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    Clinical Trial Results:
    A Randomized, Double-blind, Placebo-controlled, Phase 2 Study to Assess the Efficacy, Safety, and Dose-Response Relationship of ASP1707 in Subjects with Endometriosis Associated Pelvic Pain for 12 Weeks, Followed by a 12-Week Double-blind Extension Without Placebo Control, Including a 24-Week Open-Label Leuprorelin Acetate Treatment Group for Bone Mineral Density Assessment

    Summary
    EudraCT number
    		 2012-002791-14
    Trial protocol
    		 HU   BE   GB   PL   BG  
    Global end of trial date
    30 Jul 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Aug 2016
    First version publication date
    10 Aug 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    1707-CL-0011
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01767090
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Acronym: TERRA
    Sponsors
    Sponsor organisation name
    Astellas Pharma BV
    Sponsor organisation address
    Sylviusweg 62, Leiden, Netherlands, 2333 BE
    Public contact
    Clinical Trial Disclosure, Astellas Pharma BV, Astellas.resultsdisclosure@astellas.com
    Scientific contact
    Clinical Trial Disclosure, Astellas Pharma BV, Astellas.resultsdisclosure@astellas.com
    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
    30 Jul 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jul 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Part 1 (Weeks 1-12, Double-blind Phase; Placebo, ASP1707 and Open-label Active-control) Primary Objectives: ● To assess the efficacy of ASP1707 in reduction of endometriosis associated pelvic pain ● To assess the dose-response relationship of ASP1707 in reduction of endometriosis associated pelvic pain Part 2 (Weeks 13-24, Double-blind Extension Phase; ASP1707 and Open-label Active-control) Objectives: ● To assess 24-week safety and tolerability of ASP1707, including BMD, E2 levels and menstrual bleeding control ● To assess 24-week efficacy of ASP1707 in reduction of endometriosis associated pelvic pain ● To assess the pharmacokinetics of ASP1707 in patients with endometriosis associated pelvic pain
    Protection of trial subjects
    This clinical study was written, conducted and reported in accordance with the protocol, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Guidelines, and applicable local regulations, including the European Directive 2001/20/EC, on the protection of human rights, and with the ethical principles that have their origin in the Declaration of Helsinki. Astellas ensures that the use and disclosure of protected health information (PHI) obtained during a research study complies with the federal, national and/or regional legislation related to the privacy and protection of personal information.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 Dec 2012
    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
    Belgium: 9
    Country: Number of subjects enrolled
    Bulgaria: 15
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Hungary: 29
    Country: Number of subjects enrolled
    Japan: 149
    Country: Number of subjects enrolled
    Poland: 136
    Country: Number of subjects enrolled
    Romania: 111
    Country: Number of subjects enrolled
    Ukraine: 84
    Country: Number of subjects enrolled
    United Kingdom: 3
    Worldwide total number of subjects
    540
    EEA total number of subjects
    307
    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)
    540
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 This multinational, multicenter study was conducted at 97 contracted sites; 86 sites screened partcipants & 71 sites randomized participants in a total of 9 countries: Belgium (5 sites), Bulgaria (4 sites), Germany (2 sites), Hungary (7 sites), Poland (8 sites), Romania (6 sites), Ukraine (6 sites), the United Kingdom (2 sites) & Japan (31 sites).

    Pre-assignment
    Screening details
    		 After initial screening, eligible subjects enrolled into a non-medicated observational period, which included at least one complete menstrual cycle. After the observational period patients who met selection criteria were randomized into Part 1 of the study. Overall, 912 subjects were screened, 372 failed screening and 540 subjects were randomized.

    Period 1
    Period 1 title
    Overall Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    The study drug, except for open-label active control (leuprorelin acetate), was packed using a double-blind method. All participants took 3 tablets once daily in the morning of which none, one, two or all tablets were placebo (15 mg group: 3x5 mg, 10 mg group: 2x5 mg and 1 placebo, 5 mg group 1x5 mg and 2 placebo, 3 mg group: 3x1 mg, placebo group: 3 placebo). All tablets were identical. Participants randomized to open-label leuprorelin acetate received open-label injections only.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo - Part 1
    Arm description
    		 Participants received 3 matching placebo tablets once a day for 12 weeks in Part 1.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo to match ASP1707
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo to ASP1707 taken orally once a day.

    Arm title
    		 ASP1707 3 mg
    Arm description
    		 Participants received ASP1707 3 mg treatment for both part 1 and 2 of the study (weeks 1-24). Participants took 3 tablets once daily in the morning of which no tablets were placebo (3 mg group: 3x1 mg).
    Arm type
    		 Experimental

    Investigational medicinal product name
    ASP1707 3 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received ASP1707 3 mg (3x1 mg tablets) orally once a day. The tablets contained ASP1707 as the active compound in 1 mg dosage strengths.

    Arm title
    		 ASP1707 5 mg
    Arm description
    		 Participants received ASP1707 5 mg treatment for both part 1 and 2 of the study (weeks 1-24). Participants took 3 tablets once daily in the morning of which two tablets were placebo (5 mg group 1x5 mg and 2 placebo).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo to match ASP1707
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo to ASP1707 taken orally once a day.

    Investigational medicinal product name
    ASP1707 5 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received ASP1707 5 mg (1x5 mg tablet) orally once a day. The tablets contained ASP1707 as the active compound in 5 mg dosage strengths.

    Arm title
    		 ASP1707 10 mg
    Arm description
    		 Participants received ASP1707 10 mg treatment for both part 1 and 2 of the study (weeks 1-24). Participants took 3 tablets once daily in the morning of which one tablet was placebo (10 mg group: 2x5 mg and 1 placebo).
    Arm type
    		 Experimental

    Investigational medicinal product name
    ASP1707 10 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received ASP1707 10 mg (2x5 mg tablets) orally once a day. The tablets contained ASP1707 as the active compound in 5 mg dosage strengths.

    Investigational medicinal product name
    Placebo to match ASP1707
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo to ASP1707 taken orally once a day.

    Arm title
    		 ASP1707 15 mg
    Arm description
    		 Participants received ASP1707 15 mg treatment for both part 1 and 2 of the study (weeks 1-24). Participants took 3 tablets once daily in the morning of which no tablets were placebo (15 mg group: 3x5 mg).
    Arm type
    		 Experimental

    Investigational medicinal product name
    ASP1707 15 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received ASP1707 15 mg (3x5 mg tablets) orally once a day. The tablets contained ASP1707 as the active compound in 5 mg dosage strengths.

    Arm title
    		 Leuprorelin acetate
    Arm description
    		 Participants received open-label gonadotropin-releasing hormone (GnRH) agonist 3.75 mg leuprorelin acetate (administered by subcutaneous injection once a month) for both part 1 and 2 of the study (for up to 24 weeks).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Leuprorelin Acetate
    Investigational medicinal product code
    Other name
    Prostap® SR
    Pharmaceutical forms
    Powder and solvent for solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Leuprorelin acetate 3.75 mg monthly subcutaneous injection.

    Number of subjects in period 1
    		Placebo - Part 1 ASP1707 3 mg ASP1707 5 mg ASP1707 10 mg ASP1707 15 mg Leuprorelin acetate
    Started
    89
    87
    92
    90
    90
    92
    Treated
    88
    86
    91
    90
    88
    89
    Completed
    75
    68
    79
    72
    68
    69
    Not completed
    14
    19
    13
    18
    22
    23
         Randomized but never received study drug
    1
    1
    1
    -
    2
    3
         Protocol violation
    9
    11
    3
    9
    5
    5
         Other
    1
    -
    1
    -
    -
    1
         Pregnancy
    1
    1
    1
    -
    1
    -
         Adverse event
    -
    4
    3
    2
    7
    2
         Withdrawal by subject
    2
    2
    4
    7
    7
    12
    Period 2
    Period 2 title
    Part 2 (Placebo arm switched to ASP1707)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    The study drug, except for open- label active control, was packed using a double-blind method. All participants took 3 tablets once daily in the morning of which none, one, two or all tablets were placebo (15 mg group: 3x5 mg, 10 mg group: 2x5 mg and 1 placebo, 5 mg group 1x5 mg and 2 placebo). All tablets were identical.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ASP1707 3 mg - Part 2
    Arm description
    		 Participants who received placebo in part 1 were switched to ASP1707 3 mg treatment for part 2 of the study. Participants took 3 tablets once daily in the morning of which no tablets were placebo (3 mg group: 3x1 mg).
    Arm type
    		 Experimental

    Investigational medicinal product name
    ASP1707 3 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received ASP1707 3 mg (3x1 mg tablets) orally once a day. The tablets contained ASP1707 as the active compound in 1 mg dosage strengths.

    Arm title
    		 ASP1707 5 mg - Part 2
    Arm description
    		 Participants who received placebo in part 1 were switched to ASP1707 5 mg treatment for part 2 of the study. Participants took 3 tablets once daily in the morning of which two tablets were placebo (5 mg group 1x5 mg and 2 placebo).
    Arm type
    		 Experimental

    Investigational medicinal product name
    ASP1707 5 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received ASP1707 5 mg (1x5 mg tablet) orally once a day. The tablets contained ASP1707 as the active compound in 5 mg dosage strengths.

    Investigational medicinal product name
    Placebo to match ASP1707
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo to ASP1707 taken orally once a day.

    Arm title
    		 ASP1707 10 mg - Part 2
    Arm description
    		 Participants who received placebo in part 1 were switched to ASP1707 10 mg treatment for part 2 of the study. Participants took 3 tablets once daily in the morning of which one tablet was placebo (10 mg group: 2x5 mg and 1 placebo).
    Arm type
    		 Experimental

    Investigational medicinal product name
    ASP1707 10 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received ASP1707 10 mg (2x5 mg tablets) orally once a day. The tablets contained ASP1707 as the active compound in 5 mg dosage strengths.

    Investigational medicinal product name
    Placebo to match ASP1707
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo to ASP1707 taken orally once a day.

    Arm title
    		 ASP1707 15 mg - Part 2
    Arm description
    		 Participants who received placebo in part 1 were switched to ASP1707 15 mg treatment for part 2 of the study. Participants took 3 tablets once daily in the morning of which no tablets were placebo (15 mg group: 3x5 mg).
    Arm type
    		 Experimental

    Investigational medicinal product name
    ASP1707 15 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received ASP1707 15 mg (3x5 mg tablets) orally once a day. The tablets contained ASP1707 as the active compound in 5 mg dosage strengths.

    Number of subjects in period 2 [1]
    		ASP1707 3 mg - Part 2 ASP1707 5 mg - Part 2 ASP1707 10 mg - Part 2 ASP1707 15 mg - Part 2
    Started
    19
    18
    18
    20
    Completed
    19
    17
    18
    19
    Not completed
    0
    1
    0
    1
         Withdrawal by subject
    -
    1
    -
    1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Data for period 2 are provided for participants initially randomized to placebo and randomly switched to 1 of the 4 ASP1707 groups for Part 2.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo - Part 1
    Reporting group description
    		 Participants received 3 matching placebo tablets once a day for 12 weeks in Part 1.

    Reporting group title
    ASP1707 3 mg
    Reporting group description
    		 Participants received ASP1707 3 mg treatment for both part 1 and 2 of the study (weeks 1-24). Participants took 3 tablets once daily in the morning of which no tablets were placebo (3 mg group: 3x1 mg).

    Reporting group title
    ASP1707 5 mg
    Reporting group description
    		 Participants received ASP1707 5 mg treatment for both part 1 and 2 of the study (weeks 1-24). Participants took 3 tablets once daily in the morning of which two tablets were placebo (5 mg group 1x5 mg and 2 placebo).

    Reporting group title
    ASP1707 10 mg
    Reporting group description
    		 Participants received ASP1707 10 mg treatment for both part 1 and 2 of the study (weeks 1-24). Participants took 3 tablets once daily in the morning of which one tablet was placebo (10 mg group: 2x5 mg and 1 placebo).

    Reporting group title
    ASP1707 15 mg
    Reporting group description
    		 Participants received ASP1707 15 mg treatment for both part 1 and 2 of the study (weeks 1-24). Participants took 3 tablets once daily in the morning of which no tablets were placebo (15 mg group: 3x5 mg).

    Reporting group title
    Leuprorelin acetate
    Reporting group description
    		 Participants received open-label gonadotropin-releasing hormone (GnRH) agonist 3.75 mg leuprorelin acetate (administered by subcutaneous injection once a month) for both part 1 and 2 of the study (for up to 24 weeks).

    Reporting group values
    		 Placebo - Part 1 ASP1707 3 mg ASP1707 5 mg ASP1707 10 mg ASP1707 15 mg Leuprorelin acetate Total
    Number of subjects
    		 89 87 92 90 90 92
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 33.3 ± 5.9 34.7 ± 5.4 33.2 ± 5.4 34.2 ± 6.2 33.5 ± 6.2 33 ± 6.5 -
    Gender categorical
    Units:
        Male
    		 0 0 0 0 0 0 0
        Female
    		 89 87 92 90 90 92 540

    End points

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    End points reporting groups
    Reporting group title
    Placebo - Part 1
    Reporting group description
    		 Participants received 3 matching placebo tablets once a day for 12 weeks in Part 1.

    Reporting group title
    ASP1707 3 mg
    Reporting group description
    		 Participants received ASP1707 3 mg treatment for both part 1 and 2 of the study (weeks 1-24). Participants took 3 tablets once daily in the morning of which no tablets were placebo (3 mg group: 3x1 mg).

    Reporting group title
    ASP1707 5 mg
    Reporting group description
    		 Participants received ASP1707 5 mg treatment for both part 1 and 2 of the study (weeks 1-24). Participants took 3 tablets once daily in the morning of which two tablets were placebo (5 mg group 1x5 mg and 2 placebo).

    Reporting group title
    ASP1707 10 mg
    Reporting group description
    		 Participants received ASP1707 10 mg treatment for both part 1 and 2 of the study (weeks 1-24). Participants took 3 tablets once daily in the morning of which one tablet was placebo (10 mg group: 2x5 mg and 1 placebo).

    Reporting group title
    ASP1707 15 mg
    Reporting group description
    		 Participants received ASP1707 15 mg treatment for both part 1 and 2 of the study (weeks 1-24). Participants took 3 tablets once daily in the morning of which no tablets were placebo (15 mg group: 3x5 mg).

    Reporting group title
    Leuprorelin acetate
    Reporting group description
    		 Participants received open-label gonadotropin-releasing hormone (GnRH) agonist 3.75 mg leuprorelin acetate (administered by subcutaneous injection once a month) for both part 1 and 2 of the study (for up to 24 weeks).
    Reporting group title
    ASP1707 3 mg - Part 2
    Reporting group description
    		 Participants who received placebo in part 1 were switched to ASP1707 3 mg treatment for part 2 of the study. Participants took 3 tablets once daily in the morning of which no tablets were placebo (3 mg group: 3x1 mg).

    Reporting group title
    ASP1707 5 mg - Part 2
    Reporting group description
    		 Participants who received placebo in part 1 were switched to ASP1707 5 mg treatment for part 2 of the study. Participants took 3 tablets once daily in the morning of which two tablets were placebo (5 mg group 1x5 mg and 2 placebo).

    Reporting group title
    ASP1707 10 mg - Part 2
    Reporting group description
    		 Participants who received placebo in part 1 were switched to ASP1707 10 mg treatment for part 2 of the study. Participants took 3 tablets once daily in the morning of which one tablet was placebo (10 mg group: 2x5 mg and 1 placebo).

    Reporting group title
    ASP1707 15 mg - Part 2
    Reporting group description
    		 Participants who received placebo in part 1 were switched to ASP1707 15 mg treatment for part 2 of the study. Participants took 3 tablets once daily in the morning of which no tablets were placebo (15 mg group: 3x5 mg).

    Primary: Change from Baseline to the End of Treatment (EoT) (12 Weeks) of the Mean Numeric Rating Scale (NRS) Pain Score for Overall Pelvic Pain (Dysmenorrhea and Non-Menstrual Pelvic Pain)

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    End point title
    		 Change from Baseline to the End of Treatment (EoT) (12 Weeks) of the Mean Numeric Rating Scale (NRS) Pain Score for Overall Pelvic Pain (Dysmenorrhea and Non-Menstrual Pelvic Pain) [1]
    End point description
    Pelvic pain measured daily by participants in an e-diary using NRS (scale 0 – 10, where 0 anchors ‘no pain’ & 10 ‘worst pain you can imagine’). Score of 1-3 represented ‘mild pain’ (nagging, annoying, interfering little with Activities of Daily Living [ADL]), 4-6 ‘moderate pain’ (interferes significantly with ADL), & 7-10 ‘severe pain’ (disabling, unable to perform ADL). Overall pelvic pain calculated as the mean of the NRS scale scores from the last 28-day period (whole menstrual cycle, including menstrual & nonmenstrual bleeding days) before each visit. Analysis population consisted of Full Analysis Set 1 (FAS1), which consisted of all randomized participants who received at least 1 dose of double-blind study medication (placebo or ASP1707) or at least 1 dose of leuprorelin acetate & who had a primary NRS pain score for overall pelvic pain at baseline & at least 1 evaluable post-baseline NRS pain score for overall pelvic pain, defined as having at least 14 days of pain score.
    End point type
    Primary
    End point timeframe
    Baseline and EoT (last 28 days)
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not applicable, the leuprorelin arm was excluded from the primary analysis.
    End point values
    		 Placebo - Part 1 ASP1707 3 mg ASP1707 5 mg ASP1707 10 mg ASP1707 15 mg
    Number of subjects analysed
    81
    77
    87
    82
    84
    Units: units on a scale
        least squares mean (confidence interval 95%)
    -1.56 (-1.91 to -1.21)
    -1.63 (-1.99 to -1.27)
    -1.93 (-2.27 to -1.6)
    -2.29 (-2.64 to -1.94)
    -2.13 (-2.47 to -1.79)
    Statistical analysis title
    		 Linear Trend Analysis (Primary)
    Statistical analysis description
    ANCOVA model that includes treatment group (excluding leuprorelin group) and region as fixed factors and baseline value as a covariate. Includes linear contract based on all treatment groups (excluding leuprorelin) and information until Visit 6 (included). Last non-missing observation before first intake of study drug is used as baseline. EoT (Part 1) corresponds to the last non-missing observation during Part 1 of the study.
    Comparison groups
    Placebo - Part 1 v ASP1707 3 mg v ASP1707 5 mg v ASP1707 10 mg v ASP1707 15 mg
    Number of subjects included in analysis
    411
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.001
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [2] - A test for a linear trend was applied by using the linear contrast based on the ordinal dose (contrast coefficients: -2, -1, 0, 1, 2).

    Primary: Change from Baseline to the EoT of the Mean NRS Pain Score for Dysmenorrhea

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    End point title
    		 Change from Baseline to the EoT of the Mean NRS Pain Score for Dysmenorrhea [3]
    End point description
    Pelvic pain measured daily by participants in an e-diary using NRS (scale 0 – 10, where 0 anchors ‘no pain’ & 10 ‘worst pain you can imagine’). Score of 1-3 represented ‘mild pain’ (nagging, annoying, interfering little with Activities of Daily Living [ADL]), 4-6 ‘moderate pain’ (interferes significantly with ADL), & 7-10 ‘severe pain’ (disabling, unable to perform ADL). Dysmenorrhea pelvic pain was calculated as the mean of the NRS scale scores from the menstrual bleeding days within the 28-day period. A score of 0 was applied if there was no menstrual bleeding during the 28-day period. Analysis population consisted of the FAS1.
    End point type
    Primary
    End point timeframe
    Baseline and EoT (last 28 days)
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not applicable, the leuprorelin arm was excluded from the primary analysis.
    End point values
    		 Placebo - Part 1 ASP1707 3 mg ASP1707 5 mg ASP1707 10 mg ASP1707 15 mg
    Number of subjects analysed
    81
    77
    87
    82
    84
    Units: units on a scale
        least squares mean (confidence interval 95%)
    -1.5 (-2 to -1)
    -2.72 (-3.22 to -2.21)
    -2.85 (-3.33 to -2.38)
    -3.97 (-4.46 to -3.48)
    -4.18 (-4.66 to -3.7)
    Statistical analysis title
    		 Linear Trend Analysis (Primary)
    Statistical analysis description
    ANCOVA model that includes treatment group (excluding leuprorelin group) and region as fixed factors and baseline value as a covariate. Includes linear contract based on all treatment groups (excluding leuprorelin) and information until Visit 6 (included). Last non-missing observation before first intake of study drug is used as baseline. EoT (Part 1) corresponds to the last non-missing observation during Part 1 of the study.
    Comparison groups
    Placebo - Part 1 v ASP1707 3 mg v ASP1707 5 mg v ASP1707 10 mg v ASP1707 15 mg
    Number of subjects included in analysis
    411
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [4] - A test for a linear trend was applied by using the linear contrast based on the ordinal dose (contrast coefficients: -2, -1, 0, 1, 2).

    Primary: Change from Baseline to the EoT of the Mean NRS Pain Score for Non-Menstrual Pelvic Pain (NMPP)

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    End point title
    		 Change from Baseline to the EoT of the Mean NRS Pain Score for Non-Menstrual Pelvic Pain (NMPP) [5]
    End point description
    Pelvic pain measured daily by participants in an e-diary using NRS (scale 0 – 10, where 0 anchors ‘no pain’ & 10 ‘worst pain you can imagine’). Score of 1-3 represented ‘mild pain’ (nagging, annoying, interfering little with Activities of Daily Living [ADL]), 4-6 ‘moderate pain’ (interferes significantly with ADL), & 7-10 ‘severe pain’ (disabling, unable to perform ADL). NMPP was calculated as the mean of the NRS scale scores from all days except menstrual bleeding days within the 28-day period. The analysis population consisted of the FAS1.
    End point type
    Primary
    End point timeframe
    Baseline and EoT (last 28 days)
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not applicable, the leuprorelin arm was excluded from the primary analysis.
    End point values
    		 Placebo - Part 1 ASP1707 3 mg ASP1707 5 mg ASP1707 10 mg ASP1707 15 mg
    Number of subjects analysed
    81
    77
    87
    82
    84
    Units: units on a scale
        least squares mean (confidence interval 95%)
    -1.53 (-1.88 to -1.19)
    -1.51 (-1.87 to -1.16)
    -1.8 (-2.14 to -1.47)
    -2.03 (-2.37 to -1.68)
    -1.86 (-2.2 to -1.52)
    Statistical analysis title
    		 Linear Trend Analysis (Primary)
    Statistical analysis description
    ANCOVA model that includes treatment group (excluding leuprorelin group) and region as fixed factors and baseline value as a covariate. Includes linear contract based on all treatment groups (excluding leuprorelin) and information until Visit 6 (included). Last non-missing observation before first intake of study drug is used as baseline. EoT (Part 1) corresponds to the last non-missing observation during Part 1 of the study.
    Comparison groups
    Placebo - Part 1 v ASP1707 3 mg v ASP1707 5 mg v ASP1707 10 mg v ASP1707 15 mg
    Number of subjects included in analysis
    411
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 = 0.029
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [6] - A test for a linear trend was applied by using the linear contrast based on the ordinal dose (contrast coefficients: -2, -1, 0, 1, 2).

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first study drug administration to End of Study (EoS) visit (42 days after intake of last dose of study drug)
    Adverse event reporting additional description
    Analysis population consisted of the Safety Analysis Set 1 (SAF1), which consisted of all randomized participants who took at least 1 dose of study medication (ASP1707 or leuprorelin acetate or placebo).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.0
    Reporting groups
    Reporting group title
    Part 1 Placebo
    Reporting group description
    		 Participants received 3 matching placebo tablets once a day for 12 weeks in Part 1.

    Reporting group title
    Part 1 ASP1707 3 mg
    Reporting group description
    		 Participants received ASP1707 3 mg treatment during part 1 of the study. Participants took 3 tablets once daily in the morning of which no tablets were placebo (3 mg group: 3x1 mg).

    Reporting group title
    Part 1 ASP1707 15 mg
    Reporting group description
    		 Participants received ASP1707 15 mg treatment during part 1 of the study. Participants took 3 tablets once daily in the morning of which no tablets were placebo (15 mg group: 3x5 mg).

    Reporting group title
    Part 1 ASP1707 10 mg
    Reporting group description
    		 Participants received ASP1707 10 mg treatment during part 1 of the study. Participants took 3 tablets once daily in the morning of which one tablet was placebo (10 mg group: 2x5 mg and 1 placebo).

    Reporting group title
    Part 1 ASP1707 5 mg
    Reporting group description
    		 Participants received ASP1707 5 mg treatment during part 1 of the study. Participants took 3 tablets once daily in the morning of which two tablets were placebo (5 mg group 1x5 mg and 2 placebo).

    Reporting group title
    Part 1 Leuprorelin acetate
    Reporting group description
    		 Participants received open-label GnRH agonist 3.75 mg leuprorelin acetate (administered by subcutaneous injection once a month) for part 1 of the study (for weeks 1-12).

    Reporting group title
    Part 2 ASP1707 3 mg
    Reporting group description
    		 Participants who received 3 mg ASP1707 or who were switched from placebo in Part 1 received 3 mg ASP1707 from weeks 13-24 (Part 2), once daily. Participants took 3 tablets once daily in the morning of which no tablets were placebo (3 mg group: 3x1 mg).

    Reporting group title
    Part 2 ASP1707 5 mg
    Reporting group description
    		 Participants who received 5 mg ASP1707 or who were switched from placebo in Part 1 received 5 mg ASP1707 from weeks 13-24 (Part 2). Participants took 3 tablets once daily in the morning of which two tablets were placebo (5 mg group 1x5 mg and 2 placebo).

    Reporting group title
    Part 2 ASP1707 10 mg
    Reporting group description
    		 Participants who received 10 mg ASP1707 or who were switched from placebo in Part 1 received 10 mg ASP1707 from weeks 13-24 (Part 2). Participants took 3 tablets once daily in the morning of which one tablet was placebo (10 mg group: 2x5 mg and 1 placebo).

    Reporting group title
    Part 2 ASP1707 15 mg
    Reporting group description
    		 Participants who received 15 mg ASP1707 or who were switched from placebo in Part 1 received 15 mg ASP1707 from weeks 13-24 (Part 2). Participants took 3 tablets once daily in the morning of which no tablets were placebo (15 mg group: 3x5 mg).

    Reporting group title
    Part 2 Leuprorelin acetate
    Reporting group description
    		 Participants received open-label GnRH agonist 3.75 mg leuprorelin acetate (administered by subcutaneous injection once a month) for both in part 2 of the study (for weeks 13-24).

    Serious adverse events
    		 Part 1 Placebo Part 1 ASP1707 3 mg Part 1 ASP1707 15 mg Part 1 ASP1707 10 mg Part 1 ASP1707 5 mg Part 1 Leuprorelin acetate Part 2 ASP1707 3 mg Part 2 ASP1707 5 mg Part 2 ASP1707 10 mg Part 2 ASP1707 15 mg Part 2 Leuprorelin acetate
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 88 (1.14%)
    3 / 86 (3.49%)
    0 / 88 (0.00%)
    1 / 90 (1.11%)
    0 / 91 (0.00%)
    0 / 89 (0.00%)
    0 / 90 (0.00%)
    7 / 102 (6.86%)
    2 / 94 (2.13%)
    1 / 95 (1.05%)
    0 / 76 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Investigations
    Liver function test abnormal
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 86 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    0 / 89 (0.00%)
    0 / 90 (0.00%)
    1 / 102 (0.98%)
    1 / 94 (1.06%)
    0 / 95 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Head injury
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 86 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    0 / 89 (0.00%)
    0 / 90 (0.00%)
    1 / 102 (0.98%)
    0 / 94 (0.00%)
    0 / 95 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Tooth extraction
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 86 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    0 / 89 (0.00%)
    0 / 90 (0.00%)
    1 / 102 (0.98%)
    0 / 94 (0.00%)
    0 / 95 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Dural fistula
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 86 (1.16%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    0 / 89 (0.00%)
    0 / 90 (0.00%)
    0 / 102 (0.00%)
    0 / 94 (0.00%)
    0 / 95 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 86 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    0 / 89 (0.00%)
    0 / 90 (0.00%)
    1 / 102 (0.98%)
    0 / 94 (0.00%)
    0 / 95 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 86 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    0 / 89 (0.00%)
    0 / 90 (0.00%)
    1 / 102 (0.98%)
    0 / 94 (0.00%)
    0 / 95 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 86 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    0 / 89 (0.00%)
    0 / 90 (0.00%)
    0 / 102 (0.00%)
    0 / 94 (0.00%)
    0 / 95 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 86 (1.16%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    0 / 89 (0.00%)
    0 / 90 (0.00%)
    0 / 102 (0.00%)
    0 / 94 (0.00%)
    0 / 95 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain lower
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 86 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    0 / 89 (0.00%)
    0 / 90 (0.00%)
    1 / 102 (0.98%)
    0 / 94 (0.00%)
    0 / 95 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mallory-Weiss syndrome
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 86 (0.00%)
    0 / 88 (0.00%)
    1 / 90 (1.11%)
    0 / 91 (0.00%)
    0 / 89 (0.00%)
    0 / 90 (0.00%)
    0 / 102 (0.00%)
    0 / 94 (0.00%)
    0 / 95 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 86 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    0 / 89 (0.00%)
    0 / 90 (0.00%)
    1 / 102 (0.98%)
    0 / 94 (0.00%)
    0 / 95 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 86 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    0 / 89 (0.00%)
    0 / 90 (0.00%)
    0 / 102 (0.00%)
    1 / 94 (1.06%)
    0 / 95 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 86 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    0 / 89 (0.00%)
    0 / 90 (0.00%)
    1 / 102 (0.98%)
    0 / 94 (0.00%)
    0 / 95 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endometriosis
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 86 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    0 / 89 (0.00%)
    0 / 90 (0.00%)
    1 / 102 (0.98%)
    0 / 94 (0.00%)
    1 / 95 (1.05%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Ureteric obstruction
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 86 (1.16%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    0 / 89 (0.00%)
    0 / 90 (0.00%)
    0 / 102 (0.00%)
    0 / 94 (0.00%)
    0 / 95 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 86 (0.00%)
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    0 / 91 (0.00%)
    0 / 89 (0.00%)
    0 / 90 (0.00%)
    1 / 102 (0.98%)
    0 / 94 (0.00%)
    0 / 95 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Part 1 Placebo Part 1 ASP1707 3 mg Part 1 ASP1707 15 mg Part 1 ASP1707 10 mg Part 1 ASP1707 5 mg Part 1 Leuprorelin acetate Part 2 ASP1707 3 mg Part 2 ASP1707 5 mg Part 2 ASP1707 10 mg Part 2 ASP1707 15 mg Part 2 Leuprorelin acetate
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    24 / 88 (27.27%)
    20 / 86 (23.26%)
    35 / 88 (39.77%)
    31 / 90 (34.44%)
    24 / 91 (26.37%)
    39 / 89 (43.82%)
    14 / 90 (15.56%)
    23 / 102 (22.55%)
    16 / 94 (17.02%)
    23 / 95 (24.21%)
    14 / 76 (18.42%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    4 / 88 (4.55%)
    4 / 86 (4.65%)
    17 / 88 (19.32%)
    10 / 90 (11.11%)
    12 / 91 (13.19%)
    25 / 89 (28.09%)
    4 / 90 (4.44%)
    8 / 102 (7.84%)
    2 / 94 (2.13%)
    5 / 95 (5.26%)
    2 / 76 (2.63%)
         occurrences all number
    6
    4
    18
    11
    13
    26
    4
    9
    2
    5
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    10 / 88 (11.36%)
    9 / 86 (10.47%)
    12 / 88 (13.64%)
    12 / 90 (13.33%)
    6 / 91 (6.59%)
    15 / 89 (16.85%)
    2 / 90 (2.22%)
    4 / 102 (3.92%)
    2 / 94 (2.13%)
    5 / 95 (5.26%)
    5 / 76 (6.58%)
         occurrences all number
    11
    10
    12
    14
    6
    15
    2
    4
    2
    6
    5
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    4 / 88 (4.55%)
    2 / 86 (2.33%)
    2 / 88 (2.27%)
    7 / 90 (7.78%)
    2 / 91 (2.20%)
    4 / 89 (4.49%)
    2 / 90 (2.22%)
    1 / 102 (0.98%)
    3 / 94 (3.19%)
    2 / 95 (2.11%)
    2 / 76 (2.63%)
         occurrences all number
    4
    2
    2
    7
    2
    5
    2
    1
    3
    2
    2
    Reproductive system and breast disorders
    Menstruation delayed
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 86 (1.16%)
    2 / 88 (2.27%)
    4 / 90 (4.44%)
    4 / 91 (4.40%)
    5 / 89 (5.62%)
    2 / 90 (2.22%)
    2 / 102 (1.96%)
    2 / 94 (2.13%)
    3 / 95 (3.16%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    2
    4
    5
    5
    2
    3
    3
    3
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    3 / 88 (3.41%)
    2 / 86 (2.33%)
    3 / 88 (3.41%)
    2 / 90 (2.22%)
    1 / 91 (1.10%)
    5 / 89 (5.62%)
    1 / 90 (1.11%)
    0 / 102 (0.00%)
    0 / 94 (0.00%)
    3 / 95 (3.16%)
    2 / 76 (2.63%)
         occurrences all number
    3
    2
    3
    2
    1
    5
    1
    0
    0
    3
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    8 / 88 (9.09%)
    5 / 86 (5.81%)
    8 / 88 (9.09%)
    4 / 90 (4.44%)
    4 / 91 (4.40%)
    5 / 89 (5.62%)
    6 / 90 (6.67%)
    9 / 102 (8.82%)
    9 / 94 (9.57%)
    8 / 95 (8.42%)
    3 / 76 (3.95%)
         occurrences all number
    9
    6
    9
    6
    4
    5
    8
    11
    9
    8
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Dec 2012
    -Spermicidal foam/gel/film/cream/suppository and occlusive cap were removed from inclusion criterion 6 because they are no longer acceptable nonhormonal contraceptive methods. According to the World Health Organization (WHO), spermicidal foam/gel/film/cream/suppository can increase the risk for certain sexually transmitted infections (including human immunodeficiency virus) and can cause local irritation of mucosal surfaces. In addition, spermicidally lubricated condoms do not have increased contraceptive efficacy compared to condoms without spermicide. Because of this, spermicidal foam/gel/film/cream/suppository is difficult to obtain or not available in many countries. Occlusive cap alone is not considered to be an effective contraceptive. -Total cholesterol, high density lipoprotein (HDL), low density lipoprotein (LDL), and triglycerides were added to the planned biochemistry tests because lipid changes had been added to the ASP1707 developmental risk management plan as a potential risk requiring monitoring in clinical studies. This did not change the amount of blood taken from the patients at any visit. -Administrative changes and typographical corrections were made.
    02 Dec 2014
    -The duration for use of non-hormonal contraceptive methods after the last dose was updated from 12 weeks to 42 days to align with the period during which pregnancies had to be reported. This update did not change the benefit/risk ratio for patients. -Dunnett’s test was added to appropriately adjust the comparisons of the active dose groups against placebo. -The database cutoff, which was planned after the last follow-up visit, was to be implemented after the EoS visit instead. These outputs were final and were used for the main analyses, including primary and all secondary efficacy analyses. The only data to be collected after this release would be in a limited number of patients that had completed the EoS visit but not yet the follow-up visit. This amendment only affected the timing of the analyses, and was not a formal interim analysis. -The planned study period was extended due to delayed recruitment. -The period for collection and follow-up of serious adverse events (SAEs) was made consistent throughout the protocol. -The updated Summary of Product Characteristics (SmPC) of leuprorelin acetate was added. The changes had no significant impact on the safety or physical or mental integrity of the patients, on the scientific value of the trial, on the conduct or management of the trial or on the quality or safety of any investigational medicinal products (IMP) used in the study. -Administrative changes and typographical corrections were made.

    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
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