E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Postnatal (PN) cardiovascular dysfunction following preterm pre-eclampsia (pPE) |
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E.1.1.1 | Medical condition in easily understood language |
Heart and vessel dysfunction following preterm pre-eclampsia. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10036485 |
E.1.2 | Term | Pre-eclampsia |
E.1.2 | System Organ Class | 10036585 - Pregnancy, puerperium and perinatal conditions |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10036485 |
E.1.2 | Term | Pre-eclampsia |
E.1.2 | System Organ Class | 10036585 - Pregnancy, puerperium and perinatal conditions |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10040444 |
E.1.2 | Term | Severe pre-eclampsia |
E.1.2 | System Organ Class | 10036585 - Pregnancy, puerperium and perinatal conditions |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10007648 |
E.1.2 | Term | Cardiovascular disease, unspecified |
E.1.2 | System Organ Class | 100000004849 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | 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.
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E.2.2 | Secondary objectives of the trial |
Secondary process outcome: 1. Acceptability of the intervention to postnatal women. Secondary clinical outcomes: 1. 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); 2. 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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E.2.3 | Trial contains a sub-study | No |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Excretion of enalapril in breastmilk (V1.0, 14.02.2018). Objectives: to quantify the amount of enalapril excreted into breastmilk. This sub-study is dependent on adequate funding and therefore may not be able to be completed.
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E.3 | Principal inclusion criteria |
- Diagnosis of preterm pre-eclampsia (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 and/or low PlGF) • 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
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E.4 | Principal exclusion criteria |
• Inability to consent • Known cardiac disease • Contraindication to ACE inhibitors • Current ACE inhibitor / ARB use • Renal artery stenosis |
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E.5 End points |
E.5.1 | Primary end point(s) |
Process outcome: Recruitment rate (number of women eligible, recruited and completing study per month).
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.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary endpoint will be assessed at 6 months (26 weeks) post-randomisation. |
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E.5.2 | Secondary end point(s) |
Process outcomes 1. Acceptability of intervention in postnatal women Clinical outcomes: 1. A change in other parameters of cardiac function (E/E’ ratio, tricuspid valve regurgitation, LAVi, LVEF, CO, SV, RWT, LVMi, concentric/eccentric remodelling, GLS, LV basal strain, LV apical strain) 2. A change in biomarkers (hs-cTnT, PlGF, sFlt, NTproBNP, NOx)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The secondary process outcome will be evaluated 6 months post-randomisation.
Longitudinal analysis of the secondary clinical endpoints (using each participant as her own control) will be assessed at 6 weeks and 6 months post-randomisation. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of the trial is the date of database lock, as defined in the PICk-UP Data Management Plan. At the time of database lock, data entry privileges are withdrawn from the trial database. End of trial unblinding will be performed by the Clinical Trials Pharmacy (once approved by Sponsor and TSC statistician). The trial may be closed prematurely by the TSC. The end of trial is not defined as last visit of the last patient because there will still be data queries following this point. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |