Persistent pulmonary arterial hypertension PPHN bosentan pediatrics persisterende pulmonale arteriële hypertensie pasgeborene
Conditions
Interventions
Bosentan (2 mg/kg body weight b.i.d.) or placebo. Treatment allocation is designed to occur in a 2:1 ratio (active treatment to placebo, respectively).
Route: Nasogastric or orogastric tube.
Sponsors
ACTELION Pharmaceuticals Ltd
Gewerbestrasse 16
CH-4123 Allschwil
Switzerland
Eligibility
Inclusion criteria
Inclusion criteria: 1. Signed informed consent by the parent(s) or the legal representative(s); 2. Term and near-term newborns (gestational age > 34 weeks); 3. Post natal age more or equal to 12 hours and 2/3 of systemic arterial pressure by tricuspid regurgitant jet velocity (TRJV) or by gradient across septal defect (if present) or; C. Marked right ventricular (RV) dilation and paradoxical shift of interventricular septum. 7. Need for continued iNO at a dose > 10 ppm after at least 4h of continuous iNO treatment; 8. Last two consecutive oxygenation index (OI) values prior to randomization more or equal to 15; 9. Mechanical ventilation with fraction of inspired oxygen (FiO2) more or equal to 50%.
Exclusion criteria
Exclusion criteria: 1. PH associated with conditions other than PPHN; 2. Immediate need for cardiac resuscitation or extracorporeal membrane oxygenation (ECMO) (profound hypoxemia [PaO2] 40); 3. Lethal congenital anomalies; 4. Congenital diaphragmatic hernia; 5. Significant congenital heart disease or significant left to right shunt; 6. Pneumothorax; 7. Active seizures; 8. Expected duration of mechanical ventilation of less than 48 hours; 9. Mean systemic blood pressure 2 times upper limit of normal (ULN); 11. Renal function impairment such as serum creatinine > 3 times ULN or anuria; 12. Known intracranial hemorrhage grade III or IV; 13. Hemoglobin or hematocrit level < 75% of the lower limit of normal (LLN); 14. Thrombocytopenia (platelet count < 50,000 cells /microL); 15. Leukopenia (white blood cells [WBC] < 2,500 cells/ microL); 16. Any condition precluding the use of a nasogastric/orogastric tube; 17. Administration of prohibited medication prior to randomization.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| To assess the efficacy of bosentan in neonates with PPHN who are in need of continued inhaled iNO after at least 4 hours of continuous iNO treatment and to evaluate the PK, tolerability, and safety of bosentan in this patient population. | — |
Secondary
| Measure | Time frame |
|---|---|
| Exploratory efficacy endpoints: 1. Proportion of patients with treatment failure: A. Need for extra corporeal membrane oxygenation (ECMO) or; B. Initiation of alternative pulmonary vasodilator. 2. Time to complete weaning from iNO; 3. Time to weaning from mechanical ventilation; 4. Proportion of patients requiring re-initiation of iNO therapy; 5. Change from baseline to 3, 5, 12, and 24 hours following the first drug administration and thereafter daily until end of study treatment for: A. Oxygenation index; B. Arterial blood gas values (pH, SaO2, PaO2, PaCO2); C. Pulse oximetry (SpO2). 6. Pulmonary hypertension (assessed by echocardiography). Change from baseline to 24 hours and end of study treatment in: 1. Extra-pulmonary shunting of blood at the PFO or PDA (if present); 2. Estimated RVSP/systemic arterial pressure ratio by TRJV or by gradient across PDA or across septal defects (if present); 3. RV dilation and interventricular septal movement pattern. In order to interpret the exploratory efficacy data, the following information at 3, 5, 12, and 24 hours following the first drug administration, then daily until EOS will be collected: 1. If on mechanical ventilation: Mean airway pressure, PEEP (positive end-expiratory pressure), PIP (peak inspiratory pressure), rate, and tidal volume or; 2. If on high frequency oscillatory ventilation: Mean airway pressure, frequency, and amplitude. Tolerability/safety endpoints: Treatment-emergent adverse events (AEs) and SAEs: 1. AEs leading to premature discontinuation of study drug; 2. Change from baseline in vital signs during the treatment period; 3. Treatment-emergent electrocardiogram (ECG) abnormalities reported as AE; 4. Treatment-emergent laboratory abnormalities; 5. Incidence of treatment-emergent ALT or AST > 3 × ULN; 6. Incidence of treatment-emergent severe intracranial hemorrhage (grade III or IV), periventricular leukomalacia, and ventriculomegaly “Treatment emergent” AEs and SAEs are tho | — |
Contacts
Public ContactSofie Sledsens
Sportlaan 8
Outcome results
None listed