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    Clinical Trial Results:
    Randomized, Double-blind, Multicenter, Phase III Study Comparing the Efficacy and Safety of Retosiban Versus Atosiban Therapy for Women in Spontaneous Preterm Labor

    Summary
    EudraCT number
    2014-001826-13
    Trial protocol
    BE   GB   SE   ES   DE   IT   FR  
    Global end of trial date
    25 Aug 2017

    Results information
    Results version number
    v4(current)
    This version publication date
    23 Sep 2018
    First version publication date
    10 Mar 2018
    Other versions
    v1 , v2 , v3
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    200721
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline
    Sponsor organisation address
    980 Great West Road, Brentford, Middlesex, United Kingdom,
    Public contact
    GSK Response Center, GlaxoSmithKline, 1 866-435-7343,
    Scientific contact
    GSK Response Center, GlaxoSmithKline, 1 866-435-7343,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-001359-PIP01-12
    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
    13 Dec 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Aug 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To demonstrate the superiority of retosiban to prolong pregnancy compared with atosiban
    Protection of trial subjects
    Not applicable
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    16 Mar 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 6
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    Israel: 35
    Country: Number of subjects enrolled
    Italy: 5
    Country: Number of subjects enrolled
    Mexico: 24
    Country: Number of subjects enrolled
    Korea, Republic of: 13
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    Sweden: 3
    Country: Number of subjects enrolled
    United Kingdom: 1
    Worldwide total number of subjects
    97
    EEA total number of subjects
    25
    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)
    3
    Adults (18-64 years)
    94
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    ZINN was a randomized, double-blind, double-dummy multicenter study to compare efficacy and safety of retosiban versus atosiban in female participants aged 12 to 45 years with an uncomplicated singleton pregnancy in preterm labor with intact membranes between 24 0/7 and 33 6/7 weeks gestation.

    Pre-assignment
    Screening details
    From 330 planned participants 97 were randomized to receive either retosiban or atosiban intravenous (IV) infusion in a ratio of 1:1. The study was terminated early due to feasibility.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Retosiban
    Arm description
    Participants were administered 6 milligram (mg) IV loading dose of retosiban over 5 minutes followed by a 6 milligram per hour (mg/hour) continuous infusion of retosiban over 48 hours. Participants with an inadequate response any time after first hour of treatment were administered another 6 mg retosiban loading dose followed by 12 mg/hour continuous infusion for remainder of 48-hour treatment period.
    Arm type
    Experimental

    Investigational medicinal product name
    Retosiban
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Retosiban was available as a clear, colorless solution for infusion at a concentration of 15 milligrams per milliliter (mg/mL).

    Arm title
    Atosiban
    Arm description
    Participants were administered atosiban in 3 successive stages. An initial bolus dose of 6.75 mg using atosiban 6.75 mg/0.9 milliliter (mL) solution for injection, followed by continuous high dose infusion at 18 mg/hour for 3 hours, then a lower 6 mg/hour infusion for the remainder of the 48-hour using the atosiban 37.5 mg/5 mL concentrate for solution.
    Arm type
    Active comparator

    Investigational medicinal product name
    Atosiban
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Atosiban was available as a clear, colorless solution for injection at a concentration of 6.75 mg/0.9 mL and 7.5 mg/mL solution for infusion

    Number of subjects in period 1
    Retosiban Atosiban
    Started
    47
    50
    Completed
    43
    48
    Not completed
    4
    2
         Consent withdrawn by subject
    2
    1
         Lost to follow-up
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Retosiban
    Reporting group description
    Participants were administered 6 milligram (mg) IV loading dose of retosiban over 5 minutes followed by a 6 milligram per hour (mg/hour) continuous infusion of retosiban over 48 hours. Participants with an inadequate response any time after first hour of treatment were administered another 6 mg retosiban loading dose followed by 12 mg/hour continuous infusion for remainder of 48-hour treatment period.

    Reporting group title
    Atosiban
    Reporting group description
    Participants were administered atosiban in 3 successive stages. An initial bolus dose of 6.75 mg using atosiban 6.75 mg/0.9 milliliter (mL) solution for injection, followed by continuous high dose infusion at 18 mg/hour for 3 hours, then a lower 6 mg/hour infusion for the remainder of the 48-hour using the atosiban 37.5 mg/5 mL concentrate for solution.

    Reporting group values
    Retosiban Atosiban Total
    Number of subjects
    47 50
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    27.7 ± 6.15 27.1 ± 5.66 -
    Gender categorical
    Units: Subjects
        Female
    47 50 97
        Male
    0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Retosiban
    Reporting group description
    Participants were administered 6 milligram (mg) IV loading dose of retosiban over 5 minutes followed by a 6 milligram per hour (mg/hour) continuous infusion of retosiban over 48 hours. Participants with an inadequate response any time after first hour of treatment were administered another 6 mg retosiban loading dose followed by 12 mg/hour continuous infusion for remainder of 48-hour treatment period.

    Reporting group title
    Atosiban
    Reporting group description
    Participants were administered atosiban in 3 successive stages. An initial bolus dose of 6.75 mg using atosiban 6.75 mg/0.9 milliliter (mL) solution for injection, followed by continuous high dose infusion at 18 mg/hour for 3 hours, then a lower 6 mg/hour infusion for the remainder of the 48-hour using the atosiban 37.5 mg/5 mL concentrate for solution.

    Subject analysis set title
    Retosiban
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants were administered 6 milligram (mg) IV loading dose of retosiban over 5 minutes followed by a 6 milligram per hour (mg/hour) continuous infusion of retosiban over 48 hours. Participants with an inadequate response any time after first hour of treatment were administered another 6 mg retosiban loading dose followed by 12 mg/hour continuous infusion for remainder of 48-hour treatment period. Data is a combined data set. Data is presented for 10 participants from retosiban arm of study 200719 (NCT02377466) and 43 participants from retosiban arm of study 200721 (NCT02292771).

    Primary: Time to delivery from the start of investigational product (IP) administration

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    End point title
    Time to delivery from the start of investigational product (IP) administration
    End point description
    Time to delivery is the number of days from the first dose of study treatment until delivery. The time to delivery was calculated as the days between the delivery and start time of the study treatment infusion using the formula: Time to delivery (days) = (date and time of delivery minus date and time of start of infusion) divided by (24 multiplied by 60). The adjusted mean number of days to delivery along with standard error has been presented. Maternal intent-to-treat (ITT) Population comprised of all mothers randomly assigned to treatment who have been exposed to study treatment irrespective of their compliance to the planned course of treatment.
    End point type
    Primary
    End point timeframe
    Up to 17 weeks
    End point values
    Retosiban Atosiban
    Number of subjects analysed
    47 [1]
    50 [2]
    Units: Days
    arithmetic mean (standard error)
        Days
    32.51 ± 2.990
    33.71 ± 2.531
    Notes
    [1] - Maternal ITT Population
    [2] - Maternal ITT Population
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Retosiban v Atosiban
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3797
    Method
    Finite mixture model
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.879
         upper limit
    6.479

    Secondary: Number of participants with births prior to 37 0/7 Weeks gestation

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    End point title
    Number of participants with births prior to 37 0/7 Weeks gestation
    End point description
    Gestational age (GA) at birth (weeks) is defined as the GA when the baby is born. Participants were considered to have delivered prior to 37 0/7 weeks, that is preterm , if the GA at birth is less than 37 0/7 weeks. The number of participants who delivered prior to 37 0/7 weeks gestation has been presented. Logistic regression model was used to calculate p-values.
    End point type
    Secondary
    End point timeframe
    Up to 13 weeks
    End point values
    Retosiban Atosiban
    Number of subjects analysed
    47 [3]
    50 [4]
    Units: Participants
        Participants
    25
    28
    Notes
    [3] - Maternal ITT Population
    [4] - Maternal ITT Population
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Atosiban v Retosiban
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.952
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.44
         upper limit
    2.18

    Secondary: Number of participants with births at term

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    End point title
    Number of participants with births at term
    End point description
    Participants were considered to have delivered at term if the gestational age was >=37 0/7. The number of participants who delivered at term, that is, 37 0/7 to 41 6/7 weeks gestation has been presented. Logistic regression model was used to calculate p-values.
    End point type
    Secondary
    End point timeframe
    Up to 17 weeks
    End point values
    Retosiban Atosiban
    Number of subjects analysed
    47 [5]
    50 [6]
    Units: Participants
        Participants
    21
    22
    Notes
    [5] - Maternal ITT Population
    [6] - Maternal ITT Population
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Atosiban v Retosiban
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.952
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.46
         upper limit
    2.29

    Secondary: Length of neonatal hospital stay

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    End point title
    Length of neonatal hospital stay
    End point description
    The length of stay was collected from medical records and was calculated as the days between the delivery date and time and discharge date and time. Log of length of stay was calculated as treatment plus GA at randomization plus established progesterone use based on Analysis of covariance (ANCOVA) model. The p-value was calculated using t-test method. Neonatal ITT Population comprised of all neonates whose mothers were the randomized participants who have been exposed to study treatment, that is, mothers from the ITT Population.
    End point type
    Secondary
    End point timeframe
    Up to 28 days post estimated date of delivery (EDD) of 40 0/7 weeks gestation
    End point values
    Retosiban Atosiban
    Number of subjects analysed
    47 [7]
    50 [8]
    Units: Days
    least squares mean (confidence interval 95%)
        Days
    4.98 (3.54 to 6.99)
    4.38 (3.15 to 6.09)
    Notes
    [7] - Neonatal ITT Population
    [8] - Neonatal ITT Population
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Retosiban v Atosiban
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5672
    Method
    ANCOVA
    Parameter type
    Ratio
    Point estimate
    1.14
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.73
         upper limit
    1.76
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.222

    Secondary: Number of neonates with composite neonatal morbidity and mortality

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    End point title
    Number of neonates with composite neonatal morbidity and mortality
    End point description
    The neonatal composite endpoint was determined from review of medical records and included the following components: fetal or neonatal death, Respiratory Distress Syndrome (RDS), bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC) or isolated perforation, sepsis based on positive blood culture with clinical features of sepsis, meningitis based on positive results for cerebrospinal fluid culture performed as part of infection workup, retinopathy of prematurity (ROP), Intraventricular Hemorrhage (IVH), white matter injury and cerebellar hemorrhage.
    End point type
    Secondary
    End point timeframe
    Up to 28 weeks after EDD (40 weeks gestation)
    End point values
    Retosiban Atosiban
    Number of subjects analysed
    47 [9]
    50 [10]
    Units: Participants
        Participants
    3
    2
    Notes
    [9] - Neonatal ITT Population
    [10] - Neonatal ITT Population
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Retosiban v Atosiban
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5066
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.3
         upper limit
    11.71

    Secondary: Number of neonates with any composite neonatal morbidity and mortality, excluding RDS

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    End point title
    Number of neonates with any composite neonatal morbidity and mortality, excluding RDS
    End point description
    The neonatal composite endpoint was determined from review of medical records and included the following components: fetal or neonatal death, RDS, BPD, NEC or isolated perforation, sepsis based on positive blood culture with clinical features of sepsis, meningitis based on positive results for cerebrospinal fluid culture performed as part of infection workup, ROP, IVH, white matter injury and cerebellar hemorrhage. Number of neonates with any composite neonatal morbidity and mortality component, excluding RDS has been presented.
    End point type
    Secondary
    End point timeframe
    Up to 28 weeks after EDD (40 weeks gestation)
    End point values
    Retosiban Atosiban
    Number of subjects analysed
    47 [11]
    50 [12]
    Units: Participants
        Participants
    0
    1
    Notes
    [11] - Neonatal ITT Population
    [12] - Neonatal ITT Population
    No statistical analyses for this end point

    Secondary: Number of neonates with each individual component of composite neonatal morbidity and mortality

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    End point title
    Number of neonates with each individual component of composite neonatal morbidity and mortality
    End point description
    The neonatal composite endpoint was determined from review of medical records and included the following components: fetal or neonatal death, RDS, BPD, NEC or isolated perforation, sepsis based on positive blood culture with clinical features of sepsis, meningitis based on positive results for cerebrospinal fluid culture performed as part of infection workup, ROP, IVH, cerebellar hemorrhage and white matter injury included Periventricular Leukomalacia PVL), porencephalic cyst, and persistent ventriculomegaly. Number of neonates with with each individual component of the composite neonatal morbidity and mortality has been presented.
    End point type
    Secondary
    End point timeframe
    Up to 28 weeks after EDD (40 weeks gestation)
    End point values
    Retosiban Atosiban
    Number of subjects analysed
    47 [13]
    50 [14]
    Units: Participants
        Fetal death
    0
    0
        Neonatal death
    0
    1
        RDS
    3
    1
        BPD
    0
    0
        NEC or isolated perforation
    0
    0
        Sepsis
    0
    0
        Meningitis
    0
    0
        ROP
    0
    0
        IVH
    0
    0
        PVL
    0
    0
        Porencephalic Cyst
    0
    0
        Persistent Ventriculomegaly
    0
    0
        Cerebellar Hemorrhage
    0
    0
    Notes
    [13] - Neonatal ITT Population
    [14] - Neonatal ITT Population
    No statistical analyses for this end point

    Secondary: Length of stay in specialized care unit

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    End point title
    Length of stay in specialized care unit
    End point description
    Length of neonatal stay in specialized care unit like Intensive Care Unit (ICU) or Neonatal Intensive Care Unit (NICU) are reported.
    End point type
    Secondary
    End point timeframe
    Up to 28 days post EDD (40 0/7 weeks gestation)
    End point values
    Retosiban Atosiban
    Number of subjects analysed
    47 [15]
    50 [16]
    Units: Days
    median (full range (min-max))
        Days
    13.65 (3.5 to 57.5)
    12.49 (7.6 to 21.8)
    Notes
    [15] - Neonatal Safety Population
    [16] - Neonatal Safety Population
    No statistical analyses for this end point

    Secondary: Number of newborn participants with hospital readmission

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    End point title
    Number of newborn participants with hospital readmission
    End point description
    Newborn hospital readmission following hospitalization for birth was obtained from the newborn's medical records. Only those participants with data available at the specified data points were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to 28 days of EDD (40 0/7 weeks gestation)
    End point values
    Retosiban Atosiban
    Number of subjects analysed
    46 [17]
    50 [18]
    Units: Participants
        Participants
    2
    3
    Notes
    [17] - Neonatal Safety Population
    [18] - Neonatal Safety Population
    No statistical analyses for this end point

    Secondary: Number of participants with births prior to 28 0/7 weeks gestation

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    End point title
    Number of participants with births prior to 28 0/7 weeks gestation
    End point description
    The number of participants who delivered prior to 28 0/7 weeks gestation has been presented. Only those maternal participants who were randomized prior to 28 0/7 week's gestation and delivered were included.
    End point type
    Secondary
    End point timeframe
    Up to 4 weeks
    End point values
    Retosiban Atosiban
    Number of subjects analysed
    47
    50
    Units: Participats
        Participants
    0
    0
    No statistical analyses for this end point

    Secondary: Number of participants with births prior to 32 0/7 weeks gestation

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    End point title
    Number of participants with births prior to 32 0/7 weeks gestation
    End point description
    Number of participants who delivered prior to 32 0/7 weeks gestation has been presented. Only those maternal participants who were randomized prior to 32 0/7 week's gestation and delivered were included.
    End point type
    Secondary
    End point timeframe
    Up to 8 weeks
    End point values
    Retosiban Atosiban
    Number of subjects analysed
    47 [19]
    50 [20]
    Units: Participants
        Participants
    3
    3
    Notes
    [19] - Maternal ITT Population
    [20] - Maternal ITT Population
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Atosiban v Retosiban
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.779
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.12
         upper limit
    4.84

    Secondary: Number of participants with births prior to 35 0/7 weeks gestation

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    End point title
    Number of participants with births prior to 35 0/7 weeks gestation
    End point description
    Number of participants who delivered prior to 35 0/7 weeks gestation has been presented. Only those maternal participants who were randomized prior to 35 0/7 week's gestation and delivered were included.
    End point type
    Secondary
    End point timeframe
    Up to 11 weeks
    End point values
    Retosiban Atosiban
    Number of subjects analysed
    47 [21]
    50 [22]
    Units: Participants
        Participants
    14
    14
    Notes
    [21] - Maternal ITT Population
    [22] - Maternal ITT Population
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Retosiban v Atosiban
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6646
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.51
         upper limit
    2.9

    Secondary: Number of participants with births <=7 days from the first study treatment

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    End point title
    Number of participants with births <=7 days from the first study treatment
    End point description
    Number of participants who delivered in less than or equal to 7 days from first dose of study treatment has been presented.
    End point type
    Secondary
    End point timeframe
    Up to 7 days
    End point values
    Retosiban Atosiban
    Number of subjects analysed
    47 [23]
    50 [24]
    Units: Participants
        Participants
    10
    7
    Notes
    [23] - Maternal ITT Population
    [24] - Maternal ITT Population
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Retosiban v Atosiban
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1432
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.75
         upper limit
    7.24

    Secondary: Number of participants with births <=48 hours from the first study treatment

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    End point title
    Number of participants with births <=48 hours from the first study treatment
    End point description
    Number of participants who delivered in less than or equal to 48 hours from first dose of study treatment has been presented.
    End point type
    Secondary
    End point timeframe
    Up to 48 hours
    End point values
    Retosiban Atosiban
    Number of subjects analysed
    47 [25]
    50 [26]
    Units: Participants
        Participants
    6
    6
    Notes
    [25] - Maternal ITT Population
    [26] - Maternal ITT Population
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Atosiban v Retosiban
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.525
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.43
         upper limit
    5.15

    Secondary: Number of participants with births <=24 hours from the first study treatment

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    End point title
    Number of participants with births <=24 hours from the first study treatment
    End point description
    Number of participants who delivered in less than or equal to 24 hours from first dose of study treatment has been presented.
    End point type
    Secondary
    End point timeframe
    Up to 24 hours
    End point values
    Retosiban Atosiban
    Number of subjects analysed
    47 [27]
    50 [28]
    Units: Participants
        Participants
    3
    6
    Notes
    [27] - Maternal ITT Population
    [28] - Maternal ITT Population
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Atosiban v Retosiban
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4682
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.13
         upper limit
    2.58

    Secondary: Number of maternal participants with non-serious adverse events (AEs) and serious adverse events (SAEs)

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    End point title
    Number of maternal participants with non-serious adverse events (AEs) and serious adverse events (SAEs)
    End point description
    An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose: results in death; is life threatening; requires hospitalization or prolongation of existing hospitalization; results in disability/incapacity; is a congenital anomaly/birth defect; important medical events that may require medical or surgical intervention to prevent one of the other outcomes described before; is associated with liver injury and impaired liver function. Maternal Safety Population comprised of all mothers randomly assigned to treatment who have been exposed to study treatment. The number of maternal participants who experienced at least one non-serious AE and one SAE has been presented.
    End point type
    Secondary
    End point timeframe
    Up to 6 weeks after delivery
    End point values
    Retosiban Atosiban
    Number of subjects analysed
    47 [29]
    50 [30]
    Units: Participants
        Non-serious AE
    34
    25
        SAE
    7
    9
    Notes
    [29] - Maternal Safety Population
    [30] - Maternal Safety Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in diastolic blood pressure (DBP) and systolic blood pressure (SBP) in maternal participants

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    End point title
    Change from Baseline in diastolic blood pressure (DBP) and systolic blood pressure (SBP) in maternal participants
    End point description
    SBP and DBP were measured during inpatient randomized treatment phase (15 to 30 minutes, 4 to 8 hours, and 20 to 24 hours after the start of the infusion, at the end of the infusion) and at the post-infusion assessment. Baseline is the last available assessment prior to first dose of study treatment. Change from Baseline is the post-dose visit value minus Baseline. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).
    End point type
    Secondary
    End point timeframe
    Baseline and up to 1 week
    End point values
    Retosiban Atosiban
    Number of subjects analysed
    47 [31]
    50 [32]
    Units: Millimeter of mercury (mmHg)
    arithmetic mean (standard deviation)
        DBP; Day 1: 15 to 30 minutes, n=42,45
    -3.6 ± 10.96
    -0.7 ± 8.95
        DBP; Day 1: 4 to 8 hours, n=42,43
    -4.3 ± 11.07
    -3.7 ± 10.28
        DBP; Day 1: 20 to 24 hours, n=38,41
    -5.7 ± 9.31
    -4.1 ± 9.90
        DBP; Day 2, n=40,42
    -4.4 ± 9.57
    -2.6 ± 9.93
        DBP; Post-infusion assessment, n=35,41
    -1.6 ± 8.63
    1.3 ± 10.12
        SBP; Day 1: 15 to 30 minutes, n=42,45
    -2.5 ± 9.53
    -0.4 ± 11.02
        SBP; Day 1: 4 to 8 hours, n=42,43
    -4.3 ± 9.05
    -3.3 ± 12.21
        SBP; Day 1: 20 to 24 hours, n=38,41
    -4.1 ± 10.16
    -5.2 ± 13.03
        SBP; Day 2, n=40,42
    -3.9 ± 11.53
    -3.0 ± 11.35
        SBP; Post-infusion assessment, n=35,41
    -1.5 ± 11.04
    -2.1 ± 11.37
    Notes
    [31] - Maternal Safety Population
    [32] - Maternal Safety Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in heart rate in maternal participants

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    End point title
    Change from Baseline in heart rate in maternal participants
    End point description
    Heart rate was measured during inpatient randomized treatment phase (15 to 30 minutes, 4 to 8 hours, and 20 to 24 hours after the start of the infusion, at the end of the infusion) and at the post-infusion assessment. Baseline is the last available assessment prior to first dose of study treatment. Change from Baseline is the post-dose visit value minus Baseline. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).
    End point type
    Secondary
    End point timeframe
    Baseline and up to 1 week
    End point values
    Retosiban Atosiban
    Number of subjects analysed
    47 [33]
    50 [34]
    Units: Beats per minute
    arithmetic mean (standard deviation)
        Day 1: 15 to 30 minutes, n=42,46
    -3.0 ± 12.65
    -0.8 ± 10.45
        Day 1: 4 to 8 hours, n=42, 43
    -5.0 ± 13.69
    -3.0 ± 13.65
        Day 1: 20 to 24 hours, n=38, 41
    -1.2 ± 14.44
    -3.1 ± 13.82
        Day 2, n=39, 41
    -2.2 ± 11.81
    -2.3 ± 13.44
        Post-infusion assessment, n=35, 41
    -2.7 ± 12.90
    -1.8 ± 13.83
    Notes
    [33] - Maternal Safety Population
    [34] - Maternal Safety Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in respiratory rate in maternal participants

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    End point title
    Change from Baseline in respiratory rate in maternal participants
    End point description
    Respiratory rate was measured during inpatient randomized treatment phase (15 to 30 minutes, 4 to 8 hours, and 20 to 24 hours after the start of the infusion, at the end of the infusion) and at the post-infusion assessment. Baseline is the last available assessment prior to first dose of study treatment. Change from Baseline is the post-dose visit value minus Baseline. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).
    End point type
    Secondary
    End point timeframe
    Baseline and up to 1 week
    End point values
    Retosiban Atosiban
    Number of subjects analysed
    47 [35]
    50 [36]
    Units: breaths per minute
    arithmetic mean (standard deviation)
        Day 1: 15 to 30 minutes, n=25, 28
    0.3 ± 2.82
    -0.6 ± 1.93
        Day 1: 4 to 8 hours, n=23, 24
    0.0 ± 1.65
    -0.8 ± 2.33
        Day 1: 20 to 24 hours, n=21, 21
    0.2 ± 1.87
    -0.6 ± 2.40
        Day 2, n=23, 24
    -0.3 ± 1.64
    0.2 ± 3.45
        Post-infusion assessment, n=22, 23
    -0.3 ± 2.15
    -1.3 ± 2.70
    Notes
    [35] - Maternal Safety Population
    [36] - Maternal Safety Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in temperature in maternal participants

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    End point title
    Change from Baseline in temperature in maternal participants
    End point description
    Temperature was measured during inpatient randomized treatment phase (15 to 30 minutes, 4 to 8 hours, and 20 to 24 hours after the start of the infusion, at the end of the infusion) and at the post-infusion assessment. Baseline is the last available assessment prior to first dose of study treatment. Change from Baseline is the post-dose visit value minus Baseline. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).
    End point type
    Secondary
    End point timeframe
    Baseline and up to 1 week
    End point values
    Retosiban Atosiban
    Number of subjects analysed
    47 [37]
    50 [38]
    Units: degree Celsius
    arithmetic mean (standard deviation)
        Day 1: 15 to 30 minutes, n=41, 43
    -0.02 ± 0.379
    0.02 ± 0.467
        Day 1: 4 to 8 hours, n=40, 42
    -0.06 ± 0.359
    0.00 ± 0.507
        Day 1: 20 to 24 hours, n=37, 41
    -0.07 ± 0.366
    -0.03 ± 0.486
        Day 2, n=40, 42
    -0.07 ± 0.467
    -0.06 ± 0.353
        Post-infusion assessment, n=35, 41
    -0.18 ± 0.334
    -0.20 ± 0.422
    Notes
    [37] - Maternal Safety Population
    [38] - Maternal Safety Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in basophils, eosinophils, lymphocytes, monocytes, neutrophils, platelets and leukocytes count in maternal participants

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    End point title
    Change from Baseline in basophils, eosinophils, lymphocytes, monocytes, neutrophils, platelets and leukocytes count in maternal participants
    End point description
    Blood samples were collected for the evaluation of change in basophils, eosinophils, lymphocytes, monocytes, neutrophils, platelets and leukocytes count. Baseline is defined as the last available assessment prior to the first dose of study treatment. Change from Baseline is the post-dose visit value minus Baseline. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title). 99999 indicates standard deviation was not calculable for a single data point.
    End point type
    Secondary
    End point timeframe
    Baseline and up to 1 week
    End point values
    Retosiban Atosiban
    Number of subjects analysed
    47 [39]
    50 [40]
    Units: Billion cells per liter (L)
    arithmetic mean (standard deviation)
        Basophils;Day2,n=21,23
    0.003 ± 0.0362
    0.010 ± 0.0304
        Basophils;Post-infusion assessment,n=24,28
    0.001 ± 0.0315
    0.007 ± 0.0181
        Basophils;early withdrawal,n=1,1
    -0.020 ± 99999
    0.030 ± 99999
        Eosinophils;Day2,n=21,23
    -0.010 ± 0.0626
    -0.037 ± 0.1181
        Eosinophils;Post-infusion assessment,n=24,28
    0.023 ± 0.0442
    0.066 ± 0.1535
        Eosinophils;early withdrawal,n=1,1
    0.030 ± 99999
    0.050 ± 99999
        Lymphocytes;Day2,n=21,23
    0.186 ± 0.9115
    0.067 ± 0.6017
        Lymphocytes;Post-infusion assessment,n=24,28
    0.348 ± 0.8611
    0.233 ± 0.8047
        Lymphocytes;early withdrawal,n=1,1
    0.270 ± 99999
    -1.770 ± 99999
        Monocytes;Day2,n=21,23
    0.082 ± 0.2222
    0.044 ± 0.2702
        Monocytes;Post-infusion assessment,n=24,28
    0.222 ± 0.1904
    0.133 ± 0.3467
        Monocytes;early withdrawal,n=1,1
    -0.160 ± 99999
    0.410 ± 99999
        Neutrophils;Day2,n=21,23
    0.102 ± 2.6712
    0.559 ± 3.3890
        Neutrophils;Post-infusion assessment,n=24,28
    -1.865 ± 2.9246
    -0.670 ± 2.7063
        Neutrophils;early withdrawal,n=1,1
    -0.710 ± 99999
    -3.550 ± 99999
        Platelets;Day2,n=22,25
    0.0 ± 25.95
    -2.4 ± 36.59
        Platelets;Post-infusion assessment,n=24,31
    21.5 ± 63.14
    20.6 ± 43.74
        Platelets;early withdrawal,n=1,1
    -33.0 ± 99999
    -58.0 ± 99999
        Leukocytes;Day2,n=23,25
    0.17 ± 2.785
    0.72 ± 2.905
        Leukocytes;Post-infusion assessment,n=25,30
    -1.18 ± 2.492
    -0.05 ± 2.756
        Leukocytes;early withdrawal,n=1,1
    -0.60 ± 99999
    -4.80 ± 99999
    Notes
    [39] - Maternal Safety Population
    [40] - Maternal Safety Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in erythrocytes in maternal participants

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    End point title
    Change from Baseline in erythrocytes in maternal participants
    End point description
    Blood samples were collected for the evaluation of change in erythrocytes from Baseline. Baseline is defined as the last available assessment prior to the first dose of study treatment. Change from Baseline is the post-dose visit value minus Baseline. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title). 99999 indicates standard deviation was not calculable for a single data point.
    End point type
    Secondary
    End point timeframe
    Baseline and up to 1 week
    End point values
    Retosiban Atosiban
    Number of subjects analysed
    47 [41]
    50 [42]
    Units: Trillion cells per liter
    arithmetic mean (standard deviation)
        Day 2, n=23, 27
    -0.22 ± 0.284
    -0.29 ± 0.261
        Post-infusion assessment, n=25, 31
    0.06 ± 0.257
    0.05 ± 0.236
        Early withdrawal, n =1, 1
    -0.20 ± 99999
    -0.70 ± 99999
    Notes
    [41] - Maternal Safety Population
    [42] - Maternal Safety Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in hemoglobin and Erythrocyte Mean Corpuscular hemoglobin Concentration (MCHC) in maternal participants

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    End point title
    Change from Baseline in hemoglobin and Erythrocyte Mean Corpuscular hemoglobin Concentration (MCHC) in maternal participants
    End point description
    Blood samples were collected for the evaluation of change in hemoglobin levels and MCHC from Baseline. Baseline is defined as the last available assessment prior to the first dose of study treatment. Change from Baseline is the post-dose visit value minus. 99999 indicates standard deviation was not calculable for a single data point.
    End point type
    Secondary
    End point timeframe
    Baseline and up to 1 week
    End point values
    Retosiban Atosiban
    Number of subjects analysed
    47 [43]
    50 [44]
    Units: grams per liter (g/L)
    arithmetic mean (standard deviation)
        Hemoglobin; Day2, n=23, 27
    -5.4 ± 7.81
    -8.4 ± 6.86
        Hemoglobin; Post-infusion assessment, n=25, 31
    0.8 ± 7.55
    0.5 ± 5.37
        Hemoglobin; early withdrawal, n=1, 1
    -8.0 ± 99999
    -19.0 ± 99999
        MCHC; Day 2, n=23, 27
    1.0 ± 9.41
    0.9 ± 6.85
        MCHC; Post-infusion assessment, n=25, 31
    1.0 ± 7.36
    0.4 ± 8.98
        MCHC; early withdrawal, n=1, 1
    -3.0 ± 99999
    24.0 ± 99999
    Notes
    [43] - Maternal Safety Population
    [44] - Maternal Safety Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in erythrocyte mean corpuscular volume (MCV) and mean platelet volume (MPV) in maternal participants

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    End point title
    Change from Baseline in erythrocyte mean corpuscular volume (MCV) and mean platelet volume (MPV) in maternal participants
    End point description
    Blood samples were collected for the evaluation of change in MCV and MPV from Baseline. Baseline is defined as the last available assessment prior to the first dose of study treatment. Change from Baseline is the post-dose visit value minus Baseline. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title). 99999 indicates standard deviation was not calculable for a single data point.
    End point type
    Secondary
    End point timeframe
    Baseline and up to 1 week
    End point values
    Retosiban Atosiban
    Number of subjects analysed
    47 [45]
    50 [46]
    Units: femtoliter (fL)
    arithmetic mean (standard deviation)
        MCV; Day 2, n=23, 27
    0.3 ± 2.67
    -0.4 ± 1.82
        MCV; Post-infusion assessment, n=25, 31
    -1.2 ± 2.17
    -1.0 ± 2.22
        MCV; early withdrawal, n=1, 1
    -1.0 ± 99999
    -5.0 ± 99999
        MPV; Day 2, n=22, 25
    0.05 ± 0.607
    0.06 ± 0.553
        MPV, Post-infusion assessment, n=24, 31
    -0.10 ± 0.639
    -0.03 ± 0.803
        MPV, early withdrawal, n=1, 1
    0.00 ± 99999
    -1.40 ± 99999
    Notes
    [45] - Maternal Safety Population
    [46] - Maternal Safety Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transferase (GGT) and lactate dehydrogenase (LDH) levels in maternal participants

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    End point title
    Change from Baseline in alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transferase (GGT) and lactate dehydrogenase (LDH) levels in maternal participants
    End point description
    Blood samples were collected for the evaluation of change in ALP, ALT, AST, GGT and LDH from Baseline. Baseline is defined as the last available assessment prior to the first dose of study treatment. Change from Baseline is the post-dose visit value minus Baseline. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title). 99999 indicates standard deviation was not calculable for a single data point.
    End point type
    Secondary
    End point timeframe
    Baseline and up to 1 week
    End point values
    Retosiban Atosiban
    Number of subjects analysed
    47 [47]
    50 [48]
    Units: International Units per liter (IU/L)
    arithmetic mean (standard deviation)
        ALP; Day 2, n=35, 35
    -10.1 ± 12.12
    -12.6 ± 13.07
        ALP; Post-infusion assessment, n=30, 35
    14.1 ± 39.85
    5.9 ± 15.87
        ALP; early withdrawal, n=1, 1
    -6.0 ± 99999
    -19.0 ± 99999
        AST; Day 2, n=34, 35
    -0.9 ± 4.82
    -1.7 ± 3.07
        AST; Post-infusion assessmet, n=29, 35
    -1.3 ± 4.87
    -1.3 ± 4.09
        AST; early withdrawal, n=1, 1
    -3.0 ± 99999
    1.0 ± 99999
        ALT; Day 2, n= 35, 35
    -0.2 ± 2.53
    0.0 ± 2.40
        ALT; Post-infusion assessment, n= 30, 35
    0.0 ± 6.34
    0.8 ± 6.19
        ALT; early withdrawal, n= 1, 1
    -2.0 ± 99999
    5.0 ± 99999
        GGT; Day 2, n= 35, 35
    -0.4 ± 2.44
    -0.9 ± 3.08
        GGT; Post-infusion assessment, n=30, 35
    17.6 ± 79.05
    2.3 ± 4.39
        GGT; eearly withdrawal, n=1, 1
    0.0 ± 99999
    0.0 ± 99999
        LDH; Day 2, n=34, 35
    -9.7 ± 50.58
    -20.0 ± 29.18
        LDH; Post-infusion assessment, n=29, 35
    -2.4 ± 22.08
    -5.4 ± 30.93
        LDH; early withdrawal, n=1, 1
    -18.0 ± 99999
    -59.0 ± 99999
    Notes
    [47] - Maternal Safety Population
    [48] - Maternal Safety Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in albumin and protein levels in maternal participants

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    End point title
    Change from Baseline in albumin and protein levels in maternal participants
    End point description
    Blood samples were collected for the evaluation of change in albumin and protein levels from Baseline. Baseline is defined as the last available assessment prior to the first dose of study treatment. Change from Baseline is the post-dose visit value minus Baseline. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title). 99999 indicates standard deviation was not calculable for a single data point.
    End point type
    Secondary
    End point timeframe
    Baseline and up to 1 week
    End point values
    Retosiban Atosiban
    Number of subjects analysed
    47 [49]
    50 [50]
    Units: grams per liter (g/L)
    arithmetic mean (standard deviation)
        Albumin; Day 2, n=35, 35
    -1.9 ± 2.28
    -2.0 ± 1.95
        Albumin; Post-infusion assessment, n=30, 35
    0.3 ± 2.39
    -0.2 ± 2.26
        Albumin; early withdrawal, n=1, 1
    -4.0 ± 99999
    -8.0 ± 99999
        Protein; Day 2, n=35, 35
    -3.7 ± 4.18
    -3.3 ± 3.69
        Protein; Post-infusion assessment, n=30, 35
    0.5 ± 4.73
    0.0 ± 4.05
        Protein; early withdrawal, n=1, 1
    -5.0 ± 99999
    -12.0 ± 99999
    Notes
    [49] - Maternal Safety Population
    [50] - Maternal Safety Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in calcium, chloride, carbon dioxide, glucose, potassium, magnesium, phosphate and sodium level in maternal participants

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    End point title
    Change from Baseline in calcium, chloride, carbon dioxide, glucose, potassium, magnesium, phosphate and sodium level in maternal participants
    End point description
    Blood samples were collected for the evaluation of change from Baseline in levels of calcium, chloride, carbon dioxide, glucose, potassium, magnesium, phosphate, and sodium. Baseline is defined as the last available assessment prior to the first dose of study treatment. Change from Baseline is the post-dose visit value minus Baseline. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title). 99999 indicates standard deviation was not calculable for a single data point.
    End point type
    Secondary
    End point timeframe
    Baseline and up to 1 week
    End point values
    Retosiban Atosiban
    Number of subjects analysed
    47 [51]
    50 [52]
    Units: millimoles per liter (mmol/L)
    arithmetic mean (standard deviation)
        Calcium; Day 2, n=34, 35
    -0.097 ± 0.1125
    -0.078 ± 0.0884
        Calcium; Post-infusion assessment, n=29, 35
    0.018 ± 0.0953
    0.023 ± 0.0861
        Calcium; early withdrawal, n=1, 1
    -0.120 ± 99999
    -0.230 ± 99999
        Chloride; Day 2, n=35, 35
    1.5 ± 2.02
    1.4 ± 2.03
        Chloride; Post-infusion assessment, n=30, 35
    -1.5 ± 1.83
    -1.3 ± 2.63
        Chloride; early withdrawal, n=1, 1
    2.0 ± 99999
    8.0 ± 99999
        Carbon dioxide; Day 2, n=34, 35
    0.7 ± 2.34
    0.3 ± 2.63
        Carbon dioxide, Post-infusion assessment, n=29,35
    1.9 ± 2.06
    1.9 ± 2.67
        Carbon dioxide, early withdrawal, n=1, 1
    -2.0 ± 99999
    6.0 ± 99999
        Glucose; Day 2, n=35,35
    0.13 ± 2.013
    1.51 ± 2.156
        Glucose; Post-infusion assessment, n=30, 35
    -0.70 ± 1.994
    -0.35 ± 2.283
        Glucose; early withdrawal, n= 1, 1
    0.70 ± 99999
    -5.20 ± 99999
        Potassium; Day 2, n= 34, 35
    0.06 ± 0.392
    -0.06 ± 0.346
        Potassium; Post-infusion assessment, n= 29, 35
    0.21 ± 0.362
    0.18 ± 0.355
        Potassium; early withdrawal, n= 1,1
    -0.10 ± 99999
    0.50 ± 99999
        Magnesium; Day 2, n= 35,35
    0.073 ± 0.2098
    -0.003 ± 0.0657
        Magnesium, Post-infusion assessment, n= 30,35
    0.026 ± 0.0760
    0.009 ± 0.0772
        Magnesium; early withdrawal, n= 1,1
    -0.060 ± 99999
    0.030 ± 99999
        Phosphate; Day 2, n= 35,35
    -0.101 ± 0.2684
    -0.170 ± 0.2357
        Phosphate; Post-infusion assessment, n= 30,35
    0.041 ± 0.2267
    0.094 ± 0.2864
        Phosphate; early withdrawal, n= 1,1
    0.100 ± 99999
    -0.120 ± 99999
        Sodium; Day 2, n= 35,35
    0.7 ± 2.13
    0.1 ± 1.69
        Sodium; Post-infusion assessment, n= 30,35
    -1.1 ± 2.05
    -0.2 ± 2.11
        Sodium; early withdrawal, n= 1,1
    -1.0 ± 99999
    3.0 ± 99999
    Notes
    [51] - Maternal Safety Population
    [52] - Maternal Safety Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in direct bilirubin, bilirubin, indirect bilirubin, creatinine and urate levels in maternal participants

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    End point title
    Change from Baseline in direct bilirubin, bilirubin, indirect bilirubin, creatinine and urate levels in maternal participants
    End point description
    Blood samples were collected for the evaluation of change from Baseline in levels of direct bilirubin, bilirubin, indirect bilirubin, creatinine and urate. Baseline is defined as the last available assessment prior to the first dose of study treatment. Change from Baseline is the post-dose visit value minus Baseline. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title). 99999 indicates standard deviation was not calculable for a single data point.
    End point type
    Secondary
    End point timeframe
    Baseline and up to 1 week
    End point values
    Retosiban Atosiban
    Number of subjects analysed
    47 [53]
    50 [54]
    Units: micromoles per liter (µmol/L)
    arithmetic mean (standard deviation)
        Direct Bilirubin; Day2, n=35,35
    -0.3 ± 0.85
    -0.3 ± 0.66
        Post-infusion assessment, n=30,35
    -0.5 ± 3.41
    -0.1 ± 0.73
        Direct Bilirubin;early withdrawal, n=1,1
    0.0 ± 99999
    0.0 ± 99999
        Bilirubin;Day2, n= 35,35
    -0.7 ± 2.52
    -1.3 ± 2.03
        Bilirubin; Post-infusion assessment, n= 30, 35
    -1.1 ± 8.24
    -0.5 ± 2.01
        Bilirubin; early withdrawal, n= 1,1
    -2.0 ± 99999
    -3.0 ± 99999
        Indirect Bilirubin; Day2, n=35,35
    -0.4 ± 2.35
    -1.1 ± 1.98
        Indirect Bilirubin;Postinfusion assessment,n=30,35
    -0.6 ± 5.06
    -0.4 ± 2.03
        Indirect Bilirubin; early withdrawal, n=1,1
    -2.0 ± 99999
    -3.0 ± 99999
        Creatinine; Day2, n=35,34
    1.75 ± 6.765
    0.04 ± 5.336
        Creatinine; Post-infusion assessment, n=30,33
    2.19 ± 4.437
    0.72 ± 4.680
        Creatinine; early withdrawal, n=1,1
    -0.90 ± 99999
    -6.10 ± 99999
    Notes
    [53] - Maternal Safety Population
    [54] - Maternal Safety Population
    No statistical analyses for this end point

    Secondary: Number of maternal participants with AEs of special interest (AESI)

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    End point title
    Number of maternal participants with AEs of special interest (AESI)
    End point description
    Maternal AESI included: maternal death; chorioamnionitis and its complications (clinical chorioamnionitis, preterm premature rupture of membranes, endomyometritis, wound infection, pelvic abscess, bacteremia, septic shock, disseminated intravascular coagulation, and adult RDS); placental abruption; postpartum hemorrhage – postpartum hemorrhage and/or retained placenta and pulmonary edema. The number of participants with at least one AESI has been presented.
    End point type
    Secondary
    End point timeframe
    Up to 6 weeks post-delivery
    End point values
    Retosiban Atosiban
    Number of subjects analysed
    47 [55]
    50 [56]
    Units: Participants
        Participants
    4
    7
    Notes
    [55] - Maternal Safety Population
    [56] - Maternal Safety Population
    No statistical analyses for this end point

    Secondary: Number of maternal participants with disease related AEs (DRE)

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    End point title
    Number of maternal participants with disease related AEs (DRE)
    End point description
    Maternal DREs included: signs and symptoms of labor discomfort (example, cramping, backache, muscle aches, nausea); subsequent episodes of preterm labor and hospitalization for delivery. The number of participants with at least one DRE has been presented.
    End point type
    Secondary
    End point timeframe
    Up to 6 weeks post-delivery
    End point values
    Retosiban Atosiban
    Number of subjects analysed
    47 [57]
    50 [58]
    Units: Participants
        Participants
    5
    5
    Notes
    [57] - Maternal Safety Population
    [58] - Maternal Safety Population
    No statistical analyses for this end point

    Secondary: Number of participants with fetal non-serious AEs and SAEs

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    End point title
    Number of participants with fetal non-serious AEs and SAEs
    End point description
    An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose: results in death; is life threatening; requires hospitalization or prolongation of existing hospitalization; results in disability/incapacity; is a congenital anomaly/birth defect; important medical events that may require medical or surgical intervention to prevent one of the other outcomes described before; is associated with liver injury and impaired liver function. The number of participants who experienced at least one non-serious AE and one SAE has been presented.
    End point type
    Secondary
    End point timeframe
    Up to 17 weeks
    End point values
    Retosiban Atosiban
    Number of subjects analysed
    47 [59]
    50 [60]
    Units: Participants
        Non-serious AE
    6
    6
        SAE
    4
    2
    Notes
    [59] - Maternal Safety Population
    [60] - Maternal Safety Population
    No statistical analyses for this end point

    Secondary: Number of participants with fetal AESI

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    End point title
    Number of participants with fetal AESI
    End point description
    Fetal AESI included: intrauterine fetal demise; category II or III fetal heart rate tracing; and fetal inflammatory response syndrome characterized by cord blood interleukin-6 >11 picogram per milliliter (pg/mL), funisitis, or chorionic vasculitis. The number of participants who experienced at least one AESI has been presented.
    End point type
    Secondary
    End point timeframe
    Up to 17 weeks
    End point values
    Retosiban Atosiban
    Number of subjects analysed
    47 [61]
    50 [62]
    Units: Participants
        Participants
    5
    5
    Notes
    [61] - Maternal Safety Population
    [62] - Maternal Safety Population
    No statistical analyses for this end point

    Secondary: Neonatal APGAR Scores

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    End point title
    Neonatal APGAR Scores
    End point description
    APGAR is a quick test to assess the health of new born children. The test is performed at 1 and 5 minutes after birth. APGAR scale is determined by evaluating the new born on five categories (appearance, pulse, grimace, activity and respiration) on a scale from zero to two, then summing up the five values obtained. APGAR score ranges from 0 to 10 where a score of 7 and above is normal. The mean and standard deviation of APGAR scores at one minute and at five minutes of birth has been presented. Only those participants with data available at the specified data points were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to 5 minutes after birth
    End point values
    Retosiban Atosiban
    Number of subjects analysed
    47 [63]
    50 [64]
    Units: Score on APGAR scale
    arithmetic mean (standard deviation)
        one minute, n=46, 50
    8.2 ± 1.35
    8.4 ± 1.14
        five minutes, n=46, 50
    9.1 ± 0.96
    9.4 ± 0.67
    Notes
    [63] - Neonatal ITT Population
    [64] - Neonatal ITT Population
    No statistical analyses for this end point

    Secondary: Weight of neonates

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    End point title
    Weight of neonates
    End point description
    The weight of neonates was obtained from the neonate birth record. The mean weight of neonates and standard deviation has been presented. Only those participants with data available at the specified data points were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to 17 weeks
    End point values
    Retosiban Atosiban
    Number of subjects analysed
    46 [65]
    49 [66]
    Units: grams (g)
    arithmetic mean (standard deviation)
        grams (g)
    2761.9 ± 567.84
    2844.4 ± 664.80
    Notes
    [65] - Neonatal ITT Population
    [66] - Neonatal ITT Population
    No statistical analyses for this end point

    Secondary: Head circumference of neonates

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    End point title
    Head circumference of neonates
    End point description
    The head circumference was determined from the neonate birth record. Only those participants with data available at the specified data points were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to 17 weeks
    End point values
    Retosiban Atosiban
    Number of subjects analysed
    43 [67]
    42 [68]
    Units: centimeters (cm)
    arithmetic mean (standard deviation)
        centimeters (cm)
    32.95 ± 2.179
    33.00 ± 1.892
    Notes
    [67] - Neonatal ITT Population
    [68] - Neonatal ITT Population
    No statistical analyses for this end point

    Secondary: Number of neonatal participants with non-serious AEs and SAEs

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    End point title
    Number of neonatal participants with non-serious AEs and SAEs
    End point description
    An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose: results in death; is life threatening; requires hospitalization or prolongation of existing hospitalization; results in disability/incapacity; is a congenital anomaly/birth defect; important medical events that may require medical or surgical intervention to prevent one of the other outcomes described before; is associated with liver injury and impaired liver function. The number of participants who experienced at least one non-serious AE and one SAE has been presented. Neonatal Safety Population consisted of neonates whose mothers received randomized treatment.
    End point type
    Secondary
    End point timeframe
    Up to 28 days after the EDD of 40 weeks gestation
    End point values
    Retosiban Atosiban
    Number of subjects analysed
    47 [69]
    50 [70]
    Units: Participants
        Non-serious AEs
    23
    17
        SAEs
    10
    11
    Notes
    [69] - Neonatal Safety Population
    [70] - Neonatal Safety Population
    No statistical analyses for this end point

    Secondary: Number of neonatal participants with AESI

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    End point title
    Number of neonatal participants with AESI
    End point description
    Neonatal AESI included: Neonatal death; Asphyxia; Infections (early onset neonatal sepsis, septic shock, pneumonia, meningitis); RDS; Hypotension; IVH/periventricular leukomalacia; Bronchopulmonary dysplasia; Neonatal acidosis; Hyperbilirubinemia; Necrotizing enterocolitis; and Hypoxic ischemic encephalopathy. The number of neonatal participants who experienced at least one AESI has been presented.
    End point type
    Secondary
    End point timeframe
    Up to 28 days after EDD of 40 weeks gestation
    End point values
    Retosiban Atosiban
    Number of subjects analysed
    47 [71]
    50 [72]
    Units: Participants
        Participants
    19
    16
    Notes
    [71] - Neonatal Safety Population
    [72] - Neonatal Safety Population
    No statistical analyses for this end point

    Secondary: Number of neonatal participants with DRE

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    End point title
    Number of neonatal participants with DRE
    End point description
    The disease related neonatal events occurring in Infants born prior to 37 completed weeks included: apnea (severe), respiratory failure due to fatigue, hypoxia, or air leak from alveolar injury, patent ductus arteriosus, bradycardia, ventriculomegaly, cerebellar hemorrhage, hydrocephalus other than congenital, gastroesophageal reflux, aspiration pneumonia, anemia, retinopathy of prematurity (all stages), hearing disorder, temperature instability and hypoglycemia. The number of participants with at least one DRE has been presented.
    End point type
    Secondary
    End point timeframe
    Up to 28 days after EDD of 40 weeks gestation
    End point values
    Retosiban Atosiban
    Number of subjects analysed
    47 [73]
    50 [74]
    Units: Participants
        Participants
    5
    3
    Notes
    [73] - Neonatal Safety Population
    [74] - Neonatal Safety Population
    No statistical analyses for this end point

    Secondary: Maternal length of stay in hospital

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    End point title
    Maternal length of stay in hospital
    End point description
    The length of hospital stay associated with hospital admission for preterm labor and term labor/term delivery was collected from review of medical records. Only those participants with data available at the specified data points were analyzed (represented by n=X in category title).
    End point type
    Secondary
    End point timeframe
    Up to 28 days post EDD (40 0/7 weeks gestation)
    End point values
    Retosiban Atosiban
    Number of subjects analysed
    47 [75]
    50 [76]
    Units: Days
    median (full range (min-max))
        Preterm labor, n=13, 10
    5.549 (1.32 to 72.00)
    7.487 (0.87 to 37.82)
        Term labor, n=25, 28
    3.146 (0.17 to 62.71)
    3.398 (0.41 to 36.74)
    Notes
    [75] - Maternal Safety Population
    [76] - Maternal Safety Population
    No statistical analyses for this end point

    Secondary: Number of participants admitted to particular hospital unit

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    End point title
    Number of participants admitted to particular hospital unit
    End point description
    Maternal healthcare resource utilization associated with an episode of preterm labor and normal term delivery were collected from the review of medical records. The number of participants who were admitted to a particular hospital unit like general ward, private/semi-private room, recovery, and other has been presented.
    End point type
    Secondary
    End point timeframe
    Up to 28 days post EDD (40 0/7 weeks gestation)
    End point values
    Retosiban Atosiban
    Number of subjects analysed
    47 [77]
    50 [78]
    Units: Participants
        Preterm labor, general ward
    9
    7
        Preterm labor, private/semi-private room
    1
    0
        Preterm, Other
    3
    4
        Normal term labor, general ward
    16
    12
        Normal term labor, ward-not specified
    2
    0
        Normal term labor,private/semi-private room
    1
    7
        Normal term labor, recovery
    1
    2
        Normal term labor, Other
    5
    7
    Notes
    [77] - Maternal Safety Population
    [78] - Maternal Safety Population
    No statistical analyses for this end point

    Secondary: Retosiban clearance

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    End point title
    Retosiban clearance
    End point description
    Maternal blood samples were collected at the indicated time points for pharmacokinetic analysis. Data is a combined data set. Data is presented for 10 participants from retosiban arm of study 200719 (NCT02377466) and 43 participants from retosiban arm of study 200721 (NCT02292771).
    End point type
    Secondary
    End point timeframe
    Day 1 (2 to 4 hours, 10 to 14 hours) and Day 2 (22 to 26 hours, and 48 to 54 hours) post-infusion
    End point values
    Retosiban
    Number of subjects analysed
    53 [79]
    Units: Microgram per liter
        geometric mean (geometric coefficient of variation)
    83.4 ± 5.25
    Notes
    [79] - Maternal Safety Population. Number of participants is combined from 2 studies. Actual value is 53.
    No statistical analyses for this end point

    Secondary: Volume of distribution of retosiban

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    End point title
    Volume of distribution of retosiban
    End point description
    Maternal blood samples were collected at the indicated time points for pharmacokinetic analysis. Data is a combined data set. Data is presented for 10 participants from retosiban arm of study 200719 (NCT02377466) and 43 participants from retosiban arm of study 200721 (NCT02292771).
    End point type
    Secondary
    End point timeframe
    Day 1 (2 to 4 hours, 10 to 14 hours) and Day 2 (22 to 26 hours, and 48 to 54 hours) post-infusion
    End point values
    Retosiban
    Number of subjects analysed
    53 [80]
    Units: Liters
        geometric mean (geometric coefficient of variation)
    68.6 ± 109
    Notes
    [80] - Maternal Safety Population. Number of participants is combined from 2 studies. Actual value is 53.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study treatment and until Day 894
    Adverse event reporting additional description
    SAEs and AEs were analyzed in Maternal Safety Population and Neonatal Safety Population which comprised of mothers randomly assigned to treatment who were exposed to study treatment and neonates whose mothers received randomized treatment. One participant was withdrawn prior to delivery and was not included in the summary.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Retosiban (Maternal)
    Reporting group description
    Participants were administered 6 milligram (mg) IV loading dose of retosiban over 5 minutes followed by a 6 milligram per hour (mg/hour) continuous infusion of retosiban over 48 hours. Participants with an inadequate response any time after first hour of treatment were administered another 6 mg retosiban loading dose followed by 12 mg/hour continuous infusion for remainder of 48-hour treatment period.

    Reporting group title
    Atosiban (Maternal)
    Reporting group description
    Participants were administered atosiban in 3 successive stages. An initial bolus dose of 6.75 mg using atosiban 6.75 mg/0.9 milliliter (mL) solution for injection, followed by continuous high dose infusion at 18 mg/hour for 3 hours, then a lower 6 mg/hour infusion for the remainder of the 48-hour using the atosiban 37.5 mg/5 mL concentrate for solution.

    Reporting group title
    Retosiban (Fetal)
    Reporting group description
    Participants were administered 6 milligram (mg) IV loading dose of retosiban over 5 minutes followed by a 6 milligram per hour (mg/hour) continuous infusion of retosiban over 48 hours. Participants with an inadequate response any time after first hour of treatment were administered another 6 mg retosiban loading dose followed by 12 mg/hour continuous infusion for remainder of 48-hour treatment period.

    Reporting group title
    Atosiban (Fetal)
    Reporting group description
    Participants were administered atosiban in 3 successive stages. An initial bolus dose of 6.75 mg using atosiban 6.75 mg/0.9 milliliter (mL) solution for injection, followed by continuous high dose infusion at 18 mg/hour for 3 hours, then a lower 6 mg/hour infusion for the remainder of the 48-hour using the atosiban 37.5 mg/5 mL concentrate for solution.

    Reporting group title
    Retosiban (Neonatal)
    Reporting group description
    Participants were administered 6 milligram (mg) IV loading dose of retosiban over 5 minutes followed by a 6 milligram per hour (mg/hour) continuous infusion of retosiban over 48 hours. Participants with an inadequate response any time after first hour of treatment were administered another 6 mg retosiban loading dose followed by 12 mg/hour continuous infusion for remainder of 48-hour treatment period.

    Reporting group title
    Atosiban (Neonatal)
    Reporting group description
    Participants were administered atosiban in 3 successive stages. An initial bolus dose of 6.75 mg using atosiban 6.75 mg/0.9 milliliter (mL) solution for injection, followed by continuous high dose infusion at 18 mg/hour for 3 hours, then a lower 6 mg/hour infusion for the remainder of the 48-hour using the atosiban 37.5 mg/5 mL concentrate for solution.

    Serious adverse events
    Retosiban (Maternal) Atosiban (Maternal) Retosiban (Fetal) Atosiban (Fetal) Retosiban (Neonatal) Atosiban (Neonatal)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 47 (14.89%)
    9 / 50 (18.00%)
    4 / 47 (8.51%)
    2 / 50 (4.00%)
    10 / 46 (21.74%)
    11 / 50 (22.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    1
         number of deaths resulting from adverse events
    Investigations
    Foetal monitoring abnormal
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Abdominal wound dehiscence
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Congenital hydronephrosis
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    1 / 50 (2.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ankyloglossia congenital
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial septal defect
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cataract congenital
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    1 / 46 (2.17%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyloric stenosis
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    1 / 46 (2.17%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular septal defect
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    1 / 46 (2.17%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Foetal heart rate disorder
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    1 / 47 (2.13%)
    1 / 50 (2.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foetal heart rate deceleration abnormality
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    1 / 47 (2.13%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Postpartum haemorrhage
         subjects affected / exposed
    0 / 47 (0.00%)
    3 / 50 (6.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Preterm premature rupture of membranes
         subjects affected / exposed
    1 / 47 (2.13%)
    2 / 50 (4.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Normal labour
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pre-eclampsia
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Premature labour
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Premature separation of placenta
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oligohydramnios
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    2 / 47 (4.26%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydrops foetalis
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    1 / 47 (2.13%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaundice neonatal
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    1 / 46 (2.17%)
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Sudden infant death syndrome
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Immune system disorders
    Milk allergy
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Visual impairment
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retroperitoneal haematoma
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric perforation
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    1 / 46 (2.17%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperbilirubinaemia neonatal
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    4 / 46 (8.70%)
    3 / 50 (6.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Neonatal respiratory distress syndrome
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    1 / 46 (2.17%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Choking
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    1 / 46 (2.17%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meconium aspiration syndrome
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Amniotic cavity infection
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematoma infection
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacterial disease carrier
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    1 / 46 (2.17%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    1 / 46 (2.17%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Retosiban (Maternal) Atosiban (Maternal) Retosiban (Fetal) Atosiban (Fetal) Retosiban (Neonatal) Atosiban (Neonatal)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    34 / 47 (72.34%)
    25 / 50 (50.00%)
    6 / 47 (12.77%)
    6 / 50 (12.00%)
    23 / 46 (50.00%)
    17 / 50 (34.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Eyelid haemangioma
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    1 / 46 (2.17%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Hypotension
         subjects affected / exposed
    1 / 47 (2.13%)
    1 / 50 (2.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Pregnancy, puerperium and perinatal conditions
    Foetal hypokinesia
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
    2 / 47 (4.26%)
    1 / 50 (2.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    2
    1
    0
    0
    Oligohydramnios
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    1 / 50 (2.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Postpartum haemorrhage
         subjects affected / exposed
    1 / 47 (2.13%)
    2 / 50 (4.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    2
    0
    0
    0
    0
    Gestational hypertension
         subjects affected / exposed
    1 / 47 (2.13%)
    1 / 50 (2.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Polyhydramnios
         subjects affected / exposed
    2 / 47 (4.26%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Premature labour
         subjects affected / exposed
    2 / 47 (4.26%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Preterm premature rupture of membranes
         subjects affected / exposed
    2 / 47 (4.26%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Jaundice neonatal
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    1 / 46 (2.17%)
    2 / 50 (4.00%)
         occurrences all number
    0
    0
    0
    0
    1
    2
    Cephalhaematoma
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    1 / 46 (2.17%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    General disorders and administration site conditions
    Generalised oedema
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    1 / 46 (2.17%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Pyrexia
         subjects affected / exposed
    1 / 47 (2.13%)
    3 / 50 (6.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    3
    0
    0
    0
    0
    Asthenia
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Chest pain
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Peripheral swelling
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Suprapubic pain
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Reproductive system and breast disorders
    Scrotal oedema
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    1 / 46 (2.17%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Testicular retraction
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    1 / 46 (2.17%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Vaginal haemorrhage
         subjects affected / exposed
    2 / 47 (4.26%)
    1 / 50 (2.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    4
    2
    0
    0
    0
    0
    Breast engorgement
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Uterine atony
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Vulval oedema
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Vulvovaginal pruritus
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Neonatal respiratory distress syndrome
         subjects affected / exposed
    4 / 47 (8.51%)
    1 / 50 (2.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    4
    1
    0
    0
    0
    0
    Transient tachypnoea of the newborn
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    1 / 46 (2.17%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Apnoea
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Choking
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    1 / 46 (2.17%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Dyspnoea
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    1 / 46 (2.17%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    Respiratory acidosis
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    1 / 46 (2.17%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Respiratory disorder neonatal
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Tachypnoea
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    1 / 46 (2.17%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Use of accessory respiratory muscles
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    2 / 47 (4.26%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Agitation
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Depression
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Mood swings
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Investigations
    Escherichia test positive
         subjects affected / exposed
    2 / 47 (4.26%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Psychiatric evaluation abnormal
         subjects affected / exposed
    0 / 47 (0.00%)
    2 / 50 (4.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Candida test positive
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Klebsiella test positive
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    White blood cell count increased
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    3 / 47 (6.38%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    0
    Abdominal wound dehiscence
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Congenital, familial and genetic disorders
    Congenital hydronephrosis
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    1 / 46 (2.17%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Hydrocele
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Cardiac disorders
    Foetal heart rate disorder
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    4 / 50 (8.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    4
    0
    0
    Foetal heart rate deceleration abnormality
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    3 / 47 (6.38%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    15
    0
    0
    0
    Bradycardia foetal
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    1 / 47 (2.13%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Tachycardia
         subjects affected / exposed
    1 / 47 (2.13%)
    1 / 50 (2.00%)
    1 / 47 (2.13%)
    0 / 50 (0.00%)
    1 / 46 (2.17%)
    0 / 50 (0.00%)
         occurrences all number
    1
    1
    1
    0
    1
    0
    Bradycardia
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Tachycardia foetal
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    1 / 47 (2.13%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    1 / 46 (2.17%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Headache
         subjects affected / exposed
    8 / 47 (17.02%)
    3 / 50 (6.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    8
    3
    0
    0
    0
    0
    Dizziness
         subjects affected / exposed
    1 / 47 (2.13%)
    3 / 50 (6.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    3
    0
    0
    0
    0
    Burning sensation
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Syncope
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Blood and lymphatic system disorders
    Polycythaemia neonatorum
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    1 / 46 (2.17%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Anaemia
         subjects affected / exposed
    4 / 47 (8.51%)
    2 / 50 (4.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    4
    2
    0
    0
    0
    0
    Anaemia of pregnancy
         subjects affected / exposed
    1 / 47 (2.13%)
    1 / 50 (2.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Leukocytosis
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Ear and labyrinth disorders
    Auditory disorder
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Eye disorders
    Eyelid oedema
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    1 / 46 (2.17%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Gastrointestinal disorders
    Infantile colic
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    1 / 46 (2.17%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Constipation
         subjects affected / exposed
    10 / 47 (21.28%)
    5 / 50 (10.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    1 / 46 (2.17%)
    0 / 50 (0.00%)
         occurrences all number
    12
    5
    0
    0
    1
    0
    Flatulence
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Inguinal hernia
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Regurgitation
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Umbilical hernia
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Vomiting
         subjects affected / exposed
    1 / 47 (2.13%)
    1 / 50 (2.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    1 / 46 (2.17%)
    0 / 50 (0.00%)
         occurrences all number
    1
    1
    0
    0
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Abdominal rigidity
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Dental caries
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Gingival bleeding
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Toothache
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Hepatobiliary disorders
    Hyperbilirubinaemia neonatal
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    10 / 46 (21.74%)
    8 / 50 (16.00%)
         occurrences all number
    0
    0
    0
    0
    10
    8
    Jaundice
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    2 / 46 (4.35%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Hepatic steatosis
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Acne infantile
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Blister
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Dry skin
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    1 / 46 (2.17%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Macule
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Pruritus
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Renal and urinary disorders
    Renal pain
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 47 (2.13%)
    2 / 50 (4.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    2
    0
    0
    0
    0
    Arthralgia
         subjects affected / exposed
    1 / 47 (2.13%)
    1 / 50 (2.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Flank pain
         subjects affected / exposed
    2 / 47 (4.26%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Neck pain
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Pain in extremity
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    4 / 47 (8.51%)
    3 / 50 (6.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    4
    3
    0
    0
    0
    0
    Bacterial vaginosis
         subjects affected / exposed
    1 / 47 (2.13%)
    2 / 50 (4.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    2
    0
    0
    0
    0
    Cervicitis
         subjects affected / exposed
    1 / 47 (2.13%)
    2 / 50 (4.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    2
    0
    0
    0
    0
    Gastroenteritis
         subjects affected / exposed
    1 / 47 (2.13%)
    2 / 50 (4.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    2
    0
    0
    0
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 47 (0.00%)
    3 / 50 (6.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    0
    Asymptomatic bacteriuria
         subjects affected / exposed
    0 / 47 (0.00%)
    2 / 50 (4.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Candida infection
         subjects affected / exposed
    1 / 47 (2.13%)
    1 / 50 (2.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Vaginitis gardnerella
         subjects affected / exposed
    1 / 47 (2.13%)
    1 / 50 (2.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Genital candidiasis
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Herpes zoster
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Influenza
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Pulpitis dental
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Pyuria
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    Skin candida
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Ureaplasma infection
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Vaginal infection
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Metabolism and nutrition disorders
    Hypernatraemia
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    1 / 46 (2.17%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Hypoglycaemia
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Metabolic acidosis
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Hyperglycaemia
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Iron deficiency
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
    0 / 47 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Jan 2015
    Amendment No. 1 The following changes are reflected in the Country-Specific Protocol Amendment for Applicable Sites in France: Inclusion criteria 1 and 2 were amended to specify that subjects must be at least 18 years of age to participate in Study 200721, and subjects who participate in Study 200721 must also agree to participate in Study 200722, a separate infant follow-up study. Text was revised throughout to reflect the change in the subject age criterion and the requirement to enroll in the infant follow-up study. Section 9.2 was updated to clarify that the study would be conducted using the current version of the Declaration of Helsinki. Finally, an appendix was added that categorizes laboratory samples into those supporting study conduct and those that may be analyzed at a later date.
    29 Jan 2015
    Amendment No. 2 The following changes are reflected in the Country-Specific Protocol Amendment for Applicable United Kingdom Sites: The text from Section 5.3 has been clarified. The intent of the language remains the same, but the clarification confirms there is no requirement for the investigator to discuss unblinding with the PPD medical monitor in order to rapidly unblind treatment for a study subject if needed. In addition, Section 9.2 was updated to clarify that the study would be conducted using the current version of the Declaration of Helsinki
    04 Feb 2015
    Amendment No. 3 The following changes are reflected in the Country-Specific Protocol Amendment for Applicable Swedish Sites: An appendix was added to list the medications considered strong, moderate, and weak CYP3A4 (cytochrome P450 3A4 enzyme) inhibitors and inducers.
    22 Aug 2016
    Amendment No. 4: Clarified the methods for documenting Screening GA. Clarified that co-morbid conditions would exclude a subject with known or suspected maternal Zika infection. Revised guidance regarding adequate treatment response and defined inadequate treatment response. Added procedures to be followed for managing dose interruptions; and allowed pessary use if started before the current episode of preterm labor. Revised the requirements for continuous fetal heart rate monitoring to a minimum of 6 hours from the start of the infusion or from the start of a dose increase, provided the heart rate pattern was consistently reassuring. Clarified that confirmation of uterine contraction eligibility criterion must occur within 60 minutes before study drug dosing. Removed the follow-up amniotic fluid index (AFI) by abdominal ultrasound as a fetal safety endpoint. Removed the requirement for an ultrasound for AFI determination within 12 hours of completion of study treatment. Revised the method used for adjusting multiplicity of the key secondary endpoints from a stepwise Holm’s test to a sequential testing method.
    21 Dec 2016
    Amendment No. 5: Remove the screening urine drug and alcohol tests. Remove requirement that investigator confirm uterine contraction rate and cervical dilation after randomization and just before study drug administration. Add that after randomization and prior to study drug administration investigators will re-assess that tocolytic therapy is still indicated, according to their medical discretion. Clarify that an abdominal ultrasound to assess fetal growth is needed at Screening or before retreatment unless the most recent ultrasound is within 3 weeks (21 days) before the date of randomization or the date of retreatment. Update the list of maternal drug-related events to clarify the reporting process for events of subsequent preterm labor and hospitalization for delivery that are not worse than expected. Add that the amniotic fluid index should be measured using the 4-quadrant method. Remove changes detailed in the country-specific amendment for sites in France (dated 29 Jan 2015). Incorporate other administrative changes.

    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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