E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Congenital diaphragmatic hernia with pulmonary hypertension |
Ernia diaframmatica congenita isolata e ipertensione polmonare. |
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E.1.1.1 | Medical condition in easily understood language |
Congenital diaphragmatic hernia with pulmonary hypertension |
Ernia diaframmatica congenita isolata e ipertensione polmonare. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | SOC |
E.1.2 | Classification code | 10038738 |
E.1.2 | Term | Respiratory, thoracic and mediastinal disorders |
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 | 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 OI after 12 hours after the initiation of the study drug in CDH patients, treated either with iNO or with intravenous sildenafil. |
L'obiettivo principale di questo studio è determinare se c'è una differenza nell'OI dopo 12 ore dall'inizio del farmaco in studio nei pazienti con CDH, trattati con iNO o con sildenafil per via endovenosa. |
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E.2.2 | Secondary objectives of the trial |
• To compare the incidence of pulmonary hypertension in the absence of pulmonary vasodilator therapy and study treatment failure on day 14 on echocardiography and/or death within the first 28 days of life To compare overall mortality • To compare the incidence of treatment failure • To compare the time on intervention drug • To compare the need for ECMO • To compare the number of ventilator free days on 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 • 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 6 and 12 months • To compare the incidence of chronic lung disease • To compare the incidence of neurological abnormalities |
• Confrontare l'incidenza di ipertensione polmonare in assenza di terapia vasodilatatrice polmonare e fallimento del trattamento in studio al giorno 14 all'eco e/o morte entro i primi 28 giorni di vita Confrontare la mortalità complessiva • Confrontare l'incidenza del fallimento del trattamento • Confrontare il tempo sul farmaco di intervento • Confrontare la necessità di ECMO • Confrontare il numero di giorni senza ventilatore il giorno 28 • Confrontare il punteggio di supporto vasoattivo-inotropo prima e dopo l'inizio del farmaco di intervento • Confrontare i marker di laboratorio per il danno endoteliale vascolare polmonare e l'ipertensione polmonare • Confrontare l'uso di altri farmaci somministrati per l'ipertensione polmonare • Confrontare l'uso di farmaci polmonari e/o cardiaci dopo la dimissione • Confrontare l'incidenza della malattia a lungo termine a 6 e 12 mesi • Confrontare l'incidenza della malattia polmonare cronica • Confrontare l'incidenza di anomalie neurologiche |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
In order to be eligible to participate in this study, a subject must meet all of the following criteria in the first week of life: 1) Diagnosis of CDH and pulmonary hypertension defined as 2 of the following 4 criteria: I. Systolic PAP> 2/3 systemic systolic pressure estimated by echocardiography II. RV dilatation/septal displacement, RV dysfunction +/- LV dysfunction III. Pre-post ductal SpO2 difference > 10% IV. OI>20. 2) Parental informed consent 3) Children born at or after a gestational age of 34 weeks 4) Newborns who received a foetal intervention may be included |
Per poter partecipare a questo studio, un soggetto deve soddisfare tutti i seguenti criteri nella prima settimana di vita: 1) Neonati con ernia diaframmatica congenita isolata e ipertensione polmonare definita come 2 dei seguenti 4 criteri: • Pressione sistolica in arteria polmonare > 2/3 della pressione sistolica sistemica stimata ecocardiograficamente • Dilatazione del ventricolo destro, alterazioni del setto interventricolari, disfunsione del ventricolo destro e/o sinistro. • Saturazione pre e post duttale differenziale > 10% • Indice di ossigenazione >20 2) consenso dei genitori ottenuto 3) età gestazionale = 34 settimane 4) neonati che hanno effettuato terapia fetale (plug) |
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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 - Patients born in another centre, transported with iNO - Exclusion criteria as defined in paragraph 4.3 of the SPC of sildenafil and paragraph 4.3 of iNO. For infants the relevant exclusion criteria are severe hepatic failure, allergy for components of the elements used in sildenafil, the use of strong CYP3A4-inhibitors such as intraconazol and the presence of a severe intracardiac shunt. |
• Anomalie cromosomiche maggiori • Anomalie cardiache severe che necessitano correzione entro i primi 60 giorni di vita • Anomalie renali con oligoidramnios • Deformità scheletriche severe che influenzano lo sviluppo toracico e polmonare • Anomalie severe del sistema nervoso centrale • Pazienti nati in altri centri e già trattati con iNO • Criteri di esclusione come definiti al paragrafo 4.3 del RCP del sildenafil e al paragrafo 4.3 della iNO. Per i lattanti i criteri di esclusione rilevanti sono l'insufficienza epatica grave, l'allergia ai componenti degli elementi utilizzati nel sildenafil, l'uso di potenti inibitori del CYP3A4 come l'intraconazolo e la presenza di uno shunt intracardiaco grave. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change in oxygenation index 12 hours after initiation of treatment in CDH patients, treated either with iNO or with intravenous sildenafil. |
Differenza nell'OI dopo 12 ore di trattamento tra i pazienti affetti da CDH trattati con iNO rispetto a quelli trattati con sildenafil per via endovenosa |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
12 hours after initiation of treatment |
12 ore dopo l’inizio del trattamento |
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E.5.2 | Secondary end point(s) |
• Overall mortality in the first year of life • Requirement of ECMO (only for ECMO centres) • Treatment failure (see paragraph 8.3, failure criteria) • Severity and presence of pulmonary hypertension on day 1 and/or just before starting the study drug, after 24 hours, 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: systolic PAP < or > 2/3 systemic systolic 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 therapy free days on day 14 Fraction of days requiring 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)) (45) • 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 supplemental 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. • External validation of sildenafil PKPD mode |
- Mortalità complessiva nel primo anno di vita - Necessità di ECMO (solo per i centri ECMO) - Incidenza di fallimento del trattamento (vd par. 8.3) - Gravità e presenza di ipertensione polmonare al giorno 1 e / o appena prima di iniziare il farmaco in studio, dopo 24 ore, il giorno 14, il giorno 28 o alla dimissione, a 6 mesi e 1 anno secondo i parametri ecocardiografici descritti dal cardiologo (vd CRF) - Giorni senza ventilatore il giorno 28 - Giorni senza terapia d’intervento il giorno 14 - Trattamento con farmaci somministrati per l’ipertensione polmonare durante il ricovero ospedaliero - Livello di specifici marcatori di laboratorio e urine, fino al giorno 28, a descrivere la gravità e la presenza di ipertensione polmonare - Punteggio di supporto vasoattivo-inotropo prima e 12 ore dopo l’inizio del farmaco in studio - Necessità di farmaci alla dimissione e/o nel primo anno di vita - Gravità della malattia polmonare cronica con necessità di ossigeno supplementare nei giorni 28 e 56 - Ipertensione polmonare a lungo termine all’ecocardiografia a 6 e 12 mesi - Sviluppo di anomalie neurologiche - Validazione di sildenafil |
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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 |
12 e 24 ore giorno dell'intervento e giorno dopo l'intervento giorno di inizio ECMO e giorno dopo ECMO giorno 14 e giorno 28 o alla dimissione (a seconda del caso che si verifica per primo) giorno 56 6 e 12 mesi |
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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 |
ossido nitrico inalato |
inhaled nitric oxide gas |
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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 | 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 | Information not present in EudraCT |
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 | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
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 | 0 |