E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
The medical condition that is to be investigated in this study is essential hypertension in pregnant women. In this study it is defined as diastolic BP of ≥90 mmHg (average of two clinic readings) or ≥80 mmHg if taking antihypertensive medication or pulse wave velocity ≥9m/s before 16 weeks’ gestation.
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E.1.1.1 | Medical condition in easily understood language |
The medical condition that is to be investigated in this study is raised blood pressure in the pregnant women diagnosed before 16 weeks gestation. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Female diseases of the urinary and reproductive systems and pregancy complications [C13] |
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 | 10070538 |
E.1.2 | Term | Gestational hypertension |
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 | PT |
E.1.2 | Classification code | 10014129 |
E.1.2 | Term | 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 | 10020772 |
E.1.2 | Term | Hypertension |
E.1.2 | System Organ Class | 10047065 - Vascular disorders |
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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 |
Process outcome: Recruitment rate (number of women eligible, recruited and completing study per month per centre)
Clinical outcome: Reduction in diastolic blood pressure following L-citrulline supplementation compared with placebo (baseline compared 8 weeks post treatment)
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E.2.2 | Secondary objectives of the trial |
Process outcome: 1. Acceptability of intervention in pregnant women with chronic hypertension
Clinical outcomes: 1. Change in maternal heamodynamics (pulse wave velocity and total peripheral vascular resistance) following L-citrulline supplementation, compared with placebo 2. Change in uteroplacental blood flow indices 3. Change in maternal plasma ADMA/arginine ratio and angiogenic markers |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Viable singleton pregnancy Gestation: 12+0 to 16+0 weeks Aged 18 years or over at date of randomisation Able to provide informed consent Diastolic BP of ≥90 mmHg (average of two clinic readings) OR ≥80 mmHg if taking antihypertensive medication OR PWV ≥9m/s before 16 weeks’ gestation Creatinine <120 mmol/l at booking
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E.4 | Principal exclusion criteria |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Process Outcome: Recruitment rate (number of women eligible, recruited and completing study per month, per centre).
Primary Clinical Outcome: Reduction in diastolic blood pressure (8 weeks post treatment compared to baseline) following L- citrulline supplementation, compared with placebo. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The maximum duration of involvement of an individual patient is 36 weeks, since they will be recruited at 12 to 16 weeks gestation and will be followed up until 6 weeks postnatally.
Evaluation of this end point is intended within 2 years and 6 months. |
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E.5.2 | Secondary end point(s) |
Process outcome: Acceptability of intervention in pregnant women with chronic hypertension.
Clinical outcomes: Change in maternal haemodynamics (pulse wave velocity and total peripheral vascular resistance) following citrulline supplementation, compared with placebo; Change in uteroplacental blood flow indices; Change in maternal plasma ADMA/arginine ratio and angiogenic markers.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The maximum duration of involvement of an individual patient is 30 weeks, since they will be recruited at 12 to 16 weeks gestation and will be followed up until 6 weeks postnatally.
Evaluation of this end point is intended within 2 years and 6 months. |
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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 | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | No |
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
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
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 | Yes |
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 CHERRY Data Management Plan. At the time of database lock, data entry privileges are withdrawn from the trial database. However, the trial may be closed prematurely by the Trial Steering Committee, or on the recommendation of the Independent Data Safety and Monitoring Committee (IDSMC). 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 | 0 |
E.8.9.1 | In the Member State concerned days | 1 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 1 |