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    Clinical Trial Results:
    A Randomised Study Comparing Two Different Regimens of Ovarian Stimulation Using Pergoveris and Cetrorelix for Controlled Ovarian Superovulation in Assisted Conception Treatment.

    Summary
    EudraCT number
    2009-012847-40
    Trial protocol
    GB  
    Global end of trial date
    05 Nov 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    29 Jul 2020
    First version publication date
    29 Jul 2020
    Other versions
    Summary report(s)
    Summary

    Trial information

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    Trial identification
    Sponsor protocol code
    Pergoveris_Cetrorelix_1
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    University of Edinburgh/NHS Lothian
    Sponsor organisation address
    47 Little France Crescent, Edinburgh, United Kingdom, EH16 4TJ
    Public contact
    Dr Joo Thong, NHS Lothian, 0131 2422446, joo.thong@nhslothian.scot.nhs.uk
    Scientific contact
    Dr Joo Thong, NHS Lothian, 0131 2422446, joo.thong@nhslothian.scot.nhs.uk
    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
    16 Nov 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Nov 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Nov 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The aim of this study is to investigate whether controlled ovarian stimulation using Pergoveris with early administration of Cetrorelix (from day 2 of period, i.e. day 1 of gonadotrophin stimulation) versus administration of cetrorelix starting on day 6 of stimulation will result in more top quality embryos.
    Protection of trial subjects
    nclusion criteria: Healthy females aged 21-38 years old, regular menses 24-35 days, less than 3 failed IVF/ICSI cycles, both ovaries present (no previous surgery), able to understand protocol and no ovarian cysts of more than 20mm Exclusion criteria: PCOS, severe endmetriosis, AMH,6pmol, known history of poor ovarian response during assisted conception treatment, allergic to investigational compounds, lactation, use of depot hormonal contraceptive within 6 months or use of oral contraceptive within 8 weeks of starting treatment, hypertension (systolic.150mmHg; diastolic.90mmHG, history of alcohol/drug abuse, abnormal biochemistry/haematology at screening, administration of investigational drugs within 20 days of screening and ovarian cysts of more than 20mm.
    Background therapy
    This was a randomised pilot trial comparing two regimens of controlled ovarian stimulation. Pergoveris 150IU was used for ovarian stimulation which was started on day 2 of menstrual cycle. Cetrorelix 0.25mg was started on day 2 of menses versus day 7 of menstrual cycle (day 6 of ovarian stimulation). The dose of Pergoveris was increased if the patient had poor response (less than 4 follicles or serum oestradiol less than 500 pmol/l) on day 6 of Pergoveris administration (cycle day 7) to 225IU. If there is clinical evidence of ovarian hyperstimulation (excessive follicular response), the dose of Pergoveris was reduced to 112.5IU to reduce the risk of ovarian hyperstimulation syndrome.
    Evidence for comparator
    Patients were randomised to each of the study arms after recruitment.
    Actual start date of recruitment
    19 Oct 2010
    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
    United Kingdom: 80
    Worldwide total number of subjects
    80
    EEA total number of subjects
    80
    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)
    80
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Patients who were undergoing IVF treatment in the Assisted Conception Unit and satisfy the inclusion criteria were approached and recruited to the study. recruitment was carried out between 19 October 2010 to 4 September 2014. 80 women were recruited.

    Pre-assignment
    Screening details
    I: healthy women;21-38 yrs;regular menses 24-35 ds;<3 failed IVF/ICSI cycles;both ovaries present;understand protocol. E: PCOS;severe endometriosis;AMH < 6pmol/l;POR during IUI/IVF;allergic to IMPs; prior to COS;hypertension;alcohol/drug abuse;abnormal biochem/haematology results;IMP used in prior 20 ds, use of hormonal contraception within 2 mths

    Pre-assignment period milestones
    Number of subjects started
    80
    Number of subjects completed
    80

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Cetrorelix day 2 of menses
    Arm description
    Patients were randomised to receive Cetrorelix 0.25mg on day 2 (early administration/EA) of menses. Pergoveris rFSH/75IUrLH was used ofr ovarian stimulation and started on day 2 of menses
    Arm type
    Experimental

    Investigational medicinal product name
    Pergoveris
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered subcutaneously. Pergoveris 150IU FSH and 75IU LH starting day 2 of menses

    Investigational medicinal product name
    Cetrotide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered subcutaneously. Cetrotide 0.25mg daily starting on day 2 of menses

    Investigational medicinal product name
    Ovitrelle
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Ovitrelle 0.25mg 35h before oocyte retrieval

    Arm title
    Cetrorelix day 7
    Arm description
    Patients were randomised to receive Cetrorelix 0.25mg on day 7 (late administration/LA) on day 7 of menses. Pergoveris rFSH/75IUrLH was used for ovarian stimulation and started on day 2 of menses
    Arm type
    Active comparator

    Investigational medicinal product name
    Pergoveris
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered subcutaneously. Pergoveris 150IU FSH and 75IU LH starting day 2 of menses

    Investigational medicinal product name
    Cetrotide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Cetrotide 0.25mg daily starting day 6 of Pergoveris stimulation (cycle day 7)

    Investigational medicinal product name
    Ovitrelle
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Ovitrelle 0.25mg 35h before oocyte retrieval

    Number of subjects in period 1
    Cetrorelix day 2 of menses Cetrorelix day 7
    Started
    40
    40
    Completed
    40
    40

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cetrorelix day 2 of menses
    Reporting group description
    Patients were randomised to receive Cetrorelix 0.25mg on day 2 (early administration/EA) of menses. Pergoveris rFSH/75IUrLH was used ofr ovarian stimulation and started on day 2 of menses

    Reporting group title
    Cetrorelix day 7
    Reporting group description
    Patients were randomised to receive Cetrorelix 0.25mg on day 7 (late administration/LA) on day 7 of menses. Pergoveris rFSH/75IUrLH was used for ovarian stimulation and started on day 2 of menses

    Reporting group values
    Cetrorelix day 2 of menses Cetrorelix day 7 Total
    Number of subjects
    40 40 80
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    40 40 80
        From 65-84 years
    0 0 0
        85 years and over
    0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    32 ± 3.6 33 ± 3 -
    Gender categorical
    Units: Subjects
        Female
    40 40 80
        Male
    0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Cetrorelix day 2 of menses
    Reporting group description
    Patients were randomised to receive Cetrorelix 0.25mg on day 2 (early administration/EA) of menses. Pergoveris rFSH/75IUrLH was used ofr ovarian stimulation and started on day 2 of menses

    Reporting group title
    Cetrorelix day 7
    Reporting group description
    Patients were randomised to receive Cetrorelix 0.25mg on day 7 (late administration/LA) on day 7 of menses. Pergoveris rFSH/75IUrLH was used for ovarian stimulation and started on day 2 of menses

    Subject analysis set title
    Intention to treat
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All patients allocated to the treatment arm to which they were randomised.

    Primary: Number of top quality embryos

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    End point title
    Number of top quality embryos
    End point description
    End point type
    Primary
    End point timeframe
    Completion of treatment.
    End point values
    Cetrorelix day 2 of menses Cetrorelix day 7
    Number of subjects analysed
    40
    40
    Units: Number of embryos
    40
    40
    Statistical analysis title
    Number of top quality embryos
    Comparison groups
    Cetrorelix day 2 of menses v Cetrorelix day 7
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.05
    Method
    t-test, 2-sided
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.7
         upper limit
    0.3
    Variability estimate
    Standard deviation

    Primary: Number and size of follicles on day of hCG

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    End point title
    Number and size of follicles on day of hCG
    End point description
    End point type
    Primary
    End point timeframe
    35 hours before oocyte retrieval.
    End point values
    Cetrorelix day 2 of menses Cetrorelix day 7
    Number of subjects analysed
    39
    40
    Units: mm
    median (inter-quartile range (Q1-Q3))
        6-10mm
    3 (2 to 5)
    2 (1 to 4)
        10-14mm
    6 (4 to 8)
    5 (3.5 to 7.5)
        15-16mm
    3 (2 to 5)
    3.5 (1.5 to 5)
        17mm or larger
    5 (4 to 8)
    5 (3.5 to 6)
    Statistical analysis title
    Number and size of follicles on day of hCG
    Comparison groups
    Cetrorelix day 2 of menses v Cetrorelix day 7
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.05
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Primary: Number and quality of oocytes and transferable embyos

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    End point title
    Number and quality of oocytes and transferable embyos
    End point description
    End point type
    Primary
    End point timeframe
    Day of operation and embryo transfers.
    End point values
    Cetrorelix day 2 of menses Cetrorelix day 7
    Number of subjects analysed
    40
    40
    Units: Number and embyo quality
    40
    40
    Statistical analysis title
    Number and quality of oocytes and transferable emb
    Comparison groups
    Cetrorelix day 2 of menses v Cetrorelix day 7
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.05
    Method
    t-test, 2-sided
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.8
         upper limit
    1.7
    Variability estimate
    Standard deviation

    Primary: Endocrine profiles on day of hCG (LH)

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    End point title
    Endocrine profiles on day of hCG (LH)
    End point description
    End point type
    Primary
    End point timeframe
    On day of ovulation trigger.
    End point values
    Cetrorelix day 2 of menses Cetrorelix day 7
    Number of subjects analysed
    39
    40
    Units: IU/L
        median (inter-quartile range (Q1-Q3))
    1.6 (1.4 to 2.2)
    1.5 (1.3 to 2.6)
    Statistical analysis title
    Endocrine profiles on day of hCG (LH)
    Comparison groups
    Cetrorelix day 2 of menses v Cetrorelix day 7
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.05
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Primary: Endocrine profiles on day of hCG (E2)

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    End point title
    Endocrine profiles on day of hCG (E2)
    End point description
    End point type
    Primary
    End point timeframe
    On day of ovulation trigger.
    End point values
    Cetrorelix day 2 of menses Cetrorelix day 7
    Number of subjects analysed
    39
    40
    Units: pmol/L
        median (inter-quartile range (Q1-Q3))
    8092 (6257 to 10290)
    8586 (6766 to 10546)
    Statistical analysis title
    Endocrine profiles on day of hCG (E2)
    Comparison groups
    Cetrorelix day 7 v Cetrorelix day 2 of menses
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.05
    Method
    t-test, 2-sided
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -929
         upper limit
    1796
    Variability estimate
    Standard deviation

    Primary: Endocrine profiles on day of hCG (Progesterone)

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    End point title
    Endocrine profiles on day of hCG (Progesterone)
    End point description
    End point type
    Primary
    End point timeframe
    On day of ovulation trigger.
    End point values
    Cetrorelix day 2 of menses Cetrorelix day 7
    Number of subjects analysed
    38
    40
    Units: nmol/L
        median (inter-quartile range (Q1-Q3))
    3.3 (3.1 to 4.6)
    3.8 (3.3 to 4.5)
    Statistical analysis title
    Endocrine profiles on day of hCG (Progesterone)
    Comparison groups
    Cetrorelix day 7 v Cetrorelix day 2 of menses
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.05
    Method
    t-test, 2-sided
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.1
         upper limit
    0.6
    Variability estimate
    Standard deviation

    Secondary: Prevention of premature LH surge

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    End point title
    Prevention of premature LH surge
    End point description
    End point type
    Secondary
    End point timeframe
    Between randomisation and day 2 of treatment until ovulation trigger.
    End point values
    Cetrorelix day 2 of menses Cetrorelix day 7
    Number of subjects analysed
    40
    40
    Units: Number of patients
    40
    40
    No statistical analyses for this end point

    Secondary: Dose of r-FSH (Pergoveris)

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    End point title
    Dose of r-FSH (Pergoveris)
    End point description
    End point type
    Secondary
    End point timeframe
    From start of treatment to ovulation trigger.
    End point values
    Cetrorelix day 2 of menses Cetrorelix day 7
    Number of subjects analysed
    40
    40
    Units: IU
        number (not applicable)
    40
    40
    No statistical analyses for this end point

    Secondary: Number of days of administration of Pergoveris

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    End point title
    Number of days of administration of Pergoveris
    End point description
    End point type
    Secondary
    End point timeframe
    Starting day 2 of menses (cycle day 2), provided no ovarian cysts greater than or equal to 2 cm, up to day when three follicles are greater than or equal to 17 mm diameter.
    End point values
    Cetrorelix day 2 of menses Cetrorelix day 7
    Number of subjects analysed
    40
    40
    Units: Days
    40
    40
    No statistical analyses for this end point

    Secondary: Ovarian cyst formation

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    End point title
    Ovarian cyst formation
    End point description
    End point type
    Secondary
    End point timeframe
    From time of first administration to ovulation trigger.
    End point values
    Cetrorelix day 2 of menses Cetrorelix day 7
    Number of subjects analysed
    40
    40
    Units: Number of subjects
    40
    40
    No statistical analyses for this end point

    Secondary: Outcome of treatment cycle and pregnancy rate

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    End point title
    Outcome of treatment cycle and pregnancy rate
    End point description
    End point type
    Secondary
    End point timeframe
    Completion of treatment cycle. Clinical pregnancy rate after confirmation of heart beat at 7 weeks gestation.
    End point values
    Cetrorelix day 2 of menses Cetrorelix day 7
    Number of subjects analysed
    40
    40
    Units: Number of pregnancies
    40
    40
    No statistical analyses for this end point

    Secondary: Rate of poor ovarian response

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    End point title
    Rate of poor ovarian response
    End point description
    End point type
    Secondary
    End point timeframe
    Defined as four or less eggs retrieved at operation.
    End point values
    Cetrorelix day 2 of menses Cetrorelix day 7
    Number of subjects analysed
    40
    40
    Units: Number of subjects
    40
    40
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The adverse events refers to the study period.
    Adverse event reporting additional description
    One patient had OHSS and admitted to hospital. The patient conceived from treatment and had late OHSS. The pregnancy hormone, hCG produced endogenously, stimulates the ovaries further and late OHSS is a recognised complication of IVF treatment.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19
    Reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    -

    Serious adverse events
    Overall Trial
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 80 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Overall Trial
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 80 (1.25%)
    Pregnancy, puerperium and perinatal conditions
    Ovarian hyperstimulation syndrome
         subjects affected / exposed
    1 / 80 (1.25%)
         occurrences all number
    1

    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
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