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    Clinical Trial Results:
    Tacrolimus as Treatment of Breast Cancer-Related Lymphedema

    Summary
    EudraCT number
    		 2020-000877-25
    Trial protocol
    		 DK  
    Global end of trial date
    03 Feb 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Dec 2022
    First version publication date
    18 Dec 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    Tacrolimus2020
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04541290
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Odense University Hospital
    Sponsor organisation address
    J.B. Winsløwsvej 4, Odense C, Denmark, 5000
    Public contact
    Frederik C. Gulmark Hansen, Dept. of Plastic Surgery, Odense University Hospital, 0045 21734450, Jens.sorensen@rsyd.dk
    Scientific contact
    Jens Ahm Sørensen, Dept. of Plastic Surgery, Odense University Hospital, 0045 65412436, Jens.sorensen@rsyd.dk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    01 Dec 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Feb 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Feb 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the effect of Tacrolimus treatment on breast cancer-related lymphedema and how it influences quality of life in patients.
    Protection of trial subjects
    Prior to the injection of indocyanine green (ICG) into the subcutaneous tissue of the patients' hands, we injected local anesthesia so the participants would not feel the pain of the following injections and the possible itching sensation.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Sep 2020
    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: 20
    Worldwide total number of subjects
    20
    EEA total number of subjects
    20
    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)
    20
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The patients were recruited through an internal waiting for participating in experimental lymphedema treatment trials.

    Pre-assignment
    Screening details
    		 Initially, we screened the patients according to the following eligibility criteria: sex (female), age (30-65 years), breast cancer-related lymphedema, ISL stage I-II (yes), ipsilateral ALND (yes), bilateral breast cancer (no), allergy for tacrolimus or other macrolides (no), diagnosed immunodeficiency (no), psychiatric illness (no) and reduced kid

    Pre-assignment period milestones
    Number of subjects started
    		 20
    Number of subjects completed
    		 20

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Treatment
    Arm description
    		 This is a single arm trial with only the treatment group
    Arm type
    		 Experimental

    Investigational medicinal product name
    protopic (0,1% tacrolimus)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ointment
    Routes of administration
    Cutaneous use
    Dosage and administration details
    The participants were given 13 tubes of Protopic (0.1 % tacrolimus) (Leo Pharma, Ballerup, Denmark) at baseline. They were instructed to apply the ointment in a thin layer covering the armpit, entire arm, and hand once daily for six months.

    Number of subjects in period 1
    		Treatment
    Started
    20
    Completed
    20
    Period 2
    Period 2 title
    3 months
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Treatment
    Arm description
    		 This is a single arm trial with only the treatment group
    Arm type
    		 Experimental

    Investigational medicinal product name
    protopic (0,1% tacrolimus)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ointment
    Routes of administration
    Cutaneous use
    Dosage and administration details
    The participants were given 13 tubes of Protopic (0.1 % tacrolimus) (Leo Pharma, Ballerup, Denmark) at baseline. They were instructed to apply the ointment in a thin layer covering the armpit, entire arm, and hand once daily for six months.

    Number of subjects in period 2
    		Treatment
    Started
    20
    Completed
    18
    Not completed
    2
         Consent withdrawn by subject
    1
         Adverse event, non-fatal
    1
    Period 3
    Period 3 title
    6 months
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Treatment
    Arm description
    		 This is a single arm trial with only the treatment group
    Arm type
    		 Experimental

    Investigational medicinal product name
    protopic (0,1% tacrolimus)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ointment
    Routes of administration
    Cutaneous use
    Dosage and administration details
    The participants were given 13 tubes of Protopic (0.1 % tacrolimus) (Leo Pharma, Ballerup, Denmark) at baseline. They were instructed to apply the ointment in a thin layer covering the armpit, entire arm, and hand once daily for six months.

    Number of subjects in period 3
    		Treatment
    Started
    18
    Completed
    18
    Period 4
    Period 4 title
    12 months
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Treatment
    Arm description
    		 This is a single arm trial with only the treatment group
    Arm type
    		 Experimental

    Investigational medicinal product name
    protopic (0,1% tacrolimus)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ointment
    Routes of administration
    Cutaneous use
    Dosage and administration details
    The participants were given 13 tubes of Protopic (0.1 % tacrolimus) (Leo Pharma, Ballerup, Denmark) at baseline. They were instructed to apply the ointment in a thin layer covering the armpit, entire arm, and hand once daily for six months.

    Number of subjects in period 4
    		Treatment
    Started
    18
    Completed
    16
    Not completed
    2
         Consent withdrawn by subject
    2

    Baseline characteristics

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

    Reporting group values
    		 Baseline Total
    Number of subjects
    		 20 20
    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)
    		 55.28 ( 4.6 ) -
    Gender categorical
    Units: Subjects
        Female
    		 20 20
        Male
    		 0 0
    Type of surgery
    Type of surgery for breast cancer treatment
    Units: Subjects
        Mastectomy
    		 10 10
        Lumpectomy
    		 10 10
    BMI
    Units: kg/m^2
        arithmetic mean (standard deviation)
    		 27.24 ( 5.78 ) -
    Number of lymph nodes removed
    Units: lymph nodes
        arithmetic mean (standard deviation)
    		 19 ( 7.13 ) -
    Difference in arm volume
    Difference in volume between lymphedema arm and healthy arm
    Units: mL
        arithmetic mean (standard deviation)
    		 491.5 ( 227.55 ) -
    Time since lymphedema diagnosis
    Units: years
        arithmetic mean (standard deviation)
    		 7.33 ( 5.13 ) -

    End points

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    End points reporting groups
    Reporting group title
    Treatment
    Reporting group description
    		 This is a single arm trial with only the treatment group
    Reporting group title
    Treatment
    Reporting group description
    		 This is a single arm trial with only the treatment group
    Reporting group title
    Treatment
    Reporting group description
    		 This is a single arm trial with only the treatment group
    Reporting group title
    Treatment
    Reporting group description
    		 This is a single arm trial with only the treatment group

    Primary: Lymphedema arm volume

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    End point title
    		 Lymphedema arm volume
    End point description
    End point type
    Primary
    End point timeframe
    Baseline, 3, 6 and 12 months
    End point values
    		 Treatment Treatment Treatment
    Number of subjects analysed
    18
    18
    16
    Units: millilitre(s)
        arithmetic mean (standard deviation)
    3194 ( 833 )
    3069 ( 746 )
    2133 ( 754 )
    Statistical analysis title
    		 Paired t test
    Comparison groups
    Treatment v Treatment v Treatment
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05 [1]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [1] - Significant difference was seen from baseline to 6 months. Non significant changes were seen at 3 and 12 months

    Primary: Healthy arm volume

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    End point title
    		 Healthy arm volume
    End point description
    End point type
    Primary
    End point timeframe
    Baseline, 3, 6 and 12 months
    End point values
    		 Treatment Treatment Treatment
    Number of subjects analysed
    18
    18
    16
    Units: millilitre(s)
        arithmetic mean (standard deviation)
    2723 ( 772 )
    2671 ( 750 )
    2680 ( 729 )
    Statistical analysis title
    		 Paired t test
    Comparison groups
    Treatment v Treatment v Treatment
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [2] - Paired t test was performed. There was no significant changes in healty arm volume in the group

    Secondary: L-Dex Score

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    End point title
    		 L-Dex Score
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, 3, 6 and 12 months
    End point values
    		 Treatment Treatment Treatment
    Number of subjects analysed
    18
    18
    16
    Units: N/A
        arithmetic mean (standard deviation)
    21.2 ( 12.5 )
    17.9 ( 9.8 )
    20 ( 12.4 )
    No statistical analyses for this end point

    Secondary: LYMPH ICF

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    End point title
    		 LYMPH ICF
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, 3, 6 and 12 months
    End point values
    		 Treatment Treatment Treatment
    Number of subjects analysed
    18
    18
    16
    Units: N/A
        arithmetic mean (standard deviation)
    33.9 ( 17.4 )
    25.7 ( 17.2 )
    25.3 ( 15.2 )
    No statistical analyses for this end point

    Secondary: DASH

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    End point title
    		 DASH
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, 3, 6 and 12 months
    End point values
    		 Treatment Treatment Treatment
    Number of subjects analysed
    18
    18
    16
    Units: N/A
        arithmetic mean (standard deviation)
    22.3 ( 11.3 )
    16.9 ( 12 )
    18.3 ( 11.2 )
    No statistical analyses for this end point

    Secondary: SF-36

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    End point title
    		 SF-36
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, 3, 6, and 12 months
    End point values
    		 Treatment Treatment Treatment
    Number of subjects analysed
    18
    18
    16
    Units: N/A
        arithmetic mean (standard deviation)
    72.8 ( 19.8 )
    77.4 ( 16.9 )
    72.1 ( 19.9 )
    No statistical analyses for this end point

    Secondary: ICG-L

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    End point title
    		 ICG-L
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, 6 and 12 months
    End point values
    		 Treatment Treatment Treatment
    Number of subjects analysed
    18
    18
    13
    Units: N/A
    number (not applicable)
        Stage 0
    0
    0
    0
        Stage 1
    0
    0
    0
        Stage 2
    0
    3
    2
        Stage 3
    9
    6
    6
        Stage 4
    9
    9
    5
        Stage 5
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    SEP 2020 - MAR 2022
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 none
    Dictionary version
    0
    Reporting groups
    Reporting group title
    Treatment
    Reporting group description
    		 This is a single arm trial with only the treatment group

    Serious adverse events
    		 Treatment
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 20 (25.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Skin and subcutaneous tissue disorders
    Cellulitis
         subjects affected / exposed
    5 / 20 (25.00%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Treatment
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 20 (30.00%)
    Skin and subcutaneous tissue disorders
    Flushing
         subjects affected / exposed
    6 / 20 (30.00%)
         occurrences all number
    6

    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.
    Lack of control group
    For support, Contact us.
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