E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Bronchopulmonary dysplasia |
chronisch longziekte van de prematuur |
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E.1.1.1 | Medical condition in easily understood language |
chronic lung disease of the prematurely newborn infant |
chronische longziekte van de tevroeggeborene |
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10006475 |
E.1.2 | Term | Bronchopulmonary dysplasia |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal 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 |
To establish the efficacy of hydrocortisone given after one week of life to reduce the incidence of the combined outcome of death and bronchopulmonary dysplasia in chronically ventilated preterm infants. |
Onderzoek naar de doeltreffendheid van hydrocortisone toegediend na de eerste levensweek ter reductie van het risico op de gecombineerde uitkomst van overlijden of bronchopulmonale dysplasie bij chronisch beademde premature pasgeborenen. |
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E.2.2 | Secondary objectives of the trial |
Secondary outcomes are short term effects on the pulmonary condition, adverse effects during hospitalisation, and long-term neurodevelopmental sequelae assessed at 2 years corrected gestational age. |
Secundaire uitkomsten zijn korte termijn effecten op de pulmonale toestand, bijwerkingen gedurende de hospitalisatie en lange termijn neurologische sequelen beoordeeld op de georrigeerde leeftijd van 2 jaar. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Preterm infants with a gestational age < 30 wks and/or birth weight < 1250 g, ventilator dependency at 7-14 days postnatal age, a respiratory index (RI = MAwP x FiO2) of ≥ 3.5 for more than 12 h/day for at least 48 hours, ensuring adequate oxygen saturation (85-95%) and pCO2 values in premature infants (5.0-7.5 kPa).
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E.4 | Principal exclusion criteria |
Infants with chromosomal defects (e.g. trisomy 13, 18, 21) or major congenital malformations that compromise lung function (e.g. surfactant protein deficiencies, congenital diaphragmatic hernia), result in chronic ventilation (e.g. Pierre Robin sequence), or increase the risk of death or adverse neurodevelopmental outcome (congenital cerebral malformations) will be excluded.
Also infants who received dexamethasone or hydrocortisone for the sole purpose of improving lung function and respiratory status prior to inclusion, will be excluded.
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E.5 End points |
E.5.1 | Primary end point(s) |
The dichotomous variable BPD free survival at 36 weeks PMA. BPD at 36 weeks PMA will be assessed according to the NIHCHD Consensus Statement defining normal oxygen saturation as 86%-94%. The severity of the BPD will be assessed as proposed by Jobe et.al.21, since the severity of BPD has a high association with neurodevelopmental sequelae.12 In case of supplemental oxygen delivery >21% and < 30% or low flow at 36 weeks PMA, the oxygen reduction test as described by Walsh et.al.21,49,50 should be preformed. A positive oxygen reduction test has a high correlation with the risk on discharge home with oxygen, the length of hospital stay, and pulmonary morbidity requiring hospital readmission during the first year of life. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
36 weeks postmenstrual age |
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E.5.2 | Secondary end point(s) |
• treatment failure as defined in section 6.1.2
• mortality at 28 days PNA, 36 weeks PMA and at hospital discharge
• BPD at 28 days
• failure to extubate 3, 7, 14 and 21 days after initiating therapy
• duration of mechanical ventilation
• use of “rescue treatment” with hydrocortisone outside the study protocol
• total time on supplemental oxygen
• length of hospital stay
• incidence of hypertension, defined as systolic blood pressure > 2SD of standardized values used in the department
• hyperglycemia requiring the use of insulin therapy
• nosocomial infection, like sepsis, meningitis and pneumonia
• hemodynamic significant patent ductus arteriosus for which medical intervention or surgical ligation is needed
• necrotising enterocolitis (NEC), diagnosed at surgery, autopsy or by radiographic finding of pneumotosis intestinalis or hepatobiliary gas (Bell stage II)
• gastrointestinal bleeding
• isolated gastrointestinal perforation diagnosed on abdominal radiography
• intraventricular haemorrhage (IVH) and/or periventricular leucomalacia (PVL), including grading on cerebral ultrasonography according to protocol defined by Ment et.al.51
• retinopathy of prematurity, including grading following international classification52
• weight gain, head circumference and length gain at 36 weeks PMA
• long-term health and neurodevelopmental sequelae, assessed at 2 years CGA:
o readmissions since first discharge home
o weight, length and head circumference at 24 months c.a.
o Bayley Scales of Infant Development III, Mental Developmental Index and Psychomotor Developmental Index
o cerebral palsy and severity of cerebral palsy using gross motor function classification system
o hearing loss requiring hearing aids
o blindness
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- End of hospitalisation
- neurodevelopment will be assessed at 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 | 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) | 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 | Yes |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 14 |
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 last follow-up visit at 2 years corrected age of the last subject |
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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 | 5 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 2 |
E.8.9.2 | In all countries concerned by the trial days | 0 |