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Postnatal Enalapril to Improve Cardiovascular fUnction Following Preterm Pre-eclampsia (PICk-UP)

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ClinicalTrials.gov Identifier: NCT03466333
Recruitment Status : Recruiting
First Posted : March 15, 2018
Last Update Posted : January 23, 2019
Sponsor:
Information provided by (Responsible Party):
Manchester University NHS Foundation Trust

Brief Summary:
This is a double blind randomised controlled feasibility study investigating the effect of postnatal enalapril on cardiovascular function in women who have had preterm pre-eclampsia. Participants will be randomised to 6 months of enalapril or placebo within 3 days of delivery. Cardiovascular function will be assessed using serial echocardiography and biomarkers.

Condition or disease Intervention/treatment Phase
Cardiovascular Diseases Pre-Eclampsia Onset Less Than 37 Weeks (Diagnosis) Drug: Enalapril Maleate Drug: Placebo oral capsule Phase 2

Detailed Description:

Pre-eclampsia (PE) is a condition in pregnancy, identified by a combination of high blood pressure and protein in the urine. It affects 3-5% pregnancies. Women with preterm PE (pPE; delivery before 37 weeks) frequently develop abnormal heart function after pregnancy, which increases their risk of heart disease in later life. Subtle changes in heart function have also been shown to increase the chance of a woman getting PE again in her next pregnancy. Despite this, research to date has focused on the pregnancy and relatively little is known about what happens after pregnancy and whether outcomes can be improved with treatment. sFlt is a protein that prevents blood vessel growth and causes blood vessel constriction. sFlt levels are raised in pPE and correlate with the degree of abnormal heart function. In animal studies, sFlt has been shown to directly cause injury to the heart and it is therefore possible that sFlt mediates pPE associated heart damage. Angiotensin converting enzyme (ACE) inhibitors are commonly used to protect against heart damage following myocardial infarction, but their use has never been tested following pPE.

Objectives:

  1. To characterise abnormal heart function following pPE
  2. To determine if this can be modified by treatment with enalapril.

Study design:

Women who have had pPE, will be randomly allocated to enalapril or placebo from delivery for 6 months. Heart function will be assessed using blood tests and ultrasound scans (echocardiography). This will allow us to learn more about how pPE affects the heart (from the placebo group) and measure the protective effect of enalapril on the heart. Recruitment rates and acceptability of the intervention will also be assessed in this feasibility study.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Double blind randomised controlled trial (40 participants) Eligible women who decline to take art in the interventional arm, can consent to the observational arm of the study (up to 40 participants)
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Feasibility Study on the Effects of Postnatal Enalapril on Maternal Cardiovascular Function Following Preterm Pre-eclampsia.
Actual Study Start Date : September 5, 2018
Estimated Primary Completion Date : May 2020
Estimated Study Completion Date : November 2020


Arm Intervention/treatment
Experimental: Investigational medicinal product
Oral enalapril maleate once daily: 5mg for 1 week, then 10mg for 2 weeks, then 20mg maintenance (for total of 6 months postpartum)
Drug: Enalapril Maleate
Enalapril maleate will be encapsulated; participants will take the drug once a day for 6 months following delivery.

Placebo Comparator: Placebo
Oral placebo once daily for 6 months postpartum
Drug: Placebo oral capsule
The placebo will be encapsulated; participants will take the drug once a day for 6 months following delivery. It will be identical in appearance to the IMP.

No Intervention: Observational arm
For participants who decline to be take part in the interventional part of the study (decline randomisation to IMP/placebo) however they consent to the observational components of the study (serial echocardiography and biomarkers postpartum).



Primary Outcome Measures :
  1. Process outcome [ Time Frame: 24 months ]
    Recruitment rate (number of women eligible, recruited and completing the study per month)

  2. Clinical outcome [ Time Frame: 32 months ]
    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.


Secondary Outcome Measures :
  1. Process outcome [ Time Frame: 32 months ]
    Acceptability of the intervention to postnatal women.

  2. Clinical outcome (echocardiography measures) [ Time Frame: 32 months ]
    A change in other parameters of cardiac function (including: E/E' ratio, tricuspid valve regurgitation, left atrial volume index (LAVi), left ventricular function (LVEF), cardiac output (CO), stroke volume (SV), relative wall thickness (RWT), left ventricular mass index (LVMi), concentric/eccentric remodelling, global longitudinal strain (GLS), left ventricular (LV) basal strain, LV apical strain)

  3. Clinical outcome (biomarkers) [ Time Frame: 32 months ]
    A change in biomarkers (high sensitivity troponin (hs-cTnT), placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt1), N-terminal pro-brain natriuretic peptide (NTproBNP), nitric oxide end products (NOx).



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Ages Eligible for Study:   16 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosis of pPE in this pregnancy requiring delivery < 37 weeks gestation: new or worsening hypertension >20 weeks with proteinuria or other features suggestive of PE (abnormal haematological, biochemical parameters, fetal growth restriction (FGR) and/or abnormal sFlt:PlGF (>85)).
  • Biochemical / haematological cut-offs:
  • Platelet count <100 x109/L
  • Alanine amino transferase > 50units/L
  • Creatinine >90mmol/L
  • FGR:
  • Abdominal circumference (AC) / estimated fetal weight (EFW) <3rd centile
  • Or 2 of the following:
  • AC/EFW <10th centile
  • AC/EFW crossing centiles by >2 quartiles
  • Cerebroplacental ratio <5th centile
  • Umbilical artery PI >95th centile
  • At time of randomisation:
  • Postpartum, within 3 days of delivery
  • Aged 18 years or over
  • Able to provide informed consent
  • Serum creatinine <100 mmol/l

Exclusion Criteria:

  • Inability to consent
  • Known cardiac disease
  • Contraindication to ACE inhibitors
  • Renal artery stenosis

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03466333


Contacts
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Contact: Laura Dr Ormesher, MBChB Hon 01617016960 laura.ormesher@manchester.ac.uk

Locations
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United Kingdom
Manchester University NHS Foundation Trust Recruiting
Manchester, Greater Manchester, United Kingdom, M13 9WL
Contact: Laura Ormesher, MBChB Hon    01617016960    laura.ormesher@manchester.ac.uk   
Sponsors and Collaborators
Manchester University NHS Foundation Trust
Investigators
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Principal Investigator: Jenny Dr Myers, MBBS PhD The University of Manchester

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Responsible Party: Manchester University NHS Foundation Trust
ClinicalTrials.gov Identifier: NCT03466333     History of Changes
Other Study ID Numbers: R04725
First Posted: March 15, 2018    Key Record Dates
Last Update Posted: January 23, 2019
Last Verified: January 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Manchester University NHS Foundation Trust:
preterm pre-eclampsia
cardiovascular dysfunction
Additional relevant MeSH terms:
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Eclampsia
Pre-Eclampsia
Cardiovascular Diseases
Pregnancy Complications
Hypertension, Pregnancy-Induced
Enalapril
Enalaprilat
Maleic acid
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Angiotensin-Converting Enzyme Inhibitors
Protease Inhibitors
Antihypertensive Agents