E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Persistent Pulmonary Hypertension of the Newborn (PPHN) |
|
E.1.1.1 | Medical condition in easily understood language |
PPHN is a rare and life threatening disease causing severe breathing difficulties in babies which can lead to suffocation and death. |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10053592 |
E.1.2 | Term | Newborn persistent pulmonary hypertension |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
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 |
To assess the efficacy of bosentan in neonates with persistent pulmonary hypertension of the newborn (PPHN) who are in need of continued inhaled nitric oxide (iNO) after at least 4 hours of continuous iNO treatment |
|
E.2.2 | Secondary objectives of the trial |
To evaluate the pharmacokinetics (PK), tolerability, and safety of bosentan in this patient population |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 < 7 days.
4. Weight at birth ≥ 2,500 g.
5. Idiopathic PPHN or PPHN due to parenchymal lung disease.
6. Pulmonary hypertension (PH) confirmed by echocardiography.
7. Need for continued iNO at a dose > 10ppm 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%. |
|
E.4 | Principal exclusion criteria |
1. PH associated with conditions other than PPHN.
2. Immediate need for cardiac resuscitation or extracorporeal membrane oxygenation (ECMO) (profound hypoxemia [PaO2] < 30 mm Hg; OI > 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 < 35 mmHg despite therapy with volume infusions and cardiotonic support.
10. Hepatic failure or all conditions with AST or ALT values > 2 x ULN.
11. Renal function impairment such as serum creatinine > 3 x ULN or anuria.
12. Known intracranial hemorrhage grade III or IV.
13. Hemoglobin or hematocrit level < 75% of the LLN.
14. Thrombocytopenia (platelet count < 50,000 cells /µL).
15. Leukopenia (WBC < 2,500 cells/ µL).
16. Any condition precluding the use of a nasogastric/orogastric tube.
17. Administration of prohibited medication prior to randomization. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
It is not applicable as the trial is exploratory. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
It is not applicable as the trial is exploratory. |
|
E.5.2 | Secondary end point(s) |
It is not applicable as the trial is exploratory. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
It is not applicable as the trial is exploratory. |
|
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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
|
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 | Yes |
E.8.1.7.1 | Other trial design description |
|
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 9 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Czech Republic |
France |
Germany |
Netherlands |
Switzerland |
United Kingdom |
United States |
|
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
|
The end of study is defined as the end of treatment (EoT=date of last study drug administration) + 7 days. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
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 | 2 |
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 |