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    Clinical Trial Results:
    Phase III trial in IntrahepaTic CHolestasis of pregnancy (ICP) to Evaluate urSodeoxycholic acid (UDCA) in improving perinatal outcomes

    Summary
    EudraCT number
    		 2014-004478-41
    Trial protocol
    		 GB  
    Global end of trial date
    28 Nov 2018

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

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    LCC001
    Additional study identifiers
    ISRCTN number
    		 ISRCTN91918806
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 REC number: 15/EE/0010
    Sponsors
    Sponsor organisation name
    King's College London
    Sponsor organisation address
    The Strand, London, United Kingdom, WC2R 2LS
    Public contact
    Dr Lucy Chappell, King's College London, 0044 2071883639, lucy.chappell@kcl.ac.uk
    Scientific contact
    Dr Lucy Chappell, King's College London, 0044 2071883639, lucy.chappell@kcl.ac.uk
    Sponsor organisation name
    Guy's and St Thomas' NHS Foundation Trust
    Sponsor organisation address
    Great Maze Pond, London, United Kingdom, SE19RT
    Public contact
    Dr Lucy Chappell, Guy's and St Thomas' NHS Foundation Trust, 0044 2071883639, lucy.chappell@kcl.ac.uk
    Scientific contact
    Dr Lucy Chappell, Guy's and St Thomas' NHS Foundation Trust, 0044 2071883639, lucy.chappell@kcl.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    06 Dec 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Nov 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Intrahepatic cholestasis of pregnancy (ICP), or obstetric cholestasis (OC) is a liver condition of pregnancy. Pregnant women diagnosed with ICP are more at risk of suffering from in utero fetal death, stillbirth, perinatal death (under 7 days), preterm delivery (less than 37 weeks' gestation) and neonatal unit admission. The principal research question asks: does treatment with ursodeoxycholic acid (UDCA) in ICP women, increase the chance of having a healthy baby, by reducing the problems listed above?
    Protection of trial subjects
    N/A
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Sep 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
    United Kingdom: 605
    Worldwide total number of subjects
    605
    EEA total number of subjects
    605
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    605
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Total assessed for eligibility: 2737 Excluded - not eligible: 1319 Total eligible: 1418 Excluded - declined to participate: 813 Total randomised: 605

    Period 1
    Period 1 title
    Trial entry (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Allocation code was held by MedSciNet (database provider) and trials programmers at NPEU CTU only.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 UDCA
    Arm description
    		 Active treatment - Ursodeoxycholic Acid
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ursodeoxycholic Acid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The starting dose will be 1,000 mg daily (500 mg bd), increased in increments of 500 mg per day every 3-14 days if there is no biochemical or clinical improvement, based on clinical decision, to a maximum of 2,000 mg per day. The dose of IMP may be reduced to 500mg daily. IMP will be continued until delivery. Divided doses will be spread evenly throughout the day. There is no need to take with or without food. This will be left to participant preference.

    Arm title
    		 Placebo
    Arm description
    		 Identical tablets administered in the same dose increments orally.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The starting dose will be 1,000 mg daily (500 mg bd), increased in increments of 500 mg per day every 3-14 days if there is no biochemical or clinical improvement, based on clinical decision, to a maximum of 2,000 mg per day. The dose of IMP may be reduced to 500mg daily. IMP will be continued until delivery. Divided doses will be spread evenly throughout the day. There is no need to take with or without food. This will be left to participant preference.

    Number of subjects in period 1
    		UDCA Placebo
    Started
    305
    300
    Completed
    304
    300
    Not completed
    1
    0
         Consent withdrawn by subject
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    UDCA
    Reporting group description
    		 Active treatment - Ursodeoxycholic Acid

    Reporting group title
    Placebo
    Reporting group description
    		 Identical tablets administered in the same dose increments orally.

    Reporting group values
    		 UDCA Placebo Total
    Number of subjects
    		 305 300 605
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 30.5 ± 5.6 30.8 ± 5.3 -
    Gender categorical
    Units: Subjects
        Female
    		 305 300 605
        Male
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    UDCA
    Reporting group description
    		 Active treatment - Ursodeoxycholic Acid

    Reporting group title
    Placebo
    Reporting group description
    		 Identical tablets administered in the same dose increments orally.

    Subject analysis set title
    UDCA - Infants
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All infants born to women randomised to the UDCA arm, excluding post-randomisation exclusions

    Subject analysis set title
    Placebo - Infants
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All infants born to women randomised to the placebo arm, excluding post-randomisation exclusions

    Subject analysis set title
    UDCA - Maternal population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Women included in analysis allocated to UDCA arm

    Subject analysis set title
    Placebo - Maternal population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Women included in analysis allocated to placebo arm

    Primary: Perinatal death, preterm delivery, or neonatal unit admission for at least 4 hours

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    End point title
    		 Perinatal death, preterm delivery, or neonatal unit admission for at least 4 hours
    End point description
    Perinatal death - Defined by in utero fetal death after randomisation or neonatal death up to 7 days. Preterm delivery - Less than 37 weeks’ gestation. Neonatal unit (NNU) admission for at least 4 hours - Between infant delivery and hospital discharge.
    End point type
    Primary
    End point timeframe
    Between randomisation and discharge
    End point values
    		 UDCA - Infants Placebo - Infants
    Number of subjects analysed
    322
    318
    Units: Number of infants
    74
    85
    Statistical analysis title
    		 Adjusted effect estimate
    Statistical analysis description
    Poisson regression, adjusted for minimisation factors bile acid, gestational age at randomisation, multiple pregnancy, and centre as a random effect. Standard errors allow for intraclass correlation to account for non-independence of twins.
    Comparison groups
    UDCA - Infants v Placebo - Infants
    Number of subjects included in analysis
    640
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.279
    Method
    		 Mixed models analysis
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 1.15
    Statistical analysis title
    		 Unadjusted effect estimate
    Comparison groups
    Placebo - Infants v UDCA - Infants
    Number of subjects included in analysis
    640
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.273
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.66
         upper limit
    		 1.13

    Secondary: In utero fetal death after randomisation

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    End point title
    		 In utero fetal death after randomisation
    End point description
    End point type
    Secondary
    End point timeframe
    After randomisation
    End point values
    		 UDCA - Infants Placebo - Infants
    Number of subjects analysed
    322
    318
    Units: Number of infants
    1
    2
    Statistical analysis title
    		 Adjusted effect estimate
    Statistical analysis description
    Poisson regression adjusted for minimisation factors: bile acid, gestational age at randomisation, multiple pregnancy, and centre as a random effect. Standard errors allow for intraclass correlation to account for non-independence of twins.
    Comparison groups
    UDCA - Infants v Placebo - Infants
    Number of subjects included in analysis
    640
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.598
    Method
    		 Mixed models analysis
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.04
         upper limit
    		 6.25

    Secondary: Pre-term delivery (less than 37 weeks’ gestation)

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    End point title
    		 Pre-term delivery (less than 37 weeks’ gestation)
    End point description
    End point type
    Secondary
    End point timeframe
    Between randomisation and delivery
    End point values
    		 UDCA - Infants Placebo - Infants
    Number of subjects analysed
    322
    318
    Units: Number of infants
    54
    65
    Statistical analysis title
    		 Adjusted effect estimate
    Statistical analysis description
    Poisson regression adjusted for minimisation factors: bile acid, gestational age at randomisation, multiple pregnancy, and centre as a random effect. Standard errors allow for intraclass correlation to account for non-independence of twins.
    Comparison groups
    UDCA - Infants v Placebo - Infants
    Number of subjects included in analysis
    640
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.171
    Method
    		 Mixed models analysis
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.57
         upper limit
    		 1.1

    Secondary: Known neonatal death up to 7 days

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    End point title
    		 Known neonatal death up to 7 days
    End point description
    End point type
    Secondary
    End point timeframe
    Prior to discharge
    End point values
    		 UDCA - Infants Placebo - Infants
    Number of subjects analysed
    322
    318
    Units: Number of infants
    0
    0
    No statistical analyses for this end point

    Secondary: NNU admission for at least 4 hours until infant hospital discharge

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    End point title
    		 NNU admission for at least 4 hours until infant hospital discharge
    End point description
    End point type
    Secondary
    End point timeframe
    Until infant hospital discharge
    End point values
    		 UDCA - Infants Placebo - Infants
    Number of subjects analysed
    322
    318
    Units: Number of infants
    45
    54
    Statistical analysis title
    		 Adjusted effect estimate
    Statistical analysis description
    Poisson regression adjusted for minimisation factors: bile acid, gestational age at randomisation, multiple pregnancy, and centre as a random effect. Standard errors allow for intraclass correlation to account for non-independence of twins.
    Comparison groups
    Placebo - Infants v UDCA - Infants
    Number of subjects included in analysis
    640
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.212
    Method
    		 Mixed models analysis
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.58
         upper limit
    		 1.13

    Secondary: Known neonatal death up to 28 days

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    End point title
    		 Known neonatal death up to 28 days
    End point description
    End point type
    Secondary
    End point timeframe
    Prior to discharge
    End point values
    		 UDCA - Infants Placebo - Infants
    Number of subjects analysed
    322
    318
    Units: Number of infants
    0
    0
    No statistical analyses for this end point

    Secondary: Live birth

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    End point title
    		 Live birth
    End point description
    End point type
    Secondary
    End point timeframe
    Randomisation to delivery
    End point values
    		 UDCA - Infants Placebo - Infants
    Number of subjects analysed
    322
    318
    Units: Number of infants
    321
    316
    No statistical analyses for this end point

    Secondary: Mode of delivery

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    End point title
    		 Mode of delivery
    End point description
    End point type
    Secondary
    End point timeframe
    Up to delivery
    End point values
    		 UDCA - Infants Placebo - Infants
    Number of subjects analysed
    322
    318
    Units: Number of infants
        Spontaneous vaginal (cephalic)
    193
    182
        Spontaneous vaginal (breech)
    1
    3
        Assisted vaginal – ventouse (cephalic)
    2
    15
        Assisted vaginal – forceps (cephalic)
    19
    20
        Assisted vaginal (breech)
    0
    0
        Caesarean section
    36
    36
        Pre-labour Caesarean section
    71
    62
    Statistical analysis title
    		 Spontaneous vaginal (cephalic) vs other modes
    Statistical analysis description
    Poisson regression adjusted for minimisation factors: bile acid, gestational age at randomisation, multiple pregnancy, and centre as a random effect. Standard errors allow for intraclass correlation to account for non-independence of twins.
    Comparison groups
    UDCA - Infants v Placebo - Infants
    Number of subjects included in analysis
    640
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.562
    Method
    		 Mixed models analysis
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.91
         upper limit
    		 1.2
    Statistical analysis title
    		 Caesarean section vs. other modes of delivery
    Statistical analysis description
    Poisson regression adjusted for minimisation factors: bile acid, gestational age at randomisation, multiple pregnancy, and centre as a random effect. Standard errors allow for intraclass correlation to account for non-independence of twins.
    Comparison groups
    UDCA - Infants v Placebo - Infants
    Number of subjects included in analysis
    640
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.995
    Method
    		 Mixed models analysis
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 1.46

    Secondary: Gestational age at delivery (weeks)

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    End point title
    		 Gestational age at delivery (weeks)
    End point description
    End point type
    Secondary
    End point timeframe
    Up to delivery
    End point values
    		 UDCA - Infants Placebo - Infants
    Number of subjects analysed
    322
    318
    Units: weeks
        median (inter-quartile range (Q1-Q3))
    37.6 (37.1 to 38.1)
    37.4 (37.0 to 38.1)
    Statistical analysis title
    		 Adjusted median difference
    Comparison groups
    UDCA - Infants v Placebo - Infants
    Number of subjects included in analysis
    640
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.065
    Method
    		 Quantile regression
    Parameter type
    		 Median difference (final values)
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0.3

    Secondary: Birth weight

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    End point title
    		 Birth weight
    End point description
    End point type
    Secondary
    End point timeframe
    At delivery
    End point values
    		 UDCA - Infants Placebo - Infants
    Number of subjects analysed
    322
    318
    Units: grams
        median (inter-quartile range (Q1-Q3))
    3105 (2775 to 3390)
    3040 (2660 to 3320)
    Statistical analysis title
    		 Median difference
    Statistical analysis description
    Adjusted for minimisation factors: bile acid, gestational age at randomisation, multiple pregnancy.
    Comparison groups
    UDCA - Infants v Placebo - Infants
    Number of subjects included in analysis
    640
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.014
    Method
    		 Quantile regression
    Parameter type
    		 Median difference (final values)
    Point estimate
    94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 18.7
         upper limit
    		 169.3

    Secondary: Birth weight centile

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    End point title
    		 Birth weight centile
    End point description
    End point type
    Secondary
    End point timeframe
    At delivery
    End point values
    		 UDCA - Infants Placebo - Infants
    Number of subjects analysed
    322
    318
    Units: centile
        arithmetic mean (standard deviation)
    59.3 ± 28.4
    56.3 ± 27.8
    No statistical analyses for this end point

    Secondary: Birth weight centile - < 10th customised centile

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    End point title
    		 Birth weight centile - < 10th customised centile
    End point description
    End point type
    Secondary
    End point timeframe
    At delivery
    End point values
    		 UDCA - Infants Placebo - Infants
    Number of subjects analysed
    322
    318
    Units: Number of infants
    16
    18
    Statistical analysis title
    		 Adjusted risk ratio
    Statistical analysis description
    Poisson regression adjusted for minimisation factors: bile acid, gestational age at randomisation, multiple pregnancy, and centre as a random effect. Standard errors allow for intraclass correlation to account for non-independence of twins.
    Comparison groups
    UDCA - Infants v Placebo - Infants
    Number of subjects included in analysis
    640
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.725
    Method
    		 Mixed models analysis
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.47
         upper limit
    		 1.69

    Secondary: Birth weight centile - < 3rd customised centile

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    End point title
    		 Birth weight centile - < 3rd customised centile
    End point description
    End point type
    Secondary
    End point timeframe
    At delivery
    End point values
    		 UDCA - Infants Placebo - Infants
    Number of subjects analysed
    322
    318
    Units: Number of infants
    7
    7
    Statistical analysis title
    		 Adjusted risk ratio
    Statistical analysis description
    Poisson regression adjusted for minimisation factors: bile acid, gestational age at randomisation, multiple pregnancy, and centre as a random effect. Standard errors allow for intraclass correlation to account for non-independence of twins.
    Comparison groups
    UDCA - Infants v Placebo - Infants
    Number of subjects included in analysis
    640
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.877
    Method
    		 Mixed models analysis
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.38
         upper limit
    		 3.12

    Secondary: Presence of meconium

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    End point title
    		 Presence of meconium
    End point description
    End point type
    Secondary
    End point timeframe
    At delivery
    End point values
    		 UDCA - Infants Placebo - Infants
    Number of subjects analysed
    322
    318
    Units: Number of infants
        Yes
    34
    52
        No
    286
    264
        Missing
    2
    2
    Statistical analysis title
    		 Adjusted risk ratio
    Statistical analysis description
    Poisson regression adjusted for minimisation factors: bile acid, gestational age at randomisation, multiple pregnancy, and centre as a random effect. Standard errors allow for intraclass correlation to account for non-independence of twins.
    Comparison groups
    UDCA - Infants v Placebo - Infants
    Number of subjects included in analysis
    640
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.04
    Method
    		 Mixed models analysis
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.43
         upper limit
    		 0.98

    Secondary: APGAR score at 5 minutes post-birth

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    End point title
    		 APGAR score at 5 minutes post-birth
    End point description
    In live births only
    End point type
    Secondary
    End point timeframe
    5 minutes post-birth
    End point values
    		 UDCA - Infants Placebo - Infants
    Number of subjects analysed
    321
    316
    Units: score
        median (inter-quartile range (Q1-Q3))
    9.0 (9 to 10)
    9 (9 to 10)
    Statistical analysis title
    		 Median difference (adjusted)
    Statistical analysis description
    Adjusted for minimisation factors: bile acid, gestational age at randomisation, multiple pregnancy.
    Comparison groups
    UDCA - Infants v Placebo - Infants
    Number of subjects included in analysis
    637
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Quantile regression
    Parameter type
    		 Median difference (final values)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4
         upper limit
    		 0.4

    Secondary: APGAR score at 5 minutes post-birth - < 7

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    End point title
    		 APGAR score at 5 minutes post-birth - < 7
    End point description
    End point type
    Secondary
    End point timeframe
    5 minutes post-birth
    End point values
    		 UDCA - Infants Placebo - Infants
    Number of subjects analysed
    321
    316
    Units: Number of infants
        < 7
    8
    7
        >= 7
    313
    309
    No statistical analyses for this end point

    Secondary: Umbilical cord arterial pH - collected

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    End point title
    		 Umbilical cord arterial pH - collected
    End point description
    End point type
    Secondary
    End point timeframe
    At delivery
    End point values
    		 UDCA - Infants Placebo - Infants
    Number of subjects analysed
    322
    318
    Units: Number of infants
    114
    112
    No statistical analyses for this end point

    Secondary: Umbilical cord arterial pH

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    End point title
    		 Umbilical cord arterial pH
    End point description
    End point type
    Secondary
    End point timeframe
    At delivery
    End point values
    		 UDCA - Infants Placebo - Infants
    Number of subjects analysed
    112 [1]
    102 [2]
    Units: pH
        arithmetic mean (standard deviation)
    7.2 ± 0.1
    7.2 ± 0.1
    Notes
    [1] - 114 collected, 2 values missing
    [2] - 112 collected, 10 values missing
    Statistical analysis title
    		 Mean difference (adjusted)
    Statistical analysis description
    Linear regression adjusted for minimisation factors: bile acid, gestational age at randomisation, multiple pregnancy, and centre as a random effect. Standard errors allow for intraclass correlation to account for non-independence of twins.
    Comparison groups
    UDCA - Infants v Placebo - Infants
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.182
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.04
         upper limit
    		 0.01

    Secondary: Number of nights in each category of care - Intensive

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    End point title
    		 Number of nights in each category of care - Intensive
    End point description
    in survivors to discharge
    End point type
    Secondary
    End point timeframe
    Between birth and discharge from hospital
    End point values
    		 UDCA - Infants Placebo - Infants
    Number of subjects analysed
    10 [3]
    16 [4]
    Units: Number of nights
        median (inter-quartile range (Q1-Q3))
    3 (2 to 3)
    2 (1 to 2.5)
    Notes
    [3] - 10 infants spent at least 1 night in intensive care
    [4] - 16 infants spent at least 1 night in intensive care
    No statistical analyses for this end point

    Secondary: Number of nights in each category of care - High dependency

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    End point title
    		 Number of nights in each category of care - High dependency
    End point description
    in survivors to discharge
    End point type
    Secondary
    End point timeframe
    Delivery to discharge
    End point values
    		 UDCA - Infants Placebo - Infants
    Number of subjects analysed
    20 [5]
    17 [6]
    Units: Number of nights
        median (inter-quartile range (Q1-Q3))
    2 (1 to 5.5)
    3 (1 to 5)
    Notes
    [5] - 20 infants spent at least one night in high dependency care
    [6] - 17 infants spent at least one night in high dependency care
    No statistical analyses for this end point

    Secondary: Number of nights in each category of care - Special care

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    End point title
    		 Number of nights in each category of care - Special care
    End point description
    (with carer not present). In survivors to discharge.
    End point type
    Secondary
    End point timeframe
    Delivery to discharge
    End point values
    		 UDCA - Infants Placebo - Infants
    Number of subjects analysed
    40 [7]
    45 [8]
    Units: Number of nights
        median (inter-quartile range (Q1-Q3))
    5 (3 to 12.5)
    5 (2 to 16)
    Notes
    [7] - 40 infants spent at least one night in special care
    [8] - 45 infants spent at least one night in special care
    No statistical analyses for this end point

    Secondary: Number of nights in each category of care - Transitional

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    End point title
    		 Number of nights in each category of care - Transitional
    End point description
    (with carer present). In survivors to discharge.
    End point type
    Secondary
    End point timeframe
    Delivery to discharge
    End point values
    		 UDCA - Infants Placebo - Infants
    Number of subjects analysed
    31 [9]
    34 [10]
    Units: Number of nights
        median (inter-quartile range (Q1-Q3))
    3 (1 to 4)
    2 (1 to 4)
    Notes
    [9] - 31 infants spent at least one night in transitional care
    [10] - 34 infants spent at least one night in transitional care
    No statistical analyses for this end point

    Secondary: Number of nights in each category of care - Normal

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    End point title
    		 Number of nights in each category of care - Normal
    End point description
    In survivors to discharge
    End point type
    Secondary
    End point timeframe
    Delivery to discharge
    End point values
    		 UDCA - Infants Placebo - Infants
    Number of subjects analysed
    246 [11]
    226 [12]
    Units: Number of nights
        median (inter-quartile range (Q1-Q3))
    1 (1 to 2)
    2 (1 to 3)
    Notes
    [11] - 246 infants spent at least one night in Normal care
    [12] - 226 infants spent at least one night in Normal care
    No statistical analyses for this end point

    Secondary: Total number of nights in neonatal unit

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    End point title
    		 Total number of nights in neonatal unit
    End point description
    In survivors to discharge
    End point type
    Secondary
    End point timeframe
    Delivery to discharge
    End point values
    		 UDCA - Infants Placebo - Infants
    Number of subjects analysed
    44 [13]
    53 [14]
    Units: Number of nights
        median (inter-quartile range (Q1-Q3))
    5.5 (3 to 13)
    6 (2 to 16)
    Notes
    [13] - 44 infants spent at least one night in a neonatal unit
    [14] - 53 infants spent at least one night in a neonatal unit
    Statistical analysis title
    		 Median difference (adjusted)
    Statistical analysis description
    Adjusted for minimisation factors: bile acid, gestational age at randomisation, multiple pregnancy.
    Comparison groups
    UDCA - Infants v Placebo - Infants
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Quantile regression
    Parameter type
    		 Median difference (final values)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.2
         upper limit
    		 3.2

    Secondary: Main diagnosis for first NNU admission of at least 4 hours

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    End point title
    		 Main diagnosis for first NNU admission of at least 4 hours
    End point description
    End point type
    Secondary
    End point timeframe
    Delivery to discharge
    End point values
    		 UDCA - Infants Placebo - Infants
    Number of subjects analysed
    45 [15]
    54 [16]
    Units: Number of infants
        Congenital anomaly suspected/confirmed
    1
    0
        Continuing care
    0
    1
        Convulsions suspected/confirmed
    1
    0
        HIE suspected/confirmed
    1
    0
        Hypoglycaemia
    3
    5
        Infection suspected/confirmed
    5
    7
        IUGR/SGA
    0
    1
        Jaundice
    0
    1
        Monitoring
    0
    5
        NAS suspected/confirmed
    1
    0
        Poor condition at birth
    1
    1
        Poor feeding or weight loss
    1
    1
        Prematurity
    14
    17
        Respiratory disease
    16
    15
        Surgery
    1
    0
    Notes
    [15] - 45 infants had NNU admission of at least 4 hours
    [16] - 54 infants had NNU admission of at least 4 hours
    No statistical analyses for this end point

    Secondary: Need for supplementary oxygen prior to discharge

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    End point title
    		 Need for supplementary oxygen prior to discharge
    End point description
    End point type
    Secondary
    End point timeframe
    Delivery to discharge
    End point values
    		 UDCA - Infants Placebo - Infants
    Number of subjects analysed
    Units: Number of infants
        Yes
    16
    20
        No
    306
    296
        Missing
    0
    2
    No statistical analyses for this end point

    Secondary: Need for ventilation support

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    End point title
    		 Need for ventilation support
    End point description
    End point type
    Secondary
    End point timeframe
    Delivery to discharge
    End point values
    		 UDCA - Infants Placebo - Infants
    Number of subjects analysed
    Units: Number of infants
        Yes
    15
    18
        No
    307
    298
        Missing
    0
    2
    No statistical analyses for this end point

    Secondary: Need for ventilation support - type

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    End point title
    		 Need for ventilation support - type
    End point description
    Not mutually exclusive
    End point type
    Secondary
    End point timeframe
    Delivery to discharge
    End point values
    		 UDCA - Infants Placebo - Infants
    Number of subjects analysed
    322
    316
    Units: Number of infants
        Endotracheal ventilation
    5
    6
        CPAP
    9
    12
        High-flow oxygen
    7
    9
    No statistical analyses for this end point

    Secondary: Cerebral ultrasound scan performed

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    End point title
    		 Cerebral ultrasound scan performed
    End point description
    End point type
    Secondary
    End point timeframe
    Delivery to discharge
    End point values
    		 UDCA - Infants Placebo - Infants
    Number of subjects analysed
    322
    318
    Units: Number of infants
        Yes
    12
    11
        No
    310
    306
        Missing
    0
    1
    No statistical analyses for this end point

    Secondary: Abnormalities found in cerebral ultrasound scan

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    End point title
    		 Abnormalities found in cerebral ultrasound scan
    End point description
    End point type
    Secondary
    End point timeframe
    Delivery to discharge
    End point values
    		 UDCA - Infants Placebo - Infants
    Number of subjects analysed
    322
    317 [17]
    Units: Number of infants
    3
    3
    Notes
    [17] - 1 missing ultrasound scan performed
    No statistical analyses for this end point

    Secondary: IVH - Grade 1

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    End point title
    		 IVH - Grade 1
    End point description
    End point type
    Secondary
    End point timeframe
    Delivery to discharge
    End point values
    		 UDCA - Infants Placebo - Infants
    Number of subjects analysed
    322
    317
    Units: Number of infants
    1
    1
    No statistical analyses for this end point

    Secondary: Ventricular dilatation

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    End point title
    		 Ventricular dilatation
    End point description
    End point type
    Secondary
    End point timeframe
    Delivery to discharge
    End point values
    		 UDCA - Infants Placebo - Infants
    Number of subjects analysed
    322
    317
    Units: Number of infants
    2
    0
    No statistical analyses for this end point

    Secondary: Confirmed sepsis

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    End point title
    		 Confirmed sepsis
    End point description
    End point type
    Secondary
    End point timeframe
    Delivery to discharge
    End point values
    		 UDCA - Infants Placebo - Infants
    Number of subjects analysed
    322
    318
    Units: Number of infants
        Yes
    1
    2
        No
    320
    315
        Missing
    1
    1
    No statistical analyses for this end point

    Secondary: Necrotising Enterocolitis

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    End point title
    		 Necrotising Enterocolitis
    End point description
    Bell's stage 2 or 3
    End point type
    Secondary
    End point timeframe
    Delivery to discharge
    End point values
    		 UDCA - Infants Placebo - Infants
    Number of subjects analysed
    322
    318
    Units: Number of infants
        Yes
    0
    0
        No
    322
    316
        Missing
    0
    2
    No statistical analyses for this end point

    Secondary: Seizure prior to discharge

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    End point title
    		 Seizure prior to discharge
    End point description
    Confirmed by EEG or requiring anticonvulsant therapy
    End point type
    Secondary
    End point timeframe
    Delivery to discharge
    End point values
    		 UDCA - Infants Placebo - Infants
    Number of subjects analysed
    322
    318
    Units: Number of infants
        Yes
    0
    0
        No
    321
    317
        Missing
    1
    1
    No statistical analyses for this end point

    Secondary: Encephalopathy

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    End point title
    		 Encephalopathy
    End point description
    End point type
    Secondary
    End point timeframe
    Delivery to discharge
    End point values
    		 UDCA - Infants Placebo - Infants
    Number of subjects analysed
    322
    318
    Units: Number of infants
        Yes
    2
    0
        No
    320
    317
        Missing
    0
    1
    No statistical analyses for this end point

    Secondary: Encephalopathy treated with hypothermia

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    End point title
    		 Encephalopathy treated with hypothermia
    End point description
    End point type
    Secondary
    End point timeframe
    Delivery to discharge
    End point values
    		 UDCA - Infants Placebo - Infants
    Number of subjects analysed
    322
    318
    Units: Number of infants
        Yes
    1
    0
        No
    321
    317
        Missing
    0
    1
    No statistical analyses for this end point

    Secondary: Maximum dose of trial medication required

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    End point title
    		 Maximum dose of trial medication required
    End point description
    End point type
    Secondary
    End point timeframe
    Randomisation to delivery
    End point values
    		 UDCA - Maternal population Placebo - Maternal population
    Number of subjects analysed
    304
    300
    Units: Number of women
        One tablet once a day
    4
    5
        One tablet twice a day
    203
    198
        One tablet three times a day
    62
    65
        Two tablets twice a day
    35
    32
    No statistical analyses for this end point

    Secondary: Need for additional therapy for cholestasis

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    End point title
    		 Need for additional therapy for cholestasis
    End point description
    End point type
    Secondary
    End point timeframe
    Randomisation to delivery
    End point values
    		 UDCA - Maternal population Placebo - Maternal population
    Number of subjects analysed
    304
    300
    Units: Number of women
        Yes
    134
    125
        No
    127
    120
        Delivered before first follow-up
    33
    42
        Missing
    10
    13
    No statistical analyses for this end point

    Secondary: Additional therapy for cholestasis

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    End point title
    		 Additional therapy for cholestasis
    End point description
    Not mutually exclusive
    End point type
    Secondary
    End point timeframe
    Randomisation to delivery
    End point values
    		 UDCA - Maternal population Placebo - Maternal population
    Number of subjects analysed
    134
    125
    Units: Number of women
        Chlorphenamine
    97
    105
        Aqueous cream
    17
    27
        Menthol aqueous cream
    89
    74
        Antihistamine
    6
    1
        Topical emollient
    3
    2
        Calamine
    7
    1
        Vitamin K
    2
    1
        Rifampicin
    1
    2
        Open-label UDCA (tablets stopped)
    17
    21
        Other
    1
    0
    No statistical analyses for this end point

    Secondary: Gestational diabetes mellitus

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    End point title
    		 Gestational diabetes mellitus
    End point description
    End point type
    Secondary
    End point timeframe
    Delivery to discharge
    End point values
    		 UDCA - Maternal population Placebo - Maternal population
    Number of subjects analysed
    304
    300
    Units: Number of women
        Yes
    3
    9
        No
    300
    290
        Missing
    1
    1
    Statistical analysis title
    		 Risk ratio (adjusted)
    Statistical analysis description
    Adjusted for minimisation factors: bile acid, gestational age at randomisation, multiple pregnancy, and centre as a random effect.
    Comparison groups
    UDCA - Maternal population v Placebo - Maternal population
    Number of subjects included in analysis
    604
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.071
    Method
    		 Mixed models analysis
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.1
         upper limit
    		 1.1

    Secondary: Assessment of myometrial contractions by CTG approx. 1 week (3-14 days) post randomisation

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    End point title
    		 Assessment of myometrial contractions by CTG approx. 1 week (3-14 days) post randomisation
    End point description
    End point type
    Secondary
    End point timeframe
    3-14 days post-randomisation
    End point values
    		 UDCA - Maternal population Placebo - Maternal population
    Number of subjects analysed
    304
    300
    Units: Number of women
        Yes
    165
    153
        No
    93
    96
        Delivered before first follow-up visit
    33
    43
        Missing
    10
    8
    No statistical analyses for this end point

    Secondary: Bile acid (μmol/l) between randomisation and delivery

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    End point title
    		 Bile acid (μmol/l) between randomisation and delivery
    End point description
    End point type
    Secondary
    End point timeframe
    Between randomisation and delivery
    End point values
    		 UDCA - Maternal population Placebo - Maternal population
    Number of subjects analysed
    256 [18]
    247 [19]
    Units: μmol/l
        geometric mean (confidence interval 95%)
    22.4 (21.4 to 23.5)
    18.5 (17.7 to 19.4)
    Notes
    [18] - With baseline and at least one post-randomisation measurement.
    [19] - With baseline and at least one post-randomisation measurement.
    Statistical analysis title
    		 Repeated measures ANCOVA
    Statistical analysis description
    Accounting for within-subject correlation between measures at the post-randomisation antenatal visits, adjusting for baseline measure and minimisation factors.
    Comparison groups
    Placebo - Maternal population v UDCA - Maternal population
    Number of subjects included in analysis
    503
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.03
    Method
    		 ANCOVA
    Parameter type
    		 Geometric mean ratio
    Point estimate
    1.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.02
         upper limit
    		 1.36

    Secondary: Alanine transaminase (U/L) between randomisation and delivery

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    End point title
    		 Alanine transaminase (U/L) between randomisation and delivery
    End point description
    End point type
    Secondary
    End point timeframe
    Between randomisation and delivery
    End point values
    		 UDCA - Maternal population Placebo - Maternal population
    Number of subjects analysed
    242 [20]
    240 [21]
    Units: U/L
        geometric mean (inter-quartile range (Q1-Q3))
    49.5 (43.8 to 55.8)
    58.0 (51.0 to 65.9)
    Notes
    [20] - With baseline and at least one post-randomisation measurement.
    [21] - With baseline and at least one post-randomisation measurement.
    Statistical analysis title
    		 Repeated measures ANCOVA
    Statistical analysis description
    Accounting for within-subject correlation between measures at the post-randomisation antenatal visits, adjusting for baseline measure and minimisation factors.
    Comparison groups
    UDCA - Maternal population v Placebo - Maternal population
    Number of subjects included in analysis
    482
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Geometric mean ratio
    Point estimate
    0.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.66
         upper limit
    		 0.83

    Secondary: Aspartate transaminase (U/L) between randomisation and delivery

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    End point title
    		 Aspartate transaminase (U/L) between randomisation and delivery
    End point description
    End point type
    Secondary
    End point timeframe
    Between randomisation and delivery
    End point values
    		 UDCA - Maternal population Placebo - Maternal population
    Number of subjects analysed
    44 [22]
    39 [23]
    Units: U/L
        geometric mean (confidence interval 95%)
    44.1 (35.7 to 54.5)
    64.3 (51.1 to 81.0)
    Notes
    [22] - With baseline and at least one post-randomisation measurement.
    [23] - With baseline and at least one post-randomisation measurement.
    No statistical analyses for this end point

    Secondary: Bilirubin (μmol/l) between randomisation and delivery

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    End point title
    		 Bilirubin (μmol/l) between randomisation and delivery
    End point description
    End point type
    Secondary
    End point timeframe
    Between randomisation and delivery
    End point values
    		 UDCA - Maternal population Placebo - Maternal population
    Number of subjects analysed
    246 [24]
    226 [25]
    Units: μmol/l
        geometric mean (confidence interval 95%)
    7.0 (6.6 to 7.5)
    8.6 (8.0 to 9.3)
    Notes
    [24] - With baseline and at least one post-randomisation measurement.
    [25] - With baseline and at least one post-randomisation measurement.
    No statistical analyses for this end point

    Secondary: Gamma glutamyl transferase (U/L) between randomisation and delivery

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    End point title
    		 Gamma glutamyl transferase (U/L) between randomisation and delivery
    End point description
    End point type
    Secondary
    End point timeframe
    Between randomisation and delivery
    End point values
    		 UDCA - Maternal population Placebo - Maternal population
    Number of subjects analysed
    96 [26]
    100 [27]
    Units: U/L
        geometric mean (confidence interval 95%)
    18.3 (16.0 to 21.0)
    21.0 (18.8 to 23.4)
    Notes
    [26] - With baseline and at least one post-randomisation measurement.
    [27] - With baseline and at least one post-randomisation measurement.
    No statistical analyses for this end point

    Secondary: Itch between randomisation and delivery (measured by worst episode of itch over past 24 hours)

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    End point title
    		 Itch between randomisation and delivery (measured by worst episode of itch over past 24 hours)
    End point description
    End point type
    Secondary
    End point timeframe
    Between randomisation and delivery
    End point values
    		 UDCA - Maternal population Placebo - Maternal population
    Number of subjects analysed
    241 [28]
    227 [29]
    Units: score
        arithmetic mean (standard deviation)
    49.5 ± 12.9
    56.9 ± 13.3
    Notes
    [28] - With baseline and at least one post-randomisation measurement.
    [29] - With baseline and at least one post-randomisation measurement.
    Statistical analysis title
    		 Repeated measures ANCOVA
    Comparison groups
    UDCA - Maternal population v Placebo - Maternal population
    Number of subjects included in analysis
    468
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.005
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -5.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.68
         upper limit
    		 -1.68

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Until discharge from hospital
    Adverse event reporting additional description
    At each clinic visit, a member of the clinical or research team will ask the woman if she has had any adverse events, and will ensure that she has clinical monitoring (e.g. liver function tests and fetal monitoring) as routinely performed in each maternity unit.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 N/A
    Dictionary version
    N/A
    Reporting groups
    Reporting group title
    UDCA
    Reporting group description
    		 Active treatment - Ursodeoxycholic Acid

    Reporting group title
    Placebo
    Reporting group description
    		 Identical tablets administered in the same dose increments orally.

    Serious adverse events
    		 UDCA Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 300 (0.67%)
    6 / 296 (2.03%)
         number of deaths (all causes)
    1
    2
         number of deaths resulting from adverse events
    0
    1
    Congenital, familial and genetic disorders
    Downs syndrome
    Additional description: Baby diagnosed with Downs syndrome
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Intrauterine fetal death
    Additional description: Intrauterine fetal death at 35 weeks. CTG normal 2 days prior. FM normal. Latest scan normal. BA not above 21. Delivered. Mother making full physical recovery.
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vaginal haematoma
    Additional description: Following a normal birth and perineal suturing participant went back to theatre for an evacuation of a vaginal haematoma. Given prophylactic antibiotics and analgesia, discharged home the next day, EBL = 600 mls.
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Mild hypospadias
    Additional description: Baby was diagnosed with mild hypospadias and a referral was made to the paediatricians. Baby was passing urine well, and testes were descended. Baby was seen by the paediatric team and no further action taken.
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Overdose
    Additional description: Informed through the Pharmacy Department that participant was an inpatient having taken an overdose of Paracetamol.
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Sepsis
    Additional description: Admitted with possible sepsis, raised respiratory rate, increased heart rate. Commenced sepsis pathway. Rhinovirus detected on throat swab. Home on oral antibiotics, no further follow up. Admitted for 5 days.
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic screen
    Additional description: Maternal temperature 38.2 following delivery - septic screen performed on mother and baby, and treated with IV antibiotics.
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Urinary tract infection (possible)
    Additional description: Participant was admitted to maternity unit feeling unwell and vomiting. Possible UTI, required management of diabetic ketoacidosis.
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 UDCA Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    22 / 300 (7.33%)
    34 / 296 (11.49%)
    Vascular disorders
    Blood pressure increased
         subjects affected / exposed
    1 / 300 (0.33%)
    1 / 296 (0.34%)
         occurrences all number
    1
    1
    Hypertension
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 296 (0.34%)
         occurrences all number
    0
    1
    Cardiac disorders
    Heart rate increased
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 296 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Unresponsive
    Additional description: After Caesarean section
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 296 (0.34%)
         occurrences all number
    0
    1
    Headache
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 296 (0.00%)
         occurrences all number
    1
    0
    Migraine
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 296 (0.00%)
         occurrences all number
    1
    0
    Pregnancy, puerperium and perinatal conditions
    Intrapartum haemorrhage
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 296 (0.34%)
         occurrences all number
    0
    1
    Postpartum haemorrhage
         subjects affected / exposed
    4 / 300 (1.33%)
    9 / 296 (3.04%)
         occurrences all number
    4
    9
    Threatened pre-term labour
         subjects affected / exposed
    1 / 300 (0.33%)
    1 / 296 (0.34%)
         occurrences all number
    1
    1
    Unwell
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 296 (0.34%)
         occurrences all number
    0
    1
    Retained placenta or membranes
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 296 (0.34%)
         occurrences all number
    0
    1
    Jaundice neonatal
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 296 (0.34%)
         occurrences all number
    0
    1
    Previous pregnancy haemolytic strep B infection, prophylactic antibiotics administered
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 296 (0.34%)
         occurrences all number
    0
    1
    Caesarean section wound haematoma
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 296 (0.34%)
         occurrences all number
    0
    1
    Antepartum haemorrhage
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 296 (0.34%)
         occurrences all number
    0
    1
    Third degree tear
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 296 (0.34%)
         occurrences all number
    0
    1
    Vaginal haematoma
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 296 (0.00%)
         occurrences all number
    1
    0
    Tightenings
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 296 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Pulmonary embolism (suspected)
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 296 (0.34%)
         occurrences all number
    0
    1
    Anaemia
         subjects affected / exposed
    1 / 300 (0.33%)
    3 / 296 (1.01%)
         occurrences all number
    1
    3
    Haemoglobin low
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 296 (0.00%)
         occurrences all number
    1
    0
    Low platelets
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 296 (0.00%)
         occurrences all number
    1
    0
    Nosebleeds
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 296 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 300 (0.67%)
    2 / 296 (0.68%)
         occurrences all number
    2
    2
    Vomiting in pregnancy
         subjects affected / exposed
    3 / 300 (1.00%)
    3 / 296 (1.01%)
         occurrences all number
    3
    4
    Nausea
         subjects affected / exposed
    1 / 300 (0.33%)
    2 / 296 (0.68%)
         occurrences all number
    1
    2
    Stools abnormal
         subjects affected / exposed
    3 / 300 (1.00%)
    2 / 296 (0.68%)
         occurrences all number
    3
    2
    Intestinal disorder
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 296 (0.34%)
         occurrences all number
    0
    1
    Gastrooesophageal reflux
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 296 (0.34%)
         occurrences all number
    0
    1
    Abdominal pain
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 296 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Panic attack
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 296 (0.34%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Acute kidney injury (probable)
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 296 (0.34%)
         occurrences all number
    0
    1
    Endocrine disorders
    Goitre (possible)
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 296 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Fall
         subjects affected / exposed
    1 / 300 (0.33%)
    1 / 296 (0.34%)
         occurrences all number
    1
    1
    Hip pain
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 296 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Tachycardia
         subjects affected / exposed
    1 / 300 (0.33%)
    1 / 296 (0.34%)
         occurrences all number
    1
    1
    Dental abscess
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 296 (0.34%)
         occurrences all number
    0
    1
    Sore throat
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 296 (0.34%)
         occurrences all number
    0
    1
    Cough
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 296 (0.34%)
         occurrences all number
    0
    1
    Urinary tract infection e. coli
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 296 (0.00%)
         occurrences all number
    1
    0
    Leg infection (suspected)
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 296 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Mar 2018
    Protocol v3.0 Section 9.6 Withdrawal of Participants We have amended the wording to allow continued recruitment up to the number of women who discontinued the intervention or withdrew from the trial if there is sufficient time within the existing study time-line to do so. Removed: “There is no requirement to enrol extra participants to replace women who do not complete the study." Added: "If there is sufficient time within the existing study time-line, additional participants will be recruited up to the number of women who discontinued the intervention or withdrew”.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/30482254
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