high blood pressure in the lungs in neonates PPHN
Conditions
Interventions
Formulation: dispersible and quadrisectible 32 mg tablet of bosentan or
matching placebo.
Route: nasogastric or orogastric tube, according to site standard practice.
Dose 2 mg/kg of weight at birth
Sponsors
Actelion Pharmaceuticals
Eligibility
Age
2 Years to 11 Years
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 * 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 * 15. 9. Mechanical ventilation with fraction of inspired oxygen (FiO2) * 50%.
Exclusion criteria
Exclusion criteria: 1. Pulmonary Hypertension 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 × upper limit of normal (ULN). 11. Renal function impairment such as serum creatinine > 3 × ULN or anuria. 12. Known intracranial hemorrhage grade III or IV. 13. Hemoglobin or hematocrit level
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Exploratory efficacy endpoints: * Proportion of patients with treatment failure: - Need for extra corporeal membrane oxygenation (ECMO) or - Initiation of alternative pulmonary vasodilator * Time to complete weaning from iNO * Time to weaning from mechanical ventilation * Proportion of patients requiring re-initiation of iNO therapy * Change from baseline to 3, 5, 12, and 24 hours following the first drug administration and thereafter daily until end of study treatment for: - Oxygenation index - Arterial blood gas values (pH, SaO2, PaO2, PaCO2) - Pulse oximetry (SpO2) * Pulmonary hypertension (assessed by echocardiography) Change from baseline to 24 hours and end of study treatment in: * Extra-pulmonary shunting of blood at the PFO or PDA (if present) * Estimated RVSP/systemic arterial pressure ratio by TRJV or by gradient across PDA or across septal defects (if present) * 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: - If on mechanical ventilation: mean airway pressure, PEEP (positive end-expiratory pressure), PIP (peak inspiratory pressure), rate, and tidal volume or, - If on high frequency oscillatory ventilation: mean airway pressure, frequency, and amplitude | — |
Secondary
| Measure | Time frame |
|---|---|
| TOLERABILITY / SAFETY ENDPOINTS: Treatment-emergent adverse events (AEs) and SAEs * AEs leading to premature discontinuation of study drug * Change from baseline in vital signs during the treatment period * Treatment-emergent electrocardiogram (ECG) abnormalities reported as AE * Treatment-emergent laboratory abnormalities * Incidence of treatment-emergent ALT or AST > 3 × ULN * Incidence of treatment-emergent severe intracranial hemorrhage (grade III or IV), periventricular leukomalacia, and ventriculomegaly *Treatment emergent* AEs and SAEs are those for which onset occurs from 1st dosing with double-blind treatment and up to 7 days after last double-blind treatment administration. PHARMACOKINETIC ENDPOINTS: All PK endpoints will be evaluated based on concentrations measured in dried blood spot samples. The following endpoints will be derived by non-compartmental analysis of concentration-time profiles obtained on Day 1 and on Day 5 of bosentan treatment, if applicable. o Cmax and tmax (Days 1 and 5), AUC0-12h (Day 1), AUC0-* (Day 5), and AUC0-24h (Days 1 and 5) for bosentan and its metabolites (Ro 48-5033, Ro 47-8634, Ro 64-1056) following administration of bosentan. o For those subjects whose PK assessments will be performed on Days 1 and 5, the accumulation index, defined as the ratio between AUC0-* (Day 5) and AUC0-12h (Day 1) will be calculated. | — |
Countries
Netherlands
Outcome results
None listed