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    Clinical Trial Results:
    Feasibility study on the effects of postnatal enalapril on maternal cardiovascular function following preterm pre-eclampsia

    Summary
    EudraCT number
    		 2017-003180-35
    Trial protocol
    		 GB  
    Global end of trial date
    15 Feb 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Apr 2023
    First version publication date
    08 Apr 2023
    Other versions
    Summary report(s)
    		 PICk-UP RCT manuscript
    Observational PICk-UP manuscript

    Trial information

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    Trial identification
    Sponsor protocol code
    R04725
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03466333
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 REC reference:: 18/NW/0253
    Sponsors
    Sponsor organisation name
    Manchester University NHS Foundation Trust
    Sponsor organisation address
    Research Office, 1st Floor, Nowgen Centre, 29 Grafton Street, Manchester, United Kingdom, M13 9WU
    Public contact
    Sponsor's representative, Lynne Webster, +44 01612764125, research.sponsor@mft.nhs.uk
    Scientific contact
    Sponsor's representative, Lynne Webster, +44 01612764125, research.sponsor@mft.nhs.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
    15 Feb 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Feb 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Feb 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary Process outcome: - Recruitment rate (number of women eligible, recruited and completing the study per month). Primary Clinical outcome: - Reduction in total vascular resistance (TVR) (from baseline to 6 months post-randomisation following treatment with enalapril, compared with placebo). Whilst TVR is the nominated primary endpoint for this feasibility study, the choice of primary outcome for the definitive trial remains uncertain.
    Protection of trial subjects
    Women identified as being eligible for the study will be approached by a GCP-trained member of the clinical care team during a routine clinical appointment / inpatient admission and asked whether they would be willing to consider taking part in the study. Interested women will then have the opportunity to read through this information and further discuss the study with trial personnel. Women will then be screened against the inclusion criteria and if appropriate for inclusion and agreed to, written informed consent will be obtained. ACE inhibitors are renally excreted and therefore must be titrated to renal function. For this reason, women will have their renal function checked prior to commencing treatment and dose increments. ACE inhibitors are contraindicated in pregnancy but are safe with breastfeeding. Most of the safety data relating to the use of ACE inhibitors when breastfeeding relate to enalapril and captopril. Because enalapril is an antihypertensive that is excreted in breastmilk, there is a theoretical concern about associated neonatal hypotension in small premature babies. Premature small babies will be routinely monitored on the neonatal unit and therefore their vital signs, including BP, will be measured during their admission. NICE guidelines support the use of enalapril for breastfeeding mothers. Data will be collected in accordance with the "Caldicott Principles" and Data Protection Act. All women recruited will be allocated a study number which will be linked to their identifiable information held in a separate file stored within the research unit. Outcome data will be collected using case record forms which will be within stored within the Maternal & Fetal Health Research Centre (MFHRC), Manchester. All outcome data will be entered onto a password protected database within the MFHRC, accessible only to members of the research team. All electronic data will be anonymised and no identifiable data will be stored on this database.
    Background therapy
    		 -
    Evidence for comparator
    		 This study builds on recent data, which have highlighted the relationship between pre-eclampsia (PE) and postnatal (PN) heart and vessel dysfunction and long-term heart disease risk. Enalapril is an ACE inhibitor whose use is well-established in protecting the heart outside of the setting of pregnancy / PE. In previous studies, enalapril at similar doses has been well tolerated and effective at improving long-term health in people with and at-risk of heart and vessel disease. However it has never been tested in the context of PE. This study aims to deliver an intervention to women who have had preterm PE (pPE) during the early PN period when heart protection is likely to be most effective. Women who have persistent PN heart and vessel dysfunction are at highest risk of developing PE in their subsequent pregnancy. It is possible that continued treatment with enalapril beyond the first 6 months would be beneficial but this is beyond the scope of the current study. The study design will be the first of its kind to address whether PN treatment with enalapril will improve heart and vessel structure and function in women who have had pPE. Its design is informed by information from observational PN studies and clinical trials in non-pregnant individuals. The present study will provide essential clinical and biochemical data necessary to determine whether future longer-term PN treatment with enalapril might be warranted. It will also determine whether there are any adverse outcomes (e.g. excessive reduction in the mother's/ baby's blood pressure) that might preclude its usefulness as a therapeutic approach in the PN period, as well as identifying any recruitment, effectiveness and acceptability issues.
    Actual start date of recruitment
    05 Sep 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 100
    Worldwide total number of subjects
    100
    EEA total number of subjects
    0
    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)
    100
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Women identified as being eligible for the study will be approached by a GCP-trained member of the clinical care team during a routine clinical appointment. Interested women will then have the opportunity to read through this information and further discuss the study with trial personnel.

    Pre-assignment
    Screening details
    		 Potential participants may be identified through screening of relevant patient information against eligibility criteria by members of the primary care team.

    Period 1
    Period 1 title
    Baseline period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    This is a double-blinded, randomised controlled feasibility study. Block randomisation will be done in advance by the Clinical Trials Pharmacy. The Trials pharmacy will hold a copy of the randomisation list. Both the participant and the members of the research team assessing the clinical outcomes will be blinded to the treatment arm. There will be equal allocation between treatment arms.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Enalapril
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    UKPAR enalapril maleate
    Investigational medicinal product code
    PL:21880/0003-5
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    In this study a maximum of 20mg once daily (OD) will be given. Initially participants will take 5mg OD for 1 week then 10mg OD for 2 weeks then 20mg OD for 23 weeks (Total 6 month treatment).

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    N/A

    Arm title
    		 Observational
    Arm description
    		 -
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Enalapril Placebo Observational
    Started
    30
    30
    40
    Completed
    29
    30
    39
    Not completed
    1
    0
    1
         Consent withdrawn by subject
    1
    -
    -
         Physician decision
    -
    -
    1
    Period 2
    Period 2 title
    Treatment period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Block randomisation will be done in advance by the Clinical Trials Pharmacy. The Trials pharmacy will hold a copy of the randomisation list. Both the participant and the members of the research team assessing the clinical outcomes will be blinded to the treatment arm. There will be equal allocation between treatment arms.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Enalapril
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    UKPAR enalapril maleate
    Investigational medicinal product code
    PL:21880/0003-5
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    In this study a maximum of 20mg once daily (OD) will be given. Initially participants will take 5mg OD for 1 week then 10mg OD for 2 weeks then 20mg OD for 23 weeks (Total 6 month treatment).

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    N/A

    Arm title
    		 Observational
    Arm description
    		 -
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		Enalapril Placebo Observational
    Started
    29
    30
    39
    Completed
    19
    21
    23
    Not completed
    10
    9
    16
         Adverse event, serious fatal
    1
    -
    -
         Physician decision
    1
    -
    -
         Consent withdrawn by subject
    5
    4
    -
         Adverse event, non-fatal
    1
    -
    -
         Pregnancy
    1
    -
    3
         Pandemic
    -
    -
    8
         Lost to follow-up
    1
    5
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Enalapril
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Observational
    Reporting group description
    		 -

    Reporting group values
    		 Enalapril Placebo Observational Total
    Number of subjects
    		 30 30 40 100
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 30 30 40 100
        From 65-84 years
    		 0 0 0 0
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        geometric mean (standard deviation)
    		 34.5 ( 6.0 ) 30.9 ( 6.6 ) 31.7 ( 6.5 ) -
    Gender categorical
    All participants were female
    Units: Subjects
        Female
    		 30 30 40 100
        Male
    		 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Enalapril
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Observational
    Reporting group description
    		 -
    Reporting group title
    Enalapril
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Observational
    Reporting group description
    		 -

    Primary: Recruitment rate (number of women eligible, recruited and completing the study per month)

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    End point title
    		 Recruitment rate (number of women eligible, recruited and completing the study per month) [1]
    End point description
    Recruitment rate (number of women eligible, recruited and completing the study per month)
    End point type
    Primary
    End point timeframe
    Month
    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 process outcome and therefore only descriptive stats were required as no comparator.
    End point values
    		 Enalapril Placebo Observational
    Number of subjects analysed
    29
    30
    39
    Units: women
        number (not applicable)
    1.1
    1.2
    1.0
    No statistical analyses for this end point

    Primary: Change in TVR from baseline to six months post randomisation following treatment with enalapril, compared with placebo

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    End point title
    		 Change in TVR from baseline to six months post randomisation following treatment with enalapril, compared with placebo
    End point description
    Change in TVR from baseline to six months post randomisation following treatment with enalapril, compared with placebo
    End point type
    Primary
    End point timeframe
    6 months
    End point values
    		 Enalapril Placebo
    Number of subjects analysed
    19
    21
    Units: dyne.s-1cm-5
        arithmetic mean (standard deviation)
    1516 ( 278 )
    1579 ( 438 )
    Statistical analysis title
    		 Change in TVR from baseline to six months post ran
    Comparison groups
    Enalapril v Placebo
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [2]
    P-value
    		 = 0.59
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval
    Notes
    [2] - Standard ANCOVA with baseline measurements as a covariate

    Secondary: Change in remodelling from baseline to six months post randomisation following treatment with enalapril, compared with placebo

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    End point title
    		 Change in remodelling from baseline to six months post randomisation following treatment with enalapril, compared with placebo
    End point description
    Change in remodelling from baseline to six months post randomisation following treatment with enalapril, compared with placebo
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 Enalapril Placebo
    Number of subjects analysed
    19
    21
    Units: g/m2
        arithmetic mean (standard deviation)
    64.90 ( 14.93 )
    71.91 ( 17.96 )
    No statistical analyses for this end point

    Secondary: Change in diastolic dysfunction from baseline to six months post randomisation following treatment with enalapril, compared with placebo

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    End point title
    		 Change in diastolic dysfunction from baseline to six months post randomisation following treatment with enalapril, compared with placebo
    End point description
    Change in diastolic dysfunction from baseline to six months post randomisation following treatment with enalapril, compared with placebo
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 Enalapril Placebo
    Number of subjects analysed
    19
    21
    Units: ratio
        arithmetic mean (standard deviation)
    6.41 ( 2.03 )
    7.48 ( 1.40 )
    No statistical analyses for this end point

    Secondary: Change in diastolic blood pressure (dBP) from baseline to six months post randomisation following treatment with enalapril, compared with placebo

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    End point title
    		 Change in diastolic blood pressure (dBP) from baseline to six months post randomisation following treatment with enalapril, compared with placebo
    End point description
    Change in diastolic blood pressure (dBP) from baseline to six months post randomisation following treatment with enalapril, compared with placebo
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 Enalapril Placebo
    Number of subjects analysed
    19
    21
    Units: mmHg
        arithmetic mean (standard deviation)
    79.6 ( 10.9 )
    86.9 ( 10.6 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Throughout the duration of the trial
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    1
    Reporting groups
    Reporting group title
    Enalapril
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Observational
    Reporting group description
    		 -

    Serious adverse events
    		 Enalapril Placebo Observational
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 30 (0.00%)
    0 / 40 (0.00%)
         number of deaths (all causes)
    1
    0
    0
         number of deaths resulting from adverse events
    Cardiac disorders
    Left ventricular failure
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    myocardial infarction
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Enalapril Placebo Observational
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 29 (17.24%)
    0 / 30 (0.00%)
    0 / 40 (0.00%)
    Nervous system disorders
    Seizure
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 29 (10.34%)
    0 / 30 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    3
    0
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Aug 2018
    1. Inclusion of angio-oedema as a potential side-effect in the Participant Information Sheet (PIS) 2. Extension of the 6 month visit window to 6 months+/2 weeks 3. Collection of urine at 6 weeks and 6 months to measure Enalapril compliance 4. Correction of typographical errors in the protocol 5. Addition of urinary measures of Enalapril compliance & attendance at each research visit to the statistical analysis plan. 6. Removal of the breast milk analysis from the consent form, PIS and protocol
    07 Jan 2019
    1. An additional IMP re-supply visit (if required) between visits 4 and 5. This is due to the length (23 weeks) of the final 20mg prescription and the expiry date of the study drug/placebo (June 2019). We have added this additional visit to re-supply participants with new IMP stock and avoid the risk of patients having expired IMP at home. 2. An increase in the number of participants in the interventional arm from 36 evaluable to 40. 3. An additional investigation added at visit 5: breastfeeding status and duration of breastfeeding. 4. A typographical correction to section 18 of the protocol.
    05 Nov 2019
    1. “A change in Nitric Oxide end products (NOx)” has been removed from the secondary outcome measures as the study team considered the results unlikely to be useful in the content of this feasibility study. 2. The definition of the end of study has changed to “the date of complete database lock following the final research visit” 3. The name of the sponsor representative has been changed to Dr Lynne Webster following the departure of Dr Griffin from the trust in October 2019.

    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/33012200
    http://www.ncbi.nlm.nih.gov/pubmed/36029727
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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
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