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Persistent Pulmonary Hypertension of the Newborn (FUTURE 4)

Primary Purpose

Persistent Pulmonary Hypertension of the Newborn

Status
Terminated
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Bosentan
Matching placebo
Sponsored by
Actelion
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Persistent Pulmonary Hypertension of the Newborn focused on measuring Persistent pulmonary hypertension, newborn, PPHN

Eligibility Criteria

12 Hours - 7 Days (Child)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • LURIE CHILDREN'S HOSPITAL OF CHICAGO - Site 6021
  • Advocate Hope Children's Hospital - Site 6009
  • Advocate Lutheran General Div. of Neonatal & Development Medicine - Site 6010
  • Medical University of South Carolina, Pediatric Cardiology - Site 6019
  • The Royal Children's Hospital, Department of Neonatology - Site 3001
  • Division of Neonatology, Mater Mothers' Hospital, Mater Health Services, Brisbane Ltd. - Site 3003
  • UZ Leuven - Site 1103
  • Fakultní nemocnice v Motole Novorozenecké oddělení - Site 2001
  • Všeobecná fakultní nemocnice Klinika dětského a dorostového lékařství - Site 2002
  • CHRU de Lille - Hôpital Jeanne de Flandre - Service de réanimation néonatale - Site 1802
  • Hôpital Trousseau - Service de réanimation néonatale et pédiatrique - Site 1804
  • Hopital Necker - Site 1806
  • Charité Universitätsmedizin Berlin Campus Virchow-Klinikum Klinik für Neonatologie - Site 1201
  • Klinikum der Universität zu Köln Klinik und Poliklinik für Kinder-und Jugendmedizin, Dep. Neonatologie u. Pädiatrische Intensivmedizin - Site 1203
  • Samsung Medical Center - Site 5502
  • Instytut Centrum Zdrowia Matki Polki - Site 2106
  • Uniwersytet Medyczny im. K. Marcinkowskiego w Poznaniu - Site 2103
  • Szpital Kliniczny im. ks. Anny Mazowieckiej - Site 2101
  • 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
  • KK Women's and Children's Hospital - Site 5401
  • Centre Hospitalier Universitaire Vaudois Départment Médico-Chirurgical de Pédiatrie / Service de Néonatologie - Site 1901
  • Kantonsspital Luzern, Kinderspital Kinder-Intensivmedizin / Pädiatrie / Neonatologie - Site 1902
  • Liverpool Women's NHS Foundation Trust - Site 1702
  • Great Ormond Street Hospital, Paediatric and Neonatal Intensive Care Unit - Site 1700
  • Norfolk and Norwich University Hospitals NHS Foundation Trust - Site 1703

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

1

2

Arm Description

Bosentan

Matching placebo

Outcomes

Primary Outcome Measures

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
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
Time to Complete Weaning From Mechanical Ventilation
Calculated from the time from first study drug administration to complete weaning from mechanical ventilation

Secondary Outcome Measures

Percentage of Patients Requiring Re-initiation of iNO Therapy
Re-initiation of iNO therapy following weaning from iNO therapy
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
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.
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.
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.
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.
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.
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.
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
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
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
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
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
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
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
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.

Full Information

First Posted
June 30, 2011
Last Updated
April 9, 2015
Sponsor
Actelion
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1. Study Identification

Unique Protocol Identification Number
NCT01389856
Brief Title
Persistent Pulmonary Hypertension of the Newborn
Acronym
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)
Study Type
Interventional

2. Study Status

Record Verification Date
April 2015
Overall Recruitment Status
Terminated
Why Stopped
To be compliant with the timelines as agreed with Paediatric Committee (PC) within the Paediatric Investigational Plan
Study Start Date
December 2011 (undefined)
Primary Completion Date
December 2013 (Actual)
Study Completion Date
January 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Actelion

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Persistent Pulmonary Hypertension of the Newborn
Keywords
Persistent pulmonary hypertension, newborn, PPHN

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
23 (Actual)

8. Arms, Groups, and Interventions

Arm Title
1
Arm Type
Experimental
Arm Description
Bosentan
Arm Title
2
Arm Type
Placebo Comparator
Arm Description
Matching placebo
Intervention Type
Drug
Intervention Name(s)
Bosentan
Other Intervention Name(s)
Tracleer
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Matching placebo
Intervention Description
twice daily (b.i.d); quadrisectable 32 mg tablet of matching placebo dispersed in sterile water and administered by nasogastric or orogastric tube.
Primary Outcome Measure Information:
Title
Percentage of Patients With Treatment Failure
Description
Treatment failure was defined as the need for extra corporeal membrane oxygenation or initiation of alternative pulmonary vasodilator treatment
Time Frame
From baseline to up to 21 days
Title
Time to Complete Weaning From iNO
Description
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 Frame
From baseline to up to 21 days
Title
Time to Complete Weaning From Mechanical Ventilation
Description
Calculated from the time from first study drug administration to complete weaning from mechanical ventilation
Time Frame
From baseline to up to 21 days
Secondary Outcome Measure Information:
Title
Percentage of Patients Requiring Re-initiation of iNO Therapy
Description
Re-initiation of iNO therapy following weaning from iNO therapy
Time Frame
From baseline to up to 21 days
Title
Percentage of Patients With Pulmonary Hypertension (PH) at End of Treatment
Description
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
Time Frame
From baseline to up to 14 days
Title
Change in Oxygenation Index (OI) From Baseline to 3 Hours Following Study Drug Administration
Description
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.
Time Frame
3 hours
Title
Change in Oxygenation Index (OI) From Baseline to 5 Hours Following Study Drug Administration
Description
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.
Time Frame
5 hours
Title
Change in Oxygenation Index (OI) From Baseline to 12 Hours Following Study Drug Administration
Description
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.
Time Frame
12 hours
Title
Change in Oxygenation Index (OI) From Baseline to 24 Hours Following Study Drug Administration
Description
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.
Time Frame
24 hours
Title
Change in Oxygenation Index (OI) From Baseline to 48 Hours Following Study Drug Administration
Description
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.
Time Frame
48 hours
Title
Change in Oxygenation Index (OI) From Baseline to 72 Hours Following Study Drug Administration
Description
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.
Time Frame
72 hours
Title
Change in Arterial Blood Gas (ABG) pH From Baseline to 72 Hours Following Study Drug Administration
Description
pH was determined in arterial blood samples at baseline and 72 h after the first study drug administration
Time Frame
72 hours
Title
Change in Arterial Blood Oxygen Saturation (SaO2) From Baseline to 72 Hours Following Study Drug Administration
Description
SaO2 was determined in arterial blood samples at baseline and 72 h after the first study drug administration
Time Frame
72 hours
Title
Change in Partial Pressure of Oxygen (PaO2) in Arterial Blood From Baseline to 72 Hours Following Study Drug Administration
Description
PaO2 was determined in arterial blood samples at baseline and 72 h after the first study drug administration
Time Frame
72 hours
Title
Change in Partial Pressure of Carbon Dioxide (PaCO2) in Arterial Blood From Baseline to 72 Hours Following Study Drug Administration
Description
PaCO2 was determined in arterial blood samples at baseline and 72 h after the first study drug administration
Time Frame
72 hours
Title
Change in Pre-ductal Peripheral Oxygen Saturation (SpO2) From Baseline to 72 Hours Following Study Drug Administration
Description
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
Time Frame
72 hours
Title
Change in Post-ductal Peripheral Oxygen Saturation (SpO2) From Baseline to 72 Hours Following Study Drug Administration
Description
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
Time Frame
72 hours
Title
Change in Fraction of Inspired Oxygen (FiO2) From Baseline to 72 Hours Following Study Drug Administration
Description
FiO2 was determined according to each study centers' standard procedure at baseline and 72 h after the first study drug administration
Time Frame
72 hours
Title
Maximum Whole Blood Concentration (Cmax) for Bosentan and Its Metabolites, Ro 47-8634, Ro 48-5033, and Ro 64-1056 on Day 1
Description
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.
Time Frame
up to 12 hours
Title
Cmax for Bosentan and Its Metabolites, Ro 47-8634, Ro 48-5033, and Ro 64-1056 on Day 5
Description
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 Frame
12 hours
Title
Time to Maximum Whole Blood Concentration (Tmax) for Bosentan on Day 1
Description
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.
Time Frame
up to 12 hours
Title
Tmax for Ro 47-8634 on Day 1
Description
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.
Time Frame
up to 12 hours
Title
Tmax for Ro 48-5033 on Day 1
Description
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.
Time Frame
up to 12 hours
Title
Tmax for Ro 64-1056 on Day 1
Description
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.
Time Frame
up to 12 hours
Title
Tmax for Bosentan on Day 5
Description
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.
Time Frame
12 hours
Title
Tmax for Ro 47-8634 on Day 5
Description
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.
Time Frame
12 hours
Title
Tmax for Ro 48-5033 on Day 5
Description
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.
Time Frame
12 hours
Title
Tmax for Ro 64-1056 on Day 5
Description
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.
Time Frame
12 hours
Title
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
Description
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.
Time Frame
12 hours
Title
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
Description
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.
Time Frame
5 days
Title
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
Description
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.
Time Frame
24 hours
Title
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
Description
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.
Time Frame
24 hours
Title
Accumulation Index (AI) for Bosentan
Description
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.
Time Frame
5 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
12 Hours
Maximum Age & Unit of Time
7 Days
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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. Exclusion Criteria: 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.
Facility Information:
Facility Name
LURIE CHILDREN'S HOSPITAL OF CHICAGO - Site 6021
City
Chicago
State/Province
Illinois
Country
United States
Facility Name
Advocate Hope Children's Hospital - Site 6009
City
Oak Lawn
State/Province
Illinois
ZIP/Postal Code
60453
Country
United States
Facility Name
Advocate Lutheran General Div. of Neonatal & Development Medicine - Site 6010
City
Park Ridge
State/Province
Illinois
Country
United States
Facility Name
Medical University of South Carolina, Pediatric Cardiology - Site 6019
City
Charleston
State/Province
South Carolina
Country
United States
Facility Name
The Royal Children's Hospital, Department of Neonatology - Site 3001
City
Parkville
Country
Australia
Facility Name
Division of Neonatology, Mater Mothers' Hospital, Mater Health Services, Brisbane Ltd. - Site 3003
City
South Brisbane
Country
Australia
Facility Name
UZ Leuven - Site 1103
City
Leuven
ZIP/Postal Code
3000
Country
Belgium
Facility Name
Fakultní nemocnice v Motole Novorozenecké oddělení - Site 2001
City
Prague
Country
Czech Republic
Facility Name
Všeobecná fakultní nemocnice Klinika dětského a dorostového lékařství - Site 2002
City
Prague
Country
Czech Republic
Facility Name
CHRU de Lille - Hôpital Jeanne de Flandre - Service de réanimation néonatale - Site 1802
City
Lille Cedex
Country
France
Facility Name
Hôpital Trousseau - Service de réanimation néonatale et pédiatrique - Site 1804
City
Paris cedex 12
Country
France
Facility Name
Hopital Necker - Site 1806
City
Paris
ZIP/Postal Code
75743
Country
France
Facility Name
Charité Universitätsmedizin Berlin Campus Virchow-Klinikum Klinik für Neonatologie - Site 1201
City
Berlin
Country
Germany
Facility Name
Klinikum der Universität zu Köln Klinik und Poliklinik für Kinder-und Jugendmedizin, Dep. Neonatologie u. Pädiatrische Intensivmedizin - Site 1203
City
Köln
Country
Germany
Facility Name
Samsung Medical Center - Site 5502
City
Seoul
ZIP/Postal Code
135-710
Country
Korea, Republic of
Facility Name
Instytut Centrum Zdrowia Matki Polki - Site 2106
City
Lodz
ZIP/Postal Code
93 336
Country
Poland
Facility Name
Uniwersytet Medyczny im. K. Marcinkowskiego w Poznaniu - Site 2103
City
Poznan
ZIP/Postal Code
60535
Country
Poland
Facility Name
Szpital Kliniczny im. ks. Anny Mazowieckiej - Site 2101
City
Warszawa
ZIP/Postal Code
00315
Country
Poland
Facility Name
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
City
Moscow
ZIP/Postal Code
117997
Country
Russian Federation
Facility Name
KK Women's and Children's Hospital - Site 5401
City
Singapore
ZIP/Postal Code
229899
Country
Singapore
Facility Name
Centre Hospitalier Universitaire Vaudois Départment Médico-Chirurgical de Pédiatrie / Service de Néonatologie - Site 1901
City
Lausanne
Country
Switzerland
Facility Name
Kantonsspital Luzern, Kinderspital Kinder-Intensivmedizin / Pädiatrie / Neonatologie - Site 1902
City
Lucerne
Country
Switzerland
Facility Name
Liverpool Women's NHS Foundation Trust - Site 1702
City
Liverpool
ZIP/Postal Code
L8 7SS
Country
United Kingdom
Facility Name
Great Ormond Street Hospital, Paediatric and Neonatal Intensive Care Unit - Site 1700
City
London
Country
United Kingdom
Facility Name
Norfolk and Norwich University Hospitals NHS Foundation Trust - Site 1703
City
Norwich
ZIP/Postal Code
NR4 7 UY
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
27502103
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.
Results Reference
derived

Learn more about this trial

Persistent Pulmonary Hypertension of the Newborn

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