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    Clinical Trial Results:
    A phase III assessor-blinded randomised parallel group multi-centre study to compare efficacy and safety of two r-hFSH formulations (AFOLIA and Gonal-f®) in women for assisted reproductive treatment

    Summary
    EudraCT number
    		 2010-019287-37
    Trial protocol
    		 DE   AT   ES   GB   DK  
    Global end of trial date
    31 Dec 2012

    Results information
    Results version number
    		 v1
    This version publication date
    04 Mar 2016
    First version publication date
    04 Mar 2016
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    FIN3001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01121666
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Finox AG
    Sponsor organisation address
    Technikumstrasse 2, Burgdorf, Switzerland, 3401
    Public contact
    Julian Jenkins, Finox AG, +41 34 426 11 11, info@finoxbiotech.com
    Scientific contact
    Julian Jenkins, Finox AG, +41 34 426 11 11, info@finoxbiotech.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
    Interim
    Date of interim/final analysis
    28 Sep 2012
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Dec 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to show equivalence between AFOLIA and Gonal-f® with regard to the number of oocytes retrieved in women for assisted reproductive treatment
    Protection of trial subjects
    Study Design: This was a multi-centre, assessor-blind, comparative Phase 3 study with central patient randomization. After obtaining informed consent, patients were screened for eligibility for the study. The endogenous FSH production of eligible patients was down-regulated with a GnRH–agonist. After down-regulation of endogenous FSH, patients were randomised 2:1 to receive either AFOLIA or Gonal f daily. FSH in both groups was administered s.c. A starting dose of 150 IU/day was administered in both groups. Ovarian response was assessed by vaginal ultrasound on day 1, 6, 8, and on the day of hCG application, 16 days after start of treatment with r-hFSH at the latest. For patients’ safety serum E2 concentration was measured as well. After day 8 assessment, follicular development was monitored by vaginal ultrasound at 2-3 days interval. Patients received daily r-hFSH until at least 1 follicle reached a diameter of ≥18 mm and 2 additional follicles reached a diameter of ≥16 mm, but no longer than 16 days. At this time, hCG was given to trigger ovulation. Oocytes were removed and ICSI or IVF was done according to standard techniques. A maximum of two embryos were transferred 2 to 5 days after oocyte retrieval. Pregnancy rate was determined biochemically and clinically. Criteria for Safety Evaluation: - Adverse events - Local and systemic adverse event pattern (incl. ovarian hyper stimulation syndrome (OHSS)) - Time to first Onset of OHSS - Time to first Dose Reduction due to imminent OHSS - Percentage of patients with dose reduction due to imminent OHSS - Clinical laboratory tests - Vital signs - Physical examination / Health status
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jun 2010
    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: 52
    Country: Number of subjects enrolled
    United Kingdom: 31
    Country: Number of subjects enrolled
    Austria: 131
    Country: Number of subjects enrolled
    Denmark: 112
    Country: Number of subjects enrolled
    Germany: 35
    Country: Number of subjects enrolled
    Switzerland: 11
    Worldwide total number of subjects
    372
    EEA total number of subjects
    361
    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)
    372
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were screened and enrolled at 15 centers in six European countries from July 2010 until April 2012

    Pre-assignment
    Screening details
    		 Of 460 participants in this trial 88 were reported as screening failures prior the group assignment

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Assessor [1]

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 AFOLIA-150 (Follitropin Alfa)
    Arm description
    		 Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days
    Arm type
    		 Experimental

    Investigational medicinal product name
    AFOLIA-150 (Follitropin alfa)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    150IU per day subcutaneously for a maximum of 16 days

    Arm title
    		 Gonal-f® (Follitropin Alfa)
    Arm description
    		 Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Gonal-f® (Follitropin alfa)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    150IU per day subcutaneously for a maximum of 16 days

    Notes
    [1] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: Blinding (masking) indicates that knowledge of the intervention assignments is hidden from participants, trial investigators, or assessors. The terminology single blind usually means that one of the three categories of individuals remains unaware of intervention assignments throughout the trial. A single-blind trial might also, confusingly, mean that the participant and investigator both know the intervention, but that the assessor remains unaware of it.
    Number of subjects in period 1
    		AFOLIA-150 (Follitropin Alfa) Gonal-f® (Follitropin Alfa)
    Started
    249
    123
    Completed
    220
    113
    Not completed
    29
    10
         Protocol deviation
    29
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    AFOLIA-150 (Follitropin Alfa)
    Reporting group description
    		 Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days

    Reporting group title
    Gonal-f® (Follitropin Alfa)
    Reporting group description
    		 Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days.

    Reporting group values
    		 AFOLIA-150 (Follitropin Alfa) Gonal-f® (Follitropin Alfa) Total
    Number of subjects
    		 249 123 372
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 249 123 372
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 31.8 ( 4.02 ) 32.1 ( 3.76 ) -
    Gender categorical
    Units: Subjects
        Female
    		 249 123 372
        Male
    		 0 0 0
    FSH baseline concentration
    The FSH concentration was measured at baseline in IU/L.
    Units: IU/L
        arithmetic mean (standard deviation)
    		 6.9 ( 1.51 ) 6.9 ( 1.56 ) -
    Antral follicle count
    Units: Antral follicle count
        arithmetic mean (standard deviation)
    		 15.1 ( 3.77 ) 15.3 ( 3.83 ) -
    Body Mass Index
    Units: kilogram(s)/square meter
        arithmetic mean (standard deviation)
    		 22.7 ( 2.9 ) 22.4 ( 2.56 ) -
    GnRH-agonist duration
    Units: days
        arithmetic mean (standard deviation)
    		 23.5 ( 7.89 ) 22.7 ( 7.46 ) -
    Subject analysis sets

    Subject analysis set title
    AFOLIA-150 (Follitropin Alfa) (Per Protocol Population)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days; Per Protocol Population

    Subject analysis set title
    Gonal-f® (Follitropin Alfa) (Per Protocol Population)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days; Per Protocol Population

    Subject analysis set title
    AFOLIA-150 (Follitropin Alfa) (2nd treatment cycle)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days; Population with a second treatment cycle

    Subject analysis set title
    Gonal-f® (Follitropin Alfa) (2nd treatment cycle)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days; Population with a second treatment cycle

    Subject analysis sets values
    		 AFOLIA-150 (Follitropin Alfa) (Per Protocol Population) Gonal-f® (Follitropin Alfa) (Per Protocol Population) AFOLIA-150 (Follitropin Alfa) (2nd treatment cycle) Gonal-f® (Follitropin Alfa) (2nd treatment cycle)
    Number of subjects
    220
    113
    72
    38
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    220
    113
    72
    38
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
        Male
    FSH baseline concentration
    The FSH concentration was measured at baseline in IU/L.
    Units: IU/L
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    ( )
    Antral follicle count
    Units: Antral follicle count
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    ( )
    Body Mass Index
    Units: kilogram(s)/square meter
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    ( )
    GnRH-agonist duration
    Units: days
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    ( )

    End points

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    End points reporting groups
    Reporting group title
    AFOLIA-150 (Follitropin Alfa)
    Reporting group description
    		 Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days

    Reporting group title
    Gonal-f® (Follitropin Alfa)
    Reporting group description
    		 Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days.

    Subject analysis set title
    AFOLIA-150 (Follitropin Alfa) (Per Protocol Population)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days; Per Protocol Population

    Subject analysis set title
    Gonal-f® (Follitropin Alfa) (Per Protocol Population)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days; Per Protocol Population

    Subject analysis set title
    AFOLIA-150 (Follitropin Alfa) (2nd treatment cycle)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days; Population with a second treatment cycle

    Subject analysis set title
    Gonal-f® (Follitropin Alfa) (2nd treatment cycle)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days; Population with a second treatment cycle

    Primary: Number of Oocytes Retrieved (Per Protocol Population)

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    End point title
    		 Number of Oocytes Retrieved (Per Protocol Population)
    End point description
    As soon as ovulation criteria were reached, HCG was given to trigger ovulation and 34-36 hours later, oocytes were retrieved. If criteria for ovulation triggering could not be reached by FSH stimulation on day 16, treatment was to be stopped. The equivalence in the number of retrieved oocytes was tested using a pre-determined clinical equivalence margin of +/- 2.9 oocytes
    End point type
    Primary
    End point timeframe
    34-36 hours after hCG administration and after maximum 16 days of r-hFSH treatment
    End point values
    		 AFOLIA-150 (Follitropin Alfa) (Per Protocol Population) Gonal-f® (Follitropin Alfa) (Per Protocol Population)
    Number of subjects analysed
    220
    113
    Units: Number of retrieved oocytes
        arithmetic mean (standard deviation)
    10.8 ( 5.11 )
    10.6 ( 6.06 )
    Statistical analysis title
    		 Number of Oocytes Retrieved (Per Protocol Pop.)
    Statistical analysis description
    This study was powered to test equivalence using a two one-sided test (TOST) of the number of oocytes retrieved.
    Comparison groups
    AFOLIA-150 (Follitropin Alfa) (Per Protocol Population) v Gonal-f® (Follitropin Alfa) (Per Protocol Population)
    Number of subjects included in analysis
    333
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [1]
    P-value
    		 = 0.0003 [2]
    Method
    		 Shuirmann's TOST
    Confidence interval
    Notes
    [1] - This study was powered to test equivalence using a two one-sided test (TOST) of the number of oocytes retrieved with a power of 90%, an alpha error of 2.5% and a pre-determined clinical equivalence margin of +/-2.9 oocytes for the relevant population.
    [2] - This study was powered to test equivalence using a two one-sided test (TOST) with a power of 90%, an alpha error of 2.5% and a pre-determined clinical equivalence margin of +/-2.9 oocytes for the relevant population.

    Primary: Number of Oocytes Retrieved (Intention-to-treat Population)

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    End point title
    		 Number of Oocytes Retrieved (Intention-to-treat Population)
    End point description
    As soon as ovulation criteria were reached, HCG was given to trigger ovulation and 34-36 hours later, oocytes were retrieved. If criteria for ovulation triggering could not be reached by FSH stimulation on day 16, treatment was to be stopped. The equivalence in the number of retrieved oocytes was tested using a pre-determined clinical equivalence margin of +/- 2.9 oocytes
    End point type
    Primary
    End point timeframe
    34-36 hours after hCG administration and after maximum 16 days of r-hFSH treatment
    End point values
    		 AFOLIA-150 (Follitropin Alfa) Gonal-f® (Follitropin Alfa)
    Number of subjects analysed
    249
    123
    Units: Number of retrieved oocytes
        arithmetic mean (standard deviation)
    10.7 ( 5.62 )
    10.4 ( 6.14 )
    Statistical analysis title
    		 Number of Oocytes Retrieved (Intention to treat)
    Comparison groups
    AFOLIA-150 (Follitropin Alfa) v Gonal-f® (Follitropin Alfa)
    Number of subjects included in analysis
    372
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [3]
    P-value
    		 = 0.0003
    Method
    		 Shuirmann's TOST
    Confidence interval
    Notes
    [3] - This study was powered to test equivalence using a two one-sided test (TOST) of the number of oocytes retrieved with a power of 90%, an alpha error of 2.5% and a pre-determined clinical equivalence margin of +/-2.9 oocytes for the relevant population.

    Secondary: Number and Size of Follicles ≥ 12 mm at Day 8 of Stimulation

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    End point title
    		 Number and Size of Follicles ≥ 12 mm at Day 8 of Stimulation
    End point description
    The number and size of follicles 12 mm or over in diameter at day 8 of stimulation were evaluated as secondary end-point.
    End point type
    Secondary
    End point timeframe
    Day 8 of stimulation
    End point values
    		 AFOLIA-150 (Follitropin Alfa) Gonal-f® (Follitropin Alfa)
    Number of subjects analysed
    249
    123
    Units: Number of follicles
    arithmetic mean (standard deviation)
        ≥ 12 mm
    11.8 ( 4.73 )
    11.1 ( 4.23 )
        ≥ 15 mm
    8.3 ( 3.81 )
    7.7 ( 3.6 )
        ≥ 17 mm
    4.9 ( 3.29 )
    4.5 ( 2.71 )
    Statistical analysis title
    		 Number/Size of Follicles ≥ 12 mm day 8 of stimul.
    Comparison groups
    AFOLIA-150 (Follitropin Alfa) v Gonal-f® (Follitropin Alfa)
    Number of subjects included in analysis
    372
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2357 [4]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [4] - Follicles of 12 mm
    Statistical analysis title
    		 Number/Size of Follicles ≥ 12 mm day 8 of stimul.
    Comparison groups
    AFOLIA-150 (Follitropin Alfa) v Gonal-f® (Follitropin Alfa)
    Number of subjects included in analysis
    372
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1395 [5]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [5] - Follicles of 15 mm
    Statistical analysis title
    		 Number/Size of Follicles ≥ 12 mm day 8 of stimul.
    Comparison groups
    AFOLIA-150 (Follitropin Alfa) v Gonal-f® (Follitropin Alfa)
    Number of subjects included in analysis
    372
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.3992 [6]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [6] - Follicles of 17 mm

    Secondary: E2 Concentration at Day 8 and at Day of hCG Administration

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    End point title
    		 E2 Concentration at Day 8 and at Day of hCG Administration
    End point description
    The serum concentration of oestradiol was assessed at day 8 and the day of hCG administration.
    End point type
    Secondary
    End point timeframe
    Day 8 of stimulation and at the day of hCG administration (after max. 16 days of r-FSH treatment)
    End point values
    		 AFOLIA-150 (Follitropin Alfa) Gonal-f® (Follitropin Alfa)
    Number of subjects analysed
    249
    123
    Units: pmol/L
    arithmetic mean (standard deviation)
        Day of hCG administration
    8982.3 ( 6535.3 )
    7704.2 ( 5345.8 )
        Day 8
    3958.9 ( 3699.4 )
    3234 ( 2428.1 )
    No statistical analyses for this end point

    Secondary: Total Dose of r-hFSH Administered

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    End point title
    		 Total Dose of r-hFSH Administered
    End point description
    Total dose of r-hFSH required was assessed.
    End point type
    Secondary
    End point timeframe
    Day of hCG administration (after maximum 16 days of r-hFSH treatment)
    End point values
    		 AFOLIA-150 (Follitropin Alfa) Gonal-f® (Follitropin Alfa)
    Number of subjects analysed
    249
    123
    Units: Mean total dose of r-hFSH (IU)
        arithmetic mean (standard deviation)
    1555.7 ( 293 )
    1569.2 ( 259.2 )
    Statistical analysis title
    		 Total Dose of r-hFSH Administered
    Comparison groups
    AFOLIA-150 (Follitropin Alfa) v Gonal-f® (Follitropin Alfa)
    Number of subjects included in analysis
    372
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.9638
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Quality of Oocytes Retrieved

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    End point title
    		 Quality of Oocytes Retrieved
    End point description
    Number of patients with ovum pick-up
    End point type
    Secondary
    End point timeframe
    34-36 hours after hCG administration
    End point values
    		 AFOLIA-150 (Follitropin Alfa) Gonal-f® (Follitropin Alfa)
    Number of subjects analysed
    249
    123
    Units: Participants
        Day 2
    82
    36
        Day 3
    53
    28
    No statistical analyses for this end point

    Secondary: Fertilisation Rate of Oocytes

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    End point title
    		 Fertilisation Rate of Oocytes
    End point description
    Fertilisation rate was assessed
    End point type
    Secondary
    End point timeframe
    1 day after ovum pick-up
    End point values
    		 AFOLIA-150 (Follitropin Alfa) Gonal-f® (Follitropin Alfa)
    Number of subjects analysed
    249
    123
    Units: Participants
        arithmetic mean (standard deviation)
    66.1 ( 24.84 )
    64 ( 24.76 )
    No statistical analyses for this end point

    Secondary: Embryo Quality: Mean Number of Blastomeres

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    End point title
    		 Embryo Quality: Mean Number of Blastomeres
    End point description
    Main embryo quality parameter "mean number of blastomeres"
    End point type
    Secondary
    End point timeframe
    Day 2 of OPU/fertilisation
    End point values
    		 AFOLIA-150 (Follitropin Alfa) Gonal-f® (Follitropin Alfa)
    Number of subjects analysed
    249
    123
    Units: Number of blastomeres at day 3
        arithmetic mean (standard deviation)
    6.6 ( 2.41 )
    6.4 ( 2.49 )
    No statistical analyses for this end point

    Secondary: Number of Cryopreserved 2PNs, Embryos/Blastocysts

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    End point title
    		 Number of Cryopreserved 2PNs, Embryos/Blastocysts
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1, 2, 3 and 5 of OPU/fertilisation
    End point values
    		 AFOLIA-150 (Follitropin Alfa) Gonal-f® (Follitropin Alfa)
    Number of subjects analysed
    249
    123
    Units: Patients with cryopreservation
    103
    55
    No statistical analyses for this end point

    Secondary: Number of Days of r-hFSH Stimulation

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    End point title
    		 Number of Days of r-hFSH Stimulation
    End point description
    Mean duration of stimulation was assessed.
    End point type
    Secondary
    End point timeframe
    At the day of hCG administration
    End point values
    		 AFOLIA-150 (Follitropin Alfa) Gonal-f® (Follitropin Alfa)
    Number of subjects analysed
    249
    123
    Units: Duration of FSH medication (days)
        arithmetic mean (standard deviation)
    10.6 ( 1.91 )
    10.7 ( 1.72 )
    Statistical analysis title
    		 Number of Days of r-hFSH Stimulation
    Comparison groups
    AFOLIA-150 (Follitropin Alfa) v Gonal-f® (Follitropin Alfa)
    Number of subjects included in analysis
    372
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.8926
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Number of Patients With Cycle Cancellation

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    End point title
    		 Number of Patients With Cycle Cancellation
    End point description
    Number of patients with cycle cancellation was assessed.
    End point type
    Secondary
    End point timeframe
    At the end of the study
    End point values
    		 AFOLIA-150 (Follitropin Alfa) Gonal-f® (Follitropin Alfa)
    Number of subjects analysed
    249
    123
    Units: Cycle cancellations
    13
    5
    No statistical analyses for this end point

    Secondary: Number of Patients With Good Response

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    End point title
    		 Number of Patients With Good Response
    End point description
    Good response was defined as "patients with an oocyte retrieval of four or more oocytes"
    End point type
    Secondary
    End point timeframe
    At the end of the study
    End point values
    		 AFOLIA-150 (Follitropin Alfa) Gonal-f® (Follitropin Alfa)
    Number of subjects analysed
    249
    123
    Units: Participants
    217
    107
    No statistical analyses for this end point

    Secondary: Local and Systemic Adverse Events

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    End point title
    		 Local and Systemic Adverse Events
    End point description
    Assessment of patients with Ovarian hyperstimulation syndrome (OHSS), patients with OHSS and Anti-Müllerian Hormone (AMH) ≥ 24 pmol/L, patients with dose reduction due to risk of hyperstimulation, patients with coasting due to risk of hyperstimulation and patients with hCG withdrawal due to risk of hyperstimulation.
    End point type
    Secondary
    End point timeframe
    During the study
    End point values
    		 AFOLIA-150 (Follitropin Alfa) Gonal-f® (Follitropin Alfa)
    Number of subjects analysed
    249
    123
    Units: Number of patients
        Ovarian hyperstimulation syndrome (OHSS)
    14
    4
        Patients with OHSS and AMH ≥ 24 pmol/L
    8
    1
        Patients with dose reduction
    38
    16
        Patients with coasting
    3
    3
        Patients with hCG withdrawal
    5
    1
    No statistical analyses for this end point

    Secondary: Implantation Rate

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    End point title
    		 Implantation Rate
    End point description
    Defined as fetal sac per embryo transferred.
    End point type
    Secondary
    End point timeframe
    Five to six weeks after oocyte retrieval
    End point values
    		 AFOLIA-150 (Follitropin Alfa) Gonal-f® (Follitropin Alfa)
    Number of subjects analysed
    249
    123
    Units: Percentage of implantations
        number (not applicable)
    31.8
    36.7
    No statistical analyses for this end point

    Secondary: Clinical Pregnancy Rate

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    End point title
    		 Clinical Pregnancy Rate
    End point description
    Presence of at least one intrauterine gestational sac.
    End point type
    Secondary
    End point timeframe
    Five to six weeks after oocyte retrieval
    End point values
    		 AFOLIA-150 (Follitropin Alfa) Gonal-f® (Follitropin Alfa)
    Number of subjects analysed
    249
    123
    Units: Clinical pregnancies
    90
    55
    No statistical analyses for this end point

    Secondary: Ongoing Pregnancy

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    End point title
    		 Ongoing Pregnancy
    End point description
    Ongoing pregnancy per embryo transfer. Presence of at least one viable fetus 10 weeks after embryo transfer.
    End point type
    Secondary
    End point timeframe
    Ten weeks after embryo transfer
    End point values
    		 AFOLIA-150 (Follitropin Alfa) Gonal-f® (Follitropin Alfa)
    Number of subjects analysed
    249
    123
    Units: Ongoing pregnancies
    84
    51
    No statistical analyses for this end point

    Secondary: Live Birth Rate

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    End point title
    		 Live Birth Rate
    End point description
    Patients with liveborn children
    End point type
    Secondary
    End point timeframe
    After childbirth with questionnaire
    End point values
    		 AFOLIA-150 (Follitropin Alfa) Gonal-f® (Follitropin Alfa)
    Number of subjects analysed
    249
    123
    Units: Patients with liveborn children
    80
    51
    No statistical analyses for this end point

    Secondary: Embryo Quality: Absence of Multinucleation

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    End point title
    		 Embryo Quality: Absence of Multinucleation
    End point description
    Main embryo quality parameter "absence of multinucleation" observed.
    End point type
    Secondary
    End point timeframe
    Day 3
    End point values
    		 AFOLIA-150 (Follitropin Alfa) Gonal-f® (Follitropin Alfa)
    Number of subjects analysed
    249
    123
    Units: Percentage of absent multinucleation
        number (not applicable)
    93.6
    93.9
    No statistical analyses for this end point

    Secondary: Quality of Oocytes Retrieved

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    End point title
    		 Quality of Oocytes Retrieved
    End point description
    Number of patients with transferred blastocysts
    End point type
    Secondary
    End point timeframe
    At day 4 and 5
    End point values
    		 AFOLIA-150 (Follitropin Alfa) Gonal-f® (Follitropin Alfa)
    Number of subjects analysed
    249
    123
    Units: Participants
        Day 4
    10
    2
        Day 5
    76
    46
    No statistical analyses for this end point

    Secondary: Quality of Oocytes Retrieved

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    End point title
    		 Quality of Oocytes Retrieved
    End point description
    Number of embryos per blastocysts transferred
    End point type
    Secondary
    End point timeframe
    Day of transfer
    End point values
    		 AFOLIA-150 (Follitropin Alfa) Gonal-f® (Follitropin Alfa)
    Number of subjects analysed
    249
    123
    Units: Embryos per blastocysts transferred
        arithmetic mean (standard deviation)
    1.5 ( 0.52 )
    1.6 ( 0.53 )
    No statistical analyses for this end point

    Secondary: Clinical Pregnancy Rate (Second Treatment Cycle)

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    End point title
    		 Clinical Pregnancy Rate (Second Treatment Cycle)
    End point description
    Presence of at least one intrauterine gestational sac.
    End point type
    Secondary
    End point timeframe
    Five to six weeks after oocyte retrieval
    End point values
    		 AFOLIA-150 (Follitropin Alfa) (2nd treatment cycle) Gonal-f® (Follitropin Alfa) (2nd treatment cycle)
    Number of subjects analysed
    72
    38
    Units: Clinical pregnancies
    25
    10
    No statistical analyses for this end point

    Secondary: Ongoing Pregnancy (Second Treatment Cycle)

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    End point title
    		 Ongoing Pregnancy (Second Treatment Cycle)
    End point description
    Ongoing pregnancy per embryo transfer. Presence of at least one viable fetus 10 weeks after embryo transfer.
    End point type
    Secondary
    End point timeframe
    10 weeks after embryo transfer
    End point values
    		 AFOLIA-150 (Follitropin Alfa) (2nd treatment cycle) Gonal-f® (Follitropin Alfa) (2nd treatment cycle)
    Number of subjects analysed
    72
    38
    Units: Ongoing pregnancies
    22
    9
    No statistical analyses for this end point

    Secondary: Quality of Oocytes Retrieved

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    End point title
    		 Quality of Oocytes Retrieved
    End point description
    The maturity of the cumulus oophorus was assessed.
    End point type
    Secondary
    End point timeframe
    After oocyte retrieval
    End point values
    		 AFOLIA-150 (Follitropin Alfa) Gonal-f® (Follitropin Alfa)
    Number of subjects analysed
    249
    123
    Units: Percentage of cumulus oophori
    number (not applicable)
        very mature
    9.1
    9.4
        mature
    75.7
    75.3
        immature
    14.2
    14.2
    No statistical analyses for this end point

    Secondary: Quality of Oocytes Retrieved

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    End point title
    		 Quality of Oocytes Retrieved
    End point description
    The nuclear maturity was assessed (Germinal vesicle, Metaphase I, Metaphase II).
    End point type
    Secondary
    End point timeframe
    After oocyte retrieval
    End point values
    		 AFOLIA-150 (Follitropin Alfa) Gonal-f® (Follitropin Alfa)
    Number of subjects analysed
    249
    123
    Units: Percentage of cells
    number (not applicable)
        Germinal vesicle
    9.5
    9.1
        Metaphase I
    7.2
    7.7
        Metaphase II
    83.4
    83.3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Study period plus 30 days
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.1
    Reporting groups
    Reporting group title
    AFOLIA-150 (Follitropin Alfa)
    Reporting group description
    		 Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days

    Reporting group title
    Gonal-f® (Follitropin Alfa)
    Reporting group description
    		 Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days.

    Serious adverse events
    		 AFOLIA-150 (Follitropin Alfa) Gonal-f® (Follitropin Alfa)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 249 (4.82%)
    3 / 123 (2.44%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Body temperature increased
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 123 (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
    Syncope
         subjects affected / exposed
    0 / 249 (0.00%)
    1 / 123 (0.81%)
         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
    Ovarian hyperstimulation syndrome
         subjects affected / exposed
    7 / 249 (2.81%)
    2 / 123 (1.63%)
         occurrences causally related to treatment / all
    7 / 7
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian haemorrhage
         subjects affected / exposed
    1 / 249 (0.40%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 249 (0.80%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary colic
         subjects affected / exposed
    1 / 249 (0.40%)
    0 / 123 (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: 0%
    Non-serious adverse events
    		 AFOLIA-150 (Follitropin Alfa) Gonal-f® (Follitropin Alfa)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    182 / 249 (73.09%)
    83 / 123 (67.48%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    55 / 249 (22.09%)
    25 / 123 (20.33%)
         occurrences all number
    55
    25
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    68 / 249 (27.31%)
    44 / 123 (35.77%)
         occurrences all number
    68
    44
    Injection site haematoma
         subjects affected / exposed
    60 / 249 (24.10%)
    19 / 123 (15.45%)
         occurrences all number
    60
    19
    Injection site pain
         subjects affected / exposed
    39 / 249 (15.66%)
    21 / 123 (17.07%)
         occurrences all number
    39
    21
    Injection site swelling
         subjects affected / exposed
    15 / 249 (6.02%)
    10 / 123 (8.13%)
         occurrences all number
    15
    10
    Fatigue
         subjects affected / exposed
    13 / 249 (5.22%)
    4 / 123 (3.25%)
         occurrences all number
    13
    4
    Reproductive system and breast disorders
    Ovarian hyperstimulation syndrome
         subjects affected / exposed
    55 / 249 (22.09%)
    16 / 123 (13.01%)
         occurrences all number
    55
    16
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    23 / 249 (9.24%)
    6 / 123 (4.88%)
         occurrences all number
    23
    6
    Abdominal distension
         subjects affected / exposed
    14 / 249 (5.62%)
    6 / 123 (4.88%)
         occurrences all number
    14
    6
    Abdominal pain
         subjects affected / exposed
    13 / 249 (5.22%)
    6 / 123 (4.88%)
         occurrences all number
    13
    6
    Abdominal pain upper
         subjects affected / exposed
    7 / 249 (2.81%)
    7 / 123 (5.69%)
         occurrences all number
    7
    7

    More information

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

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

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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/25735918
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