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    Clinical Trial Results:
    Randomised clinical trial comparing highly purified FSH formulation (Fostimon®) and recombinant FSH (Gonal-F®) in GnRH-antagonist controlled ovarian hyperstimulation cycles.

    Summary
    EudraCT number
    		 2013-002482-19
    Trial protocol
    		 IT   GB   ES   BE  
    Global end of trial date
    12 Aug 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Sep 2018
    First version publication date
    30 Sep 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    13EU/FSH01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01969201
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    IBSA Institut Biochimique SA
    Sponsor organisation address
    via del Piano, Pambio-Noranco, Switzerland, 6995
    Public contact
    Barbara Cometti, IBSA Institut Biochimique SA, +41 583601000, sd@ibsa.ch
    Scientific contact
    Barbara Cometti, IBSA Institut Biochimique SA, +41 583601000, sd@ibsa.ch
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    22 Aug 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Aug 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of the non-inferiority study is to evaluate the clinical efficacy and the safety of two different subcutaneous FSH preparations (Fostimon®, IBSA Institut Biochimique SA versus Gonal-F®) for controlled ovarian hyperstimulation in a GnRH-antagonist cycle
    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
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jan 2014
    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
    Spain: 200
    Country: Number of subjects enrolled
    United Kingdom: 88
    Country: Number of subjects enrolled
    Belgium: 80
    Country: Number of subjects enrolled
    Italy: 179
    Country: Number of subjects enrolled
    Turkey: 114
    Country: Number of subjects enrolled
    Switzerland: 49
    Worldwide total number of subjects
    710
    EEA total number of subjects
    547
    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)
    710
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 17 sites randomised subjects into the trial: 4 in Spain, 6 in Italy, 1 in UK, 2 in Belgium, 2 in Switzerland, 2 in Turkey.

    Pre-assignment
    Screening details
    		 A total of 819subjects were screened in the trial, of whom 712 subjects were randomised: 354 subjects to Fostimon and 358 subjects to GONAL-F. Two subjects in the Fostimon group were randomisation failures and did not receive investigational medicinal product (IMP).

    Period 1
    Period 1 title
    Overall trial period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind [1]
    Roles blinded
    		 Assessor, Investigator [2]
    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 monitors and the participating subjects knew the treatment allocation once the subjects were randomised.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Test product - Fostimon
    Arm description
    		 Subject randomised and exposed to Fostimon IMP were included in this group
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fostimon
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The starting dose regimen was fixed for the first 5 days for both the study treatment: 150 IU of FSH administered daily by subcutaneous injection.

    Arm title
    		 Reference product - 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
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The starting dose regimen was fixed for the first 5 days for both the study treatment: 150 IU of FSH administered daily by subcutaneous injection.

    Notes
    [1] - The number of roles blinded appears inconsistent with a single blinded trial. It is expected that there will be one role blinded in a single blind trial.
    Justification: 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 monitors and the participating subjects knew the treatment allocation once the subjects were randomised.
    [2] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: 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 monitors and the participating subjects knew the treatment allocation once the subjects were randomised.
    Number of subjects in period 1
    		Test product - Fostimon Reference product - Gonal F
    Started
    352
    358
    Completed
    307
    313
    Not completed
    45
    45
         Embryo transfer not performed
    29
    29
         Consent withdrawn by subject
    -
    1
         Adverse event, non-fatal
    3
    5
         Lack of efficacy
    13
    8
         Protocol deviation
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Test product - Fostimon
    Reporting group description
    		 Subject randomised and exposed to Fostimon IMP were included in this group

    Reporting group title
    Reference product - Gonal F
    Reporting group description
    		 Subjects randomised and exposed to Gonal F IMP were included in this group

    Reporting group values
    		 Test product - Fostimon Reference product - Gonal F Total
    Number of subjects
    		 352 358 710
    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)
    		 0 0 0
        From 65-84 years
    		 352 358 710
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 32.39 ( 3.83 ) 32.68 ( 3.52 ) -
    Gender categorical
    Units: Subjects
        Female
    		 352 358 710
        Male
    		 0 0 0
    Infertility diagnosis
    Units: Subjects
        Male factor
    		 156 150 306
        Tubal factor
    		 30 32 62
        Male + Tubal factor
    		 15 13 28
        Idiopathic
    		 126 136 262
        Other factors
    		 25 27 52
    BMI
    Body mass index
    Units: Kg/m2
        arithmetic mean (standard deviation)
    		 22.81 ( 2.74 ) 22.59 ( 2.87 ) -
    Duration of infertility
    Units: months
        arithmetic mean (standard deviation)
    		 41.8 ( 30.15 ) 41.76 ( 27.5 ) -
    Basal FSH
    Units: IU/l
        arithmetic mean (standard deviation)
    		 6.78 ( 1.55 ) 6.75 ( 1.58 ) -
    Basal AMH levels
    Basal anti-mullerian hormone levels
    Units: ng/ml
        arithmetic mean (standard deviation)
    		 2.69 ( 1.15 ) 2.70 ( 1.12 ) -

    End points

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    End points reporting groups
    Reporting group title
    Test product - Fostimon
    Reporting group description
    		 Subject randomised and exposed to Fostimon IMP were included in this group

    Reporting group title
    Reference product - Gonal F
    Reporting group description
    		 Subjects randomised and exposed to Gonal F IMP were included in this group

    Primary: Clinical pregnancy rate

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    End point title
    		 Clinical pregnancy rate
    End point description
    End point type
    Primary
    End point timeframe
    8 weeks of gestation.
    End point values
    		 Test product - Fostimon Reference product - Gonal F
    Number of subjects analysed
    352 [1]
    358 [2]
    Units: Percentage of subjects
        number (not applicable)
    36.9
    39.7
    Notes
    [1] - ITT population
    [2] - ITT population
    Statistical analysis title
    		 Treatment comparison: clinical pregnancy rate
    Statistical analysis description
    The non-inferiority of Fostimon® vs. Gonal-F® was evaluated by calculating the 95% confidence interval (CI) for the differences in pregnancy rates between the two treatment groups. If the lower bound of the 95% CI of the difference between the two proportions was greater than -0.10 (i.e. -10%), then Fostimon® was to be considered not inferior to the control treatment.
    Comparison groups
    Test product - Fostimon v Reference product - Gonal F
    Number of subjects included in analysis
    710
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    Method
    Parameter type
    		 Treatment difference
    Point estimate
    -2.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.88
         upper limit
    		 4.42
    Notes
    [3] - The lower bound of the 95% CI was above the pre-specified non-inferiority limit of -8.0%. Thus non inferiority of Fostimon to Gonal-F with regard to the ongoing pregnancy rate was demonstrated.

    Secondary: Mean FSH dose

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    End point title
    		 Mean FSH dose
    End point description
    End point type
    Secondary
    End point timeframe
    at the end of the stimulation.
    End point values
    		 Test product - Fostimon Reference product - Gonal F
    Number of subjects analysed
    352
    358
    Units: IU
        median (standard deviation)
    1550.6 ( 549.8 )
    1478.1 ( 450.0 )
    Statistical analysis title
    		 Treatment comparison: Mean FSH dose (total)
    Comparison groups
    Test product - Fostimon v Reference product - Gonal F
    Number of subjects included in analysis
    710
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.05
    Method
    		 ANOVA
    Confidence interval

    Secondary: Duration of FSH stimulation

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    End point title
    		 Duration of FSH stimulation
    End point description
    End point type
    Secondary
    End point timeframe
    At the end of the stimulation.
    End point values
    		 Test product - Fostimon Reference product - Gonal F
    Number of subjects analysed
    352
    358
    Units: days
        arithmetic mean (standard deviation)
    9.20 ( 2.14 )
    9.00 ( 1.75 )
    Statistical analysis title
    		 Treatment comparison: Duration of FSH Stimulation
    Comparison groups
    Test product - Fostimon v Reference product - Gonal F
    Number of subjects included in analysis
    710
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.16
    Method
    		 ANOVA
    Confidence interval

    Secondary: Number of follicles > 16 mm on the day of hCG

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    End point title
    		 Number of follicles > 16 mm on the day of hCG
    End point description
    End point type
    Secondary
    End point timeframe
    On the day of hCG triggering.
    End point values
    		 Test product - Fostimon Reference product - Gonal F
    Number of subjects analysed
    347 [4]
    350 [5]
    Units: number of follicles
        arithmetic mean (standard deviation)
    4.10 ( 2.47 )
    4.47 ( 2.33 )
    Notes
    [4] - For 5 subjects, this parameter was not available.
    [5] - For 8 subjects, this parameter was not available.
    Statistical analysis title
    		 Treatment comparison: Number of follicles > 16 mm
    Comparison groups
    Test product - Fostimon v Reference product - Gonal F
    Number of subjects included in analysis
    697
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.003
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Progesterone levels on the day of hCG triggering

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    End point title
    		 Progesterone levels on the day of hCG triggering
    End point description
    End point type
    Secondary
    End point timeframe
    On the day of hCG triggering.
    End point values
    		 Test product - Fostimon Reference product - Gonal F
    Number of subjects analysed
    327 [6]
    336 [7]
    Units: ng/ml
        arithmetic mean (standard deviation)
    0.63 ( 0.93 )
    0.76 ( 0.99 )
    Notes
    [6] - For 25 subjects, this parameter was not available or below the detection limit.
    [7] - For 22 subjects, this parameter was not available or below the detection limit.
    Statistical analysis title
    		 Treatment comparison: Progesterone levels
    Comparison groups
    Test product - Fostimon v Reference product - Gonal F
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.001
    Method
    		 ANOVA
    Confidence interval

    Secondary: 17b-Estradiol levels on the day of hCG

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    End point title
    		 17b-Estradiol levels on the day of hCG
    End point description
    End point type
    Secondary
    End point timeframe
    On the day of hCG triggering
    End point values
    		 Test product - Fostimon Reference product - Gonal F
    Number of subjects analysed
    334 [8]
    339 [9]
    Units: pg/ml
        arithmetic mean (standard deviation)
    1173.24 ( 699.06 )
    1311.31 ( 828.31 )
    Notes
    [8] - For 18 subjects Estradiol level was not available.
    [9] - For 19 subjects Estradiol levels were not available.
    Statistical analysis title
    		 Treatment comparison: Estradiol levels on hCG day
    Comparison groups
    Test product - Fostimon v Reference product - Gonal F
    Number of subjects included in analysis
    673
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.05
    Method
    		 ANOVA
    Confidence interval

    Secondary: Total number of oocytes retrieved

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    End point title
    		 Total number of oocytes retrieved
    End point description
    End point type
    Secondary
    End point timeframe
    On the day of oocytes retrieval.
    End point values
    		 Test product - Fostimon Reference product - Gonal F
    Number of subjects analysed
    337 [10]
    346 [11]
    Units: oocytes
        arithmetic mean (standard deviation)
    8.45 ( 4.72 )
    9.33 ( 4.90 )
    Notes
    [10] - Subjects who underwent oocyte retrieval.
    [11] - Subjects who underwent oocyte retrieval.
    Statistical analysis title
    		 Treatment comparison: n of oocytes retrieved.
    Comparison groups
    Test product - Fostimon v Reference product - Gonal F
    Number of subjects included in analysis
    683
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.02
    Method
    		 ANOVA
    Confidence interval

    Secondary: Fertilisation rate

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    End point title
    		 Fertilisation rate
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1 after oocytes retrieval.
    End point values
    		 Test product - Fostimon Reference product - Gonal F
    Number of subjects analysed
    331 [12]
    338 [13]
    Units: Percentage of oocytes
        arithmetic mean (standard deviation)
    73.98 ( 26.44 )
    75.85 ( 21.48 )
    Notes
    [12] - Subjects with at least one oocyte inseminated (IVF/ICSI).
    [13] - Subjects with at least one oocyte inseminated (IVF/ICSI)
    Statistical analysis title
    		 Treatment comparison: Fertilisation rate
    Comparison groups
    Reference product - Gonal F v Test product - Fostimon
    Number of subjects included in analysis
    669
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.32
    Method
    		 ANOVA
    Confidence interval

    Secondary: Cleavage rate

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    End point title
    		 Cleavage rate
    End point description
    End point type
    Secondary
    End point timeframe
    Day 2 after oocytes retrieval.
    End point values
    		 Test product - Fostimon Reference product - Gonal F
    Number of subjects analysed
    331 [14]
    338 [15]
    Units: Percentage of oocytes
        arithmetic mean (standard deviation)
    59.61 ( 31.96 )
    61.95 ( 30.83 )
    Notes
    [14] - Subjects with at least one oocyte inseminated (IVF/ICSI).
    [15] - Subjects with at least one oocyte inseminated (IVF/ICSI).
    Statistical analysis title
    		 Treatment comparison: cleavage rate
    Comparison groups
    Test product - Fostimon v Reference product - Gonal F
    Number of subjects included in analysis
    669
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.34
    Method
    		 ANOVA
    Confidence interval

    Secondary: Total number of embryos obtained

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    End point title
    		 Total number of embryos obtained
    End point description
    End point type
    Secondary
    End point timeframe
    Day 3 after oocytes retrieval.
    End point values
    		 Test product - Fostimon Reference product - Gonal F
    Number of subjects analysed
    332 [16]
    338 [17]
    Units: embryos
        arithmetic mean (standard deviation)
    4.29 ( 2.83 )
    5.26 ( 3.19 )
    Notes
    [16] - Subjects with at least one oocyte inseminated (IVF/ICSI).
    [17] - Subjects with at least one oocyte inseminated (IVF/ICSI).
    Statistical analysis title
    		 Treatment comparison: Total n of embryos
    Comparison groups
    Test product - Fostimon v Reference product - Gonal F
    Number of subjects included in analysis
    670
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.0001
    Method
    		 ANOVA
    Confidence interval

    Secondary: Number of transferred embryos

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    End point title
    		 Number of transferred embryos
    End point description
    End point type
    Secondary
    End point timeframe
    Day 3 after oocytes retrieval
    End point values
    		 Test product - Fostimon Reference product - Gonal F
    Number of subjects analysed
    306 [18]
    314 [19]
    Units: n of patients
        Single embryo transfer
    144
    121
        Double embryo transfer
    162
    193
    Notes
    [18] - Subject with at least one embryo transferred.
    [19] - Subject with at least one embryo transferred.
    Statistical analysis title
    		 Treatment comparison
    Comparison groups
    Test product - Fostimon v Reference product - Gonal F
    Number of subjects included in analysis
    620
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.03
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: N of top quality of embryos transferred per patient

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    End point title
    		 N of top quality of embryos transferred per patient
    End point description
    End point type
    Secondary
    End point timeframe
    Day 3 after oocytes retrieval
    End point values
    		 Test product - Fostimon Reference product - Gonal F
    Number of subjects analysed
    304 [20]
    314 [21]
    Units: top embryos
        arithmetic mean (standard deviation)
    0.47 ( 0.64 )
    0.48 ( 0.64 )
    Notes
    [20] - Subject with at least one embryo transferred, with embryo scoring available.
    [21] - Subject with at least one embryo transferred, with embryo scoring available.
    Statistical analysis title
    		 Treatment comparison: Top embryos transferred
    Comparison groups
    Test product - Fostimon v Reference product - Gonal F
    Number of subjects included in analysis
    618
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.89
    Method
    		 ANOVA
    Confidence interval

    Secondary: Positive βhCG rate

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    End point title
    		 Positive βhCG rate
    End point description
    End point type
    Secondary
    End point timeframe
    15 ± 2 days after oocytes retrieval.
    End point values
    		 Test product - Fostimon Reference product - Gonal F
    Number of subjects analysed
    352
    358
    Units: Percentage of subjects
        number (not applicable)
    47.2
    49.7
    Statistical analysis title
    		 Treatment comparison: Positive βhCG rate
    Comparison groups
    Test product - Fostimon v Reference product - Gonal F
    Number of subjects included in analysis
    710
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.5
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Implantation rate

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    End point title
    		 Implantation rate
    End point description
    Implantation rate defined as the number of gestational sacs divided by the number of embryos transferred.
    End point type
    Secondary
    End point timeframe
    8 weeks of pregnancy
    End point values
    		 Test product - Fostimon Reference product - Gonal F
    Number of subjects analysed
    306 [22]
    314 [23]
    Units: transferred embryos
        arithmetic mean (standard deviation)
    35.62 ( 43.67 )
    38.22 ( 45.79 )
    Notes
    [22] - subjects with at least one embryo transferred.
    [23] - Subjects with at least one embryo transferred.
    Statistical analysis title
    		 Treatment comparison: implantation rate
    Comparison groups
    Reference product - Gonal F v Test product - Fostimon
    Number of subjects included in analysis
    620
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.47
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Delivery rate

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    End point title
    		 Delivery rate
    End point description
    End point type
    Secondary
    End point timeframe
    After delivery.
    End point values
    		 Test product - Fostimon Reference product - Gonal F
    Number of subjects analysed
    349
    357
    Units: Percentage of subjects
        number (not applicable)
    34.4
    36.7
    Statistical analysis title
    		 Treatment comparison: Delivery rate
    Comparison groups
    Test product - Fostimon v Reference product - Gonal F
    Number of subjects included in analysis
    706
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.53
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Live birth rate

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    End point title
    		 Live birth rate
    End point description
    End point type
    Secondary
    End point timeframe
    after delivery.
    End point values
    		 Test product - Fostimon Reference product - Gonal F
    Number of subjects analysed
    349
    357
    Units: Percentage of subjects
        number (not applicable)
    34.1
    35.9
    Statistical analysis title
    		 Treatment comparison: Live birth rate
    Comparison groups
    Test product - Fostimon v Reference product - Gonal F
    Number of subjects included in analysis
    706
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.64
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Cumulative pregnancy rate

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    End point title
    		 Cumulative pregnancy rate
    End point description
    Subjects not getting pregnant during the fresh IVF cycles, were allowed to undergo a frozen embryo transfer with the embryos frozen during the study, within one year from randomisation.
    End point type
    Secondary
    End point timeframe
    Within 15 months from randomisation.
    End point values
    		 Test product - Fostimon Reference product - Gonal F
    Number of subjects analysed
    352
    358
    Units: Percentage of subjects
        number (not applicable)
    45.2
    52.0
    Statistical analysis title
    		 Treatment comparison: cumulative pregnancy rate
    Comparison groups
    Reference product - Gonal F v Test product - Fostimon
    Number of subjects included in analysis
    710
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.07
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Cumulative Delivery Rate

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    End point title
    		 Cumulative Delivery Rate
    End point description
    Subjects not getting pregnant during the fresh IVF cycles, were allowed to undergo a frozen embryo transfer with the embryos frozen during the study, within one year from randomisation.
    End point type
    Secondary
    End point timeframe
    Within 21 months from randomisation.
    End point values
    		 Test product - Fostimon Reference product - Gonal F
    Number of subjects analysed
    352
    358
    Units: Percentage of subjects
        number (not applicable)
    42.0
    48.3
    Statistical analysis title
    		 Treatment comparison: cumulative delivery rate
    Comparison groups
    Test product - Fostimon v Reference product - Gonal F
    Number of subjects included in analysis
    710
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.1
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Cumulative Live birth rate

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    End point title
    		 Cumulative Live birth rate
    End point description
    End point type
    Secondary
    End point timeframe
    Within 21 months from randomisation.
    End point values
    		 Test product - Fostimon Reference product - Gonal F
    Number of subjects analysed
    352
    358
    Units: Percentage of patients
        number (not applicable)
    42.0
    47.8
    Statistical analysis title
    		 Treatment comparison: Cumulative Live birth rate
    Comparison groups
    Test product - Fostimon v Reference product - Gonal F
    Number of subjects included in analysis
    710
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.13
    Method
    		 Fisher exact
    Confidence interval

    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.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19
    Reporting groups
    Reporting group title
    Test product - Fostimon
    Reporting group description
    		 Subject randomised and exposed to Fostimon IMP were included in this group

    Reporting group title
    Reference product - Gonal F
    Reporting group description
    		 Subjects randomised and exposed to Gonal F IMP were included in this group

    Serious adverse events
    		 Test product - Fostimon Reference product - Gonal F
    Total subjects affected by serious adverse events
         subjects affected / exposed
    24 / 352 (6.82%)
    31 / 358 (8.66%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Road traffic accident
         subjects affected / exposed
    0 / 352 (0.00%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Abortion induced
         subjects affected / exposed
    1 / 352 (0.28%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Seizure
         subjects affected / exposed
    0 / 352 (0.00%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion early
         subjects affected / exposed
    1 / 352 (0.28%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abortion incomplete
         subjects affected / exposed
    0 / 352 (0.00%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abortion missed
         subjects affected / exposed
    1 / 352 (0.28%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abortion spontaneous
         subjects affected / exposed
    3 / 352 (0.85%)
    3 / 358 (0.84%)
         occurrences causally related to treatment / all
    0 / 3
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical incompetence
         subjects affected / exposed
    2 / 352 (0.57%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ectopic pregnancy
         subjects affected / exposed
    3 / 352 (0.85%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gestational diabetes
         subjects affected / exposed
    0 / 352 (0.00%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperemesis gravidarum
         subjects affected / exposed
    1 / 352 (0.28%)
    2 / 358 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Imminent abortion
         subjects affected / exposed
    2 / 352 (0.57%)
    2 / 358 (0.56%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple pregnancy
         subjects affected / exposed
    0 / 352 (0.00%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oligohydramnios
         subjects affected / exposed
    1 / 352 (0.28%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Placenta praevia haemorrage
         subjects affected / exposed
    0 / 352 (0.00%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postpartum haemorrhage
         subjects affected / exposed
    0 / 352 (0.00%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pre-eclampsia
         subjects affected / exposed
    1 / 352 (0.28%)
    2 / 358 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Premature delivery
         subjects affected / exposed
    3 / 352 (0.85%)
    7 / 358 (1.96%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Premature labour
         subjects affected / exposed
    1 / 352 (0.28%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Premature rupture of membranes
         subjects affected / exposed
    2 / 352 (0.57%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Threatened labour
         subjects affected / exposed
    1 / 352 (0.28%)
    2 / 358 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting in pregnancy
         subjects affected / exposed
    1 / 352 (0.28%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain lower
         subjects affected / exposed
    1 / 352 (0.28%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intra-abdominal haemorrage
         subjects affected / exposed
    0 / 352 (0.00%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritoneal haemorrage
         subjects affected / exposed
    0 / 352 (0.00%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Adnexal torsion
         subjects affected / exposed
    0 / 352 (0.00%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    1 / 352 (0.28%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian hyperstimulation syndrome
         subjects affected / exposed
    2 / 352 (0.57%)
    4 / 358 (1.12%)
         occurrences causally related to treatment / all
    2 / 2
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic pain
         subjects affected / exposed
    1 / 352 (0.28%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine polyp
         subjects affected / exposed
    1 / 352 (0.28%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 352 (0.00%)
    2 / 358 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 352 (0.00%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infection
         subjects affected / exposed
    1 / 352 (0.28%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Test product - Fostimon Reference product - Gonal F
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    74 / 352 (21.02%)
    47 / 358 (13.13%)
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    7 / 352 (1.99%)
    8 / 358 (2.23%)
         occurrences all number
    7
    8
    Nervous system disorders
    Headache
         subjects affected / exposed
    7 / 352 (1.99%)
    11 / 358 (3.07%)
         occurrences all number
    7
    15
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    15 / 352 (4.26%)
    15 / 358 (4.19%)
         occurrences all number
    15
    15
    Reproductive system and breast disorders
    Vaginal haemorrhage
         subjects affected / exposed
    7 / 352 (1.99%)
    8 / 358 (2.23%)
         occurrences all number
    8
    8

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Jul 2014
    The upper limit of AMH at inclusion was enlarged to 5.6 ng/ml as it was too restrictive and the new limit was considered as safe; an upper limit (30) for the total number of antral follicles at inclusion was added to further reduce the risk of including high responder subjects (i.e. subjects at higher risk of developing OHSS);

    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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    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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