E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Persistent pulmonary hypertension of the newborn (PPHN) is a relatively common condition occurring in 7/1000 births and can result in significant cardiovascular instability in the newborn. It occurs when there is a failure of the normal circulatory transition in the early newborn period. Persistence of the fetal circulation occurs,resulting in pulmonary hypertension,low oxygen levels and marked right-to-left shunting of blood in the newborn heart. Mortality ranges from 4 to 33%. |
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E.1.1.1 | Medical condition in easily understood language |
Persistent pulmonary hypertension of the newborn(PPHN) is a relatively common condition occurring in 7/1000 births.It can cause serious respiratory(breathing)and cardiac(heart)problems in the newborn |
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E.1.1.2 | Therapeutic area | Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Investigative Techniques [E05] |
MedDRA Classification |
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 |
The primary study objective is to predict the occurrence of neonatal pulmonary hypertension by measuring the pulmonary artery reactivity to maternal hyperoxygenation in fetuses at risk of neonatal respiratory morbidity. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of the trial are to:
1. Assess vasoreactive response to maternal hyperoxygenation (MH) in utero.
2. Assess the ability of MH to predict the degree of pulmonary vasculopathy present prior to birth.
3. Evaluate if pulmonary artery (PA) reactivity to MH identifies fetuses that will develop pulmonary hypertension.
4. Predict neonatal survival and pulmonary hypertension by measurement of PA reactivity to MH in fetuses at risk of neonatal respiratory morbidity.
5. Assess serial changes in maternal haemodynamics (cardiac output (CO), stroke volume (SV) and systemic vascular resistance (SVR)) before, during and after MH.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
The inclusion criteria can be divided into 3 main categories:
A) Those at risk of respiratory morbidity at term
• Iatrogenic elective Caesarean section being performed < 38 gestational weeks in an otherwise well baby. This subgroup will be informative in relation to circulatory adaptation close to term.
B) Those at risk of pulmonary hypoplasia
• Patients with mid trimester PPROM • Patients with persistent oligohydramnios of renal or nonrenal origin • Patients whose fetuses have known: Congenital diaphragmatic hernia (CDH), Congenital cystic adenomatoid malformation (CCAM) • Other space occupying lesions of the thorax (cardiomegaly, pleural effusion and skeletal dysplasia).
C) Those at risk of respiratory morbidity due to a cardiac cause
• Women whose fetuses have a prenatal diagnosis of moderate/severe perimembranous ventricular septal defect (VSD)/atrioventricular septal defect (AVSD) in the absence of other structural heart disease including cases of Trisomy 21. The MH test may contribute to prediction of the need for neonatal intervention in this group.
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E.4 | Principal exclusion criteria |
The exclusion criteria are as follows:
• Maternal age < 18 years • Known fetal chromosomal abnormality excluding Trisomy 21 • Gestational age <31 weeks and >40 weeks • Maternal chronic respiratory disease (including COPD, Cystic Fibrosis, Pulmonary Fibrosis) • Maternal congenital heart disease • Maternal use of bleomycin or amiodarone
The justification for the exclusion criteria are as follows:
• An adult is defined as a person aged 18 years or over. • The literature indicates that maternal hyperoxygenation does not alter fetal pulmonary circulation until after 31 weeks and therefore we will perform the test after 31 weeks gestation. • The use of high flow oxygen is contraindicated in patients with chronic respiratory disease. • Pregnant women with congenital heart disease are high risk antenatal patients and will be excluded to avoid them being exposed to high flow oxygen and to avoid any misinterpretation of the NICOM. • High flow oxygen should be avoided in any person taking the medications bleomycin or amiodarone.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the occurrence pulmonary hypertension in the neonate measured using echocardiography on Day 1 and 2 of age.
The presence of pulmonary hypertension in the neonate will be formally assessed with a neonatal echocardiogram performed at two separate time points, at 6-12hours of life and at 36-48 hours of life. Persistent pulmonary hypertension will be defined as a pulmonary pressure greater than two thirds the systemic pressure beyond the initial 12 hours of life. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Secondary endpoints: Severity of pulmonary hypertension Composite of neonatal respiratory morbidity (Respiratory Distress Syndrome and Transient Tachypnea of the Newborn) Neonatal intensive care unit (NICU) admission 28 day survival Survival to discharge from hospital Umbilical Artery and vein pHs and base excess Neonatal interventions required: • Chest compressions • Intubation • Peak inspiratory pressure (PIP) • Mean arterial pressure (MAP) • Positive end expiratory pressure (PEEP) • Adrenaline bolus at birth • Hydrocortisone pre transfer • Inotrope infusion pre transfer • Nitric • Surfactant • High frequency oscillatory ventilation (HFOV) at birth • Intravenous antibiotics • Nitric oxide duration
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Yes |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Pilot Study. Prospective cohort Study. |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
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.8.5 | 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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |