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    Clinical Trial Results:
    A Phase 3 multicenter, randomized, double-blind, placebo-controlled, clinical study to assess the efficacy and safety of linzagolix in subjects with moderate to severe endometriosis-associated pain.

    Summary
    EudraCT number
    		 2019-000283-26
    Trial protocol
    		 FR   HU   AT   CZ   PL   ES   BG   RO  
    Global end of trial date
    28 Jun 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Jul 2023
    First version publication date
    23 Jul 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    18-OBE2109-003
    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
    22 Dec 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Apr 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Jun 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the efficacy and safety of linzagolix administered orally once daily for 3 months at a dose of 75 mg alone or of 200 mg in combination with add-back therapy versus placebo, in the management of moderate to severe endometriosis-associated pain.
    Protection of trial subjects
    The study was conducted in accordance with the ethical principles that have their origins in the Declaration of Helsinki and with Good Clinical Practice (GCP) rules and in line with local regulatory requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Jun 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
    Poland: 179
    Country: Number of subjects enrolled
    Romania: 49
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Bulgaria: 13
    Country: Number of subjects enrolled
    Czechia: 6
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Hungary: 2
    Country: Number of subjects enrolled
    Ukraine: 205
    Country: Number of subjects enrolled
    United States: 26
    Worldwide total number of subjects
    486
    EEA total number of subjects
    255
    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)
    486
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 71 clinical sites throughout the world, including centers in Austria, Bulgaria, Czech Republic, France, Hungary, Poland, Romania, Spain, Ukraine, and United States

    Pre-assignment
    Screening details
    		 Number of subjects: - 854 screened - 486 randomized; 2 discontinued study between randomization and Day 1 due to protocol deviation - 484 included in both of Full Analysis Set (FAS) and Safety Analysis Set (SAF)

    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, Monitor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 LGX 75 mg group
    Arm description
    		 Linzagolix 75 mg + Placebo ABT Once daily for 6 months
    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
    75 mg

    Arm title
    		 LGX 200 mg + ABT group
    Arm description
    		 Linzagolix 200 mg + ABT Once daily for 6 months
    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
    200 mg

    Investigational medicinal product name
    ESTRADIOL HEMIHYDRATE/NORETHISTERONE ACETATE
    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
    		 Placebo group
    Arm description
    		 Placebo Linzagolix + Placebo ABT Once daily for 6 months
    Arm type
    		 Placebo

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

    Investigational medicinal product name
    Placebo ABT
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    0 mg

    Number of subjects in period 1 [1]
    		LGX 75 mg group LGX 200 mg + ABT group Placebo group
    Started
    160
    162
    162
    Day 1
    160
    162
    162
    Month 3
    149
    155
    149
    Month 6
    140
    143
    137
    Completed
    140
    143
    137
    Not completed
    20
    19
    25
         Consent withdrawn by subject
    8
    10
    20
         Adverse event, non-fatal
    8
    6
    3
         Other
    1
    -
    -
         Pregnancy
    2
    -
    1
         Lost to follow-up
    -
    1
    1
         Protocol deviation
    1
    2
    -
    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: The number of subjects reported to be in the baseline period are as per the Full Analysis Set (FAS). A total of 486 subjects were randomized, 484 subjects were included in the FAS. Two randomized subjects were excluded: these 2 subjects discontinued the study between randomization and Day 1 due to protocol deviation.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    LGX 75 mg group
    Reporting group description
    		 Linzagolix 75 mg + Placebo ABT Once daily for 6 months

    Reporting group title
    LGX 200 mg + ABT group
    Reporting group description
    		 Linzagolix 200 mg + ABT Once daily for 6 months

    Reporting group title
    Placebo group
    Reporting group description
    		 Placebo Linzagolix + Placebo ABT Once daily for 6 months

    Reporting group values
    		 LGX 75 mg group LGX 200 mg + ABT group Placebo group Total
    Number of subjects
    		 160 162 162 484
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 160 162 162 484
        From 65-84 years
    		 0 0 0 0
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 35.1 ( 6.4 ) 34.6 ( 6.8 ) 34.9 ( 6.8 ) -
    Gender categorical
    Units: Subjects
        Female
    		 160 162 162 484
        Male
    		 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    LGX 75 mg group
    Reporting group description
    		 Linzagolix 75 mg + Placebo ABT Once daily for 6 months

    Reporting group title
    LGX 200 mg + ABT group
    Reporting group description
    		 Linzagolix 200 mg + ABT Once daily for 6 months

    Reporting group title
    Placebo group
    Reporting group description
    		 Placebo Linzagolix + Placebo ABT Once daily for 6 months

    Primary: Reduction of DYS at Month 3 - Proportion of responders

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    End point title
    		 Reduction of DYS at Month 3 - Proportion of responders
    End point description
    End point type
    Primary
    End point timeframe
    3 months
    End point values
    		 LGX 75 mg group LGX 200 mg + ABT group Placebo group
    Number of subjects analysed
    160
    162
    162
    Units: percent
        number (confidence interval 95%)
    44.0 (36.3 to 52.0)
    72.9 (65.3 to 79.4)
    23.5 (17.5 to 30.7)
    Statistical analysis title
    		 p-value of treatment effect
    Comparison groups
    LGX 75 mg group v Placebo group
    Number of subjects included in analysis
    322
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 Bonferroni-corrected p-value
    Confidence interval
    Statistical analysis title
    		 p-value of treatment effect
    Comparison groups
    LGX 200 mg + ABT group v Placebo group
    Number of subjects included in analysis
    324
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 Bonferroni-corrected p-value
    Confidence interval

    Primary: Reduction of NMPP at Month 3 - Proportion of responders

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    End point title
    		 Reduction of NMPP at Month 3 - Proportion of responders
    End point description
    End point type
    Primary
    End point timeframe
    3 months
    End point values
    		 LGX 75 mg group LGX 200 mg + ABT group Placebo group
    Number of subjects analysed
    160
    162
    162
    Units: percent
        number (confidence interval 95%)
    38.9 (31.5 to 46.9)
    47.3 (39.5 to 55.3)
    30.9 (24.1 to 38.6)
    Statistical analysis title
    		 p-value of treatment effect
    Comparison groups
    LGX 75 mg group v Placebo group
    Number of subjects included in analysis
    322
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.279
    Method
    		 Bonferroni-corrected p-value
    Confidence interval
    Statistical analysis title
    		 p-value of treatment effect
    Comparison groups
    LGX 200 mg + ABT group v Placebo group
    Number of subjects included in analysis
    324
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.007
    Method
    		 Bonferroni-corrected p-value
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 to Month 6
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    LGX 75 mg group
    Reporting group description
    		 -

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

    Reporting group title
    Placebo group
    Reporting group description
    		 -

    Serious adverse events
    		 LGX 75 mg group LGX 200 mg + ABT group Placebo group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 160 (1.25%)
    2 / 162 (1.23%)
    0 / 162 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 162 (0.62%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Endometriosis
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 162 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Peritonitis
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 162 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 162 (0.62%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 LGX 75 mg group LGX 200 mg + ABT group Placebo group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    83 / 160 (51.88%)
    94 / 162 (58.02%)
    69 / 162 (42.59%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    12 / 160 (7.50%)
    11 / 162 (6.79%)
    4 / 162 (2.47%)
         occurrences all number
    15
    11
    4
    Nervous system disorders
    Headache
         subjects affected / exposed
    13 / 160 (8.13%)
    17 / 162 (10.49%)
    13 / 162 (8.02%)
         occurrences all number
    17
    24
    25
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    6 / 160 (3.75%)
    11 / 162 (6.79%)
    4 / 162 (2.47%)
         occurrences all number
    6
    11
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 160 (3.13%)
    4 / 162 (2.47%)
    10 / 162 (6.17%)
         occurrences all number
    5
    4
    13
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    6 / 160 (3.75%)
    6 / 162 (3.70%)
    7 / 162 (4.32%)
         occurrences all number
    6
    6
    7
    Abdominal distension
         subjects affected / exposed
    4 / 160 (2.50%)
    6 / 162 (3.70%)
    3 / 162 (1.85%)
         occurrences all number
    4
    6
    4
    Diarrhoea
         subjects affected / exposed
    4 / 160 (2.50%)
    2 / 162 (1.23%)
    5 / 162 (3.09%)
         occurrences all number
    4
    2
    5
    Constipation
         subjects affected / exposed
    3 / 160 (1.88%)
    5 / 162 (3.09%)
    2 / 162 (1.23%)
         occurrences all number
    3
    5
    2
    Reproductive system and breast disorders
    Vaginal haemorrhage
         subjects affected / exposed
    4 / 160 (2.50%)
    6 / 162 (3.70%)
    1 / 162 (0.62%)
         occurrences all number
    5
    7
    1
    Breast pain
         subjects affected / exposed
    1 / 160 (0.63%)
    2 / 162 (1.23%)
    5 / 162 (3.09%)
         occurrences all number
    1
    2
    5
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 160 (0.63%)
    3 / 162 (1.85%)
    5 / 162 (3.09%)
         occurrences all number
    1
    3
    5
    Psychiatric disorders
    Mood swings
         subjects affected / exposed
    8 / 160 (5.00%)
    5 / 162 (3.09%)
    3 / 162 (1.85%)
         occurrences all number
    8
    6
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    8 / 160 (5.00%)
    3 / 162 (1.85%)
    2 / 162 (1.23%)
         occurrences all number
    8
    3
    2
    Infections and infestations
    COVID-19
         subjects affected / exposed
    5 / 160 (3.13%)
    6 / 162 (3.70%)
    5 / 162 (3.09%)
         occurrences all number
    5
    6
    5
    Urinary tract infection
         subjects affected / exposed
    3 / 160 (1.88%)
    7 / 162 (4.32%)
    0 / 162 (0.00%)
         occurrences all number
    3
    7
    0

    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
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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