Persistent Pulmonary Hypertension of the Newborn
Conditions
Keywords
Persistent pulmonary hypertension, newborn, PPHN
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.
Interventions
DRUGBosentan
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.
DRUGMatching placebo
twice daily (b.i.d); quadrisectable 32 mg tablet of matching placebo dispersed in sterile water and administered by nasogastric or orogastric tube.
Sponsors
Actelion
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Hours to 7 Days
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With Treatment Failure | From baseline to up to 21 days | 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 | From baseline to up to 21 days | 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 | From baseline to up to 21 days | Calculated from the time from first study drug administration to complete weaning from mechanical ventilation |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Oxygenation Index (OI) From Baseline to 5 Hours Following Study Drug Administration | 5 hours | 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 | 12 hours | 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 | 24 hours | 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 | 48 hours | 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 | 72 hours | 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 | 72 hours | 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 | 72 hours | 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 | 72 hours | 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 | 72 hours | 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 | 72 hours | 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 | 72 hours | 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 | 72 hours | 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 | up to 12 hours | 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. |
| Percentage of Patients Requiring Re-initiation of iNO Therapy | From baseline to up to 21 days | Re-initiation of iNO therapy following weaning from iNO therapy |
| Time to Maximum Whole Blood Concentration (Tmax) for Bosentan on Day 1 | up to 12 hours | 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 | up to 12 hours | 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 | up to 12 hours | 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 | up to 12 hours | 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 | 12 hours | 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 | 12 hours | 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 | 12 hours | 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 | 12 hours | 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 | 12 hours | 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 | 5 days | 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 | 24 hours | 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 | 24 hours | 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 | 5 days | 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. |
| Cmax for Bosentan and Its Metabolites, Ro 47-8634, Ro 48-5033, and Ro 64-1056 on Day 5 | 12 hours | 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. |
| Percentage of Patients With Pulmonary Hypertension (PH) at End of Treatment | From baseline to up to 14 days | 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 | 3 hours | 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. |
Participant flow
Recruitment details
First patient, first visit was 8 December 2011 and last patient, last visit was 5 December 2013. The investigational sites were tertiary care centers with neonatal intensive care unit facilities at which inhaled nitric oxide (iNO) was used as standard of care for persistent pulmonary hypertension of the newborn (PPHN).
Pre-assignment details
Term or near-term (gestational age \> 34 weeks) hypoxic newborns with respiratory distress refractory to supplemental oxygen were considered, provided they had no significant structural cardiac anomalies documented in the pre-natal period and had no immediate need for extra corporeal membrane oxygenation (ECMO).
Participants by arm
| Arm | Count |
|---|---|
| Bosentan Bosentan
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. | 13 |
| Placebo Matching placebo
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. | 8 |
| Total | 21 |
Baseline characteristics
| Characteristic | Bosentan | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 1.4 days | 1.7 days | 1.4 days |
| Gestational age | 40.0 weeks | 38.5 weeks | 39.0 weeks |
| Race/Ethnicity, Customized Asian | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Caucasian/white | 11 participants | 6 participants | 17 participants |
| Race/Ethnicity, Customized Hispanic | 1 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized Other | 0 participants | 1 participants | 1 participants |
| Region of Enrollment Czech Republic | 1 participants | 1 participants | 2 participants |
| Region of Enrollment France | 1 participants | 0 participants | 1 participants |
| Region of Enrollment Korea, Republic of | 1 participants | 0 participants | 1 participants |
| Region of Enrollment Poland | 5 participants | 3 participants | 8 participants |
| Region of Enrollment United Kingdom | 4 participants | 2 participants | 6 participants |
| Region of Enrollment United States | 1 participants | 2 participants | 3 participants |
| Sex: Female, Male Female | 9 Participants | 6 Participants | 15 Participants |
| Sex: Female, Male Male | 4 Participants | 2 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 9 / 13 | 2 / 8 |
| serious Total, serious adverse events | 2 / 13 | 3 / 8 |
Outcome results
Primary
Percentage of Patients With Treatment Failure
Treatment failure was defined as the need for extra corporeal membrane oxygenation or initiation of alternative pulmonary vasodilator treatment
Time frame: From baseline to up to 21 days
Population: Randomized and treated patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bosentan | Percentage of Patients With Treatment Failure | 7.7 percentage of participants |
| Placebo | Percentage of Patients With Treatment Failure | 0 percentage of participants |
p-value: 1Fisher Exact
Primary
Time to Complete Weaning From iNO
Calculated from the time from first study drug administration to complete weaning from iNO. Weaning from iNO was considered complete if there was no requirement for the re-initiation of iNO within 24 h after stopping
Time frame: From baseline to up to 21 days
Population: Randomized and treated patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bosentan | Time to Complete Weaning From iNO | 3.7 days |
| Placebo | Time to Complete Weaning From iNO | 2.9 days |
p-value: 0.3407Log Rank
Primary
Time to Complete Weaning From Mechanical Ventilation
Calculated from the time from first study drug administration to complete weaning from mechanical ventilation
Time frame: From baseline to up to 21 days
Population: Randomized and treated patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bosentan | Time to Complete Weaning From Mechanical Ventilation | 10.8 days |
| Placebo | Time to Complete Weaning From Mechanical Ventilation | 8.6 days |
p-value: 0.2399Log Rank
Secondary
Accumulation Index (AI) for Bosentan
Concentrations were measured directly in dried blood spot samples scheduled to be taken immediately prior to first study drug administration and at 0.5, 1, 2, 3, 7.5 and 12 hours post-dose on Days 1 and 5. Pharmacokinetic parameters were determined on the basis of scheduled blood sampling time points using non-compartmental analysis. Actual blood sampling times were used only if there was a deviation of more than 5% from the scheduled times. AI was calculated as the ratio AUCtau /AUC0-12 for the subjects having PK samples collected on Day 1 and Day 5 and with AUC0-12 \> 0 ng.h/mL.
Time frame: 5 days
Population: PK analysis set. This analysis set comprised all patients included in the all-treated set who were able to provide at least 5 of the 7 blood samples requested for at least one evaluable profile of PK assessment and who did not violate the protocol in a way that might affect the evaluation of the PK endpoints.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Bosentan | Accumulation Index (AI) for Bosentan | 61.6 accumulation index |
Secondary
Area Under the Concentration-time Curve Over a Dosing Interval at Steady State on Day 5 (AUCtau) for Bosentan and Its Metabolites, Ro 47-8634, Ro 48-5033, and Ro 64-1056
Concentrations were measured directly in dried blood spot samples scheduled to be taken immediately prior to study drug administration and at 0.5, 1, 2, 3, 7.5, and 12 hours post-dose on Day 5. Pharmacokinetic parameters were determined on the basis of scheduled blood sampling time points using non-compartmental analysis. Actual blood sampling times were used only if there was a deviation of more than 5% from the scheduled times. AUCtau Day 5 was calculated according to the trapezoidal rule using the measured concentration-time values above the limit of quantification.
Time frame: 5 days
Population: PK analysis set. This analysis set comprised all patients included in the all-treated set who were able to provide at least 5 of the 7 blood samples requested for at least one evaluable profile of PK assessment and who did not violate the protocol in a way that might affect the evaluation of the PK endpoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Bosentan | 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 | Bosentan | 6165.4 h*ng/mL |
| Bosentan | 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 | Ro 47-8634 | 217.3 h*ng/mL |
| Bosentan | 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 | Ro 48-5033 | 2839.5 h*ng/mL |
| Bosentan | 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 | Ro 64-1056 | 1321.7 h*ng/mL |
Secondary
Area Under the Concentration-time Curve Over a Period of 12 h (AUC0-12 Day 1)) for Bosentan and Its Metabolites, Ro 47-8634, Ro 48-5033, and Ro 64-1056 on Day 1
Concentrations were measured directly in dried blood spot samples scheduled to be taken immediately prior to first study drug administration and at 0.5, 1, 2, 3, 7.5 and 12 hours post-dose on Day 1. Pharmacokinetic parameters were determined on the basis of scheduled blood sampling time points using non-compartmental analysis. Actual blood sampling times were used only if there was a deviation of more than 5% from the scheduled times. AUC0-12 Day 1 was calculated according to the trapezoidal rule using the measured concentration-time values above the limit of quantification.
Time frame: 12 hours
Population: PK analysis set. This analysis set comprised all patients included in the all-treated set who were able to provide at least 5 of the 7 blood samples requested for at least one evaluable profile of PK assessment and who did not violate the protocol in a way that might affect the evaluation of the PK endpoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Bosentan | 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 | Bosentan | 163.9 h*ng/mL |
| Bosentan | 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 | Ro 47-8634 | 0.1 h*ng/mL |
| Bosentan | 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 | Ro 48-5033 | 1.4 h*ng/mL |
| Bosentan | 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 | Ro 64-1056 | 2.2 h*ng/mL |
Secondary
Area Under the Concentration-time Curve Over a Period of 24 h (Dose-corrected to 2 mg/kg) on Day 1 (AUC0-24C Day 1) for Bosentan and Its Metabolites, Ro 47-8634, Ro 48-5033, and Ro 64-1056
Concentrations were measured directly in dried blood spot samples scheduled to be taken immediately prior to first study drug administration and at 0.5, 1, 2, 3, 7.5 and 12 hours post-dose on Day 1. Pharmacokinetic parameters were determined on the basis of scheduled blood sampling time points using non-compartmental analysis. Actual blood sampling times were used only if there was a deviation of more than 5% from the scheduled times. AUC0-24C Day 1 was calculated as a multiple of AUC0-12, (2 × AUC0-12 for 2 times daily dosing) corrected to 2 mg/kg.
Time frame: 24 hours
Population: PK analysis set. This analysis set comprised all patients included in the all-treated set who were able to provide at least 5 of the 7 blood samples requested for at least one evaluable profile of PK assessment and who did not violate the protocol in a way that might affect the evaluation of the PK endpoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Bosentan | 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 | Bosentan | 287.5 h*ng/mL |
| Bosentan | 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 | Ro 47-8634 | 0.1 h*ng/mL |
| Bosentan | 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 | Ro 48-5033 | 2.0 h*ng/mL |
| Bosentan | 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 | Ro 64-1056 | 3.4 h*ng/mL |
Secondary
Area Under the Concentration-time Curve Over a Period of 24 h (Dose-corrected to 2 mg/kg) on Day 5 (AUC0-24C Day 5) for Bosentan and Its Metabolites, Ro 47-8634, Ro 48-5033, and Ro 64-1056
Concentrations were measured directly in dried blood spot samples scheduled to be taken immediately prior to study drug administration and at 0.5, 1, 2, 3, 7.5, and 12 hours post-dose on Day 5. Pharmacokinetic parameters were determined on the basis of scheduled blood sampling time points using non-compartmental analysis. Actual blood sampling times were used only if there was a deviation of more than 5% from the scheduled times. AUC0-24C Day 5 was calculated as a multiple of AUCtau, (2 × AUCtau for 2 times daily dosing) corrected to 2 mg/kg.
Time frame: 24 hours
Population: PK analysis set. This analysis set comprised all patients included in the all-treated set who were able to provide at least 5 of the 7 blood samples requested for at least one evaluable profile of PK assessment and who did not violate the protocol in a way that might affect the evaluation of the PK endpoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Bosentan | 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 | Bosentan | 11530.2 h*ng/mL |
| Bosentan | 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 | Ro 47-8634 | 406.3 h*ng/mL |
| Bosentan | 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 | Ro 48-5033 | 5310.3 h*ng/mL |
| Bosentan | 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 | Ro 64-1056 | 2471.9 h*ng/mL |
Secondary
Change in Arterial Blood Gas (ABG) pH From Baseline to 72 Hours Following Study Drug Administration
pH was determined in arterial blood samples at baseline and 72 h after the first study drug administration
Time frame: 72 hours
Population: Randomized and treated patients with available data
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Bosentan | Change in Arterial Blood Gas (ABG) pH From Baseline to 72 Hours Following Study Drug Administration | Change from baseline | 0.04 pH |
| Bosentan | Change in Arterial Blood Gas (ABG) pH From Baseline to 72 Hours Following Study Drug Administration | Baseline | 7.37 pH |
| Bosentan | Change in Arterial Blood Gas (ABG) pH From Baseline to 72 Hours Following Study Drug Administration | 72 hours | 7.37 pH |
| Placebo | Change in Arterial Blood Gas (ABG) pH From Baseline to 72 Hours Following Study Drug Administration | Change from baseline | 0.02 pH |
| Placebo | Change in Arterial Blood Gas (ABG) pH From Baseline to 72 Hours Following Study Drug Administration | Baseline | 7.31 pH |
| Placebo | Change in Arterial Blood Gas (ABG) pH From Baseline to 72 Hours Following Study Drug Administration | 72 hours | 7.36 pH |
p-value: 0.0824Non-parametric ANCOVA
Secondary
Change in Arterial Blood Oxygen Saturation (SaO2) From Baseline to 72 Hours Following Study Drug Administration
SaO2 was determined in arterial blood samples at baseline and 72 h after the first study drug administration
Time frame: 72 hours
Population: Randomized and treated patients with available data
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Bosentan | Change in Arterial Blood Oxygen Saturation (SaO2) From Baseline to 72 Hours Following Study Drug Administration | Baseline | 95.0 percentage saturation |
| Bosentan | Change in Arterial Blood Oxygen Saturation (SaO2) From Baseline to 72 Hours Following Study Drug Administration | 72 hours | 98.0 percentage saturation |
| Bosentan | Change in Arterial Blood Oxygen Saturation (SaO2) From Baseline to 72 Hours Following Study Drug Administration | Change from baseline | 1.0 percentage saturation |
| Placebo | Change in Arterial Blood Oxygen Saturation (SaO2) From Baseline to 72 Hours Following Study Drug Administration | Baseline | 95.5 percentage saturation |
| Placebo | Change in Arterial Blood Oxygen Saturation (SaO2) From Baseline to 72 Hours Following Study Drug Administration | 72 hours | 97.0 percentage saturation |
| Placebo | Change in Arterial Blood Oxygen Saturation (SaO2) From Baseline to 72 Hours Following Study Drug Administration | Change from baseline | 0.0 percentage saturation |
p-value: 0.3863Non-parametric ANCOVA
Secondary
Change in Fraction of Inspired Oxygen (FiO2) From Baseline to 72 Hours Following Study Drug Administration
FiO2 was determined according to each study centers' standard procedure at baseline and 72 h after the first study drug administration
Time frame: 72 hours
Population: Randomized and treated patients with available data
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Bosentan | Change in Fraction of Inspired Oxygen (FiO2) From Baseline to 72 Hours Following Study Drug Administration | Baseline | 90.0 percentage of oxygen |
| Bosentan | Change in Fraction of Inspired Oxygen (FiO2) From Baseline to 72 Hours Following Study Drug Administration | Change from baseline | -33.5 percentage of oxygen |
| Bosentan | Change in Fraction of Inspired Oxygen (FiO2) From Baseline to 72 Hours Following Study Drug Administration | 72 hours | 51.5 percentage of oxygen |
| Placebo | Change in Fraction of Inspired Oxygen (FiO2) From Baseline to 72 Hours Following Study Drug Administration | Baseline | 78.0 percentage of oxygen |
| Placebo | Change in Fraction of Inspired Oxygen (FiO2) From Baseline to 72 Hours Following Study Drug Administration | 72 hours | 40.0 percentage of oxygen |
| Placebo | Change in Fraction of Inspired Oxygen (FiO2) From Baseline to 72 Hours Following Study Drug Administration | Change from baseline | -35.5 percentage of oxygen |
p-value: 0.14Non-parametric ANCOVA
Secondary
Change in Oxygenation Index (OI) From Baseline to 12 Hours Following Study Drug Administration
The change in OI from baseline following study drug administration was determined. OI was calculated as the mean airway pressure multiplied by the fraction of inspired oxygen (expressed in %), and the product was divided by the partial pressure of oxygen in arterial blood.
Time frame: 12 hours
Population: Randomized and treated patients
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Bosentan | Change in Oxygenation Index (OI) From Baseline to 12 Hours Following Study Drug Administration | Baseline | 18.3 oxygenation index |
| Bosentan | Change in Oxygenation Index (OI) From Baseline to 12 Hours Following Study Drug Administration | 12 hours | 14.3 oxygenation index |
| Bosentan | Change in Oxygenation Index (OI) From Baseline to 12 Hours Following Study Drug Administration | Change from baseline | -0.8 oxygenation index |
| Placebo | Change in Oxygenation Index (OI) From Baseline to 12 Hours Following Study Drug Administration | Baseline | 13.2 oxygenation index |
| Placebo | Change in Oxygenation Index (OI) From Baseline to 12 Hours Following Study Drug Administration | 12 hours | 11.1 oxygenation index |
| Placebo | Change in Oxygenation Index (OI) From Baseline to 12 Hours Following Study Drug Administration | Change from baseline | -3.9 oxygenation index |
p-value: 0.0789Non-parametric ANCOVA
Secondary
Change in Oxygenation Index (OI) From Baseline to 24 Hours Following Study Drug Administration
The change in OI from baseline following study drug administration was determined. OI was calculated as the mean airway pressure multiplied by the fraction of inspired oxygen (expressed in %), and the product was divided by the partial pressure of oxygen in arterial blood.
Time frame: 24 hours
Population: Randomized and treated patients
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Bosentan | Change in Oxygenation Index (OI) From Baseline to 24 Hours Following Study Drug Administration | Baseline | 18.3 oxygenation index |
| Bosentan | Change in Oxygenation Index (OI) From Baseline to 24 Hours Following Study Drug Administration | 24 hours | 13.1 oxygenation index |
| Bosentan | Change in Oxygenation Index (OI) From Baseline to 24 Hours Following Study Drug Administration | Change from baseline | -4.9 oxygenation index |
| Placebo | Change in Oxygenation Index (OI) From Baseline to 24 Hours Following Study Drug Administration | Baseline | 13.2 oxygenation index |
| Placebo | Change in Oxygenation Index (OI) From Baseline to 24 Hours Following Study Drug Administration | 24 hours | 11.8 oxygenation index |
| Placebo | Change in Oxygenation Index (OI) From Baseline to 24 Hours Following Study Drug Administration | Change from baseline | -6.9 oxygenation index |
p-value: 0.3723Non-parametric ANCOVA
Secondary
Change in Oxygenation Index (OI) From Baseline to 3 Hours Following Study Drug Administration
The change in OI from baseline following study drug administration was determined. OI was calculated as the mean airway pressure multiplied by the fraction of inspired oxygen (expressed in %), and the product was divided by the partial pressure of oxygen in arterial blood.
Time frame: 3 hours
Population: Randomized and treated patients
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Bosentan | Change in Oxygenation Index (OI) From Baseline to 3 Hours Following Study Drug Administration | Baseline | 18.3 oxygenation index |
| Bosentan | Change in Oxygenation Index (OI) From Baseline to 3 Hours Following Study Drug Administration | 3 hours | 17.3 oxygenation index |
| Bosentan | Change in Oxygenation Index (OI) From Baseline to 3 Hours Following Study Drug Administration | Change from baseline | -1.6 oxygenation index |
| Placebo | Change in Oxygenation Index (OI) From Baseline to 3 Hours Following Study Drug Administration | Baseline | 13.2 oxygenation index |
| Placebo | Change in Oxygenation Index (OI) From Baseline to 3 Hours Following Study Drug Administration | 3 hours | 13.0 oxygenation index |
| Placebo | Change in Oxygenation Index (OI) From Baseline to 3 Hours Following Study Drug Administration | Change from baseline | 1.1 oxygenation index |
p-value: 0.2235Non-parametric ANCOVA
Secondary
Change in Oxygenation Index (OI) From Baseline to 48 Hours Following Study Drug Administration
The change in OI from baseline following study drug administration was determined. OI was calculated as the mean airway pressure multiplied by the fraction of inspired oxygen (expressed in %), and the product was divided by the partial pressure of oxygen in arterial blood.
Time frame: 48 hours
Population: Randomized and treated patients with available data
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Bosentan | Change in Oxygenation Index (OI) From Baseline to 48 Hours Following Study Drug Administration | Baseline | 19.4 oxygenation index |
| Bosentan | Change in Oxygenation Index (OI) From Baseline to 48 Hours Following Study Drug Administration | 48 hours | 11.5 oxygenation index |
| Bosentan | Change in Oxygenation Index (OI) From Baseline to 48 Hours Following Study Drug Administration | Change from baseline | -4.9 oxygenation index |
| Placebo | Change in Oxygenation Index (OI) From Baseline to 48 Hours Following Study Drug Administration | Baseline | 13.2 oxygenation index |
| Placebo | Change in Oxygenation Index (OI) From Baseline to 48 Hours Following Study Drug Administration | 48 hours | 3.8 oxygenation index |
| Placebo | Change in Oxygenation Index (OI) From Baseline to 48 Hours Following Study Drug Administration | Change from baseline | -9.9 oxygenation index |
p-value: 0.0569Non-parametric ANCOVA
Secondary
Change in Oxygenation Index (OI) From Baseline to 5 Hours Following Study Drug Administration
The change in OI from baseline following study drug administration was determined. OI was calculated as the mean airway pressure multiplied by the fraction of inspired oxygen (expressed in %), and the product was divided by the partial pressure of oxygen in arterial blood.
Time frame: 5 hours
Population: Randomized and treated patients
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Bosentan | Change in Oxygenation Index (OI) From Baseline to 5 Hours Following Study Drug Administration | Baseline | 18.3 oxygenation index |
| Bosentan | Change in Oxygenation Index (OI) From Baseline to 5 Hours Following Study Drug Administration | 5 hours | 16.7 oxygenation index |
| Bosentan | Change in Oxygenation Index (OI) From Baseline to 5 Hours Following Study Drug Administration | Change from baseline | -0.9 oxygenation index |
| Placebo | Change in Oxygenation Index (OI) From Baseline to 5 Hours Following Study Drug Administration | Baseline | 13.2 oxygenation index |
| Placebo | Change in Oxygenation Index (OI) From Baseline to 5 Hours Following Study Drug Administration | 5 hours | 13.3 oxygenation index |
| Placebo | Change in Oxygenation Index (OI) From Baseline to 5 Hours Following Study Drug Administration | Change from baseline | -5.6 oxygenation index |
p-value: 0.1468Non-parametric ANCOVA
Secondary
Change in Oxygenation Index (OI) From Baseline to 72 Hours Following Study Drug Administration
The change in OI from baseline following study drug administration was determined. OI was calculated as the mean airway pressure multiplied by the fraction of inspired oxygen (expressed in %), and the product was divided by the partial pressure of oxygen in arterial blood.
Time frame: 72 hours
Population: Randomized and treated patients with available data
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Bosentan | Change in Oxygenation Index (OI) From Baseline to 72 Hours Following Study Drug Administration | Baseline | 19.4 oxygenation index |
| Bosentan | Change in Oxygenation Index (OI) From Baseline to 72 Hours Following Study Drug Administration | 72 hours | 6.7 oxygenation index |
| Bosentan | Change in Oxygenation Index (OI) From Baseline to 72 Hours Following Study Drug Administration | Change from baseline | -8.9 oxygenation index |
| Placebo | Change in Oxygenation Index (OI) From Baseline to 72 Hours Following Study Drug Administration | Baseline | 13.2 oxygenation index |
| Placebo | Change in Oxygenation Index (OI) From Baseline to 72 Hours Following Study Drug Administration | 72 hours | 3.9 oxygenation index |
| Placebo | Change in Oxygenation Index (OI) From Baseline to 72 Hours Following Study Drug Administration | Change from baseline | -9.4 oxygenation index |
p-value: 0.1015Non-parametric ANCOVA
Secondary
Change in Partial Pressure of Carbon Dioxide (PaCO2) in Arterial Blood From Baseline to 72 Hours Following Study Drug Administration
PaCO2 was determined in arterial blood samples at baseline and 72 h after the first study drug administration
Time frame: 72 hours
Population: Randomized and treated patients with available data
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Bosentan | Change in Partial Pressure of Carbon Dioxide (PaCO2) in Arterial Blood From Baseline to 72 Hours Following Study Drug Administration | Baseline | 40.5 mm Hg |
| Bosentan | Change in Partial Pressure of Carbon Dioxide (PaCO2) in Arterial Blood From Baseline to 72 Hours Following Study Drug Administration | 72 hours | 45.5 mm Hg |
| Bosentan | Change in Partial Pressure of Carbon Dioxide (PaCO2) in Arterial Blood From Baseline to 72 Hours Following Study Drug Administration | Change from baseline | 6.0 mm Hg |
| Placebo | Change in Partial Pressure of Carbon Dioxide (PaCO2) in Arterial Blood From Baseline to 72 Hours Following Study Drug Administration | Baseline | 46.0 mm Hg |
| Placebo | Change in Partial Pressure of Carbon Dioxide (PaCO2) in Arterial Blood From Baseline to 72 Hours Following Study Drug Administration | 72 hours | 46.0 mm Hg |
| Placebo | Change in Partial Pressure of Carbon Dioxide (PaCO2) in Arterial Blood From Baseline to 72 Hours Following Study Drug Administration | Change from baseline | 8.0 mm Hg |
p-value: 0.2436Non-parametric ANCOVA
Secondary
Change in Partial Pressure of Oxygen (PaO2) in Arterial Blood From Baseline to 72 Hours Following Study Drug Administration
PaO2 was determined in arterial blood samples at baseline and 72 h after the first study drug administration
Time frame: 72 hours
Population: Randomized and treated patients with available data
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Bosentan | Change in Partial Pressure of Oxygen (PaO2) in Arterial Blood From Baseline to 72 Hours Following Study Drug Administration | Baseline | 61.0 mm Hg |
| Bosentan | Change in Partial Pressure of Oxygen (PaO2) in Arterial Blood From Baseline to 72 Hours Following Study Drug Administration | 72 hours | 81.0 mm Hg |
| Bosentan | Change in Partial Pressure of Oxygen (PaO2) in Arterial Blood From Baseline to 72 Hours Following Study Drug Administration | Change from baseline | 18.0 mm Hg |
| Placebo | Change in Partial Pressure of Oxygen (PaO2) in Arterial Blood From Baseline to 72 Hours Following Study Drug Administration | Baseline | 69.5 mm Hg |
| Placebo | Change in Partial Pressure of Oxygen (PaO2) in Arterial Blood From Baseline to 72 Hours Following Study Drug Administration | 72 hours | 81.5 mm Hg |
| Placebo | Change in Partial Pressure of Oxygen (PaO2) in Arterial Blood From Baseline to 72 Hours Following Study Drug Administration | Change from baseline | 6.0 mm Hg |
p-value: 0.3936Non-parametric ANCOVA
Secondary
Change in Post-ductal Peripheral Oxygen Saturation (SpO2) From Baseline to 72 Hours Following Study Drug Administration
Simultaneous pre- (right hand) and post-ductal (lower extremities) SpO2 were measured using pulse oximetry device at baseline and 72 h after the first study drug administration
Time frame: 72 hours
Population: Randomized and treated patients with available data
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Bosentan | Change in Post-ductal Peripheral Oxygen Saturation (SpO2) From Baseline to 72 Hours Following Study Drug Administration | Baseline | 96.5 percentage saturation |
| Bosentan | Change in Post-ductal Peripheral Oxygen Saturation (SpO2) From Baseline to 72 Hours Following Study Drug Administration | 72 hours | 95.5 percentage saturation |
| Bosentan | Change in Post-ductal Peripheral Oxygen Saturation (SpO2) From Baseline to 72 Hours Following Study Drug Administration | Change from baseline | 0.0 percentage saturation |
| Placebo | Change in Post-ductal Peripheral Oxygen Saturation (SpO2) From Baseline to 72 Hours Following Study Drug Administration | Baseline | 96.0 percentage saturation |
| Placebo | Change in Post-ductal Peripheral Oxygen Saturation (SpO2) From Baseline to 72 Hours Following Study Drug Administration | 72 hours | 97.5 percentage saturation |
| Placebo | Change in Post-ductal Peripheral Oxygen Saturation (SpO2) From Baseline to 72 Hours Following Study Drug Administration | Change from baseline | 2.0 percentage saturation |
p-value: 0.1155Non-parametric ANCOVA
Secondary
Change in Pre-ductal Peripheral Oxygen Saturation (SpO2) From Baseline to 72 Hours Following Study Drug Administration
Simultaneous pre- (right hand) and post-ductal (lower extremities) SpO2 were measured using pulse oximetry device at baseline and 72 h after the first study drug administration
Time frame: 72 hours
Population: Randomized and treated patients with available data
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Bosentan | Change in Pre-ductal Peripheral Oxygen Saturation (SpO2) From Baseline to 72 Hours Following Study Drug Administration | Baseline | 95.00 percentage saturation |
| Bosentan | Change in Pre-ductal Peripheral Oxygen Saturation (SpO2) From Baseline to 72 Hours Following Study Drug Administration | 72 hours | 96.00 percentage saturation |
| Bosentan | Change in Pre-ductal Peripheral Oxygen Saturation (SpO2) From Baseline to 72 Hours Following Study Drug Administration | Change from baseline | 0.50 percentage saturation |
| Placebo | Change in Pre-ductal Peripheral Oxygen Saturation (SpO2) From Baseline to 72 Hours Following Study Drug Administration | Baseline | 97.00 percentage saturation |
| Placebo | Change in Pre-ductal Peripheral Oxygen Saturation (SpO2) From Baseline to 72 Hours Following Study Drug Administration | 72 hours | 96.00 percentage saturation |
| Placebo | Change in Pre-ductal Peripheral Oxygen Saturation (SpO2) From Baseline to 72 Hours Following Study Drug Administration | Change from baseline | -1.00 percentage saturation |
p-value: 0.1756Non-parametric ANCOVA
Secondary
Cmax for Bosentan and Its Metabolites, Ro 47-8634, Ro 48-5033, and Ro 64-1056 on Day 5
Concentrations were measured directly in dried blood spot samples scheduled to be taken immediately prior to study drug administration and at 0.5, 1, 2, 3, 7.5, and 12 hours post-dose on Day 5. Cmax obtained directly from the measured concentrations . Cmax was corrected to a dose of 2 mg/kg bosentan (Cmaxc). The target dose was 2 mg/kg. However, as the smallest dose unit was 8 mg (quarter of a tablet), it was not possible to achieve the exact target dose in all patients. Therefore, Cmax was divided by the actual dose (in mg/kg) and multiplied by 2 mg/kg.
Time frame: 12 hours
Population: PK analysis set. This analysis set comprised all patients included in the all-treated set who were able to provide at least 5 of the 7 blood samples requested for at least one evaluable profile of PK assessment and who did not violate the protocol in a way that might affect the evaluation of the PK endpoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Bosentan | Cmax for Bosentan and Its Metabolites, Ro 47-8634, Ro 48-5033, and Ro 64-1056 on Day 5 | Bosentan | 880.0 ng/mL |
| Bosentan | Cmax for Bosentan and Its Metabolites, Ro 47-8634, Ro 48-5033, and Ro 64-1056 on Day 5 | Ro 47-8634 | 24.9 ng/mL |
| Bosentan | Cmax for Bosentan and Its Metabolites, Ro 47-8634, Ro 48-5033, and Ro 64-1056 on Day 5 | Ro 48-5033 | 292.3 ng/mL |
| Bosentan | Cmax for Bosentan and Its Metabolites, Ro 47-8634, Ro 48-5033, and Ro 64-1056 on Day 5 | Ro 64-1056 | 136.0 ng/mL |
Secondary
Maximum Whole Blood Concentration (Cmax) for Bosentan and Its Metabolites, Ro 47-8634, Ro 48-5033, and Ro 64-1056 on Day 1
Concentrations were measured directly in dried blood spot samples scheduled to be taken immediately prior to first study drug administration and at 0.5, 1, 2, 3, 7.5 and 12 hours post-dose on Day 1. Cmax was obtained directly from the measured concentrations. Cmax was corrected to a dose of 2 mg/kg bosentan (Cmaxc). The target dose was 2 mg/kg. However, as the smallest dose unit was 8 mg (quarter of a tablet), it was not possible to achieve the exact target dose in all patients. Therefore, Cmax was divided by the actual dose (in mg/kg) and multiplied by 2 mg/kg.
Time frame: up to 12 hours
Population: Pharmacokinetic (PK) analysis set. This analysis set comprised all patients included in the all-treated set who were able to provide at least 5 of the 7 blood samples requested for at least one evaluable profile of PK assessment and who did not violate the protocol in a way that might affect the evaluation of the PK endpoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Bosentan | Maximum Whole Blood Concentration (Cmax) for Bosentan and Its Metabolites, Ro 47-8634, Ro 48-5033, and Ro 64-1056 on Day 1 | Bosentan | 30.1 ng/mL |
| Bosentan | Maximum Whole Blood Concentration (Cmax) for Bosentan and Its Metabolites, Ro 47-8634, Ro 48-5033, and Ro 64-1056 on Day 1 | Ro 47-8634 | 0.1 ng/mL |
| Bosentan | Maximum Whole Blood Concentration (Cmax) for Bosentan and Its Metabolites, Ro 47-8634, Ro 48-5033, and Ro 64-1056 on Day 1 | Ro 48-5033 | 0.6 ng/mL |
| Bosentan | Maximum Whole Blood Concentration (Cmax) for Bosentan and Its Metabolites, Ro 47-8634, Ro 48-5033, and Ro 64-1056 on Day 1 | Ro 64-1056 | 0.9 ng/mL |
Secondary
Percentage of Patients Requiring Re-initiation of iNO Therapy
Re-initiation of iNO therapy following weaning from iNO therapy
Time frame: From baseline to up to 21 days
Population: Randomized and treated patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bosentan | Percentage of Patients Requiring Re-initiation of iNO Therapy | 0 percentage of participants |
| Placebo | Percentage of Patients Requiring Re-initiation of iNO Therapy | 0 percentage of participants |
Secondary
Percentage of Patients With Pulmonary Hypertension (PH) at End of Treatment
The presence of PH was assessed by echocardiography. PH was reported as 'present' if at least one of the following criteria was met: * Shunt through ductus arteriosus was either 'predominant right to left' or 'bidirectional' * Shunt through foramen ovale was either 'predominant right to left' or 'bidirectional' * Marked right ventricular dilation was ticked 'present' * Paradoxical shift of intraventricular septum was ticked 'present' * Right ventricular systolic pressure (mmHg) was \> 2/3 of the reported systemic blood pressure
Time frame: From baseline to up to 14 days
Population: Randomized and treated patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bosentan | Percentage of Patients With Pulmonary Hypertension (PH) at End of Treatment | 41.7 percentage of participants |
| Placebo | Percentage of Patients With Pulmonary Hypertension (PH) at End of Treatment | 37.5 percentage of participants |
p-value: 1Fisher Exact
Secondary
Time to Maximum Whole Blood Concentration (Tmax) for Bosentan on Day 1
Concentrations were measured directly in dried blood spot samples scheduled to be taken immediately prior to first study drug administration and at 0.5, 1, 2, 3, 7.5 and 12 hours post-dose on Day 1. Tmax was obtained directly from the measured concentrations.
Time frame: up to 12 hours
Population: PK analysis set. This analysis set comprised all patients included in the all-treated set who were able to provide at least 5 of the 7 blood samples requested for at least one evaluable profile of PK assessment and who did not violate the protocol in a way that might affect the evaluation of the PK endpoints.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bosentan | Time to Maximum Whole Blood Concentration (Tmax) for Bosentan on Day 1 | 12.0 hours |
Secondary
Tmax for Bosentan on Day 5
Concentrations were measured directly in dried blood spot samples scheduled to be taken immediately prior to study drug administration and at 0.5, 1, 2, 3, 7.5, and 12 hours post-dose on Day 5. Tmax was obtained directly from the measured concentrations.
Time frame: 12 hours
Population: PK analysis set. This analysis set comprised all patients included in the all-treated set who were able to provide at least 5 of the 7 blood samples requested for at least one evaluable profile of PK assessment and who did not violate the protocol in a way that might affect the evaluation of the PK endpoints.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bosentan | Tmax for Bosentan on Day 5 | 7.5 hours |
Secondary
Tmax for Ro 47-8634 on Day 1
Concentrations were measured directly in dried blood spot samples scheduled to be taken immediately prior to first study drug administration and at 0.5, 1, 2, 3, 7.5 and 12 hours post-dose on Day 1. Tmax was obtained directly from the measured concentrations.
Time frame: up to 12 hours
Population: PK analysis set. This analysis set comprised all patients included in the all-treated set who were able to provide at least 5 of the 7 blood samples requested for at least one evaluable profile of PK assessment and who did not violate the protocol in a way that might affect the evaluation of the PK endpoints.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bosentan | Tmax for Ro 47-8634 on Day 1 | 12.0 hours |
Secondary
Tmax for Ro 47-8634 on Day 5
Concentrations were measured directly in dried blood spot samples scheduled to be taken immediately prior to study drug administration and at 0.5, 1, 2, 3, 7.5, and 12 hours post-dose on Day 5. Tmax was obtained directly from the measured concentrations.
Time frame: 12 hours
Population: PK analysis set. This analysis set comprised all patients included in the all-treated set who were able to provide at least 5 of the 7 blood samples requested for at least one evaluable profile of PK assessment and who did not violate the protocol in a way that might affect the evaluation of the PK endpoints.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bosentan | Tmax for Ro 47-8634 on Day 5 | 6.5 hours |
Secondary
Tmax for Ro 48-5033 on Day 1
Concentrations were measured directly in dried blood spot samples scheduled to be taken immediately prior to first study drug administration and at 0.5, 1, 2, 3, 7.5 and 12 hours post-dose on Day 1. Tmax was obtained directly from the measured concentrations.
Time frame: up to 12 hours
Population: PK analysis set. This analysis set comprised all patients included in the all-treated set who were able to provide at least 5 of the 7 blood samples requested for at least one evaluable profile of PK assessment and who did not violate the protocol in a way that might affect the evaluation of the PK endpoints.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bosentan | Tmax for Ro 48-5033 on Day 1 | 12.0 hours |
Secondary
Tmax for Ro 48-5033 on Day 5
Concentrations were measured directly in dried blood spot samples scheduled to be taken immediately prior to study drug administration and at 0.5, 1, 2, 3, 7.5, and 12 hours post-dose on Day 5. Tmax was obtained directly from the measured concentrations.
Time frame: 12 hours
Population: PK analysis set. This analysis set comprised all patients included in the all-treated set who were able to provide at least 5 of the 7 blood samples requested for at least one evaluable profile of PK assessment and who did not violate the protocol in a way that might affect the evaluation of the PK endpoints.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bosentan | Tmax for Ro 48-5033 on Day 5 | 7.5 hours |
Secondary
Tmax for Ro 64-1056 on Day 1
Concentrations were measured directly in dried blood spot samples scheduled to be taken immediately prior to first study drug administration and at 0.5, 1, 2, 3, 7.5 and 12 hours post-dose on Day 1. Tmax was obtained directly from the measured concentrations.
Time frame: up to 12 hours
Population: PK analysis set. This analysis set comprised all patients included in the all-treated set who were able to provide at least 5 of the 7 blood samples requested for at least one evaluable profile of PK assessment and who did not violate the protocol in a way that might affect the evaluation of the PK endpoints.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bosentan | Tmax for Ro 64-1056 on Day 1 | 12 hours |
Secondary
Tmax for Ro 64-1056 on Day 5
Concentrations were measured directly in dried blood spot samples scheduled to be taken immediately prior to study drug administration and at 0.5, 1, 2, 3, 7.5, and 12 hours post-dose on Day 5. Tmax was obtained directly from the measured concentrations.
Time frame: 12 hours
Population: PK analysis set. This analysis set comprised all patients included in the all-treated set who were able to provide at least 5 of the 7 blood samples requested for at least one evaluable profile of PK assessment and who did not violate the protocol in a way that might affect the evaluation of the PK endpoints.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bosentan | Tmax for Ro 64-1056 on Day 5 | 12.0 hours |