E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patent ductus arteriosus of the newborn |
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E.1.1.1 | Medical condition in easily understood language |
PDA is a vessel which does not close and remains "patent" (open) resulting in irregular transmission of blood between 2 of the most important arteries in the heart, the aorta and the pulmonary artery. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
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 |
To determine if the selective treatment of confirmed large PDAs in extremely preterm babies with ibuprofen within 72 hours of birth reduces the incidence of death or bronchopulmonary dysplasia (BPD) at 36 weeks' post-menstrual age.
To find this out babies who are eligible to take part in the study will be given either ibuprofen (a drug which is approved for the treatment of PDA in premature babies), or placebo (salt water). Researchers will then record the number of babies that develop a condition called Bronchopulmonary Dysplasia (BPD) which is a known complication of PDA and baby deaths by a defined time point, to determine if there is any difference between the babies given ibuprofen and those given placebo. |
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E.2.2 | Secondary objectives of the trial |
The other aims of the study are to find out if there is any difference in the health and welfare between babies given ibuprofen and those given placebo both in the short term (while the baby is still in hospital) and also in the longer term (when the baby is 2 years of age, calculated from their due date). |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Babies will be considered eligible for inclusion into the study if they are; • Born at 23+0 to 28+6 weeks of gestation • Less than 72 hours old • Confirmed by echocardiography to have a large PDA which o Is ≥ 1.5 mm in diameter (determined by gain optimised colour Doppler) o Has unrestrictive pulsatile left to right flow In addition: The responsible clinician is uncertain about whether this baby might benefit from treatment to close the PDA Written informed consent has been obtained from the parent(s) |
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E.4 | Principal exclusion criteria |
Babies will be excluded from participation in the study if they have; • No realistic prospect of survival • Severe congenital anomaly • Structural heart disease requiring treatment • Other conditions that would contraindicate the use of ibuprofen (intracranial or gastrointestinal haemorrhage, coagulopathy, thrombocytopenia (platelet count <50,000), renal failure, pulmonary hypertension, known or suspected necrotising enterocolitis) • Antenatal treatment with a COX inhibitors • Received indomethacin, ibuprofen or paracetamol after birth. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary outcome for the study is to determine if selective treatment of confirmed large Patent Ductus Arteriosus in extremely preterm babies with ibuprofen, within 72 hours of birth, reduces the incidence of death or Bronchopulmonary Dysplasia at 36 weeks post-menstrual age. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
36 week's postmenstrual age |
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E.5.2 | Secondary end point(s) |
Secondary Short Term Endpoints: •Death before discharge Incidence or duration of the following up to discharge from NNU: •Severity of BPD at 36 weeks of postmenstrual age •Severe IVH (grade 3/4 with ventricular dilation or intraparenchymal bleeding) •Cystic PVL •ROP requiring treatment •Pulmonary haemorrhage •Pulmonary hypertension •NEC definitive and/or complicated (Bell stage II and above) confirmed by radiography or histopathology •NEC requiring surgery •Gastrointestinal bleeding within 7 days of the first dose of trial drug administration •Spontaneous intestinal perforation •PDA closure at 3 weeks of age (or hospital discharge if discharged before this age) •Medical rescue treatment with a COX inhibitor/surgical treatment of a symptomatic PDA •Administration and duration of inotropic support •Duration of mechanical ventilation •Total duration of respiratory support (ventilation + nCPAP/high flow oxygen therapy) •Discharge home on oxygen •Duration of initial hospitalisation (birth to NNU discharge) •Postnatal steroid use •Safety and tolerability of ibuprofen treatment •Number of doses of trial medication received during intervention period
Secondary Long Term Endpoints (at 2 years of age, corrected for prematurity) •Survival without moderate or severe neurodevelopment disability •Individual components of survival without moderate or severe disability (in the four domains of motor, cognitive, hearing and visual function) •Survival without respiratory morbidity
A cost-effectiveness analysis will be conducted of death and BPD events avoided and national health services used up to 2 years of age corrected for prematurity.
Secondary Long Term Endpoints (at primary school) •Neurological and developmental outcomes (separate funding may be applied for depending on the results of the trial).
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- 36 Weeks Postmenstrual Age - Discharge - Infant, 2 Years Corrected Age
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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 | 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) | Yes |
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.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 4 |
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 | 6 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 31 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 31 |