E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Congenital diaphragmatic hernia with pulmonary hypertension |
Hernia diafragmatica met pulmonale hypertensie |
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E.1.1.1 | Medical condition in easily understood language |
Defect in diaphragm resulting in high blood pressure in the lungs |
Defect in het middenrif resulterend in hoge bloeddruk in de longen |
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E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this study is to determine if there is a difference in the incidence of pulmonary hypertension in the absence of pulmonary vasodilator therapy on day 14 on echocardiography and/or death within the first 28 days of life between CDH patients treated with iNO versus those treated with intravenous sildenafil. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are:
• To compare the change in oxygenation index before and after start treatment
• To compare overall mortality
• To compare the incidence of treatment failure (see paragraph 6.5)
• To compare the time on intervention drug
• To compare the need for ECMO
• To compare the number of ventilator free days at day 28
• To compare the vasoactive-inotropic support score before and after starting the intervention drug
• To compare laboratory markers for pulmonary vascular endothelial damage and pulmonary hypertension (see paragraph 6.3)
• To compare the use of other medication given for pulmonary hypertension
• To compare the use of pulmonary and/or cardiac medication after discharge
• To compare the incidence of long-term pulmonary hypertension at the age of 1 year
• To compare the incidence of chronic lung disease
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Diagnosis of CDH and pulmonary hypertension defined as 2 of the following 4 criteria:
I. PAP> 2/3 systemic pressure estimated by echocardiography
II. RV dilatation/septal displacement, RV dysfunction +/- LV dysfunction
III. Pre-post ductal SpO2 difference > 10%
IV. OI>20.
• Parental informed consent
• Children born at or after a gestational age of 34 weeks
• Newborns who received a fetal intervention may be included
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E.4 | Principal exclusion criteria |
• Severe chromosomal anomaly, like trisomy 18 or trisomy 13, which may imply a decision to stop or not to start life-saving medical treatment
• Severe cardiac anomaly, expected to need corrective surgery in the first 60 days of life (such as transposition of the great arteries, truncus arteriosus, coarctation aortae or double outlet right ventricle)
• Renal anomalies associated with oligohydramnios
• Severe orthopaedic and skeletal deformities, which are likely to influence thoracic, and / or lung development (such as chest wall deformities and spine anomalies)
• Severe anomalies of the central nervous system
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E.5 End points |
E.5.1 | Primary end point(s) |
The main study endpoint is pulmonary hypertension in the absence of pulmonary vasodilator therapy on echocardiography on day 14 and/or death within the first 28 days 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) |
• Change in oxygenation index after 12 hours of treatment
• Overall mortality in the first year of life
• Requirement of ECMO (only for ECMO centres)
• Treatment failure (see paragraph 6.5, failure criteria)
• Severity and presence of pulmonary hypertension on day 1 and/or just before starting the study drug, on day 14, on day 28 or at discharge (whatever comes first), at 6 months and 1 year according to the following echocardiographic parameters as described by the cardiologist: PAP < or > 2/3 systemic pressure, RV dilatation/septal displacement, RV dysfunction +/- LV dysfunction. (see Case Record Form)
• Number ventilator free days on day 28 (deaths are counted as worst outcome)
• Number of intervention drug free days on day 14
• Fraction of days requiring medical treatment for pulmonary hypertension during the hospital admission, described as the use of iNO, sildenafil, prostanoids, endothelin 1 antagonists, and/or other medication for pulmonary hypertension
• The level of specific laboratory markers and urine, up to day 28, to describe the severity and presence of pulmonary hypertension.
• Vasoactive-inotropic support score before and 12 hours after starting study medication.
This score is calculated with: (dopamine (mcg/kg/min) + dobutamine (mcg/kg/min) + 100x adrenaline (mcg/kg/min) + 10x milrinone (mcg/kg/min) + 10.000x vasopressin (U/kg/min) + 100x noradrenaline (mcg/kg/min)) [31]
• Requirement of PH medication, described as oral sildenafil, bosentan and/or a prostanoid at discharge and/or during the first year of life.
• Severity of chronic lung disease using need for oxygen on day 28 and 56.
• Long-term pulmonary hypertension using echocardiography at the age of 6 and 12 months.
• The development of neurological abnormalities evaluated with an ultrasound of the brain before start of intervention drug, after surgery and before discharge.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
12 and 24 hours
day of surgery and day after surgery
day of starting ECMO and day after ECMO
day 14 and day 28 or at discharge (whichever comes first)
day 56
6 and 12 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 | 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 | Yes |
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 | No |
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 | Yes |
E.8.2.3.1 | Comparator description |
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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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 28 |
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 trial is ended when 330 have been included and the last patient is seen at the age of 12 months. |
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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 | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |