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    Clinical Trial Results:
    A randomised, controlled, assessor-blind, parallel groups, multicentre, multinational trial comparing the efficacy and safety of FE 999049 with follitropin alfa (GONAL-F) in controlled ovarian stimulation in women undergoing an assisted reproductive technology programme

    Summary
    EudraCT number
    		 2013-001669-17
    Trial protocol
    		 BE   GB   CZ   DK   PL   ES   IT  
    Global end of trial date
    03 Jan 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 May 2017
    First version publication date
    04 May 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    000004
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01956110
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Ferring Pharmaceuticals A/S
    Sponsor organisation address
    Kay Fiskers Plads 11, Copenhagen S, Denmark, 2300
    Public contact
    Clinical Development Support, Ferring Pharmaceuticals, DK0-Disclosure@ferring.com
    Scientific contact
    Clinical Development Support, Ferring Pharmaceuticals, 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
    26 Jan 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 May 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Jan 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate non-inferiority of FE 999049 compared with GONAL-F with respect to ongoing pregnancy rate and ongoing implantation rate in the fresh cycle in women undergoing controlled ovarian stimulation.
    Protection of trial subjects
    The trial was performed in accordance with the Declaration of Helsinki and its amendments in force at the initiation of the trial.
    Background therapy
    		 As concomitant therapy in the controlled ovarian stimulation cycle, CETROTIDE (gonadotropin releasing hormone [GnRH] antagonist), OVITRELLE (human chorionic gonadotropin [hCG]), GONAPEPTYL (GnRH agonist), and ENDOMETRIN (progesterone) were used as non-investigational medicinal products (NIMPs). All NIMPs were used in line with the recommendations in the respective products’ labelling for the indication of assisted reproductive technologies (ART) and/or standard clinical practice and supported by literature.
    Evidence for comparator
    		 This was a randomised, controlled trial with GONAL-F as the comparator to adequately document the efficacy and safety of FE 999049. GONAL-F is a commercially available recombinant follicle stimulating hormone (rFSH) preparation.
    Actual start date of recruitment
    08 Oct 2013
    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
    Brazil: 58
    Country: Number of subjects enrolled
    Canada: 152
    Country: Number of subjects enrolled
    Russian Federation: 72
    Country: Number of subjects enrolled
    Poland: 117
    Country: Number of subjects enrolled
    Spain: 510
    Country: Number of subjects enrolled
    United Kingdom: 44
    Country: Number of subjects enrolled
    Belgium: 78
    Country: Number of subjects enrolled
    Czech Republic: 161
    Country: Number of subjects enrolled
    Denmark: 64
    Country: Number of subjects enrolled
    France: 9
    Country: Number of subjects enrolled
    Italy: 64
    Worldwide total number of subjects
    1329
    EEA total number of subjects
    1047
    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)
    1329
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 37 sites randomised subjects into the trial : 3 in Belgium, 3 in Brazil, 3 in Canada, 4 in the Czech Republic, 2 in Denmark, 2 in France, 2 in Italy, 2 in Poland, 4 in Russia, 10 in Spain and 2 in United Kingdom.

    Pre-assignment
    Screening details
    		 A total of 1501 subjects were screened in the trial, of whom 1329 subjects were randomised: 666 subjects to FE 999049 and 663 subjects to GONAL-F. Three subjects were randomisation failures and did not receive investigational medicinal product (IMP); 1 in the FE 999049 group and 2 in the GONAL-F group.

    Period 1
    Period 1 title
    Overall Trial Period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Assessor [1]
    Blinding implementation details
    The trial was assessor-blind, and all investigators, embryologists and central laboratory personnel were blinded to treatment allocation during the trial. The trial medication delegate at site (person responsible for IMP/NIMP), the trial coordinator at site (person entering data into e-CRF), the monitors and the participating subjects knew the treatment allocation once the subjects were randomised. The Ferring clinical trial team was blinded to treatment allocation until breaking of the blind.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 FE 999049
    Arm description
    		 Subjects randomised and exposed to FE 999049 IMP were included in this group.
    Arm type
    		 Experimental

    Investigational medicinal product name
    FE 999049
    Investigational medicinal product code
    Other name
    Follitropin delta
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    FE 999049 was administered as single daily subcutaneous injections in the abdomen. Subjects randomised to FE 999049 had their individual dose determined on the basis of their anti-Müllerian hormone (AMH) level at screening and their body weight at randomisation. The daily FE 999049 dose was fixed throughout the stimulation period and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.

    Arm title
    		 GONAL-F
    Arm description
    		 Subjects randomised and exposed to GONAL-F IMP were included in this group.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    GONAL-F
    Investigational medicinal product code
    Other name
    Follitropin alfa
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    GONAL-F was administered as single daily subcutaneous injections in the abdomen. The starting dose of GONAL-F was 150 international units (IU) and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 450 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.

    Notes
    [1] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: Due to differences in formulation and packaging of the two IMPs, subject blinding was not feasible.
    Number of subjects in period 1 [2]
    		FE 999049 GONAL-F
    Started
    665
    661
    Completed
    630
    639
    Not completed
    35
    22
         Personal reasons
    1
    1
         Adverse event, non-fatal
    9
    10
         Protocol deviation
    25
    11
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Three subjects were randomisation failures and did not receive IMP; 1 in the FE 999049 group and 2 in the GONAL-F group.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    FE 999049
    Reporting group description
    		 Subjects randomised and exposed to FE 999049 IMP were included in this group.

    Reporting group title
    GONAL-F
    Reporting group description
    		 Subjects randomised and exposed to GONAL-F IMP were included in this group.

    Reporting group values
    		 FE 999049 GONAL-F Total
    Number of subjects
    		 665 661 1326
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 665 661 1326
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 33.4 ± 3.89 33.2 ± 3.85 -
    Gender categorical
    Units: Subjects
        Female
    		 665 661 1326
        Male
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    FE 999049
    Reporting group description
    		 Subjects randomised and exposed to FE 999049 IMP were included in this group.

    Reporting group title
    GONAL-F
    Reporting group description
    		 Subjects randomised and exposed to GONAL-F IMP were included in this group.

    Subject analysis set title
    Modified intention-to-treat (mITT) analysis set
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The mITT analysis set was defined as all randomised and exposed subjects. Subjects were analysed according to actual treatment received.

    Subject analysis set title
    Safety analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety analysis set was defined as all randomised and exposed subjects. Subjects were analysed according to actual treatment received. The safety analysis set was identical to the mITT analysis set.

    Primary: Ongoing pregnancy rate

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    End point title
    		 Ongoing pregnancy rate
    End point description
    Ongoing pregnancy was defined as at least one intrauterine viable fetus 10-11 weeks after blastocyst transfer. Data are presented for the mITT analysis set.
    End point type
    Primary
    End point timeframe
    10-11 weeks after blastocyst transfer
    End point values
    		 FE 999049 GONAL-F
    Number of subjects analysed
    665
    661
    Units: Percentage of subjects
        number (not applicable)
    30.7
    31.6
    Statistical analysis title
    		 Treatment comparison: Ongoing pregnancy rate
    Statistical analysis description
    The pre-specified non-inferiority margin was -8.0% (absolute). Non-inferiority was evaluated based on a two-sided 95% confidence interval derived based on the asymptotic normal distribution. The treatment comparison was adjusted for age (<35, 35-37 and 38-40 years) by using the Mantel-Haenszel method to combine results across age-strata.
    Comparison groups
    FE 999049 v GONAL-F
    Number of subjects included in analysis
    1326
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 Treatment difference
    Point estimate
    -0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.9
         upper limit
    		 4.1
    Notes
    [1] - The lower bound of the 95% CI was well above the pre-specified non-inferiority limit of -8.0%. Thus, non-inferiority of FE 999049 to GONAL-F with regard to ongoing pregnancy rate was demonstrated.

    Primary: Ongoing implantation rate

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    End point title
    		 Ongoing implantation rate
    End point description
    Ongoing implantation rate was defined as the number of intrauterine viable fetuses 10-11 weeks after transfer divided by number of blastocysts transferred. Data are presented for the mITT analysis set.
    End point type
    Primary
    End point timeframe
    10-11 weeks after blastocyst transfer
    End point values
    		 FE 999049 GONAL-F
    Number of subjects analysed
    562 [2]
    560 [3]
    Units: Percentage
        number (not applicable)
    35.2
    35.8
    Notes
    [2] - Subjects with blastocyst transfer. A total of 585 blastocysts were transferred
    [3] - Subjects with blastocyst transfer. A total of 584 blastocysts were transferred.
    Statistical analysis title
    		 Treatment comparison: Ongoing implantation rate
    Statistical analysis description
    The pre-specified non-inferiority margin was -8.0% (absolute). Non-inferiority was evaluated based on a two-sided 95% confidence interval derived based on the asymptotic normal distribution. The treatment comparison was adjusted for age (<35, 35-37 and 38-40 years) by using the Mantel-Haenszel method to combine results across age-strata.
    Comparison groups
    GONAL-F v FE 999049
    Number of subjects included in analysis
    1122
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [4]
    Method
    Parameter type
    		 Treatment difference
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.1
         upper limit
    		 4.8
    Notes
    [4] - The lower bound of the 95% CI was well above the pre-specified non-inferiority limit of -8.0%. Thus, non-inferiority of FE 999049 to GONAL-F with regard to ongoing implantation rate was demonstrated.

    Secondary: Positive βhCG rate

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    End point title
    		 Positive βhCG rate
    End point description
    Positive beta unit of human chorionic gonadotropin (βhCG) was confirmed by a blood test 13-15 days after blastocyst transfer. Data are presented for the mITT analysis set.
    End point type
    Secondary
    End point timeframe
    13-15 days after blastocyst transfer
    End point values
    		 FE 999049 GONAL-F
    Number of subjects analysed
    665
    661
    Units: Percentage of subject
        number (not applicable)
    38.6
    40.2
    Statistical analysis title
    		 Treatment comparison: Positive βhCG rate
    Statistical analysis description
    Treatment groups were compared using a two-sided 95% confidence interval derived based on the asymptotic normal distribution. The treatment comparison was adjusted for age (<35, 35-37 and 38-40 years) by using the Mantel-Haenszel method to combine results across age-strata.
    Comparison groups
    FE 999049 v GONAL-F
    Number of subjects included in analysis
    1326
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Treatment difference
    Point estimate
    -1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.8
         upper limit
    		 3.7

    Secondary: Clinical pregnancy rate

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    End point title
    		 Clinical pregnancy rate
    End point description
    Clinical pregnancy was defined as at least one gestational sac 5-6 weeks after blastocyst transfer. Data are presented for the mITT analysis set.
    End point type
    Secondary
    End point timeframe
    5-6 weeks after blastocyst transfer
    End point values
    		 FE 999049 GONAL-F
    Number of subjects analysed
    665
    661
    Units: Percentage of subjects
        number (not applicable)
    34.9
    36.5
    Statistical analysis title
    		 Treatment comparison: Clinical pregnancy rate
    Statistical analysis description
    Treatment groups were compared using a two-sided 95% confidence interval derived based on the asymptotic normal distribution. The treatment comparison was adjusted for age (<35, 35-37 and 38-40 years) by using the Mantel-Haenszel method to combine results across age-strata.
    Comparison groups
    FE 999049 v GONAL-F
    Number of subjects included in analysis
    1326
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Treatment difference
    Point estimate
    -1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.6
         upper limit
    		 3.6

    Secondary: Vital pregnancy rate

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    End point title
    		 Vital pregnancy rate
    End point description
    Vital pregnancy was defined as at least one intrauterine gestational sac with fetal heart beat 5-6 weeks after blastocyst transfer. Data are presented for the mITT analysis set.
    End point type
    Secondary
    End point timeframe
    5-6 weeks after blastocyst transfer
    End point values
    		 FE 999049 GONAL-F
    Number of subjects analysed
    665
    661
    Units: Percentage of subjects
        number (not applicable)
    31.7
    33.4
    Statistical analysis title
    		 Treatment comparison: Vital pregnancy rate
    Statistical analysis description
    Treatment groups were compared using a two-sided 95% confidence interval derived based on the asymptotic normal distribution. The treatment comparison was adjusted for age (<35, 35-37 and 38-40 years) by using the Mantel-Haenszel method to combine results across age-strata.
    Comparison groups
    FE 999049 v GONAL-F
    Number of subjects included in analysis
    1326
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Treatment difference
    Point estimate
    -1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.7
         upper limit
    		 3.4

    Secondary: Implantation rate

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    End point title
    		 Implantation rate
    End point description
    Implantation rate was defined as the number of gestational sacs 5-6 weeks after transfer divided by number of blastocysts transferred. Data are presented for the mITT analysis set.
    End point type
    Secondary
    End point timeframe
    5-6 weeks after blastocyst transfer
    End point values
    		 FE 999049 GONAL-F
    Number of subjects analysed
    562 [5]
    560 [6]
    Units: Percentage
        number (not applicable)
    39.8
    41.3
    Notes
    [5] - Subjects with blastocyst transfer. A total of 585 blastocysts were transferred.
    [6] - Subjects with blastocyst transfer. A total of 584 blastocysts were transferred.
    Statistical analysis title
    		 Treatment comparison: Implantation rate
    Statistical analysis description
    Treatment groups were compared using a two-sided 95% confidence interval derived based on the asymptotic normal distribution. The treatment comparison was adjusted for age (<35, 35-37 and 38-40 years) by using the Mantel-Haenszel method to combine results across age-strata.
    Comparison groups
    FE 999049 v GONAL-F
    Number of subjects included in analysis
    1122
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Treatment difference
    Point estimate
    -1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7
         upper limit
    		 4.2

    Secondary: Proportion of subjects with extreme ovarian responses

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    End point title
    		 Proportion of subjects with extreme ovarian responses
    End point description
    Extreme ovarian response was defined as <4, ≥15 or ≥20 oocytes retrieved. Data are presented for the mITT analysis set.
    End point type
    Secondary
    End point timeframe
    Oocyte retrieval visit (36 hr [±2 hr] after triggering of final follicular maturation)
    End point values
    		 FE 999049 GONAL-F
    Number of subjects analysed
    635 [7]
    643 [8]
    Units: Percentage of subjects
    number (not applicable)
        <4 or >=15 oocytes retrieved
    26.6
    31.3
        <4 or >=20 oocytes retrieved
    14.5
    18.4
    Notes
    [7] - Subjects who underwent triggering of follicular maturation.
    [8] - Subjects who underwent triggering of follicular maturation.
    Statistical analysis title
    		 Treatment comparison: <4 or >=15 oocytes retrieved
    Statistical analysis description
    Nested logistic regression models were compared using the likelihood ratio test. The full logistic regression model included treatment as factor, AMH as covariate and the interaction term. The nested model did not include the interaction term.
    Comparison groups
    FE 999049 v GONAL-F
    Number of subjects included in analysis
    1278
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.001
    Method
    		 Likelihood ratio test
    Confidence interval
    Statistical analysis title
    		 Treatment comparison: <4 or >=20 oocytes retrieved
    Statistical analysis description
    Nested logistic regression models were compared using the likelihood ratio test. The full logistic regression model included treatment as factor, AMH as covariate and the interaction term. The nested model did not include the interaction term.
    Comparison groups
    FE 999049 v GONAL-F
    Number of subjects included in analysis
    1278
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.002
    Method
    		 Likelihood ratio test
    Confidence interval

    Secondary: Proportion of subjects with early OHSS and/or preventive interventions for early OHSS

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    End point title
    		 Proportion of subjects with early OHSS and/or preventive interventions for early OHSS
    End point description
    The proportion of subjects with early ovarian hyperstimulation syndrome (OHSS), early OHSS of moderate or severe grade, preventive interventions for early OHSS, early OHSS and/or preventive interventions for early OHSS, and early OHSS of moderate or severe grade and/or preventive interventions for early OHSS are presented for the mITT analysis set.
    End point type
    Secondary
    End point timeframe
    9 days after triggering of final follicular maturation
    End point values
    		 FE 999049 GONAL-F
    Number of subjects analysed
    665
    661
    Units: Percentage of subjects
    number (not applicable)
        Early OHSS (any grade)
    2.6
    3
        Early OHSS (moderate/severe)
    1.4
    1.4
        Any preventive intervention
    2.3
    4.5
        Early OHSS (any grade) / preventive interventions
    4.7
    6.2
        Early OHSS (mod/severe) / preventive interventions
    3.6
    5.1
    Statistical analysis title
    		 Treatment comparison: Early OHSS (any grade)
    Statistical analysis description
    Nested logistic regression models were compared using the likelihood ratio test. The full logistic regression model included treatment as factor, AMH as covariate and the interaction term. The nested model did not include the interaction term.
    Comparison groups
    FE 999049 v GONAL-F
    Number of subjects included in analysis
    1326
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.291
    Method
    		 Likelihood ratio test
    Confidence interval
    Statistical analysis title
    		 Treatment comparison: Early OHSS (mod/sev)
    Statistical analysis description
    Nested logistic regression models were compared using the likelihood ratio test. The full logistic regression model included treatment as factor, AMH as covariate and the interaction term. The nested model did not include the interaction term.
    Comparison groups
    FE 999049 v GONAL-F
    Number of subjects included in analysis
    1326
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.644
    Method
    		 Likelihood ratio test
    Confidence interval
    Statistical analysis title
    		 Treatment comparison: Preventive interventions
    Statistical analysis description
    Nested logistic regression models were compared using the likelihood ratio test. The full logistic regression model included treatment as factor, AMH as covariate and the interaction term. The nested model did not include the interaction term.
    Comparison groups
    FE 999049 v GONAL-F
    Number of subjects included in analysis
    1326
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.005
    Method
    		 Likelihood ratio test
    Confidence interval
    Statistical analysis title
    		 Treatment comp: Early OHSS (any grade)/preventive
    Statistical analysis description
    Nested logistic regression models were compared using the likelihood ratio test. The full logistic regression model included treatment as factor, AMH as covariate and the interaction term. The nested model did not include the interaction term.
    Comparison groups
    FE 999049 v GONAL-F
    Number of subjects included in analysis
    1326
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.046
    Method
    		 Likelihood ratio test
    Confidence interval
    Statistical analysis title
    		 Treatment comp: Early OHSS (mod/sev)/preventive
    Statistical analysis description
    Nested logistic regression models were compared using the likelihood ratio test. The full logistic regression model included treatment as factor, AMH as covariate and the interaction term. The nested model did not include the interaction term.
    Comparison groups
    FE 999049 v GONAL-F
    Number of subjects included in analysis
    1326
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.019
    Method
    		 Likelihood ratio test
    Confidence interval

    Secondary: Proportion of subjects with cycle cancellation due to poor or excessive ovarian response

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    End point title
    		 Proportion of subjects with cycle cancellation due to poor or excessive ovarian response
    End point description
    Proportion of subjects with cycle cancellation due to poor ovarian response, excessive ovarian response, and triggering with GnRH agonist are presented for the mITT analysis set.
    End point type
    Secondary
    End point timeframe
    End-of-stimulation
    End point values
    		 FE 999049 GONAL-F
    Number of subjects analysed
    665
    661
    Units: Percentage of subjects
    number (not applicable)
        Cycle cancelled due to poor ovarian response
    3.8
    2.7
        Cycle cancelled due to excessive ovarian response
    0
    0
        Triggering with GnRH agonist
    1.5
    3.5
    Statistical analysis title
    		 Treatment comp: Cycle cancelled due to poor resp.
    Statistical analysis description
    Treatment groups were compared using a logistic regression model with treatment and age (<35, 35-37, and 38-40 years) as factors.
    Comparison groups
    FE 999049 v GONAL-F
    Number of subjects included in analysis
    1326
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.302
    Method
    		 Likelihood ratio test
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 2.57
    Statistical analysis title
    		 Treatment comparison:Triggering with GnRH agonist
    Statistical analysis description
    Treatment groups were compared using a logistic regression model with treatment and age (<35, 35-37, and 38-40 years) as factors.
    Comparison groups
    FE 999049 v GONAL-F
    Number of subjects included in analysis
    1326
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.019
    Method
    		 Likelihood ratio test
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 0.9

    Secondary: Number and size of follicles on stimulation day 6 and end-of-stimulation

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    End point title
    		 Number and size of follicles on stimulation day 6 and end-of-stimulation
    End point description
    Total number of follicles with size >= 12 mm on stimulation day 6 and at end-of-stimulation are presented for the mITT analysis set.
    End point type
    Secondary
    End point timeframe
    Stimulation day 6 and end-of-stimulaition
    End point values
    		 FE 999049 GONAL-F
    Number of subjects analysed
    665
    661
    Units: Number of follicles
    arithmetic mean (standard deviation)
        Follicles with size >= 12 mm on stimulation Day 6
    3.3 ± 2.7
    3.6 ± 3
        Follicles with size >= 12 mm at End-of-stimulation
    10.8 ± 5.4
    11.1 ± 6
    Statistical analysis title
    		 Treatment comparison: Follicles on Day 6
    Statistical analysis description
    Treatment groups were compared using the van Elteren test adjusted for age (<35, 35-37, and 38-40 years).
    Comparison groups
    FE 999049 v GONAL-F
    Number of subjects included in analysis
    1326
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.076
    Method
    		 van Elteren
    Confidence interval
    Statistical analysis title
    		 Treatment comp: Follicles at end-of-stimulation
    Statistical analysis description
    Treatment groups were compared using the van Elteren test adjusted for age (<35, 35-37, and 38-40 years).
    Comparison groups
    GONAL-F v FE 999049
    Number of subjects included in analysis
    1326
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.954
    Method
    		 van Elteren
    Confidence interval

    Secondary: Metaphase II oocytes (inseminated through ICSI)

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    End point title
    		 Metaphase II oocytes (inseminated through ICSI)
    End point description
    Number of oocytes in metaphase II prior to intracytoplasmic sperm injection (ICSI) insemination is presented for the mITT analysis set.
    End point type
    Secondary
    End point timeframe
    Prior to insemination
    End point values
    		 FE 999049 GONAL-F
    Number of subjects analysed
    531 [9]
    522 [10]
    Units: Number of oocytes
        arithmetic mean (standard deviation)
    7.4 ± 4.3
    7.7 ± 5.2
    Notes
    [9] - Subjects with all oocytes inseminated using ICSI.
    [10] - Subjects with all oocytes inseminated using ICSI.
    Statistical analysis title
    		 Treatment comparison: No. of metaphase II oocytes
    Statistical analysis description
    Treatment groups were compared using the van Elteren test adjusted for age (<35, 35-37, and 38-40 years).
    Comparison groups
    FE 999049 v GONAL-F
    Number of subjects included in analysis
    1053
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.909
    Method
    		 van Elteren
    Confidence interval

    Secondary: Fertilisation rate

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    End point title
    		 Fertilisation rate
    End point description
    Fertilisation rate was defined as the number of oocytes with 2 pronuclei divided by the number of oocytes retrieved. Data are presented for the mITT analysis set.
    End point type
    Secondary
    End point timeframe
    Day 1 after oocyte retrieval (19 hr ± 2 hr)
    End point values
    		 FE 999049 GONAL-F
    Number of subjects analysed
    634 [11]
    640 [12]
    Units: Percentage of oocytes
        arithmetic mean (standard deviation)
    56 ± 24.5
    57 ± 23.8
    Notes
    [11] - Subjects with oocytes retrieved.
    [12] - Subjects with oocytes retrieved.
    Statistical analysis title
    		 Treatment comparison: Fertilisation rate
    Statistical analysis description
    Treatment groups were compared using the van Elteren test adjusted for age (<35, 35-37, and 38-40 years).
    Comparison groups
    FE 999049 v GONAL-F
    Number of subjects included in analysis
    1274
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.53
    Method
    		 van Elteren
    Confidence interval

    Secondary: Number and quality of embryos on Day 3

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    End point title
    		 Number and quality of embryos on Day 3
    End point description
    Number of embryos (total and good-quality) on Day 3 are presented. A good-quality embryo was defined as an embryo with ≥6 blastomeres and fragmentation ≤20% on Day 3. Data are presented for the mITT analysis set.
    End point type
    Secondary
    End point timeframe
    Day 3 after oocyte retrieval
    End point values
    		 FE 999049 GONAL-F
    Number of subjects analysed
    634 [13]
    640 [14]
    Units: Number of embryos
    arithmetic mean (standard deviation)
        Number of embryos
    5.4 ± 3.7
    5.7 ± 4.3
        Number of good-quality embryos
    4.2 ± 3.3
    4.5 ± 3.7
    Notes
    [13] - Subjects with oocytes retrieved.
    [14] - Subjects with oocytes retrieved.
    Statistical analysis title
    		 Treatment comparison: Number of embryos
    Statistical analysis description
    Treatment groups were compared using the van Elteren test adjusted for age (<35, 35-37, and 38-40 years).
    Comparison groups
    GONAL-F v FE 999049
    Number of subjects included in analysis
    1274
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.59
    Method
    		 van Elteren
    Confidence interval
    Statistical analysis title
    		 Treatment comparison: Good quality embryos
    Statistical analysis description
    Treatment groups were compared using the van Elteren test adjusted for age (<35, 35-37, and 38-40 years).
    Comparison groups
    FE 999049 v GONAL-F
    Number of subjects included in analysis
    1274
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.414
    Method
    		 van Elteren
    Confidence interval

    Secondary: Number and quality of blastocysts on Day 5

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    End point title
    		 Number and quality of blastocysts on Day 5
    End point description
    Number of blastocysts (total and good-quality) on Day 5 are presented. A good-quality blastocyst was defined as a blastocyst of grade 3BB or higher. Data are presented for the mITT analysis set.
    End point type
    Secondary
    End point timeframe
    Day 5 after oocyte retrieval
    End point values
    		 FE 999049 GONAL-F
    Number of subjects analysed
    634 [15]
    640 [16]
    Units: Number of blastocyst
    arithmetic mean (standard deviation)
        Number of blastocysts
    3.3 ± 2.8
    3.5 ± 3.2
        Number of good-quality blastocysts
    2 ± 2.2
    2.1 ± 2.4
    Notes
    [15] - Subjects with oocytes retrieved.
    [16] - Subjects with oocytes retrieved.
    Statistical analysis title
    		 Treatment comparison: Number of blastocysts
    Statistical analysis description
    Treatment groups were compared using the van Elteren test adjusted for age (<35, 35-37, and 38-40 years).
    Comparison groups
    FE 999049 v GONAL-F
    Number of subjects included in analysis
    1274
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.344
    Method
    		 van Elteren
    Confidence interval
    Statistical analysis title
    		 Treatment comparison: Good-quality blastocysts
    Statistical analysis description
    Treatment groups were compared using the van Elteren test adjusted for age (<35, 35-37, and 38-40 years).
    Comparison groups
    FE 999049 v GONAL-F
    Number of subjects included in analysis
    1274
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.58
    Method
    		 van Elteren
    Confidence interval

    Secondary: Circulating concentration of FSH, LH, estradiol, progesterone, inhibin A, and inhibin B

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    End point title
    		 Circulating concentration of FSH, LH, estradiol, progesterone, inhibin A, and inhibin B
    End point description
    Ratio of circulating concentrations of hormones; follicle stimulating hormone (FSH), luteinising hormone (LH), estradiol, progesterone, inhibin A, and inhibin B are presented for the mITT analysis set.
    End point type
    Secondary
    End point timeframe
    Stimulation day 6 and end-of-stimulation
    End point values
    		 Modified intention-to-treat (mITT) analysis set
    Number of subjects analysed
    1326
    Units: Ratio
    number (confidence interval 95%)
        Stimulation Day 6 - FSH
    1.15 (1.11 to 1.19)
        Stimulation Day 6 - LH
    0.94 (0.86 to 1.03)
        Stimulation Day 6 - estradiol
    0.92 (0.85 to 0.99)
        Stimulation Day 6 - progesterone
    0.97 (0.9 to 1.03)
        Stimulation Day 6 - inhibin A
    0.92 (0.85 to 0.99)
        Stimulation Day 6 - inhibin B
    0.95 (0.89 to 1.02)
        End-of-stimulation - FSH
    1.1 (1.07 to 1.14)
        End-of-stimulation - LH
    0.95 (0.86 to 1.04)
        End-of-stimulation - estradiol
    0.95 (0.89 to 1.03)
        End-of-stimulation - progesterone
    0.95 (0.89 to 1.01)
        End-of-stimulation - inhibin A
    0.92 (0.86 to 0.99)
        End-of-stimulation - inhibin B
    0.95 (0.88 to 1.03)
    No statistical analyses for this end point

    Secondary: Total gonadotropin dose

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    End point title
    		 Total gonadotropin dose
    End point description
    The total gonadotropin dose was recorded. Data are presented for the mITT analysis set.
    End point type
    Secondary
    End point timeframe
    End-of-stimulation
    End point values
    		 FE 999049 GONAL-F
    Number of subjects analysed
    665
    661
    Units: ug
        arithmetic mean (standard deviation)
    90 ± 25.3
    103.7 ± 33.6
    Statistical analysis title
    		 Treatment comparison: Total gonadotropin dose
    Statistical analysis description
    Treatment groups were compared using the van Elteren test adjusted for age (<35, 35-37, and 38-40 years).
    Comparison groups
    FE 999049 v GONAL-F
    Number of subjects included in analysis
    1326
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.001
    Method
    		 van Elteren
    Confidence interval

    Secondary: Number of stimulation days

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    End point title
    		 Number of stimulation days
    End point description
    The number of stimulation days are presented for the mITT analysis set.
    End point type
    Secondary
    End point timeframe
    End-of-stimulation
    End point values
    		 FE 999049 GONAL-F
    Number of subjects analysed
    665
    661
    Units: Days
        arithmetic mean (standard deviation)
    8.9 ± 1.9
    8.6 ± 1.7
    Statistical analysis title
    		 Treatment comparison: Number of stimulation days
    Statistical analysis description
    Treatment groups were compared using the van Elteren test adjusted for age (<35, 35-37, and 38-40 years).
    Comparison groups
    FE 999049 v GONAL-F
    Number of subjects included in analysis
    1326
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.062
    Method
    		 van Elteren
    Confidence interval

    Secondary: Proportion of subjects with markedly abnormal changes in clinical chemistry and haematology parameters

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    End point title
    		 Proportion of subjects with markedly abnormal changes in clinical chemistry and haematology parameters
    End point description
    Number of subjects with a markedly abnormal value at end-of-stimulation or end-of-trial after a normal baseline value, judged as clinically significant by the investigator (all parameters combined) are presented for the safety analysis set.
    End point type
    Secondary
    End point timeframe
    Stimulation day 1, end-of-stimulation and end-of-trial
    End point values
    		 FE 999049 GONAL-F
    Number of subjects analysed
    665
    661
    Units: Percentage of subjects
    number (not applicable)
        Clinical chemistry
    0.15
    0
        Hematology
    0.3
    0
    No statistical analyses for this end point

    Secondary: Frequency of injection site reactions

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    End point title
    		 Frequency of injection site reactions
    End point description
    Subjects self-assessed injection site reactions (redness, itching, pain, swelling and bruising) immediately, 30 minutes and 24 hours after each injection. The injection site reactions were assessed as none, mild, moderate and severe. The frequency of injection site reactions (mild, moderate or severe) based on all assessment performed is presented for the safety analysis set.
    End point type
    Secondary
    End point timeframe
    End-of-stimulation
    End point values
    		 FE 999049 GONAL-F
    Number of subjects analysed
    665
    661
    Units: Percentage of events
        number (not applicable)
    3.4
    3.5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AEs) were recorded from signed informed consent to the end-of-trial.
    Adverse event reporting additional description
    AEs with onset after start of first administration of IMP were considered treatment-emergent and are presented for the safety analysis set.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    FE 999049
    Reporting group description
    		 Subjects randomised and exposed to FE 999049 IMP were included in this group.

    Reporting group title
    GONAL-F
    Reporting group description
    		 Subjects randomised and exposed to GONAL-F IMP were included in this group.

    Serious adverse events
    		 FE 999049 GONAL-F
    Total subjects affected by serious adverse events
         subjects affected / exposed
    16 / 665 (2.41%)
    10 / 661 (1.51%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Post procedural haemorrhage
         subjects affected / exposed
    2 / 665 (0.30%)
    0 / 661 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Haemorrhage in pregnancy
         subjects affected / exposed
    5 / 665 (0.75%)
    1 / 661 (0.15%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abortion spontaneous
         subjects affected / exposed
    2 / 665 (0.30%)
    1 / 661 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biochemical pregnancy
         subjects affected / exposed
    1 / 665 (0.15%)
    2 / 661 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abortion threatened
         subjects affected / exposed
    1 / 665 (0.15%)
    0 / 661 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperemesis gravidarum
         subjects affected / exposed
    0 / 665 (0.00%)
    1 / 661 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis ulcerative
         subjects affected / exposed
    1 / 665 (0.15%)
    0 / 661 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Ovarian hyperstimulation syndrome
         subjects affected / exposed
    3 / 665 (0.45%)
    6 / 661 (0.91%)
         occurrences causally related to treatment / all
    2 / 3
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adnexal torsion
         subjects affected / exposed
    1 / 665 (0.15%)
    0 / 661 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Affect lability
         subjects affected / exposed
    1 / 665 (0.15%)
    0 / 661 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Post procedural infection
         subjects affected / exposed
    0 / 665 (0.00%)
    1 / 661 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 FE 999049 GONAL-F
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    356 / 665 (53.53%)
    330 / 661 (49.92%)
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    49 / 665 (7.37%)
    52 / 661 (7.87%)
         occurrences all number
    51
    54
    Nervous system disorders
    Headache
         subjects affected / exposed
    97 / 665 (14.59%)
    88 / 661 (13.31%)
         occurrences all number
    131
    110
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    46 / 665 (6.92%)
    41 / 661 (6.20%)
         occurrences all number
    54
    59
    Pelvic discomfort
         subjects affected / exposed
    38 / 665 (5.71%)
    25 / 661 (3.78%)
         occurrences all number
    46
    31

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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