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    Clinical Trial Results:
    The exogenous progesterone free luteal phase after GnRHa trigger – a randomized controlled pilot study in high-responder IVF patients

    Summary
    EudraCT number
    		 2014-000448-13
    Trial protocol
    		 DK  
    Global end of trial date
    15 Oct 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Dec 2020
    First version publication date
    17 Dec 2020
    Other versions
    Summary report(s)
    		 Summary of outcomes

    Trial information

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    Trial identification
    Sponsor protocol code
    Agonist6
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    The Fertility Clinic Skive
    Sponsor organisation address
    Resenvej 25, Skive, Denmark, 7800
    Public contact
    Peter Humaidan, The Fertility Clinic, +45 78445773, peter.humaidan@midt.rm.dk
    Scientific contact
    Peter Humaidan, The Fertility Clinic, 78445760 78445773, 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 Oct 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Oct 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Oct 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of this pilot RCT is to explore the exogenous progesterone free luteal phase after GnRHa trigger in a population of IVF patients at risk of OHSS development, characterized by the development of 14-25 follicles ≥11 mm on the day of triggering of final follicular maturation.
    Protection of trial subjects
    The study was approved by the scientific Ethics Committee of the Central Denmark Region – Project number: M201337713. Written informed consent was obtained from all participants prior to inclusion.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Mar 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: 120
    Worldwide total number of subjects
    120
    EEA total number of subjects
    120
    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)
    120
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The first patient was enrolled in November 2014 and the last patient was enrolled in August 2019. All patients were from The fertility clinic, Skive Regional Hospital, Denmark.

    Pre-assignment
    Screening details
    		 A total of 275 IVF patients were assessed for eligibility and 250 patients were subsequently recruited for two studies, 2014-000448-13 and 2014-000447-32. 120 patients were randomized in 2014-000448-13 and 130 patients were randomized in 2014-000447-32. No patient was lost to follow-up.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 hCG trigger
    Arm description
    		 Ovulation trigger with 6500 IU hCG (Ovitrelle®), followed by 100 mg vaginal progesterone (Lutinus®) three times daily until the pregnancy test (14 days after OR), after which LPS was stopped.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Ovitrelle
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intradermal use
    Dosage and administration details
    Ovulation trigger with 6500 IU hCG (Ovitrelle®)

    Arm title
    		 GnRHa trigger
    Arm description
    		 Ovulation trigger with a bolus of 0.5 mg Buserelin (Suprefact®), followed by a bolus of 1000 IU hCG (Pregnyl®) after OR and an additional bolus of 500 IU hCG (Pregnyl®) on OR + 4
    Arm type
    		 Experimental

    Investigational medicinal product name
    Buserelin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for cutaneous solution, Concentrate for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    trigger with a bolus of 0.5 mg Buserelin (Suprefact®, Sanofi A/S, Copenhagen, Denmark)

    Number of subjects in period 1
    		hCG trigger GnRHa trigger
    Started
    60
    60
    Completed
    52
    46
    Not completed
    8
    14
         Protocol deviation
    8
    14

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall period
    Reporting group description
    		 -

    Reporting group values
    		 Overall period Total
    Number of subjects
    		 120 120
    Age categorical
    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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    We adjusted for female age as continous parameter
    Units: years
        arithmetic mean (standard deviation)
    		 28.9 ± 3.9 -
    Gender categorical
    All were women
    Units: Subjects
        Female
    		 120 120
        Male
    		 0 0
    Subject analysis sets

    Subject analysis set title
    modified intention to treat analysis
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The primary analysis was the modified intention to treat analysis (White et al., 2011) of all randomized patients having an embryo transfer under the assumption that missing outcome data (patients not having an embryo transfer) was missing conditionally at random.

    Subject analysis set title
    Intention to treat
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Strict intention to treat for all patients randomized

    Subject analysis set title
    Per protocol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Per prootocol defined by those meeting all the eligibility criteria as well as complying with the protocol

    Subject analysis sets values
    		 modified intention to treat analysis Intention to treat Per protocol
    Number of subjects
    101
    120
    98
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    We adjusted for female age as continous parameter
    Units: years
        arithmetic mean (standard deviation)
    28.9 ± 3.9
    28.9 ± 3.9
    28.9 ± 3.9
    Gender categorical
    All were women
    Units: Subjects
        Female
        Male

    End points

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    End points reporting groups
    Reporting group title
    hCG trigger
    Reporting group description
    		 Ovulation trigger with 6500 IU hCG (Ovitrelle®), followed by 100 mg vaginal progesterone (Lutinus®) three times daily until the pregnancy test (14 days after OR), after which LPS was stopped.

    Reporting group title
    GnRHa trigger
    Reporting group description
    		 Ovulation trigger with a bolus of 0.5 mg Buserelin (Suprefact®), followed by a bolus of 1000 IU hCG (Pregnyl®) after OR and an additional bolus of 500 IU hCG (Pregnyl®) on OR + 4

    Subject analysis set title
    modified intention to treat analysis
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The primary analysis was the modified intention to treat analysis (White et al., 2011) of all randomized patients having an embryo transfer under the assumption that missing outcome data (patients not having an embryo transfer) was missing conditionally at random.

    Subject analysis set title
    Intention to treat
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Strict intention to treat for all patients randomized

    Subject analysis set title
    Per protocol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Per prootocol defined by those meeting all the eligibility criteria as well as complying with the protocol

    Primary: Ongoing pregnancy week 12

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    End point title
    		 Ongoing pregnancy week 12
    End point description
    End point type
    Primary
    End point timeframe
    12 weeks
    End point values
    		 hCG trigger GnRHa trigger modified intention to treat analysis
    Number of subjects analysed
    52
    49
    101
    Units: Fetal heartbeat at scan
    52
    49
    101
    Statistical analysis title
    		 Binary regression
    Statistical analysis description
    A binary regression model was used to calculate the crude relative risks and relative differences (cRR, cRD) and adjusted relative risks and relative differences (aRR, aRD) for the primary outcome.
    Comparison groups
    hCG trigger v GnRHa trigger v modified intention to treat analysis
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    		 Regression, Linear
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 1.22

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Approximately 14 weeks.
    Adverse event reporting additional description
    We did not investigate adverse events other than OHSS.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23
    Frequency threshold for reporting non-serious adverse events: 5%
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: We did not observe any adverse events. OHSS rates will be reported in the publication.

    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.
    Sample size, lack of blinding. Full manuscript has been submitted for publication.
    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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