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    Clinical Trial Results:
    GENOTYPE AND PHENOTYPE GUIDED SUPPLEMENTATION OF TAMOXIFEN STANDARD THERAPY WITH ENDOXIFEN IN BREAST CANCER PATIENTS.

    Summary
    EudraCT number
    		 2016-000418-31
    Trial protocol
    		 DE  
    Global end of trial date
    03 May 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Dec 2025
    First version publication date
    04 Dec 2025
    Other versions
    Summary report(s)
    		 Clinical Study Report

    Trial information

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    Trial identification
    Sponsor protocol code
    IKP275
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03931928
    WHO universal trial number (UTN)
    		 U1111-1237-9906
    Other trial identifiers
    		 GBG Forschungs GmbH: GBG 91
    Sponsors
    Sponsor organisation name
    Robert Bosch Gesellschaft für medizinische Forschung mbH
    Sponsor organisation address
    Auerbachstr. 112, Stuttgart, Germany, 70376
    Public contact
    Sponsor, Robert Bosch Gesellschaft für medizinische Forschung mbH, 49 7118101 3700, matthias.schwab@ikp-stuttgart.de
    Scientific contact
    Sponsor, Robert Bosch Gesellschaft für medizinische Forschung mbH, +49 071181013700, matthias.schwab@ikp-stuttgart.de
    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
    24 Jan 2025
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 May 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    03 May 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To increase (Z)-endoxifen steady state concentrations in patients with compromised CYP2D6 to levels observed in patients with full CYP2D6 activity. The target concentration is >32 nM.
    Protection of trial subjects
    The clinical study was conducted in accordance with the Declaration of Helsinki (Sommerset West, 1996), lastly amended by the 64th WMA General Assembly, Fortaleza, Brazil, October 2013, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) – Guideline for Good Clinical Practice E6(R2), and the respective Commission Directives in the European Community, as well as the German Medicinal Products Act and the German GCP Ordinance, and other applicable national German laws and regulations. Prior to the start of the study, the favourable opinion of the Competent Ethics Committee (EC) (25 March 2019) and the approval of the Competent Authority (CA) (01 April 2019) were obtained. The clinical study was also submitted to the local EC of each study centre for review.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Sep 2019
    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
    Germany: 338
    Worldwide total number of subjects
    338
    EEA total number of subjects
    338
    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)
    314
    From 65 to 84 years
    24
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients who were receiving Tamoxifen therapy (20 mg/day) for at least three months and presumably matched the inclusion and exclusion criteria were approached and informed on the scope of the study.

    Pre-assignment
    Screening details
    		 Main Inclusion Criteria: Pre- and postmenopausal female patients with DCIS or stage I, IIA, IIB or IIIA invasive breast cancer who have received at least three months standard tamoxifen treatment before baseline visit Main Exclusion Criteria: Locally advanced (Stage IIIB or IIIC) or metastatic (Stage IV) breast cancer at time of surgery, ongoing c

    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
    		 Subject
    Blinding implementation details
    Patients were randomly assigned to one of the three groups: Group 1 was the control group, received placebo; group 2: (Z)-endoxifen supplementation according to CYP2D6 genotype; group 3: (Z)-endoxifen supplementation according to basal (Z)-endoxifen plasma concentration in a 1:1:1 ratio. A permuted block design with random blocks was applied and the allocation sequence was generated using a computerized algorithm. The resulting randomization list was implemented in MedCODES®.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Control group
    Arm description
    		 Patients received placebo independent of CYP2D6 genotype
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Enteric-coated tablets containing 0 mg (Z)-endoxifen (Placebo)

    Arm title
    		 Genotype group
    Arm description
    		 Patients received (Z)-endoxifen dosed according to CYP2D6 “genotype” (i.e. genotype predicted IM or PM activity) or placebo (genotype predicted EM /UM).
    Arm type
    		 Experimental

    Investigational medicinal product name
    (Z)-endoxifen
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One tablet 1.5 mg per day or one tablet 3 mg per day or placebo depending on genotype

    Arm title
    		 Phenotype group
    Arm description
    		 Patients received (Z)-endoxifen dosed according to (Z)-endoxifen steady state plasma concentrations (phenotype) at screening (i.e. ≤ 15 nM or > 15 and ≤ 25 nM) under tamoxifen treatment with 20 mg/day or placebo (> 25 nM).
    Arm type
    		 Experimental

    Investigational medicinal product name
    (Z)-endoxifen
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One tablet 1.5 mg per day or one tablet 3 mg per day or placebo depending on phenotype

    Number of subjects in period 1 [1]
    		Control group Genotype group Phenotype group
    Started
    83
    81
    82
    Completed
    79
    78
    78
    Not completed
    4
    3
    4
         Physician decision
    1
    -
    1
         Patient’s decision
    3
    2
    2
         COVID-19 infection
    -
    1
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Recruitment was interrupted from March to August 2020 due to COVID-19, and patient numbers were lower than expected. Thus, amendment 1 (26.06.2020) introduced an interim analysis with a corresponding SAP (29.12.2020). The interim results met the primary endpoint, so the study was terminated with 235 analyzed patients, within the sample range for stage 2 of the revised SAP (29.12.2020). Reaching the initially planned number of patients was therefore unnecessary.

    Baseline characteristics

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

    Reporting group values
    		 overall trial Total
    Number of subjects
    		 246 246
    Age categorical
    18 -76 years
    Units: Subjects
        18 - 76 years
    		 246 246
    Gender categorical
    Units: Subjects
        Female
    		 246 246
    Subject analysis sets

    Subject analysis set title
    Genotype versus control
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Genotype group was compared with the control group

    Subject analysis set title
    Phenotype versus control
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Phenotype group was compared with the control group

    Subject analysis sets values
    		 Genotype versus control Phenotype versus control
    Number of subjects
    157
    157
    Age categorical
    18 -76 years
    Units: Subjects
        18 - 76 years
    157
    157
    Age continuous
    Units:
        
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    157
    157

    End points

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    End points reporting groups
    Reporting group title
    Control group
    Reporting group description
    		 Patients received placebo independent of CYP2D6 genotype

    Reporting group title
    Genotype group
    Reporting group description
    		 Patients received (Z)-endoxifen dosed according to CYP2D6 “genotype” (i.e. genotype predicted IM or PM activity) or placebo (genotype predicted EM /UM).

    Reporting group title
    Phenotype group
    Reporting group description
    		 Patients received (Z)-endoxifen dosed according to (Z)-endoxifen steady state plasma concentrations (phenotype) at screening (i.e. ≤ 15 nM or > 15 and ≤ 25 nM) under tamoxifen treatment with 20 mg/day or placebo (> 25 nM).

    Subject analysis set title
    Genotype versus control
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Genotype group was compared with the control group

    Subject analysis set title
    Phenotype versus control
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Phenotype group was compared with the control group

    Primary: proportion of patients in the control group that reaches steady state (Z)-endoxifen plasma concentration of > 32 nM

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    End point title
    		 proportion of patients in the control group that reaches steady state (Z)-endoxifen plasma concentration of > 32 nM
    End point description
    The primary endpoint is reached if in one or both intervention groups, the proportion of patients with steady state (Z)-endoxifen plasma concentration > 32 nM is greater or equal to the proportion of patients in the control group that reaches steady state (Z)-endoxifen plasma concentration of > 32 nM
    End point type
    Primary
    End point timeframe
    6 weeks
    End point values
    		 Control group Genotype group Phenotype group Genotype versus control Phenotype versus control
    Number of subjects analysed
    79
    78
    78
    157
    157
    Units: 1
    79
    78
    78
    157
    157
    Statistical analysis title
    		 Efficacy Analyses
    Statistical analysis description
    Comparison of the proportion of patients with steady state (Z)-endoxifen plasma levels above 32 nM endoxifen following (Z)-endoxifen supplementation after 6 weeks.
    Comparison groups
    Control group v Genotype group v Phenotype group
    Number of subjects included in analysis
    235
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 ≤ 0.05
    Method
    		 Mantel-Haenszel
    Confidence interval
    Notes
    [1] - The proportion of patients with steady state (Z)-endoxifen plasma levels above 32 nM endoxifen following (Z)-endoxifen supplementation after 6 weeks were compared to the control group (Group 1) and statistically assessed by means of two Mantel-Haenszel χ2-tests (Group 2 vs. control and Group 3 vs. control) to examine the null hypothesis of equal proportions in the supplementation groups and the control group.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were monitored from the date of the first administration of study medication (6 weeks) and 4 weeks of follow-up (visits 1–4).
    Adverse event reporting additional description
    All AEs in patients who received 3 mg (Z)-endoxifen, 1.5 mg (Z)-endoxifen, or placebo are listed. AEs were monitored from the date of the first administration of study medication and 4 weeks of follow-up (visits 1–4). In case the same AE was observed several times, it was counted only once with the greatest severity monitored. For the individual or
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Control group
    Reporting group description
    		 Placebo group

    Reporting group title
    Genotype group
    Reporting group description
    		 -

    Reporting group title
    Phenotype group
    Reporting group description
    		 -

    Serious adverse events
    		 Control group Genotype group Phenotype group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 78 (0.00%)
    0 / 78 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Control group Genotype group Phenotype group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    67 / 79 (84.81%)
    63 / 78 (80.77%)
    65 / 78 (83.33%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 79 (5.06%)
    9 / 78 (11.54%)
    3 / 78 (3.85%)
         occurrences all number
    16
    16
    16
    Aspartate aminotransferase increased
         subjects affected / exposed
    6 / 79 (7.59%)
    7 / 78 (8.97%)
    4 / 78 (5.13%)
         occurrences all number
    17
    17
    17
    Blood alkaline phosphatase increased
         subjects affected / exposed
    10 / 79 (12.66%)
    8 / 78 (10.26%)
    4 / 78 (5.13%)
         occurrences all number
    22
    22
    22
    Blood creatine increased
         subjects affected / exposed
    5 / 79 (6.33%)
    6 / 78 (7.69%)
    4 / 78 (5.13%)
         occurrences all number
    15
    15
    15
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    9 / 79 (11.39%)
    11 / 78 (14.10%)
    6 / 78 (7.69%)
         occurrences all number
    26
    26
    26
    Vascular disorders
    Hot flush
         subjects affected / exposed
    23 / 79 (29.11%)
    25 / 78 (32.05%)
    26 / 78 (33.33%)
         occurrences all number
    74
    74
    74
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    5 / 79 (6.33%)
    7 / 78 (8.97%)
    2 / 78 (2.56%)
         occurrences all number
    14
    14
    14
    Headache
         subjects affected / exposed
    21 / 79 (26.58%)
    19 / 78 (24.36%)
    19 / 78 (24.36%)
         occurrences all number
    59
    59
    59
    Paraesthesia
         subjects affected / exposed
    7 / 79 (8.86%)
    1 / 78 (1.28%)
    3 / 78 (3.85%)
         occurrences all number
    11
    11
    11
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    19 / 79 (24.05%)
    10 / 78 (12.82%)
    14 / 78 (17.95%)
         occurrences all number
    43
    43
    43
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    2 / 79 (2.53%)
    1 / 78 (1.28%)
    5 / 78 (6.41%)
         occurrences all number
    8
    8
    8
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    5 / 79 (6.33%)
    1 / 78 (1.28%)
    5 / 78 (6.41%)
         occurrences all number
    11
    11
    11
    Nausea
         subjects affected / exposed
    8 / 79 (10.13%)
    2 / 78 (2.56%)
    4 / 78 (5.13%)
         occurrences all number
    14
    14
    14
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    0 / 79 (0.00%)
    4 / 78 (5.13%)
    0 / 78 (0.00%)
         occurrences all number
    4
    4
    4
    Vaginal discharge
         subjects affected / exposed
    8 / 79 (10.13%)
    7 / 78 (8.97%)
    3 / 78 (3.85%)
         occurrences all number
    18
    18
    18
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    5 / 79 (6.33%)
    3 / 78 (3.85%)
    4 / 78 (5.13%)
         occurrences all number
    12
    12
    12
    Dry skin
         subjects affected / exposed
    2 / 79 (2.53%)
    4 / 78 (5.13%)
    2 / 78 (2.56%)
         occurrences all number
    8
    8
    8
    Rash
         subjects affected / exposed
    4 / 79 (5.06%)
    2 / 78 (2.56%)
    2 / 78 (2.56%)
         occurrences all number
    8
    8
    8
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    7 / 79 (8.86%)
    2 / 78 (2.56%)
    4 / 78 (5.13%)
         occurrences all number
    13
    13
    13
    Sleep disorder
         subjects affected / exposed
    2 / 79 (2.53%)
    3 / 78 (3.85%)
    4 / 78 (5.13%)
         occurrences all number
    9
    9
    9
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    6 / 79 (7.59%)
    8 / 78 (10.26%)
    4 / 78 (5.13%)
         occurrences all number
    18
    18
    18
    Bone pain
         subjects affected / exposed
    0 / 79 (0.00%)
    4 / 78 (5.13%)
    1 / 78 (1.28%)
         occurrences all number
    5
    5
    5
    Muscle spasms
         subjects affected / exposed
    10 / 79 (12.66%)
    8 / 78 (10.26%)
    7 / 78 (8.97%)
         occurrences all number
    25
    25
    25
    Myalgia
         subjects affected / exposed
    8 / 79 (10.13%)
    4 / 78 (5.13%)
    5 / 78 (6.41%)
         occurrences all number
    17
    17
    17
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    3 / 79 (3.80%)
    2 / 78 (2.56%)
    6 / 78 (7.69%)
         occurrences all number
    11
    11
    11
    Metabolism and nutrition disorders
    Fluid retention
         subjects affected / exposed
    6 / 79 (7.59%)
    2 / 78 (2.56%)
    5 / 78 (6.41%)
         occurrences all number
    13
    13
    13

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Jun 2020
    Due to the COVID-19 pandemic, the patient recruitment had to be stopped in March 2020. In the substantial protocol amendment no. 1, dated 26-Jun-2020, an interim analysis was implemented and recruitment was restarted in August 2020. A hierarchical design was chosen to reduce the total number of patients necessary.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    31 Mar 2020
    Due to the COVID-19 pandemic, patient recruitment had to be stopped in March 2020. In August 2020, a substantial amendment was prepared to resume the study (Amendment No. 1 (substantial), Version 1.0, dated 26 June 2020).
    24 Aug 2020

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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