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    Clinical Trial Results:
    Pregnancy And chronic hypertension: NifeDipine or labetalol as Antihypertensive treatment

    Summary
    EudraCT number
    		 2013-003144-23
    Trial protocol
    		 GB  
    Global end of trial date
    18 May 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Oct 2018
    First version publication date
    03 Oct 2018
    Other versions
    Summary report(s)
    		 PANDA PUBLICATION

    Trial information

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    Trial identification
    Sponsor protocol code
    PANDA
    Additional study identifiers
    ISRCTN number
    		 ISRCTN40973936
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    King's College London
    Sponsor organisation address
    The Strand, London, United Kingdom, WC2R 2LS
    Public contact
    Lucy Chappell, King's Colllege London, 44 0207188 3639, lucy.chappell@kcl.ac.uk
    Scientific contact
    Lucy Chappell, King's Colllege London, 44 0207188 3639, lucy.chappell@kcl.ac.uk
    Sponsor organisation name
    Guy's and St Thomas' NHS Foundation Trust
    Sponsor organisation address
    Great Maze Pond, London, United Kingdom, SE19RT
    Public contact
    Lucy Chappell, Guy's and St Thomas' NHS Foundation Trust, 44 0207188 3639, lucy.chappell@kcl.ac.uk
    Scientific contact
    Lucy Chappell, Guy's and St Thomas' NHS Foundation Trust, 44 0207188 3639, lucy.chappell@kcl.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    18 May 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 May 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    18 May 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To undertake a feasibility study for a randomised controlled trial comparing labetalol and nifedipine in pregnant women with chronic hypertension, with planned assessment of ethnic variation in drug response
    Protection of trial subjects
    Routine clinical blood tests are normally taken at 12 weeks, 20 weeks, 28 weeks, on admission/around the time of delivery and 6 weeks postnataly, with additional bloods taken at other times in this high risk population given their increased risk of pre-eclampsia. Participants will be reviewed by an appropriate clinician within two weeks of commencing the trial treatment. Three BP measurements will be taken at each clinical visit to ensure blood pressure is suitably controlled.
    Background therapy
    		 N/A
    Evidence for comparator
    		 There is currently disparity regarding antihypertensive use in chronic hypertension in pregnancy in the UK and internationally. There are sufficient data to recommend avoidance of angiotensin converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARBs), which are recommended by NICE for first line use outside pregnancy in White Europeans. Antihypertensive drugs commonly used in pregnancy include labetalol, calcium channel blockers (nifedipine or amlodipine) and methyldopa. Only labetalol holds a licence for use in pregnancy before 20 weeks gestation, but this is primarily a reflection of the difficulties surrounding licensing drugs for use in pregnancy and the manufacturers of Labetalol advise avoidance in the first trimester. Nifedipine is a calcium channel blocker which blocks the voltage-gated calcium channels in cardiac muscle and blood vessels. A decrease in cellular calcium results in less contraction of the vascular smooth muscle and therefore vasodilation. Side-effects include headache, oedema, flushing, and fatigue. Nifedipine does not hold a licence for use before 20 weeks gestation due to animal data suggesting teratogenic risk, but this increased risk has not been observed in human pregnancy. Both labetalol and nifedipine are already widely used in obstetric practice. The 2010 NICE guidance also states that there are 'no obvious associations with congenital abnormalities' for either drug
    Actual start date of recruitment
    21 Aug 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
    United Kingdom: 114
    Worldwide total number of subjects
    114
    EEA total number of subjects
    114
    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)
    114
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were recruited between 21/08/2014 and 8/05/2016. Participants were recruited from ante natal clinics within the UK.

    Pre-assignment
    Screening details
    		 Participants were eligible to participate in the trial with singleton pregnancy, aged >=18rs and have chronic hypertension - defined as diastolic BP >=90mmHg present at booking or before 20 weeks' gestation, or requiring treatment outside pregnancy and/or at time of referral)Gestation 12-27+6 weeks’ at recruitment. 285 Participants were screened.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group A
    Arm description
    		 Participants were randomised to recieve oral Labetalol 100mg twice per day increasing to 100mg three times per day (TDS) then to 200mg, then 300mg, then 400mg, with a maximum of 600mg TDS (1800mg/day).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Labetalol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral Labetalol 100mg twice per day increasing to 100mg three times per day (TDS) then to 200mg, then 300mg, then 400mg, with a maximum of 600mg TDS (1800mg/day).

    Arm title
    		 Group B
    Arm description
    		 Participants were randomised to receive oral Nifedipine Modified Release (MR) 10mg twice per day (BD) increasing to 20mg, then 30mg, with a maximum dose of 40mg BD (80mg/day).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nifedipine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral Nifedipine Modified Release (MR) 10mg twice per day (BD) increasing to 20mg, then 30mg, with a maximum dose of 40mg BD(80mg/day)

    Number of subjects in period 1
    		Group A Group B
    Started
    56
    58
    Completed
    55
    57
    Not completed
    1
    1
         Lost to follow-up
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group A
    Reporting group description
    		 Participants were randomised to recieve oral Labetalol 100mg twice per day increasing to 100mg three times per day (TDS) then to 200mg, then 300mg, then 400mg, with a maximum of 600mg TDS (1800mg/day).

    Reporting group title
    Group B
    Reporting group description
    		 Participants were randomised to receive oral Nifedipine Modified Release (MR) 10mg twice per day (BD) increasing to 20mg, then 30mg, with a maximum dose of 40mg BD (80mg/day).

    Reporting group values
    		 Group A Group B Total
    Number of subjects
    		 56 58 114
    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 0 0
        Adults (18-64 years)
    		 56 58 114
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Females with singleton pregnancy
    Units: years
        median (full range (min-max))
    		 36 (32.0 to 39.1) 35 (33.0 to 3.8.5) -
    Gender categorical
    Units: Subjects
        Female
    		 56 58 114
        Male
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Group A
    Reporting group description
    		 Participants were randomised to recieve oral Labetalol 100mg twice per day increasing to 100mg three times per day (TDS) then to 200mg, then 300mg, then 400mg, with a maximum of 600mg TDS (1800mg/day).

    Reporting group title
    Group B
    Reporting group description
    		 Participants were randomised to receive oral Nifedipine Modified Release (MR) 10mg twice per day (BD) increasing to 20mg, then 30mg, with a maximum dose of 40mg BD (80mg/day).

    Primary: Primary Process Endpoint

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    End point title
    		 Primary Process Endpoint [1]
    End point description
    Number of participants recruited per site per month
    End point type
    Primary
    End point timeframe
    Recruitment phase of the trial.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This is a feasibility trial.
    End point values
    		 Group A Group B
    Number of subjects analysed
    56
    58
    Units: whole
    56
    58
    Attachments
    		 Primary Process Endpoint
    No statistical analyses for this end point

    Primary: Primary Clinical Endpoint

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    End point title
    		 Primary Clinical Endpoint [2]
    End point description
    Highest systolic BP post-randomisation
    End point type
    Primary
    End point timeframe
    Entire duration of trial post dosing.
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This is a feasibility trial
    End point values
    		 Group A Group B
    Number of subjects analysed
    55
    57
    Units: mmHG
        number (not applicable)
    55
    57
    Attachments
    		 Primary Clinical Endpoint
    No statistical analyses for this end point

    Secondary: Maternal & Perinatal Outcomes

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    End point title
    		 Maternal & Perinatal Outcomes
    End point description
    Maternal and perinatal morbidity •Acceptability (adherence to dosing regimen,side-effects of drugs and participant satisfaction) •Health resource use (attendances andadmissions) •Explanatory biomarker and vascular function assessments
    End point type
    Secondary
    End point timeframe
    Throughout duration of participation in trial
    End point values
    		 Group A Group B
    Number of subjects analysed
    55
    57
    Units: whole
    55
    57
    Attachments
    		 Secondary Maternal & Perinatal Outcomes
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From recruitment until 6 week post natal visit.
    Adverse event reporting additional description
    Adverse events were analysed in all randomised patients including those lost to follow-up.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Group A
    Reporting group description
    		 Participants were randomised to recieve oral Labetalol 100mg twice per day increasing to 100mg three times per day (TDS) then to 200mg, then 300mg, then 400mg, with a maximum of 600mg TDS (1800mg/day).

    Reporting group title
    Group B
    Reporting group description
    		 Participants were randomised to receive oral Nifedipine Modified Release (MR) 10mg twice per day (BD) increasing to 20mg, then 30mg, with a maximum dose of 40mg BD (80mg/day).

    Serious adverse events
    		 Group A Group B
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 56 (1.79%)
    3 / 58 (5.17%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Blood and lymphatic system disorders
    Epistaxis
    Additional description: Unplanned admission to hospital
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
    Additional description: Participant admitted to hospital with DVT
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastroenteritis enteroviral
    Additional description: Participant admitted overnight to hospital.
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Influenza like illness
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 58 (1.72%)
         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
    		 Group A Group B
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 56 (37.50%)
    15 / 58 (25.86%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    10 / 56 (17.86%)
    11 / 58 (18.97%)
         occurrences all number
    10
    11
    Dizziness
         subjects affected / exposed
    5 / 56 (8.93%)
    2 / 58 (3.45%)
         occurrences all number
    5
    2
    Pregnancy, puerperium and perinatal conditions
    Lethargy
         subjects affected / exposed
    2 / 56 (3.57%)
    0 / 58 (0.00%)
         occurrences all number
    2
    0
    Hot flushes
         subjects affected / exposed
    1 / 56 (1.79%)
    1 / 58 (1.72%)
         occurrences all number
    1
    1
    Nipple pain
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 58 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Epistaxis
         subjects affected / exposed
    1 / 56 (1.79%)
    1 / 58 (1.72%)
         occurrences all number
    1
    1
    Peripheral oedema neonatal
         subjects affected / exposed
    2 / 56 (3.57%)
    1 / 58 (1.72%)
         occurrences all number
    2
    1
    Ear and labyrinth disorders
    Nasal congestion
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 58 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Eye spasm
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 58 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 56 (3.57%)
    2 / 58 (3.45%)
         occurrences all number
    2
    2
    Nausea
         subjects affected / exposed
    2 / 56 (3.57%)
    2 / 58 (3.45%)
         occurrences all number
    2
    2
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    5 / 56 (8.93%)
    1 / 58 (1.72%)
         occurrences all number
    5
    1
    Chest pain
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 58 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Scalp tingling
         subjects affected / exposed
    2 / 56 (3.57%)
    0 / 58 (0.00%)
         occurrences all number
    2
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Mar 2014
    Changes to eligibility criteria, schedule flow chart and additionally biomarker blood sampling.

    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.
    Labetalol and nifedipine control mean systolic and diastolic BP to target in pregnant women with chronic hypertension. Good recruitment was demonstrated and mechanistic treatment effects observed. This study provides support for a larger definitive t

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/28893900
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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