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

Feasibility Study on the Effects of Postnatal Enalapril on Maternal Cardiovascular Function Following Preterm Pre-eclampsia.

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.

Study Overview

• Status: Completed
• Conditions: Cardiovascular Diseases; Pre-Eclampsia Onset Less Than 37 Weeks (Diagnosis)
• Intervention / Treatment: Drug: Enalapril Maleate; Drug: Placebo oral capsule

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.

• Study Type: Interventional
• Enrollment (Actual): 118
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • Greater Manchester
    • Manchester, Greater Manchester, United Kingdom, M13 9WL
      • Manchester University NHS Foundation Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / 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).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Process outcome	Recruitment rate (number of women eligible, recruited and completing the study per month)	24 months
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.	32 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Process outcome	Acceptability of the intervention to postnatal women.	32 months
Clinical outcome (echocardiography measures)	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)	32 months
Clinical outcome (biomarkers)	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).	32 months

Collaborators and Investigators

• Sponsor: Manchester University NHS Foundation Trust
• Investigators: Principal Investigator: Jenny Dr Myers, MBBS PhD, The University of Manchester

Publications and helpful links

General Publications

• Ormesher L, Higson S, Luckie M, Roberts SA, Glossop H, Trafford A, Cottrell E, Johnstone ED, Myers JE. Postnatal Enalapril to Improve Cardiovascular Function Following Preterm Preeclampsia (PICk-UP):: A Randomized Double-Blind Placebo-Controlled Feasibility Trial. Hypertension. 2020 Dec;76(6):1828-1837. doi: 10.1161/HYPERTENSIONAHA.120.15875. Epub 2020 Oct 5.

Study record dates

Study Major Dates

• Study Start (Actual): September 5, 2018
• Primary Completion (Actual): September 11, 2020
• Study Completion (Actual): September 11, 2020

Study Registration Dates

• First Submitted: March 8, 2018
• First Submitted That Met QC Criteria: March 8, 2018
• First Posted (Actual): March 15, 2018

Study Record Updates

• Last Update Posted (Actual): February 24, 2021
• Last Update Submitted That Met QC Criteria: February 23, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Keywords: preterm pre-eclampsia; cardiovascular dysfunction
• Additional Relevant MeSH Terms: Pregnancy Complications; Hypertension, Pregnancy-Induced; Cardiovascular Diseases; Eclampsia; Pre-Eclampsia; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Enzyme Inhibitors; Protease Inhibitors; Angiotensin-Converting Enzyme Inhibitors; Enalaprilat; Enalapril
• Other Study ID Numbers: R04725

Drug and device information, study documents

• 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