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    Clinical Trial Results:
    STRIDER: A randomised controlled trial of sildenafil therapy in dismal prognosis early-onset intrauterine growth restriction.

    Summary
    EudraCT number
    		 2013-005398-32
    Trial protocol
    		 GB  
    Global end of trial date
    13 Feb 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Mar 2019
    First version publication date
    01 Mar 2019
    Other versions
    Summary report(s)
    		 2013-005398-32 - End of Study Clinical Trial Report
    STRIDER UK Manuscript_17TLCHILD0261_Alfirevic_Published 06-12-2017

    Trial information

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    Trial identification
    Sponsor protocol code
    UoL000984
    Additional study identifiers
    ISRCTN number
    		 ISRCTN39133303
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 MHRA CTA reference: 04196/0032/001-0001, REC reference: 14/NE/0011, NIHR Portfolio reference: 16986, NIHR / EME Funding reference: 12/62/109
    Sponsors
    Sponsor organisation name
    University of Liverpool
    Sponsor organisation address
    Block D Waterhouse Building, 3 Brownlow Street, Liverpool, United Kingdom, L69 3GL
    Public contact
    Dr Jane Harrold, Liverpool Clinical Trials Unit, 0151 7959565, jlh7@liverpool.ac.uk
    Scientific contact
    Professor Zarko Alfirevic , Women's and Children's Health, 0151 7959550, zarko@liverpool.ac.uk
    Sponsor organisation name
    Liverpool Women's NHS Foundation Trust
    Sponsor organisation address
    Liverpool Women's Hospital, Crown Street, Liverpool, United Kingdom, L8 7SS
    Public contact
    Louise Hardman, Research and Development, 0151 7024241, louise.hardman@lwh.nhs.uk
    Scientific contact
    Dr Andrew Sharp, Fetal Medicine Unit, 0151 7959560, asharp@liverpool.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
    27 Apr 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 Feb 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Feb 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Severe early-onset intrauterine growth restriction (IUGR) can lead to a range of adverse outcomes including fetal and neonatal death, neurodisability and lifelong risks to the health of the affected child. Sildenafil, a phosphodiesterase type 5 inhibitor, potentiates the actions of nitric oxide, which leads to vasodilatation of the uterine vessels and might improve fetal growth in utero. The overarching aim is to determine whether maternal treatment of oral sildenafil citrate improves perinatal outcomes in pregnancies complicated by severe early-onset IUGR without increasing risks to the mother. This study has a specific objective to evaluate the clinical efficacy of sildenafil i.e. its ability to lead to a delay of a clinical indication for delivery on fetal grounds by at least one week. The other specific objective is to add to the understanding of the mechanism of action of sildenafil by monitoring changes in the maternal, utero-placental and fetal circulation.
    Protection of trial subjects
    Central and on-site monitoring was conducted to ensure the safety of participants and that study procedures, IMP administration, and laboratory and data collection processes were of high quality and met Sponsor and, where appropriate, regulatory requirements. A risk-based approach was adopted in order to determine the frequency and level of monitoring required, and a subsequent trial specific monitoring plan was developed. Throughout the course of the study regular Central Monitoring Reports were produced and reviewed by the Trial Management Team. In addition, on-site monitoring visits were performed for each research site following the hospital discharge of the first participant and surviving child. Safety was monitored via Liverpool Clinical Trials Unit (LCTU) pharmacovigilance procedures and oversight was provided by an ISDMC.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Nov 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Scientific research
    Long term follow-up duration
    		 33 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 135
    Worldwide total number of subjects
    135
    EEA total number of subjects
    135
    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)
    1
    Adults (18-64 years)
    134
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The STRIDER trial recruited participants from within the UK only; 19 fetal medicine centres across England and Scotland opened for the study. A total of 135 women aged 16 years or older with a singleton pregnancy between 22+0 and 29+6 weeks gestation and a confirmed diagnosis of IUGR were recruited between 21st November 2014 and 6th July 2016.

    Pre-assignment
    Screening details
    		 In total 149 women were screened for trial eligibility. A physical examination, full history and first trimester ultrasound were used to determine if the study requirements were met. In each case, the diagnosis of severe early-onset IUGR was confirmed by a fetal medicine expert having excluded fetal anatomical abnormalities.

    Period 1
    Period 1 title
    Study Intervention Phase (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Assessor
    Blinding implementation details
    Blinding in terms of data and IMP were managed separately to the main study by the Clinical Trials Unit, British Columbia Women's Hospital and Sharp Clinical Services respectively.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A
    Arm description
    		 Experimental arm
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sildenafil
    Investigational medicinal product code
    EU/1/09/595
    Other name
    Viagra
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sildenafil was manufactured by Actavis and supplied to each fetal medicine centre by Sharp Clinical Services. The encapsulated sildenafil tablets were prescribed at a dose of 25mg three times per day (orally) from baseline to 32+0 weeks gestation or delivery, whichever came first. Medication was issued weekly as 10-day (30 tablets) treatment packs to participants for self-administration if managed as an out-patient, or dispensed directly from pharmacy for those requiring in-patient care. In all cases, the initial study dose was administered in clinic, with participants being monitored 2 hours post treatment by research staff.

    Arm title
    		 Arm B
    Arm description
    		 Standard arm
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo was supplied to each fetal medicine centre by Sharp Clinical Services. Placebo tablets were prescribed as per treatment arm A, three times per day (orally) from baseline to 32+0 weeks gestation or delivery, whichever came first. Medication was issued weekly as 10-day (30 tablets) treatment packs to participants for self-administration if managed as an out-patient, or dispensed directly from pharmacy for those requiring in-patient care. In all cases, the initial study dose was administered in clinic, with participants being monitored 2 hours post treatment by research staff.

    Number of subjects in period 1
    		Arm A Arm B
    Started
    70
    65
    Completed
    70
    65

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Experimental arm

    Reporting group title
    Arm B
    Reporting group description
    		 Standard arm

    Reporting group values
    		 Arm A Arm B Total
    Number of subjects
    		 70 65 135
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 1 1
        Adults (18-64 years)
    		 70 64 134
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 29 (26 to 34) 33 (28 to 36) -
    Gender categorical
    Units: Subjects
        Female
    		 70 65 135
        Male
    		 0 0 0
    Ethnicity
    Units: Subjects
        White
    		 48 43 91
        Asian
    		 6 8 14
        African
    		 6 7 13
        Other
    		 10 7 17
    Smoking
    Units: Subjects
        Current smoker
    		 12 2 14
        Non-smoker
    		 58 63 121
    Parity
    Units: Subjects
        Nulliparous
    		 35 25 60
        Multiparous
    		 35 40 75
    Pre-eclampsia
    Units: Subjects
        Present
    		 13 11 24
        Absent
    		 57 54 111
    Gestational hypertension
    Units: Subjects
        Present
    		 12 23 35
        Absent
    		 58 42 100
    Current antihypertensive treatment
    Units: Subjects
        Yes
    		 25 27 52
        No
    		 45 38 83
    Gestational diabetes
    Units: Subjects
        Present
    		 2 3 5
        Absent
    		 68 62 130
    Antepartum haemorrhage
    Units: Subjects
        Present
    		 1 0 1
        Absent
    		 69 65 134
    Preterm prelabour rupture of membranes
    Units: Subjects
        Present
    		 0 1 1
        Absent
    		 70 64 134
    Gestation <26+0 weeks
    Units: Subjects
        <26+0 weeks
    		 40 35 75
        ≥26+0 weeks
    		 30 30 60
    Umbilical Artery Doppler
    Units: Subjects
        End-diastolic flow absent
    		 46 45 91
        End-diastolic flow reversed
    		 24 20 44
    Ductus Venosus a-wave
    Units: Subjects
        Present
    		 66 61 127
        Absent
    		 4 4 8
    Uterine Artery Doppler
    Units: Subjects
        Normal
    		 24 18 42
        Abnormal (PI >1.45 or bilateral notching)
    		 46 45 91
        Missing
    		 0 2 2
    Estimated fetal weight <500g
    Units: Subjects
        <500g
    		 33 36 69
        ≥500g
    		 37 29 66
    Height
    Units: centimetres (cm)
        median (inter-quartile range (Q1-Q3))
    		 164 (158 to 167) 163 (158 to 166) -
    Weight
    Units: kilogram(s) (kg)
        median (inter-quartile range (Q1-Q3))
    		 68 (59 to 82) 70 (60 to 82) -
    Body-mass index
    Units: kilogram(s)/square meter (kg/m²)
        median (inter-quartile range (Q1-Q3))
    		 25 (23 to 32) 26 (23 to 31) -
    Estimated fetal weight
    Units: gram(s) (g)
        median (inter-quartile range (Q1-Q3))
    		 451 (352 to 613) 436 (326 to 594) -
    Gestation
    Units: weeks
        median (inter-quartile range (Q1-Q3))
    		 25.1 (24.0 to 27.5) 25.6 (24.1 to 27.4) -
    Systolic blood pressure
    Units: millimetre of mercury (mm Hg)
        median (inter-quartile range (Q1-Q3))
    		 135.5 (125.5 to 147.5) 134.0 (120.5 to 144.5) -
    Diastolic blood pressure
    Units: millimetre of mercury (mm Hg)
        median (inter-quartile range (Q1-Q3))
    		 88.5 (80.5 to 95.5) 86.5 (78.0 to 94.5) -
    Mean arterial pressure
    Units: millimetre of mercury (mm Hg)
        arithmetic mean (standard deviation)
    		 103 ( 12 ) 109 ( 38 ) -
    Creatinine
    Units: mole(s)/litre (mol/L)
        arithmetic mean (standard deviation)
    		 57.4 ( 1.9 ) 62.4 ( 2.7 ) -
    Urea
    Units: millimole(s)/litre (mmol/L)
        arithmetic mean (standard deviation)
    		 4.0 ( 0.2 ) 4.4 ( 0.5 ) -
    Uric acid
    Units: millimole(s)/litre (mmol/L)
        arithmetic mean (standard deviation)
    		 300.6 ( 13.4 ) 288.6 ( 14.7 ) -
    Aspartate transaminase
    Units: units per litre (U/L)
        arithmetic mean (standard deviation)
    		 26.0 ( 3.3 ) 32.4 ( 5.7 ) -
    Albumin
    Units: gram(s)/litre (g/L)
        arithmetic mean (standard deviation)
    		 31.8 ( 0.7 ) 32.4 ( 0.7 ) -

    End points

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    End points reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Experimental arm

    Reporting group title
    Arm B
    Reporting group description
    		 Standard arm

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The final analysis dataset following the Intention to treat principle

    Subject analysis set title
    Per Protocol Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    29 Patients removed due to major protocol deviation

    Primary: Randomisation to birth interval

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    End point title
    		 Randomisation to birth interval
    End point description
    Primary outcome was randomisation to birth interval. One week difference in the mean randomisation to birth interval was considered to be clinically important.
    End point type
    Primary
    End point timeframe
    From randomisation to birth
    End point values
    		 Arm A Arm B Full analysis set
    Number of subjects analysed
    70
    65
    135
    Units: Days
        median (inter-quartile range (Q1-Q3))
    17 (7 to 24)
    18 (8 to 28)
    18 (7.5 to 27)
    Attachments
    		 Primary outcome according to treatment
    Primary outcome - Kaplan-Meier plot
    Statistical analysis title
    		 Analysis of Randomisation to Birth Interval
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.282
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Neonatal Outcome - Birthweight

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    End point title
    		 Neonatal Outcome - Birthweight
    End point description
    End point type
    Secondary
    End point timeframe
    At delivery
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    70
    65
    Units: Weight (g)
        arithmetic mean (inter-quartile range (Q1-Q3))
    604 (496 to 766)
    590 (430 to 842)
    Statistical analysis title
    		 Secondary Outcome: Neonatal
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.815
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Notes
    [1] - Intention To Treat (ITT)

    Secondary: Neonatal Outcome - NICU Admission Duration

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    End point title
    		 Neonatal Outcome - NICU Admission Duration
    End point description
    End point type
    Secondary
    End point timeframe
    From delivery to neonatal discharge / death
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    49
    43
    Units: Days
        arithmetic mean (inter-quartile range (Q1-Q3))
    25 (10 to 50)
    16 (8 to 55)
    Statistical analysis title
    		 Secondary Outcome: Neonatal
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.684
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Notes
    [2] - Intention To Treat (ITT)

    Secondary: Neonatal Outcome - Intracranial Haemorrhage

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    End point title
    		 Neonatal Outcome - Intracranial Haemorrhage
    End point description
    End point type
    Secondary
    End point timeframe
    From delivery to discharge
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    39
    33
    Units: Yes / No (BInary)
    13
    8
    Statistical analysis title
    		 Secondary Outcome: Neonatal
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.75
    Method
    		 Fisher exact
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 2.91
    Notes
    [3] - Intention To Treat (ITT)

    Secondary: Neonatal Outcome - Retinopathy of Prematurity

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    End point title
    		 Neonatal Outcome - Retinopathy of Prematurity
    End point description
    End point type
    Secondary
    End point timeframe
    From delivery to discharge / death
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    49
    43
    Units: Yes / No (Binary)
    6
    10
    Statistical analysis title
    		 Secondary Outcome: Neonatal
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 = 0.27
    Method
    		 Fisher exact
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.21
         upper limit
    		 1.36
    Notes
    [4] - Intention To Treat (ITT)

    Secondary: Neonatal Outcome - Necrotising Enterocolitis

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    End point title
    		 Neonatal Outcome - Necrotising Enterocolitis
    End point description
    End point type
    Secondary
    End point timeframe
    From delivery to discharge / death
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    49
    43
    Units: Yes / No (Binary)
    8
    12
    Statistical analysis title
    		 Secondary Outcome: Neonatal
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.393
    Method
    		 Fisher exact
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.26
         upper limit
    		 1.3
    Notes
    [5] - Intention To Treat (ITT)

    Secondary: Neonatal Outcome - Ventilator Days

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    End point title
    		 Neonatal Outcome - Ventilator Days
    End point description
    End point type
    Secondary
    End point timeframe
    From delivery to discharge / death
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    49
    43
    Units: Days
        arithmetic mean (inter-quartile range (Q1-Q3))
    7 (2 to 21)
    10 (3 to 27)
    Statistical analysis title
    		 Secondary Outcome: Neonatal
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 = 0.576
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    -3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12
         upper limit
    		 7
    Notes
    [6] - Intention To Treat (ITT)

    Secondary: Maternal Outcome - Pre-eclampsia

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    End point title
    		 Maternal Outcome - Pre-eclampsia
    End point description
    End point type
    Secondary
    End point timeframe
    From randomisation to delivery
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    70
    65
    Units: Yes / No (Binary)
    15
    12
    Statistical analysis title
    		 Secondary Outcome: Maternal
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 = 0.83
    Method
    		 Fisher exact
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.59
         upper limit
    		 2.29
    Notes
    [7] - Intention To Treat (ITT)

    Secondary: Maternal Outcome - Antenatal Corticosteroids

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    End point title
    		 Maternal Outcome - Antenatal Corticosteroids
    End point description
    End point type
    Secondary
    End point timeframe
    From randomisation to delivery
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    70
    65
    Units: Yes / No (Binary)
    41
    37
    Statistical analysis title
    		 Secondary Outcome: Maternal
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    P-value
    		 = 0.862
    Method
    		 Fisher exact
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.77
         upper limit
    		 1.37
    Notes
    [8] - Intention To Treat (ITT)

    Secondary: Maternal Outcome - Magnesium Sulphate

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    End point title
    		 Maternal Outcome - Magnesium Sulphate
    End point description
    End point type
    Secondary
    End point timeframe
    At delivery
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    70
    65
    Units: Yes / No (Binary)
    40
    25
    Statistical analysis title
    		 Secondary Outcome: Maternal
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 = 0.04
    Method
    		 Fisher exact
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.03
         upper limit
    		 2.14
    Notes
    [9] - Intention To Treat (ITT)

    Secondary: Maternal Outcome - Caesarean Section

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    End point title
    		 Maternal Outcome - Caesarean Section
    End point description
    End point type
    Secondary
    End point timeframe
    At delivery
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    70
    65
    Units: Yes / No (Binary)
    47
    43
    Statistical analysis title
    		 Secondary Outcome: Maternal
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    		 other [10]
    P-value
    		 = 0.247
    Method
    		 Fisher exact
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 1.29
    Notes
    [10] - Intention To Treat (ITT)

    Secondary: Fetal Outcome - Umbilical Artery Doppler

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    End point title
    		 Fetal Outcome - Umbilical Artery Doppler
    End point description
    End point type
    Secondary
    End point timeframe
    From randomisation to delivery
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    51
    47
    Units: Yes / No (Categorical, 3 levels)
        Improvement
    5
    5
        No change
    25
    25
        Deterioration
    21
    17
    Statistical analysis title
    		 Secondary Outcome: Fetal
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    P-value
    		 = 0.915
    Method
    		 Fisher exact
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 1.88
    Notes
    [11] - Intention To Treat (ITT)

    Secondary: Fetal Outcome - Ductus Venosus a-wave

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    End point title
    		 Fetal Outcome - Ductus Venosus a-wave
    End point description
    End point type
    Secondary
    End point timeframe
    From randomisation to delivery
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    51
    42
    Units: Yes / No (Categorical, 3 levels)
        Improvement
    0
    0
        No change
    36
    38
        Deterioration
    15
    4
    Statistical analysis title
    		 Secondary Outcome: Fetal
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    		 other [12]
    P-value
    		 = 0.021
    Method
    		 Fisher exact
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    3.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.11
         upper limit
    		 8.6
    Notes
    [12] - Intention To Treat (ITT)

    Secondary: Fetal Outcome - Middle Cerebral Artery

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    End point title
    		 Fetal Outcome - Middle Cerebral Artery
    End point description
    End point type
    Secondary
    End point timeframe
    From randomisation to delivery
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    50
    40
    Units: Yes / No (Categorical, 3 levels)
        Improvement
    4
    2
        No change
    33
    24
        Deterioration
    13
    14
    Statistical analysis title
    		 Secondary Outcome: Fetal
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    		 other [13]
    P-value
    		 = 0.65
    Method
    		 Chi-squared
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 1.39
    Notes
    [13] - Intention To Treat (ITT)

    Secondary: Fetal Outcome - Uterine Artery Doppler

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    End point title
    		 Fetal Outcome - Uterine Artery Doppler
    End point description
    End point type
    Secondary
    End point timeframe
    From randomisation to delivery
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    45
    42
    Units: Yes / No (Categorical, 3 levels)
        Improvement
    41
    36
        No change
    1
    3
        Deterioration
    3
    3
    Statistical analysis title
    		 Secondary Outcome: Fetal
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 other [14]
    P-value
    		 = 0.608
    Method
    		 Chi-squared
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.19
         upper limit
    		 4.38
    Notes
    [14] - Intention To Treat (ITT)

    Secondary: Fetal Outcome - Abdominal Circumference Change

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    End point title
    		 Fetal Outcome - Abdominal Circumference Change
    End point description
    End point type
    Secondary
    End point timeframe
    From randomisation to delivery
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    46
    41
    Units: millimetres (mm)
        median (inter-quartile range (Q1-Q3))
    14 (6 to 20)
    18 (8 to 25)
    Statistical analysis title
    		 Secondary Outcome: Fetal
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 other [15]
    P-value
    		 = 0.449
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    -4.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.5
         upper limit
    		 4.5
    Notes
    [15] - Intention To Treat (ITT)

    Secondary: NEONATAL - Gestation Time

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    End point title
    		 NEONATAL - Gestation Time
    End point description
    Outcome Measures as the estimated time of gestation until delivery.
    End point type
    Secondary
    End point timeframe
    Analysis conducted at the end of the study.
    End point values
    		 Arm A Arm B Full analysis set
    Number of subjects analysed
    70
    65
    135
    Units: Weeks
        median (inter-quartile range (Q1-Q3))
    28.1 (26.7 to 29.7)
    28.4 (27.3 to 30.1)
    28.3 (26.9 to 29.7)
    Statistical analysis title
    		 Analysis of Gestation Time
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.23
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events (AE) were recorded by clinicians on an eCRF platform at weekly clinic visits from recruitment to discharge. Participants were encouraged to record any side-effects or AEs that would then be reviewed and documented during each clinical visit
    Adverse event reporting additional description
    All Serious Adverse Events (SAE) were reported in accordance with the study specific Pharmacovigilance plan from recruitment to the end of the follow up period. A Development Safety Update Report (DSUR) was submitted annually in line with the Development International Birth Date (DIBD) to the regulatory authorities.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19
    Reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Experimental arm

    Reporting group title
    Arm B
    Reporting group description
    		 Standard arm

    Serious adverse events
    		 Arm A Arm B
    Total subjects affected by serious adverse events
         subjects affected / exposed
    33 / 70 (47.14%)
    35 / 65 (53.85%)
         number of deaths (all causes)
    31
    29
         number of deaths resulting from adverse events
    2
    0
    Pregnancy, puerperium and perinatal conditions
    Congenital, familial & genetic disorder - other
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac abnormality
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 70 (0.00%)
    2 / 65 (3.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage - other (fetal - IVH)
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture (fetal fracture / osteopenia)
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage - other (maternal - antepartum)
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fetal death
    Additional description: Please note: all fetal and neonatal deaths were reported as SAEs as per Sponsor requirements, despite being expected within this study population.
         subjects affected / exposed
    21 / 70 (30.00%)
    22 / 65 (33.85%)
         occurrences causally related to treatment / all
    0 / 21
    0 / 22
         deaths causally related to treatment / all
    0 / 21
    0 / 22
    Death neonatal
    Additional description: Please note: all fetal and neonatal deaths were reported as SAEs as per Sponsor requirements, despite being expected within this study population.
         subjects affected / exposed
    10 / 70 (14.29%)
    7 / 65 (10.77%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 7
         deaths causally related to treatment / all
    0 / 10
    0 / 7
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm A Arm B
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    24 / 70 (34.29%)
    18 / 65 (27.69%)
    Pregnancy, puerperium and perinatal conditions
    Flushing
         subjects affected / exposed
    16 / 70 (22.86%)
    10 / 65 (15.38%)
         occurrences all number
    29
    16
    Other
    Additional description: Including nasal congestion, dry mouth and headache.
         subjects affected / exposed
    19 / 70 (27.14%)
    10 / 65 (15.38%)
         occurrences all number
    31
    18

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Sep 2014
    STRIDER Protocol Version 3.0 (18/AUG/2014) Main changes from version 2.0: Date: 20/FEB/2014 1. Clarification on reporting of SAE’s - section 9.3 2. A list of individual study drug discontinuation criteria included - section 7.3 3. Inclusion of prohibited medications to the exclusion criteria - section 4.2 4. Guidance about concomitant medication has been added with reference to the SmPC - section 7.7 5. Justification as to why only one dose range has been proposed in section 7.1 - rationale for why a dose of 25mg 3 times per day is deemed appropriate has been included 6. Clarification on infant outcomes in fetal, infant and maternal outcomes table - section 6.3.2 7. Additional information added to the Placental sampling studies - section 8.2
    07 Mar 2016
    STRIDER Protocol Version 4.0 (03/FEB/2016) Main changes from version 3.0: Date: 18/AUG/2014 1. Change of R&D Lead at LWH - page 3 2. Trial design – patient recruitment figure – 135 - page 8 3. Number of patients - page 9 4. System Failure number for Canada - section 5.3 5. Visit Schedule - section 6.1 6. Vascular profiling, amended wording and clarification for the Angiogenic bloods, placenta biobanking and the cardiovascular assessments - section 8 7. PV – removal of MACRO PV database for sites - section 9.3.1 8. PV – neonatal SAE’s clarification on prolonged admission to be recorded on the eCRF as an AE - section 9.3.1 9. PV – removal of LCTU PV system details - section 9.6.1 10. Steps for reporting – addition of date of offset and gestation age etc. - section 9.6.1 11. General Typos/corrections

    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/29282009
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