Trial Outcomes & Findings for Persistent Pulmonary Hypertension of the Newborn (NCT NCT01389856)
NCT ID: NCT01389856
Last Updated: 2025-02-04
Results Overview
Treatment failure was defined as the need for extra corporeal membrane oxygenation or initiation of alternative pulmonary vasodilator treatment
TERMINATED
PHASE3
23 participants
From baseline to up to 21 days
2025-02-04
Participant Flow
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).
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).
Participant milestones
| Measure |
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.
|
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.
|
|---|---|---|
|
Overall Study
STARTED
|
13
|
8
|
|
Overall Study
COMPLETED
|
13
|
8
|
|
Overall Study
NOT COMPLETED
|
0
|
0
|
Reasons for withdrawal
Withdrawal data not reported
Baseline Characteristics
Persistent Pulmonary Hypertension of the Newborn
Baseline characteristics by cohort
| Measure |
Bosentan
n=13 Participants
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.
|
Placebo
n=8 Participants
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.
|
Total
n=21 Participants
Total of all reporting groups
|
|---|---|---|---|
|
Age, Continuous
|
1.4 days
n=5 Participants
|
1.7 days
n=7 Participants
|
1.4 days
n=5 Participants
|
|
Sex: Female, Male
Female
|
9 Participants
n=5 Participants
|
6 Participants
n=7 Participants
|
15 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
4 Participants
n=5 Participants
|
2 Participants
n=7 Participants
|
6 Participants
n=5 Participants
|
|
Race/Ethnicity, Customized
Caucasian/white
|
11 participants
n=5 Participants
|
6 participants
n=7 Participants
|
17 participants
n=5 Participants
|
|
Race/Ethnicity, Customized
Asian
|
1 participants
n=5 Participants
|
0 participants
n=7 Participants
|
1 participants
n=5 Participants
|
|
Race/Ethnicity, Customized
Hispanic
|
1 participants
n=5 Participants
|
1 participants
n=7 Participants
|
2 participants
n=5 Participants
|
|
Race/Ethnicity, Customized
Other
|
0 participants
n=5 Participants
|
1 participants
n=7 Participants
|
1 participants
n=5 Participants
|
|
Region of Enrollment
Czech Republic
|
1 participants
n=5 Participants
|
1 participants
n=7 Participants
|
2 participants
n=5 Participants
|
|
Region of Enrollment
France
|
1 participants
n=5 Participants
|
0 participants
n=7 Participants
|
1 participants
n=5 Participants
|
|
Region of Enrollment
Korea, Republic of
|
1 participants
n=5 Participants
|
0 participants
n=7 Participants
|
1 participants
n=5 Participants
|
|
Region of Enrollment
Poland
|
5 participants
n=5 Participants
|
3 participants
n=7 Participants
|
8 participants
n=5 Participants
|
|
Region of Enrollment
United Kingdom
|
4 participants
n=5 Participants
|
2 participants
n=7 Participants
|
6 participants
n=5 Participants
|
|
Region of Enrollment
United States
|
1 participants
n=5 Participants
|
2 participants
n=7 Participants
|
3 participants
n=5 Participants
|
|
Gestational age
|
40.0 weeks
n=5 Participants
|
38.5 weeks
n=7 Participants
|
39.0 weeks
n=5 Participants
|
PRIMARY outcome
Timeframe: From baseline to up to 21 daysPopulation: Randomized and treated patients
Treatment failure was defined as the need for extra corporeal membrane oxygenation or initiation of alternative pulmonary vasodilator treatment
Outcome measures
| Measure |
Bosentan
n=13 Participants
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.
|
Placebo
n=8 Participants
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.
|
|---|---|---|
|
Percentage of Patients With Treatment Failure
|
7.7 percentage of participants
|
0 percentage of participants
|
PRIMARY outcome
Timeframe: From baseline to up to 21 daysPopulation: Randomized and treated patients
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
Outcome measures
| Measure |
Bosentan
n=13 Participants
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.
|
Placebo
n=8 Participants
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.
|
|---|---|---|
|
Time to Complete Weaning From iNO
|
3.7 days
Interval 1.17 to 6.95
|
2.9 days
Interval 1.26 to 4.23
|
PRIMARY outcome
Timeframe: From baseline to up to 21 daysPopulation: Randomized and treated patients
Calculated from the time from first study drug administration to complete weaning from mechanical ventilation
Outcome measures
| Measure |
Bosentan
n=13 Participants
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.
|
Placebo
n=8 Participants
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.
|
|---|---|---|
|
Time to Complete Weaning From Mechanical Ventilation
|
10.8 days
Interval 3.21 to 12.21
|
8.6 days
Interval 3.71 to 9.66
|
SECONDARY outcome
Timeframe: From baseline to up to 21 daysPopulation: Randomized and treated patients
Re-initiation of iNO therapy following weaning from iNO therapy
Outcome measures
| Measure |
Bosentan
n=13 Participants
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.
|
Placebo
n=8 Participants
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.
|
|---|---|---|
|
Percentage of Patients Requiring Re-initiation of iNO Therapy
|
0 percentage of participants
|
0 percentage of participants
|
SECONDARY outcome
Timeframe: From baseline to up to 14 daysPopulation: Randomized and treated patients
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
Outcome measures
| Measure |
Bosentan
n=13 Participants
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.
|
Placebo
n=8 Participants
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.
|
|---|---|---|
|
Percentage of Patients With Pulmonary Hypertension (PH) at End of Treatment
|
41.7 percentage of participants
|
37.5 percentage of participants
|
SECONDARY outcome
Timeframe: 3 hoursPopulation: Randomized and treated patients
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.
Outcome measures
| Measure |
Bosentan
n=13 Participants
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.
|
Placebo
n=8 Participants
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.
|
|---|---|---|
|
Change in Oxygenation Index (OI) From Baseline to 3 Hours Following Study Drug Administration
Baseline
|
18.3 oxygenation index
Interval 8.2 to 35.4
|
13.2 oxygenation index
Interval 7.9 to 39.4
|
|
Change in Oxygenation Index (OI) From Baseline to 3 Hours Following Study Drug Administration
3 hours
|
17.3 oxygenation index
Interval 6.9 to 33.3
|
13.0 oxygenation index
Interval 8.5 to 42.9
|
|
Change in Oxygenation Index (OI) From Baseline to 3 Hours Following Study Drug Administration
Change from baseline
|
-1.6 oxygenation index
Interval -5.1 to 3.3
|
1.1 oxygenation index
Interval -6.1 to 6.1
|
SECONDARY outcome
Timeframe: 5 hoursPopulation: Randomized and treated patients
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.
Outcome measures
| Measure |
Bosentan
n=13 Participants
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.
|
Placebo
n=8 Participants
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.
|
|---|---|---|
|
Change in Oxygenation Index (OI) From Baseline to 5 Hours Following Study Drug Administration
Baseline
|
18.3 oxygenation index
Interval 8.2 to 35.4
|
13.2 oxygenation index
Interval 7.9 to 39.4
|
|
Change in Oxygenation Index (OI) From Baseline to 5 Hours Following Study Drug Administration
5 hours
|
16.7 oxygenation index
Interval 7.9 to 36.7
|
13.3 oxygenation index
Interval 6.7 to 28.6
|
|
Change in Oxygenation Index (OI) From Baseline to 5 Hours Following Study Drug Administration
Change from baseline
|
-0.9 oxygenation index
Interval -4.7 to 4.5
|
-5.6 oxygenation index
Interval -7.5 to 15.7
|
SECONDARY outcome
Timeframe: 12 hoursPopulation: Randomized and treated patients
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.
Outcome measures
| Measure |
Bosentan
n=13 Participants
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.
|
Placebo
n=8 Participants
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.
|
|---|---|---|
|
Change in Oxygenation Index (OI) From Baseline to 12 Hours Following Study Drug Administration
Baseline
|
18.3 oxygenation index
Interval 8.2 to 35.4
|
13.2 oxygenation index
Interval 7.9 to 39.4
|
|
Change in Oxygenation Index (OI) From Baseline to 12 Hours Following Study Drug Administration
12 hours
|
14.3 oxygenation index
Interval 8.3 to 26.7
|
11.1 oxygenation index
Interval 4.9 to 19.6
|
|
Change in Oxygenation Index (OI) From Baseline to 12 Hours Following Study Drug Administration
Change from baseline
|
-0.8 oxygenation index
Interval -12.9 to 2.8
|
-3.9 oxygenation index
Interval -14.6 to 12.5
|
SECONDARY outcome
Timeframe: 24 hoursPopulation: Randomized and treated patients
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.
Outcome measures
| Measure |
Bosentan
n=13 Participants
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.
|
Placebo
n=8 Participants
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.
|
|---|---|---|
|
Change in Oxygenation Index (OI) From Baseline to 24 Hours Following Study Drug Administration
Baseline
|
18.3 oxygenation index
Interval 8.2 to 35.4
|
13.2 oxygenation index
Interval 7.9 to 39.4
|
|
Change in Oxygenation Index (OI) From Baseline to 24 Hours Following Study Drug Administration
24 hours
|
13.1 oxygenation index
Interval 6.5 to 32.9
|
11.8 oxygenation index
Interval 5.2 to 26.4
|
|
Change in Oxygenation Index (OI) From Baseline to 24 Hours Following Study Drug Administration
Change from baseline
|
-4.9 oxygenation index
Interval -17.0 to 1.1
|
-6.9 oxygenation index
Interval -9.9 to 19.4
|
SECONDARY outcome
Timeframe: 48 hoursPopulation: Randomized and treated patients with available data
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.
Outcome measures
| Measure |
Bosentan
n=12 Participants
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.
|
Placebo
n=8 Participants
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.
|
|---|---|---|
|
Change in Oxygenation Index (OI) From Baseline to 48 Hours Following Study Drug Administration
Baseline
|
19.4 oxygenation index
Interval 8.2 to 35.4
|
13.2 oxygenation index
Interval 7.9 to 39.4
|
|
Change in Oxygenation Index (OI) From Baseline to 48 Hours Following Study Drug Administration
48 hours
|
11.5 oxygenation index
Interval 4.7 to 21.0
|
3.8 oxygenation index
Interval 2.5 to 10.8
|
|
Change in Oxygenation Index (OI) From Baseline to 48 Hours Following Study Drug Administration
Change from baseline
|
-4.9 oxygenation index
Interval -15.5 to -2.1
|
-9.9 oxygenation index
Interval -18.0 to 3.4
|
SECONDARY outcome
Timeframe: 72 hoursPopulation: Randomized and treated patients with available data
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.
Outcome measures
| Measure |
Bosentan
n=12 Participants
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.
|
Placebo
n=8 Participants
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.
|
|---|---|---|
|
Change in Oxygenation Index (OI) From Baseline to 72 Hours Following Study Drug Administration
Baseline
|
19.4 oxygenation index
Interval 8.2 to 35.4
|
13.2 oxygenation index
Interval 7.9 to 39.4
|
|
Change in Oxygenation Index (OI) From Baseline to 72 Hours Following Study Drug Administration
72 hours
|
6.7 oxygenation index
Interval 4.2 to 17.0
|
3.9 oxygenation index
Interval 3.7 to 10.8
|
|
Change in Oxygenation Index (OI) From Baseline to 72 Hours Following Study Drug Administration
Change from baseline
|
-8.9 oxygenation index
Interval -23.1 to -1.8
|
-9.4 oxygenation index
Interval -17.7 to 2.2
|
SECONDARY outcome
Timeframe: 72 hoursPopulation: Randomized and treated patients with available data
pH was determined in arterial blood samples at baseline and 72 h after the first study drug administration
Outcome measures
| Measure |
Bosentan
n=12 Participants
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.
|
Placebo
n=8 Participants
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.
|
|---|---|---|
|
Change in Arterial Blood Gas (ABG) pH From Baseline to 72 Hours Following Study Drug Administration
Baseline
|
7.37 pH
Interval 7.3 to 7.43
|
7.31 pH
Interval 7.21 to 7.49
|
|
Change in Arterial Blood Gas (ABG) pH From Baseline to 72 Hours Following Study Drug Administration
72 hours
|
7.37 pH
Interval 7.36 to 7.43
|
7.36 pH
Interval 7.3 to 7.39
|
|
Change in Arterial Blood Gas (ABG) pH From Baseline to 72 Hours Following Study Drug Administration
Change from baseline
|
0.04 pH
Interval -0.06 to 0.07
|
0.02 pH
Interval -0.09 to 0.19
|
SECONDARY outcome
Timeframe: 72 hoursPopulation: Randomized and treated patients with available data
SaO2 was determined in arterial blood samples at baseline and 72 h after the first study drug administration
Outcome measures
| Measure |
Bosentan
n=11 Participants
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.
|
Placebo
n=8 Participants
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.
|
|---|---|---|
|
Change in Arterial Blood Oxygen Saturation (SaO2) From Baseline to 72 Hours Following Study Drug Administration
Baseline
|
95.0 percentage saturation
Interval 92.0 to 99.0
|
95.5 percentage saturation
Interval 89.0 to 99.0
|
|
Change in Arterial Blood Oxygen Saturation (SaO2) From Baseline to 72 Hours Following Study Drug Administration
72 hours
|
98.0 percentage saturation
Interval 95.0 to 100.0
|
97.0 percentage saturation
Interval 93.0 to 100.0
|
|
Change in Arterial Blood Oxygen Saturation (SaO2) From Baseline to 72 Hours Following Study Drug Administration
Change from baseline
|
1.0 percentage saturation
Interval 0.0 to 8.0
|
0.0 percentage saturation
Interval -4.0 to 21.0
|
SECONDARY outcome
Timeframe: 72 hoursPopulation: Randomized and treated patients with available data
PaO2 was determined in arterial blood samples at baseline and 72 h after the first study drug administration
Outcome measures
| Measure |
Bosentan
n=12 Participants
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.
|
Placebo
n=8 Participants
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.
|
|---|---|---|
|
Change in Partial Pressure of Oxygen (PaO2) in Arterial Blood From Baseline to 72 Hours Following Study Drug Administration
Baseline
|
61.0 mm Hg
Interval 53.0 to 132.0
|
69.5 mm Hg
Interval 46.0 to 111.0
|
|
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
Interval 61.0 to 104.0
|
81.5 mm Hg
Interval 56.0 to 187.0
|
|
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
Interval -13.0 to 32.0
|
6.0 mm Hg
Interval -12.0 to 115.0
|
SECONDARY outcome
Timeframe: 72 hoursPopulation: Randomized and treated patients with available data
PaCO2 was determined in arterial blood samples at baseline and 72 h after the first study drug administration
Outcome measures
| Measure |
Bosentan
n=12 Participants
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.
|
Placebo
n=8 Participants
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.
|
|---|---|---|
|
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
Interval 31.0 to 47.0
|
46.0 mm Hg
Interval 35.0 to 57.0
|
|
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
Interval 36.0 to 49.0
|
46.0 mm Hg
Interval 41.0 to 64.0
|
|
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
Interval -1.0 to 12.0
|
8.0 mm Hg
Interval -8.0 to 21.0
|
SECONDARY outcome
Timeframe: 72 hoursPopulation: Randomized and treated patients with available data
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
Outcome measures
| Measure |
Bosentan
n=12 Participants
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.
|
Placebo
n=7 Participants
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.
|
|---|---|---|
|
Change in Pre-ductal Peripheral Oxygen Saturation (SpO2) From Baseline to 72 Hours Following Study Drug Administration
72 hours
|
96.00 percentage saturation
Interval 93.0 to 100.0
|
96.00 percentage saturation
Interval 85.0 to 100.0
|
|
Change in Pre-ductal Peripheral Oxygen Saturation (SpO2) From Baseline to 72 Hours Following Study Drug Administration
Baseline
|
95.00 percentage saturation
Interval 91.0 to 99.0
|
97.00 percentage saturation
Interval 91.0 to 99.0
|
|
Change in Pre-ductal Peripheral Oxygen Saturation (SpO2) From Baseline to 72 Hours Following Study Drug Administration
Change from baseline
|
0.50 percentage saturation
Interval -2.0 to 2.0
|
-1.00 percentage saturation
Interval -10.0 to 2.0
|
SECONDARY outcome
Timeframe: 72 hoursPopulation: Randomized and treated patients with available data
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
Outcome measures
| Measure |
Bosentan
n=12 Participants
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.
|
Placebo
n=8 Participants
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.
|
|---|---|---|
|
Change in Post-ductal Peripheral Oxygen Saturation (SpO2) From Baseline to 72 Hours Following Study Drug Administration
Baseline
|
96.5 percentage saturation
Interval 92.0 to 99.0
|
96.0 percentage saturation
Interval 89.0 to 98.0
|
|
Change in Post-ductal Peripheral Oxygen Saturation (SpO2) From Baseline to 72 Hours Following Study Drug Administration
72 hours
|
95.5 percentage saturation
Interval 94.0 to 99.0
|
97.5 percentage saturation
Interval 95.0 to 100.0
|
|
Change in Post-ductal Peripheral Oxygen Saturation (SpO2) From Baseline to 72 Hours Following Study Drug Administration
Change from baseline
|
0.0 percentage saturation
Interval -2.0 to 3.0
|
2.0 percentage saturation
Interval 1.0 to 12.0
|
SECONDARY outcome
Timeframe: 72 hoursPopulation: Randomized and treated patients with available data
FiO2 was determined according to each study centers' standard procedure at baseline and 72 h after the first study drug administration
Outcome measures
| Measure |
Bosentan
n=12 Participants
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.
|
Placebo
n=8 Participants
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.
|
|---|---|---|
|
Change in Fraction of Inspired Oxygen (FiO2) From Baseline to 72 Hours Following Study Drug Administration
Baseline
|
90.0 percentage of oxygen
Interval 62.0 to 97.0
|
78.0 percentage of oxygen
Interval 60.0 to 100.0
|
|
Change in Fraction of Inspired Oxygen (FiO2) From Baseline to 72 Hours Following Study Drug Administration
72 hours
|
51.5 percentage of oxygen
Interval 28.0 to 60.0
|
40.0 percentage of oxygen
Interval 25.0 to 60.0
|
|
Change in Fraction of Inspired Oxygen (FiO2) From Baseline to 72 Hours Following Study Drug Administration
Change from baseline
|
-33.5 percentage of oxygen
Interval -50.0 to -15.0
|
-35.5 percentage of oxygen
Interval -60.0 to 0.0
|
SECONDARY outcome
Timeframe: up to 12 hoursPopulation: 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.
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.
Outcome measures
| Measure |
Bosentan
n=11 Participants
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.
|
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.
|
|---|---|---|
|
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
Interval 2.4 to 372.2
|
—
|
|
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
Interval 0.0 to 1.1
|
—
|
|
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
Interval 0.0 to 18.3
|
—
|
|
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
Interval 0.0 to 16.2
|
—
|
SECONDARY outcome
Timeframe: 12 hoursPopulation: 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.
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.
Outcome measures
| Measure |
Bosentan
n=7 Participants
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.
|
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.
|
|---|---|---|
|
Cmax for Bosentan and Its Metabolites, Ro 47-8634, Ro 48-5033, and Ro 64-1056 on Day 5
Bosentan
|
880.0 ng/mL
Interval 339.2 to 2282.7
|
—
|
|
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
Interval 9.0 to 69.1
|
—
|
|
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
Interval 115.8 to 738.1
|
—
|
|
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
Interval 77.4 to 238.8
|
—
|
SECONDARY outcome
Timeframe: up to 12 hoursPopulation: 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.
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.
Outcome measures
| Measure |
Bosentan
n=10 Participants
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.
|
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.
|
|---|---|---|
|
Time to Maximum Whole Blood Concentration (Tmax) for Bosentan on Day 1
|
12.0 hours
Interval 7.5 to 12.0
|
—
|
SECONDARY outcome
Timeframe: up to 12 hoursPopulation: 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.
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.
Outcome measures
| Measure |
Bosentan
n=5 Participants
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.
|
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.
|
|---|---|---|
|
Tmax for Ro 47-8634 on Day 1
|
12.0 hours
Interval 7.5 to 12.0
|
—
|
SECONDARY outcome
Timeframe: up to 12 hoursPopulation: 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.
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.
Outcome measures
| Measure |
Bosentan
n=7 Participants
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.
|
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.
|
|---|---|---|
|
Tmax for Ro 48-5033 on Day 1
|
12.0 hours
Interval 12.0 to 12.0
|
—
|
SECONDARY outcome
Timeframe: up to 12 hoursPopulation: 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.
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.
Outcome measures
| Measure |
Bosentan
n=8 Participants
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.
|
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.
|
|---|---|---|
|
Tmax for Ro 64-1056 on Day 1
|
12 hours
Interval 0.5 to 12.0
|
—
|
SECONDARY outcome
Timeframe: 12 hoursPopulation: 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.
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.
Outcome measures
| Measure |
Bosentan
n=7 Participants
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.
|
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.
|
|---|---|---|
|
Tmax for Bosentan on Day 5
|
7.5 hours
Interval 0.8 to 12.0
|
—
|
SECONDARY outcome
Timeframe: 12 hoursPopulation: 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.
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.
Outcome measures
| Measure |
Bosentan
n=7 Participants
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.
|
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.
|
|---|---|---|
|
Tmax for Ro 47-8634 on Day 5
|
6.5 hours
Interval 0.8 to 12.0
|
—
|
SECONDARY outcome
Timeframe: 12 hoursPopulation: 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.
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.
Outcome measures
| Measure |
Bosentan
n=7 Participants
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.
|
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.
|
|---|---|---|
|
Tmax for Ro 48-5033 on Day 5
|
7.5 hours
Interval 0.8 to 12.0
|
—
|
SECONDARY outcome
Timeframe: 12 hoursPopulation: 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.
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.
Outcome measures
| Measure |
Bosentan
n=7 Participants
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.
|
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.
|
|---|---|---|
|
Tmax for Ro 64-1056 on Day 5
|
12.0 hours
Interval 7.5 to 12.0
|
—
|
SECONDARY outcome
Timeframe: 12 hoursPopulation: 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.
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.
Outcome measures
| Measure |
Bosentan
n=11 Participants
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.
|
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.
|
|---|---|---|
|
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
Interval 9.6 to 2795.4
|
—
|
|
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
Interval 0.0 to 3.7
|
—
|
|
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
Interval 0.0 to 69.9
|
—
|
|
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
Interval 0.1 to 64.1
|
—
|
SECONDARY outcome
Timeframe: 5 daysPopulation: 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.
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.
Outcome measures
| Measure |
Bosentan
n=7 Participants
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.
|
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.
|
|---|---|---|
|
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
Interval 2429.6 to 15645.3
|
—
|
|
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
Interval 1155.2 to 6979.2
|
—
|
|
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
Interval 729.5 to 2395.0
|
—
|
|
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
Interval 75.3 to 626.8
|
—
|
SECONDARY outcome
Timeframe: 24 hoursPopulation: 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.
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.
Outcome measures
| Measure |
Bosentan
n=11 Participants
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.
|
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.
|
|---|---|---|
|
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
Interval 15.0 to 5504.7
|
—
|
|
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
Interval 0.0 to 6.1
|
—
|
|
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
Interval 0.0 to 125.8
|
—
|
|
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
Interval 0.1 to 120.8
|
—
|
SECONDARY outcome
Timeframe: 24 hoursPopulation: 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.
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.
Outcome measures
| Measure |
Bosentan
n=7 Participants
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.
|
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.
|
|---|---|---|
|
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
Interval 4507.0 to 29497.5
|
—
|
|
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
Interval 139.8 to 1180.9
|
—
|
|
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
Interval 2184.4 to 12908.9
|
—
|
|
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
Interval 1386.1 to 4408.0
|
—
|
SECONDARY outcome
Timeframe: 5 daysPopulation: 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.
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.
Outcome measures
| Measure |
Bosentan
n=7 Participants
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.
|
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.
|
|---|---|---|
|
Accumulation Index (AI) for Bosentan
|
61.6 accumulation index
Interval 0.5 to 7813.9
|
—
|
Adverse Events
Bosentan
Placebo
Serious adverse events
| Measure |
Bosentan
n=13 participants at risk
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.
|
Placebo
n=8 participants at risk
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.
|
|---|---|---|
|
Hepatobiliary disorders
HEPATITIS
|
7.7%
1/13 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
0.00%
0/8 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
|
Metabolism and nutrition disorders
METABOLIC ACIDOSIS
|
7.7%
1/13 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
0.00%
0/8 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
|
Respiratory, thoracic and mediastinal disorders
HYPERCAPNIA
|
7.7%
1/13 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
0.00%
0/8 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
|
Respiratory, thoracic and mediastinal disorders
PNEUMOTHORAX
|
0.00%
0/13 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
25.0%
2/8 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
|
Vascular disorders
CIRCULATORY COLLAPSE
|
7.7%
1/13 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
0.00%
0/8 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
|
Infections and infestations
SEPSIS
|
0.00%
0/13 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
12.5%
1/8 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
Other adverse events
| Measure |
Bosentan
n=13 participants at risk
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.
|
Placebo
n=8 participants at risk
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.
|
|---|---|---|
|
Blood and lymphatic system disorders
ANAEMIA
|
23.1%
3/13 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
12.5%
1/8 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
|
General disorders
GENERALISED OEDEMA
|
23.1%
3/13 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
0.00%
0/8 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
|
Blood and lymphatic system disorders
COAGULOPATHY
|
7.7%
1/13 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
12.5%
1/8 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
|
Gastrointestinal disorders
VOMITING
|
15.4%
2/13 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
0.00%
0/8 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
|
Investigations
BILIRUBIN CONJUGATED INCREASED
|
7.7%
1/13 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
0.00%
0/8 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
|
Investigations
BODY TEMPERATURE INCREASED
|
7.7%
1/13 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
0.00%
0/8 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
|
Investigations
C-REACTIVE PROTEIN INCREASED
|
7.7%
1/13 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
0.00%
0/8 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
|
Respiratory, thoracic and mediastinal disorders
DYSPHONIA
|
7.7%
1/13 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
0.00%
0/8 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
|
Injury, poisoning and procedural complications
ENDOTRACHEAL INTUBATION COMPLICATION
|
7.7%
1/13 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
0.00%
0/8 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
|
Gastrointestinal disorders
GASTRIC HAEMORRHAGE
|
7.7%
1/13 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
0.00%
0/8 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
|
Metabolism and nutrition disorders
HYPOGLYCAEMIA
|
0.00%
0/13 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
12.5%
1/8 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
|
Metabolism and nutrition disorders
HYPOKALAEMIA
|
0.00%
0/13 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
12.5%
1/8 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
|
Metabolism and nutrition disorders
HYPOPHOSPHATAEMIA
|
0.00%
0/13 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
12.5%
1/8 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
|
Infections and infestations
INFECTIOUS DISEASE CARRIER
|
7.7%
1/13 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
0.00%
0/8 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
|
Metabolism and nutrition disorders
METABOLIC ACIDOSIS
|
0.00%
0/13 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
12.5%
1/8 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
|
Blood and lymphatic system disorders
METHAEMOGLOBINAEMIA
|
7.7%
1/13 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
0.00%
0/8 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
|
Cardiac disorders
MITRAL VALVE INCOMPETENCE
|
7.7%
1/13 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
0.00%
0/8 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
|
Respiratory, thoracic and mediastinal disorders
PNEUMOMEDIASTINUM
|
7.7%
1/13 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
0.00%
0/8 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
|
Respiratory, thoracic and mediastinal disorders
PNEUMOTHORAX
|
7.7%
1/13 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
0.00%
0/8 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
|
Injury, poisoning and procedural complications
PROCEDURAL COMPLICATION
|
7.7%
1/13 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
0.00%
0/8 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
|
Blood and lymphatic system disorders
THROMBOCYTOPENIA
|
7.7%
1/13 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
0.00%
0/8 • Up to 21 Days, plus up to 60 days after end of treatment for serious adverse events
|
Additional Information
Pegah Nowbakht/Senior Clinical Trial Scientist
Actelion Pharmaceuticals Ltd
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place
Restriction type: OTHER