Persistent Pulmonary Hypertension of the Newborn (FUTURE 4)

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)

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.

Study Overview

• Status: Terminated
• Conditions: Persistent Pulmonary Hypertension of the Newborn
• Intervention / Treatment: Drug: Bosentan; Drug: Matching placebo

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Parkville, Australia
    • The Royal Children's Hospital, Department of Neonatology - Site 3001
  • South Brisbane, Australia
    • Division of Neonatology, Mater Mothers' Hospital, Mater Health Services, Brisbane Ltd. - Site 3003
• Belgium
  • Leuven, Belgium, 3000
    • UZ Leuven - Site 1103
• Czech Republic
  • Prague, Czech Republic
    • Fakultní nemocnice v Motole Novorozenecké oddělení - Site 2001
  • Prague, Czech Republic
    • Všeobecná fakultní nemocnice Klinika dětského a dorostového lékařství - Site 2002
• France
  • Lille Cedex, France
    • CHRU de Lille - Hôpital Jeanne de Flandre - Service de réanimation néonatale - Site 1802
  • Paris, France, 75743
    • Hopital Necker - Site 1806
  • Paris cedex 12, France
    • Hôpital Trousseau - Service de réanimation néonatale et pédiatrique - Site 1804
• Germany
  • Berlin, Germany
    • Charité Universitätsmedizin Berlin Campus Virchow-Klinikum Klinik für Neonatologie - Site 1201
  • Köln, Germany
    • Klinikum der Universität zu Köln Klinik und Poliklinik für Kinder-und Jugendmedizin, Dep. Neonatologie u. Pädiatrische Intensivmedizin - Site 1203
• Korea, Republic of
  • Seoul, Korea, Republic of, 135-710
    • Samsung Medical Center - Site 5502
• Poland
  • Lodz, Poland, 93 336
    • Instytut Centrum Zdrowia Matki Polki - Site 2106
  • Poznan, Poland, 60535
    • Uniwersytet Medyczny im. K. Marcinkowskiego w Poznaniu - Site 2103
  • Warszawa, Poland, 00315
    • Szpital Kliniczny im. ks. Anny Mazowieckiej - Site 2101
• Russian Federation
  • Moscow, Russian Federation, 117997
    • 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
• Singapore
  • Singapore, Singapore, 229899
    • KK Women's and Children's Hospital - Site 5401
• Switzerland
  • Lausanne, Switzerland
    • Centre Hospitalier Universitaire Vaudois Départment Médico-Chirurgical de Pédiatrie / Service de Néonatologie - Site 1901
  • Lucerne, Switzerland
    • Kantonsspital Luzern, Kinderspital Kinder-Intensivmedizin / Pädiatrie / Neonatologie - Site 1902
• United Kingdom
  • Liverpool, United Kingdom, L8 7SS
    • Liverpool Women's NHS Foundation Trust - Site 1702
  • London, United Kingdom
    • Great Ormond Street Hospital, Paediatric and Neonatal Intensive Care Unit - Site 1700
  • Norwich, United Kingdom, NR4 7 UY
    • Norfolk and Norwich University Hospitals NHS Foundation Trust - Site 1703
• United States
  • Illinois
    • Chicago, Illinois, United States
      • LURIE CHILDREN'S HOSPITAL OF CHICAGO - Site 6021
    • Oak Lawn, Illinois, United States, 60453
      • Advocate Hope Children's Hospital - Site 6009
    • Park Ridge, Illinois, United States
      • Advocate Lutheran General Div. of Neonatal & Development Medicine - Site 6010
  • South Carolina
    • Charleston, South Carolina, United States
      • Medical University of South Carolina, Pediatric Cardiology - Site 6019

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 hours to 1 week (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: 2; Matching placebo	Drug: 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.
Experimental: 1; Bosentan	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.; Other Names: Tracleer

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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

Collaborators and Investigators

• Sponsor: Actelion

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: December 1, 2011
• Primary Completion (Actual): December 1, 2013
• Study Completion (Actual): January 1, 2014

Study Registration Dates

• First Submitted: June 30, 2011
• First Submitted That Met QC Criteria: July 7, 2011
• First Posted (Estimate): July 8, 2011

Study Record Updates

• Last Update Posted (Estimate): May 1, 2015
• Last Update Submitted That Met QC Criteria: April 9, 2015
• Last Verified: April 1, 2015

More Information

Terms related to this study

• Keywords: PPHN; Persistent pulmonary hypertension, newborn
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Hypertension; Hypertension, Pulmonary; Persistent Fetal Circulation Syndrome; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Endothelin Receptor Antagonists; Bosentan
• Other Study ID Numbers: AC-052-391