Trial Outcomes & Findings for Effects of the Combination of Bosentan and Sildenafil Versus Sildenafil Monotherapy on Pulmonary Arterial Hypertension (PAH) (NCT NCT00303459)

Last Updated: 2025-02-04

Results Overview

Kaplan-Meier estimate of percentage of participants without a morbidity/mortality event. A morbidity/mortality event is defined as the occurrence of a) death, b) hospitalization for worsening or complication of PAH or intravenous prostanoid initiation, c) atrial septostomy, d) lung transplantation, or e) worsening PAH, defined as "moderately" or "markedly" worsened PAH symptoms using a patient global self-assessment (PGSA) scale AND initiation of inhaled or subcutaneous prostanoids or the disease progression package (open-label bosentan). If a patient replied "no change" or "mildly worse" on the PGSA, a decrease in 6MWT of 20% versus last visit or 30% versus baseline is also required to confirm the event.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

334 participants

Primary outcome timeframe

From baseline to end of study, approximately 86 months

Results posted on

2025-02-04

Participant Flow

First subject, first visit was17 May 2006 and last subject, last visit was 05 Dec 2013.

There was a screening period of up to 14 days to assess eligibility. A total of 377 patients were screened.

Participant milestones

Participant milestones
Measure	Bosentan Bosentan bosentan: bosentan/62.5 mg tablet, twice a day (b.i.d.) for 4 weeks then bosentan/125 mg tablet/b.i.d.	Placebo Placebo placebo: Matching bosentan placebo/b.i.d.
Overall Study STARTED	159	175
Overall Study COMPLETED	76	86
Overall Study NOT COMPLETED	83	89

Reasons for withdrawal

Reasons for withdrawal
Measure	Bosentan Bosentan bosentan: bosentan/62.5 mg tablet, twice a day (b.i.d.) for 4 weeks then bosentan/125 mg tablet/b.i.d.	Placebo Placebo placebo: Matching bosentan placebo/b.i.d.
Overall Study Death	33	44
Overall Study Withdrawal of consent	32	26
Overall Study Lost to Follow-up	5	4
Overall Study Administrative reason	7	7
Overall Study Decision by the investigator	5	7
Overall Study Lung transplantation	1	1

Baseline Characteristics

Effects of the Combination of Bosentan and Sildenafil Versus Sildenafil Monotherapy on Pulmonary Arterial Hypertension (PAH)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Bosentan n=159 Participants Bosentan bosentan: bosentan/62.5 mg tablet/b.i.d. for 4 weeks then bosentan/125 mg tablet/b.i.d.	Placebo n=175 Participants Placebo placebo: Matching bosentan placebo/b.i.d.	Total n=334 Participants Total of all reporting groups
Age, Continuous	52.9 years STANDARD_DEVIATION 15.44 • n=5 Participants	54.7 years STANDARD_DEVIATION 15.73 • n=7 Participants	53.9 years STANDARD_DEVIATION 15.60 • n=5 Participants
Sex: Female, Male Female	125 Participants n=5 Participants	128 Participants n=7 Participants	253 Participants n=5 Participants
Sex: Female, Male Male	34 Participants n=5 Participants	47 Participants n=7 Participants	81 Participants n=5 Participants
Race/Ethnicity, Customized Caucasian/White	147 participants n=5 Participants	149 participants n=7 Participants	296 participants n=5 Participants
Race/Ethnicity, Customized Black	7 participants n=5 Participants	12 participants n=7 Participants	19 participants n=5 Participants
Race/Ethnicity, Customized Hispanic	5 participants n=5 Participants	6 participants n=7 Participants	11 participants n=5 Participants
Race/Ethnicity, Customized Other	0 participants n=5 Participants	8 participants n=7 Participants	8 participants n=5 Participants
Region of Enrollment Brazil	36 participants n=5 Participants	35 participants n=7 Participants	71 participants n=5 Participants
Region of Enrollment Czech Republic	12 participants n=5 Participants	15 participants n=7 Participants	27 participants n=5 Participants
Region of Enrollment Denmark	3 participants n=5 Participants	4 participants n=7 Participants	7 participants n=5 Participants
Region of Enrollment Germany	19 participants n=5 Participants	22 participants n=7 Participants	41 participants n=5 Participants
Region of Enrollment Greece	4 participants n=5 Participants	5 participants n=7 Participants	9 participants n=5 Participants
Region of Enrollment Portugal	3 participants n=5 Participants	0 participants n=7 Participants	3 participants n=5 Participants
Region of Enrollment Saudi Arabia	0 participants n=5 Participants	1 participants n=7 Participants	1 participants n=5 Participants
Region of Enrollment Slovakia	4 participants n=5 Participants	3 participants n=7 Participants	7 participants n=5 Participants
Region of Enrollment Spain	1 participants n=5 Participants	1 participants n=7 Participants	2 participants n=5 Participants
Region of Enrollment Sweden	4 participants n=5 Participants	5 participants n=7 Participants	9 participants n=5 Participants
Region of Enrollment United Kingdom	0 participants n=5 Participants	1 participants n=7 Participants	1 participants n=5 Participants
Region of Enrollment United States	73 participants n=5 Participants	83 participants n=7 Participants	156 participants n=5 Participants

PRIMARY outcome

Timeframe: From baseline to end of study, approximately 86 months

Population: All randomized set

Outcome measures

SECONDARY outcome

Timeframe: Baseline to end of study, approximately 86 months

Population: All randomized set

Kaplan-Meier estimate of percentage of participants without an event of death, hospitalization (for worsening or complication of PAH or initiation of intravenous prostanoids), atrial septostomy or lung transplantation. Time to first confirmed death, hospitalization (for worsening or complication of PAH or initiation of intravenous prostanoids), atrial septostomy or lung transplantation from baseline to end of study was confirmed by an independent Clinical Endpoint Committee.

Outcome measures

SECONDARY outcome

Timeframe: From baseline to week 16

Population: All randomized set

The 6MWT is a non-encouraged test, which measures the distance covered over a 6 minute walk; the patient is instructed to walk as far as possible in a 30 m long flat corridor, back and forth around two cones, with the permission to slow down, rest, or stop if needed. Areas were to be well ventilated with air temperature controlled between 20 °C and 23 °C (68 °F to 76 °F). The test was to be administered at the same time of day and by the same tester throughout the study. The tester measured the distance walked by non-encouraged patients during the timed 6 minute period.

Outcome measures

Outcome measures
Measure	Bosentan n=159 Participants Bosentan bosentan: bosentan/62.5 mg tablet/b.i.d. for 4 weeks then bosentan/125 mg tablet/b.i.d.	Placebo n=175 Participants Placebo placebo: Matching bosentan placebo/b.i.d.
Change From Baseline to Week 16 in 6 Minute Walk Test (6MWT) Baseline	363 m Standard Deviation 78.5	358 m Standard Deviation 73.1
Change From Baseline to Week 16 in 6 Minute Walk Test (6MWT) Week 16	370 m Standard Deviation 98.3	343 m Standard Deviation 107.3
Change From Baseline to Week 16 in 6 Minute Walk Test (6MWT) Change from baseline	7.2 m Standard Deviation 66.01	-14.6 m Standard Deviation 80.42

SECONDARY outcome

Timeframe: From baseline to Week 16

Population: All randomized set

Class I: no limitation of usual physical activity (PA) which does not increase dyspnea, fatigue, chest pain, or presyncope. Class II: mild limitation of PA. No discomfort at rest. Normal PA increases dyspnea, fatigue, chest pain, or presyncope. Class III: marked limitation of PA. No discomfort at rest. Less than ordinary activity increases dyspnea, fatigue, chest pain, or presyncope. Class IV: unable to perform any PA and who may have signs of right ventricular failure. Dyspnea and/or fatigue may be present at rest and symptoms are increased by almost any PA.

Outcome measures

Outcome measures
Measure	Bosentan n=159 Participants Bosentan bosentan: bosentan/62.5 mg tablet/b.i.d. for 4 weeks then bosentan/125 mg tablet/b.i.d.	Placebo n=175 Participants Placebo placebo: Matching bosentan placebo/b.i.d.
Number of Participants With Improved, No Change, or Worsened World Health Organisation Functional Class From Baseline to Week 16 Improved	25 participants	28 participants
Number of Participants With Improved, No Change, or Worsened World Health Organisation Functional Class From Baseline to Week 16 No change	121 participants	130 participants
Number of Participants With Improved, No Change, or Worsened World Health Organisation Functional Class From Baseline to Week 16 Worsened	13 participants	17 participants

SECONDARY outcome

Timeframe: Baseline to End of Study, approximately 86 months

Population: All randomized set

Kaplan-Meier estimate of percentage of participants without a mortality event.Time to death due to any cause.

Outcome measures

SECONDARY outcome

Timeframe: Baseline to Month 20

Population: All randomized patients with a baseline and at least one post-baseline value. Assessments considered are those where at least 60% of the patients have a post-baseline value

Blood sampling for the measurement of NT-pro-BNP was performed and the plasma concentrations of NT-pro-BNP were determined by a certified centralized laboratory.

Outcome measures

Outcome measures
Measure	Bosentan n=109 Participants Bosentan bosentan: bosentan/62.5 mg tablet/b.i.d. for 4 weeks then bosentan/125 mg tablet/b.i.d.	Placebo n=117 Participants Placebo placebo: Matching bosentan placebo/b.i.d.
Adjusted Percentage Ratio From Baseline in N-terminal Pro-B-type Natriuretic Peptide (NT-pro-BNP) Month 16 to Baseline	92.69 Adjusted percentage ratio from baseline Interval 75.75 to 113.42	129.92 Adjusted percentage ratio from baseline Interval 106.69 to 158.2
Adjusted Percentage Ratio From Baseline in N-terminal Pro-B-type Natriuretic Peptide (NT-pro-BNP) Month 20 to Baseline	98.36 Adjusted percentage ratio from baseline Interval 79.46 to 121.75	143.17 Adjusted percentage ratio from baseline Interval 115.86 to 176.91
Adjusted Percentage Ratio From Baseline in N-terminal Pro-B-type Natriuretic Peptide (NT-pro-BNP) Treatment effect over 20 months	92.54 Adjusted percentage ratio from baseline Interval 82.72 to 103.52	121.00 Adjusted percentage ratio from baseline Interval 108.42 to 135.05
Adjusted Percentage Ratio From Baseline in N-terminal Pro-B-type Natriuretic Peptide (NT-pro-BNP) Month 1 to Baseline	87.46 Adjusted percentage ratio from baseline Interval 77.12 to 99.18	110.02 Adjusted percentage ratio from baseline Interval 97.56 to 124.06
Adjusted Percentage Ratio From Baseline in N-terminal Pro-B-type Natriuretic Peptide (NT-pro-BNP) Month 4 to Baseline	92.65 Adjusted percentage ratio from baseline Interval 81.2 to 105.72	113.20 Adjusted percentage ratio from baseline Interval 99.61 to 128.65
Adjusted Percentage Ratio From Baseline in N-terminal Pro-B-type Natriuretic Peptide (NT-pro-BNP) Month 8 to Baseline	85.21 Adjusted percentage ratio from baseline Interval 72.58 to 100.05	122.87 Adjusted percentage ratio from baseline Interval 104.82 to 144.02
Adjusted Percentage Ratio From Baseline in N-terminal Pro-B-type Natriuretic Peptide (NT-pro-BNP) Month 12 to Baseline	84.48 Adjusted percentage ratio from baseline Interval 71.48 to 99.83	132.11 Adjusted percentage ratio from baseline Interval 111.95 to 155.89

SECONDARY outcome

Timeframe: Baseline to Week 16

Population: All randomized set

The Borg dyspnea index was evaluated immediately after the 6MWT to obtain a rating of dyspnea at the end of the exercise using a scale from 0 ('Nothing at all') to 10 ('Very, very severe - maximal').

Outcome measures

Outcome measures
Measure	Bosentan n=159 Participants Bosentan bosentan: bosentan/62.5 mg tablet/b.i.d. for 4 weeks then bosentan/125 mg tablet/b.i.d.	Placebo n=175 Participants Placebo placebo: Matching bosentan placebo/b.i.d.
Change From Baseline to Week 16 in Borg Dyspnea Index Week 16	3.4 units on a scale Standard Deviation 2.12	3.6 units on a scale Standard Deviation 2.24
Change From Baseline to Week 16 in Borg Dyspnea Index Change from baseline	-0.09 units on a scale Standard Deviation 1.693	-0.08 units on a scale Standard Deviation 2.035
Change From Baseline to Week 16 in Borg Dyspnea Index Baseline	3.5 units on a scale Standard Deviation 1.99	3.7 units on a scale Standard Deviation 2.18

SECONDARY outcome

Timeframe: From baseline to Week 16

Population: All randomized set

The EQ-5D questionnaire is a patient-reported outcome consisting of a 5 dimensional descriptive system and a visual analog scale (VAS). The descriptive system asks respondents to describe their health status. Health is defined in 5 dimensions: (1) mobility, (2) self care, (3) usual activities, (4) pain or discomfort, and (5) anxiety or depression. Each dimension is divided into 3 levels, indicating (a) no problem, (b) some or moderate problems, or (c) extreme problems. Respondents record their problem(s) in each of the 5 dimensions. Combinations of these levels define a total of 243 health states. A health state defined by the descriptive system of EQ-5D can be described by a 5-digit number with full health is indicated by 11111 and poorest health state by 33333. The EQ-5D calculated score was derived by re-assigning local scores for answers to each question and combining these local scores into a global score with ranges from 0 (worst possible outcome) to 1 (best possible outcome).

Outcome measures

Outcome measures
Measure	Bosentan n=159 Participants Bosentan bosentan: bosentan/62.5 mg tablet/b.i.d. for 4 weeks then bosentan/125 mg tablet/b.i.d.	Placebo n=175 Participants Placebo placebo: Matching bosentan placebo/b.i.d.
Change From Baseline to Week 16 in the EuroQol 5 Dimensions (EQ-5D) Questionnaire Calculated Score Baseline	0.678 units on a scale Standard Deviation 0.2172	0.681 units on a scale Standard Deviation 0.2138
Change From Baseline to Week 16 in the EuroQol 5 Dimensions (EQ-5D) Questionnaire Calculated Score Week 16	0.662 units on a scale Standard Deviation 0.2807	0.645 units on a scale Standard Deviation 0.3062
Change From Baseline to Week 16 in the EuroQol 5 Dimensions (EQ-5D) Questionnaire Calculated Score Change from Baseline	-0.0161 units on a scale Standard Deviation 0.25232	-0.0361 units on a scale Standard Deviation 0.26671

SECONDARY outcome

Timeframe: Baseline to Week 16

Population: All randomized set

The EQ-5D questionnaire is a patient-reported outcome consisting of a 5 dimensional descriptive system and a visual analog scale (VAS) together with brief demographic questions. EQ-5D VAS asks respondents to rate their perception of their overall health on a vertical visual analogue scale with 'best imaginable health state' set at 100 and 'worst imaginable health state' set at 0.

Outcome measures

Outcome measures
Measure	Bosentan n=159 Participants Bosentan bosentan: bosentan/62.5 mg tablet/b.i.d. for 4 weeks then bosentan/125 mg tablet/b.i.d.	Placebo n=175 Participants Placebo placebo: Matching bosentan placebo/b.i.d.
Change From Baseline to Week 16 in the EuroQol 5 Dimensions (EQ-5D) Visual Analogue Scale Score Baseline	67 units on a scale Standard Deviation 17.4	64 units on a scale Standard Deviation 17.5
Change From Baseline to Week 16 in the EuroQol 5 Dimensions (EQ-5D) Visual Analogue Scale Score Week 16	69 units on a scale Standard Deviation 19.9	66 units on a scale Standard Deviation 19.9
Change From Baseline to Week 16 in the EuroQol 5 Dimensions (EQ-5D) Visual Analogue Scale Score Change from Baseline	2.1 units on a scale Standard Deviation 18.83	2.0 units on a scale Standard Deviation 17.01

SECONDARY outcome

Timeframe: Week 16

Population: All randomized set, patients who completed the assessment

The PGSA is a questionnaire that allows the patient to compare his/her PAH status in response to the question "How do you feel about your PAH today compared with your last visit?" asked by the investigator. Patients use a seven-point scale to respond: markedly better, moderately better, mildly better, no change, markedly worse, moderately worse, or mildly worse.

Outcome measures

Outcome measures
Measure	Bosentan n=150 Participants Bosentan bosentan: bosentan/62.5 mg tablet/b.i.d. for 4 weeks then bosentan/125 mg tablet/b.i.d.	Placebo n=162 Participants Placebo placebo: Matching bosentan placebo/b.i.d.
Patient Global Self Assessment (PGSA) Status at Week 16 Moderately better	23 participants	30 participants
Patient Global Self Assessment (PGSA) Status at Week 16 Mildly better	32 participants	36 participants
Patient Global Self Assessment (PGSA) Status at Week 16 Mildly worse	16 participants	15 participants
Patient Global Self Assessment (PGSA) Status at Week 16 Moderately worse	3 participants	5 participants
Patient Global Self Assessment (PGSA) Status at Week 16 Markedly worse	2 participants	4 participants
Patient Global Self Assessment (PGSA) Status at Week 16 Markedly better	24 participants	13 participants
Patient Global Self Assessment (PGSA) Status at Week 16 No change	50 participants	59 participants

Adverse Events

Bosentan

Serious events: 73 serious events

Other events: 135 other events

Deaths: 0 deaths

Placebo

Serious events: 102 serious events

Other events: 147 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Jonathan Tolson

Actelion Pharmaceuticals Ltd

Phone: +41 61 565 56 04

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60

Measure	Bosentan n=159 Participants Bosentan bosentan: bosentan/62.5 mg tablet/b.i.d. for 4 weeks then bosentan/125 mg tablet/b.i.d.	Placebo n=175 Participants Placebo placebo: Matching bosentan placebo/b.i.d.
Time to First Confirmed Morbidity/Mortality Event up to the End of Study Kaplan-Meier estimate at Month 12	82.7 percentage of participants-Kaplan Meier	74.0 percentage of participants-Kaplan Meier
Time to First Confirmed Morbidity/Mortality Event up to the End of Study Kaplan-Meier estimate at Month 20	71.8 percentage of participants-Kaplan Meier	66.1 percentage of participants-Kaplan Meier
Time to First Confirmed Morbidity/Mortality Event up to the End of Study Kaplan-Meier estimate at Month 28	65.8 percentage of participants-Kaplan Meier	55.0 percentage of participants-Kaplan Meier
Time to First Confirmed Morbidity/Mortality Event up to the End of Study Kaplan-Meier estimate at Month 48	46.7 percentage of participants-Kaplan Meier	45.2 percentage of participants-Kaplan Meier
Time to First Confirmed Morbidity/Mortality Event up to the End of Study Kaplan-Meier estimate at Month 68	40.1 percentage of participants-Kaplan Meier	39.7 percentage of participants-Kaplan Meier
Time to First Confirmed Morbidity/Mortality Event up to the End of Study Kaplan-Meier estimate at Month 76	40.1 percentage of participants-Kaplan Meier	36.1 percentage of participants-Kaplan Meier
Time to First Confirmed Morbidity/Mortality Event up to the End of Study Kaplan-Meier estimate at Month 80	40.1 percentage of participants-Kaplan Meier	36.1 percentage of participants-Kaplan Meier
Time to First Confirmed Morbidity/Mortality Event up to the End of Study Kaplan-Meier estimate at Month 84	40.1 percentage of participants-Kaplan Meier	36.1 percentage of participants-Kaplan Meier
Time to First Confirmed Morbidity/Mortality Event up to the End of Study Kaplan-Meier estimate at Month 4	96.1 percentage of participants-Kaplan Meier	90.6 percentage of participants-Kaplan Meier
Time to First Confirmed Morbidity/Mortality Event up to the End of Study Kaplan-Meier estimate at Month 8	90.5 percentage of participants-Kaplan Meier	83.0 percentage of participants-Kaplan Meier
Time to First Confirmed Morbidity/Mortality Event up to the End of Study Kaplan-Meier estimate at Month 16	74.7 percentage of participants-Kaplan Meier	71.0 percentage of participants-Kaplan Meier
Time to First Confirmed Morbidity/Mortality Event up to the End of Study Kaplan-Meier estimate at Month 24	66.6 percentage of participants-Kaplan Meier	61.5 percentage of participants-Kaplan Meier
Time to First Confirmed Morbidity/Mortality Event up to the End of Study Kaplan-Meier estimate at Month 32	62.4 percentage of participants-Kaplan Meier	52.7 percentage of participants-Kaplan Meier
Time to First Confirmed Morbidity/Mortality Event up to the End of Study Kaplan-Meier estimate at Month 34	57.5 percentage of participants-Kaplan Meier	48.8 percentage of participants-Kaplan Meier
Time to First Confirmed Morbidity/Mortality Event up to the End of Study Kaplan-Meier estimate at Month 40	56.4 percentage of participants-Kaplan Meier	48.0 percentage of participants-Kaplan Meier
Time to First Confirmed Morbidity/Mortality Event up to the End of Study Kaplan-Meier estimate at Month 44	50.6 percentage of participants-Kaplan Meier	46.2 percentage of participants-Kaplan Meier
Time to First Confirmed Morbidity/Mortality Event up to the End of Study Kaplan-Meier estimate at Month 52	45.1 percentage of participants-Kaplan Meier	45.2 percentage of participants-Kaplan Meier
Time to First Confirmed Morbidity/Mortality Event up to the End of Study Kaplan-Meier estimate at Month 56	45.1 percentage of participants-Kaplan Meier	42.6 percentage of participants-Kaplan Meier
Time to First Confirmed Morbidity/Mortality Event up to the End of Study Kaplan-Meier estimate at Month 60	45.1 percentage of participants-Kaplan Meier	39.7 percentage of participants-Kaplan Meier
Time to First Confirmed Morbidity/Mortality Event up to the End of Study Kaplan-Meier estimate at Month 64	45.1 percentage of participants-Kaplan Meier	39.7 percentage of participants-Kaplan Meier
Time to First Confirmed Morbidity/Mortality Event up to the End of Study Kaplan-Meier estimate at Month 72	40.1 percentage of participants-Kaplan Meier	39.7 percentage of participants-Kaplan Meier
Time to First Confirmed Morbidity/Mortality Event up to the End of Study Kaplan-Meier estimate at End of Study	40.1 percentage of participants-Kaplan Meier	36.1 percentage of participants-Kaplan Meier

Measure	Bosentan n=159 Participants Bosentan bosentan: bosentan/62.5 mg tablet/b.i.d. for 4 weeks then bosentan/125 mg tablet/b.i.d.	Placebo n=175 Participants Placebo placebo: Matching bosentan placebo/b.i.d.
Time to First Confirmed Death, Hospitalization for Worsening or Complication of PAH or Initiation of Intravenous Prostanoids, Atrial Septostomy, or Lung Transplantation Kaplan-Meier estimate at Month 24	76.9 percentage of participants-Kaplan Meier	79.8 percentage of participants-Kaplan Meier
Time to First Confirmed Death, Hospitalization for Worsening or Complication of PAH or Initiation of Intravenous Prostanoids, Atrial Septostomy, or Lung Transplantation Kaplan-Meier estimate at Month 36	72.2 percentage of participants-Kaplan Meier	64.4 percentage of participants-Kaplan Meier
Time to First Confirmed Death, Hospitalization for Worsening or Complication of PAH or Initiation of Intravenous Prostanoids, Atrial Septostomy, or Lung Transplantation Kaplan-Meier estimate at Month 40	72.2 percentage of participants-Kaplan Meier	61.9 percentage of participants-Kaplan Meier
Time to First Confirmed Death, Hospitalization for Worsening or Complication of PAH or Initiation of Intravenous Prostanoids, Atrial Septostomy, or Lung Transplantation Kaplan-Meier estimate at Month 44	64.2 percentage of participants-Kaplan Meier	60.1 percentage of participants-Kaplan Meier
Time to First Confirmed Death, Hospitalization for Worsening or Complication of PAH or Initiation of Intravenous Prostanoids, Atrial Septostomy, or Lung Transplantation Kaplan-Meier estimate at Month 56	53.8 percentage of participants-Kaplan Meier	52.7 percentage of participants-Kaplan Meier
Time to First Confirmed Death, Hospitalization for Worsening or Complication of PAH or Initiation of Intravenous Prostanoids, Atrial Septostomy, or Lung Transplantation Kaplan-Meier estimate at Month 60	53.8 percentage of participants-Kaplan Meier	51.3 percentage of participants-Kaplan Meier
Time to First Confirmed Death, Hospitalization for Worsening or Complication of PAH or Initiation of Intravenous Prostanoids, Atrial Septostomy, or Lung Transplantation Kaplan-Meier estimate at Month 72	39.8 percentage of participants-Kaplan Meier	49.2 percentage of participants-Kaplan Meier
Time to First Confirmed Death, Hospitalization for Worsening or Complication of PAH or Initiation of Intravenous Prostanoids, Atrial Septostomy, or Lung Transplantation Kaplan-Meier estimate at End of Study	39.8 percentage of participants-Kaplan Meier	45.1 percentage of participants-Kaplan Meier
Time to First Confirmed Death, Hospitalization for Worsening or Complication of PAH or Initiation of Intravenous Prostanoids, Atrial Septostomy, or Lung Transplantation Kaplan-Meier estimate at Month 52	57.4 percentage of participants-Kaplan Meier	56.8 percentage of participants-Kaplan Meier
Time to First Confirmed Death, Hospitalization for Worsening or Complication of PAH or Initiation of Intravenous Prostanoids, Atrial Septostomy, or Lung Transplantation Kaplan-Meier estimate at Month 4	97.4 percentage of participants-Kaplan Meier	95.3 percentage of participants-Kaplan Meier
Time to First Confirmed Death, Hospitalization for Worsening or Complication of PAH or Initiation of Intravenous Prostanoids, Atrial Septostomy, or Lung Transplantation Kaplan-Meier estimate at Month 8	94.6 percentage of participants-Kaplan Meier	91.8 percentage of participants-Kaplan Meier
Time to First Confirmed Death, Hospitalization for Worsening or Complication of PAH or Initiation of Intravenous Prostanoids, Atrial Septostomy, or Lung Transplantation Kaplan-Meier estimate at Month 12	89.6 percentage of participants-Kaplan Meier	88.8 percentage of participants-Kaplan Meier
Time to First Confirmed Death, Hospitalization for Worsening or Complication of PAH or Initiation of Intravenous Prostanoids, Atrial Septostomy, or Lung Transplantation Kaplan-Meier estimate at Month 16	85.3 percentage of participants-Kaplan Meier	86.9 percentage of participants-Kaplan Meier
Time to First Confirmed Death, Hospitalization for Worsening or Complication of PAH or Initiation of Intravenous Prostanoids, Atrial Septostomy, or Lung Transplantation Kaplan-Meier estimate at Month 20	82.3 percentage of participants-Kaplan Meier	83.8 percentage of participants-Kaplan Meier
Time to First Confirmed Death, Hospitalization for Worsening or Complication of PAH or Initiation of Intravenous Prostanoids, Atrial Septostomy, or Lung Transplantation Kaplan-Meier estimate at Month 28	76.1 percentage of participants-Kaplan Meier	74.7 percentage of participants-Kaplan Meier
Time to First Confirmed Death, Hospitalization for Worsening or Complication of PAH or Initiation of Intravenous Prostanoids, Atrial Septostomy, or Lung Transplantation Kaplan-Meier estimate at Month 32	75.2 percentage of participants-Kaplan Meier	73.1 percentage of participants-Kaplan Meier
Time to First Confirmed Death, Hospitalization for Worsening or Complication of PAH or Initiation of Intravenous Prostanoids, Atrial Septostomy, or Lung Transplantation Kaplan-Meier estimate at Month 48	60.3 percentage of participants-Kaplan Meier	58.1 percentage of participants-Kaplan Meier
Time to First Confirmed Death, Hospitalization for Worsening or Complication of PAH or Initiation of Intravenous Prostanoids, Atrial Septostomy, or Lung Transplantation Kaplan-Meier estimate at Month 64	53.8 percentage of participants-Kaplan Meier	51.3 percentage of participants-Kaplan Meier
Time to First Confirmed Death, Hospitalization for Worsening or Complication of PAH or Initiation of Intravenous Prostanoids, Atrial Septostomy, or Lung Transplantation Kaplan-Meier estimate at Month 68	39.8 percentage of participants-Kaplan Meier	49.2 percentage of participants-Kaplan Meier
Time to First Confirmed Death, Hospitalization for Worsening or Complication of PAH or Initiation of Intravenous Prostanoids, Atrial Septostomy, or Lung Transplantation Kaplan-Meier estimate at Month 76	39.8 percentage of participants-Kaplan Meier	45.1 percentage of participants-Kaplan Meier
Time to First Confirmed Death, Hospitalization for Worsening or Complication of PAH or Initiation of Intravenous Prostanoids, Atrial Septostomy, or Lung Transplantation Kaplan-Meier estimate at Month 80	39.8 percentage of participants-Kaplan Meier	45.1 percentage of participants-Kaplan Meier
Time to First Confirmed Death, Hospitalization for Worsening or Complication of PAH or Initiation of Intravenous Prostanoids, Atrial Septostomy, or Lung Transplantation Kaplan-Meier estimate at Month 84	39.8 percentage of participants-Kaplan Meier	45.1 percentage of participants-Kaplan Meier

Measure	Bosentan n=159 Participants Bosentan bosentan: bosentan/62.5 mg tablet/b.i.d. for 4 weeks then bosentan/125 mg tablet/b.i.d.	Placebo n=175 Participants Placebo placebo: Matching bosentan placebo/b.i.d.
Time to Death of All Causes From Baseline to End of Study Kaplan-Meier estimate at Month 4	99.4 percentage of participants-Kaplan Meier	98.2 percentage of participants-Kaplan Meier
Time to Death of All Causes From Baseline to End of Study Kaplan-Meier estimate at Month 8	98.7 percentage of participants-Kaplan Meier	95.8 percentage of participants-Kaplan Meier
Time to Death of All Causes From Baseline to End of Study Kaplan-Meier estimate at Month 16	92.8 percentage of participants-Kaplan Meier	92.8 percentage of participants-Kaplan Meier
Time to Death of All Causes From Baseline to End of Study Kaplan-Meier estimate at Month 20	90.6 percentage of participants-Kaplan Meier	89.5 percentage of participants-Kaplan Meier
Time to Death of All Causes From Baseline to End of Study Kaplan-Meier estimate at Month 48	77.7 percentage of participants-Kaplan Meier	71.8 percentage of participants-Kaplan Meier
Time to Death of All Causes From Baseline to End of Study Kaplan-Meier estimate at Month 12	96.5 percentage of participants-Kaplan Meier	94.0 percentage of participants-Kaplan Meier
Time to Death of All Causes From Baseline to End of Study Kaplan-Meier estimate at Month 24	89.1 percentage of participants-Kaplan Meier	88.2 percentage of participants-Kaplan Meier
Time to Death of All Causes From Baseline to End of Study Kaplan-Meier estimate at Month 28	85.8 percentage of participants-Kaplan Meier	85.9 percentage of participants-Kaplan Meier
Time to Death of All Causes From Baseline to End of Study Kaplan-Meier estimate at Month 32	85.8 percentage of participants-Kaplan Meier	84.3 percentage of participants-Kaplan Meier
Time to Death of All Causes From Baseline to End of Study Kaplan-Meier estimate at Month 36	85.8 percentage of participants-Kaplan Meier	78.5 percentage of participants-Kaplan Meier
Time to Death of All Causes From Baseline to End of Study Kaplan-Meier estimate at Month 40	85.8 percentage of participants-Kaplan Meier	76.8 percentage of participants-Kaplan Meier
Time to Death of All Causes From Baseline to End of Study Kaplan-Meier estimate at Month 44	81.4 percentage of participants-Kaplan Meier	74.9 percentage of participants-Kaplan Meier
Time to Death of All Causes From Baseline to End of Study Kaplan-Meier estimate at Month 52	75.0 percentage of participants-Kaplan Meier	70.5 percentage of participants-Kaplan Meier
Time to Death of All Causes From Baseline to End of Study Kaplan-Meier estimate at Month 56	70.1 percentage of participants-Kaplan Meier	66.4 percentage of participants-Kaplan Meier
Time to Death of All Causes From Baseline to End of Study Kaplan-Meier estimate at Month 60	67.8 percentage of participants-Kaplan Meier	64.9 percentage of participants-Kaplan Meier
Time to Death of All Causes From Baseline to End of Study Kaplan-Meier estimate at Month 64	67.8 percentage of participants-Kaplan Meier	64.9 percentage of participants-Kaplan Meier
Time to Death of All Causes From Baseline to End of Study Kaplan-Meier estimate at Month 68	67.8 percentage of participants-Kaplan Meier	64.9 percentage of participants-Kaplan Meier
Time to Death of All Causes From Baseline to End of Study Kaplan-Meier estimate at Month 72	67.8 percentage of participants-Kaplan Meier	64.9 percentage of participants-Kaplan Meier
Time to Death of All Causes From Baseline to End of Study Kaplan-Meier estimate at Month 76	67.8 percentage of participants-Kaplan Meier	60.3 percentage of participants-Kaplan Meier
Time to Death of All Causes From Baseline to End of Study Kaplan-Meier estimate at Month 80	58.1 percentage of participants-Kaplan Meier	60.3 percentage of participants-Kaplan Meier
Time to Death of All Causes From Baseline to End of Study Kaplan-Meier estimate at Month 84	58.1 percentage of participants-Kaplan Meier	60.3 percentage of participants-Kaplan Meier
Time to Death of All Causes From Baseline to End of Study Kaplan-Meier estimate at End of Study	58.1 percentage of participants-Kaplan Meier	60.3 percentage of participants-Kaplan Meier

Measure	Bosentan n=159 participants at risk Bosentan bosentan: bosentan/62.5 mg tablet/b.i.d. for 4 weeks then bosentan/125 mg tablet/b.i.d.	Placebo n=174 participants at risk Placebo placebo: Matching bosentan placebo/b.i.d.
General disorders OEDEMA PERIPHERAL	18.9% 30/159 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.	14.9% 26/174 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.
Nervous system disorders HEADACHE	15.1% 24/159 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.	13.8% 24/174 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.
Respiratory, thoracic and mediastinal disorders COUGH	13.8% 22/159 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.	12.1% 21/174 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.
Infections and infestations UPPER RESPIRATORY TRACT INFECTION	13.2% 21/159 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.	16.7% 29/174 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.
Respiratory, thoracic and mediastinal disorders DYSPNOEA	13.2% 21/159 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.	10.9% 19/174 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.
Gastrointestinal disorders DIARRHOEA	11.9% 19/159 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.	10.9% 19/174 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.
General disorders CHEST PAIN	11.3% 18/159 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.	5.7% 10/174 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.
Nervous system disorders DIZZINESS	10.7% 17/159 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.	9.8% 17/174 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.
Gastrointestinal disorders NAUSEA	10.1% 16/159 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.	12.6% 22/174 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.
Infections and infestations URINARY TRACT INFECTION	10.1% 16/159 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.	7.5% 13/174 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.
Investigations ALANINE AMINOTRANSFERASE INCREASED	10.1% 16/159 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.	4.0% 7/174 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.
Respiratory, thoracic and mediastinal disorders PULMONARY ARTERIAL HYPERTENSION	9.4% 15/159 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.	20.1% 35/174 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.
Musculoskeletal and connective tissue disorders BACK PAIN	9.4% 15/159 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.	12.6% 22/174 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.
Blood and lymphatic system disorders ANAEMIA	9.4% 15/159 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.	5.7% 10/174 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.
Infections and infestations BRONCHITIS	8.8% 14/159 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.	10.3% 18/174 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.
Musculoskeletal and connective tissue disorders ARTHRALGIA	8.2% 13/159 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.	11.5% 20/174 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.
General disorders FATIGUE	8.2% 13/159 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.	10.9% 19/174 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.
Investigations ASPARTATE AMINOTRANSFERASE INCREASED	8.2% 13/159 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.	4.6% 8/174 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.
Respiratory, thoracic and mediastinal disorders EPISTAXIS	7.5% 12/159 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.	3.4% 6/174 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.
Infections and infestations NASOPHARYNGITIS	6.9% 11/159 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.	8.6% 15/174 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.
Gastrointestinal disorders ABDOMINAL PAIN	6.9% 11/159 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.	6.9% 12/174 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.
Infections and infestations SINUSITIS	6.9% 11/159 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.	6.9% 12/174 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.
Investigations LIVER FUNCTION TEST ABNORMAL	6.9% 11/159 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.	2.3% 4/174 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.
Skin and subcutaneous tissue disorders RASH	6.3% 10/159 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.	3.4% 6/174 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.
Musculoskeletal and connective tissue disorders PAIN IN EXTREMITY	5.7% 9/159 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.	8.6% 15/174 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.
Psychiatric disorders ANXIETY	5.7% 9/159 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.	6.3% 11/174 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.
Investigations HEPATIC ENZYME INCREASED	5.7% 9/159 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.	1.7% 3/174 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.
Gastrointestinal disorders VOMITING	5.0% 8/159 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.	6.9% 12/174 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.
Psychiatric disorders INSOMNIA	5.0% 8/159 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.	6.3% 11/174 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.
Infections and infestations PNEUMONIA	5.0% 8/159 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.	4.6% 8/174 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.
Injury, poisoning and procedural complications FALL	5.0% 8/159 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.	3.4% 6/174 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.
Musculoskeletal and connective tissue disorders MUSCLE SPASMS	5.0% 8/159 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.	3.4% 6/174 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.
Respiratory, thoracic and mediastinal disorders NASAL CONGESTION	5.0% 8/159 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.	0.00% 0/174 • Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks All treated patients. Treatment emergent adverse events.