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    Clinical Trial Results:
    Combined Multi-Marker Screening and Randomised Patient Treatment with Aspirin for Evidence-based Pre-eclampsia Prevention

    Summary
    EudraCT number
    		 2013-003778-29
    Trial protocol
    		 GB   IT   BE   GR  
    Global end of trial date
    03 Nov 2016

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

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CTU/2013/064
    Additional study identifiers
    ISRCTN number
    		 ISRCTN13633058
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 U1111-1140-4837
    Sponsors
    Sponsor organisation name
    Comprehensive Clinical Trials Unit at UCL
    Sponsor organisation address
    Institute of Clinical Trials and Methodology, 90 High Holborn, London, United Kingdom, WC1V 6LJ
    Public contact
    CCTU Enquiry Desk, Comprehensive Clinical Trials Unit at UCL, CCTU-enquiries@ucl.ac.uk
    Scientific contact
    CCTU Enquiry Desk, Comprehensive Clinical Trials Unit at UCL, CCTU-enquiries@ucl.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
    02 Dec 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Nov 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Nov 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To examine if the use of low-dose aspirin starting at 11-14 weeks gestation in women at increased risk for pre-eclampsia (high blood pressure) can reduce the incidence and severity of this complication.
    Protection of trial subjects
    The trial was conducted in compliance with the approved protocol, UCL CCTU Standard Operating Procedures (SOPs), the Declaration of Helsinki (2008), the principles of Good Clinical Practice (GCP) as laid down by the Commission Directive 2005/28/EC with implementation in national legislation in the UK by Statutory Instrument 2004/1031 and subsequent amendments, the UK Data Protection Act, and the National Health Service (NHS) Research Governance Framework for Health and Social Care (RGF). International sites complied with the approved protocol, UCL CCTU SOPs, the principles of GCP as laid down by ICH topic E6 (Note for Guidance on GCP), Commission Directive 2005/28/EC, the European Directive 2001/20/EC (where applicable) and other national and local applicable regulations. Irrespective of indications, there were no dose modifications. One fixed dose of 150 mg aspirin or placebo was used. This dosage was carefully selected based on aspirin pharmacology. Protocol pre-defined reasons for discontinuation of trial medication were in place in the event of participants experiencing: unacceptable treatment toxicity or adverse event; inter-current illness that prevents further treatment; any change in the participant’s condition that in the clinician’s opinion justifies the discontinuation of treatment; protocol violations; cure; administrative reasons or other reasons. All participants could choose to discontinue trial treatment at any time, without giving a reason, without penalty or loss of benefits to which they would otherwise be entitled. Investigation and treatment of adverse events were as per NHS standard of care.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Apr 2014
    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
    Israel: 2
    Country: Number of subjects enrolled
    Spain: 356
    Country: Number of subjects enrolled
    United Kingdom: 1227
    Country: Number of subjects enrolled
    Belgium: 88
    Country: Number of subjects enrolled
    Greece: 53
    Country: Number of subjects enrolled
    Italy: 50
    Worldwide total number of subjects
    1776
    EEA total number of subjects
    1774
    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)
    1776
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial was conducted in 13 maternity hospitals in England, Spain, Italy, Belgium, Greece and Israel. All women attending for a routine hospital visit at 11+0 to 13+6 weeks of gestation in the participating hospitals are offered screening for preeclampsia by the same algorithm.

    Pre-assignment
    Screening details
    		 High-risk (>1 in 100) for preterm preeclampsia.

    Period 1
    Period 1 title
    Randomization (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
    Eligible women were randomly assigned, in a 1:1 ratio, with the use of a web-based system (Sealed Envelope, London, UK), to receive either aspirin or placebo and in the random-sequence generation there was stratification according to participating center. The placebo and aspirin tablets were manufactured by Actavis UK Ltd, Devon, UK and were packaged, labelled, stored and distributed by Mawdsley Brooks and Co, Salford, UK.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Aspirin
    Arm description
    		 150mg of Aspirin taken at bedtime commencing between 11-14 weeks gestation, depending on recruitment,... more
    Arm type
    		 Experimental

    Investigational medicinal product name
    Aspirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    150mg taken orally at bedtime

    Arm title
    		 Placebo
    Arm description
    		 Identical in appearance and packaging to experimental treatment.
    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
    Matched placebo taken at bedtime.

    Number of subjects in period 1
    		Aspirin Placebo
    Started
    878
    898
    Completed
    798
    822
    Not completed
    80
    76
         Consent withdrawn by subject
    78
    74
         Lost to follow-up
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Aspirin
    Reporting group description
    		 150mg of Aspirin taken at bedtime commencing between 11-14 weeks gestation, depending on recruitment,... more

    Reporting group title
    Placebo
    Reporting group description
    		 Identical in appearance and packaging to experimental treatment.

    Reporting group values
    		 Aspirin Placebo Total
    Number of subjects
    		 878 898 1776
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 31.5 (27.3 to 35.8) 31.4 (26.9 to 35.8) -
    Gender categorical
    Units: Subjects
        Female
    		 878 898 1776
        Male
    		 0 0 0
    Race or ethnic group
    Units: Subjects
        White
    		 529 560 1089
        Black
    		 208 202 410
        South Asian
    		 38 37 75
        East Asian
    		 13 16 29
        Mixed race
    		 12 9 21
        Withdrew consent
    		 78 74 152
    Method of conception
    Units: Subjects
        Natural
    		 749 781 1530
        Assisted by ovulation drugs
    		 6 7 13
        In virto fertilization
    		 45 36 81
        Withdrew consent
    		 78 74 152
    Smoking
    Units: Subjects
        Smoker
    		 57 60 117
        None smoker
    		 743 764 1507
        Withdrew consent
    		 78 74 152
    Chronic hypertension
    Units: Subjects
        Yes
    		 49 61 110
        No
    		 751 763 1514
        Withdrew consent
    		 78 74 152
    Systemic lupus erythematosus
    Units: Subjects
        Yes
    		 3 1 4
        No
    		 797 823 1620
        Withdrew consent
    		 78 74 152
    Antiphospholipid syndrome
    Units: Subjects
        Yes
    		 2 2 4
        No
    		 798 822 1620
        Withdrew consent
    		 78 74 152
    Diabetes mellitus
    Units: Subjects
        Type 1
    		 7 2 9
        Type 2
    		 8 8 16
        None
    		 785 814 1599
        Withdrew consent
    		 78 74 152
    Obstetrical history
    Units: Subjects
        Nulliparous
    		 548 545 1093
        Multiparous without preeclampsia
    		 165 195 360
        Multiparous with preeclampsia
    		 87 84 171
        Withdrew consent
    		 78 74 152
    Gestational age at randomization
    Units: Weeks
        median (inter-quartile range (Q1-Q3))
    		 12.7 (12.3 to 13.1) 12.6 (12.3 to 13.0) -
    Body-mass index
    Units: Weight in kg/square of height m
        median (inter-quartile range (Q1-Q3))
    		 26.7 (23.3 to 31.1) 26.5 (23.0 to 31.5) -
    Interval from last pregnancy
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 4.2 (2.5 to 7.0) 4.6 (2.9 to 7.5) -

    End points

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    End points reporting groups
    Reporting group title
    Aspirin
    Reporting group description
    		 150mg of Aspirin taken at bedtime commencing between 11-14 weeks gestation, depending on recruitment,... more

    Reporting group title
    Placebo
    Reporting group description
    		 Identical in appearance and packaging to experimental treatment.

    Primary: Preeclampsia with delivery before 37 week

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    End point title
    		 Preeclampsia with delivery before 37 week
    End point description
    End point type
    Primary
    End point timeframe
    Delivery
    End point values
    		 Aspirin Placebo
    Number of subjects analysed
    798
    822
    Units: Subjects
        Yes
    13
    35
        No
    785
    787
    Statistical analysis title
    		 Mixed effects logistic regression
    Statistical analysis description
    Logistic regression adjusted for participating center (random effect) and logit of risk at screening (fixed effect).
    Comparison groups
    Aspirin v Placebo
    Number of subjects included in analysis
    1620
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.004
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 0.74

    Secondary: Adverse outcomes with delivery before 37 weeks

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    End point title
    		 Adverse outcomes with delivery before 37 weeks
    End point description
    Delivery before 37 weeks gestation associated with preeclampsia, gestational hypertension, miscarriage, stillbirth, small-for-gestational-age abruption or spontaneous delivery. Please see attached chart for details.
    End point type
    Secondary
    End point timeframe
    Delivery before 37 weeks gestation
    End point values
    		 Aspirin Placebo
    Number of subjects analysed
    798
    822
    Units: Subjects
        Yes
    79
    116
        No
    719
    706
    Attachments
    		 Odds ratios (aspirin/placebo) with 99% CIs.
    Statistical analysis title
    		 Mixed effects logistic regression
    Statistical analysis description
    Logistic regression adjusted for participating center (random effect) and logit of risk at screening (fixed effect).
    Comparison groups
    Aspirin v Placebo
    Number of subjects included in analysis
    1620
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.69
    Confidence interval
         level
    		 99%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 1.03

    Secondary: Adverse outcomes with delivery before 34 weeks

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    End point title
    		 Adverse outcomes with delivery before 34 weeks
    End point description
    Delivery before 34 weeks gestation associated with preeclampsia, gestational hypertension, miscarriage, stillbirth, small-for-gestational-age abruption or spontaneous delivery. Please see attached chart for details.
    End point type
    Secondary
    End point timeframe
    Adverse outcomes before 34 weeks.
    End point values
    		 Aspirin Placebo
    Number of subjects analysed
    798
    822
    Units: Subjects
        Yes
    32
    53
        No
    766
    769
    Attachments
    		 Odds ratios (aspirin/placebo) with 99% CIs.
    Statistical analysis title
    		 Mixed effects logistic regression
    Statistical analysis description
    Logistic regression adjusted for participating center (random effect) and logit of risk at screening (fixed effect).
    Comparison groups
    Aspirin v Placebo
    Number of subjects included in analysis
    1620
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.62
    Confidence interval
         level
    		 99%
         sides
    2-sided
         lower limit
    		 0.34
         upper limit
    		 1.14

    Secondary: Adverse outcomes with delivery at 37 weeks or later

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    End point title
    		 Adverse outcomes with delivery at 37 weeks or later
    End point description
    Adverse outcomes with delivery at 37 weeks gestation or later associated with preeclampsia, gestational hypertension, stillbirth, small-for-gestational-age abruption or spontaneous delivery. Please see attached chart for details.
    End point type
    Secondary
    End point timeframe
    Delivery at 37 weeks gestation or later.
    End point values
    		 Aspirin Placebo
    Number of subjects analysed
    798
    822
    Units: Subjects
        Yes
    178
    171
        No
    620
    651
    Attachments
    		 Odds ratios (aspirin/placebo) with 99% CIs.
    Statistical analysis title
    		 Mixed effects logistic regression
    Statistical analysis description
    Logistic regression adjusted for participating center (random effect) and logit of risk at screening (fixed effect).
    Comparison groups
    Aspirin v Placebo
    Number of subjects included in analysis
    1620
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.12
    Confidence interval
         level
    		 99%
         sides
    2-sided
         lower limit
    		 0.82
         upper limit
    		 1.54

    Secondary: All stillbirths or deaths

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    End point title
    		 All stillbirths or deaths
    End point description
    Miscarriages, stillbirths or deaths. For breakdown by preeclampsia, small-for-gestation and placental abruption or bleeding see chart.
    End point type
    Secondary
    End point timeframe
    Miscarriages and births.
    End point values
    		 Aspirin Placebo
    Number of subjects analysed
    798
    822
    Units: Subjects
        Yes
    8
    14
        No
    790
    808
    Attachments
    		 Odds ratios (aspirin/placebo) with 99% Cis.
    Statistical analysis title
    		 Mixed effects logistic regression
    Statistical analysis description
    Logistic regression adjusted for participating center (random effect) and logit of risk at screening (fixed effect).
    Comparison groups
    Aspirin v Placebo
    Number of subjects included in analysis
    1620
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.59
    Confidence interval
         level
    		 99%
         sides
    2-sided
         lower limit
    		 0.19
         upper limit
    		 1.85

    Secondary: Death or complications

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    End point title
    		 Death or complications
    End point description
    Death, miscarriage or complications from intraventricular hemorrage of grade II or above, sepsis with confirmed bacteremia in cultures, anemia resulting in blood transfusion, respitoratory distress syndrome treated with surfactant and ventilation or necrotizing enterocolitis resulting in surgery. See chart for breakdown.
    End point type
    Secondary
    End point timeframe
    Miscarriage or birth.
    End point values
    		 Aspirin Placebo
    Number of subjects analysed
    798
    822
    Units: Subjects
        Yes
    32
    48
        No
    766
    774
    Attachments
    		 Odds ratios (aspirin/placebo) with 99% CIs.
    Statistical analysis title
    		 Mixed effects logistic regression
    Statistical analysis description
    Logistic regression adjusted for participating center (random effect) and logit of risk at screening (fixed effect).
    Comparison groups
    Aspirin v Placebo
    Number of subjects included in analysis
    1620
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.69
    Confidence interval
         level
    		 99%
         sides
    2-sided
         lower limit
    		 0.37
         upper limit
    		 1.27

    Secondary: Poor fetal growth: Birth weight below 3rd percentile

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    End point title
    		 Poor fetal growth: Birth weight below 3rd percentile
    End point description
    End point type
    Secondary
    End point timeframe
    Weight at birth for babies born after 24 weeks gestation.
    End point values
    		 Aspirin Placebo
    Number of subjects analysed
    785 [1]
    807 [2]
    Units: Subjects
        Yes
    57
    63
        No
    728
    744
    Notes
    [1] - Birth weight for deliveries before 24 weeks was not recorded.
    [2] - Birth weight for deliveries before 24 weeks was not recorded.
    Statistical analysis title
    		 Mixed effects logistic regression
    Statistical analysis description
    Logistic regression adjusted for participating center (random effect) and logit of risk at screening (fixed effect).
    Comparison groups
    Aspirin v Placebo
    Number of subjects included in analysis
    1592
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.92
    Confidence interval
         level
    		 99%
         sides
    2-sided
         lower limit
    		 0.57
         upper limit
    		 1.51

    Secondary: Poor fetal growth: Birth weight below 5th percentile

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    End point title
    		 Poor fetal growth: Birth weight below 5th percentile
    End point description
    End point type
    Secondary
    End point timeframe
    Weight at birth.
    End point values
    		 Aspirin Placebo
    Number of subjects analysed
    785 [3]
    807 [4]
    Units: Subjects
        Yes
    82
    96
        No
    703
    744
    Notes
    [3] - Birth weight for deliveries before 24 weeks was not recorded.
    [4] - Birth weight for deliveries before 24 weeks was not recorded.
    Statistical analysis title
    		 Mixed effects logistic regression
    Statistical analysis description
    Logistic regression adjusted for participating center (random effect) and logit of risk at screening (fixed effect).
    Comparison groups
    Aspirin v Placebo
    Number of subjects included in analysis
    1592
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.86
    Confidence interval
         level
    		 99%
         sides
    2-sided
         lower limit
    		 0.57
         upper limit
    		 1.3

    Secondary: Poor fetal growth: Birth weight below 10th percentile

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    End point title
    		 Poor fetal growth: Birth weight below 10th percentile
    End point description
    End point type
    Secondary
    End point timeframe
    Weight at birth.
    End point values
    		 Aspirin Placebo
    Number of subjects analysed
    785 [5]
    807 [6]
    Units: Subjects
        Yes
    148
    187
        No
    637
    620
    Notes
    [5] - Birth weight for deliveries before 24 weeks was not recorded.
    [6] - Birth weight for deliveries before 24 weeks was not recorded.
    Statistical analysis title
    		 Mixed effects logistic regression.
    Statistical analysis description
    Logistic regression adjusted for participating center (random effect) and logit of risk at screening (fixed effect).
    Comparison groups
    Aspirin v Placebo
    Number of subjects included in analysis
    1592
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.77
    Confidence interval
         level
    		 99%
         sides
    2-sided
         lower limit
    		 0.56
         upper limit
    		 1.06

    Secondary: Admission to intensive care unit

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    End point title
    		 Admission to intensive care unit
    End point description
    End point type
    Secondary
    End point timeframe
    Birth.
    End point values
    		 Aspirin Placebo
    Number of subjects analysed
    798
    822
    Units: Subjects
        Yes
    48
    54
        No
    750
    768
    Statistical analysis title
    		 Mixed effects logistic regression
    Statistical analysis description
    Logistic regression adjusted for participating center (random effect) and logit of risk at screening (fixed effect).
    Comparison groups
    Aspirin v Placebo
    Number of subjects included in analysis
    1620
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.93
    Confidence interval
         level
    		 99%
         sides
    2-sided
         lower limit
    		 0.55
         upper limit
    		 1.59

    Secondary: Ventilation with positive airway pressure intubation

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    End point title
    		 Ventilation with positive airway pressure intubation
    End point description
    End point type
    Secondary
    End point timeframe
    Birth.
    End point values
    		 Aspirin Placebo
    Number of subjects analysed
    798
    822
    Units: Subjects
        Yes
    37
    46
        No
    761
    776
    Statistical analysis title
    		 Mixed effects logistic regression
    Statistical analysis description
    Logistic regression adjusted for participating center (random effect) and logit of risk at screening (fixed effect).
    Comparison groups
    Aspirin v Placebo
    Number of subjects included in analysis
    1620
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.85
    Confidence interval
         level
    		 99%
         sides
    2-sided
         lower limit
    		 0.47
         upper limit
    		 1.52

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The period for adverse events reporting was from the time of first dose until 30 days post final IMP administration. The participants were be followed up by a telephone interview 30 days after the last dose of IMP.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    Aspirin
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Aspirin Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 878 (1.48%)
    26 / 898 (2.90%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    1
    Surgical and medical procedures
    Maternal appendicitis requiring surgery
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 878 (0.00%)
    2 / 898 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Maternal cholangitis requiring surgery
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 878 (0.11%)
    0 / 898 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Fetal chromosomal abnormality: Trisomy 21
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 878 (0.34%)
    1 / 898 (0.11%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fetal chromosomal abnormality: Klinefelter syndrome
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 878 (0.00%)
    1 / 898 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fetal chromosomal abnormality: Microdeletion chromosome 16
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 878 (0.00%)
    1 / 898 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fetal chromosomal abnormality: Microdeletion chromosome 15
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 878 (0.00%)
    1 / 898 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fetal chromosomal abnormality: Di George syndrome
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 878 (0.11%)
    1 / 898 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fetal structural defect: Intracranial hemorrhage due to traumatic delivery
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 878 (0.00%)
    1 / 898 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fetal structural defect: Ventriculomegaly, talipes, deformed hand
         subjects affected / exposed
    0 / 878 (0.00%)
    1 / 898 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fetal structural defect: Cleft lip
         subjects affected / exposed
    0 / 878 (0.00%)
    1 / 898 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fetal structural defect: Congenital diaphragmatic hernia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 878 (0.00%)
    2 / 898 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fetal structural defect: Tetralogy of Fallot, Dandy Walker malformation
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 878 (0.00%)
    1 / 898 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fetal structural defect: Tetrallogy of Fallot
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 878 (0.11%)
    1 / 898 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fetal structural defect: Ventricular septal defect
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 878 (0.23%)
    1 / 898 (0.11%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Maternal death due to pulmonary embolism
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 878 (0.00%)
    1 / 898 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ventricular septal defect and right aortic arch
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 878 (0.00%)
    1 / 898 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fetal structural defect: Pulmonary stenosis and ambiguous genitalia
         subjects affected / exposed
    0 / 878 (0.00%)
    1 / 898 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fetal structural defect: Mild pulmonary stenosis
         subjects affected / exposed
    0 / 878 (0.00%)
    1 / 898 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fetal structural defect: Multicyclic dysplastic kidney unilateral
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 878 (0.23%)
    0 / 898 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fetal structural defect: Duplex kidney unilateral
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 878 (0.00%)
    1 / 898 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fetal structural defect: Renal agenesis unilateral
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 878 (0.11%)
    1 / 898 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fetal structural defect: Absent right forearm
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 878 (0.00%)
    1 / 898 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fetal structural defect: Talipes equinivarus bilateral
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 878 (0.11%)
    0 / 898 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fetal structural defect: Rectal stenosis requiring surgery
         subjects affected / exposed
    1 / 878 (0.11%)
    0 / 898 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fetal structural defect: Cutaneous angioma
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 878 (0.00%)
    1 / 898 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fetal structural defect: Hypoplastic left heart syndrome (fetal)
         subjects affected / exposed
    0 / 878 (0.00%)
    2 / 898 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fetal structural defects: Coartcation of the aorta
    Additional description: Withdrawal from trial.
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 878 (0.11%)
    0 / 898 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fetal chromosomal abnormalities: Di George Syndrome
    Additional description: Withdrawal from trial.
         subjects affected / exposed
    0 / 878 (0.00%)
    1 / 898 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Maternal abdominal pain with prolonged hospital stay (4d)
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 878 (0.00%)
    1 / 898 (0.11%)
         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: 0%
    Non-serious adverse events
    		 Aspirin Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    207 / 878 (23.58%)
    210 / 898 (23.39%)
    Nervous system disorders
    Headache and/or dizziness
         subjects affected / exposed
    78 / 878 (8.88%)
    74 / 898 (8.24%)
         occurrences all number
    78
    74
    Blood and lymphatic system disorders
    Vaginal bleeding
         subjects affected / exposed
    29 / 878 (3.30%)
    21 / 898 (2.34%)
         occurrences all number
    29
    21
    Nasal bleeding
         subjects affected / exposed
    16 / 878 (1.82%)
    27 / 898 (3.01%)
         occurrences all number
    16
    27
    Other bleeding
         subjects affected / exposed
    7 / 878 (0.80%)
    5 / 898 (0.56%)
         occurrences all number
    7
    5
    Anemia
         subjects affected / exposed
    4 / 878 (0.46%)
    7 / 898 (0.78%)
         occurrences all number
    4
    7
    General disorders and administration site conditions
    Infections
         subjects affected / exposed
    17 / 878 (1.94%)
    17 / 898 (1.89%)
         occurrences all number
    17
    17
    Pain in chest, back or limbs
         subjects affected / exposed
    10 / 878 (1.14%)
    10 / 898 (1.11%)
         occurrences all number
    10
    10
    Pruritus
         subjects affected / exposed
    8 / 878 (0.91%)
    8 / 898 (0.89%)
         occurrences all number
    8
    9
    Peripheral edema
         subjects affected / exposed
    8 / 878 (0.91%)
    6 / 898 (0.67%)
         occurrences all number
    8
    6
    Shortness of breath
         subjects affected / exposed
    5 / 878 (0.57%)
    6 / 898 (0.67%)
         occurrences all number
    5
    6
    Visual disturbance
         subjects affected / exposed
    5 / 878 (0.57%)
    4 / 898 (0.45%)
         occurrences all number
    5
    4
    Palpitations
         subjects affected / exposed
    6 / 878 (0.68%)
    3 / 898 (0.33%)
         occurrences all number
    6
    3
    Paraesthesia
         subjects affected / exposed
    6 / 878 (0.68%)
    2 / 898 (0.22%)
         occurrences all number
    6
    2
    Fatigue or weakness
         subjects affected / exposed
    2 / 878 (0.23%)
    3 / 898 (0.33%)
         occurrences all number
    2
    3
    Other
         subjects affected / exposed
    13 / 878 (1.48%)
    18 / 898 (2.00%)
         occurrences all number
    13
    18
    Gastrointestinal disorders
    Nausea and/or vomiting
         subjects affected / exposed
    40 / 878 (4.56%)
    36 / 898 (4.01%)
         occurrences all number
    40
    36
    Abdominal and/or pelvic pain
         subjects affected / exposed
    28 / 878 (3.19%)
    33 / 898 (3.67%)
         occurrences all number
    28
    33
    Dyspepsia and/or heartburn
         subjects affected / exposed
    20 / 878 (2.28%)
    22 / 898 (2.45%)
         occurrences all number
    20
    22
    Diarrhoea
         subjects affected / exposed
    9 / 878 (1.03%)
    6 / 898 (0.67%)
         occurrences all number
    9
    6
    Constipation
         subjects affected / exposed
    3 / 878 (0.34%)
    4 / 898 (0.45%)
         occurrences all number
    3
    4
    Skin and subcutaneous tissue disorders
    Skin rash
         subjects affected / exposed
    9 / 878 (1.03%)
    11 / 898 (1.22%)
         occurrences all number
    9
    11

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Jun 2014
    Protocol updated to v2.5 08 May 2014 to include the following: criteria for screening updated from 11-13 weeks gestation to 11-13 weeks gestation or a crown-rump length of 45-84mm; window for randomisation visits has been extended from 11-13 to 11-14 weeks gestation; extension of follow-up visit 2 window on screen negative participants from 32-34 to 30-37 weeks gestation; and other administrative changes and clarifications. Regulatory authorities receiving and approving substantial amendment: UK, Belgium and Italy.
    25 Nov 2014
    Protocol updated to v3.0 21 Oct 2014 to include the following: introduction of the Screening Quality Study (SQS) to precede the main trial; eligibility criteria updated to denote those criteria which are applicable to the SQS and screening stage of the main trial; and removal of interim analysis as no longer feasible due to reduced recruitment timelines for the main trial. Regulatory authorities receiving and approving substantial amendment: UK, Belgium, Spain and Italy.
    11 Jun 2015
    Protocol updated to v4.0, 16 Apr 2015 to include the following: clarification of exclusion criteria in relation to aspirin administration; amendments to IMP supply arrangements; extension of first clinical visit window to coincide with those which form part of routine clinical care at more study sites; the minimum recruitment period for the Screening Quality Study amended from three months to one to three months (dependent on sites’ performance); sites being given the option of dispensing IMP from ward where it is not practical to dispense directly from pharmacy; compliance testing by blood test will now be conducted on all RCT participants rather than 10%; safety reporting period amended from ceasing 30 days after the last IMP administration to 30 days after the last IMP administration for events relating directly to participants and 30 days after delivery or the expected date of delivery, whichever is the latter, for congenital abnormalities/birth defects identified in participant’s baby; clarification of trial closure; and clarification of exceptions to SAE reporting (miscarriage added as exception). Regulatory authorities receiving and approving substantial amendment: UK, Belgium, Spain and Italy.
    25 Nov 2015
    Protocol updated to v5.0 23 Sep 2015 to incorporate the addition of a sub-study at UK study sites only to evaluate maternal cardiac function by a non-invasive method and other minor changes throughout the protocol. Regulatory authorities receiving and approving substantial amendment: UK.
    01 Mar 2016
    Details: Protocol updated to v6.0 25 Jan 2016 to include the following: clarification of secondary objectives and secondary outcomes; changes to safety reporting (non-serious AE/AR no longer reported to UCL CCTU and introduction of reporting of protocol-defined exceptions to SAE to UCL CCTU); changes to compliance testing (cut-offs defined for assessment of compliance testing by tablet count and biochemical assessment of compliance by blood test changed to post hoc analysis); and an increase in the sample size from 1684 to 1760. Regulatory authorities receiving and approving substantial amendment: UK, Belgium, Spain, Italy and Greece.
    27 Jul 2016
    Protocol updated to v 7.0 07 Jul 2016 to include changes to the type of analysis and statistical tests which will be performed on main ASPRE trial data, collection of additional samples of placenta and cord blood for the cardiac sub-study at King’s College Hospital and minor administrative changes throughout the protocol. Regulatory authorities receiving and approving substantial amendment: UK, Belgium, Spain, Italy and Greece.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    20 Jun 2014
    A temporary halt was placed on the trial in June 2014 due to administrative problems with the supply of investigational medicinal product (IMP). The trial was restarted in July 2015 following securing an alternative IMP supplier and recruitment was completed in April 2016. The temporary halt followed the recruitment of 56 participants to the pilot study, the start of the randomised control trial, at King’s College Hospital in the United Kingdom. The manufacture and composition of the IMP were the same throughout the trial, and the women who were enrolled during 2014 were included in the trial population.
    16 Jul 2015

    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/28657417
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