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    Clinical Trial Results:
    Lymphatic dysfunction as a cause of calcium channel blocker oedema in post-menopausal women

    Summary
    EudraCT number
    2015-001761-11
    Trial protocol
    DK  
    Global end of trial date
    11 Oct 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    26 Oct 2019
    First version publication date
    26 Oct 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    300488
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Aarhus University Hospital
    Sponsor organisation address
    Palle Juul Jensens Boulevard, Aarhus N, Denmark,
    Public contact
    T-forskning, Aarhus University Hosp, The Department of Cardiothoracic and Vascular Surgery, Aarhus University Hospital., 0045 50720716, shey@clin.au.dk
    Scientific contact
    T-forskning, Aarhus University Hosp, The Department of Cardiothoracic and Vascular Surgery, Aarhus University Hospital., 0045 50720716, shey@clin.au.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
    11 Oct 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Oct 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Oct 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The aim with this study is to investigate the mechanism behind the oedema development often associated with treatment of cardiovascular disease with calcium channel blockers. The current belief is that a preferential arterial over venous dilation leads to increased fluid filtration. We will test this concept by measuring capillary filtration, which surprisingly has never been done before. The current belief will furthermore be challenged by also measuring the lymphatic removal of interstitial fluid during treatment with calcium channel blockers. Lymph vessels could potentially be an off-target effect of the drugs and augment oedema formation. This might explain why some patients treated with these drugs develop oedemas.
    Protection of trial subjects
    Participants where contacted a week after completion of trial to ensure there well-being. GCP-unit monitered the trial
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Oct 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 16
    Worldwide total number of subjects
    16
    EEA total number of subjects
    16
    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)
    13
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study subjects were included from June 2016 to April 2017 in four blocks of four subjects and assigned a unique number (1–16). The trial was completed in October 2017. Aarhus University Hospital Pharmacy performed randomization and blinding. The were recruited by flyers and post varies of social platforms.

    Pre-assignment
    Screening details
    The inclusion criteria were postmenopausal women. Exclusion criteria were arterial hypotension, orthostatic hypotension, angina pectoris, previous acute myocardial infarction, previous gastrointestinal bleeding, peripheral edema at inclusion in the trial, currently under treatment with any type of CCB, angiotensin converting enzyme inhibitor.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Data analyst
    Blinding implementation details
    Aarhus University Hospital Pharmacy performed randomization and blinding.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Placebo
    Arm description
    Placebo treatment for 12 weeks before crossing over to treatment
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    During the first 8 weeks, the dose was 5mg (1 capsule) amlodipine or placebo per day. During the last 4 weeks, the dose was increased to 10 mg (2 capsules) (Fig. 1). Amlodipine Actavis and placebo pills were packed in identical empty hard gelatine capsules (CAPSUGEL) to blind the subjects and investigator.

    Arm title
    Amlodipine treatment
    Arm description
    12 weeks og amlodipine treatment before crossing over to placebo
    Arm type
    Experimental

    Investigational medicinal product name
    Amlodipine actavis
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    During the first 8 weeks, the dose was 5mg (1 capsule) amlodipine or placebo per day. During the last 4 weeks, the dose was increased to 10 mg (2 capsules) (Fig. 1). Amlodipine Actavis and placebo pills were packed in identical empty hard gelatine capsules (CAPSUGEL) to blind the subjects and investigator.

    Number of subjects in period 1
    Placebo Amlodipine treatment
    Started
    16
    16
    Completed
    16
    16

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    16

    Reporting group values
    Overall Trial Total
    Number of subjects
    16 16
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    13 13
        From 65-84 years
    3 3
        85 years and over
    0 0
    Gender categorical
    Units: Subjects
        Female
    16 16
        Male
    0 0
    Subject analysis sets

    Subject analysis set title
    NIRF measurements
    Subject analysis set type
    Full analysis
    Subject analysis set description
    NIRF imaging was analyzed as already explained. Data storage was done in Microsoft Excel, whereas GraphPad Prism and Stata/SE 15.1 were used for all statistical analyses and graphical presentation of the data. All data were tested for normality and presented as mean – standard deviation (SD) and for significance with paired and unpaired Student’s t-test (data with

    Subject analysis sets values
    NIRF measurements
    Number of subjects
    16
    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)
    13
        From 65-84 years
    3
        85 years and over
    0
    Age continuous
    Units:
        
    ±
    Gender categorical
    Units: Subjects
        Female
    16
        Male
    0

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo treatment for 12 weeks before crossing over to treatment

    Reporting group title
    Amlodipine treatment
    Reporting group description
    12 weeks og amlodipine treatment before crossing over to placebo

    Subject analysis set title
    NIRF measurements
    Subject analysis set type
    Full analysis
    Subject analysis set description
    NIRF imaging was analyzed as already explained. Data storage was done in Microsoft Excel, whereas GraphPad Prism and Stata/SE 15.1 were used for all statistical analyses and graphical presentation of the data. All data were tested for normality and presented as mean – standard deviation (SD) and for significance with paired and unpaired Student’s t-test (data with

    Primary: Pumping Pressure

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    End point title
    Pumping Pressure
    End point description
    End point type
    Primary
    End point timeframe
    Full trial
    End point values
    Placebo Amlodipine treatment
    Number of subjects analysed
    16
    16
    Units: mmHg
        arithmetic mean (standard deviation)
    54.7 ± 9.4
    53.9 ± 13.9
    Statistical analysis title
    Students T-test
    Comparison groups
    Placebo v Amlodipine treatment
    Number of subjects included in analysis
    32
    Analysis specification
    Post-hoc
    Analysis type
    other
    P-value
    < 0.05
    Method
    t-test, 2-sided
    Parameter type
    Mean difference (final values)
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -
         upper limit
    -

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    7 participants developed edema during treatment. But was not excluded, but the measurements were completed before ending treatment. This was a part of the trial.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    1
    Frequency threshold for reporting non-serious adverse events: 1%
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: 7 participant developed edema during treatment, which was expected as a part of the trial. These patients remained included in the study and completed examination

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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