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    Clinical Trial Results:
    A Randomized, Open-label, Two-arm, Multicenter Study Comparing the Efficacy, Safety and Tolerability of Oral Dydrogesterone 30 mg Daily Versus Crinone 8% Intravaginal Progesterone Gel 90 mg Daily for Luteal Support in In-Vitro Fertilization (LOTUS II)

    Summary
    EudraCT number
    2012-002993-29
    Trial protocol
    BE  
    Global end of trial date
    26 May 2017

    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
    M13-625
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02491437
    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
    26 May 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 May 2017
    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 as vaginal gel 90 mg once daily for luteal support in in vitro fertilization (IVF). The primary efficacy endpoint was the presence of fetal heart beats at 12 weeks of gestation (10 weeks of pregnancy) 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
    17 Aug 2015
    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
    Australia: 5
    Country: Number of subjects enrolled
    Belgium: 177
    Country: Number of subjects enrolled
    China: 239
    Country: Number of subjects enrolled
    Germany: 166
    Country: Number of subjects enrolled
    Hong Kong: 17
    Country: Number of subjects enrolled
    India: 211
    Country: Number of subjects enrolled
    Russian Federation: 81
    Country: Number of subjects enrolled
    Singapore: 19
    Country: Number of subjects enrolled
    Thailand: 27
    Country: Number of subjects enrolled
    Ukraine: 92
    Worldwide total number of subjects
    1034
    EEA total number of subjects
    343
    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)
    1034
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Premenopausal females, aged > 18 years < 42 years were enrolled in this randomized, open-label, multicenter study from August 2015. The study was conducted at 37 sites in Australia, Belgium, China, Germany, Hong-Kong, India, Russia, Singapore, Thailand and Ukraine. The study completed in May 2017.

    Pre-assignment
    Screening details
    Subjects had to have a documented history of infertility, with a clinically indicated protocol for induction of IVF with a fresh embryo. 4 subjects who were randomized did not receive treatment with study drug.

    Period 1
    Period 1 title
    Randomized through Treatment Start
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Duphaston
    Arm description
    Subjects were randomized to receive Duphaston, oral dydrogesterone 10 mg tablets TID (30 mg daily) from Visit 2 (Day 1). Embryo transfer was performed at Visit 3 (Day 3 to 6). Pregnancy was confirmed 2 weeks after embryo transfer at Visit 4 (Day 17 to 20) by a routine pregnancy test. If positive, luteal support was continued up to Visit 6 (Week 10).
    Arm type
    Experimental

    Investigational medicinal product name
    Duphaston
    Investigational medicinal product code
    Other name
    Oral Dydrogesterone
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Duphaston was supplied as micronized, film-coated 10.0 mg tablets in blister strips of aluminium foil and polyvinylchloride film. Subjects received oral dydrogesterone 10 mg tablets TID from Day 1 to Week 10 (if pregnancy was confirmed at Visit 4).

    Arm title
    Crinone
    Arm description
    Subjects were randomized to receive Crinone 8%, intravaginal micronized progesterone gel 90 mg, once daily from Visit 2 (Day 1). Embryo transfer was performed at Visit 3 (Day 3 to 6). Pregnancy was confirmed 2 weeks after embryo transfer at Visit 4 (Day 17 to 20) by a routine pregnancy test. If positive, luteal support was continued up to Visit 6 (Week 10).
    Arm type
    Active comparator

    Investigational medicinal product name
    Crinone
    Investigational medicinal product code
    Other name
    Micronized progesterone
    Pharmaceutical forms
    Vaginal gel
    Routes of administration
    Vaginal use
    Dosage and administration details
    Crinone 8% was supplied as a vaginal gel contained in single use, one-piece polyethylene vaginal applicators. Each applicator delivered 1.125 grams of Crinone gel containing 90 mg (8% gel) of micronized progesterone and subjects administered one applicator daily from Day 1 to Week 10 (if pregnancy was confirmed at Visit 4).

    Number of subjects in period 1
    Duphaston Crinone
    Started
    520
    514
    Completed
    518
    512
    Not completed
    2
    2
         No randomized study drug taken
    2
    2
    Period 2
    Period 2 title
    Treatment through Trial Completion
    Is this the baseline period?
    Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Duphaston
    Arm description
    Subjects were randomized to receive Duphaston, oral dydrogesterone 10 mg tablets TID (30 mg daily) from Visit 2 (Day 1). Embryo transfer was performed at Visit 3 (Day 3 to 6). Pregnancy was confirmed 2 weeks after embryo transfer at Visit 4 (Day 17 to 20) by a routine pregnancy test. If positive, luteal support was continued up to Visit 6 (Week 10).
    Arm type
    Experimental

    Investigational medicinal product name
    Duphaston
    Investigational medicinal product code
    Other name
    Oral Dydrogesterone
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Duphaston was supplied as micronized, film-coated 10.0 mg tablets in blister strips of aluminium foil and polyvinylchloride film. Subjects received oral dydrogesterone 10 mg tablets TID from Day 1 to Week 10 (if pregnancy was confirmed at Visit 4).

    Arm title
    Crinone
    Arm description
    Subjects were randomized to receive Crinone 8%, intravaginal micronized progesterone gel 90 mg, once daily from Visit 2 (Day 1). Embryo transfer was performed at Visit 3 (Day 3 to 6). Pregnancy was confirmed 2 weeks after embryo transfer at Visit 4 (Day 17 to 20) by a routine pregnancy test. If positive, luteal support was continued up to Visit 6 (Week 10).
    Arm type
    Active comparator

    Investigational medicinal product name
    Crinone
    Investigational medicinal product code
    Other name
    Micronized progesterone
    Pharmaceutical forms
    Vaginal gel
    Routes of administration
    Vaginal use
    Dosage and administration details
    Crinone 8% was supplied as a vaginal gel contained in single use, one-piece polyethylene vaginal applicators. Each applicator delivered 1.125 grams of Crinone gel containing 90 mg (8% gel) of micronized progesterone and subjects administered one applicator daily from Day 1 to Week 10 (if pregnancy was confirmed at Visit 4).

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Worldwide number enrolled is based on the subjects who were randomized and allocated to treatment. Baseline characteristics is based on subjects who received at least one administration of study drug. 4 subjects who were randomized did not receive study drug.
    Number of subjects in period 2 [2]
    Duphaston Crinone
    Started
    518
    512
    Pregnancies at Week 2 (Visit 4)
    234
    214
    Pregnancies at Week 10 (Visit 6)
    191
    171
    Giving Live Birth
    170
    159
    Completed
    168
    157
    Not completed
    350
    355
         Protocol deviation
    10
    11
         Pregnancy not confirmed after 2 weeks (Day 17-20)
    253
    272
         Adverse event, non-fatal
    65
    58
         Consent withdrawn by subject
    13
    5
         Administrative
    3
    5
         Lost to follow-up
    6
    4
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Number of subjects starting Period 1 is based on those randomized and allocated to treatment. Number of subjects starting Period 2 is based on those who received at least one administration of study drug. The baseline demographics table presents data for the Safety subject sample (ie, subjects receiving treatment); therefore Period 2 is the baseline period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Duphaston
    Reporting group description
    Subjects were randomized to receive Duphaston, oral dydrogesterone 10 mg tablets TID (30 mg daily) from Visit 2 (Day 1). Embryo transfer was performed at Visit 3 (Day 3 to 6). Pregnancy was confirmed 2 weeks after embryo transfer at Visit 4 (Day 17 to 20) by a routine pregnancy test. If positive, luteal support was continued up to Visit 6 (Week 10).

    Reporting group title
    Crinone
    Reporting group description
    Subjects were randomized to receive Crinone 8%, intravaginal micronized progesterone gel 90 mg, once daily from Visit 2 (Day 1). Embryo transfer was performed at Visit 3 (Day 3 to 6). Pregnancy was confirmed 2 weeks after embryo transfer at Visit 4 (Day 17 to 20) by a routine pregnancy test. If positive, luteal support was continued up to Visit 6 (Week 10).

    Reporting group values
    Duphaston Crinone Total
    Number of subjects
    518 512
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    31.8 ± 4.5 31.6 ± 4.6 -
    Gender categorical
    Units: Subjects
        Female
    518 512 1030
        Male
    0 0 0
    Ethnicity
    Units: Subjects
        Hispanic
    4 5 9
        Not Hispanic
    514 507 1021
    Race
    Units: Subjects
        Asian
    260 254 514
        Black
    1 0 1
        White
    251 253 504
        Other
    6 5 11

    End points

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    End points reporting groups
    Reporting group title
    Duphaston
    Reporting group description
    Subjects were randomized to receive Duphaston, oral dydrogesterone 10 mg tablets TID (30 mg daily) from Visit 2 (Day 1). Embryo transfer was performed at Visit 3 (Day 3 to 6). Pregnancy was confirmed 2 weeks after embryo transfer at Visit 4 (Day 17 to 20) by a routine pregnancy test. If positive, luteal support was continued up to Visit 6 (Week 10).

    Reporting group title
    Crinone
    Reporting group description
    Subjects were randomized to receive Crinone 8%, intravaginal micronized progesterone gel 90 mg, once daily from Visit 2 (Day 1). Embryo transfer was performed at Visit 3 (Day 3 to 6). Pregnancy was confirmed 2 weeks after embryo transfer at Visit 4 (Day 17 to 20) by a routine pregnancy test. If positive, luteal support was continued up to Visit 6 (Week 10).
    Reporting group title
    Duphaston
    Reporting group description
    Subjects were randomized to receive Duphaston, oral dydrogesterone 10 mg tablets TID (30 mg daily) from Visit 2 (Day 1). Embryo transfer was performed at Visit 3 (Day 3 to 6). Pregnancy was confirmed 2 weeks after embryo transfer at Visit 4 (Day 17 to 20) by a routine pregnancy test. If positive, luteal support was continued up to Visit 6 (Week 10).

    Reporting group title
    Crinone
    Reporting group description
    Subjects were randomized to receive Crinone 8%, intravaginal micronized progesterone gel 90 mg, once daily from Visit 2 (Day 1). Embryo transfer was performed at Visit 3 (Day 3 to 6). Pregnancy was confirmed 2 weeks after embryo transfer at Visit 4 (Day 17 to 20) by a routine pregnancy test. If positive, luteal support was 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 at Visit 6 was defined as the percentage of subjects with the presence of fetal heart beats at 12 weeks of gestation (10 weeks of pregnancy) as determined by transvaginal ultrasound. The primary efficacy analysis was performed on the PP subject sample (in line with the objective of non-inferiority) and repeated for the Full Analysis (FA) subject sample. Results are presented here for the PP subject sample which was defined through blind data review and consisted of all subjects who were included in the FA sample, did not present any major protocol deviations, and had a successful embryo transfer at Visit 3 (Day 3 to 6).
    End point type
    Primary
    End point timeframe
    At Visit 6 (Week 10)
    End point values
    Duphaston Crinone
    Number of subjects analysed
    490
    481
    Units: percentage of subjects
        number (confidence interval 95%)
    36.7 (32.5 to 41.2)
    34.7 (30.5 to 39.2)
    Statistical analysis title
    Non-inferiority: Pregnancy Rate at Visit 6
    Statistical analysis description
    Analysis of difference (non-inferiority) between treatments (Duphaston – Crinone) for Pregnancy Rate at Visit 6 in the PP subject sample, performed using Cochran-Mantel-Haenszel test, stratified for country and age groups (older or younger than 35 years).
    Comparison groups
    Duphaston v Crinone
    Number of subjects included in analysis
    971
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [1]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Treatment difference (%)
    Point estimate
    2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4
         upper limit
    8
    Notes
    [1] - In order to declare non-inferiority, the lower bound of the two-sided 95% confidence interval (CI) for the difference in ongoing pregnancy rates between Crinone and Duphaston had to exclude a difference greater than 10% in favor of Duphaston.

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

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    End point title
    Pregnancy Rate at Visit 6 (Week 10): FA Subject Sample
    End point description
    The pregnancy rate at Visit 6 was defined as the percentage of subjects with the presence of fetal heart beats at 12 weeks of gestation (10 weeks of pregnancy) as determined by transvaginal ultrasound. The primary efficacy analysis was performed on the PP subject sample (in line with the objective of non-inferiority) and repeated for the FA subject sample. Results are presented here for the FA subject sample which consisted of all subjects who received at least one dose of study drug and had a successful embryo transfer performed at Visit 3 (Day 3 to 6) or prematurely discontinued prior to embryo transfer at Visit 3 (Day 3 to 6) due to study drug-related issues.
    End point type
    Primary
    End point timeframe
    At Visit 6 (Week 10)
    End point values
    Duphaston Crinone
    Number of subjects analysed
    494
    489
    Units: percentage of subjects
        number (confidence interval 95%)
    38.7 (34.4 to 43.1)
    35.0 (30.7 to 39.4)
    Statistical analysis title
    Non-inferiority: Pregnancy Rate at Visit 6
    Statistical analysis description
    Analysis of difference (non-inferiority) between treatments (Duphaston – Crinone) for Pregnancy Rate at Visit 6 in the FA subject sample, performed using Cochran-Mantel-Haenszel test, stratified for country and age groups (older or younger than 35 years).
    Comparison groups
    Duphaston v Crinone
    Number of subjects included in analysis
    983
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [2]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Treatment difference (%)
    Point estimate
    3.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.3
         upper limit
    9.7
    Notes
    [2] - In order to declare non-inferiority, the lower bound of the two-sided 95% CI for the difference in ongoing pregnancy rates between Crinone and Duphaston had to exclude a difference greater than 10% in favor of Duphaston.

    Secondary: Pregnancy Rate at Visit 4 (Week 2)

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    End point title
    Pregnancy Rate at Visit 4 (Week 2)
    End point description
    A routine pregnancy test (serum beta human chorionic gonadotropin) was performed 2 weeks after embryo transfer to confirm the subject’s pregnancy. The pregnancy rate at Visit 4 (Day 17 to 20) was calculated as the percentage of subjects who had a positive pregnancy test at Visit 4. Analysis was performed using the FA subject sample which consisted of all subjects who had received at least one dose of study drug and had a successful embryo transfer performed at Visit 3 (Day 3 to 6) or prematurely discontinued prior to embryo transfer at Visit 3 due to study drug-related issues.
    End point type
    Secondary
    End point timeframe
    At Visit 4 (Day 17 to 20)
    End point values
    Duphaston Crinone
    Number of subjects analysed
    494
    489
    Units: percentage of subjetcs
        number (confidence interval 95%)
    47.4 (42.9 to 51.9)
    43.8 (39.3 to 48.3)
    Statistical analysis title
    Non-inferiority: Pregnancy Rate at Visit 4
    Statistical analysis description
    Analysis of difference (non-inferiority) between treatments (Duphaston – Crinone) for Pregnancy Rate at Visit 4, performed using Cochran-Mantel-Haenszel test, stratified for country and age groups (older or younger than 35 years).
    Comparison groups
    Duphaston v Crinone
    Number of subjects included in analysis
    983
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Treatment difference (%)
    Point estimate
    3.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.6
         upper limit
    9.8

    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 pregnancy rate at Visit 5 was calculated as the percentage of subjects who had pregnancy confirmed at Visit 5. Analysis was performed using the FA subject sample which consisted of all subjects who had received at least one dose of study drug and had a successful embryo transfer performed at Visit 3 (Day 3 to 6) or prematurely discontinued prior to embryo transfer at Visit 3 due to study drug-related issues.
    End point type
    Secondary
    End point timeframe
    At Visit 5 (Week 6)
    End point values
    Duphaston Crinone
    Number of subjects analysed
    494
    489
    Units: percentage of subjects
        number (confidence interval 95%)
    40.7 (36.3 to 45.2)
    36.8 (32.5 to 41.3)
    Statistical analysis title
    Non-inferiority: Pregnancy Rate at Visit 5
    Statistical analysis description
    Analysis of difference (non-inferiority) between treatments (Duphaston – Crinone) for Pregnancy Rate at Visit 5, performed using Cochran-Mantel-Haenszel test, stratified for country and age groups (older or younger than 35 years).
    Comparison groups
    Duphaston v Crinone
    Number of subjects included in analysis
    983
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Treatment difference (%)
    Point estimate
    3.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.2
         upper limit
    9.9

    Secondary: Abortion (Miscarriage) Rate

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    End point title
    Abortion (Miscarriage) Rate
    End point description
    A pregnancy outcome was defined as an abortion if the pregnancy was ongoing at Visit 5 (Week 6) and gestational age was ≤ 22 weeks. The abortion rate was calculated as the percentage of subjects who had an abortion during the study. Analysis was performed using the FA subject sample which consisted of all subjects who had received at least one dose of study drug and had a successful embryo transfer performed at Visit 3 (Day 3 to 6) or prematurely discontinued prior to embryo transfer at Visit 3 due to study drug-related issues.
    End point type
    Secondary
    End point timeframe
    From Visit 5 (Week 6) up to 22 weeks of gestation (20 weeks of pregnancy)
    End point values
    Duphaston Crinone
    Number of subjects analysed
    494
    489
    Units: percentage of subjects
        number (confidence interval 95%)
    3.0 (1.7 to 5.0)
    2.5 (1.3 to 4.3)
    Statistical analysis title
    Non-inferiority: Abortion (Miscarriage) Rate
    Statistical analysis description
    Analysis of difference (non-inferiority) between treatments (Crinone - Duphaston) for Abortion Rate, performed using Cochran-Mantel-Haenszel test, stratified for country and age groups (older or younger than 35 years).
    Comparison groups
    Duphaston v Crinone
    Number of subjects included in analysis
    983
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Treatment difference (%)
    Point estimate
    -0.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.6
         upper limit
    1.5

    Secondary: Preterm Birth Rate

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    End point title
    Preterm Birth Rate
    End point description
    Preterm birth was defined as a pregnancy outcome with gestational age > 22 weeks and < 37 weeks. Pregnancy outcomes with gestational age ≥ 37 weeks were considered as birth. The preterm birth rate was calculated as the percentage of subjects who had preterm birth during the study. Analysis was performed using the FA subject sample which consisted of all subjects who had received at least one dose of study drug and had a successful embryo transfer performed at Visit 3 (Day 3 to 6) or prematurely discontinued prior to embryo transfer at Visit 3 due to study drug-related issues.
    End point type
    Secondary
    End point timeframe
    From 22 weeks up to 37 weeks of gestation (from 20 weeks up to 35 weeks of pregnancy)
    End point values
    Duphaston Crinone
    Number of subjects analysed
    494
    489
    Units: percentage of subjects
        number (confidence interval 95%)
    7.5 (5.3 to 10.2)
    6.1 (4.2 to 8.6)
    Statistical analysis title
    Non-inferiority: Preterm Birth Rate
    Statistical analysis description
    Analysis of difference (non-inferiority) between treatments (Crinone - Duphaston) for Preterm Birth Rate, performed using Cochran-Mantel-Haenszel test, stratified for country and age groups (older or younger than 35 years).
    Comparison groups
    Duphaston v Crinone
    Number of subjects included in analysis
    983
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Treatment difference (%)
    Point estimate
    -1.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.5
         upper limit
    1.8

    Secondary: Live Birth Rate

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    End point title
    Live Birth Rate
    End point description
    The live birth rate (sum of preterm births and births) was calculated as the percentage of subjects who had a live birth during the study. Analysis was performed using the FA subject sample which consisted of all subjects who had received at least one dose of study drug and had a successful embryo transfer performed at Visit 3 (Day 3 to 6) or prematurely discontinued prior to embryo transfer at Visit 3 due to study drug-related issues.
    End point type
    Secondary
    End point timeframe
    After delivery (up to approximately 9 months after embryo transfer)
    End point values
    Duphaston Crinone
    Number of subjects analysed
    494
    489
    Units: percentage of subjects
        number (confidence interval 95%)
    34.4 (30.2 to 38.8)
    32.5 (28.4 to 36.9)
    Statistical analysis title
    Non-inferiority: Live Birth Rate
    Statistical analysis description
    Analysis of difference (non-inferiority) between treatments (Duphaston – Crinone) for Live Birth Rate, performed using Cochran-Mantel-Haenszel test, stratified for country and age groups (older or younger than 35 years).
    Comparison groups
    Duphaston v Crinone
    Number of subjects included in analysis
    983
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Treatment difference (%)
    Point estimate
    1.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4
         upper limit
    7.8

    Secondary: Healthy Newborn Rate

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    End point title
    Healthy Newborn Rate
    End point description
    The healthy newborn rate was calculated as the percentage of subjects who gave birth to a healthy newborn during the study. Subjects who gave birth to more than one healthy newborn were counted only once. Analysis was performed using the FA subject sample which consisted of all subjects who had received at least one dose of study drug and had a successful embryo transfer performed at Visit 3 (Day 3 to 6) or prematurely discontinued prior to embryo transfer at Visit 3 due to study drug-related issues.
    End point type
    Secondary
    End point timeframe
    After delivery (up to approximately 9 months after embryo transfer)
    End point values
    Duphaston Crinone
    Number of subjects analysed
    494
    489
    Units: percentage of subjects
        number (confidence interval 95%)
    32.2 (28.1 to 36.5)
    31.3 (27.2 to 35.6)
    Statistical analysis title
    Non-inferiority: Healthy Newborn Rate
    Statistical analysis description
    Analysis of difference (non-inferiority) between treatments (Duphaston – Crinone) for Healthy Newborn Rate, performed using Cochran-Mantel-Haenszel test, stratified for country and age groups (older or younger than 35 years).
    Comparison groups
    Duphaston v Crinone
    Number of subjects included in analysis
    983
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Treatment difference (%)
    Point estimate
    0.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.9
         upper limit
    6.7

    Secondary: Mean Gestational Age

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    End point title
    Mean Gestational Age
    End point description
    After successful delivery (Visit 9), the time of delivery (gestational age) was obtained. The gestational age (weeks) was derived as: (date of birth - date of embryo transfer + 1 day) / 7 + 2 weeks. Results are based on the number of newborns in each reporting group for the FA subject sample with data available for analysis. Note: Subjects with biochemical pregnancy were not included in the analysis.
    End point type
    Secondary
    End point timeframe
    After delivery (up to approximately 9 months after embryo transfer)
    End point values
    Duphaston Crinone
    Number of subjects analysed
    191
    178
    Units: weeks
        arithmetic mean (standard deviation)
    34.932 ± 8.767
    35.260 ± 8.941
    No statistical analyses for this end point

    Secondary: Newborn Status: Healthy Status, Gender, Abnormal Findings and Malformations

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    End point title
    Newborn Status: Healthy Status, Gender, Abnormal Findings and Malformations
    End point description
    After successful delivery (Visit 9), healthy newborn status (Yes or No) and gender were recorded. In addition, a physical examination of the newborn was performed and any abnormal findings and malformations were recorded. Percentages for each of the indicated parameters are based on the number of newborns in each reporting group for the FA subject sample with data available for analysis. Note: A subject could have more than one newborn. 'n' in category title indicates number of newborns analysed for each individual parameter.
    End point type
    Secondary
    End point timeframe
    After delivery (up to approximately 9 months after embryo transfer)
    End point values
    Duphaston Crinone
    Number of subjects analysed
    205
    188
    Units: percentage of newborns
    number (not applicable)
        Heathy Newborn: Yes (n=205, 188)
    92.7
    93.1
        Heathy Newborn: No (n=205, 188)
    7.3
    6.9
        Gender: Male (n=205, 188)
    51.2
    50.5
        Gender: Female (n=205, 188)
    48.8
    49.5
        Abnormal Physical Examination (n=204, 185)
    7.8
    6.5
        Malformations (n=205, 185)
    3.4
    3.8
    No statistical analyses for this end point

    Secondary: Newborn Status: Height, Weight and Head Circumference

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    End point title
    Newborn Status: Height, Weight and Head Circumference
    End point description
    After successful delivery (Visit 9), the height, weight and head circumference of the newborn were recorded. Results for each of the indicated parameters are based on the number of newborns in each reporting group for the FA subject sample with data available for analysis. Note: A subject could have more than one newborn. 'n' in category title indicates number of newborns analysed for each individual parameter.
    End point type
    Secondary
    End point timeframe
    After delivery (up to approximately 9 months after embryo transfer)
    End point values
    Duphaston Crinone
    Number of subjects analysed
    205
    188
    Units: centimetres (cm) or grams (g)
    arithmetic mean (standard deviation)
        Height (cm) (n=200, 177)
    48.8 ± 4.0
    48.8 ± 3.9
        Weight (g) (n=203, 184)
    2934.3 ± 684.2
    2963.3 ± 719.2
        Head Circumference (cm) (n=188, 173)
    33.6 ± 2.5
    33.9 ± 2.6
    No statistical analyses for this end point

    Secondary: Newborn Status: Mean APGAR (standing for Appearance, Pulse, Grimace, Activity, and Respiration) Score

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    End point title
    Newborn Status: Mean APGAR (standing for Appearance, Pulse, Grimace, Activity, and Respiration) Score
    End point description
    After successful delivery (Visit 9), the newborn APGAR score at 1 minute and 5 minutes postpartal were obtained. Results are based on the number of newborns in each reporting group for the FA subject sample with data available for analysis. Note: A subject could have more than one newborn. 'n' in category title indicates number of newborns analysed for each individual parameter.
    End point type
    Secondary
    End point timeframe
    After delivery (up to approximately 9 months after embryo transfer)
    End point values
    Duphaston Crinone
    Number of subjects analysed
    198
    176
    Units: units on a scale
    arithmetic mean (standard deviation)
        1 Minute Postpartal (n=198, 176)
    8.7 ± 1.2
    8.5 ± 1.4
        5 Minutes Postpartal (n=197, 176)
    9.3 ± 1.1
    9.3 ± 0.9
    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 consisted 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
    18.1
    Reporting groups
    Reporting group title
    Duphaston - Maternal
    Reporting group description
    Reporting group represents the Safety subject sample (ie, maternal subjects) who received Duphaston oral dydrogesterone 10 mg tablets TID (30 mg daily).

    Reporting group title
    Crinone - Maternal
    Reporting group description
    Reporting group represents the Safety subject sample (ie, maternal subjects) who received Crinone 8%, intravaginal micronized progesterone gel 90 mg, once daily.

    Reporting group title
    Duphaston - Fetus/Newborn
    Reporting group description
    Reporting group represents the fetus/newborns arising from the Duphaston reporting group. The mothers of the fetus/newborns received Duphaston oral dydrogesterone 10 mg tablets TID (30 mg daily).

    Reporting group title
    Crinone - Fetus/Newborn
    Reporting group description
    Reporting group represents the fetus/newborns arising from the Crinone reporting group. The mothers of the fetus/newborns received Crinone 8%, intravaginal micronized progesterone gel 90 mg, once daily.

    Serious adverse events
    Duphaston - Maternal Crinone - Maternal Duphaston - Fetus/Newborn Crinone - Fetus/Newborn
    Total subjects affected by serious adverse events
         subjects affected / exposed
    71 / 518 (13.71%)
    67 / 512 (13.09%)
    28 / 221 (12.67%)
    23 / 201 (11.44%)
         number of deaths (all causes)
    0
    0
    4
    0
         number of deaths resulting from adverse events
    0
    0
    4
    0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 518 (0.19%)
    0 / 512 (0.00%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Abortion induced
         subjects affected / exposed
    3 / 518 (0.58%)
    1 / 512 (0.20%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Selective abortion
         subjects affected / exposed
    1 / 518 (0.19%)
    2 / 512 (0.39%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Caesarean section
         subjects affected / exposed
    0 / 518 (0.00%)
    2 / 512 (0.39%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Papillary thyroid cancer
         subjects affected / exposed
    1 / 518 (0.19%)
    0 / 512 (0.00%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion threatened
         subjects affected / exposed
    6 / 518 (1.16%)
    7 / 512 (1.37%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 7
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abortion spontaneous
         subjects affected / exposed
    6 / 518 (1.16%)
    6 / 512 (1.17%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 6
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Imminent abortion
         subjects affected / exposed
    0 / 518 (0.00%)
    1 / 512 (0.20%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ectopic pregnancy
         subjects affected / exposed
    6 / 518 (1.16%)
    8 / 512 (1.56%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 8
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervical incompetence
         subjects affected / exposed
    1 / 518 (0.19%)
    1 / 512 (0.20%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ruptured ectopic pregnancy
         subjects affected / exposed
    1 / 518 (0.19%)
    1 / 512 (0.20%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperemesis gravidarum
         subjects affected / exposed
    0 / 518 (0.00%)
    1 / 512 (0.20%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Premature labour
         subjects affected / exposed
    6 / 518 (1.16%)
    2 / 512 (0.39%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Premature delivery
         subjects affected / exposed
    4 / 518 (0.77%)
    2 / 512 (0.39%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Premature rupture of membranes
         subjects affected / exposed
    2 / 518 (0.39%)
    1 / 512 (0.20%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Threatened labour
         subjects affected / exposed
    1 / 518 (0.19%)
    2 / 512 (0.39%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abortion missed
         subjects affected / exposed
    12 / 518 (2.32%)
    2 / 512 (0.39%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abortion
         subjects affected / exposed
    1 / 518 (0.19%)
    0 / 512 (0.00%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abortion complete
         subjects affected / exposed
    0 / 518 (0.00%)
    1 / 512 (0.20%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abortion late
         subjects affected / exposed
    0 / 518 (0.00%)
    1 / 512 (0.20%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Premature baby
         subjects affected / exposed
    7 / 518 (1.35%)
    6 / 512 (1.17%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 6
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foetal death
         subjects affected / exposed
    1 / 518 (0.19%)
    4 / 512 (0.78%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stillbirth
         subjects affected / exposed
    1 / 518 (0.19%)
    1 / 512 (0.20%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pre-eclampsia
         subjects affected / exposed
    0 / 518 (0.00%)
    4 / 512 (0.78%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HELLP syndrome
         subjects affected / exposed
    1 / 518 (0.19%)
    0 / 512 (0.00%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Placenta praevia
         subjects affected / exposed
    2 / 518 (0.39%)
    1 / 512 (0.20%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vasa praevia
         subjects affected / exposed
    1 / 518 (0.19%)
    0 / 512 (0.00%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage in pregnancy
         subjects affected / exposed
    0 / 518 (0.00%)
    2 / 512 (0.39%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Placenta praevia haemorrhage
         subjects affected / exposed
    1 / 518 (0.19%)
    1 / 512 (0.20%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blighted ovum
         subjects affected / exposed
    1 / 518 (0.19%)
    1 / 512 (0.20%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gestational diabetes
         subjects affected / exposed
    1 / 518 (0.19%)
    1 / 512 (0.20%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oligohydramnios
         subjects affected / exposed
    1 / 518 (0.19%)
    0 / 512 (0.00%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retained placenta or membranes
         subjects affected / exposed
    0 / 518 (0.00%)
    1 / 512 (0.20%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postpartum haemorrhage
         subjects affected / exposed
    0 / 518 (0.00%)
    1 / 512 (0.20%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Low birth weight baby
         subjects affected / exposed
    0 / 518 (0.00%)
    0 / 512 (0.00%)
    6 / 221 (2.71%)
    3 / 201 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Foetal distress syndrome
         subjects affected / exposed
    0 / 518 (0.00%)
    0 / 512 (0.00%)
    1 / 221 (0.45%)
    3 / 201 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foetal acidosis
         subjects affected / exposed
    0 / 518 (0.00%)
    0 / 512 (0.00%)
    0 / 221 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foetal growth restriction
         subjects affected / exposed
    0 / 518 (0.00%)
    0 / 512 (0.00%)
    0 / 221 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Ovarian hyperstimulation syndrome
         subjects affected / exposed
    11 / 518 (2.12%)
    14 / 512 (2.73%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 14
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adnexal torsion
         subjects affected / exposed
    1 / 518 (0.19%)
    1 / 512 (0.20%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vaginal haemorrhage
         subjects affected / exposed
    2 / 518 (0.39%)
    2 / 512 (0.39%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine haemorrhage
         subjects affected / exposed
    0 / 518 (0.00%)
    1 / 512 (0.20%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 518 (0.00%)
    1 / 512 (0.20%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Foetal monitoring abnormal
         subjects affected / exposed
    0 / 518 (0.00%)
    0 / 512 (0.00%)
    1 / 221 (0.45%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foetal heart rate abnormal
         subjects affected / exposed
    0 / 518 (0.00%)
    0 / 512 (0.00%)
    1 / 221 (0.45%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    0 / 518 (0.00%)
    0 / 512 (0.00%)
    3 / 221 (1.36%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 518 (0.00%)
    0 / 512 (0.00%)
    1 / 221 (0.45%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bradycardia neonatal
         subjects affected / exposed
    0 / 518 (0.00%)
    0 / 512 (0.00%)
    0 / 221 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 518 (0.00%)
    0 / 512 (0.00%)
    2 / 221 (0.90%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Atrial septal defect
         subjects affected / exposed
    0 / 518 (0.00%)
    0 / 512 (0.00%)
    5 / 221 (2.26%)
    7 / 201 (3.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 5
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Heart disease congenital
         subjects affected / exposed
    0 / 518 (0.00%)
    0 / 512 (0.00%)
    2 / 221 (0.90%)
    4 / 201 (1.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Patent ductus arteriosus
         subjects affected / exposed
    0 / 518 (0.00%)
    0 / 512 (0.00%)
    1 / 221 (0.45%)
    4 / 201 (1.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Amniotic band syndrome
         subjects affected / exposed
    0 / 518 (0.00%)
    0 / 512 (0.00%)
    1 / 221 (0.45%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital hand malformation
         subjects affected / exposed
    0 / 518 (0.00%)
    0 / 512 (0.00%)
    1 / 221 (0.45%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital cystic kidney disease
         subjects affected / exposed
    0 / 518 (0.00%)
    0 / 512 (0.00%)
    1 / 221 (0.45%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal dysplasia
         subjects affected / exposed
    0 / 518 (0.00%)
    0 / 512 (0.00%)
    1 / 221 (0.45%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital central nervous system anomaly
         subjects affected / exposed
    0 / 518 (0.00%)
    0 / 512 (0.00%)
    1 / 221 (0.45%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital aortic anomaly
         subjects affected / exposed
    0 / 518 (0.00%)
    0 / 512 (0.00%)
    0 / 221 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal malrotation
         subjects affected / exposed
    0 / 518 (0.00%)
    0 / 512 (0.00%)
    1 / 221 (0.45%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystic lymphangioma
         subjects affected / exposed
    0 / 518 (0.00%)
    0 / 512 (0.00%)
    1 / 221 (0.45%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Kinematic imbalances due to suboccipital strain
         subjects affected / exposed
    0 / 518 (0.00%)
    0 / 512 (0.00%)
    1 / 221 (0.45%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Turner's syndrome
         subjects affected / exposed
    0 / 518 (0.00%)
    0 / 512 (0.00%)
    1 / 221 (0.45%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Blood and lymphatic system disorders
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 518 (0.00%)
    0 / 512 (0.00%)
    1 / 221 (0.45%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Neonatal respiratory distress syndrome
         subjects affected / exposed
    0 / 518 (0.00%)
    0 / 512 (0.00%)
    5 / 221 (2.26%)
    5 / 201 (2.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Apnoea neonatal
         subjects affected / exposed
    0 / 518 (0.00%)
    0 / 512 (0.00%)
    0 / 221 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neonatal respiratory failure
         subjects affected / exposed
    0 / 518 (0.00%)
    0 / 512 (0.00%)
    1 / 221 (0.45%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 518 (0.00%)
    0 / 512 (0.00%)
    2 / 221 (0.90%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 518 (0.00%)
    0 / 512 (0.00%)
    1 / 221 (0.45%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 518 (0.00%)
    0 / 512 (0.00%)
    0 / 221 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral circulatory failure
         subjects affected / exposed
    1 / 518 (0.19%)
    0 / 512 (0.00%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    VIIth nerve paralysis
         subjects affected / exposed
    0 / 518 (0.00%)
    1 / 512 (0.20%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxic-ischaemic encephalopathy
         subjects affected / exposed
    0 / 518 (0.00%)
    0 / 512 (0.00%)
    2 / 221 (0.90%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain injury
         subjects affected / exposed
    0 / 518 (0.00%)
    0 / 512 (0.00%)
    0 / 221 (0.00%)
    2 / 201 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    0 / 518 (0.00%)
    0 / 512 (0.00%)
    1 / 221 (0.45%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 518 (0.19%)
    0 / 512 (0.00%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    0 / 518 (0.00%)
    1 / 512 (0.20%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 518 (0.19%)
    0 / 512 (0.00%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal distension
         subjects affected / exposed
    1 / 518 (0.19%)
    0 / 512 (0.00%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Volvulus
         subjects affected / exposed
    0 / 518 (0.00%)
    1 / 512 (0.20%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Necrotising colitis
         subjects affected / exposed
    0 / 518 (0.00%)
    0 / 512 (0.00%)
    0 / 221 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 518 (0.00%)
    0 / 512 (0.00%)
    0 / 221 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hydronephrosis
         subjects affected / exposed
    1 / 518 (0.19%)
    0 / 512 (0.00%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    1 / 518 (0.19%)
    0 / 512 (0.00%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 518 (0.00%)
    1 / 512 (0.20%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 518 (0.00%)
    1 / 512 (0.20%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 518 (0.19%)
    0 / 512 (0.00%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neonatal pneumonia
         subjects affected / exposed
    0 / 518 (0.00%)
    0 / 512 (0.00%)
    1 / 221 (0.45%)
    7 / 201 (3.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis neonatal
         subjects affected / exposed
    0 / 518 (0.00%)
    0 / 512 (0.00%)
    4 / 221 (1.81%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Neonatal infection
         subjects affected / exposed
    0 / 518 (0.00%)
    0 / 512 (0.00%)
    0 / 221 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia respiratory syncytial viral
         subjects affected / exposed
    0 / 518 (0.00%)
    0 / 512 (0.00%)
    0 / 221 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Duphaston - Maternal Crinone - Maternal Duphaston - Fetus/Newborn Crinone - Fetus/Newborn
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    50 / 518 (9.65%)
    35 / 512 (6.84%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
    Pregnancy, puerperium and perinatal conditions
    Vaginal haemorrhage
         subjects affected / exposed
    50 / 518 (9.65%)
    35 / 512 (6.84%)
    0 / 221 (0.00%)
    0 / 201 (0.00%)
         occurrences all number
    50
    35
    0
    0

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Mar 2015
    An updated version of the Investigator’s Brochure was released in January 2015. The clinical trial protocol was updated to reflect that the reference safety information for the expectedness assessment was the Investigator’s Brochure and not the Summary of Product Characteristics (SPC) for Duphaston issued on 29 April 2011, which was mentioned in the protocol. For the comparative study drug, Crinone 8% intravaginal gel 90 mg, the reference safety information was the current SPC issued in the United Kingdom.
    07 Sep 2015
    The following main changes were included: • Inclusion Criterion #8: the wording for the negative pregnancy test was changed to reflect that it was not the only method used to confirm that the subject was not pregnant: most of the IVF centers did not routinely perform a serum or urine pregnancy test before they started the downregulation process with either gonadotropin agonists or antagonists; for them, the vaginal exam, which was performed prior to any IVF-related procedures, was the basis for further treatment decisions/options. • The protocol was adjusted to the current more frequently used long (downregulation/ovarian stimulation) protocol by increasing the screening and enrollment phase from 14 to 40 days prior to the oocyte retrieval/randomization visit. • Due to the delay in the start of recruitment, the study dates and duration were updated. • Wording was added to explain the expectedness of early miscarriages before presence of fetal heart beats at 12 weeks of gestation (10 weeks of pregnancy), to explain AE/serious AE reporting of pregnancy, and to include definitions of biochemical pregnancy and miscarriage. • The fasting requirement for some laboratory tests was changed to “if possible fasting,” as the Investigators informed that many subjects were not fasting when they went to the study sites, particularly for the end of treatment at Week 10, when subjects were pregnant. • The timing of posttreatment visits was adapted to the visit days in the study flow chart.
    04 Jan 2016
    For subject eligibility (Inclusion Criterion #5), a selection of hormones, including luteinizing hormone (LH), prolactin (PRL), testosterone, and thyrotropin (TSH), had to be within the normal limits for the clinical laboratory, or considered not clinically significant by the Investigator within 6 months prior to screening. During the study progress it became clear that most of the Asian IVF centers participating in this study were not routinely performing this hormone testing prior to any IVF cycles. Therefore, the assessment of some hormone values (follicle-stimulating hormone, estradiol, LH, PRL, testosterone, and TSH) was added as a requirement at screening for those subjects who did not have available values prior to screening. Wording of Inclusion Criteria #4 and #5, the flow chart of study assessments, and some other sections in the protocol were updated accordingly.

    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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