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

June 30, 2011
April 9, 2015
December 2011
December 2013   (final data collection date for primary outcome measure)
  • 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
Proportion of patients with treatment failure [ Time Frame: From baseline to up to 14 days ] [ Designated as safety issue: No ]

Exploratory Endpoint:

Proportion of patients with treatment failure:

  • Need for extra corporeal membrane oxygenation (ECMO) or
  • Initiation of alternative pulmonary vasodilator
Complete list of historical versions of study NCT01389856 on ClinicalTrials.gov Archive Site
  • 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.
Time to complete weaning from inhaled nitric oxide (iNO) [ Time Frame: From baseline to up to 14 days ] [ Designated as safety issue: No ]

Exploratory Endpoint:

Time to complete weaning from inhaled nitric oxide (iNO)

Not Provided
Not Provided
 
Persistent Pulmonary Hypertension of the Newborn
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.

Not Provided
Interventional
Phase 3
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Persistent Pulmonary Hypertension of the Newborn
  • 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
  • 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
    Intervention: Drug: Bosentan
  • Placebo Comparator: 2
    Matching placebo
    Intervention: Drug: Matching placebo
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Terminated
23
January 2014
December 2013   (final data collection date for primary outcome measure)

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.
Both
up to 7 Days
No
Contact information is only displayed when the study is recruiting subjects
United States,   Australia,   Belgium,   Czech Republic,   France,   Germany,   Korea, Republic of,   Poland,   Russian Federation,   Singapore,   Switzerland,   United Kingdom
Netherlands
 
NCT01389856
AC-052-391
Yes
Actelion
Actelion
Not Provided
Not Provided
Actelion
April 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP