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    Clinical Trial Results:
    A Proof of Principle, Double-Blind, Randomised Placebo-Controlled,Multi-centre Trial of pravaStatin to Ameliorate Early Onset Pre-eclampsia

    Summary
    EudraCT number
    		 2009-012968-13
    Trial protocol
    		 GB  
    Global end of trial date
    09 Sep 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Jul 2018
    First version publication date
    12 Jul 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    UCL08/0350
    Additional study identifiers
    ISRCTN number
    		 ISRCTN23410175
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University College London
    Sponsor organisation address
    149 Tottenham Court Road, London, United Kingdom, W1T 7DN
    Public contact
    Anne Downey, University College London, a.downey@ucl.ac.uk
    Scientific contact
    Anne Downey, University College London, a.downey@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
    22 Dec 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Aug 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Sep 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The aim of the trial is to establish whether pravastatin will lead to a significant reduction of circulating anti-angiogenic factors in women with early-onset pre-eclampsia. To test this hypothesis, we will ask the following questions: 1. Does pravastatin cause a greater inhibition of circulating anti-angiogenic factors in women with early-onset pre-eclampsia compared with placebo? 2. Are there any beneficial or adverse clinical effects to the mother or the baby following gestational exposure to pravastatin? 3. If pravastatin appears to safely inhibit circulatating anti-angiogenic factors, how best can a substantive trial/health technology assessment be undertaken to develop guidance for routine use of statins to prevent or ameliorate pre-eclampsia?
    Protection of trial subjects
    No specific measures
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Jun 2011
    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: 62
    Worldwide total number of subjects
    62
    EEA total number of subjects
    62
    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)
    62
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The first patient was recruited and randomised into the trial on the 18-Jun-2011 and the last patient was randomised into the trial on 30-Jun-2014. The study was open in the UK only and was open in 16 centres.

    Pre-assignment
    Screening details
    		 There were 388 women screened in order to randomise 62 women.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Assessor
    Blinding implementation details
    Overencapsulated IMP and matching placebo

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pravastatin
    Arm description
    		 Pravastatin
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pravastatin
    Investigational medicinal product code
    IMP1
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    40mg daily until delivery

    Arm title
    		 Placebo
    Arm description
    		 Placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Daily until delivery

    Number of subjects in period 1
    		Pravastatin Placebo
    Started
    30
    32
    Completed
    30
    32

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pravastatin
    Reporting group description
    		 Pravastatin

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Reporting group values
    		 Pravastatin Placebo Total
    Number of subjects
    		 30 32 62
    Age categorical
    Units: Subjects
        Adults
    		 30 32 62
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 32.4 ( 5.6 ) 30.4 ( 6.3 ) -
    Gender categorical
    Sex, as subjects all pregnant
    Units: Subjects
        Female
    		 30 32 62
        Male
    		 0 0 0
    Gestational age at diagnosis
    Gestational age of fetus, in weeks, at diagnosis of severe pre-eclampsia. Eligible if <32+6 weeks.
    Units: Subjects
        <30 weeks
    		 23 24 47
        >= 30 weeks
    		 7 8 15
    Smoking status at diagnosis
    Self-declared smoking status
    Units: Subjects
        Smoker
    		 2 1 3
        Stopped smoking when became pregnant
    		 1 1 2
        Non-smoker
    		 27 30 57
    Severity of pre-eclampsia at randomisation
    All Using internationally recognised standard definitions, two categories of severity were defined: 1. Blood pressure >140mmHg systolic or 90mmHg diastolic but <160mmHg and <110mmHg respectively 2. Blood pressure ≥160mmHg systolic or 110mmHg diastolic
    Units: Subjects
        Blood pressure >140mmHg systolic or 90mmHg diastol
    		 13 14 27
        Blood pressure ≥160mmHg systolic or 110mmHg diasto
    		 17 18 35
    Subject analysis sets

    Subject analysis set title
    Pravastatin
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All subjects analysed according to the arm to which they were randomised, regardless of compliance.

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All subjects analysed according to the arm to which they were randomised, regardless of compliance.

    Subject analysis sets values
    		 Pravastatin Placebo
    Number of subjects
    30
    32
    Age categorical
    Units: Subjects
        Adults
    62
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    32.4 ( 5.6 )
    30.4 ( 6.3 )
    Gender categorical
    Sex, as subjects all pregnant
    Units: Subjects
        Female
    30
    32
        Male
    0
    0
    Gestational age at diagnosis
    Gestational age of fetus, in weeks, at diagnosis of severe pre-eclampsia. Eligible if <32+6 weeks.
    Units: Subjects
        <30 weeks
    23
    24
        >= 30 weeks
    7
    8
    Smoking status at diagnosis
    Self-declared smoking status
    Units: Subjects
        Smoker
    2
    1
        Stopped smoking when became pregnant
    1
    1
        Non-smoker
    27
    30
    Severity of pre-eclampsia at randomisation
    All Using internationally recognised standard definitions, two categories of severity were defined: 1. Blood pressure >140mmHg systolic or 90mmHg diastolic but <160mmHg and <110mmHg respectively 2. Blood pressure ≥160mmHg systolic or 110mmHg diastolic
    Units: Subjects
        Blood pressure >140mmHg systolic or 90mmHg diastol
    13
    14
        Blood pressure ≥160mmHg systolic or 110mmHg diasto
    17
    18

    End points

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    End points reporting groups
    Reporting group title
    Pravastatin
    Reporting group description
    		 Pravastatin

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Subject analysis set title
    Pravastatin
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All subjects analysed according to the arm to which they were randomised, regardless of compliance.

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All subjects analysed according to the arm to which they were randomised, regardless of compliance.

    Primary: sFLT-1

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    End point title
    		 sFLT-1
    End point description
    End point type
    Primary
    End point timeframe
    First 3 days after randomisation
    End point values
    		 Pravastatin Placebo
    Number of subjects analysed
    27 [1]
    29 [2]
    Units: ng/ml
        arithmetic mean (standard deviation)
    8.52 ( 4.8 )
    12.24 ( 6.39 )
    Notes
    [1] - Number of subjects providing at least 1 sample/ datapoint
    [2] - Number of subjects providing at least 1 sample/ datapoint
    Statistical analysis title
    		 Primary analysis
    Comparison groups
    Placebo v Pravastatin
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Regression, Logistic
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.17
         upper limit
    		 0.6
    Variability estimate
    Standard deviation

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first administration of trial treatment to 6 weeks post-delivery
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    11
    Reporting groups
    Reporting group title
    Pravastatin
    Reporting group description
    		 Pravastatin

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Serious adverse events
    		 Pravastatin Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 30 (16.67%)
    5 / 29 (17.24%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Cardiac disorders
    Hypertensive emergency
    Additional description: Uncontrolled and/or exacerbation of hypertension
         subjects affected / exposed
    3 / 30 (10.00%)
    3 / 29 (10.34%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Haemorrhage in pregnancy
    Additional description: Antepartum haemorrhage requiring Caesarean delivery
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Haematoma
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Liver function test abnormal
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Postpartum neurosis
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Postpartum sepsis
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Pravastatin Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 30 (13.33%)
    9 / 29 (31.03%)
    Vascular disorders
    Nephrotic syndrome
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 30 (6.67%)
    4 / 29 (13.79%)
         occurrences all number
    2
    4
    Dizziness
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Photopsia
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    0
    0
    Gastrointestinal disorders
    Vomiting in pregnancy
         subjects affected / exposed
    2 / 30 (6.67%)
    3 / 29 (10.34%)
         occurrences all number
    2
    3
    Nausea
         subjects affected / exposed
    0 / 30 (0.00%)
    5 / 29 (17.24%)
         occurrences all number
    0
    0
    Diarrhoea
         subjects affected / exposed
    0 / 30 (0.00%)
    3 / 29 (10.34%)
         occurrences all number
    0
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 29 (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
    05 Jan 2011
    Version 3.1 from AM01 (modification)
    22 Nov 2011
    Version 4.0 from AM02
    16 Apr 2012
    Version 5.0 from AM03
    19 Jul 2012
    Version 6.0 from AM04
    18 Jan 2013
    Version 7.0 from AM05

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

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