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    Clinical Trial Results:
    Karisma II: A randomized, double blinded, six-armed placebo controlled study to investigate optimal dose of tamoxifen with the most favourable side effect spectra and with mammographic density reduction non-inferior to that of 20 mg tamoxifen.

    Summary
    EudraCT number
    2016-000882-22
    Trial protocol
    SE  
    Global end of trial date
    25 Oct 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    18 Jul 2021
    First version publication date
    18 Jul 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    KARISMAII
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03346200
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Karolinska Institutet
    Sponsor organisation address
    Fatburs Brunnsgata 7, Stockholm, Sweden, SE-118 28
    Public contact
    Karma Study Center at Södersjukhuset Breast Center, Karolinska Institutet at Södersjukhuset Breast Center, 0046 70750 2110, per.hall@ki.se
    Scientific contact
    Karma Study Center at Södersjukhuset Breast Center, Karolinska Institutet at Södersjukhuset Breast Center, 0046 70750 2110, per.hall@ki.se
    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
    20 Apr 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Sep 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Oct 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Identify the minimal dose of tamoxifen non-inferior in its ability to reduce mammographic density and with less side effects compared to 20 mg of tamoxifen.
    Protection of trial subjects
    The study was performed in accordance with the recommendations guiding physicians in biomedical research involving human subjects that were adopted in 1964 by the 18th World Medical Assembly, in Helsinki, Finland, with later revisions and the International Conference on Harmonisation (ICH) Guidelines.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    14 Nov 2016
    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
    Sweden: 1440
    Worldwide total number of subjects
    1440
    EEA total number of subjects
    1440
    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)
    1096
    From 65 to 84 years
    344
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Study invitations were sent to women invited for mammography in the Swedish mammography screening program. Of 159 027 women invited, 2 314 showed interest of participating and were assessed for eligibility. At study screening 874 did not meet the inclusion/exclusion criteria and eventually 1 440 women were randomized.

    Pre-assignment
    Screening details
    Exclusion criteria were made to not allowing women with previous cancer or with elevated risk for cardiovascular disorders.

    Period 1
    Period 1 title
    6 months on IMP (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Assessor, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    0 mg of IMP (tamoxifen)
    Arm type
    Placebo

    Investigational medicinal product name
    Tamoxifen
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Once daily for 6 months.

    Arm title
    1 mg of IMP
    Arm description
    1 mg of IMP (tamoxifen)
    Arm type
    Experimental

    Investigational medicinal product name
    Tamoxifen
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Once daily for 6 months.

    Arm title
    2,5 mg of IMP
    Arm description
    2,5 mg of IMP (tamoxifen)
    Arm type
    Experimental

    Investigational medicinal product name
    Tamoxifen
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Once daily for 6 months.

    Arm title
    5 mg of IMP
    Arm description
    5 mg of IMP (tamoxifen)
    Arm type
    Experimental

    Investigational medicinal product name
    Tamoxifen
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Once daily for 6 months.

    Arm title
    10 mg of IMP
    Arm description
    10 mg of IMP (tamoxifen)
    Arm type
    Experimental

    Investigational medicinal product name
    Tamoxifen
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Once daily for 6 months.

    Arm title
    20 mg of IMP
    Arm description
    20 mg of IMP (tamoxifen)
    Arm type
    Active comparator

    Investigational medicinal product name
    Tamoxifen
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Once daily for 6 months.

    Number of subjects in period 1
    Placebo 1 mg of IMP 2,5 mg of IMP 5 mg of IMP 10 mg of IMP 20 mg of IMP
    Started
    242
    239
    235
    240
    243
    241
    Completed
    211
    205
    200
    201
    210
    203
    Not completed
    31
    34
    35
    39
    33
    38
         Adverse event, non-fatal
    9
    12
    15
    17
    14
    21
         Consent withdrawn by subject
    22
    22
    20
    22
    19
    17

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    0 mg of IMP (tamoxifen)

    Reporting group title
    1 mg of IMP
    Reporting group description
    1 mg of IMP (tamoxifen)

    Reporting group title
    2,5 mg of IMP
    Reporting group description
    2,5 mg of IMP (tamoxifen)

    Reporting group title
    5 mg of IMP
    Reporting group description
    5 mg of IMP (tamoxifen)

    Reporting group title
    10 mg of IMP
    Reporting group description
    10 mg of IMP (tamoxifen)

    Reporting group title
    20 mg of IMP
    Reporting group description
    20 mg of IMP (tamoxifen)

    Reporting group values
    Placebo 1 mg of IMP 2,5 mg of IMP 5 mg of IMP 10 mg of IMP 20 mg of IMP Total
    Number of subjects
    242 239 235 240 243 241 1440
    Age categorical
    Age categories, all 1 440 randomized, stratified per dose arm.
    Units: Subjects
        Adults (18-64 years)
    177 193 181 185 179 181 1096
        From 65-84 years
    65 46 54 55 64 60 344
    Gender categorical
    Units: Subjects
        Female
    242 239 235 240 243 241 1440
        Male
    0 0 0 0 0 0 0
    Subject analysis sets

    Subject analysis set title
    Efficacy
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Mean relative dense area change (%) and difference in mean change at six-months in the primary intention to treat population

    Subject analysis sets values
    Efficacy
    Number of subjects
    1230
    Age categorical
    Age categories, all 1 440 randomized, stratified per dose arm.
    Units: Subjects
        Adults (18-64 years)
    982
        From 65-84 years
    248
    Age continuous
    Units:
        
    ±
    Gender categorical
    Units: Subjects
        Female
    1230
        Male
    0

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    0 mg of IMP (tamoxifen)

    Reporting group title
    1 mg of IMP
    Reporting group description
    1 mg of IMP (tamoxifen)

    Reporting group title
    2,5 mg of IMP
    Reporting group description
    2,5 mg of IMP (tamoxifen)

    Reporting group title
    5 mg of IMP
    Reporting group description
    5 mg of IMP (tamoxifen)

    Reporting group title
    10 mg of IMP
    Reporting group description
    10 mg of IMP (tamoxifen)

    Reporting group title
    20 mg of IMP
    Reporting group description
    20 mg of IMP (tamoxifen)

    Subject analysis set title
    Efficacy
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Mean relative dense area change (%) and difference in mean change at six-months in the primary intention to treat population

    Primary: Efficacy

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    End point title
    Efficacy
    End point description
    Mean relative dense area change (%) and difference in mean change at six-months in the primary intention to treat population
    End point type
    Primary
    End point timeframe
    Evaluated after 6 months on IMP.
    End point values
    Placebo 1 mg of IMP 2,5 mg of IMP 5 mg of IMP 10 mg of IMP 20 mg of IMP Efficacy
    Number of subjects analysed
    211 [1]
    205
    200
    201
    210
    203
    1230
    Units: Absolute numbers
    211
    205
    200
    201
    210
    203
    1230
    Attachments
    Efficacy figure
    Notes
    [1] - Absolute difference in mammographic density
    Statistical analysis title
    Intention to treat
    Statistical analysis description
    For primary efficacy endpoint, evaluating the primary intention to treat population (N=1,230) the difference in mean change (compared with the 20 mg treatment group) at six-months, stratified by menopausal status and tamoxifen dose.
    Comparison groups
    Placebo v 1 mg of IMP v 2,5 mg of IMP v 5 mg of IMP v 10 mg of IMP v 20 mg of IMP v Efficacy
    Number of subjects included in analysis
    2460
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [2]
    P-value
    < 0.025 [3]
    Method
    Wald tests
    Parameter type
    Mean difference (net)
    Confidence interval
         level
    97.5%
         sides
    1-sided
         lower limit
    -
         upper limit
    -
    Variability estimate
    Standard error of the mean
    Notes
    [2] - Non-inferiority was declared if the corrected p-values were less than 0.025. We reported one-sided 97.5% normal-based confidence intervals.
    [3] - For the primary endpoint, we calculated one-sided p-values for non-inferiority using Wald tests.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    During the 6 months of participation.
    Adverse event reporting additional description
    Safety and adverse events were assessed by study personnel available through study center phone, a phone app for spontaneous reports, and through scheduled questionnaires at month 1, 3, and 6.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    All participants
    Reporting group description
    -

    Serious adverse events
    All participants
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 1440 (0.76%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Vascular disorders
    Varicophlebitis
         subjects affected / exposed
    1 / 1440 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    3 / 1440 (0.21%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Monoclonal gammopathy
         subjects affected / exposed
    1 / 1440 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Squamous cell carcinoma of head and neck
         subjects affected / exposed
    1 / 1440 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Meningioma benign
         subjects affected / exposed
    1 / 1440 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Transient ischaemic attack
    Additional description: Suspicion of Transient ischaemic attack
         subjects affected / exposed
    1 / 1440 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Peptic ulcer haemorrhage
         subjects affected / exposed
    1 / 1440 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Pyelonephritis acute
         subjects affected / exposed
    2 / 1440 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    All participants
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    342 / 1440 (23.75%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    140 / 1440 (9.72%)
         occurrences all number
    193
    Night sweats
         subjects affected / exposed
    109 / 1440 (7.57%)
         occurrences all number
    189
    Reproductive system and breast disorders
    Vaginal discharge
         subjects affected / exposed
    93 / 1440 (6.46%)
         occurrences all number
    121

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/33734864
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