Persistent Pulmonary Hypertension of the Newborn (FUTURE 4)

This study has been terminated.
(To be compliant with the timelines as agreed with Paediatric Committee (PC) within the Paediatric Investigational Plan)
Sponsor:
Information provided by (Responsible Party):
Actelion
ClinicalTrials.gov Identifier:
NCT01389856
First received: June 30, 2011
Last updated: April 9, 2015
Last verified: April 2015
  Purpose

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.


Condition Intervention Phase
Persistent Pulmonary Hypertension of the Newborn
Drug: Bosentan
Drug: Matching placebo
Phase 3

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

Resource links provided by NLM:


Further study details as provided by Actelion:

Primary Outcome Measures:
  • Percentage of Patients With Treatment Failure [ Time Frame: From baseline to up to 21 days ] [ Designated as safety issue: No ]
    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 [ Time Frame: From baseline to up to 21 days ] [ Designated as safety issue: No ]
    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 [ Time Frame: From baseline to up to 21 days ] [ Designated as safety issue: No ]
    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 [ Time Frame: From baseline to up to 21 days ] [ Designated as safety issue: No ]
    Re-initiation of iNO therapy following weaning from iNO therapy

  • Percentage of Patients With Pulmonary Hypertension (PH) at End of Treatment [ Time Frame: From baseline to up to 14 days ] [ Designated as safety issue: No ]

    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 [ Time Frame: 3 hours ] [ Designated as safety issue: No ]
    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 [ Time Frame: 5 hours ] [ Designated as safety issue: No ]
    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 [ Time Frame: 12 hours ] [ Designated as safety issue: No ]
    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 [ Time Frame: 24 hours ] [ Designated as safety issue: No ]
    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 [ Time Frame: 48 hours ] [ Designated as safety issue: No ]
    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 [ Time Frame: 72 hours ] [ Designated as safety issue: No ]
    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 [ Time Frame: 72 hours ] [ Designated as safety issue: No ]
    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 [ Time Frame: 72 hours ] [ Designated as safety issue: No ]
    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 [ Time Frame: 72 hours ] [ Designated as safety issue: No ]
    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 [ Time Frame: 72 hours ] [ Designated as safety issue: No ]
    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 [ Time Frame: 72 hours ] [ Designated as safety issue: No ]
    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 [ Time Frame: 72 hours ] [ Designated as safety issue: No ]
    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 [ Time Frame: 72 hours ] [ Designated as safety issue: No ]
    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 [ Time Frame: up to 12 hours ] [ Designated as safety issue: No ]
    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 [ Time Frame: 12 hours ] [ Designated as safety issue: No ]
    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 [ Time Frame: up to 12 hours ] [ Designated as safety issue: No ]
    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 [ Time Frame: up to 12 hours ] [ Designated as safety issue: No ]
    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 [ Time Frame: up to 12 hours ] [ Designated as safety issue: No ]
    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 [ Time Frame: up to 12 hours ] [ Designated as safety issue: No ]
    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 [ Time Frame: 12 hours ] [ Designated as safety issue: No ]
    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 [ Time Frame: 12 hours ] [ Designated as safety issue: No ]
    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 [ Time Frame: 12 hours ] [ Designated as safety issue: No ]
    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 [ Time Frame: 12 hours ] [ Designated as safety issue: No ]
    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 [ Time Frame: 12 hours ] [ Designated as safety issue: No ]
    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 [ Time Frame: 5 days ] [ Designated as safety issue: No ]
    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 [ Time Frame: 24 hours ] [ Designated as safety issue: No ]
    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 [ Time Frame: 24 hours ] [ Designated as safety issue: No ]
    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 [ Time Frame: 5 days ] [ Designated as safety issue: No ]
    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.


Enrollment: 23
Study Start Date: December 2011
Study Completion Date: January 2014
Primary Completion Date: December 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: Tracleer
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.

  Eligibility

Ages Eligible for Study:   up to 7 Days
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Signed informed consent by the parent(s) or the legal representative(s).
  2. Term and near term newborns (gestational age > 34 weeks).
  3. Post natal age ≥ 12 hours and < 7 days.
  4. Weight at birth ≥ 2,000 g.
  5. Idiopathic PPHN or PPHN due to parenchymal lung disease
  6. Documented diagnosis of pulmonary hypertension (PH) confirmed by echocardiography.
  7. Need for continued inhaled nitric oxide (iNO) at a dose > 10ppm after at least 4 hours of continuous iNO treatment.
  8. Two oxygenation index (OI) values ≥ 12 taken at least 30 minutes apart, in the 12 hours prior to randomization and while the patient is receiving iNO treatment.
  9. Mechanical ventilation with fraction of inspired oxygen (FiO2) ≥ 50% at randomization.

Exclusion Criteria:

  1. PH associated with conditions other than PPHN.
  2. Immediate need for cardiac resuscitation or extracorporeal membrane oxygenation (ECMO).
  3. Lethal congenital anomalies.
  4. Congenital Diaphragmatic Hernia.
  5. Significant structural cardiac anomalies.
  6. Medically significant pneumothorax.
  7. Active seizures.
  8. Expected duration of mechanical ventilation of less than 48 hours.
  9. Mean systemic blood pressure < 35 mmHg despite therapy with volume infusions and cardiotonic support.
  10. Hepatic failure or all conditions with alanine aminotransferase (ALT) values > 2 x upper limit of normal (ULN).
  11. Renal function impairment such as serum creatinine > 3 x ULN or anuria.
  12. Known intracranial hemorrhage grade III or IV.
  13. Either hemoglobin or hematocrit level < 75% of the lower limit of normal (LLN).
  14. Thrombocytopenia (platelet count < 50,000 cells /µL).
  15. Leukopenia (WBC < 2,500 cells/ µL).
  16. Any condition precluding the use of a nasogastric/orogastric tube.
  17. Administration of prohibited medication prior to randomization.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01389856

  Show 25 Study Locations
Sponsors and Collaborators
Actelion
  More Information

No publications provided

Responsible Party: Actelion
ClinicalTrials.gov Identifier: NCT01389856     History of Changes
Other Study ID Numbers: AC-052-391
Study First Received: June 30, 2011
Results First Received: March 9, 2015
Last Updated: April 9, 2015
Health Authority: Australia: Department of Health and Ageing Therapeutic Goods Administration
Australia: Human Research Ethics Committee
Czech Republic: Ethics Committee
Czech Republic: State Institute for Drug Control
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
France: Committee for the Protection of Personnes
Germany: Ethics Commission
Germany: Federal Institute for Drugs and Medical Devices
Switzerland: Ethikkommission
Switzerland: Swissmedic
United Kingdom: Medicines and Healthcare Products Regulatory Agency
United Kingdom: Research Ethics Committee
United States: Food and Drug Administration
United States: Institutional Review Board
Belgium: Ethics Committee
Belgium: Federal Agency for Medicinal Products and Health Products
Poland: Ethics Committee
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
South Korea: Institutional Review Board
Korea: Ministry of Food and Drug Safety
Singapore: Institutional Review Board
Singapore: Health Sciences Authority
Russia: Ethics Committee
Russia: Ministry of Health of the Russian Federation

Keywords provided by Actelion:
Persistent pulmonary hypertension, newborn
PPHN

Additional relevant MeSH terms:
Hypertension
Hypertension, Pulmonary
Persistent Fetal Circulation Syndrome
Cardiovascular Diseases
Infant, Newborn, Diseases
Lung Diseases
Respiratory Tract Diseases
Vascular Diseases
Bosentan
Antihypertensive Agents
Cardiovascular Agents
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on September 01, 2015