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    Clinical Trial Results:
    Assisted reproduction and the early luteal phase The effect of ovulation induction on the endocrine profile

    Summary
    EudraCT number
    		 2013-003304-39
    Trial protocol
    		 DK  
    Global end of trial date
    28 Aug 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Jan 2022
    First version publication date
    21 Jan 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    13.010
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Odense University Hospital
    Sponsor organisation address
    Kløvervænget 23, Odense, Denmark,
    Public contact
    Fertilitycenter, Odense University Hospital, 0045 20342687, Peter.Humaidan@midt.rm.dk
    Scientific contact
    Fertilitycenter, Odense University Hospital, 0045 20342687, Peter.Humaidan@midt.rm.dk
    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
    30 Nov 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Aug 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Aug 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the endocrine hormone levels in the luteal phase during fertility treatment.
    Protection of trial subjects
    Ethics Committee of Southern of Denmark, the Danish Health and Medicines Authority, the Danish Data Protection Agency and Local Good Clinical Practice Unit.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Dec 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 222
    Worldwide total number of subjects
    222
    EEA total number of subjects
    222
    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)
    222
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Fertility Clinic, Patients in fertility treatment.

    Pre-assignment
    Screening details
    		 Healthy women in infertility treatment, 18-40 years, healthy with normal screening blood samples RCT I: In total ≤ 11 follicles ≤ 12 mm, on both ovaries at the last ultrasonography before oocyte retrieval RCT II: In total ≥ 12 or ≤ 25 follicles ≤ 12 mm, on both ovaries at the last ultrasonography before oocyte retrieval

    Period 1
    Period 1 title
    overall periode
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 RCT I, group 1
    Arm description
    		 5.000 IU (urinary hCG) + 17α OH P4
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Lentogest
    Investigational medicinal product code
    G03DA03
    Other name
    Pharmaceutical forms
    Suspension for suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    341 mg every 3.th day

    Arm title
    		 RCT I, group 2
    Arm description
    		 6.500 IU (recombinant hCG) + 17α OH P4
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Lentogest
    Investigational medicinal product code
    G03DA03
    Other name
    Pharmaceutical forms
    Suspension for suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    341 mg every 3.th day

    Arm title
    		 RCT I, group 3
    Arm description
    		 10.000 IU (urinary hCG) + 17α OH P4
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Lentogest
    Investigational medicinal product code
    G03DA03
    Other name
    Pharmaceutical forms
    Suspension for suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    341 mg every 3.th day

    Arm title
    		 RCT I, group 4
    Arm description
    		 6500 IU (recombinant hCG) + P4
    Arm type
    		 control

    Investigational medicinal product name
    Progesterone, Crinone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Vaginal gel
    Routes of administration
    Vaginal use
    Dosage and administration details
    180 mg every day

    Arm title
    		 RCT II, group 1
    Arm description
    		 Trigger: 6.500 IU hCG. Luteal support: P4
    Arm type
    		 control

    Investigational medicinal product name
    Progesterone, Crinone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Vaginal gel
    Routes of administration
    Vaginal use
    Dosage and administration details
    180 mg every day

    Arm title
    		 RCT II, group 2
    Arm description
    		 Trigger: GnRh agonist 0.5 mg. Luteal support: 1500 IU hCG at OPU, P4
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Progesterone, Crinone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Vaginal gel
    Routes of administration
    Vaginal use
    Dosage and administration details
    180 mg every day

    Arm title
    		 RCT II, group 3
    Arm description
    		 Trigger: GnRha agonist 0.5 mg. Luteal support: 1000 IU hCG at OPU, 500 IU hCG at OPU+5, P4
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Progesterone, Crinone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Vaginal gel
    Routes of administration
    Vaginal use
    Dosage and administration details
    180 mg every day

    Number of subjects in period 1
    		RCT I, group 1 RCT I, group 2 RCT I, group 3 RCT I, group 4 RCT II, group 1 RCT II, group 2 RCT II, group 3
    Started
    30
    33
    32
    32
    33
    32
    30
    Completed
    21
    22
    25
    26
    25
    22
    22
    Not completed
    9
    11
    7
    6
    8
    10
    8
         Consent withdrawn by subject
    1
    1
    1
    1
    1
    -
    -
         missed blood samples
    1
    1
    -
    1
    -
    1
    3
         Adverse event, non-fatal
    -
    -
    1
    -
    -
    -
    -
         missing ovary
    -
    -
    -
    -
    -
    1
    -
         total freeze
    -
    2
    1
    3
    1
    5
    1
         wrong medicine
    -
    -
    -
    -
    -
    1
    -
         no oocytes
    2
    1
    1
    -
    -
    -
    1
         cancelled transfer
    -
    3
    3
    1
    6
    2
    3
         endocrinological diseases
    -
    3
    -
    -
    -
    -
    -
         transfer cancelled
    5
    -
    -
    -
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    RCT I, group 1
    Reporting group description
    		 5.000 IU (urinary hCG) + 17α OH P4

    Reporting group title
    RCT I, group 2
    Reporting group description
    		 6.500 IU (recombinant hCG) + 17α OH P4

    Reporting group title
    RCT I, group 3
    Reporting group description
    		 10.000 IU (urinary hCG) + 17α OH P4

    Reporting group title
    RCT I, group 4
    Reporting group description
    		 6500 IU (recombinant hCG) + P4

    Reporting group title
    RCT II, group 1
    Reporting group description
    		 Trigger: 6.500 IU hCG. Luteal support: P4

    Reporting group title
    RCT II, group 2
    Reporting group description
    		 Trigger: GnRh agonist 0.5 mg. Luteal support: 1500 IU hCG at OPU, P4

    Reporting group title
    RCT II, group 3
    Reporting group description
    		 Trigger: GnRha agonist 0.5 mg. Luteal support: 1000 IU hCG at OPU, 500 IU hCG at OPU+5, P4

    Reporting group values
    		 RCT I, group 1 RCT I, group 2 RCT I, group 3 RCT I, group 4 RCT II, group 1 RCT II, group 2 RCT II, group 3 Total
    Number of subjects
    		 30 33 32 32 33 32 30 222
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 29.1 ± 5.0 31.1 ± 4.44 30.1 ± 4.4 31.7 ± 4.3 30.9 ± 3.6 31.0 ± 4.2 30.1 ± 3.9 -
    Gender categorical
    Units: Subjects
        Female
    		 30 33 32 32 33 32 30 222
        Male
    		 0 0 0 0 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    RCT I, group 1
    Reporting group description
    		 5.000 IU (urinary hCG) + 17α OH P4

    Reporting group title
    RCT I, group 2
    Reporting group description
    		 6.500 IU (recombinant hCG) + 17α OH P4

    Reporting group title
    RCT I, group 3
    Reporting group description
    		 10.000 IU (urinary hCG) + 17α OH P4

    Reporting group title
    RCT I, group 4
    Reporting group description
    		 6500 IU (recombinant hCG) + P4

    Reporting group title
    RCT II, group 1
    Reporting group description
    		 Trigger: 6.500 IU hCG. Luteal support: P4

    Reporting group title
    RCT II, group 2
    Reporting group description
    		 Trigger: GnRh agonist 0.5 mg. Luteal support: 1500 IU hCG at OPU, P4

    Reporting group title
    RCT II, group 3
    Reporting group description
    		 Trigger: GnRha agonist 0.5 mg. Luteal support: 1000 IU hCG at OPU, 500 IU hCG at OPU+5, P4

    Primary: Progesterone

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    End point title
    		 Progesterone
    End point description
    End point type
    Primary
    End point timeframe
    At randomization
    End point values
    		 RCT I, group 1 RCT I, group 2 RCT I, group 3 RCT I, group 4 RCT II, group 1 RCT II, group 2 RCT II, group 3
    Number of subjects analysed
    20
    22
    25
    25
    25
    22
    22
    Units: nmol/l
        median (inter-quartile range (Q1-Q3))
    1.9 (1.5 to 2.3)
    2.1 (1.3 to 2.9)
    1.6 (1.0 to 2.4)
    2.3 (1.6 to 2.7)
    2.5 (2.0 to 3.9)
    2.7 (1.7 to 3.5)
    2.9 (2.1 to 3.6)
    Statistical analysis title
    		 progesterone levels
    Comparison groups
    RCT I, group 1 v RCT I, group 2 v RCT I, group 3 v RCT I, group 4 v RCT II, group 1 v RCT II, group 2 v RCT II, group 3
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Confidence interval

    Primary: Progesterone

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    End point title
    		 Progesterone
    End point description
    End point type
    Primary
    End point timeframe
    Oocyte pick up (OPU)
    End point values
    		 RCT I, group 1 RCT I, group 2 RCT I, group 3 RCT I, group 4 RCT II, group 1 RCT II, group 2 RCT II, group 3
    Number of subjects analysed
    21
    22
    25
    26
    25
    22
    22
    Units: nmol/l
        median (inter-quartile range (Q1-Q3))
    20.4 (15.7 to 28)
    21.4 (17.7 to 35.0)
    16.8 (11.1 to 25.7)
    21.0 (17.3 to 31.0)
    35.0 (27.2 to 38.5)
    17.3 (14.5 to 27.8)
    23.4 (17.2 to 26.1)
    Statistical analysis title
    		 progesterone levels
    Comparison groups
    RCT I, group 1 v RCT I, group 2 v RCT I, group 3 v RCT I, group 4 v RCT II, group 1 v RCT II, group 2 v RCT II, group 3
    Number of subjects included in analysis
    163
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Confidence interval

    Primary: Progesterone

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    End point title
    		 Progesterone
    End point description
    End point type
    Primary
    End point timeframe
    OPU+2
    End point values
    		 RCT I, group 1 RCT I, group 2 RCT I, group 3 RCT I, group 4 RCT II, group 1 RCT II, group 2 RCT II, group 3
    Number of subjects analysed
    21
    21
    25
    26
    25
    22
    22
    Units: nmol/l
        median (inter-quartile range (Q1-Q3))
    79.5 (60.7 to 110.0)
    104.0 (74.4 to 168.0)
    94.1 (58.2 to 177.0)
    125.5 (70.0 to 246.0)
    208.0 (114.0 to 266.0)
    204.5 (113.0 to 261.0)
    241.0 (119.0 to 282.0)
    Statistical analysis title
    		 progesterone levels
    Comparison groups
    RCT I, group 1 v RCT I, group 2 v RCT I, group 3 v RCT I, group 4 v RCT II, group 1 v RCT II, group 2 v RCT II, group 3
    Number of subjects included in analysis
    162
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Confidence interval

    Primary: Progesterone

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    End point title
    		 Progesterone
    End point description
    End point type
    Primary
    End point timeframe
    OPU+4
    End point values
    		 RCT I, group 1 RCT I, group 2 RCT I, group 3 RCT I, group 4 RCT II, group 1 RCT II, group 2 RCT II, group 3
    Number of subjects analysed
    20
    21
    24
    26
    25
    21
    22
    Units: nmol/l
        median (inter-quartile range (Q1-Q3))
    122 (105.0 to 281.0)
    228 (104.0 to 287.0)
    234.5 (120.0 to 364.0)
    286.5 (125.0 to 382.0)
    385.0 (290.0 to 442.0)
    363.0 (256.0 to 385.0)
    278.0 (186.0 to 417.0)
    Statistical analysis title
    		 progesterone levels
    Comparison groups
    RCT I, group 1 v RCT I, group 2 v RCT I, group 3 v RCT I, group 4 v RCT II, group 1 v RCT II, group 2 v RCT II, group 3
    Number of subjects included in analysis
    159
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Confidence interval

    Primary: Progesterone

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    End point title
    		 Progesterone
    End point description
    End point type
    Primary
    End point timeframe
    OPU+6
    End point values
    		 RCT I, group 1 RCT I, group 2 RCT I, group 3 RCT I, group 4 RCT II, group 1 RCT II, group 2 RCT II, group 3
    Number of subjects analysed
    20
    22
    25
    26
    24
    22
    22
    Units: nmol/l
        median (inter-quartile range (Q1-Q3))
    61.7 (36.0 to 181.0)
    171.5 (89.7 to 285.0)
    216 (125.0 to 299.0)
    207.0 (82.7 to 278.0)
    234.0 (183.0 to 300.0)
    112.5 (57.9 to 236.0)
    354.5 (177.0 to 541.0)
    Statistical analysis title
    		 progesterone levels
    Comparison groups
    RCT I, group 1 v RCT I, group 2 v RCT I, group 3 v RCT I, group 4 v RCT II, group 1 v RCT II, group 2 v RCT II, group 3
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Confidence interval

    Primary: progesterone

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    End point title
    		 progesterone
    End point description
    End point type
    Primary
    End point timeframe
    OPU+8
    End point values
    		 RCT I, group 1 RCT I, group 2 RCT I, group 3 RCT I, group 4 RCT II, group 1 RCT II, group 2 RCT II, group 3
    Number of subjects analysed
    21
    22
    25
    26
    24
    21
    21
    Units: nmol/l
        median (inter-quartile range (Q1-Q3))
    8.4 (6.4 to 24.5)
    19.1 (13.0 to 59.1)
    47.4 (31.4 to 116.0)
    47.2 (33.1 to 63.6)
    46.1 (34.7 to 55.8)
    42.0 (34.0 to 46.7)
    230.0 (75.7 to 321.0)
    Statistical analysis title
    		 progesterone levels
    Comparison groups
    RCT I, group 1 v RCT I, group 2 v RCT I, group 3 v RCT I, group 4 v RCT II, group 1 v RCT II, group 2 v RCT II, group 3
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Confidence interval

    Primary: progesterone

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    End point title
    		 progesterone
    End point description
    End point type
    Primary
    End point timeframe
    OPU+10
    End point values
    		 RCT I, group 1 RCT I, group 2 RCT I, group 3 RCT I, group 4 RCT II, group 1 RCT II, group 2 RCT II, group 3
    Number of subjects analysed
    21
    22
    24
    24
    23
    22
    21
    Units: nmol/l
        median (inter-quartile range (Q1-Q3))
    3.8 (1.2 to 7.4)
    5.8 (3.5 to 10.4)
    11.7 (7.1 to 56.0)
    36.1 (28.0 to 45.8)
    30.7 (26.2 to 45.1)
    31.9 (27.0 to 51.2)
    42.9 (32.4 to 252.0)
    Statistical analysis title
    		 progesterone levels
    Comparison groups
    RCT I, group 2 v RCT I, group 1 v RCT I, group 3 v RCT I, group 4 v RCT II, group 1 v RCT II, group 2 v RCT II, group 3
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Confidence interval

    Primary: Progesterone

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    End point title
    		 Progesterone
    End point description
    End point type
    Primary
    End point timeframe
    OPU+14
    End point values
    		 RCT I, group 1 RCT I, group 2 RCT I, group 3 RCT I, group 4 RCT II, group 1 RCT II, group 2 RCT II, group 3
    Number of subjects analysed
    21
    20
    23
    25
    24
    22
    21
    Units: nmol/l
        median (inter-quartile range (Q1-Q3))
    1.6 (1.2 to 7.4)
    1.5 (1.1 to 4.4)
    2.6 (1.1 to 90.3)
    34.0 (27.1 to 48.0)
    31.3 (25.3 to 53.8)
    33.2 (25.5 to 58.8)
    29.1 (24.0 to 461.0)
    Statistical analysis title
    		 progesterone levels
    Comparison groups
    RCT I, group 1 v RCT I, group 2 v RCT I, group 3 v RCT I, group 4 v RCT II, group 1 v RCT II, group 2 v RCT II, group 3
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    14 dec. 2014 until 29. aug 2020, for each patient from randomization until OPU+14 or ultrasonography in gestational week 7.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 none
    Dictionary version
    0
    Reporting groups
    Reporting group title
    RCT I
    Reporting group description
    		 Group 1, 2, 3, 4

    Reporting group title
    RCT II
    Reporting group description
    		 Group 5, 6, 7

    Serious adverse events
    		 RCT I RCT II
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 127 (0.00%)
    0 / 95 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 RCT I RCT II
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    27 / 127 (21.26%)
    20 / 95 (21.05%)
    General disorders and administration site conditions
    Local reaction
    Additional description: Pain at the injection site
         subjects affected / exposed
    13 / 127 (10.24%)
    0 / 95 (0.00%)
         occurrences all number
    13
    0
    OHSS
    Additional description: ovarian hyperstimulation syndrome
         subjects affected / exposed
    5 / 127 (3.94%)
    7 / 95 (7.37%)
         occurrences all number
    5
    7
    bloated stomach
         subjects affected / exposed
    8 / 127 (6.30%)
    12 / 95 (12.63%)
         occurrences all number
    3
    8
    Endocrine disorders
    sore breasts
         subjects affected / exposed
    1 / 127 (0.79%)
    5 / 95 (5.26%)
         occurrences all number
    1
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Dec 2015
    Before randomization of the first patient into group 4-5-6-7, Prolutex was changed to Crinone. It was not possible to have Prolutex for all the patients. It didn´t affect the study outcome.
    11 Sep 2017
    extension of the inclusion periode

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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