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    Clinical Trial Results:
    A randomised, controlled, open label, parallel group, multicentre trial comparing the efficacy and safety of individualised FE 999049 (follitropin delta) dosing, using a long GnRH agonist protocol and a GnRH antagonist protocol in women undergoing controlled ovarian stimulation

    Summary
    EudraCT number
    		 2017-002783-40
    Trial protocol
    		 AT   DK   NO   NL   IT  
    Global end of trial date
    16 Feb 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Mar 2023
    First version publication date
    03 Mar 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    000304
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03809429
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Ferring Pharmaceuticals A/S
    Sponsor organisation address
    International PharmaScience Center, Amager Strandvej 405, Kastrup, Denmark, 2770
    Public contact
    Global Clinical Compliance, Ferring Pharmaceuticals A/S, DK0-Disclosure@ferring.com
    Scientific contact
    Global Clinical Compliance, Ferring Pharmaceuticals A/S, DK0-Disclosure@ferring.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
    24 Mar 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Feb 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Feb 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effect of individualised FE 999049 treatment on ovarian response in a long GnRH agonist protocol versus a GnRH antagonist protocol
    Protection of trial subjects
    The trial was performed in compliance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guideline on Good Clinical Practice (GCP).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Feb 2019
    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
    Netherlands: 57
    Country: Number of subjects enrolled
    Norway: 231
    Country: Number of subjects enrolled
    Austria: 60
    Country: Number of subjects enrolled
    Denmark: 31
    Country: Number of subjects enrolled
    Italy: 21
    Country: Number of subjects enrolled
    Switzerland: 10
    Country: Number of subjects enrolled
    Israel: 25
    Worldwide total number of subjects
    435
    EEA total number of subjects
    400
    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)
    435
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial was performed at 16 investigational sites in 7 countries between May 2019 to Feb 2022.

    Pre-assignment
    Screening details
    		 In total, 532 subjects were screened of which 437 were randomized. Of the 437 subjects, 435 subjects were included in the FAS: 220 subjects to long GnRH agonist and 215 subjects to GnRH antagonist. 406 subjects were exposed to the investigational medicinal product (IMP): 202 subjects to long GnRH agonist and 204 subjects to GnRH antagonist.

    Period 1
    Period 1 title
    Randomised Treatment Period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Open Label

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 FE 999049 + GnRH agonist (GONAPEPTYL)
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    FE 999049 + GnRH agonist
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Injection
    Dosage and administration details
    FE 999049 in solution for subcutaneous injection; 72 µg follitropin delta in 2.16 mL pre-filled injection pen

    Arm title
    		 FE 999049 + GnRH Antagonist (CETROTIDE)
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    FE 999049 + GnRH Antagonist (CETROTIDE)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection/infusion
    Routes of administration
    Injection
    Dosage and administration details
    CETROTIDE (cetrorelix acetate) is provided as powder and solvent for solution for injection. After reconstitution, 1 mL solvent contains 0.25 mg cetrorelix acetate.

    Number of subjects in period 1
    		FE 999049 + GnRH agonist (GONAPEPTYL) FE 999049 + GnRH Antagonist (CETROTIDE)
    Started
    220
    215
    Completed
    192
    195
    Not completed
    28
    20
         Consent withdrawn by subject
    7
    3
         Physician decision
    12
    7
         Adverse event, non-fatal
    6
    9
         COVID-19
    3
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    FE 999049 + GnRH agonist (GONAPEPTYL)
    Reporting group description
    		 -

    Reporting group title
    FE 999049 + GnRH Antagonist (CETROTIDE)
    Reporting group description
    		 -

    Reporting group values
    		 FE 999049 + GnRH agonist (GONAPEPTYL) FE 999049 + GnRH Antagonist (CETROTIDE) Total
    Number of subjects
    		 220 215 435
    Age categorical
    Units: Subjects
        <35 years
    		 143 141 284
        35-37 years
    		 47 48 95
        38-40 years
    		 30 26 56
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 32.3 ± 4.4 32.4 ± 4.2 -
    Gender categorical
    Units: Subjects
        Female
    		 220 215 435
        Male
    		 0 0 0
    Body Mass Index (BMI)
    Units: kg/m^2
        arithmetic mean (standard deviation)
    		 24.36 ± 3.50 24.39 ± 3.55 -

    End points

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    End points reporting groups
    Reporting group title
    FE 999049 + GnRH agonist (GONAPEPTYL)
    Reporting group description
    		 -

    Reporting group title
    FE 999049 + GnRH Antagonist (CETROTIDE)
    Reporting group description
    		 -

    Primary: Number of Oocytes Retrieved

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    End point title
    		 Number of Oocytes Retrieved
    End point description
    The number of oocytes retrieved was recorded at the oocyte retrieval visit.
    End point type
    Primary
    End point timeframe
    On day of oocyte retrieval (up to 22 days after start of stimulation)
    End point values
    		 FE 999049 + GnRH agonist (GONAPEPTYL) FE 999049 + GnRH Antagonist (CETROTIDE)
    Number of subjects analysed
    202
    204
    Units: Oocytes
        arithmetic mean (standard deviation)
    11.1 ± 5.9
    9.6 ± 5.5
    Statistical analysis title
    		 FE 999049 GnRH Agonist, FE 999049 GnRH Antagonist
    Comparison groups
    FE 999049 + GnRH agonist (GONAPEPTYL) v FE 999049 + GnRH Antagonist (CETROTIDE)
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.0185 [2]
    Method
    		 Negative binomial regression
    Parameter type
    		 Difference
    Point estimate
    1.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.22
         upper limit
    		 2.4
    Notes
    [1] - Subjects in this analysis: 435
    [2] - Negative binomial regression model with treatment, age strata, and AMH group as factors.

    Secondary: Proportion of Subjects With Cycle Cancellation Due to Poor Ovarian Response or Excessive Ovarian Response

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    End point title
    		 Proportion of Subjects With Cycle Cancellation Due to Poor Ovarian Response or Excessive Ovarian Response
    End point description
    For each subject, the reason for cycle cancellation was recorded.
    End point type
    Secondary
    End point timeframe
    At end-of-stimulation (up to 20 days)
    End point values
    		 FE 999049 + GnRH agonist (GONAPEPTYL) FE 999049 + GnRH Antagonist (CETROTIDE)
    Number of subjects analysed
    202
    204
    Units: Subjects
    number (not applicable)
        Excessive response
    2
    3
        Poor response
    1
    3
        Other reason
    1
    1
    No statistical analyses for this end point

    Secondary: Proportion of Subjects With Blastocyst Transfer Cancellation After Oocyte Retrieval Due to (Risk of) Ovarian Hyperstimulation Syndrome (OHSS)

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    End point title
    		 Proportion of Subjects With Blastocyst Transfer Cancellation After Oocyte Retrieval Due to (Risk of) Ovarian Hyperstimulation Syndrome (OHSS)
    End point description
    For each subject, the reason for blastocyst transfer cancellation was recorded.
    End point type
    Secondary
    End point timeframe
    At end of transfer (up to 4 weeks)
    End point values
    		 FE 999049 + GnRH agonist (GONAPEPTYL) FE 999049 + GnRH Antagonist (CETROTIDE)
    Number of subjects analysed
    202
    204
    Units: Subjects
    number (not applicable)
        Transfer cancellation
    27
    30
        No transfer cancellation
    171
    167
        N/A
    4
    7
        Reason for transfer cancellation: Adverse Event
    5
    8
        Reason for transfer cancellation: Risk of OHSS
    1
    1
        Reason for transfer cancellation: No blastocyst
    13
    18
        Reason for transfer cancellation: COVID-19
    3
    1
        Reason for transfer cancellation: Other reason
    5
    2
    No statistical analyses for this end point

    Secondary: Number of Follicles

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    End point title
    		 Number of Follicles
    End point description
    The total number of follicles and the number of follicles per size category will be reported
    End point type
    Secondary
    End point timeframe
    On stimulation day 6 and at end-of-stimulation (up to 20 days)
    End point values
    		 FE 999049 + GnRH agonist (GONAPEPTYL) FE 999049 + GnRH Antagonist (CETROTIDE)
    Number of subjects analysed
    202
    204
    Units: Follicles
    arithmetic mean (standard deviation)
        Total number of follicles at Stimulation Day 6
    15.2 ± 6.3
    14.9 ± 6.3
        Follicles >= 10 mm at Stimulation Day 6
    4.6 ± 4.3
    7.1 ± 3.6
        Follicles >= 12 mm at Stimulation Day 6
    1.6 ± 2.7
    3.8 ± 2.9
        Total number of follicles at End-of-stimulation
    18.3 ± 7.1
    17.1 ± 8.0
        Follicles >= 10 mm at End-of-stimulation visit
    14.8 ± 6.4
    13.3 ± 6.1
        Follicles >= 12 mm at End-of-stimulation visit
    12.2 ± 5.3
    10.9 ± 5.1
        Follicles >= 15 mm at End-of-stimulation visit
    7.9 ± 3.7
    7.2 ± 3.3
        Follicles >= 17 mm at End-of-stimulation visit
    4.8 ± 2.1
    4.6 ± 2.0
    Statistical analysis title
    		 FE 999049 GnRH Agonist, FE 999049 GnRH Antagonist
    Statistical analysis description
    >=8 mm at end-of-stimulation
    Comparison groups
    FE 999049 + GnRH agonist (GONAPEPTYL) v FE 999049 + GnRH Antagonist (CETROTIDE)
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1095 [3]
    Method
    		 Negative binomial regression
    Parameter type
    		 Difference
    Point estimate
    0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2
         upper limit
    		 2.02
    Notes
    [3] - Negative binomial regression model with treatment, age strata, and AMH group as factors.
    Statistical analysis title
    		 FE 999049 GnRH Agonist, FE 999049 GnRH Antagonist
    Statistical analysis description
    >=10 mm at end-of-stimulation
    Comparison groups
    FE 999049 + GnRH agonist (GONAPEPTYL) v FE 999049 + GnRH Antagonist (CETROTIDE)
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0281 [4]
    Method
    		 Negative binomial regression
    Parameter type
    		 Difference
    Point estimate
    1.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.12
         upper limit
    		 2.15
    Notes
    [4] - Negative binomial regression model with treatment, age strata, and AMH group as factors.
    Statistical analysis title
    		 FE 999049 GnRH Agonist, FE 999049 GnRH Antagonist
    Statistical analysis description
    >=12 mm at end-of-stimulation
    Comparison groups
    FE 999049 + GnRH agonist (GONAPEPTYL) v FE 999049 + GnRH Antagonist (CETROTIDE)
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0258 [5]
    Method
    		 Negative-binomial regression
    Parameter type
    		 Difference
    Point estimate
    0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.12
         upper limit
    		 1.86
    Notes
    [5] - Negative binomial regression model with treatment, age strata, and AMH group as factors.
    Statistical analysis title
    		 FE 999049 GnRH Agonist, FE 999049 GnRH Antagonist
    Statistical analysis description
    >=15 mm at end-of-stimulation
    Comparison groups
    FE 999049 + GnRH agonist (GONAPEPTYL) v FE 999049 + GnRH Antagonist (CETROTIDE)
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0672 [6]
    Method
    		 Negative binomial regression
    Parameter type
    		 Difference
    Point estimate
    0.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.04
         upper limit
    		 1.2
    Notes
    [6] - Negative binomial regression model with treatment, age strata, and AMH group as factors.
    Statistical analysis title
    		 FE 999049 GnRH Agonist, FE 999049 GnRH Antagonist
    Statistical analysis description
    >=17 mm at end-of-stimulation
    Comparison groups
    FE 999049 + GnRH agonist (GONAPEPTYL) v FE 999049 + GnRH Antagonist (CETROTIDE)
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.339 [7]
    Method
    		 Negative binomial regression
    Parameter type
    		 Difference
    Point estimate
    0.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.22
         upper limit
    		 0.63
    Notes
    [7] - Negative binomial regression model with treatment, age strata, and AMH group as factors.

    Secondary: Proportion of Subjects With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved

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    End point title
    		 Proportion of Subjects With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved
    End point description
    Grouped according to number of oocytes
    End point type
    Secondary
    End point timeframe
    On day of oocyte retrieval (up to 22 days after start of stimulation)
    End point values
    		 FE 999049 + GnRH agonist (GONAPEPTYL) FE 999049 + GnRH Antagonist (CETROTIDE)
    Number of subjects analysed
    202
    204
    Units: Subjects
    number (not applicable)
        <4
    13
    26
        4-7
    47
    56
        8-14
    84
    82
        15-19
    42
    29
        >=20
    16
    11
    No statistical analyses for this end point

    Secondary: Number of Metaphase II Oocytes

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    End point title
    		 Number of Metaphase II Oocytes
    End point description
    Only applicable for those inseminated using ICSI
    End point type
    Secondary
    End point timeframe
    On day of oocyte retrieval (up to 22 days after start of stimulation)
    End point values
    		 FE 999049 + GnRH agonist (GONAPEPTYL) FE 999049 + GnRH Antagonist (CETROTIDE)
    Number of subjects analysed
    96
    99
    Units: MII oocytes
        arithmetic mean (standard deviation)
    9.2 ± 4.8
    7.9 ± 4.7
    Statistical analysis title
    		 FE 999049 GnRH Agonist, FE 999049 GnRH Antagonist
    Comparison groups
    FE 999049 + GnRH agonist (GONAPEPTYL) v FE 999049 + GnRH Antagonist (CETROTIDE)
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0962 [8]
    Method
    		 Negative binomial regression
    Parameter type
    		 Difference
    Point estimate
    1.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2
         upper limit
    		 2.41
    Notes
    [8] - Negative binomial regression model with treatment, age strata, and AMH group as factors.

    Secondary: Fertilization Rate

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    End point title
    		 Fertilization Rate
    End point description
    Measured by the number of pronuclei. Fertilized oocytes with 2 pronuclei were regarded as correctly fertilized
    End point type
    Secondary
    End point timeframe
    On day 1 after oocyte retrieval (up to 23 days after start of stimulation)
    End point values
    		 FE 999049 + GnRH agonist (GONAPEPTYL) FE 999049 + GnRH Antagonist (CETROTIDE)
    Number of subjects analysed
    197
    197
    Units: Percentage of fertilized oocytes
        arithmetic mean (standard deviation)
    53.8 ± 24.1
    54.4 ± 26.8
    No statistical analyses for this end point

    Secondary: Number of Embryos

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    End point title
    		 Number of Embryos
    End point description
    The number of embryos (total and good-quality) was reported. Embryo quality is determined by combined assessment of cleavage stage (number of blastomeres/compaction status) and embryo morphology parameters
    End point type
    Secondary
    End point timeframe
    On day 3 after oocyte retrieval (up to 25 days after start of stimulation)
    End point values
    		 FE 999049 + GnRH agonist (GONAPEPTYL) FE 999049 + GnRH Antagonist (CETROTIDE)
    Number of subjects analysed
    202
    204
    Units: Embryos
    arithmetic mean (standard deviation)
        Total number of embryos
    5.7 ± 3.9
    5.0 ± 3.9
        Number of good-quality embryos
    4.0 ± 3.2
    3.9 ± 3.3
    Statistical analysis title
    		 FE 999049 GnRH Agonist, FE 999049 GnRH Antagonist
    Statistical analysis description
    Number of embryos
    Comparison groups
    FE 999049 + GnRH agonist (GONAPEPTYL) v FE 999049 + GnRH Antagonist (CETROTIDE)
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 = 0.1894 [10]
    Method
    		 Negative binomial regression
    Parameter type
    		 Difference
    Point estimate
    0.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.25
         upper limit
    		 1.27
    Notes
    [9] - Subjects in this analysis: 435
    [10] - Negative binomial regression model with treatment, age strata, and AMH group as factors.
    Statistical analysis title
    		 FE 999049 GnRH Agonist, FE 999049 GnRH Antagonist
    Statistical analysis description
    Number of Good-quality embryos
    Comparison groups
    FE 999049 + GnRH agonist (GONAPEPTYL) v FE 999049 + GnRH Antagonist (CETROTIDE)
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    P-value
    		 = 0.9361 [12]
    Method
    		 Negative binomial regression
    Parameter type
    		 Difference
    Point estimate
    -0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.68
         upper limit
    		 0.63
    Notes
    [11] - Subjects in this analysis: 435
    [12] - Negative binomial regression model with treatment, age strata, and AMH group as factors

    Secondary: Number of Blastocysts

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    End point title
    		 Number of Blastocysts
    End point description
    The number of blastocysts (total and good-quality) was reported. Blastocyst quality is assessed by blastocyst expansion and hatching status, blastocyst inner cell mass grading, and trophectoderm grading. The scoring is based on the classification system by Gardner and Schoolcraft, with additional categories for inner cell mass (degenerative or no inner cell mass) and trophectoderm (degenerative or very large cells)
    End point type
    Secondary
    End point timeframe
    On day 5 after oocyte retrieval (up to 27 days after start of stimulation)
    End point values
    		 FE 999049 + GnRH agonist (GONAPEPTYL) FE 999049 + GnRH Antagonist (CETROTIDE)
    Number of subjects analysed
    202
    204
    Units: Blastocysts
    arithmetic mean (standard deviation)
        Total number of blastocysts
    3.8 ± 3.1
    3.3 ± 2.9
        Number of good-quality blastocysts
    2.3 ± 2.3
    2.1 ± 2.2
    Statistical analysis title
    		 FE 999049 GnRH Agonist, FE 999049 GnRH Antagonist
    Statistical analysis description
    Total number of blastocysts
    Comparison groups
    FE 999049 + GnRH agonist (GONAPEPTYL) v FE 999049 + GnRH Antagonist (CETROTIDE)
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    		 other [13]
    P-value
    		 = 0.2025 [14]
    Method
    		 Negative binomial regression
    Parameter type
    		 Difference
    Point estimate
    0.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2
         upper limit
    		 0.94
    Notes
    [13] - Subjects in this analysis: 435
    [14] - Negative binomial regression model with treatment, age strata, and AMH group as factors.
    Statistical analysis title
    		 FE 999049 GnRH Agonist, FE 999049 GnRH Antagonist
    Statistical analysis description
    Number of good-quality blastocysts
    Comparison groups
    FE 999049 + GnRH agonist (GONAPEPTYL) v FE 999049 + GnRH Antagonist (CETROTIDE)
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    		 other [15]
    P-value
    		 = 0.5946 [16]
    Method
    		 Negative binomial regression
    Parameter type
    		 Difference
    Point estimate
    0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.31
         upper limit
    		 0.54
    Notes
    [15] - Subjects in this analysis: 435
    [16] - Negative binomial regression model with treatment, age strata, and AMH group as factors.

    Secondary: Circulating Concentrations of Follicle-stimulating Hormone (FSH)

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    End point title
    		 Circulating Concentrations of Follicle-stimulating Hormone (FSH)
    End point description
    Blood samples for analysis of circulating concentrations of FSH were drawn. FE 999049 + GnRH agonist (GONAPEPTYL): Stimulation Day 6 (n=198), End-of-stimulation (n=199), Oocyte retrieval (n=196) FE 999049 + GnRH Antagonist (CETROTIDE): Stimulation Day 6 (n=198), End-of-stimulation (n=200), Oocyte retrieval (n=195)
    End point type
    Secondary
    End point timeframe
    On stimulation day 6, at end-of-stimulation (up to 20 days after start of stimulation) and at oocyte retrieval (up to 22 days after start of stimulation)
    End point values
    		 FE 999049 + GnRH agonist (GONAPEPTYL) FE 999049 + GnRH Antagonist (CETROTIDE)
    Number of subjects analysed
    199
    200
    Units: IU/L
    arithmetic mean (standard deviation)
        Stimulation Day 6
    15.5 ± 4.3
    16.7 ± 4.5
        End-of-stimulation
    16.2 ± 4.4
    15.8 ± 4.0
        Oocyte retrieval
    9.4 ± 2.8
    9.8 ± 2.9
    No statistical analyses for this end point

    Secondary: Circulating Concentrations of Luteinizing Hormone (LH)

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    End point title
    		 Circulating Concentrations of Luteinizing Hormone (LH)
    End point description
    Blood samples for analysis of circulating concentrations of LH were drawn FE 999049 + GnRH agonist (GONAPEPTYL): Stimulation Day 6 (n=199), End-of-stimulation (n=199), Oocyte retrieval (n=196) FE 999049 + GnRH Antagonist (CETROTIDE): Stimulation Day 6 (n=198), End-of-stimulation (n=200), Oocyte retrieval (n=195)
    End point type
    Secondary
    End point timeframe
    On stimulation day 6, at end-of-stimulation (up to 20 days after start of stimulation) and at oocyte retrieval (up to 22 days after start of stimulation)
    End point values
    		 FE 999049 + GnRH agonist (GONAPEPTYL) FE 999049 + GnRH Antagonist (CETROTIDE)
    Number of subjects analysed
    199
    200
    Units: IU/L
    arithmetic mean (standard deviation)
        Stimulation Day 6
    1.5 ± 0.9
    5.6 ± 6.0
        End-of-stimulation
    1.8 ± 0.9
    1.8 ± 1.5
        Oocyte retrieval
    0.2 ± 0.2
    2.0 ± 2.1
    No statistical analyses for this end point

    Secondary: Circulating Concentrations of Estradiol

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    End point title
    		 Circulating Concentrations of Estradiol
    End point description
    Blood samples for analysis of circulating concentrations of estradiol were drawn FE 999049 + GnRH agonist (GONAPEPTYL): Stimulation Day 6 (n=198), End-of-stimulation (n=199), Oocyte retrieval (n=196) FE 999049 + GnRH Antagonist (CETROTIDE): Stimulation Day 6 (n=200), End-of-stimulation (n=201), Oocyte retrieval (n=195)
    End point type
    Secondary
    End point timeframe
    On stimulation day 6, at end-of-stimulation (up to 20 days after start of stimulation) and at oocyte retrieval (up to 22 days after start of stimulation)
    End point values
    		 FE 999049 + GnRH agonist (GONAPEPTYL) FE 999049 + GnRH Antagonist (CETROTIDE)
    Number of subjects analysed
    199
    201
    Units: pmol/L
    arithmetic mean (standard deviation)
        Stimulation Day 6
    1190.1 ± 1101.2
    2675.8 ± 1544.3
        End-of-stimulation
    7542.7 ± 4106.8
    6487.7 ± 3960.2
        Oocyte retrieval
    3485.1 ± 2129.0
    3163.5 ± 1865.0
    No statistical analyses for this end point

    Secondary: Circulating Concentrations of Progesterone

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    End point title
    		 Circulating Concentrations of Progesterone
    End point description
    Blood samples for analysis of circulating concentrations of progesterone were drawn FE 999049 + GnRH agonist (GONAPEPTYL): Stimulation Day 6 (n=198), End-of-stimulation (n=200), Oocyte retrieval (n=195) FE 999049 + GnRH Antagonist (CETROTIDE): Stimulation Day 6 (n=198), End-of-stimulation (n=200), Oocyte retrieval (n=195)
    End point type
    Secondary
    End point timeframe
    On stimulation day 6, at end-of-stimulation (up to 20 days after start of stimulation) and at oocyte retrieval (up to 22 days after start of stimulation)
    End point values
    		 FE 999049 + GnRH agonist (GONAPEPTYL) FE 999049 + GnRH Antagonist (CETROTIDE)
    Number of subjects analysed
    200
    200
    Units: nmol/L
    arithmetic mean (standard deviation)
        Stimulation Day 6
    1.8 ± 1.0
    2.6 ± 1.5
        End-of-stimulation
    3.1 ± 1.4
    3.5 ± 2.0
        Oocyte retrieval
    25.9 ± 12.9
    26.0 ± 13.2
    No statistical analyses for this end point

    Secondary: Circulating Concentrations of Inhibin B

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    End point title
    		 Circulating Concentrations of Inhibin B
    End point description
    Blood samples for analysis of circulating concentrations of Inhibin B were drawn FE 999049 + GnRH agonist (GONAPEPTYL): Stimulation Day 6 (n=195), End-of-stimulation (n=196), Oocyte retrieval (n=192) FE 999049 + GnRH Antagonist (CETROTIDE): Stimulation Day 6 (n=198), End-of-stimulation (n=197), Oocyte retrieval (n=191)
    End point type
    Secondary
    End point timeframe
    On stimulation day 6, at end-of-stimulation (up to 20 days after start of stimulation) and at oocyte retrieval (up to 22 days after start of stimulation)
    End point values
    		 FE 999049 + GnRH agonist (GONAPEPTYL) FE 999049 + GnRH Antagonist (CETROTIDE)
    Number of subjects analysed
    196
    198
    Units: pg/mL
    arithmetic mean (standard deviation)
        Stimulation Day 6
    690.4 ± 419.1
    808.2 ± 428.5
        End-of-stimulation
    1032.6 ± 605.2
    938.1 ± 570.0
        Oocyte retrieval
    416.6 ± 253.9
    389.0 ± 226.6
    No statistical analyses for this end point

    Secondary: Total Gonadotropin Dose

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    End point title
    		 Total Gonadotropin Dose
    End point description
    Calculated by start dates, end dates and daily dose of investigational medicinal product
    End point type
    Secondary
    End point timeframe
    Up to 20 days
    End point values
    		 FE 999049 + GnRH agonist (GONAPEPTYL) FE 999049 + GnRH Antagonist (CETROTIDE)
    Number of subjects analysed
    202
    204
    Units: ug
        arithmetic mean (standard deviation)
    112.2 ± 28.9
    96.5 ± 26.0
    Statistical analysis title
    		 FE 999049 GnRH Agonist, FE 999049 GnRH Antagonist
    Comparison groups
    FE 999049 + GnRH agonist (GONAPEPTYL) v FE 999049 + GnRH Antagonist (CETROTIDE)
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001 [17]
    Method
    		 ANOVA
    Parameter type
    		 Difference
    Point estimate
    16.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 12.13
         upper limit
    		 21.74
    Notes
    [17] - ANOVA model with treatment, age strata, and AMH group as factors.

    Secondary: Number of Stimulation Days

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    End point title
    		 Number of Stimulation Days
    End point description
    Calculated by start dates and end dates
    End point type
    Secondary
    End point timeframe
    Up to 20 days
    End point values
    		 FE 999049 + GnRH agonist (GONAPEPTYL) FE 999049 + GnRH Antagonist (CETROTIDE)
    Number of subjects analysed
    202
    204
    Units: Days
        arithmetic mean (standard deviation)
    10.4 ± 1.9
    8.8 ± 1.8
    Statistical analysis title
    		 FE 999049 GnRH Agonist, FE 999049 GnRH Antagonist
    Comparison groups
    FE 999049 + GnRH agonist (GONAPEPTYL) v FE 999049 + GnRH Antagonist (CETROTIDE)
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001 [18]
    Method
    		 ANOVA
    Parameter type
    		 Difference
    Point estimate
    1.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.19
         upper limit
    		 1.92
    Notes
    [18] - ANOVA model with treatment, age strata, and AMH group as factors.

    Secondary: Positive Beta Human Chorionic Gonadotropin (βhCG) Rate

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    End point title
    		 Positive Beta Human Chorionic Gonadotropin (βhCG) Rate
    End point description
    Defined as positive serum βhCG test
    End point type
    Secondary
    End point timeframe
    13-15 days after transfer (up to approximately 1.5 months after start of stimulation)
    End point values
    		 FE 999049 + GnRH agonist (GONAPEPTYL) FE 999049 + GnRH Antagonist (CETROTIDE)
    Number of subjects analysed
    202
    204
    Units: Subjects
    number (not applicable)
        Positive βhCG test
    91
    79
        Negative βhCG test
    111
    125
    Statistical analysis title
    		 FE 999049 GnRH Agonist, FE 999049 GnRH Antagonist
    Comparison groups
    FE 999049 + GnRH agonist (GONAPEPTYL) v FE 999049 + GnRH Antagonist (CETROTIDE)
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    		 other [19]
    P-value
    		 = 0.1579 [20]
    Method
    		 Regression, Logistic
    Parameter type
    		 Difference
    Point estimate
    6.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.71
         upper limit
    		 16.7
    Notes
    [19] - Subjects in this analysis: 431
    [20] - Logistic regression model with treatment, age strata, and AMH group as factors.

    Secondary: Implantation Rate

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    End point title
    		 Implantation Rate
    End point description
    Defined as the number of gestational sacs after transfer divided by number of blastocysts transferred
    End point type
    Secondary
    End point timeframe
    5-6 weeks after transfer (up to approximately 2.5 months after start of stimulation)
    End point values
    		 FE 999049 + GnRH agonist (GONAPEPTYL) FE 999049 + GnRH Antagonist (CETROTIDE)
    Number of subjects analysed
    173
    167
    Units: Embryos
        number (not applicable)
    82
    68
    No statistical analyses for this end point

    Secondary: Clinical Pregnancy Rate

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    End point title
    		 Clinical Pregnancy Rate
    End point description
    Defined as at least one gestational sac
    End point type
    Secondary
    End point timeframe
    5-6 weeks after transfer (up to approximately 2.5 months after start of stimulation)
    End point values
    		 FE 999049 + GnRH agonist (GONAPEPTYL) FE 999049 + GnRH Antagonist (CETROTIDE)
    Number of subjects analysed
    202
    204
    Units: Subjects
    number (not applicable)
        Positive
    81
    68
        Negative
    121
    136
    Statistical analysis title
    		 FE 999049 GnRH Agonist, FE 999049 GnRH Antagonist
    Comparison groups
    FE 999049 + GnRH agonist (GONAPEPTYL) v FE 999049 + GnRH Antagonist (CETROTIDE)
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    		 other [21]
    P-value
    		 = 0.1134 [22]
    Method
    		 Regression, Logistic
    Parameter type
    		 Difference
    Point estimate
    7.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.82
         upper limit
    		 17.14
    Notes
    [21] - Subjects in this analysis: 431
    [22] - Logistic regression model with treatment, age strata, and AMH group as factors.

    Secondary: Vital Pregnancy Rate

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    End point title
    		 Vital Pregnancy Rate
    End point description
    Defined as at least one intrauterine gestational sac with fetal heart beat
    End point type
    Secondary
    End point timeframe
    5-6 weeks after transfer (up to approximately 2.5 months after start of stimulation)
    End point values
    		 FE 999049 + GnRH agonist (GONAPEPTYL) FE 999049 + GnRH Antagonist (CETROTIDE)
    Number of subjects analysed
    202
    204
    Units: Subjects
    number (not applicable)
        Positive
    77
    62
        Negative
    125
    142
    Statistical analysis title
    		 FE 999049 GnRH Agonist, FE 999049 GnRH Antagonist
    Comparison groups
    FE 999049 + GnRH agonist (GONAPEPTYL) v FE 999049 + GnRH Antagonist (CETROTIDE)
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    		 other [23]
    P-value
    		 = 0.0642 [24]
    Method
    		 Regression, Logistic
    Parameter type
    		 Difference
    Point estimate
    8.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.52
         upper limit
    		 18.14
    Notes
    [23] - Subjects in this analysis: 431
    [24] - Logistic regression model with treatment, age strata, and AMH group as factors.

    Secondary: Ongoing Pregnancy Rate

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    End point title
    		 Ongoing Pregnancy Rate
    End point description
    At least one intrauterine viable fetus
    End point type
    Secondary
    End point timeframe
    10-11 weeks after transfer (up to approximately 4 months after start of stimulation)
    End point values
    		 FE 999049 + GnRH agonist (GONAPEPTYL) FE 999049 + GnRH Antagonist (CETROTIDE)
    Number of subjects analysed
    202
    204
    Units: Subjects
    number (not applicable)
        Positive
    73
    60
        Negative
    129
    144
    Statistical analysis title
    		 FE 999049 GnRH Agonist, FE 999049 GnRH Antagonist
    Comparison groups
    FE 999049 + GnRH agonist (GONAPEPTYL) v FE 999049 + GnRH Antagonist (CETROTIDE)
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    		 other [25]
    P-value
    		 = 0.1002 [26]
    Method
    		 Regression, Logistic
    Parameter type
    		 Difference
    Point estimate
    7.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.49
         upper limit
    		 16.97
    Notes
    [25] - Subjects in this analysis: 431
    [26] - Logistic regression model with treatment, age strata, and AMH group as factors.

    Secondary: Ongoing Implantation Rate

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    End point title
    		 Ongoing Implantation Rate
    End point description
    Defined as number of intrauterine viable fetuses divided by the number of blastocysts transferred
    End point type
    Secondary
    End point timeframe
    10-11 weeks after transfer (up to approximately 4 months after start of stimulation)
    End point values
    		 FE 999049 + GnRH agonist (GONAPEPTYL) FE 999049 + GnRH Antagonist (CETROTIDE)
    Number of subjects analysed
    173
    167
    Units: Embryos
        number (not applicable)
    74
    60
    No statistical analyses for this end point

    Secondary: Proportion of Subjects With Early OHSS (Including OHSS of Moderate/Severe Grade)

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    End point title
    		 Proportion of Subjects With Early OHSS (Including OHSS of Moderate/Severe Grade)
    End point description
    Measured as mild, moderate or severe
    End point type
    Secondary
    End point timeframe
    Up to 9 days after triggering of final follicular maturation
    End point values
    		 FE 999049 + GnRH agonist (GONAPEPTYL) FE 999049 + GnRH Antagonist (CETROTIDE)
    Number of subjects analysed
    202
    204
    Units: Subjects
        number (not applicable)
    8
    5
    No statistical analyses for this end point

    Secondary: Proportion of Subjects With Late OHSS (Including OHSS of Moderate/Severe Grade)

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    End point title
    		 Proportion of Subjects With Late OHSS (Including OHSS of Moderate/Severe Grade)
    End point description
    Measured as mild, moderate or severe
    End point type
    Secondary
    End point timeframe
    >9 days after triggering of final follicular maturation
    End point values
    		 FE 999049 + GnRH agonist (GONAPEPTYL) FE 999049 + GnRH Antagonist (CETROTIDE)
    Number of subjects analysed
    202
    204
    Units: Subjects
        number (not applicable)
    4
    6
    No statistical analyses for this end point

    Secondary: Frequency of Adverse Events

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    End point title
    		 Frequency of Adverse Events
    End point description
    Any untoward medical occurrence
    End point type
    Secondary
    End point timeframe
    From time of signing informed consent until the end-of-trial (approximately 7 months)
    End point values
    		 FE 999049 + GnRH agonist (GONAPEPTYL) FE 999049 + GnRH Antagonist (CETROTIDE)
    Number of subjects analysed
    202
    204
    Units: Subjects
        number (not applicable)
    112
    109
    No statistical analyses for this end point

    Secondary: Intensity of Adverse Events

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    End point title
    		 Intensity of Adverse Events
    End point description
    Categorized as mild, moderate or severe
    End point type
    Secondary
    End point timeframe
    From time of signing informed consent until the end-of-trial (approximately 7 months)
    End point values
    		 FE 999049 + GnRH agonist (GONAPEPTYL) FE 999049 + GnRH Antagonist (CETROTIDE)
    Number of subjects analysed
    202
    204
    Units: Percentage of subjects
    number (not applicable)
        Mild adverse events
    42.6
    41.7
        Moderate adverse events
    18.8
    16.7
        Severe adverse events
    4.0
    3.4
    No statistical analyses for this end point

    Secondary: Technical Malfunctions of the Pre-filled Injection Pen

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    End point title
    		 Technical Malfunctions of the Pre-filled Injection Pen
    End point description
    Incidences of technical malfunctions of the pre-filled injection pen were recorded
    End point type
    Secondary
    End point timeframe
    Up to 20 days
    End point values
    		 FE 999049 + GnRH agonist (GONAPEPTYL) FE 999049 + GnRH Antagonist (CETROTIDE)
    Number of subjects analysed
    202
    204
    Units: Subjects
        number (not applicable)
    2
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were recorded from signing of the informed consent until end-of-trial.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    FE 999049 + GnRH agonist (GONAPEPTYL)
    Reporting group description
    		 -

    Reporting group title
    FE 999049 + GnRH Antagonist (CETROTIDE)
    Reporting group description
    		 -

    Serious adverse events
    		 FE 999049 + GnRH agonist (GONAPEPTYL) FE 999049 + GnRH Antagonist (CETROTIDE)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 202 (1.98%)
    6 / 204 (2.94%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Pregnancy, puerperium and perinatal conditions
    Hyperemesis gravidarum
         subjects affected / exposed
    0 / 202 (0.00%)
    1 / 204 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Reproductive system and breast disorders
    Adnexal torsion
         subjects affected / exposed
    0 / 202 (0.00%)
    1 / 204 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ovarian hyperstimulation syndrome
         subjects affected / exposed
    2 / 202 (0.99%)
    4 / 204 (1.96%)
         occurrences causally related to treatment / all
    2 / 2
    4 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 4
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 202 (0.50%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bacterial abdominal infection
         subjects affected / exposed
    1 / 202 (0.50%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 FE 999049 + GnRH agonist (GONAPEPTYL) FE 999049 + GnRH Antagonist (CETROTIDE)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    68 / 202 (33.66%)
    69 / 204 (33.82%)
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    20 / 202 (9.90%)
    12 / 204 (5.88%)
         occurrences all number
    20
    12
    Nervous system disorders
    Headache
         subjects affected / exposed
    27 / 202 (13.37%)
    29 / 204 (14.22%)
         occurrences all number
    31
    30
    Pregnancy, puerperium and perinatal conditions
    Biochemical pregnancy
         subjects affected / exposed
    10 / 202 (4.95%)
    11 / 204 (5.39%)
         occurrences all number
    10
    11
    Reproductive system and breast disorders
    Ovarian hyperstimulation syndrome
         subjects affected / exposed
    12 / 202 (5.94%)
    11 / 204 (5.39%)
         occurrences all number
    12
    11
    Pelvic pain
         subjects affected / exposed
    14 / 202 (6.93%)
    11 / 204 (5.39%)
         occurrences all number
    15
    12

    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? Yes
    Date
    Interruption
    Restart date
    20 Mar 2020
    A clinical trial application amendment was issued as an urgent safety measure due to the COVID-19 pandemic to protect subjects against immediate hazard to their health and safety. This amendment described a temporary halt of recruitment, i.e. a pause of screening and randomisation in the trial, and provided guidance for continued trial conduct and management of subjects included in the trial. All actively recruiting sites were informed about the temporary halt of recruitment on 20 March 2020. Sites in Israel were also informed about the temporary halt of recruitment, although they were not yet actively recruiting at the time of the COVID-19 pandemic trial hold. Trial activities were allowed to be resumed as per protocol in June 2020 in Austria, Denmark, Italy, the Netherlands, Norway and Switzerland, when it was judged that the situation allowed for this.
    -

    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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