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    Clinical Trial Results:
    A randomised, placebo-controlled, double-blind, parallel groups, multinational, multicentre trial assessing the effect of barusiban administered subcutaneously on the day of transfer on implantation and pregnancy rates in IVF/ICSI patients.

    Summary
    EudraCT number
    		 2012-001622-10
    Trial protocol
    		 BE   CZ   ES   PL  
    Global end of trial date
    28 Apr 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Aug 2018
    First version publication date
    05 Aug 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    000048
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01723982
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Ferring Pharmaceuticals A/S
    Sponsor organisation address
    Kay Fiskers Plads 11, Copenhagen S, Denmark, 2300
    Public contact
    Clinical Development Support, Ferring Pharmaceuticals, DK0-Disclosure@ferring.com
    Scientific contact
    Clinical Development Support, Ferring Pharmaceuticals, DK0-Disclosure@ferring.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
    08 Jul 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Oct 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Apr 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effect of barusiban compared to placebo on implantation rate in in-vitro fertilisation (IVF)/intracytoplasmic sperm injection (ICSI) patients.
    Protection of trial subjects
    The trial was performed in accordance with the Declaration of Helsinki and its amendments in force at the initiation of the trial.
    Background therapy
    		 Vaginal progesterone tablets (LUTINUS/ENDOMETRIN, Ferring Pharmaceuticals) 100 mg twice daily were provided for luteal phase support from the day after oocyte retrieval and until the day of the clinical pregnancy visit. On the day of transfer, subjects inserted the progesterone tablets at least 3 hours before transfer and at least 3 hours after transfer. Progesterone support could be terminated earlier than the clinical pregnancy visit in case of a negative beta unit of human chorionic gonadotropin (βhCG) test or menses.
    Evidence for comparator
    		 This was a randomised controlled trial with placebo as the comparator to adequately document the efficacy and safety of barusiban. A placebo group was justified for this trial as there is no therapy available for this indication.
    Actual start date of recruitment
    14 Nov 2012
    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: 8
    Country: Number of subjects enrolled
    Canada: 12
    Country: Number of subjects enrolled
    Poland: 33
    Country: Number of subjects enrolled
    Spain: 85
    Country: Number of subjects enrolled
    Belgium: 60
    Country: Number of subjects enrolled
    Czech Republic: 57
    Worldwide total number of subjects
    255
    EEA total number of subjects
    235
    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)
    255
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The participating subjects were recruited among the patients attending the clinics. A total of 12 sites randomised subjects into the trial : 1 in Australia, 2 in Belgium, 1 in Canada, 1 in Czech Republic, 1 in Poland and 6 in Spain.

    Pre-assignment
    Screening details
    		 A total of 363 subjects were screened in the trial, of whom 255 subjects were randomised: 130 to barusiban and 125 to placebo.

    Period 1
    Period 1 title
    Randomisation to End-of-Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Barusiban
    Arm description
    		 Subjects randomised to barusiban IMP were included in this group.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Barusiban
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The barusiban IMP was a 20 mg/mL isotonic solution in acetate buffer. The 1st IMP administration of barusiban 40 mg subcutaneously (SC) was 45 min prior to transfer and 2nd administration of barusiban 10 mg SC was 60 min after the 1st administration.

    Arm title
    		 Placebo
    Arm description
    		 Subjects randomised to placebo IMP were included in this group.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The placebo IMP was an isotonic acetate buffer solution. The 1st administration of isotonic acetate buffer SC was 45 min prior to transfer and 2nd administration of isotonic acetate buffer SC was 60 min after the 1st administration.

    Number of subjects in period 1
    		Barusiban Placebo
    Started
    130
    125
    Completed
    123
    118
    Not completed
    7
    7
         Protocol deviation
    7
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Barusiban
    Reporting group description
    		 Subjects randomised to barusiban IMP were included in this group.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects randomised to placebo IMP were included in this group.

    Reporting group values
    		 Barusiban Placebo Total
    Number of subjects
    		 130 125 255
    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)
    		 130 125 255
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 32.7 ( 3.42 ) 33.5 ( 3.31 ) -
    Gender categorical
    Units: Subjects
        Female
    		 130 125 255
        Male
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Barusiban
    Reporting group description
    		 Subjects randomised to barusiban IMP were included in this group.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects randomised to placebo IMP were included in this group.

    Subject analysis set title
    Intention-to-Treat (ITT) Analysis Set
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT analysis set was defined as all randomised subjects.

    Subject analysis set title
    Per-Protocol (PP) Analysis Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PP analysis set was defined as all randomised and exposed subjects except those excluded as a result of major protocol deviations.

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety analysis set was defined as all randomised and exposed subjects.

    Primary: Ongoing Implantation Rate

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    End point title
    		 Ongoing Implantation Rate
    End point description
    Ongoing implantation rate was defined as the number of viable fetuses 10-11 weeks after transfer divided by the number of embryos/blastocysts transferred. Data are presented for the ITT analysis set.
    End point type
    Primary
    End point timeframe
    10-11 weeks after transfer.
    End point values
    		 Barusiban Placebo
    Number of subjects analysed
    130 [1]
    125 [2]
    Units: Adjusted response rate (%)
        number (not applicable)
    25
    23.1
    Notes
    [1] - Number of embryos/blastocysts = 225
    [2] - Number of embryos/blastocysts = 215
    Statistical analysis title
    		 Adjusted Ongoing Implantation Rate
    Statistical analysis description
    Analysis of hypothesis of ‘equal effect’ against the alternative of ‘different effect’ between the probability that an embryo/blastocyst would implant in the barusiban and placebo groups.
    Comparison groups
    Barusiban v Placebo
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.663 [4]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 1.78
    Notes
    [3] - Comparison between the groups was based on logistic regression model with treatment, trial site, primary reason for infertility, and embryo/blastocyst quality as factors.
    [4] - p-value corresponds to a two-sided test of superiority.

    Primary: Ongoing Implantation Rate - Transfer Day 3

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    End point title
    		 Ongoing Implantation Rate - Transfer Day 3
    End point description
    Ongoing implantation rate was analysed for subjects with transfer on day 3. Data are presented for the ITT analysis set.
    End point type
    Primary
    End point timeframe
    10-11 weeks after transfer.
    End point values
    		 Barusiban Placebo
    Number of subjects analysed
    65 [5]
    62 [6]
    Units: Adjusted response rate (%)
        number (not applicable)
    11.8
    17.6
    Notes
    [5] - Number of embryos transferred = 117
    [6] - Number of embryos transferred = 111
    Statistical analysis title
    		 Adjusted Ongoing Implantation Rate-Transfer Day 3
    Statistical analysis description
    Analysis of ongoing implantation rate in subjects with transfer on day 3.
    Comparison groups
    Barusiban v Placebo
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.227 [8]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.628
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3
         upper limit
    		 1.34
    Notes
    [7] - Comparison between the groups was based on logistic regression model with treatment, number of embryos transferred, trial site, and primary reason for infertility as factors.
    [8] - p-value corresponds to a two-sided test of superiority.

    Primary: Ongoing Implantation Rate - Transfer Day 5

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    End point title
    		 Ongoing Implantation Rate - Transfer Day 5
    End point description
    Ongoing implantation rate was analysed for subjects with transfer on day 5. Data are presented for the ITT analysis set.
    End point type
    Primary
    End point timeframe
    10-11 weeks after transfer.
    End point values
    		 Barusiban Placebo
    Number of subjects analysed
    65 [9]
    63 [10]
    Units: Adjusted response rate (%)
        number (not applicable)
    41.3
    23.2
    Notes
    [9] - Number of blastocysts transferred = 108
    [10] - Number of blastocysts transferred = 104
    Statistical analysis title
    		 Adjusted Ongoing Implantation Rate-Transfer Day 5
    Statistical analysis description
    Analysis of ongoing implantation rate in subjects with transfer on day 5.
    Comparison groups
    Barusiban v Placebo
    Number of subjects included in analysis
    128
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 = 0.022 [12]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.337
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.13
         upper limit
    		 4.84
    Notes
    [11] - Comparison between the groups was based on logistic regression model with treatment, number of blastocysts transferred, trial site, primary reason for infertility, and blastocyst quality parameters as factors.
    [12] - p-value corresponds to a two-sided test of superiority.

    Secondary: Ongoing Pregnancy Rate

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    End point title
    		 Ongoing Pregnancy Rate
    End point description
    Ongoing pregnancy was defined as at least one intrauterine viable fetus 10-11 weeks after transfer. Data are presented for the ITT analysis set.
    End point type
    Secondary
    End point timeframe
    10-11 weeks after transfer.
    End point values
    		 Barusiban Placebo
    Number of subjects analysed
    130
    125
    Units: Adjusted response rate (%)
        number (not applicable)
    34.2
    35.1
    Statistical analysis title
    		 Adjusted Ongoing Pregnancy Rate
    Statistical analysis description
    Analysis of ongoing pregnancy rate was intended to provide supportive evidence of treatment effect of barusiban.
    Comparison groups
    Barusiban v Placebo
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 = 0.897 [14]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.963
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.54
         upper limit
    		 1.71
    Notes
    [13] - Comparison between the groups was based on logistic regression model with treatment, trial site, primary reason for infertility, and embryo/blastocyst quality as factors.
    [14] - p-value corresponds to a two-sided test of superiority.

    Secondary: Ongoing Pregnancy Rate - Transfer Day 3

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    End point title
    		 Ongoing Pregnancy Rate - Transfer Day 3
    End point description
    Ongoing pregnancy was analysed for subjects with transfer on day 3. Data are presented for the ITT analysis set.
    End point type
    Secondary
    End point timeframe
    10-11 weeks after transfer.
    End point values
    		 Barusiban Placebo
    Number of subjects analysed
    65
    62
    Units: Adjusted response rate (%)
        number (not applicable)
    19.2
    29.9
    Statistical analysis title
    		 Adjusted Ongoing Pregnancy Rate- Transfer Day 3
    Statistical analysis description
    Analysis of ongoing pregnancy rate in subjects with transfer on day 3.
    Comparison groups
    Barusiban v Placebo
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    P-value
    		 = 0.219 [16]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.557
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.22
         upper limit
    		 1.42
    Notes
    [15] - Comparison between the groups was based on logistic regression model with treatment, number of embryos transferred, trial site, and primary reason for infertility as factors.
    [16] - p-value corresponds to a two-sided test of superiority.

    Secondary: Ongoing Pregnancy Rate - Transfer Day 5

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    End point title
    		 Ongoing Pregnancy Rate - Transfer Day 5
    End point description
    Ongoing pregnancy was analysed for subjects with transfer on day 5. Data are presented for the ITT analysis set.
    End point type
    Secondary
    End point timeframe
    10-11 weeks after transfer.
    End point values
    		 Barusiban Placebo
    Number of subjects analysed
    65
    63
    Units: Adjusted response rate (%)
        number (not applicable)
    49.7
    33.4
    Statistical analysis title
    		 Adjusted Ongoing Pregnancy Rate- Transfer Day 5
    Statistical analysis description
    Analysis of ongoing pregnancy rate in subjects with transfer on day 5.
    Comparison groups
    Barusiban v Placebo
    Number of subjects included in analysis
    128
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [17]
    P-value
    		 = 0.147 [18]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.967
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.79
         upper limit
    		 4.9
    Notes
    [17] - Comparison between the groups was based on logistic regression model with treatment, number of blastocysts transferred, trial site, primary reason for infertility, and blastocyst quality parameters as factors.
    [18] - p-value corresponds to a two-sided test of superiority.

    Secondary: Implantation Rate

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    End point title
    		 Implantation Rate
    End point description
    Implantation rate was defined as the number of intrauterine gestational sacs with fetal heart beat (5-6 weeks after transfer) divided by the number of embryos/blastocysts transferred. Data are presented for the ITT analysis set.
    End point type
    Secondary
    End point timeframe
    5-6 weeks after transfer.
    End point values
    		 Barusiban Placebo
    Number of subjects analysed
    130 [19]
    125 [20]
    Units: Adjusted response rate (%)
        number (not applicable)
    27.1
    24.4
    Notes
    [19] - Number of embryos/blastocysts = 225
    [20] - Number of embryos/blastocysts = 215
    Statistical analysis title
    		 Adjusted Implantation Rate
    Statistical analysis description
    Analysis of implantation rate was intended to provide supportive evidence of treatment effect of barusiban.
    Comparison groups
    Barusiban v Placebo
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [21]
    P-value
    		 = 0.546 [22]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.154
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 1.83
    Notes
    [21] - Comparison between the groups was based on logistic regression model with treatment, trial site, primary reason for infertility, and embryo/blastocyst quality as factors.
    [22] - p-value corresponds to a two-sided test of superiority.

    Secondary: Implantation Rate - Transfer Day 3

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    End point title
    		 Implantation Rate - Transfer Day 3
    End point description
    Implantation rate was analysed for subjects with transfer on day 3. Data are presented for the ITT analysis set.
    End point type
    Secondary
    End point timeframe
    5-6 weeks after transfer.
    End point values
    		 Barusiban Placebo
    Number of subjects analysed
    65 [23]
    62 [24]
    Units: Adjusted response rate (%)
        number (not applicable)
    13.7
    19.6
    Notes
    [23] - Number of embryos transferred = 117
    [24] - Number of embryos transferred = 111
    Statistical analysis title
    		 Adjusted Implantation Rate - Transfer Day 3
    Statistical analysis description
    Analysis of implantation rate in subjects with transfer on day 3.
    Comparison groups
    Barusiban v Placebo
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [25]
    P-value
    		 = 0.251 [26]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.31
         upper limit
    		 1.35
    Notes
    [25] - Comparison between the groups was based on logistic regression model with treatment, number of embryos transferred, trial site, and primary reason for infertility as factors.
    [26] - p-value corresponds to a two-sided test of superiority.

    Secondary: Implantation Rate - Transfer Day 5

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    End point title
    		 Implantation Rate - Transfer Day 5
    End point description
    Implantation rate was analysed for subjects with transfer on day 5. Data are presented for the ITT analysis set.
    End point type
    Secondary
    End point timeframe
    5-6 weeks after transfer.
    End point values
    		 Barusiban Placebo
    Number of subjects analysed
    65 [27]
    63 [28]
    Units: Adjusted response rate (%)
        number (not applicable)
    44.6
    24.6
    Notes
    [27] - Number of blastocysts transferred = 108
    [28] - Number of blastocysts transferred = 104
    Statistical analysis title
    		 Adjusted Implantation Rate - Transfer Day 5
    Statistical analysis description
    Analysis of implantation rate in subjects with transfer on day 5.
    Comparison groups
    Barusiban v Placebo
    Number of subjects included in analysis
    128
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [29]
    P-value
    		 = 0.013 [30]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.471
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.21
         upper limit
    		 5.06
    Notes
    [29] - Comparison between the groups was based on logistic regression model with treatment, number of blastocysts transferred, trial site, primary reason for infertility, and blastocyst quality parameters as factors.
    [30] - p-value corresponds to a two-sided test of superiority.

    Secondary: Clinical Pregnancy with Fetal Heart Beat Rate

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    End point title
    		 Clinical Pregnancy with Fetal Heart Beat Rate
    End point description
    Clinical pregnancy with fetal heart beat was defined as at least one intrauterine gestational sac with fetal heart beat 5-6 weeks after transfer. Data are presented for the ITT analysis set.
    End point type
    Secondary
    End point timeframe
    5-6 weeks after transfer.
    End point values
    		 Barusiban Placebo
    Number of subjects analysed
    130
    125
    Units: Adjusted response rate (%)
        number (not applicable)
    37.4
    36.4
    Statistical analysis title
    		 Adj. Clinical Pregnancy with Fetal Heart Beat Rate
    Statistical analysis description
    Analysis of clinical pregnancy with fetal heart beat rate was intended to provide supportive evidence of treatment effect of barusiban.
    Comparison groups
    Barusiban v Placebo
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [31]
    P-value
    		 = 0.882 [32]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.044
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.59
         upper limit
    		 1.83
    Notes
    [31] - Comparison between the groups was based on logistic regression model with treatment, trial site, primary reason for infertility, and embryo/blastocyst quality as factors.
    [32] - p-value corresponds to a two-sided test of superiority.

    Secondary: Clinical Pregnancy with Fetal Heart Beat Rate - Transfer Day 3

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    End point title
    		 Clinical Pregnancy with Fetal Heart Beat Rate - Transfer Day 3
    End point description
    Clinical pregnancy with fetal heart beat rate was analysed for subjects with transfer on day 3. Data are presented for the ITT analysis set.
    End point type
    Secondary
    End point timeframe
    5-6 weeks after transfer.
    End point values
    		 Barusiban Placebo
    Number of subjects analysed
    65
    62
    Units: Adjusted response rate (%)
        number (not applicable)
    22.3
    32.7
    Statistical analysis title
    		 Adj. Clin. Pregnancy with Fetal Heart Beat Rate
    Statistical analysis description
    Analysis of clinical pregnancy with fetal heart beat rate in subjects with transfer on day 3.
    Comparison groups
    Barusiban v Placebo
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [33]
    P-value
    		 = 0.254 [34]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.592
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.24
         upper limit
    		 1.46
    Notes
    [33] - Comparison between the groups was based on logistic regression model with treatment, number of embryos transferred, trial site, and primary reason for infertility as factors.
    [34] - p-value corresponds to a two-sided test of superiority.

    Secondary: Clinical Pregnancy with Fetal Heart Beat Rate - Transfer Day 5

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    End point title
    		 Clinical Pregnancy with Fetal Heart Beat Rate - Transfer Day 5
    End point description
    Clinical pregnancy with fetal heart beat rate was analysed for subjects with transfer on day 5. Data are presented for the ITT analysis set.
    End point type
    Secondary
    End point timeframe
    5-6 weeks after transfer.
    End point values
    		 Barusiban Placebo
    Number of subjects analysed
    65
    63
    Units: Adjusted response rate (%)
        number (not applicable)
    53.9
    33.8
    Statistical analysis title
    		 Adj. Clin. Pregnancy with Fetal Heart Beat Rate
    Statistical analysis description
    Analysis of clinical pregnancy with fetal heat beat rate in subjects with transfer on day 5.
    Comparison groups
    Barusiban v Placebo
    Number of subjects included in analysis
    128
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [35]
    P-value
    		 = 0.074 [36]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.92
         upper limit
    		 5.68
    Notes
    [35] - Comparison between the groups was based on logistic regression model with treatment, number of blastocysts transferred, trial site, primary reason for infertility, and blastocyst quality parameters as factors.
    [36] - p-value corresponds to a two-sided test of superiority.

    Secondary: Positive βhCG Rate

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    End point title
    		 Positive βhCG Rate
    End point description
    Positive βhCG was confirmed by a blood test 13-15 days after transfer. Data are presented for the ITT analysis set.
    End point type
    Secondary
    End point timeframe
    13-15 days after transfer.
    End point values
    		 Barusiban Placebo
    Number of subjects analysed
    130
    125
    Units: Adjusted response rate (%)
        number (not applicable)
    47.9
    44.4
    Statistical analysis title
    		 Adjusted Positive βhCG Rate
    Statistical analysis description
    Analysis of positive βhCG rate was intended to provide supportive evidence of treatment effect of barusiban.
    Comparison groups
    Barusiban v Placebo
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [37]
    P-value
    		 = 0.612 [38]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.154
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.66
         upper limit
    		 2
    Notes
    [37] - Comparison between the groups was based on logistic regression model with treatment, trial site, primary reason for infertility, and embryo/blastocyst quality as factors.
    [38] - p-value corresponds to a two-sided test of superiority.

    Secondary: Positive βhCG Rate - Transfer Day 3

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    End point title
    		 Positive βhCG Rate - Transfer Day 3
    End point description
    Positive βhCG rate was analysed for subjects with transfer on day 3. Data are presented for the ITT analysis set.
    End point type
    Secondary
    End point timeframe
    13-15 days after transfer.
    End point values
    		 Barusiban Placebo
    Number of subjects analysed
    65
    62
    Units: Adjusted response rate (%)
        number (not applicable)
    33.5
    43.3
    Statistical analysis title
    		 Adjusted Positive βhCG Rate - Transfer Day 3
    Statistical analysis description
    Analysis of positive βhCG rate in subjects with transfer on day 3.
    Comparison groups
    Barusiban v Placebo
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [39]
    P-value
    		 = 0.313 [40]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.658
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.29
         upper limit
    		 1.48
    Notes
    [39] - Comparison between the groups was based on logistic regression model with treatment, number of embryos transferred, trial site, and primary reason for infertility as factors.
    [40] - p-value corresponds to a two-sided test of superiority.

    Secondary: Positive βhCG Rate - Transfer Day 5

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    End point title
    		 Positive βhCG Rate - Transfer Day 5
    End point description
    Positive βhCG rate was analysed for subjects with transfer on day 5. Data are presented for the ITT analysis set.
    End point type
    Secondary
    End point timeframe
    13-15 days after transfer.
    End point values
    		 Barusiban Placebo
    Number of subjects analysed
    65
    63
    Units: Adjusted response rate (%)
        number (not applicable)
    63.4
    43
    Statistical analysis title
    		 Adjusted Positive βhCG Rate - Transfer Day 5
    Statistical analysis description
    Analysis of positive βhCG rate in subjects with transfer on day 5.
    Comparison groups
    Barusiban v Placebo
    Number of subjects included in analysis
    128
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [41]
    P-value
    		 = 0.077 [42]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.91
         upper limit
    		 5.73
    Notes
    [41] - Comparison between the groups was based on logistic regression model with treatment, number of blastocysts transferred, trial site, primary reason for infertility, and blastocyst quality parameters as factors.
    [42] - p-value corresponds to a two-sided test of superiority.

    Secondary: Barusiban Concentration

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    End point title
    		 Barusiban Concentration [43]
    End point description
    The plasma concentration of barusiban at the expected tmax was analysed. Data are presented for the ITT analysis set.
    End point type
    Secondary
    End point timeframe
    30 minutes after the 2nd IMP administration.
    Notes
    [43] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Results for this endpoint is only reported for the barusiban group since barusiban was not administered in the placebo group.
    End point values
    		 Barusiban
    Number of subjects analysed
    130
    Units: ng/mL
        arithmetic mean (standard deviation)
    2643 ( 565 )
    No statistical analyses for this end point

    Secondary: Injection Site Reactions

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    End point title
    		 Injection Site Reactions
    End point description
    Presence and intensity (none, mild, moderate or severe) of redness, pain, itching, swelling and bruising was assessed by the investigator directly or by asking the subject, as applicable. Data are presented for the safety analysis set. The numbers presented refer to number of subjects with at least one mild/moderate/severe reaction (out of a total of 20 assessments per subject).
    End point type
    Secondary
    End point timeframe
    Injection site reactions were assessed immediately and 30 min after each IMP administration (i.e. post-1st IMP and post-2nd IMP).
    End point values
    		 Barusiban Placebo
    Number of subjects analysed
    130
    125
    Units: Number of subjects
        Mild
    121
    95
        Moderate
    67
    37
        Severe
    7
    9
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were recorded from signing of informed consent to the end-of-trial.
    Adverse event reporting additional description
    Adverse events with onset after start of the first IMP administration were considered treatment-emergent and are presented for the safety analysis set.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Barusiban
    Reporting group description
    		 Subjects randomised to barusiban IMP were included in this group.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects randomised to placebo IMP were included in this group.

    Serious adverse events
    		 Barusiban Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 130 (2.31%)
    4 / 125 (3.20%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Pregnancy, puerperium and perinatal conditions
    Haemorrhage in pregnancy
         subjects affected / exposed
    3 / 130 (2.31%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ectopic pregnancy
         subjects affected / exposed
    0 / 130 (0.00%)
    2 / 125 (1.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abortion spontaneous
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 125 (0.80%)
         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
    Pelvic pain
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 125 (0.80%)
         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
    		 Barusiban Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    59 / 130 (45.38%)
    46 / 125 (36.80%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 130 (3.85%)
    8 / 125 (6.40%)
         occurrences all number
    5
    10
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    15 / 130 (11.54%)
    12 / 125 (9.60%)
         occurrences all number
    15
    13
    Haemorrhage in pregnancy
         subjects affected / exposed
    12 / 130 (9.23%)
    2 / 125 (1.60%)
         occurrences all number
    13
    2
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    14 / 130 (10.77%)
    2 / 125 (1.60%)
         occurrences all number
    26
    2
    Injection site swelling
         subjects affected / exposed
    10 / 130 (7.69%)
    2 / 125 (1.60%)
         occurrences all number
    15
    2
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    6 / 130 (4.62%)
    9 / 125 (7.20%)
         occurrences all number
    7
    10

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None
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