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    Clinical Trial Results:
    A Double-Blind, Double-Dummy, Randomized, Two-arm, Multicenter Study Comparing the Efficacy, Safety, and Tolerability of Oral Dydrogesterone 30 mg Daily Versus Intravaginal Micronized Progesterone Capsules 600 mg Daily for Luteal Support in In-Vitro Fertilization (LOTUS I)

    Summary
    EudraCT number
    2012-002215-26
    Trial protocol
    BE   AT   ES   FI  
    Global end of trial date
    23 Mar 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    18 Jul 2019
    First version publication date
    18 Jul 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    M13-563
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01850030
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Abbott Laboratories GmbH
    Sponsor organisation address
    Freundallee 9A, Hannover, Germany, 30173
    Public contact
    Senior Global Medical Director, Abbott Laboratories GmbH, claire.pexman-fieth@abbott.com
    Scientific contact
    Senior Global Medical Director, Abbott Laboratories GmbH, claire.pexman-fieth@abbott.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    23 Mar 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Mar 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the non-inferiority of oral dydrogesterone 10 milligrams (mg) three times daily (TID) versus micronized progesterone vaginal capsules 200 mg TID. The primary efficacy variable was the presence of fetal heartbeats at 12 weeks gestation determined by transvaginal ultrasound.
    Protection of trial subjects
    The study was conducted in compliance with Good Clinical Practice and the applicable national regulations to assure that the rights, safety, and well-being of the participating study subjects were protected, consistent with the ethical principles that have their origin in the Declaration of Helsinki. All study subjects were required to read and sign an informed consent form.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    26 Aug 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 15
    Country: Number of subjects enrolled
    Belgium: 390
    Country: Number of subjects enrolled
    Finland: 10
    Country: Number of subjects enrolled
    Germany: 136
    Country: Number of subjects enrolled
    Israel: 144
    Country: Number of subjects enrolled
    Russian Federation: 216
    Country: Number of subjects enrolled
    Spain: 120
    Worldwide total number of subjects
    1031
    EEA total number of subjects
    671
    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)
    1031
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Adult female subjects aged >18 and <42 years entered this randomized, double-blind, double-dummy multicenter study from August 2013. The study was conducted at 38 sites in Europe, Russia and Israel. The study completed in March 2016.

    Pre-assignment
    Screening details
    Subjects were premenopausal and had a documented history of infertility, with a clinically indicated protocol for induction of in vitro fertilization with a fresh embryo.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Oral Dydrogesterone
    Arm description
    Subjects were randomized to receive oral dydrogesterone 10 mg tablets TID (30 mg daily) and placebo intravaginal micronized progesterone 200 mg capsules TID (600 mg daily) from Visit 2 (Day 1). At Visit 3 (Day 3 to Day 6) subjects received a single or dual fresh embryo transfer. Pregnancy was confirmed at Visit 4 (Day 15 [+/- 3 days]) by a serum beta human chorionic gonadotropin (beta-hCG) or urine strip test. If positive, luteal support continued up to Visit 6 (Week 10).
    Arm type
    Experimental

    Investigational medicinal product name
    Placebo intravaginal micronized progesterone capsules
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Vaginal capsule
    Routes of administration
    Vaginal use
    Dosage and administration details
    Subjects received placebo intravaginal micronized progesterone 200 mg capsules TID from Day 1 to Week 10 (if pregnancy confirmed at Visit 4).

    Investigational medicinal product name
    Dydrogesterone
    Investigational medicinal product code
    Other name
    Duphaston
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received oral dydrogesterone 10 mg tablets TID from Day 1 to Week 10 (if pregnancy confirmed at Visit 4).

    Arm title
    Intravaginal Micronized Progesterone
    Arm description
    Subjects were randomized to receive intravaginal micronized progesterone 200 mg capsules TID (600 mg daily) and placebo oral dydrogesterone 10 mg tablets TID (30 mg daily) from Visit 2 (Day 1). At Visit 3 (Day 3 to Day 6) subjects received a single or dual fresh embryo transfer. Pregnancy was confirmed at Visit 4 (Day 15 [+/- 3 days]) by a serum beta-hCG or urine strip test. If positive, luteal support continued up to Visit 6 (Week 10).
    Arm type
    Active comparator

    Investigational medicinal product name
    Placebo dydrogesterone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received placebo dydrogesterone 10 mg tablets TID from Day 1 to Week 10 (if pregnancy confirmed at Visit 4).

    Investigational medicinal product name
    Intravaginal micronized progesterone capsules
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Vaginal capsule
    Routes of administration
    Vaginal use
    Dosage and administration details
    Subjects received intravaginal micronized progesterone 200 mg capsules TID from Day 1 to Week 10 (if pregnancy confirmed at Visit 4).

    Number of subjects in period 1
    Oral Dydrogesterone Intravaginal Micronized Progesterone
    Started
    520
    511
    Confirmed pregnancy at Day 15
    234
    217
    Ongoing pregnancy at Week 6
    197
    169
    Confirmed pregnancy at Week 10
    187
    158
    Giving live birth(s)
    172 [1]
    142
    Completed
    173
    142
    Not completed
    347
    369
         Protocol deviation
    24
    28
         Pregnancy not confirmed at Day 15
    248
    249
         Lack of efficacy
    3
    1
         Adverse event, non-fatal
    64
    82
         Consent withdrawn by subject
    3
    4
         Lost to follow-up
    5
    5
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: One subject was recorded as lost to follow-up and was recorded as having a live birth.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Oral Dydrogesterone
    Reporting group description
    Subjects were randomized to receive oral dydrogesterone 10 mg tablets TID (30 mg daily) and placebo intravaginal micronized progesterone 200 mg capsules TID (600 mg daily) from Visit 2 (Day 1). At Visit 3 (Day 3 to Day 6) subjects received a single or dual fresh embryo transfer. Pregnancy was confirmed at Visit 4 (Day 15 [+/- 3 days]) by a serum beta human chorionic gonadotropin (beta-hCG) or urine strip test. If positive, luteal support continued up to Visit 6 (Week 10).

    Reporting group title
    Intravaginal Micronized Progesterone
    Reporting group description
    Subjects were randomized to receive intravaginal micronized progesterone 200 mg capsules TID (600 mg daily) and placebo oral dydrogesterone 10 mg tablets TID (30 mg daily) from Visit 2 (Day 1). At Visit 3 (Day 3 to Day 6) subjects received a single or dual fresh embryo transfer. Pregnancy was confirmed at Visit 4 (Day 15 [+/- 3 days]) by a serum beta-hCG or urine strip test. If positive, luteal support continued up to Visit 6 (Week 10).

    Reporting group values
    Oral Dydrogesterone Intravaginal Micronized Progesterone Total
    Number of subjects
    520 511 1031
    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)
    520 511 1031
        From 65-84 years
    0 0 0
        85 years and over
    0 0 0
    Gender categorical
    Units: Subjects
        Female
    520 511 1031
        Male
    0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Oral Dydrogesterone
    Reporting group description
    Subjects were randomized to receive oral dydrogesterone 10 mg tablets TID (30 mg daily) and placebo intravaginal micronized progesterone 200 mg capsules TID (600 mg daily) from Visit 2 (Day 1). At Visit 3 (Day 3 to Day 6) subjects received a single or dual fresh embryo transfer. Pregnancy was confirmed at Visit 4 (Day 15 [+/- 3 days]) by a serum beta human chorionic gonadotropin (beta-hCG) or urine strip test. If positive, luteal support continued up to Visit 6 (Week 10).

    Reporting group title
    Intravaginal Micronized Progesterone
    Reporting group description
    Subjects were randomized to receive intravaginal micronized progesterone 200 mg capsules TID (600 mg daily) and placebo oral dydrogesterone 10 mg tablets TID (30 mg daily) from Visit 2 (Day 1). At Visit 3 (Day 3 to Day 6) subjects received a single or dual fresh embryo transfer. Pregnancy was confirmed at Visit 4 (Day 15 [+/- 3 days]) by a serum beta-hCG or urine strip test. If positive, luteal support continued up to Visit 6 (Week 10).

    Primary: Pregnancy Rate at Visit 6 (Week 10): Per Protocol (PP) Subject Sample

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    End point title
    Pregnancy Rate at Visit 6 (Week 10): Per Protocol (PP) Subject Sample
    End point description
    The pregnancy rate, defined as the percentage of subjects for whom a fetal heartbeat was detected by transvaginal ultrasound at Visit 6 (Week 10) (12 weeks gestation), in the PP Subject Sample is presented. The PP Subject Sample consisted of all subjects who were allocated to treatment who received at least one administration of study drug, had a successful single or dual embryo transfer at Visit 3 (Day 3 to 6) and did not have any major protocol deviations unrelated to treatment. Subjects who prematurely discontinued after having a pregnancy test were counted as failures if the test was negative or if the test was positive but the reason for discontinuation was related to study drug or pregnancy related issues.
    End point type
    Primary
    End point timeframe
    At Visit 6 (Week 10).
    End point values
    Oral Dydrogesterone Intravaginal Micronized Progesterone
    Number of subjects analysed
    492
    475
    Units: Percentage of subjects
        number (confidence interval 95%)
    37.6 (33.3 to 42.1)
    33.1 (28.8 to 37.5)
    Statistical analysis title
    Treatment difference: PP Subject Sample
    Comparison groups
    Oral Dydrogesterone v Intravaginal Micronized Progesterone
    Number of subjects included in analysis
    967
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [1]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Treatment difference (%)
    Point estimate
    4.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.2
         upper limit
    10.6
    Notes
    [1] - To show that oral dydrogesterone was non-inferior to intravaginal micronized progesterone, a two-sided 95% confidence interval (CI) with a non-inferiority margin of 10% for the difference in pregnancy rates was used.

    Primary: Pregnancy Rate at Visit 6 (Week 10): Full Analysis (FA) Subject Sample

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    End point title
    Pregnancy Rate at Visit 6 (Week 10): Full Analysis (FA) Subject Sample
    End point description
    The pregnancy rate, defined as the percentage of subjects for whom a fetal heartbeat was detected by transvaginal ultrasound at Visit 6 (Week 10) (12 weeks gestation), in the FA Subject Sample is presented. The FA Subject Sample consisted of all subjects allocated to treatment who received at least one administration of study drug and had a successful embryo transfer performed at Visit 3 (Day 3 to 6) or did not prematurely discontinue prior to embryo transfer at Visit 3 due to non-study drug related issues. Subjects who prematurely discontinued after having a pregnancy test were counted as failures if the test was negative or if the test was positive but the reason for discontinuation was related to study drug or pregnancy related issues.
    End point type
    Primary
    End point timeframe
    At Visit 6 (Week 10).
    End point values
    Oral Dydrogesterone Intravaginal Micronized Progesterone
    Number of subjects analysed
    497
    477
    Units: Percentage of subjects
        number (confidence interval 95%)
    37.6 (33.4 to 42.1)
    33.1 (28.9 to 37.6)
    Statistical analysis title
    Treatment difference: FA Subject Sample
    Comparison groups
    Oral Dydrogesterone v Intravaginal Micronized Progesterone
    Number of subjects included in analysis
    974
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [2]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Treatment difference (%)
    Point estimate
    4.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.2
         upper limit
    10.6
    Notes
    [2] - To show that oral dydrogesterone was non-inferior to intravaginal micronized progesterone, a two-sided 95% CI with a non-inferiority margin of 10% for the difference in pregnancy rates was used.

    Secondary: Pregnancy Rate at Visit 4 (Day 15)

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    End point title
    Pregnancy Rate at Visit 4 (Day 15)
    End point description
    The percentage of subjects who were pregnant at Visit 4 (Day 15) as determined by a positive beta-hCG serum test are presented for the FA Subject Sample. The FA Subject Sample consisted of all subjects allocated to treatment who received at least one administration of study drug and had a successful embryo transfer performed at Visit 3 (Day 3 to 6) or did not prematurely discontinue prior to embryo transfer at Visit 3 due to non-study drug related issues.
    End point type
    Secondary
    End point timeframe
    At Visit 4 (Day 15).
    End point values
    Oral Dydrogesterone Intravaginal Micronized Progesterone
    Number of subjects analysed
    497
    477
    Units: Percentage of subjects
        number (confidence interval 95%)
    47.1 (42.6 to 51.6)
    45.5 (41.0 to 50.1)
    No statistical analyses for this end point

    Secondary: Pregnancy Rate at Visit 5 (Week 6)

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    End point title
    Pregnancy Rate at Visit 5 (Week 6)
    End point description
    Ongoing pregnancy at Visit 5 (Week 6) was confirmed based on clinical evidence. The percentage of subjects in the FA Subject Sample who had pregnancy confirmed at Visit 5 are presented. The FA Subject Sample consisted of all subjects allocated to treatment who received at least one administration of study drug and had a successful embryo transfer performed at Visit 3 (Day 3 to 6) or did not prematurely discontinue prior to embryo transfer at Visit 3 due to non-study drug related issues.
    End point type
    Secondary
    End point timeframe
    At Visit 5 (Week 6).
    End point values
    Oral Dydrogesterone Intravaginal Micronized Progesterone
    Number of subjects analysed
    497
    477
    Units: Percentage of subjects
        number (confidence interval 95%)
    39.6 (35.3 to 44.1)
    35.4 (31.1 to 39.9)
    No statistical analyses for this end point

    Secondary: Abortion Rate

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    End point title
    Abortion Rate
    End point description
    The percentage of subjects in the FA Subject Sample who had an abortion (abortion rate) is presented. Subjects with abortions reported from Visit 5 (Week 6) onwards were included, since abortions reported before Visit 5 (Week 6) were considered biochemical pregnancies and were therefore not to be considered in the efficacy analysis of abortion rate. The Investigator determined whether the subject had an abortion. The FA Subject Sample consisted of all subjects allocated to treatment who received at least one administration of study drug and had a successful embryo transfer performed at Visit 3 (Day 3 to 6) or did not prematurely discontinue prior to embryo transfer at Visit 3 due to non-study drug related issues.
    End point type
    Secondary
    End point timeframe
    From Visit 5 (Week 6) up to 20-24 weeks gestation (18-22 weeks pregnancy).
    End point values
    Oral Dydrogesterone Intravaginal Micronized Progesterone
    Number of subjects analysed
    497
    477
    Units: Percentage of subjects
        number (confidence interval 95%)
    1.6 (0.7 to 3.2)
    2.1 (1.0 to 3.8)
    No statistical analyses for this end point

    Secondary: Preterm Birth Rate

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    End point title
    Preterm Birth Rate
    End point description
    The percentage of subjects in the FA Subject Sample who had a preterm birth (preterm birth rate) is presented. The Investigator determined whether the subject had a preterm birth. The FA Subject Sample consisted of all subjects allocated to treatment who received at least one administration of study drug and had a successful embryo transfer performed at Visit 3 (Day 3 to 6) or did not prematurely discontinue prior to embryo transfer at Visit 3 due to non-study drug related issues.
    End point type
    Secondary
    End point timeframe
    Up to 37 weeks of gestation (35 weeks of pregnancy).
    End point values
    Oral Dydrogesterone Intravaginal Micronized Progesterone
    Number of subjects analysed
    497
    477
    Units: Percentage of subjects
        number (confidence interval 95%)
    7.9 (5.6 to 10.6)
    5.2 (3.4 to 7.6)
    No statistical analyses for this end point

    Secondary: Live Birth Rate

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    End point title
    Live Birth Rate
    End point description
    The percentage of subjects in the FA Subject Sample who had at least one live birth (live birth rate) are presented. The FA Subject Sample consisted of all subjects allocated to treatment who received at least one administration of study drug, had a successful embryo transfer performed at Visit 3 (Day 3 to 6) or did not prematurely discontinue prior to embryo transfer at Visit 3 due to non-study drug related issues.
    End point type
    Secondary
    End point timeframe
    After delivery (up to approximately 9 months after embryo transfer).
    End point values
    Oral Dydrogesterone Intravaginal Micronized Progesterone
    Number of subjects analysed
    497
    477
    Units: Percentage of subjects
        number (confidence interval 95%)
    34.6 (30.4 to 39.0)
    29.8 (25.7 to 34.1)
    No statistical analyses for this end point

    Secondary: Healthy Newborn Rate

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    End point title
    Healthy Newborn Rate
    End point description
    The percentage of subjects in the FA Subject Sample who gave birth to at least one healthy newborn (healthy newborn rate) is presented. The FA Subject Sample consisted of all subjects allocated to treatment who received at least one administration of study drug and had a successful embryo transfer performed at Visit 3 (Day 3 to 6) or did not prematurely discontinue prior to embryo transfer at Visit 3 due to non-study drug related issues.
    End point type
    Secondary
    End point timeframe
    After delivery (up to approximately 9 months after embryo transfer).
    End point values
    Oral Dydrogesterone Intravaginal Micronized Progesterone
    Number of subjects analysed
    497
    477
    Units: Percentage of subjects
        number (confidence interval 95%)
    32.0 (27.9 to 36.3)
    27.7 (23.7 to 31.9)
    No statistical analyses for this end point

    Other pre-specified: Gender of the Newborn

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    End point title
    Gender of the Newborn
    End point description
    The number of male and female live newborns is presented for the FA Subject Sample.
    End point type
    Other pre-specified
    End point timeframe
    After delivery (up to approximately 9 months after embryo transfer).
    End point values
    Oral Dydrogesterone Intravaginal Micronized Progesterone
    Number of subjects analysed
    497
    477
    Units: Newborns
        Male
    120
    88
        Female
    93
    70
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AEs) were collected from the start of treatment (Day 1) to the follow-up phone call at Visit 10 (30 days after delivery).
    Adverse event reporting additional description
    The Safety Subject Sample consists of all subjects who were allocated to treatment and received at least one administration of study drug.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Oral Dydrogesterone
    Reporting group description
    Subjects were randomized to receive oral dydrogesterone 20 mg tablets TID (30 mg daily) and placebo intravaginal micronized progesterone 200 mg capsules TID (600 mg daily) from Visit 2 (Day 1). At Visit 3 (Day 3 to Day 6) subjects received a single or dual fresh embryo transfer. Pregnancy was confirmed at Visit 4 (Day 15 [+/- 3 days]) by a serum beta-hCG or urine strip test. If positive, luteal support continued up to Visit 6 (Week 10).

    Reporting group title
    Intravaginal Micronized Progesterone
    Reporting group description
    Subjects were randomized to receive intravaginal micronized progesterone 200 mg capsules TID (600 mg daily) and placebo oral dydrogesterone 20 mg tablets TID (30 mg daily) from Visit 2 (Day 1). At Visit 3 (Day 3 to Day 6) subjects received a single or dual fresh embryo transfer. Pregnancy was confirmed at Visit 4 (Day 15 [+/- 3 days]) by a serum beta-hCG or urine strip test. If positive, luteal support continued up to Visit 6 (Week 10).

    Serious adverse events
    Oral Dydrogesterone Intravaginal Micronized Progesterone
    Total subjects affected by serious adverse events
         subjects affected / exposed
    56 / 518 (10.81%)
    68 / 511 (13.31%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 518 (0.19%)
    0 / 511 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jugular vein thrombosis
         subjects affected / exposed
    0 / 518 (0.00%)
    1 / 511 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 518 (0.19%)
    1 / 511 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    0 / 518 (0.00%)
    1 / 511 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Abortion induced
         subjects affected / exposed
    2 / 518 (0.39%)
    3 / 511 (0.59%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Selective abortion
         subjects affected / exposed
    1 / 518 (0.19%)
    1 / 511 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Labour induction
         subjects affected / exposed
    1 / 518 (0.19%)
    0 / 511 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    9 / 518 (1.74%)
    15 / 511 (2.94%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abortion threatened
         subjects affected / exposed
    2 / 518 (0.39%)
    1 / 511 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abortion missed
         subjects affected / exposed
    6 / 518 (1.16%)
    9 / 511 (1.76%)
         occurrences causally related to treatment / all
    0 / 6
    3 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abortion
         subjects affected / exposed
    0 / 518 (0.00%)
    1 / 511 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abortion complete
         subjects affected / exposed
    0 / 518 (0.00%)
    1 / 511 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abortion of ectopic pregnancy
         subjects affected / exposed
    1 / 518 (0.19%)
    0 / 511 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ectopic pregnancy
         subjects affected / exposed
    4 / 518 (0.77%)
    4 / 511 (0.78%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical incompetence
         subjects affected / exposed
    3 / 518 (0.58%)
    3 / 511 (0.59%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperemesis gravidarum
         subjects affected / exposed
    1 / 518 (0.19%)
    0 / 511 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Premature labour
         subjects affected / exposed
    4 / 518 (0.77%)
    2 / 511 (0.39%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Premature rupture of membranes
         subjects affected / exposed
    1 / 518 (0.19%)
    2 / 511 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Premature delivery
         subjects affected / exposed
    1 / 518 (0.19%)
    1 / 511 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Threatened labour
         subjects affected / exposed
    1 / 518 (0.19%)
    0 / 511 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foetal death
         subjects affected / exposed
    0 / 518 (0.00%)
    6 / 511 (1.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foetal distress syndrome
         subjects affected / exposed
    1 / 518 (0.19%)
    2 / 511 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foetal disorder
         subjects affected / exposed
    1 / 518 (0.19%)
    0 / 511 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foetal hypokinesia
         subjects affected / exposed
    0 / 518 (0.00%)
    1 / 511 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pre-eclampsia
         subjects affected / exposed
    2 / 518 (0.39%)
    1 / 511 (0.20%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HELLP syndrome
         subjects affected / exposed
    0 / 518 (0.00%)
    2 / 511 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oligohydramnios
         subjects affected / exposed
    2 / 518 (0.39%)
    1 / 511 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyhydramnios
         subjects affected / exposed
    1 / 518 (0.19%)
    0 / 511 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Premature baby
         subjects affected / exposed
    2 / 518 (0.39%)
    1 / 511 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Premature separation of placenta
         subjects affected / exposed
    1 / 518 (0.19%)
    1 / 511 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage in pregnancy
         subjects affected / exposed
    0 / 518 (0.00%)
    1 / 511 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retroplacental haematoma
         subjects affected / exposed
    0 / 518 (0.00%)
    1 / 511 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy of unknown location
         subjects affected / exposed
    1 / 518 (0.19%)
    1 / 511 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine contractions during pregnancy
         subjects affected / exposed
    1 / 518 (0.19%)
    1 / 511 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical cord around neck
         subjects affected / exposed
    1 / 518 (0.19%)
    0 / 511 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical cord vascular disorder
         subjects affected / exposed
    1 / 518 (0.19%)
    0 / 511 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blighted ovum
         subjects affected / exposed
    1 / 518 (0.19%)
    0 / 511 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foetal growth restriction
         subjects affected / exposed
    0 / 518 (0.00%)
    1 / 511 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retained placenta or membranes
         subjects affected / exposed
    0 / 518 (0.00%)
    1 / 511 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postpartum haemorrhage
         subjects affected / exposed
    0 / 518 (0.00%)
    1 / 511 (0.20%)
         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
    8 / 518 (1.54%)
    5 / 511 (0.98%)
         occurrences causally related to treatment / all
    1 / 8
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adnexal torsion
         subjects affected / exposed
    0 / 518 (0.00%)
    1 / 511 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian haemorrhage
         subjects affected / exposed
    0 / 518 (0.00%)
    1 / 511 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shortened cervix
         subjects affected / exposed
    1 / 518 (0.19%)
    1 / 511 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    1 / 518 (0.19%)
    1 / 511 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metrorrhagia
         subjects affected / exposed
    0 / 518 (0.00%)
    1 / 511 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Genital haemorrhage
         subjects affected / exposed
    0 / 518 (0.00%)
    1 / 511 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 518 (0.00%)
    1 / 511 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 518 (0.19%)
    0 / 511 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    1 / 518 (0.19%)
    0 / 511 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder injury
         subjects affected / exposed
    0 / 518 (0.00%)
    1 / 511 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Foetal heart rate abnormal
         subjects affected / exposed
    1 / 518 (0.19%)
    0 / 511 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    0 / 518 (0.00%)
    1 / 511 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Foetal heart rate deceleration
         subjects affected / exposed
    1 / 518 (0.19%)
    0 / 511 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foetal heart rate disorder
         subjects affected / exposed
    0 / 518 (0.00%)
    1 / 511 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Trisomy 21
         subjects affected / exposed
    1 / 518 (0.19%)
    2 / 511 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Trisomy 13
         subjects affected / exposed
    0 / 518 (0.00%)
    1 / 511 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary artery atresia
         subjects affected / exposed
    0 / 518 (0.00%)
    1 / 511 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Univentricular heart
         subjects affected / exposed
    0 / 518 (0.00%)
    1 / 511 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital tricuspid valve atresia
         subjects affected / exposed
    0 / 518 (0.00%)
    1 / 511 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spina bifida
         subjects affected / exposed
    0 / 518 (0.00%)
    1 / 511 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital hydrocephalus
         subjects affected / exposed
    0 / 518 (0.00%)
    1 / 511 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Turner's Syndrome
         subjects affected / exposed
    1 / 518 (0.19%)
    0 / 511 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    0 / 518 (0.00%)
    1 / 511 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 518 (0.19%)
    0 / 511 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 518 (0.19%)
    0 / 511 (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
    Orthostatic intolerance
         subjects affected / exposed
    0 / 518 (0.00%)
    1 / 511 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 518 (0.19%)
    0 / 511 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 518 (0.19%)
    0 / 511 (0.00%)
         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
    1 / 518 (0.19%)
    3 / 511 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    0 / 518 (0.00%)
    1 / 511 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 518 (0.19%)
    0 / 511 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 518 (0.19%)
    0 / 511 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Diverticulitis
         subjects affected / exposed
    0 / 518 (0.00%)
    1 / 511 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    0 / 518 (0.00%)
    1 / 511 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 518 (0.00%)
    1 / 511 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 518 (0.00%)
    1 / 511 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Oral Dydrogesterone Intravaginal Micronized Progesterone
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    156 / 518 (30.12%)
    147 / 511 (28.77%)
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    39 / 518 (7.53%)
    40 / 511 (7.83%)
         occurrences all number
    40
    41
    Nervous system disorders
    Headache
         subjects affected / exposed
    27 / 518 (5.21%)
    32 / 511 (6.26%)
         occurrences all number
    31
    36
    Pregnancy, puerperium and perinatal conditions
    Pregnancy of unknown location
         subjects affected / exposed
    19 / 518 (3.67%)
    29 / 511 (5.68%)
         occurrences all number
    19
    29
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    24 / 518 (4.63%)
    31 / 511 (6.07%)
         occurrences all number
    25
    33
    Nausea
         subjects affected / exposed
    44 / 518 (8.49%)
    26 / 511 (5.09%)
         occurrences all number
    46
    27
    Reproductive system and breast disorders
    Vaginal haemorrhage
         subjects affected / exposed
    60 / 518 (11.58%)
    46 / 511 (9.00%)
         occurrences all number
    74
    54

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Apr 2013
    Implemented a change in the time for embryo transfer at Visit 3 from 'Day2/3' to 'Day 2 to Day 5'.
    24 Nov 2015
    The definition and AE/serious AE reporting requirements of a biochemical pregnancy and clinical pregnancy were clarified. Clarified that pregnancy was to be confirmed according to clinical evidence. The definition of miscarriage and explanatory text on the expectedness of early miscarriages before Week 10 of pregnancy (12 weeks gestation) were also added.

    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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