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    Clinical Trial Results:
    A long-term follow-up study to assess bone mineral density in subjects with uterine fibroids completing the Phase 3 studies of linzagolix, PRIMROSE 1 or PRIMROSE 2

    Summary
    EudraCT number
    		 2021-000452-19
    Trial protocol
    		 HU   PL   LV   BG   RO  
    Global end of trial date
    14 Nov 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Nov 2023
    First version publication date
    18 Nov 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    20-OBE2109-007
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Kissei Pharmaceutical Co., Ltd.
    Sponsor organisation address
    3-1-3 Koishikawa, Bunkyo-ku, Tokyo, Japan, 112-0002
    Public contact
    Kissei Pharmaceutical Co., Ltd., Clinical Projects Management, rinsyousiken@pharm.kissei.co.jp
    Scientific contact
    Kissei Pharmaceutical Co., Ltd., Clinical Projects Management, rinsyousiken@pharm.kissei.co.jp
    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
    14 Nov 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Nov 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to describe BMD changes for up to 24 months following previous treatment with placebo or linzagolix at 100 mg or 200 mg alone or with ABT for at least 20 weeks in the context of the PRIMROSE 1 and PRIMROSE 2 studies.
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki (adopted Version Fortaleza, Brazil October 2013) as well as with the valid national law(s) of the participating countries, with the International Conference on Harmonisation (ICH) Harmonised Tripartite Guideline for GCP, the US Code of Federal Regulations or the EU Clinical Trial Directive and applicable local laws and regulations.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Apr 2021
    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
    Poland: 27
    Country: Number of subjects enrolled
    Romania: 4
    Country: Number of subjects enrolled
    Bulgaria: 4
    Country: Number of subjects enrolled
    Czechia: 5
    Country: Number of subjects enrolled
    Hungary: 7
    Country: Number of subjects enrolled
    Latvia: 1
    Country: Number of subjects enrolled
    Ukraine: 11
    Country: Number of subjects enrolled
    United States: 75
    Worldwide total number of subjects
    134
    EEA total number of subjects
    48
    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)
    134
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial was conducted in 3 sites in Bulgaria, 4 sites in Czech Republic, 4 sites in Hungary, 1 site in Latvia, 6 sites in Poland, 1 site in Romania, 5 sites in Ukraine and 32 sites in the US.

    Pre-assignment
    Screening details
    		 Of the 137 screened subjects, 134 were enrolled, and 130 were included in SS. Although this study consists of 7 arms, the values of "LGX 200 mg + AB Placebo" group is not included in the below tables because it consists of only 1 subject. Therefore, the No. of "Started" subjects of Period 1 are equal to neither the No. of SS nor enrolled subjects.

    Period 1
    Period 1 title
    For BMD and Safety Evaluation (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 LGX Placebo + AB Placebo
    Arm description
    		 Linzagolix Placebo + Add-back Placebo for 52 weeks
    Arm type
    		 Placebo

    Investigational medicinal product name
    Linzagolix placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Linzagolix: 0 mg

    Investigational medicinal product name
    E2/NETA placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    ESTRADIOL HEMIHYDRATE: 0 mg NORETHISTERONE ACETATE: 0 mg

    Arm title
    		 LGX Placebo + AB Placebo / LGX 200 mg + AB
    Arm description
    		 Linzagolix Placebo + Add-back Placebo for 24 weeks, then Linzagolix 200 mg + Add-back for 28 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Linzagolix placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Linzagolix: 0 mg

    Investigational medicinal product name
    E2/NETA placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    ESTRADIOL HEMIHYDRATE: 0 mg NORETHISTERONE ACETATE: 0 mg

    Investigational medicinal product name
    Linzagolix
    Investigational medicinal product code
    Other name
    OBE2109
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Linzagolix: 100 mg X 2

    Investigational medicinal product name
    E2/NETA
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    ESTRADIOL HEMIHYDRATE: 1 mg NORETHISTERONE ACETATE: 0.5 mg

    Arm title
    		 LGX 100 mg + AB Placebo
    Arm description
    		 Linzagolix 100 mg + Add-back Placebo for 52 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Linzagolix
    Investigational medicinal product code
    Other name
    OBE2109
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Linzagolix: 100 mg

    Investigational medicinal product name
    E2/NETA placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    ESTRADIOL HEMIHYDRATE: 0 mg NORETHISTERONE ACETATE: 0 mg

    Arm title
    		 LGX 100 mg + AB
    Arm description
    		 Linzagolix 100 mg + Add-back for 52 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Linzagolix
    Investigational medicinal product code
    Other name
    OBE2109
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Linzagolix: 100 mg

    Investigational medicinal product name
    E2/NETA
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    ESTRADIOL HEMIHYDRATE: 1 mg NORETHISTERONE ACETATE: 0.5 mg

    Arm title
    		 LGX 200 mg + AB Placebo / LGX 200 mg + AB
    Arm description
    		 Linzagolix 200 mg + Add-back Placebo for 24 weeks, then Linzagolix 200 mg + Add-back for 28 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Linzagolix
    Investigational medicinal product code
    Other name
    OBE2109
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Linzagolix: 100 mg X 2

    Investigational medicinal product name
    E2/NETA placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    ESTRADIOL HEMIHYDRATE: 0 mg NORETHISTERONR ACETATE: 0 mg

    Investigational medicinal product name
    E2/NETA
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    ESTRADIOL HEMIHYDRATE: 1 mg NORETHISTERONE ACETATE: 0.5 mg

    Arm title
    		 LGX 200 mg + AB
    Arm description
    		 Linzagolix 200 mg + add-back for 52 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Linzagolix
    Investigational medicinal product code
    Other name
    OBE2109
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Linzagolix: 100 mg X 2

    Investigational medicinal product name
    E2/NETA
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    ESTRADIOL HEMIHYDRATE: 1 mg NORETHISTERONE ACETATE: 0.5 mg

    Number of subjects in period 1 [1]
    		LGX Placebo + AB Placebo LGX Placebo + AB Placebo / LGX 200 mg + AB LGX 100 mg + AB Placebo LGX 100 mg + AB LGX 200 mg + AB Placebo / LGX 200 mg + AB LGX 200 mg + AB
    Started
    7
    26
    22
    23
    30
    21
    Completed
    7
    23
    16
    21
    23
    19
    Not completed
    0
    3
    6
    2
    7
    2
         Consent withdrawn by subject
    -
    -
    2
    2
    3
    1
         Special military situation in Ukraine
    -
    3
    1
    -
    1
    1
         Lost to follow-up
    -
    -
    2
    -
    2
    -
         Facility closed
    -
    -
    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: A total of 134 subjects were enrolled in the study and 130 subjects were used in BMD and Safety evaluation, and the remaining four subjects were excluded because no DXA data were obtained during the study. Moreover, because the LGX 200mg group was excluded from reporting group, one subject of this group is not presented in the below tables.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    LGX Placebo + AB Placebo
    Reporting group description
    		 Linzagolix Placebo + Add-back Placebo for 52 weeks

    Reporting group title
    LGX Placebo + AB Placebo / LGX 200 mg + AB
    Reporting group description
    		 Linzagolix Placebo + Add-back Placebo for 24 weeks, then Linzagolix 200 mg + Add-back for 28 weeks

    Reporting group title
    LGX 100 mg + AB Placebo
    Reporting group description
    		 Linzagolix 100 mg + Add-back Placebo for 52 weeks

    Reporting group title
    LGX 100 mg + AB
    Reporting group description
    		 Linzagolix 100 mg + Add-back for 52 weeks

    Reporting group title
    LGX 200 mg + AB Placebo / LGX 200 mg + AB
    Reporting group description
    		 Linzagolix 200 mg + Add-back Placebo for 24 weeks, then Linzagolix 200 mg + Add-back for 28 weeks

    Reporting group title
    LGX 200 mg + AB
    Reporting group description
    		 Linzagolix 200 mg + add-back for 52 weeks

    Reporting group values
    		 LGX Placebo + AB Placebo LGX Placebo + AB Placebo / LGX 200 mg + AB LGX 100 mg + AB Placebo LGX 100 mg + AB LGX 200 mg + AB Placebo / LGX 200 mg + AB LGX 200 mg + AB Total
    Number of subjects
    		 7 26 22 23 30 21 129
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0 0
        Adults (18-64 years)
    		 7 26 22 23 30 21 129
        From 65-84 years
    		 0 0 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 39.9 ± 9.0 42.2 ± 6.3 43.9 ± 4.2 43.0 ± 5.4 41.6 ± 5.7 44.7 ± 5.0 -
    Gender categorical
    Units: Subjects
        Female
    		 7 26 22 23 30 21 129
        Male
    		 0 0 0 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    LGX Placebo + AB Placebo
    Reporting group description
    		 Linzagolix Placebo + Add-back Placebo for 52 weeks

    Reporting group title
    LGX Placebo + AB Placebo / LGX 200 mg + AB
    Reporting group description
    		 Linzagolix Placebo + Add-back Placebo for 24 weeks, then Linzagolix 200 mg + Add-back for 28 weeks

    Reporting group title
    LGX 100 mg + AB Placebo
    Reporting group description
    		 Linzagolix 100 mg + Add-back Placebo for 52 weeks

    Reporting group title
    LGX 100 mg + AB
    Reporting group description
    		 Linzagolix 100 mg + Add-back for 52 weeks

    Reporting group title
    LGX 200 mg + AB Placebo / LGX 200 mg + AB
    Reporting group description
    		 Linzagolix 200 mg + Add-back Placebo for 24 weeks, then Linzagolix 200 mg + Add-back for 28 weeks

    Reporting group title
    LGX 200 mg + AB
    Reporting group description
    		 Linzagolix 200 mg + add-back for 52 weeks

    Primary: Change in Lumbar Spine BMD at 24 Months from Post-treatment Baselinee

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    End point title
    		 Change in Lumbar Spine BMD at 24 Months from Post-treatment Baselinee [1]
    End point description
    End point type
    Primary
    End point timeframe
    24 months
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses for this end point.
    End point values
    		 LGX Placebo + AB Placebo LGX Placebo + AB Placebo / LGX 200 mg + AB LGX 100 mg + AB Placebo LGX 100 mg + AB LGX 200 mg + AB Placebo / LGX 200 mg + AB LGX 200 mg + AB
    Number of subjects analysed
    7
    20
    15
    17
    21
    18
    Units: g/cm2
        arithmetic mean (standard deviation)
    0.120 ± 1.848
    -0.375 ± 4.187
    1.477 ± 5.935
    1.507 ± 6.771
    3.173 ± 5.885
    -0.319 ± 4.083
    No statistical analyses for this end point

    Primary: Change in Femoral Neck BMD at 24 Months from Post-treatment Baseline

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    End point title
    		 Change in Femoral Neck BMD at 24 Months from Post-treatment Baseline [2]
    End point description
    End point type
    Primary
    End point timeframe
    24 months
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses for this end point.
    End point values
    		 LGX Placebo + AB Placebo LGX Placebo + AB Placebo / LGX 200 mg + AB LGX 100 mg + AB Placebo LGX 100 mg + AB LGX 200 mg + AB Placebo / LGX 200 mg + AB LGX 200 mg + AB
    Number of subjects analysed
    7
    21
    15
    17
    20
    18
    Units: g/cm2
        arithmetic mean (standard deviation)
    3.230 ± 7.789
    -2.071 ± 10.565
    1.236 ± 6.635
    -0.113 ± 5.861
    1.643 ± 4.749
    -1.259 ± 3.352
    No statistical analyses for this end point

    Primary: Change in Total Hip BMD at 24 Months from Post-treatment Baseline

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    End point title
    		 Change in Total Hip BMD at 24 Months from Post-treatment Baseline [3]
    End point description
    End point type
    Primary
    End point timeframe
    24 months
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses for this end point.
    End point values
    		 LGX Placebo + AB Placebo LGX Placebo + AB Placebo / LGX 200 mg + AB LGX 100 mg + AB Placebo LGX 100 mg + AB LGX 200 mg + AB Placebo / LGX 200 mg + AB LGX 200 mg + AB
    Number of subjects analysed
    7
    21
    15
    17
    20
    18
    Units: g/cm2
        arithmetic mean (standard deviation)
    5.263 ± 5.548
    -2.633 ± 9.196
    0.431 ± 3.337
    -0.377 ± 3.842
    1.559 ± 4.431
    0.697 ± 4.951
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Up to 24 months
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    LGX Placebo + AB Placebo
    Reporting group description
    		 -

    Reporting group title
    LGX Placebo + AB Placebo / LGX 200 mg + AB
    Reporting group description
    		 -

    Reporting group title
    LGX 100 mg + AB Placebo
    Reporting group description
    		 -

    Reporting group title
    LGX 100 mg + AB
    Reporting group description
    		 -

    Reporting group title
    LGX 200 mg + AB Placebo / LGX 200 mg + AB
    Reporting group description
    		 -

    Reporting group title
    LGX 200 mg + AB
    Reporting group description
    		 -

    Serious adverse events
    		 LGX Placebo + AB Placebo LGX Placebo + AB Placebo / LGX 200 mg + AB LGX 100 mg + AB Placebo LGX 100 mg + AB LGX 200 mg + AB Placebo / LGX 200 mg + AB LGX 200 mg + AB
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
    0 / 23 (0.00%)
    0 / 30 (0.00%)
    0 / 21 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 LGX Placebo + AB Placebo LGX Placebo + AB Placebo / LGX 200 mg + AB LGX 100 mg + AB Placebo LGX 100 mg + AB LGX 200 mg + AB Placebo / LGX 200 mg + AB LGX 200 mg + AB
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
    0 / 23 (0.00%)
    0 / 30 (0.00%)
    0 / 21 (0.00%)
    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: This is a long-term follow-up study, and no procedure-related AE during the study.

    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
    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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