Persistent Pulmonary Hypertension of the Newborn

Persistent Pulmonary Hypertension of the Newborn Clinical Trial

— FUTURE 4  

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)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01389856
• Other study ID #: AC-052-391
• Status: Terminated
• Phase: Phase 3
• First received: June 30, 2011
• Last updated: April 9, 2015
• Start date: December 2011
• Est. completion date: January 2014

Study information

• Verified date: April 2015
• Source: Actelion
• Contact: n/a
• Is FDA regulated: No
• Health authority: Australia: Department of Health and Ageing Therapeutic Goods AdministrationAustralia: Human Research Ethics CommitteeCzech Republic: Ethics CommitteeCzech Republic: State Institute for Drug ControlFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)France: Committee for the Protection of PersonnesGermany: Ethics CommissionGermany: Federal Institute for Drugs and Medical DevicesSwitzerland: EthikkommissionSwitzerland: SwissmedicUnited Kingdom: Medicines and Healthcare Products Regulatory AgencyUnited Kingdom: Research Ethics CommitteeUnited States: Food and Drug AdministrationUnited States: Institutional Review BoardBelgium: Ethics CommitteeBelgium: Federal Agency for Medicinal Products and Health ProductsPoland: Ethics CommitteePoland: Office for Registration of Medicinal Products, Medical Devices and Biocidal ProductsSouth Korea: Institutional Review BoardKorea: Ministry of Food and Drug SafetySingapore: Institutional Review BoardSingapore: Health Sciences AuthorityRussia: Ethics CommitteeRussia: Ministry of Health of the Russian Federation
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 23
• Est. completion date: January 2014
• Est. primary completion date: December 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 7 Days

Eligibility

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.

Study Design

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Hypertension
• Hypertension, Pulmonary
• Persistent Fetal Circulation Syndrome
• Persistent Pulmonary Hypertension of the Newborn

Intervention

Drug:
• Bosentan
2 mg/kg of weight at birth twice daily (b.i.d); quadrisectable 32 mg tablet of bosentan dispersed in sterile water and administered by nasogastric or orogastric tube.
• Matching placebo
twice daily (b.i.d); quadrisectable 32 mg tablet of matching placebo dispersed in sterile water and administered by nasogastric or orogastric tube.

Locations

Country	Name	City	State
Australia	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
Belgium	UZ Leuven - Site 1103	Leuven
Czech Republic	Fakultní nemocnice v Motole Novorozenecké oddelení - Site 2001	Prague
Czech Republic	Všeobecná fakultní nemocnice Klinika detského a dorostového lékarství - Site 2002	Prague
France	CHRU de Lille - Hôpital Jeanne de Flandre - Service de réanimation néonatale - Site 1802	Lille Cedex
France	Hopital Necker - Site 1806	Paris
France	Hôpital Trousseau - Service de réanimation néonatale et pédiatrique - Site 1804	Paris cedex 12
Germany	Charité Universitätsmedizin Berlin Campus Virchow-Klinikum Klinik für Neonatologie - Site 1201	Berlin
Germany	Klinikum der Universität zu Köln Klinik und Poliklinik für Kinder-und Jugendmedizin, Dep. Neonatologie u. Pädiatrische Intensivmedizin - Site 1203	Köln
Korea, Republic of	Samsung Medical Center - Site 5502	Seoul
Poland	Instytut Centrum Zdrowia Matki Polki - Site 2106	Lodz
Poland	Uniwersytet Medyczny im. K. Marcinkowskiego w Poznaniu - Site 2103	Poznan
Poland	Szpital Kliniczny im. ks. Anny Mazowieckiej - Site 2101	Warszawa
Russian Federation	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
Singapore	KK Women's and Children's Hospital - Site 5401	Singapore
Switzerland	Centre Hospitalier Universitaire Vaudois Départment Médico-Chirurgical de Pédiatrie / Service de Néonatologie - Site 1901	Lausanne
Switzerland	Kantonsspital Luzern, Kinderspital Kinder-Intensivmedizin / Pädiatrie / Neonatologie - Site 1902	Lucerne
United Kingdom	Liverpool Women's NHS Foundation Trust - Site 1702	Liverpool
United Kingdom	Great Ormond Street Hospital, Paediatric and Neonatal Intensive Care Unit - Site 1700	London
United Kingdom	Norfolk and Norwich University Hospitals NHS Foundation Trust - Site 1703	Norwich
United States	Medical University of South Carolina, Pediatric Cardiology - Site 6019	Charleston	South Carolina
United States	LURIE CHILDREN'S HOSPITAL OF CHICAGO - Site 6021	Chicago	Illinois
United States	Advocate Hope Children's Hospital - Site 6009	Oak Lawn	Illinois
United States	Advocate Lutheran General Div. of Neonatal & Development Medicine - Site 6010	Park Ridge	Illinois

Sponsors (1)

Lead Sponsor	Collaborator
Actelion

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Czech Republic,  France,  Germany,  Korea, Republic of,  Poland,  Russian Federation,  Singapore,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Patients With Treatment Failure	Treatment failure was defined as the need for extra corporeal membrane oxygenation or initiation of alternative pulmonary vasodilator treatment	From baseline to up to 21 days	No
Primary	Time to Complete Weaning From iNO	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	From baseline to up to 21 days	No
Primary	Time to Complete Weaning From Mechanical Ventilation	Calculated from the time from first study drug administration to complete weaning from mechanical ventilation	From baseline to up to 21 days	No
Secondary	Percentage of Patients Requiring Re-initiation of iNO Therapy	Re-initiation of iNO therapy following weaning from iNO therapy	From baseline to up to 21 days	No
Secondary	Percentage of Patients With Pulmonary Hypertension (PH) at End of Treatment	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 pressure	From baseline to up to 14 days	No
Secondary	Change in Oxygenation Index (OI) From Baseline to 3 Hours Following Study Drug Administration	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.	3 hours	No
Secondary	Change in Oxygenation Index (OI) From Baseline to 5 Hours Following Study Drug Administration	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.	5 hours	No
Secondary	Change in Oxygenation Index (OI) From Baseline to 12 Hours Following Study Drug Administration	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.	12 hours	No
Secondary	Change in Oxygenation Index (OI) From Baseline to 24 Hours Following Study Drug Administration	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.	24 hours	No
Secondary	Change in Oxygenation Index (OI) From Baseline to 48 Hours Following Study Drug Administration	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.	48 hours	No
Secondary	Change in Oxygenation Index (OI) From Baseline to 72 Hours Following Study Drug Administration	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.	72 hours	No
Secondary	Change in Arterial Blood Gas (ABG) pH From Baseline to 72 Hours Following Study Drug Administration	pH was determined in arterial blood samples at baseline and 72 h after the first study drug administration	72 hours	No
Secondary	Change in Arterial Blood Oxygen Saturation (SaO2) From Baseline to 72 Hours Following Study Drug Administration	SaO2 was determined in arterial blood samples at baseline and 72 h after the first study drug administration	72 hours	No
Secondary	Change in Partial Pressure of Oxygen (PaO2) in Arterial Blood From Baseline to 72 Hours Following Study Drug Administration	PaO2 was determined in arterial blood samples at baseline and 72 h after the first study drug administration	72 hours	No
Secondary	Change in Partial Pressure of Carbon Dioxide (PaCO2) in Arterial Blood From Baseline to 72 Hours Following Study Drug Administration	PaCO2 was determined in arterial blood samples at baseline and 72 h after the first study drug administration	72 hours	No
Secondary	Change in Pre-ductal Peripheral Oxygen Saturation (SpO2) From Baseline to 72 Hours Following Study Drug Administration	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	72 hours	No
Secondary	Change in Post-ductal Peripheral Oxygen Saturation (SpO2) From Baseline to 72 Hours Following Study Drug Administration	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	72 hours	No
Secondary	Change in Fraction of Inspired Oxygen (FiO2) From Baseline to 72 Hours Following Study Drug Administration	FiO2 was determined according to each study centers' standard procedure at baseline and 72 h after the first study drug administration	72 hours	No
Secondary	Maximum Whole Blood Concentration (Cmax) for Bosentan and Its Metabolites, Ro 47-8634, Ro 48-5033, and Ro 64-1056 on Day 1	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.	up to 12 hours	No
Secondary	Cmax for Bosentan and Its Metabolites, Ro 47-8634, Ro 48-5033, and Ro 64-1056 on Day 5	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.	12 hours	No
Secondary	Time to Maximum Whole Blood Concentration (Tmax) for Bosentan on Day 1	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.	up to 12 hours	No
Secondary	Tmax for Ro 47-8634 on Day 1	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.	up to 12 hours	No
Secondary	Tmax for Ro 48-5033 on Day 1	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.	up to 12 hours	No
Secondary	Tmax for Ro 64-1056 on Day 1	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.	up to 12 hours	No
Secondary	Tmax for Bosentan on Day 5	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.	12 hours	No
Secondary	Tmax for Ro 47-8634 on Day 5	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.	12 hours	No
Secondary	Tmax for Ro 48-5033 on Day 5	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.	12 hours	No
Secondary	Tmax for Ro 64-1056 on Day 5	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.	12 hours	No
Secondary	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	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.	12 hours	No
Secondary	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	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.	5 days	No
Secondary	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	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.	24 hours	No
Secondary	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	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.	24 hours	No
Secondary	Accumulation Index (AI) for Bosentan	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.	5 days	No