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    Clinical Trial Results:
    A Phase II, Multicentre, Multinational, Randomised, Assessor-Blind Trial to Investigate the Efficacy and Safety of Various Dosages of FSH-GEX™ in Comparison With 150 IU Gonal-f® in Women Undergoing ICSI Treatment

    Summary
    EudraCT number
    		 2012-003006-27
    Trial protocol
    		 HU   DE  
    Global end of trial date
    30 Jul 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Jun 2020
    First version publication date
    21 Jun 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    GEXGP24201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01794208
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Glycotope GmbH
    Sponsor organisation address
    Robert Roessle St 10, Berlin, Germany, 13125
    Public contact
    Reception, Glycotope GmbH, +49 3094892600, Trials@glycotope.com
    Scientific contact
    Reception, Glycotope GmbH, +49 3094892600, Trials@glycotope.com
    Sponsor organisation name
    Glycotope GmbH
    Sponsor organisation address
    Robert Roessle St 10, Berlin, Germany, 13125
    Public contact
    Isabelle Ahrens-Fath, PhD, Glycotope GmbH, +49 3094892600, Isabelle.Ahrens-Fath@glycotope.com
    Scientific contact
    Lars Stoeckl, PhD, Glycotope GmbH, +49 3094892600, Lars.Stoeckl@glycotope.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
    27 Aug 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Jul 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jul 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is the determination of the recommended standard treatment dose of FSH-GEX™ as assessed by follicle growth dynamics in women between 18 and 37 years of age undergoing intracytoplasmic sperm injection (ICSI) treatment.
    Protection of trial subjects
    Patients were closely monitored and seen daily or every-other day by their Investigators.
    Background therapy
    		 Triptorelin acetate (Decapeptyl® in Germany, Gonapeptyl® in Hungary), a gonadotropin releasing hormone agonist, was administered to all patients for down-regulation. Triptorelin acetate (100 µg) was administered once daily subcutaneously. Recombinant hCG: A human recombinant chorionic gonadotropin (Ovitrelle® in Germany and Hungary) was administered to all patients for stimulation of follicle maturation prior to IVF procedures. Recombinant hCG (250 µg) was administered as one single dose subcutaneously according to the instructions of the investigator. Progesterone: A progesterone derivative (Crinone® in Germany and Hungary) was administered to all patients for luteal support. Progesterone (90 mg) gel was administered once daily by vaginal application.
    Evidence for comparator
    		 Gonal-f®, a recombinant human FSH, was the comparator drug used in this study. Gonal-f® has been used as comparator in the two Phase 1 studies. It is widely used and comprises a broad documentation of efficacy and safety.
    Actual start date of recruitment
    08 Jan 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
    Germany: 147
    Country: Number of subjects enrolled
    Hungary: 120
    Worldwide total number of subjects
    267
    EEA total number of subjects
    267
    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)
    267
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 During the study period from 08-Jan-2013 to 30-Jul-2013, a total of 267 patients were enrolled in six study centers in Germany and in two centers in Hungary.

    Pre-assignment
    Screening details
    		 Of the 267 patients enrolled, 9 were screening failures: 5 patients violated inclusion criterion 4 (AMH level of 1 to 4 ng/mL), 1 patient violated inclusion criterion 6 (BMI 18.5-30 kg/m²), 1 patient fulfilled exclusion criterion 14 (history of thrombosis or other risk factors), and 2 patients violated inclusion criterion 10 (comply with protocol)

    Pre-assignment period milestones
    Number of subjects started
    		 267
    Intermediate milestone: Number of subjects
    Starting Down-regulation: 258
    Number of subjects completed
    		 247

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Adverse event, non-fatal: 2
    Reason: Number of subjects
    		 pregnancy: 4
    Reason: Number of subjects
    		 Consent withdrawn by subject: 2
    Reason: Number of subjects
    		 non-compliance: 1
    Reason: Number of subjects
    		 treatment failure: 2
    Reason: Number of subjects
    		 Protocol deviation: 9
    Period 1
    Period 1 title
    Assessor-blind treatment period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Assessor [1]
    Blinding implementation details
    Blinding of the patient was not possible. Study blind was maintained using an “independent” third party; the drug administrators in each center, e.g. a physician or nurse, who was not involved in any study assessments, received the randomization information regarding the treatment allocation. Investigator, who was performing all assessments, and the embryologist, who was performing the counting of the oocytes as well as evaluating the oocyte maturity and quality, were blinded during the study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Treatment 1
    Arm description
    		 Patients received FSH-GEX: 52.5 IU QD
    Arm type
    		 Experimental

    Investigational medicinal product name
    FSH-GEX
    Investigational medicinal product code
    Other name
    follitropin epsilon
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Dosage: 52.5 IU QD Dosage form: Solution for subcutaneous injection, provided in single-use vials. Strength: 750 IU/ml. Volume: 0.5 ml/vial (375 IU/vial). Excipients: Sucrose, disodium phosphate dihydrate, sodium dihydrogen phosphate monohydrate, methionine, and poloxamer 1886

    Arm title
    		 Treatment 2
    Arm description
    		 Patients received FSH-GEX: 75 IU QD
    Arm type
    		 Experimental

    Investigational medicinal product name
    FSH-GEX
    Investigational medicinal product code
    Other name
    follitropin epsilon
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Dosage: FSH-GEX: 52.5 IU QD Dosage form: Solution for subcutaneous injection, provided in single-use vials. Strength: 750 IU/ml. Volume: 0.5 ml/vial (375 IU/vial). Excipients: Sucrose, disodium phosphate dihydrate, sodium dihydrogen phosphate monohydrate, methionine, and poloxamer 1886

    Arm title
    		 Treatment 3
    Arm description
    		 Patients received FSH-GEX: 112.5 IU QD
    Arm type
    		 Experimental

    Investigational medicinal product name
    FSH-GEX
    Investigational medicinal product code
    Other name
    follitropin epsilon
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Dosage 112.5 IU QD

    Arm title
    		 Treatment 4
    Arm description
    		 Patients received FSH-GEX:150 IU QD
    Arm type
    		 Experimental

    Investigational medicinal product name
    FSH-GEX
    Investigational medicinal product code
    Other name
    follitropin epsilon
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Dosage: 150 IU QD

    Arm title
    		 Treatment 5
    Arm description
    		 Patients received FSH-GEX: 150 IU QAD
    Arm type
    		 Experimental

    Investigational medicinal product name
    FSH-GEX
    Investigational medicinal product code
    Other name
    follitropin epsilon
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Dosage: 150 IU QAD

    Arm title
    		 Treatment 6
    Arm description
    		 Patients received Gonal-f: 150 IU QD
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Gonal-f
    Investigational medicinal product code
    Other name
    follitropin alfa
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Dosage 150 IU QD Dosage form: Powder and solvent for solution for injection. Appearance of powder: Lyophilized white pellet, provided in vials (glass). Appearance of solvent: Clear colorless solution, provided in pre-filled syringe (glass). Excipients: Powder: sucrose, sodium dihydrogen phosphate monohydrate, disodium phosphate dehydrate, methionine, polysorbate 20, phosphoric acid (concentrated), sodium hydroxide, and solvent: water for injections

    Notes
    [1] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: Blinding of the patient was not possible. Study blind was maintained using an “independent” third party; the drug administrators in each center, e.g. a physician or nurse, who was not involved in any study assessments, received the randomization information regarding the treatment allocation. Investigator, who was performing all assessments, and the embryologist, who was performing the counting of the oocytes as well as evaluating the oocyte maturity and quality, were blinded during the study.
    Number of subjects in period 1 [2]
    		Treatment 1 Treatment 2 Treatment 3 Treatment 4 Treatment 5 Treatment 6
    Started
    41
    42
    40
    43
    42
    39
    Meeting hCG criteria
    38
    40
    38
    41
    41
    37
    Completed
    38
    40
    38
    41
    41
    37
    Not completed
    3
    2
    2
    2
    1
    2
         Physician decision
    1
    1
    1
    -
    -
    -
         Adverse event, non-fatal
    -
    1
    -
    -
    -
    1
         Lack of efficacy
    2
    -
    1
    2
    1
    1
    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: Baseline values were only taken from patients who fulfilled criteria for starting with experimental treatment

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment 1
    Reporting group description
    		 Patients received FSH-GEX: 52.5 IU QD

    Reporting group title
    Treatment 2
    Reporting group description
    		 Patients received FSH-GEX: 75 IU QD

    Reporting group title
    Treatment 3
    Reporting group description
    		 Patients received FSH-GEX: 112.5 IU QD

    Reporting group title
    Treatment 4
    Reporting group description
    		 Patients received FSH-GEX:150 IU QD

    Reporting group title
    Treatment 5
    Reporting group description
    		 Patients received FSH-GEX: 150 IU QAD

    Reporting group title
    Treatment 6
    Reporting group description
    		 Patients received Gonal-f: 150 IU QD

    Reporting group values
    		 Treatment 1 Treatment 2 Treatment 3 Treatment 4 Treatment 5 Treatment 6 Total
    Number of subjects
    		 41 42 40 43 42 39 247
    Age categorical
    Age at screening
    Units: Subjects
        In utero
    		 0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0 0
        Adults (18-64 years)
    		 41 42 40 43 42 39 247
        From 65-84 years
    		 0 0 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0 0 0
    Age continuous
    Only female patients aged 18 to 37 years at Screening were enrolled
    Units: years
        arithmetic mean (standard deviation)
    		 32.54 ( 3.769 ) 31.86 ( 3.339 ) 31.88 ( 3.897 ) 32.28 ( 2.865 ) 32.07 ( 2.709 ) 32.10 ( 2.683 ) -
    Gender categorical
    Population
    Units: Subjects
        Female
    		 41 42 40 43 42 39 247
        Male
    		 0 0 0 0 0 0 0
    Subject analysis sets

    Subject analysis set title
    Intent-to-treat
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT consisted of all randomized patients who received at least one dose of randomized study medication (IMP). The ITT was the primary population for the efficacy analysis.

    Subject analysis sets values
    		 Intent-to-treat
    Number of subjects
    247
    Age categorical
    Age at screening
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    247
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Only female patients aged 18 to 37 years at Screening were enrolled
    Units: years
        arithmetic mean (standard deviation)
    32.07 ( 3.226 )
    Gender categorical
    Population
    Units: Subjects
        Female
    247
        Male
    0

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Treatment 1
    Reporting group description
    		 Patients received FSH-GEX: 52.5 IU QD

    Reporting group title
    Treatment 2
    Reporting group description
    		 Patients received FSH-GEX: 75 IU QD

    Reporting group title
    Treatment 3
    Reporting group description
    		 Patients received FSH-GEX: 112.5 IU QD

    Reporting group title
    Treatment 4
    Reporting group description
    		 Patients received FSH-GEX:150 IU QD

    Reporting group title
    Treatment 5
    Reporting group description
    		 Patients received FSH-GEX: 150 IU QAD

    Reporting group title
    Treatment 6
    Reporting group description
    		 Patients received Gonal-f: 150 IU QD

    Subject analysis set title
    Intent-to-treat
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT consisted of all randomized patients who received at least one dose of randomized study medication (IMP). The ITT was the primary population for the efficacy analysis.

    Primary: number of follicles with a diameter of ≥ 12 mm

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    End point title
    		 number of follicles with a diameter of ≥ 12 mm
    End point description
    The primary efficacy variable was the number of follicles with a diameter of ≥ 12 mm on the day of r hCG injection or the day before.
    End point type
    Primary
    End point timeframe
    Assessor-blind Treatment period
    End point values
    		 Treatment 1 Treatment 2 Treatment 3 Treatment 4 Treatment 5 Treatment 6 Intent-to-treat
    Number of subjects analysed
    41
    42
    40
    43
    42
    39
    247
    Units: Number
        arithmetic mean (standard deviation)
    11.2 ( 4.61 )
    13.0 ( 4.16 )
    13.9 ( 4.35 )
    13.7 ( 4.18 )
    12.8 ( 3.84 )
    12.4 ( 5.14 )
    12.8 ( 4.43 )
    Statistical analysis title
    		 number of follicles with a diameter of ≥ 12 mm
    Statistical analysis description
    H0(1): μ (FSH-GEX™ 150 IU quaque die [QD]) ≤ μ (Gonal-f® 150 IU QD) vs. H1(1): μ (FSH-GEX™ 150 IU QD) > μ (Gonal-f® 150 IU QD).
    Comparison groups
    Treatment 4 v Treatment 6
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 ≤ 0.025 [2]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.81
         upper limit
    		 3.37
    Variability estimate
    Standard deviation
    Dispersion value
    0.2
    Notes
    [1] - The primary analysis was conducted based on the ITT population using sequential (hierarchical) testing for the pair-wise comparison of the four FSH-GEX™ daily dosing regimens with Gonal-f® 150 IU per day. Each of these comparisons was performed using an analysis of covariance (ANCOVA) model, which included treatment (two levels) and site as factors and age as a covariate.
    [2] - Given the one sided hypotheses to be tested, the analysis of treatment effects was performed as one-sided tests at a significance level of 0.025.
    Statistical analysis title
    		 number of follicles with a diameter of ≥ 12 mm
    Statistical analysis description
    H0(2): μ (FSH-GEX™ 112.5 IU QD) ≤ μ (Gonal-f® 150 IU QD) vs. H1(2): μ (FSH-GEX™ 112.5 IU QD) > μ (Gonal-f® 150 IU QD)
    Comparison groups
    Treatment 6 v Treatment 3
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 ≤ 0.025 [4]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.52
         upper limit
    		 3.36
    Variability estimate
    Standard deviation
    Dispersion value
    0.16
    Notes
    [3] - The primary analysis was conducted based on the ITT population using sequential (hierarchical) testing for the pair-wise comparison of the four FSH-GEX™ daily dosing regimens with Gonal-f® 150 IU per day. Each of these comparisons was performed using an analysis of covariance (ANCOVA) model, which included treatment (two levels) and site as factors and age as a covariate.
    [4] - Given the one sided hypotheses to be tested, the analysis of treatment effects was performed as one-sided tests at a significance level of 0.025.
    Statistical analysis title
    		 Copy of number of follicles with a diameter of ...
    Statistical analysis description
    H0(3): μ (FSH-GEX™ 75 IU QD) ≤ μ (Gonal-f® 150 IU QD) vs. H1(3): μ (FSH-GEX™ 75 IU QD) > μ (Gonal-f® 150 IU QD).
    Comparison groups
    Treatment 2 v Treatment 6
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 ≤ 0.025 [6]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.42
         upper limit
    		 2.45
    Variability estimate
    Standard deviation
    Dispersion value
    0.17
    Notes
    [5] - The primary analysis was conducted based on the ITT population using sequential (hierarchical) testing for the pair-wise comparison of the four FSH-GEX™ daily dosing regimens with Gonal-f® 150 IU per day. Each of these comparisons was performed using an analysis of covariance (ANCOVA) model, which included treatment (two levels) and site as factors and age as a covariate.
    [6] - Given the one sided hypotheses to be tested, the analysis of treatment effects was performed as one-sided tests at a significance level of 0.025.
    Statistical analysis title
    		 Copy of number of follicles with a diameter of ...
    Statistical analysis description
    H0(4): μ (FSH-GEX™ 52.5 IU QD) ≤ μ (Gonal-f®) 150 IU QD vs. H1(4): μ (FSH-GEX™ 52.5 IU QD) > μ (Gonal-f® 150 IU QD).
    Comparison groups
    Treatment 6 v Treatment 1
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 ≤ 0.025 [8]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.43
         upper limit
    		 0.8
    Variability estimate
    Standard deviation
    Dispersion value
    0.17
    Notes
    [7] - The primary analysis was conducted based on the ITT population using sequential (hierarchical) testing for the pair-wise comparison of the four FSH-GEX™ daily dosing regimens with Gonal-f® 150 IU per day. Each of these comparisons was performed using an analysis of covariance (ANCOVA) model, which included treatment (two levels) and site as factors and age as a covariate.
    [8] - Given the one sided hypotheses to be tested, the analysis of treatment effects was performed as one-sided tests at a significance level of 0.025.

    Secondary: Number of retrieved COCs

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    End point title
    		 Number of retrieved COCs
    End point description
    Number of retrieved COCs
    End point type
    Secondary
    End point timeframe
    Day of follicle puncture
    End point values
    		 Treatment 1 Treatment 2 Treatment 3 Treatment 4 Treatment 5 Treatment 6 Intent-to-treat
    Number of subjects analysed
    41
    41
    40
    41
    42
    38
    243
    Units: number
        arithmetic mean (standard deviation)
    10.2 ( 6.97 )
    12.6 ( 5.03 )
    14.5 ( 5.84 )
    12.6 ( 5.69 )
    13.4 ( 5.69 )
    11.1 ( 5.39 )
    12.4 ( 5.91 )
    Statistical analysis title
    		 Number of retrieved COCs T1 vs T6
    Statistical analysis description
    H0(4): μ (FSH-GEX™ 52.5 IU QD) ≤ μ (Gonal-f®) 150 IU QD vs. H1(4): μ (FSH-GEX™ 52.5 IU QD) > μ (Gonal-f® 150 IU QD).
    Comparison groups
    Treatment 6 v Treatment 1
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 ≤ 0.025 [10]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.73
         upper limit
    		 1.88
    Variability estimate
    Standard deviation
    Dispersion value
    0.23
    Notes
    [9] - The primary analysis was conducted based on the ITT population using sequential (hierarchical) testing for the pair-wise comparison of the four FSH-GEX™ daily dosing regimens with Gonal-f® 150 IU per day. Each of these comparisons was performed using an analysis of covariance (ANCOVA) model, which included treatment (two levels) and site as factors and age as a covariate.
    [10] - Given the one sided hypotheses to be tested, the analysis of treatment effects was performed as one-sided tests at a significance level of 0.025.
    Statistical analysis title
    		 Copy of Number of retrieved COCs T3 vs T6
    Statistical analysis description
    H0(2): μ (FSH-GEX™ 112.5 IU QD) ≤ μ (Gonal-f® 150 IU QD) vs. H1(2): μ (FSH-GEX™ 112.5 IU QD) > μ (Gonal-f® 150 IU QD).
    Comparison groups
    Treatment 3 v Treatment 6
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 ≤ 0.025 [12]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    3.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.95
         upper limit
    		 5.72
    Variability estimate
    Standard deviation
    Dispersion value
    0.2
    Notes
    [11] - The primary analysis was conducted based on the ITT population using sequential (hierarchical) testing for the pair-wise comparison of the four FSH-GEX™ daily dosing regimens with Gonal-f® 150 IU per day. Each of these comparisons was performed using an analysis of covariance (ANCOVA) model, which included treatment (two levels) and site as factors and age as a covariate.
    [12] - Given the one sided hypotheses to be tested, the analysis of treatment effects was performed as one-sided tests at a significance level of 0.025.
    Statistical analysis title
    		 Copy of Copy of Number of retrieved COCs T2 vs T6
    Statistical analysis description
    H0(3): μ (FSH-GEX™ 75 IU QD) ≤ μ (Gonal-f® 150 IU QD) vs. H1(3): μ (FSH-GEX™ 75 IU QD) > μ (Gonal-f® 150 IU QD).
    Comparison groups
    Treatment 6 v Treatment 2
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 ≤ 0.025 [14]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.82
         upper limit
    		 3.71
    Variability estimate
    Standard deviation
    Dispersion value
    0.19
    Notes
    [13] - The primary analysis was conducted based on the ITT population using sequential (hierarchical) testing for the pair-wise comparison of the four FSH-GEX™ daily dosing regimens with Gonal-f® 150 IU per day. Each of these comparisons was performed using an analysis of covariance (ANCOVA) model, which included treatment (two levels) and site as factors and age as a covariate.
    [14] - Given the one sided hypotheses to be tested, the analysis of treatment effects was performed as one-sided tests at a significance level of 0.025.
    Statistical analysis title
    		 Copy of Number of retrieved COCs T4 vs T6
    Statistical analysis description
    H0(1): μ (FSH-GEX™ 150 IU quaque die [QD]) ≤ μ (Gonal-f® 150 IU QD) vs. H1(1): μ (FSH-GEX™ 150 IU QD) > μ (Gonal-f® 150 IU QD).
    Comparison groups
    Treatment 6 v Treatment 4
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    P-value
    		 ≤ 0.025 [16]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.03
         upper limit
    		 4.05
    Variability estimate
    Standard deviation
    Dispersion value
    0.24
    Notes
    [15] - The primary analysis was conducted based on the ITT population using sequential (hierarchical) testing for the pair-wise comparison of the four FSH-GEX™ daily dosing regimens with Gonal-f® 150 IU per day. Each of these comparisons was performed using an analysis of covariance (ANCOVA) model, which included treatment (two levels) and site as factors and age as a covariate.
    [16] - Given the one sided hypotheses to be tested, the analysis of treatment effects was performed as one-sided tests at a significance level of 0.025.

    Secondary: Number of Metaphase II Oocytes

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    End point title
    		 Number of Metaphase II Oocytes
    End point description
    Number of Metaphase II Oocytes Retrieved
    End point type
    Secondary
    End point timeframe
    After follicle puncture
    End point values
    		 Treatment 1 Treatment 2 Treatment 3 Treatment 4 Treatment 5 Treatment 6 Intent-to-treat
    Number of subjects analysed
    41
    41
    40
    41
    42
    38
    243
    Units: number
        arithmetic mean (standard deviation)
    7.9 ( 4.99 )
    9.4 ( 4.76 )
    10.7 ( 4.94 )
    8.8 ( 4.60 )
    10.1 ( 3.97 )
    8.6 ( 4.40 )
    9.2 ( 4.67 )
    Statistical analysis title
    		 Number of metaphase II oocytes
    Statistical analysis description
    H0(1): μ (FSH-GEX™ 150 IU quaque die [QD]) ≤ μ (Gonal-f® 150 IU QD) vs. H1(1): μ (FSH-GEX™ 150 IU QD) > μ (Gonal-f® 150 IU QD).
    Comparison groups
    Treatment 6 v Treatment 4
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [17]
    P-value
    		 ≤ 0.025 [18]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.87
         upper limit
    		 2.14
    Variability estimate
    Standard deviation
    Dispersion value
    0.19
    Notes
    [17] - The analysis was conducted based on the ITT population using sequential (hierarchical) testing for the pair-wise comparison of the four FSH-GEX™ daily dosing regimens with Gonal-f® 150 IU per day. Each of these comparisons was performed using an analysis of covariance (ANCOVA) model, which included treatment (two levels) and site as factors and age as a covariate.
    [18] - Given the one sided hypotheses to be tested, the analysis of treatment effects was performed as one-sided tests at a significance level of 0.025.
    Statistical analysis title
    		 Number of metaphase II oocytes
    Statistical analysis description
    H0(2): μ (FSH-GEX™ 112.5 IU QD) ≤ μ (Gonal-f® 150 IU QD) vs. H1(2): μ (FSH-GEX™ 112.5 IU QD) > μ (Gonal-f® 150 IU QD).
    Comparison groups
    Treatment 6 v Treatment 3
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [19]
    P-value
    		 ≤ 0.025 [20]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.22
         upper limit
    		 3.88
    Variability estimate
    Standard deviation
    Dispersion value
    0.15
    Notes
    [19] - The analysis was conducted based on the ITT population using sequential (hierarchical) testing for the pair-wise comparison of the four FSH-GEX™ daily dosing regimens with Gonal-f® 150 IU per day. Each of these comparisons was performed using an analysis of covariance (ANCOVA) model, which included treatment (two levels) and site as factors and age as a covariate.
    [20] - Given the one sided hypotheses to be tested, the analysis of treatment effects was performed as one-sided tests at a significance level of 0.025.
    Statistical analysis title
    		 Number of metaphase II oocytes
    Statistical analysis description
    H0(3): μ (FSH-GEX™ 75 IU QD) ≤ μ (Gonal-f® 150 IU QD) vs. H1(3): μ (FSH-GEX™ 75 IU QD) > μ (Gonal-f® 150 IU QD).
    Comparison groups
    Treatment 6 v Treatment 2
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [21]
    P-value
    		 ≤ 0.025 [22]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.19
         upper limit
    		 2.7
    Variability estimate
    Standard deviation
    Dispersion value
    0.16
    Notes
    [21] - The analysis was conducted based on the ITT population using sequential (hierarchical) testing for the pair-wise comparison of the four FSH-GEX™ daily dosing regimens with Gonal-f® 150 IU per day. Each of these comparisons was performed using an analysis of covariance (ANCOVA) model, which included treatment (two levels) and site as factors and age as a covariate.
    [22] - Given the one sided hypotheses to be tested, the analysis of treatment effects was performed as one-sided tests at a significance level of 0.025.
    Statistical analysis title
    		 Number of metaphase II oocytes
    Statistical analysis description
    H0(4): μ (FSH-GEX™ 52.5 IU QD) ≤ μ (Gonal-f®) 150 IU QD vs. H1(4): μ (FSH-GEX™ 52.5 IU QD) > μ (Gonal-f® 150 IU QD).
    Comparison groups
    Treatment 6 v Treatment 1
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [23]
    P-value
    		 ≤ 0.025 [24]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.89
         upper limit
    		 1.18
    Variability estimate
    Standard deviation
    Dispersion value
    0.16
    Notes
    [23] - The analysis was conducted based on the ITT population using sequential (hierarchical) testing for the pair-wise comparison of the four FSH-GEX™ daily dosing regimens with Gonal-f® 150 IU per day. Each of these comparisons was performed using an analysis of covariance (ANCOVA) model, which included treatment (two levels) and site as factors and age as a covariate.
    [24] - Given the one sided hypotheses to be tested, the analysis of treatment effects was performed as one-sided tests at a significance level of 0.025.

    Secondary: Number of 2PN Oocytes

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    End point title
    		 Number of 2PN Oocytes
    End point description
    Number of 2PN Oocytes one Day after Follicle Puncture
    End point type
    Secondary
    End point timeframe
    One Day after Follicle Puncture
    End point values
    		 Treatment 1 Treatment 2 Treatment 3 Treatment 4 Treatment 5 Treatment 6 Intent-to-treat
    Number of subjects analysed
    40
    41
    39
    41
    42
    38
    241
    Units: Number
        arithmetic mean (standard deviation)
    6.0 ( 4.60 )
    7.3 ( 3.99 )
    7.5 ( 3.99 )
    6.6 ( 3.66 )
    7.5 ( 4.62 )
    6.2 ( 3.81 )
    6.9 ( 4.14 )
    Statistical analysis title
    		 Number of 2PN oocytes
    Statistical analysis description
    H0(1): μ (FSH-GEX™ 150 IU quaque die [QD]) ≤ μ (Gonal-f® 150 IU QD) vs. H1(1): μ (FSH-GEX™ 150 IU QD) > μ (Gonal-f® 150 IU QD).
    Comparison groups
    Treatment 6 v Treatment 4
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [25]
    P-value
    		 ≤ 0.025 [26]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.34
         upper limit
    		 2.03
    Variability estimate
    Standard deviation
    Dispersion value
    0.16
    Notes
    [25] - The analysis was conducted based on the ITT population using sequential (hierarchical) testing for the pair-wise comparison of the four FSH-GEX™ daily dosing regimens with Gonal-f® 150 IU per day. Each of these comparisons was performed using an analysis of covariance (ANCOVA) model, which included treatment (two levels) and site as factors and age as a covariate.
    [26] - Given the one sided hypotheses to be tested, the analysis of treatment effects was performed as one-sided tests at a significance level of 0.025.
    Statistical analysis title
    		 Number of 2PN oocytes
    Statistical analysis description
    H0(2): μ (FSH-GEX™ 112.5 IU QD) ≤ μ (Gonal-f® 150 IU QD) vs. H1(2): μ (FSH-GEX™ 112.5 IU QD) > μ (Gonal-f® 150 IU QD).
    Comparison groups
    Treatment 6 v Treatment 3
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [27]
    P-value
    		 ≤ 0.025 [28]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4
         upper limit
    		 3.06
    Variability estimate
    Standard deviation
    Dispersion value
    0.15
    Notes
    [27] - The analysis was conducted based on the ITT population using sequential (hierarchical) testing for the pair-wise comparison of the four FSH-GEX™ daily dosing regimens with Gonal-f® 150 IU per day. Each of these comparisons was performed using an analysis of covariance (ANCOVA) model, which included treatment (two levels) and site as factors and age as a covariate.
    [28] - Given the one sided hypotheses to be tested, the analysis of treatment effects was performed as one-sided tests at a significance level of 0.025.
    Statistical analysis title
    		 Number of 2PN oocytes
    Statistical analysis description
    H0(3): μ (FSH-GEX™ 75 IU QD) ≤ μ (Gonal-f® 150 IU QD) vs. H1(3): μ (FSH-GEX™ 75 IU QD) > μ (Gonal-f® 150 IU QD).
    Comparison groups
    Treatment 6 v Treatment 2
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [29]
    P-value
    		 ≤ 0.025 [30]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.64
         upper limit
    		 2.75
    Variability estimate
    Standard deviation
    Dispersion value
    0.14
    Notes
    [29] - The analysis was conducted based on the ITT population using sequential (hierarchical) testing for the pair-wise comparison of the four FSH-GEX™ daily dosing regimens with Gonal-f® 150 IU per day. Each of these comparisons was performed using an analysis of covariance (ANCOVA) model, which included treatment (two levels) and site as factors and age as a covariate.
    [30] - Given the one sided hypotheses to be tested, the analysis of treatment effects was performed as one-sided tests at a significance level of 0.025.
    Statistical analysis title
    		 Number of 2PN oocytes
    Statistical analysis description
    H0(4): μ (FSH-GEX™ 52.5 IU QD) ≤ μ (Gonal-f®) 150 IU QD vs. H1(4): μ (FSH-GEX™ 52.5 IU QD) > μ (Gonal-f® 150 IU QD).
    Comparison groups
    Treatment 6 v Treatment 1
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [31]
    P-value
    		 ≤ 0.025 [32]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.22
         upper limit
    		 1.62
    Variability estimate
    Standard deviation
    Dispersion value
    0.15
    Notes
    [31] - The analysis was conducted based on the ITT population using sequential (hierarchical) testing for the pair-wise comparison of the four FSH-GEX™ daily dosing regimens with Gonal-f® 150 IU per day. Each of these comparisons was performed using an analysis of covariance (ANCOVA) model, which included treatment (two levels) and site as factors and age as a covariate.
    [32] - Given the one sided hypotheses to be tested, the analysis of treatment effects was performed as one-sided tests at a significance level of 0.025.

    Secondary: Estradiol concentration

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    End point title
    		 Estradiol concentration
    End point description
    Pharmacodynamic effect of FSH-GEX and Gonal-f on Estradiol
    End point type
    Secondary
    End point timeframe
    The pharmacodynamic effect of FSH-GEX™ and Gonal-f on Estradiol was measured on the day of HCG injection or the day before.
    End point values
    		 Treatment 1 Treatment 2 Treatment 3 Treatment 4 Treatment 5 Treatment 6
    Number of subjects analysed
    41
    42
    40
    43
    42
    39
    Units: pmol/L
        arithmetic mean (standard deviation)
    8425.7 ( 9665.14 )
    11157.3 ( 7794.47 )
    13692.8 ( 8945.99 )
    13014.0 ( 9462.37 )
    11991.1 ( 9127.09 )
    8405.6 ( 5677.45 )
    Statistical analysis title
    		 Estradiol T1 vs T6
    Statistical analysis description
    Comparison of FSH-GEX 52.5 IU QD versus Gonal-f 150 IU QD
    Comparison groups
    Treatment 1 v Treatment 6
    Number of subjects included in analysis
    80
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 p-value
    Point estimate
    0.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.001
         upper limit
    		 1
    Statistical analysis title
    		 Estradiol T2 vs T6
    Statistical analysis description
    Comparison of FSH.GEX 75 IU QD versus Gonal-f 150 IU QD
    Comparison groups
    Treatment 2 v Treatment 6
    Number of subjects included in analysis
    81
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 p-value
    Point estimate
    0.143
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.001
         upper limit
    		 1
    Statistical analysis title
    		 Estradiol T3 vs T6
    Statistical analysis description
    Comparison of FSH-GEX 112.5 IU QD versus Gonal-f 150 IU QD
    Comparison groups
    Treatment 3 v Treatment 6
    Number of subjects included in analysis
    79
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 p-value
    Point estimate
    0.004
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.001
         upper limit
    		 1
    Statistical analysis title
    		 Estradiol T4 vs T6
    Statistical analysis description
    Comparison of FSH-GEX 150 IU QD versus Gonal-f 150 IU QD
    Comparison groups
    Treatment 4 v Treatment 6
    Number of subjects included in analysis
    82
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 p-value
    Point estimate
    0.014
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.001
         upper limit
    		 1
    Statistical analysis title
    		 Estradiol T5 vs T6
    Statistical analysis description
    Comparison of FSH-GEX 150 IU QAD vs 150 IU QD
    Comparison groups
    Treatment 5 v Treatment 6
    Number of subjects included in analysis
    81
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 p-value
    Point estimate
    0.474
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.001
         upper limit
    		 1

    Secondary: Inhibin B concentration

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    End point title
    		 Inhibin B concentration
    End point description
    Pharmacodynamic effect of FSH-GEX and Gonal-f on Inhibin B
    End point type
    Secondary
    End point timeframe
    The pharmacodynamic effect of FSH-GEX™ and Gonal-f on Inhibin B was measured on the day of HCG injection or the day before.
    End point values
    		 Treatment 1 Treatment 2 Treatment 3 Treatment 4 Treatment 5 Treatment 6
    Number of subjects analysed
    41
    42
    40
    43
    42
    39
    Units: U/L
        arithmetic mean (standard deviation)
    883.3 ( 631.41 )
    902.0 ( 461.87 )
    871.4 ( 428.93 )
    724.2 ( 465.30 )
    998.7 ( 496.53 )
    694.5 ( 420.11 )
    Statistical analysis title
    		 Inhibin B T1 vs T6
    Statistical analysis description
    Comparison of 52.5 IU QD versus Gonal-f 150 IU QD
    Comparison groups
    Treatment 1 v Treatment 6
    Number of subjects included in analysis
    80
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 p-value
    Point estimate
    0.166
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.001
         upper limit
    		 1
    Statistical analysis title
    		 Inhibin B T2 vs T6
    Statistical analysis description
    Comparison of FSH-GEX 75 IU QD versus Gonal-f 150 IU QD
    Comparison groups
    Treatment 2 v Treatment 6
    Number of subjects included in analysis
    81
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 p-value
    Point estimate
    0.011
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.001
         upper limit
    		 1
    Statistical analysis title
    		 Inhibin B T3 vs T6
    Statistical analysis description
    Comparison of FSH-GEX 112.5 IU QD vs Gonal-f 150 IU QD
    Comparison groups
    Treatment 3 v Treatment 6
    Number of subjects included in analysis
    79
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 p-value
    Point estimate
    0.028
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.001
         upper limit
    		 1
    Statistical analysis title
    		 Inhibin B T4 vs T6
    Statistical analysis description
    Comparison of FSH-GEX 150 IU QD versus Gonal-f 150 IU QD
    Comparison groups
    Treatment 4 v Treatment 6
    Number of subjects included in analysis
    82
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 p-value
    Point estimate
    0.956
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.001
         upper limit
    		 1
    Statistical analysis title
    		 Inhibin B T5 vs T6
    Statistical analysis description
    Comparison of FSH-GEX 150 IU QAD versus Gonal-f 150 IU QD
    Comparison groups
    Treatment 5 v Treatment 6
    Number of subjects included in analysis
    81
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 p-value
    Point estimate
    0.002
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.001
         upper limit
    		 1

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent AEs were defined as AEs occurring or worsening with an onset at the time of or following the first administration of IMP (FSH-GEX or Gonal-f).
    Adverse event reporting additional description
    FSH (both FSH-GEX and Gonal-f) was to be administered once daily for a maximum duration of 18 days, with the exception of the FSH-GEX 150 IU QAD group, where patient were to receive treatment every second day.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Treatment 1
    Reporting group description
    		 Patients received FSH-GEX: 52.5 IU QD

    Reporting group title
    Treatment 2
    Reporting group description
    		 Patients received FSH-GEX: 75 IU QD

    Reporting group title
    Treatment 3
    Reporting group description
    		 Patients received FSH-GEX: 112.5 IU QD

    Reporting group title
    Treatment 4
    Reporting group description
    		 Patients received FSH-GEX:150 IU QD

    Reporting group title
    Treatment 5
    Reporting group description
    		 Patients received FSH-GEX: 150 IU QAD

    Reporting group title
    Treatment 6
    Reporting group description
    		 Patients received Gonal-f: 150 IU QD

    Serious adverse events
    		 Treatment 1 Treatment 2 Treatment 3 Treatment 4 Treatment 5 Treatment 6
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 42 (0.00%)
    1 / 40 (2.50%)
    1 / 43 (2.33%)
    0 / 42 (0.00%)
    1 / 39 (2.56%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Pregnancy, puerperium and perinatal conditions
    Ectopic pregnancy
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    1 / 43 (2.33%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    1 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Ovarian hyperstimulation syndrome
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 42 (0.00%)
    1 / 40 (2.50%)
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    1 / 2
    0 / 2
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ascites
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 42 (0.00%)
    1 / 40 (2.50%)
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Treatment 1 Treatment 2 Treatment 3 Treatment 4 Treatment 5 Treatment 6
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 41 (39.02%)
    13 / 42 (30.95%)
    16 / 40 (40.00%)
    15 / 43 (34.88%)
    19 / 42 (45.24%)
    11 / 39 (28.21%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    9 / 41 (21.95%)
    5 / 42 (11.90%)
    6 / 40 (15.00%)
    4 / 43 (9.30%)
    8 / 42 (19.05%)
    4 / 39 (10.26%)
         occurrences all number
    36
    36
    36
    36
    36
    36
    Pregnancy, puerperium and perinatal conditions
    Abortion missed
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 42 (0.00%)
    2 / 40 (5.00%)
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    3
    3
    3
    3
    3
    3
    Ectopic pregnancy
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 42 (2.38%)
    0 / 40 (0.00%)
    1 / 43 (2.33%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    2
    2
    2
    2
    2
    2
    Abortion imminent
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    1
    1
    1
    1
    1
    1
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    3 / 41 (7.32%)
    2 / 42 (4.76%)
    1 / 40 (2.50%)
    4 / 43 (9.30%)
    2 / 42 (4.76%)
    1 / 39 (2.56%)
         occurrences all number
    13
    13
    13
    13
    13
    13
    Injection site pain
         subjects affected / exposed
    3 / 41 (7.32%)
    1 / 42 (2.38%)
    0 / 40 (0.00%)
    4 / 43 (9.30%)
    2 / 42 (4.76%)
    1 / 39 (2.56%)
         occurrences all number
    11
    11
    11
    11
    11
    11
    Injection site swelling
         subjects affected / exposed
    2 / 41 (4.88%)
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    3 / 43 (6.98%)
    2 / 42 (4.76%)
    0 / 39 (0.00%)
         occurrences all number
    7
    7
    7
    7
    7
    7
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    4 / 41 (9.76%)
    1 / 42 (2.38%)
    2 / 40 (5.00%)
    3 / 43 (6.98%)
    3 / 42 (7.14%)
    3 / 39 (7.69%)
         occurrences all number
    16
    16
    16
    16
    16
    16
    Abdominal discomfort
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 42 (0.00%)
    4 / 40 (10.00%)
    0 / 43 (0.00%)
    1 / 42 (2.38%)
    1 / 39 (2.56%)
         occurrences all number
    7
    7
    7
    7
    7
    7
    Nausea
         subjects affected / exposed
    3 / 41 (7.32%)
    2 / 42 (4.76%)
    1 / 40 (2.50%)
    1 / 43 (2.33%)
    1 / 42 (2.38%)
    2 / 39 (5.13%)
         occurrences all number
    10
    10
    10
    10
    10
    10
    Reproductive system and breast disorders
    Ovarian hyperstimulation syndrome
         subjects affected / exposed
    2 / 41 (4.88%)
    2 / 42 (4.76%)
    1 / 40 (2.50%)
    1 / 43 (2.33%)
    2 / 42 (4.76%)
    3 / 39 (7.69%)
         occurrences all number
    11
    11
    11
    11
    11
    11
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 42 (4.76%)
    0 / 40 (0.00%)
    2 / 43 (4.65%)
    2 / 42 (4.76%)
    1 / 39 (2.56%)
         occurrences all number
    7
    7
    7
    7
    7
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Mar 2013
    The Sponsor amended the protocol in order to 1. determine the FSH concentration in serum during the FSH treatment period in order to ex-plore the exposure-response relationship. Blood sampling for the analysis of FSH serum concentrations should be performed on Day 1 and Day 2 of FSH treatment and at least every second day thereafter as well as on visit 4 (record of hCG criterion). Since these sampling timepoints corresponded to serum samples taken for the central lab un-der the current protocol (version 1.0) no additional blood sampling was required. Also, no in-crease in blood sampling volumes, either of individual samples or in total, was required.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/31982355
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