    2 / 303 (0.66%)
    1 / 305 (0.33%)
         occurrences all number
    2
    1
    Thrombosis
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    1
    Surgical and medical procedures
    cardiac general-chest tightness
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    1
    Immune system disorders
    Allergy/Immunology - Other (rash)
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    1
    Hypersensitivity NOS
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    1
    Pregnancy, puerperium and perinatal conditions
    Sexual/reproductive function-other (4.5 cm cyst on right ovary)
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    1
    Sexual/reproductive function-other (abnormal pap smear)
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    bilateral pedal edema
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    1
    Chest pain
         subjects affected / exposed
    16 / 303 (5.28%)
    17 / 305 (5.57%)
         occurrences all number
    18
    18
    Constitutional symptoms -other(flu)
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    Constitutional symptoms-other (unusual dreams)
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    Constitutional-other (general body cold sensation)
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    1
    Edema:head and neck
         subjects affected / exposed
    2 / 303 (0.66%)
    2 / 305 (0.66%)
         occurrences all number
    2
    2
    Edema: limb
         subjects affected / exposed
    1 / 303 (0.33%)
    1 / 305 (0.33%)
         occurrences all number
    1
    2
    falling asleep
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    Fatigue
         subjects affected / exposed
    18 / 303 (5.94%)
    11 / 305 (3.61%)
         occurrences all number
    19
    12
    Hypothermia
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    1
    influenza-like illness
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    Nightmare
         subjects affected / exposed
    7 / 303 (2.31%)
    13 / 305 (4.26%)
         occurrences all number
    8
    13
    pain-other (right hip pain)
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    Pain-other:chest pain/costochondritis (diagnosed in ER as costochondritis)
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    11 / 303 (3.63%)
    3 / 305 (0.98%)
         occurrences all number
    12
    3
    Anxiety
         subjects affected / exposed
    5 / 303 (1.65%)
    2 / 305 (0.66%)
         occurrences all number
    5
    2
    Confusional state
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    Depression
         subjects affected / exposed
    9 / 303 (2.97%)
    2 / 305 (0.66%)
         occurrences all number
    11
    3
    Insomnia
         subjects affected / exposed
    10 / 303 (3.30%)
    12 / 305 (3.93%)
         occurrences all number
    10
    12
    mood alteration
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    Neurology-other (expression of anger and sadness)
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    Neurology-other (irritability)
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    1
    Personality change
         subjects affected / exposed
    6 / 303 (1.98%)
    3 / 305 (0.98%)
         occurrences all number
    6
    3
    Reproductive system and breast disorders
    gyneacomastia
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Haematoma
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    Investigations
    neutrphil count
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    1
    Weight decreased
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    cardiac general, other, murmur
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    1
    cardiac general- other - nonresponsive and pale
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    Palpitations
         subjects affected / exposed
    9 / 303 (2.97%)
    10 / 305 (3.28%)
         occurrences all number
    9
    10
    Sinus tachycardia
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    1
    Haemoglobin
         subjects affected / exposed
    0 / 303 (0.00%)
    2 / 305 (0.66%)
         occurrences all number
    0
    2
    Lymph node pain
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Pneumonia
         subjects affected / exposed
    1 / 303 (0.33%)
    4 / 305 (1.31%)
         occurrences all number
    1
    4
    Bronchospasm
         subjects affected / exposed
    3 / 303 (0.99%)
    4 / 305 (1.31%)
         occurrences all number
    3
    4
    Cough
         subjects affected / exposed
    3 / 303 (0.99%)
    4 / 305 (1.31%)
         occurrences all number
    3
    4
    Dyspnoea
         subjects affected / exposed
    6 / 303 (1.98%)
    5 / 305 (1.64%)
         occurrences all number
    6
    5
    Epistaxis
         subjects affected / exposed
    9 / 303 (2.97%)
    7 / 305 (2.30%)
         occurrences all number
    9
    7
    Hemorrhage/Bleeding - other
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    Hypoxia
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    Nasal congestion
         subjects affected / exposed
    2 / 303 (0.66%)
    3 / 305 (0.98%)
         occurrences all number
    2
    3
    Nasal congestion/inf with unk ANC upper airway NOS
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    Obstructive sleep apnea
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    1
    Pulmonary/upper respiratory-other
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    Upper Respiratory - Other
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    1
    Nervous system disorders
    Cognitive disorder
         subjects affected / exposed
    2 / 303 (0.66%)
    2 / 305 (0.66%)
         occurrences all number
    2
    2
    Convulsions NOS
         subjects affected / exposed
    3 / 303 (0.99%)
    0 / 305 (0.00%)
         occurrences all number
    3
    0
    Dizziness
         subjects affected / exposed
    29 / 303 (9.57%)
    17 / 305 (5.57%)
         occurrences all number
    29
    18
    dizziness upon standing
         subjects affected / exposed
    1 / 303 (0.33%)
    1 / 305 (0.33%)
         occurrences all number
    1
    1
    Extrapyramidal disorder
         subjects affected / exposed
    2 / 303 (0.66%)
    0 / 305 (0.00%)
         occurrences all number
    2
    0
    Headache
         subjects affected / exposed
    31 / 303 (10.23%)
    18 / 305 (5.90%)
         occurrences all number
    36
    19
    Memory impairment
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    1
    Mental status changes
         subjects affected / exposed
    1 / 303 (0.33%)
    1 / 305 (0.33%)
         occurrences all number
    1
    1
    neuralgia NOS
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    1
    neurology - other
         subjects affected / exposed
    0 / 303 (0.00%)
    2 / 305 (0.66%)
         occurrences all number
    0
    2
    Neurology-other (panic attacks)
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    2
    panick attacks
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    Syncope
         subjects affected / exposed
    13 / 303 (4.29%)
    9 / 305 (2.95%)
         occurrences all number
    14
    9
    syncope vasovagal
         subjects affected / exposed
    2 / 303 (0.66%)
    2 / 305 (0.66%)
         occurrences all number
    2
    3
    Tremor
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    1
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    3 / 303 (0.99%)
    1 / 305 (0.33%)
         occurrences all number
    3
    1
    eyelid function disorder NOS
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    Lacrimation increased
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    1
    Ocular-other (L eye burning/redness 4 mos. s/p lensectomy with lens insertion)
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    Ocular - other (right eye hemorrhage)
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    Ocular/Visual - Squinting of OS to see things more clearly
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    Ocular/visual-other (redness and itching of eyes)
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    1
    Photopsia
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    1
    Vision blurred
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    Ear and labyrinth disorders
    auditory/ear-other
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    1
    Hypersensitivity to sound
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    abdominal pain NOS
         subjects affected / exposed
    7 / 303 (2.31%)
    7 / 305 (2.30%)
         occurrences all number
    7
    7
    Constipation
         subjects affected / exposed
    4 / 303 (1.32%)
    2 / 305 (0.66%)
         occurrences all number
    4
    2
    diarrhoea NOS
         subjects affected / exposed
    4 / 303 (1.32%)
    2 / 305 (0.66%)
         occurrences all number
    6
    2
    Dysgeusia
         subjects affected / exposed
    3 / 303 (0.99%)
    2 / 305 (0.66%)
         occurrences all number
    3
    2
    Dyspepsia
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    Dysphagia
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    1
    Gastrointestinal - HERNIA
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    1
    Haemorrhoids
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    intestinal hernia
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    2 / 303 (0.66%)
    2 / 305 (0.66%)
         occurrences all number
    2
    3
    Oesophageal pain
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    1
    Oral pain
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    oesophagitis NOS
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    peridontal disorder NOS
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    stomach discomfort
         subjects affected / exposed
    5 / 303 (1.65%)
    3 / 305 (0.98%)
         occurrences all number
    5
    3
    tooth disorder NOS
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    vomiting NOS
         subjects affected / exposed
    2 / 303 (0.66%)
    5 / 305 (1.64%)
         occurrences all number
    3
    7
    Renal and urinary disorders
    Chromaturia
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    1
    Pollakiuria
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    Renal/genitourinary-increased urinary frequency, daytime only, associated w/ po water intake
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    1
    Urinary incontinence
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    2
    0
    Urogenital haemorrhage
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    acne NOS
         subjects affected / exposed
    2 / 303 (0.66%)
    2 / 305 (0.66%)
         occurrences all number
    2
    2
    Alopecia
         subjects affected / exposed
    1 / 303 (0.33%)
    4 / 305 (1.31%)
         occurrences all number
    1
    4
    burn on skin
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    decubitis ulcer
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    Derm/skin-other (Poison Ivy)
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    Derm/skin-other (mild chin rash)
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    Derm/skin-other (possible eczema)
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    Derm/skin-other (worsening of underlying hand skin disorder)
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    1
    Dermatitis exfoliative NOS
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    Dermatology - other - Erythema Nodosum
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    Dermatology/skin-other (cervical dysplasia)
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    Dermatology/skin-other (papules on legs)
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    1
    Dermatology/skin-other (rash: nonspecific maculopapular rash)
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    1
    Ecchymosis
         subjects affected / exposed
    1 / 303 (0.33%)
    2 / 305 (0.66%)
         occurrences all number
    1
    2
    Eczema
         subjects affected / exposed
    1 / 303 (0.33%)
    1 / 305 (0.33%)
         occurrences all number
    1
    1
    Erythema multiforme
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    1
    Pruritus
         subjects affected / exposed
    3 / 303 (0.99%)
    0 / 305 (0.00%)
         occurrences all number
    4
    0
    Rash
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    rash on torso and neck
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    1
    Skin irritation
         subjects affected / exposed
    1 / 303 (0.33%)
    2 / 305 (0.66%)
         occurrences all number
    1
    3
    sweating increased
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    Urticaria
         subjects affected / exposed
    3 / 303 (0.99%)
    4 / 305 (1.31%)
         occurrences all number
    3
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 303 (0.99%)
    3 / 305 (0.98%)
         occurrences all number
    3
    3
    Back pain
         subjects affected / exposed
    8 / 303 (2.64%)
    8 / 305 (2.62%)
         occurrences all number
    8
    8
    chest wall pain
         subjects affected / exposed
    6 / 303 (1.98%)
    5 / 305 (1.64%)
         occurrences all number
    6
    5
    joint disorder NOS
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    1
    Joint effusion
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    1
    Msk/soft tissue, other (Nodule on back)
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    1
    Muscle weakness, generalized or specific area
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal (other) (loose joints-causing pain)
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal/soft tissue - other (patellar dislocation)
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal/soft tissue-other (Bursa on left shoulder blade due to back brace)
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    1
    Musculoskeletal/soft tissue-other (nodule on back)
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    1
    Musculoskeletal/soft tissue-other( left arm pain)
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    1
    Myalgia
         subjects affected / exposed
    3 / 303 (0.99%)
    12 / 305 (3.93%)
         occurrences all number
    3
    12
    Neck pain
         subjects affected / exposed
    1 / 303 (0.33%)
    2 / 305 (0.66%)
         occurrences all number
    1
    2
    Pain in extremity
         subjects affected / exposed
    5 / 303 (1.65%)
    4 / 305 (1.31%)
         occurrences all number
    5
    4
    Endocrine disorders
    hot flushes NOS
         subjects affected / exposed
    1 / 303 (0.33%)
    1 / 305 (0.33%)
         occurrences all number
    1
    1
    Metabolism and nutrition disorders
    anorexia
         subjects affected / exposed
    1 / 303 (0.33%)
    3 / 305 (0.98%)
         occurrences all number
    1
    3
    Dehydration
         subjects affected / exposed
    1 / 303 (0.33%)
    1 / 305 (0.33%)
         occurrences all number
    1
    1
    Infections and infestations
    Pyrexia
         subjects affected / exposed
    4 / 303 (1.32%)
    2 / 305 (0.66%)
         occurrences all number
    6
    2
    abcessed tooth
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    bronchitis NOS
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    1
    Gum infection
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    1
    infection - Eye NOS
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    infection - other - parvovirus
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    1
    infection Pharynx
         subjects affected / exposed
    1 / 303 (0.33%)
    1 / 305 (0.33%)
         occurrences all number
    1
    1
    Infection with unknown ANC-eye, NOS
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    1
    Infection with unknown ANC-middle ear
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    1
    Infection with unknown ANC-pharynx
         subjects affected / exposed
    0 / 303 (0.00%)
    2 / 305 (0.66%)
         occurrences all number
    0
    2
    Infection with unknown ANC-sinus
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    1
    Infection with unknown ANC-upper ariway NOS
         subjects affected / exposed
    2 / 303 (0.66%)
    0 / 305 (0.00%)
         occurrences all number
    2
    0
    Infection-bladder(urinary)
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    1
    Infection-other (sinus, bronchitis, pharyngeal)
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    Infection-other (skin on foot)
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    1
    Infection-other-Lyme disease
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    1
    Infection: Dental - Tooth
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    middle ear infection
         subjects affected / exposed
    1 / 303 (0.33%)
    2 / 305 (0.66%)
         occurrences all number
    1
    2
    mononucleosis
         subjects affected / exposed
    3 / 303 (0.99%)
    1 / 305 (0.33%)
         occurrences all number
    3
    1
    shingles
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    1
    sinus infection
         subjects affected / exposed
    2 / 303 (0.66%)
    0 / 305 (0.00%)
         occurrences all number
    2
    0
    sinusitis NOS
         subjects affected / exposed
    2 / 303 (0.66%)
    1 / 305 (0.33%)
         occurrences all number
    2
    1
    Urinary tract infection NOS
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 305 (0.33%)
         occurrences all number
    0
    1
    vaginitis
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0
    Viral infection coxsackievirus
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 305 (0.00%)
         occurrences all number
    1
    0

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Feb 2008
    Reasons for substantial amendment a. subject availability and aditional PHN Trial Ceners b. subject re-consent c. protocol windows d. interim monitoring e. drug preperations Brief description of the changes a. Subject Availability and Additional PHN Trial Centers: minor protocol modifications were made to highlight the addition of new auxiliary centers and to characterize the development of referral centers as ways to fulfill trial recruitment goals. b. Subject Re-consent: U.S. and Canadian trial subjects who reach the age of consent, as determined by the local Regulatory agency, during their trial participation will undergo the informed consent process as an adult and will be required to sign the subject (adult) Informed Consent Form. c. protocol Windows: timeframes for completing each drug Uptitration Cycle and for obtaining the end of uptitration safety labs are clarified. d. Interim Monitoring: clarifies how variation in within- and between-subject measurements may influence statistical power and to define methods that would be employed if an increase in sample size is required. e. Drug Preparations: requires that both suspensions will now require refrigeration.
    19 Sep 2009
    Reasons for substantial amendment: Addition of site Brief description of the changes: Addition of site: Cliniques Universitaires Saint-Luc - UCL
    05 Mar 2010
    Reasons for substantial amendment: change in drug preparations Brief description of the changes: Change in drug preparations - the atenolol suspension preparation recipe has been amended based on results of the atenolol suspension stability study required by the FDA
    18 Nov 2010
    Reasons for substantial amendment: Addition of ancillary study: "Musculoskeletal Phenotype of Marfan Patients"
    02 Feb 2012
    Reasons for substantial amendment: The protocol is amended to conform to the new FDA Final Rule for Safety Reporting in IND Trials.

    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.
    The effect of losartan on TGF-β was not assessed. The study results do not apply to Marfan subjects whose BSA–adj. aortic-root z score is ≤3. Subjects may find their treatment based on the appearance of the drug.

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/17892982
    http://www.ncbi.nlm.nih.gov/pubmed/30115424
    http://www.ncbi.nlm.nih.gov/pubmed/29631804
    http://www.ncbi.nlm.nih.gov/pubmed/29948025
    http://www.ncbi.nlm.nih.gov/pubmed/30270167
    http://www.ncbi.nlm.nih.gov/pubmed/32586526
    http://www.ncbi.nlm.nih.gov/pubmed/25405392
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