Persistent Pulmonary Hypertension of the Newborn
- Conditions
- Persistent Pulmonary Hypertension of the Newborn
- Interventions
- Drug: Matching placebo
- Registration Number
- NCT01389856
- Lead Sponsor
- Actelion
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 23
- Signed informed consent by the parent(s) or the legal representative(s).
- Term and near term newborns (gestational age > 34 weeks).
- Post natal age ≥ 12 hours and < 7 days.
- Weight at birth ≥ 2,000 g.
- Idiopathic PPHN or PPHN due to parenchymal lung disease
- Documented diagnosis of pulmonary hypertension (PH) confirmed by echocardiography.
- Need for continued inhaled nitric oxide (iNO) at a dose > 10ppm after at least 4 hours of continuous iNO treatment.
- 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.
- Mechanical ventilation with fraction of inspired oxygen (FiO2) ≥ 50% at randomization.
- PH associated with conditions other than PPHN.
- Immediate need for cardiac resuscitation or extracorporeal membrane oxygenation (ECMO).
- Lethal congenital anomalies.
- Congenital Diaphragmatic Hernia.
- Significant structural cardiac anomalies.
- Medically significant pneumothorax.
- Active seizures.
- Expected duration of mechanical ventilation of less than 48 hours.
- Mean systemic blood pressure < 35 mmHg despite therapy with volume infusions and cardiotonic support.
- Hepatic failure or all conditions with alanine aminotransferase (ALT) values > 2 x upper limit of normal (ULN).
- Renal function impairment such as serum creatinine > 3 x ULN or anuria.
- Known intracranial hemorrhage grade III or IV.
- Either hemoglobin or hematocrit level < 75% of the lower limit of normal (LLN).
- Thrombocytopenia (platelet count < 50,000 cells /µL).
- Leukopenia (WBC < 2,500 cells/ µL).
- Any condition precluding the use of a nasogastric/orogastric tube.
- Administration of prohibited medication prior to randomization.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description 2 Matching placebo Matching placebo 1 Bosentan Bosentan
- Primary Outcome Measures
Name Time Method Percentage of Patients With Treatment Failure From baseline to up to 21 days Treatment failure was defined as the need for extra corporeal membrane oxygenation or initiation of alternative pulmonary vasodilator treatment
Time to Complete Weaning From iNO From baseline to up to 21 days Calculated from the time from first study drug administration to complete weaning from iNO. Weaning from iNO was considered complete if there was no requirement for the re-initiation of iNO within 24 h after stopping
Time to Complete Weaning From Mechanical Ventilation From baseline to up to 21 days Calculated from the time from first study drug administration to complete weaning from mechanical ventilation
- Secondary Outcome Measures
Name Time Method Change in Oxygenation Index (OI) From Baseline to 48 Hours Following Study Drug Administration 48 hours The change in OI from baseline following study drug administration was determined. OI was calculated as the mean airway pressure multiplied by the fraction of inspired oxygen (expressed in %), and the product was divided by the partial pressure of oxygen in arterial blood.
Change in Oxygenation Index (OI) From Baseline to 72 Hours Following Study Drug Administration 72 hours The change in OI from baseline following study drug administration was determined. OI was calculated as the mean airway pressure multiplied by the fraction of inspired oxygen (expressed in %), and the product was divided by the partial pressure of oxygen in arterial blood.
Change in Oxygenation Index (OI) From Baseline to 24 Hours Following Study Drug Administration 24 hours The change in OI from baseline following study drug administration was determined. OI was calculated as the mean airway pressure multiplied by the fraction of inspired oxygen (expressed in %), and the product was divided by the partial pressure of oxygen in arterial blood.
Percentage of Patients Requiring Re-initiation of iNO Therapy From baseline to up to 21 days Re-initiation of iNO therapy following weaning from iNO therapy
Percentage of Patients With Pulmonary Hypertension (PH) at End of Treatment From baseline to up to 14 days The presence of PH was assessed by echocardiography. PH was reported as 'present' if at least one of the following criteria was met:
* Shunt through ductus arteriosus was either 'predominant right to left' or 'bidirectional'
* Shunt through foramen ovale was either 'predominant right to left' or 'bidirectional'
* Marked right ventricular dilation was ticked 'present'
* Paradoxical shift of intraventricular septum was ticked 'present'
* Right ventricular systolic pressure (mmHg) was \> 2/3 of the reported systemic blood pressureChange in Oxygenation Index (OI) From Baseline to 3 Hours Following Study Drug Administration 3 hours The change in OI from baseline following study drug administration was determined. OI was calculated as the mean airway pressure multiplied by the fraction of inspired oxygen (expressed in %), and the product was divided by the partial pressure of oxygen in arterial blood.
Change in Oxygenation Index (OI) From Baseline to 5 Hours Following Study Drug Administration 5 hours The change in OI from baseline following study drug administration was determined. OI was calculated as the mean airway pressure multiplied by the fraction of inspired oxygen (expressed in %), and the product was divided by the partial pressure of oxygen in arterial blood.
Change in Oxygenation Index (OI) From Baseline to 12 Hours Following Study Drug Administration 12 hours The change in OI from baseline following study drug administration was determined. OI was calculated as the mean airway pressure multiplied by the fraction of inspired oxygen (expressed in %), and the product was divided by the partial pressure of oxygen in arterial blood.
Change in Arterial Blood Gas (ABG) pH From Baseline to 72 Hours Following Study Drug Administration 72 hours pH was determined in arterial blood samples at baseline and 72 h after the first study drug administration
Change in Arterial Blood Oxygen Saturation (SaO2) From Baseline to 72 Hours Following Study Drug Administration 72 hours SaO2 was determined in arterial blood samples at baseline and 72 h after the first study drug administration
Change in Partial Pressure of Oxygen (PaO2) in Arterial Blood From Baseline to 72 Hours Following Study Drug Administration 72 hours PaO2 was determined in arterial blood samples at baseline and 72 h after the first study drug administration
Change in Partial Pressure of Carbon Dioxide (PaCO2) in Arterial Blood From Baseline to 72 Hours Following Study Drug Administration 72 hours PaCO2 was determined in arterial blood samples at baseline and 72 h after the first study drug administration
Change in Pre-ductal Peripheral Oxygen Saturation (SpO2) From Baseline to 72 Hours Following Study Drug Administration 72 hours Simultaneous pre- (right hand) and post-ductal (lower extremities) SpO2 were measured using pulse oximetry device at baseline and 72 h after the first study drug administration
Change in Post-ductal Peripheral Oxygen Saturation (SpO2) From Baseline to 72 Hours Following Study Drug Administration 72 hours Simultaneous pre- (right hand) and post-ductal (lower extremities) SpO2 were measured using pulse oximetry device at baseline and 72 h after the first study drug administration
Change in Fraction of Inspired Oxygen (FiO2) From Baseline to 72 Hours Following Study Drug Administration 72 hours FiO2 was determined according to each study centers' standard procedure at baseline and 72 h after the first study drug administration
Maximum Whole Blood Concentration (Cmax) for Bosentan and Its Metabolites, Ro 47-8634, Ro 48-5033, and Ro 64-1056 on Day 1 up to 12 hours Concentrations were measured directly in dried blood spot samples scheduled to be taken immediately prior to first study drug administration and at 0.5, 1, 2, 3, 7.5 and 12 hours post-dose on Day 1. Cmax was obtained directly from the measured concentrations. Cmax was corrected to a dose of 2 mg/kg bosentan (Cmaxc). The target dose was 2 mg/kg. However, as the smallest dose unit was 8 mg (quarter of a tablet), it was not possible to achieve the exact target dose in all patients. Therefore, Cmax was divided by the actual dose (in mg/kg) and multiplied by 2 mg/kg.
Cmax for Bosentan and Its Metabolites, Ro 47-8634, Ro 48-5033, and Ro 64-1056 on Day 5 12 hours Concentrations were measured directly in dried blood spot samples scheduled to be taken immediately prior to study drug administration and at 0.5, 1, 2, 3, 7.5, and 12 hours post-dose on Day 5. Cmax obtained directly from the measured concentrations . Cmax was corrected to a dose of 2 mg/kg bosentan (Cmaxc). The target dose was 2 mg/kg. However, as the smallest dose unit was 8 mg (quarter of a tablet), it was not possible to achieve the exact target dose in all patients. Therefore, Cmax was divided by the actual dose (in mg/kg) and multiplied by 2 mg/kg.
Time to Maximum Whole Blood Concentration (Tmax) for Bosentan on Day 1 up to 12 hours Concentrations were measured directly in dried blood spot samples scheduled to be taken immediately prior to first study drug administration and at 0.5, 1, 2, 3, 7.5 and 12 hours post-dose on Day 1. Tmax was obtained directly from the measured concentrations.
Tmax for Ro 47-8634 on Day 1 up to 12 hours Concentrations were measured directly in dried blood spot samples scheduled to be taken immediately prior to first study drug administration and at 0.5, 1, 2, 3, 7.5 and 12 hours post-dose on Day 1. Tmax was obtained directly from the measured concentrations.
Tmax for Ro 48-5033 on Day 1 up to 12 hours Concentrations were measured directly in dried blood spot samples scheduled to be taken immediately prior to first study drug administration and at 0.5, 1, 2, 3, 7.5 and 12 hours post-dose on Day 1. Tmax was obtained directly from the measured concentrations.
Tmax for Ro 64-1056 on Day 1 up to 12 hours Concentrations were measured directly in dried blood spot samples scheduled to be taken immediately prior to first study drug administration and at 0.5, 1, 2, 3, 7.5 and 12 hours post-dose on Day 1. Tmax was obtained directly from the measured concentrations.
Tmax for Bosentan on Day 5 12 hours Concentrations were measured directly in dried blood spot samples scheduled to be taken immediately prior to study drug administration and at 0.5, 1, 2, 3, 7.5, and 12 hours post-dose on Day 5. Tmax was obtained directly from the measured concentrations.
Tmax for Ro 47-8634 on Day 5 12 hours Concentrations were measured directly in dried blood spot samples scheduled to be taken immediately prior to study drug administration and at 0.5, 1, 2, 3, 7.5, and 12 hours post-dose on Day 5. Tmax was obtained directly from the measured concentrations.
Tmax for Ro 48-5033 on Day 5 12 hours Concentrations were measured directly in dried blood spot samples scheduled to be taken immediately prior to study drug administration and at 0.5, 1, 2, 3, 7.5, and 12 hours post-dose on Day 5. Tmax was obtained directly from the measured concentrations.
Tmax for Ro 64-1056 on Day 5 12 hours Concentrations were measured directly in dried blood spot samples scheduled to be taken immediately prior to study drug administration and at 0.5, 1, 2, 3, 7.5, and 12 hours post-dose on Day 5. Tmax was obtained directly from the measured concentrations.
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 12 hours Concentrations were measured directly in dried blood spot samples scheduled to be taken immediately prior to first study drug administration and at 0.5, 1, 2, 3, 7.5 and 12 hours post-dose on Day 1. Pharmacokinetic parameters were determined on the basis of scheduled blood sampling time points using non-compartmental analysis. Actual blood sampling times were used only if there was a deviation of more than 5% from the scheduled times. AUC0-12 Day 1 was calculated according to the trapezoidal rule using the measured concentration-time values above the limit of quantification.
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 5 days Concentrations were measured directly in dried blood spot samples scheduled to be taken immediately prior to study drug administration and at 0.5, 1, 2, 3, 7.5, and 12 hours post-dose on Day 5. Pharmacokinetic parameters were determined on the basis of scheduled blood sampling time points using non-compartmental analysis. Actual blood sampling times were used only if there was a deviation of more than 5% from the scheduled times. AUCtau Day 5 was calculated according to the trapezoidal rule using the measured concentration-time values above the limit of quantification.
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 24 hours Concentrations were measured directly in dried blood spot samples scheduled to be taken immediately prior to first study drug administration and at 0.5, 1, 2, 3, 7.5 and 12 hours post-dose on Day 1. Pharmacokinetic parameters were determined on the basis of scheduled blood sampling time points using non-compartmental analysis. Actual blood sampling times were used only if there was a deviation of more than 5% from the scheduled times. AUC0-24C Day 1 was calculated as a multiple of AUC0-12, (2 × AUC0-12 for 2 times daily dosing) corrected to 2 mg/kg.
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 24 hours Concentrations were measured directly in dried blood spot samples scheduled to be taken immediately prior to study drug administration and at 0.5, 1, 2, 3, 7.5, and 12 hours post-dose on Day 5. Pharmacokinetic parameters were determined on the basis of scheduled blood sampling time points using non-compartmental analysis. Actual blood sampling times were used only if there was a deviation of more than 5% from the scheduled times. AUC0-24C Day 5 was calculated as a multiple of AUCtau, (2 × AUCtau for 2 times daily dosing) corrected to 2 mg/kg.
Accumulation Index (AI) for Bosentan 5 days Concentrations were measured directly in dried blood spot samples scheduled to be taken immediately prior to first study drug administration and at 0.5, 1, 2, 3, 7.5 and 12 hours post-dose on Days 1 and 5. Pharmacokinetic parameters were determined on the basis of scheduled blood sampling time points using non-compartmental analysis. Actual blood sampling times were used only if there was a deviation of more than 5% from the scheduled times. AI was calculated as the ratio AUCtau /AUC0-12 for the subjects having PK samples collected on Day 1 and Day 5 and with AUC0-12 \> 0 ng.h/mL.
Trial Locations
- Locations (25)
LURIE CHILDREN'S HOSPITAL OF CHICAGO - Site 6021
🇺🇸Chicago, Illinois, United States
Advocate Hope Children's Hospital - Site 6009
🇺🇸Oak Lawn, Illinois, United States
The Royal Children's Hospital, Department of Neonatology - Site 3001
🇦🇺Parkville, Australia
Division of Neonatology, Mater Mothers' Hospital, Mater Health Services, Brisbane Ltd. - Site 3003
🇦🇺South Brisbane, Australia
Centre Hospitalier Universitaire Vaudois Départment Médico-Chirurgical de Pédiatrie / Service de Néonatologie - Site 1901
🇨🇭Lausanne, Switzerland
Great Ormond Street Hospital, Paediatric and Neonatal Intensive Care Unit - Site 1700
🇬🇧London, United Kingdom
Klinikum der Universität zu Köln Klinik und Poliklinik für Kinder-und Jugendmedizin, Dep. Neonatologie u. Pädiatrische Intensivmedizin - Site 1203
🇩🇪Köln, Germany
Instytut Centrum Zdrowia Matki Polki - Site 2106
🇵🇱Lodz, Poland
Charité Universitätsmedizin Berlin Campus Virchow-Klinikum Klinik für Neonatologie - Site 1201
🇩🇪Berlin, Germany
Federal State Budgetary Institution "Scientific Center for obstetrics, gynecology and perinatology named after V.I. Kulakov" Ministry of Healthcare of the Russian Federation - Site 2501
🇷🇺Moscow, Russian Federation
UZ Leuven - Site 1103
🇧🇪Leuven, Belgium
Szpital Kliniczny im. ks. Anny Mazowieckiej - Site 2101
🇵🇱Warszawa, Poland
Kantonsspital Luzern, Kinderspital Kinder-Intensivmedizin / Pädiatrie / Neonatologie - Site 1902
🇨🇭Lucerne, Switzerland
Samsung Medical Center - Site 5502
🇰🇷Seoul, Korea, Republic of
Všeobecná fakultní nemocnice Klinika dětského a dorostového lékařství - Site 2002
🇨🇿Prague, Czech Republic
Advocate Lutheran General Div. of Neonatal & Development Medicine - Site 6010
🇺🇸Park Ridge, Illinois, United States
Medical University of South Carolina, Pediatric Cardiology - Site 6019
🇺🇸Charleston, South Carolina, United States
Fakultní nemocnice v Motole Novorozenecké oddělení - Site 2001
🇨🇿Prague, Czech Republic
CHRU de Lille - Hôpital Jeanne de Flandre - Service de réanimation néonatale - Site 1802
🇫🇷Lille Cedex, France
Hôpital Trousseau - Service de réanimation néonatale et pédiatrique - Site 1804
🇫🇷Paris cedex 12, France
Hopital Necker - Site 1806
🇫🇷Paris, France
Liverpool Women's NHS Foundation Trust - Site 1702
🇬🇧Liverpool, United Kingdom
Norfolk and Norwich University Hospitals NHS Foundation Trust - Site 1703
🇬🇧Norwich, United Kingdom
Uniwersytet Medyczny im. K. Marcinkowskiego w Poznaniu - Site 2103
🇵🇱Poznan, Poland
KK Women's and Children's Hospital - Site 5401
🇸🇬Singapore, Singapore