Clinical trial NCT01389856: Persistent Pulmonary Hypertension of the Newborn
Official title: Multicenter, Double-blind, Placebo-controlled, Randomized, Prospective Study of Bosentan as Adjunctive Therapy to Inhaled Nitric Oxide in the Management of Persistent Pulmonary Hypertension of the Newborn (PPHN)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Persistent Pulmonary Hypertension of the Newborn
Keywords: Persistent pulmonary hypertension, newborn
PPHN
Lead sponsor: Actelion
Sponsor class: INDUSTRY
First posted: 2011-07-08
Enrollment: 23
Sex: ALL
Minimum age (years): 12
Maximum age (years): 7
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The AC-052-391-study is a phase 3 study to investigate whether adding bosentan to inhaled nitric oxide in newborns with persistent pulmonary hypertension of newborns (PPHN) is a supporting and safe therapy and to evaluate the pharmacokinetics of bosentan and its metabolites.


Eligibility 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 \< 7 days.
4. Weight at birth ≥ 2,000 g.
5. Idiopathic PPHN or PPHN due to parenchymal lung disease
6. Documented diagnosis of pulmonary hypertension (PH) confirmed by echocardiography.
7. Need for continued inhaled nitric oxide (iNO) at a dose \> 10ppm after at least 4 hours of continuous iNO treatment.
8. Two oxygenation index (OI) values ≥ 12 taken at least 30 minutes apart, in the 12 hours prior to randomization and while the patient is receiving iNO treatment.
9. Mechanical ventilation with fraction of inspired oxygen (FiO2) ≥ 50% at randomization.

Exclusion Criteria:

1. PH associated with conditions other than PPHN.
2. Immediate need for cardiac resuscitation or extracorporeal membrane oxygenation (ECMO).
3. Lethal congenital anomalies.
4. Congenital Diaphragmatic Hernia.
5. Significant structural cardiac anomalies.
6. Medically significant 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 alanine aminotransferase (ALT) values \> 2 x upper limit of normal (ULN).
11. Renal function impairment such as serum creatinine \> 3 x ULN or anuria.
12. Known intracranial hemorrhage grade III or IV.
13. Either hemoglobin or hematocrit level \< 75% of the lower limit of normal (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.

Primary outcomes:
measure: Percentage of Patients With Treatment Failure
timeFrame: From baseline to up to 21 days
measure: Time to Complete Weaning From iNO
timeFrame: From baseline to up to 21 days
measure: Time to Complete Weaning From Mechanical Ventilation
timeFrame: From baseline to up to 21 days
Secondary outcomes:
measure: Percentage of Patients Requiring Re-initiation of iNO Therapy
timeFrame: From baseline to up to 21 days
measure: Percentage of Patients With Pulmonary Hypertension (PH) at End of Treatment
timeFrame: From baseline to up to 14 days
measure: Change in Oxygenation Index (OI) From Baseline to 3 Hours Following Study Drug Administration
timeFrame: 3 hours
measure: Change in Oxygenation Index (OI) From Baseline to 5 Hours Following Study Drug Administration
timeFrame: 5 hours
measure: Change in Oxygenation Index (OI) From Baseline to 12 Hours Following Study Drug Administration
timeFrame: 12 hours
measure: Change in Oxygenation Index (OI) From Baseline to 24 Hours Following Study Drug Administration
timeFrame: 24 hours
measure: Change in Oxygenation Index (OI) From Baseline to 48 Hours Following Study Drug Administration
timeFrame: 48 hours
measure: Change in Oxygenation Index (OI) From Baseline to 72 Hours Following Study Drug Administration
timeFrame: 72 hours
measure: Change in Arterial Blood Gas (ABG) pH From Baseline to 72 Hours Following Study Drug Administration
timeFrame: 72 hours
measure: Change in Arterial Blood Oxygen Saturation (SaO2) From Baseline to 72 Hours Following Study Drug Administration
timeFrame: 72 hours
measure: Change in Partial Pressure of Oxygen (PaO2) in Arterial Blood From Baseline to 72 Hours Following Study Drug Administration
timeFrame: 72 hours
measure: Change in Partial Pressure of Carbon Dioxide (PaCO2) in Arterial Blood From Baseline to 72 Hours Following Study Drug Administration
timeFrame: 72 hours
measure: Change in Pre-ductal Peripheral Oxygen Saturation (SpO2) From Baseline to 72 Hours Following Study Drug Administration
timeFrame: 72 hours
measure: Change in Post-ductal Peripheral Oxygen Saturation (SpO2) From Baseline to 72 Hours Following Study Drug Administration
timeFrame: 72 hours
measure: Change in Fraction of Inspired Oxygen (FiO2) From Baseline to 72 Hours Following Study Drug Administration
timeFrame: 72 hours
measure: Maximum Whole Blood Concentration (Cmax) for Bosentan and Its Metabolites, Ro 47-8634, Ro 48-5033, and Ro 64-1056 on Day 1
timeFrame: up to 12 hours
measure: Cmax for Bosentan and Its Metabolites, Ro 47-8634, Ro 48-5033, and Ro 64-1056 on Day 5
timeFrame: 12 hours
measure: Time to Maximum Whole Blood Concentration (Tmax) for Bosentan on Day 1
timeFrame: up to 12 hours
measure: Tmax for Ro 47-8634 on Day 1
timeFrame: up to 12 hours
measure: Tmax for Ro 48-5033 on Day 1
timeFrame: up to 12 hours
measure: Tmax for Ro 64-1056 on Day 1
timeFrame: up to 12 hours
measure: Tmax for Bosentan on Day 5
timeFrame: 12 hours
measure: Tmax for Ro 47-8634 on Day 5
timeFrame: 12 hours
measure: Tmax for Ro 48-5033 on Day 5
timeFrame: 12 hours
measure: Tmax for Ro 64-1056 on Day 5
timeFrame: 12 hours
measure: Area Under the Concentration-time Curve Over a Period of 12 h (AUC0-12 Day 1)) for Bosentan and Its Metabolites, Ro 47-8634, Ro 48-5033, and Ro 64-1056 on Day 1
timeFrame: 12 hours
measure: Area Under the Concentration-time Curve Over a Dosing Interval at Steady State on Day 5 (AUCtau) for Bosentan and Its Metabolites, Ro 47-8634, Ro 48-5033, and Ro 64-1056
timeFrame: 5 days
measure: Area Under the Concentration-time Curve Over a Period of 24 h (Dose-corrected to 2 mg/kg) on Day 1 (AUC0-24C Day 1) for Bosentan and Its Metabolites, Ro 47-8634, Ro 48-5033, and Ro 64-1056
timeFrame: 24 hours
measure: Area Under the Concentration-time Curve Over a Period of 24 h (Dose-corrected to 2 mg/kg) on Day 5 (AUC0-24C Day 5) for Bosentan and Its Metabolites, Ro 47-8634, Ro 48-5033, and Ro 64-1056
timeFrame: 24 hours
measure: Accumulation Index (AI) for Bosentan
timeFrame: 5 days
Other outcomes:
Locations:
Study officials:
References:
citation: Steinhorn RH, Fineman J, Kusic-Pajic A, Cornelisse P, Gehin M, Nowbakht P, Pierce CM, Beghetti M; FUTURE-4 study investigators. Bosentan as Adjunctive Therapy for Persistent Pulmonary Hypertension of the Newborn: Results of the Randomized Multicenter Placebo-Controlled Exploratory Trial. J Pediatr. 2016 Oct;177:90-96.e3. doi: 10.1016/j.jpeds.2016.06.078. Epub 2016 Aug 5.