Effects of the Combination of Bosentan and Sildenafil Versus Sildenafil Monotherapy on Pulmonary Arterial Hypertension (PAH) (Compass-2)

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ClinicalTrials.gov Identifier: NCT00303459

Recruitment Status : Completed

First Posted : March 17, 2006

Results First Posted : January 26, 2015

Last Update Posted : November 11, 2015

View this study on Beta.ClinicalTrials.gov

Sponsor:

Information provided by (Responsible Party):

Actelion

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Condition	Pulmonary Arterial Hypertension
Interventions	Drug: bosentan Drug: placebo
Enrollment	334

Participant Flow

Recruitment Details	First subject, first visit was17 May 2006 and last subject, last visit was 05 Dec 2013.
Pre-assignment Details	There was a screening period of up to 14 days to assess eligibility. A total of 377 patients were screened.


Arm/Group Title	Bosentan	Placebo
Arm/Group Description	Bosentan ...	Placebo ...
Arm/Group Description	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: Matching bosentan placebo/b.i.d.
Period Title: Overall Study
Started	159	175 ^[1]
Completed	76	86
Not Completed	83	89
Reason Not Completed
Death	33	44
Withdrawal of consent	32	26
Lost to Follow-up	5	4
Administrative reason	7	7
Decision by the investigator	5	7
Lung transplantation	1	1
[1] One subject randomized to placebo did not receive study treatment

Baseline Characteristics

Arm/Group Title		Bosentan	Placebo	Total
Arm/Group Description		Bosentan ...	Placebo ...	Total of all reporting groups
Arm/Group Description		Bosentan bosentan: bosentan/62.5 mg tablet/b.i.d. for 4 weeks then bosentan/125 mg tablet/b.i.d.	Placebo placebo: Matching bosentan placebo/b.i.d.	Total of all reporting groups
Overall Number of Baseline Participants		159	175	334
Baseline Analysis Population Description		...
Baseline Analysis Population Description		All randomized set
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	159 participants	175 participants	334 participants
		52.9 (15.44)	54.7 (15.73)	53.9 (15.60)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	159 participants	175 participants	334 participants
	Female	125 78.6%	128 73.1%	253 75.7%
	Male	34 21.4%	47 26.9%	81 24.3%
Race/Ethnicity, Customized Measure Type: Number Unit of measure: Participants	Number Analyzed	159 participants	175 participants	334 participants
Caucasian/White		147	149	296
Black		7	12	19
Hispanic		5	6	11
Other		0	8	8
Region of Enrollment Measure Type: Number Unit of measure: Participants	Number Analyzed	159 participants	175 participants	334 participants
Brazil		36	35	71
Czech Republic		12	15	27
Denmark		3	4	7
Germany		19	22	41
Greece		4	5	9
Portugal		3	0	3
Saudi Arabia		0	1	1
Slovakia		4	3	7
Spain		1	1	2
Sweden		4	5	9
United Kingdom		0	1	1
United States		73	83	156

Outcome Measures

1.Primary Outcome


Title	Time to First Confirmed Morbidity/Mortality Event up to the End of Study
Description	Kaplan-Meier estimate of percentage of participants without a morbidit...
Description	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.
Time Frame	From baseline to end of study, approximately 86 months

Outcome Measure Data

Analysis Population Description

All randomized set


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

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bosentan, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.2508
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.831
	Confidence Interval	(2-Sided) 97.31% 0.582 to 1.187
	Estimation Comments	[Not Specified]

2.Secondary Outcome


Title	Time to First Confirmed Death, Hospitalization for Worsening or Complication of PAH or Initiation of Intravenous Prostanoids, Atrial Septostomy, or Lung Transplantation
Description	Kaplan-Meier estimate of percentage of participants without an event o...
Description	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.
Time Frame	Baseline to end of study, approximately 86 months

Outcome Measure Data

Analysis Population Description

All randomized set


Arm/Group Title	Bosentan	Placebo
Arm/Group Description:	Bosentan ...	Placebo ...
Arm/Group Description:	Bosentan bosentan: bosentan/62.5 mg tablet/b.i.d. for 4 weeks then bosentan/125 mg tablet/b.i.d.	Placebo placebo: Matching bosentan placebo/b.i.d.
Overall Number of Participants Analyzed	159	175
Measure Type: Number Unit of Measure: percentage of participants-Kaplan Meier
Kaplan-Meier estimate at Month 4	97.4	95.3
Kaplan-Meier estimate at Month 8	94.6	91.8
Kaplan-Meier estimate at Month 12	89.6	88.8
Kaplan-Meier estimate at Month 16	85.3	86.9
Kaplan-Meier estimate at Month 20	82.3	83.8
Kaplan-Meier estimate at Month 24	76.9	79.8
Kaplan-Meier estimate at Month 28	76.1	74.7
Kaplan-Meier estimate at Month 32	75.2	73.1
Kaplan-Meier estimate at Month 36	72.2	64.4
Kaplan-Meier estimate at Month 40	72.2	61.9
Kaplan-Meier estimate at Month 44	64.2	60.1
Kaplan-Meier estimate at Month 48	60.3	58.1
Kaplan-Meier estimate at Month 52	57.4	56.8
Kaplan-Meier estimate at Month 56	53.8	52.7
Kaplan-Meier estimate at Month 60	53.8	51.3
Kaplan-Meier estimate at Month 64	53.8	51.3
Kaplan-Meier estimate at Month 68	39.8	49.2
Kaplan-Meier estimate at Month 72	39.8	49.2
Kaplan-Meier estimate at Month 76	39.8	45.1
Kaplan-Meier estimate at Month 80	39.8	45.1
Kaplan-Meier estimate at Month 84	39.8	45.1
Kaplan-Meier estimate at End of Study	39.8	45.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bosentan, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.8385
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.963
	Confidence Interval	(2-Sided) 95% 0.673 to 1.380
	Estimation Comments	[Not Specified]

3.Secondary Outcome


Title	Change From Baseline to Week 16 in 6 Minute Walk Test (6MWT)
Description	The 6MWT is a non-encouraged test, which measures the distance covered...
Description	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.
Time Frame	From baseline to week 16

Outcome Measure Data

Analysis Population Description

All randomized set


Arm/Group Title	Bosentan	Placebo
Arm/Group Description:	Bosentan ...	Placebo ...
Arm/Group Description:	Bosentan bosentan: bosentan/62.5 mg tablet/b.i.d. for 4 weeks then bosentan/125 mg tablet/b.i.d.	Placebo placebo: Matching bosentan placebo/b.i.d.
Overall Number of Participants Analyzed	159	175
Mean (Standard Deviation) Unit of Measure: m
Baseline	363 (78.5)	358 (73.1)
Week 16	370 (98.3)	343 (107.3)
Change from baseline	7.2 (66.01)	-14.6 (80.42)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bosentan, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0106
	Comments	[Not Specified]
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	21.8
	Confidence Interval	(2-Sided) 95% 5.9 to 37.8
	Estimation Comments	[Not Specified]

4.Secondary Outcome


Title	Number of Participants With Improved, No Change, or Worsened World Health Organisation Functional Class From Baseline to Week 16
Description	Class I: no limitation of usual physical activity (PA) which does not ...
Description	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.
Time Frame	From baseline to Week 16

Outcome Measure Data

Analysis Population Description

All randomized set


Arm/Group Title	Bosentan	Placebo
Arm/Group Description:	Bosentan ...	Placebo ...
Arm/Group Description:	Bosentan bosentan: bosentan/62.5 mg tablet/b.i.d. for 4 weeks then bosentan/125 mg tablet/b.i.d.	Placebo placebo: Matching bosentan placebo/b.i.d.
Overall Number of Participants Analyzed	159	175
Measure Type: Number Unit of Measure: participants
Improved	25	28
No change	121	130
Worsened	13	17

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bosentan, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	1.0000
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Relative risk of improvement
	Estimated Value	0.98
	Confidence Interval	(2-Sided) 95% 0.60 to 1.61
	Estimation Comments	[Not Specified]

5.Secondary Outcome


Title	Time to Death of All Causes From Baseline to End of Study
Description	Kaplan-Meier estimate of percentage of participants without a mortalit...
Description	Kaplan-Meier estimate of percentage of participants without a mortality event.Time to death due to any cause.
Time Frame	Baseline to End of Study, approximately 86 months

Outcome Measure Data

Analysis Population Description

All randomized set


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

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bosentan, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.4974
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.855
	Confidence Interval	(2-Sided) 95% 0.544 to 1.344
	Estimation Comments	[Not Specified]

6.Secondary Outcome


Title	Adjusted Percentage Ratio From Baseline in N-terminal Pro-B-type Natriuretic Peptide (NT-pro-BNP)
Description	Blood sampling for the measurement of NT-pro-BNP was performed and the...
Description	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.
Time Frame	Baseline to Month 20

Outcome Measure Data

Analysis Population Description

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


Arm/Group Title	Bosentan	Placebo
Arm/Group Description:	Bosentan ...	Placebo ...
Arm/Group Description:	Bosentan bosentan: bosentan/62.5 mg tablet, b.i.d. for 4 weeks then bosentan/125 mg tablet/b.i.d.	Placebo placebo: Matching bosentan placebo/b.i.d.
Overall Number of Participants Analyzed	109	117
Geometric Mean (95% Confidence Interval) Unit of Measure: Adjusted percentage ratio from baseline
Month 1 to Baseline	87.46 (77.12 to 99.18)	110.02 (97.56 to 124.06)
Month 4 to Baseline	92.65 (81.20 to 105.72)	113.20 (99.61 to 128.65)
Month 8 to Baseline	85.21 (72.58 to 100.05)	122.87 (104.82 to 144.02)
Month 12 to Baseline	84.48 (71.48 to 99.83)	132.11 (111.95 to 155.89)
Month 16 to Baseline	92.69 (75.75 to 113.42)	129.92 (106.69 to 158.20)
Month 20 to Baseline	98.36 (79.46 to 121.75)	143.17 (115.86 to 176.91)
Treatment effect over 20 months	92.54 (82.72 to 103.52)	121.00 (108.42 to 135.05)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bosentan, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0003
	Comments	[Not Specified]
	Method	Repeated measures analysis
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Percentage change over placebo
	Estimated Value	-23.52
	Confidence Interval	(2-Sided) 95% -33.69 to -11.79
	Estimation Comments	[Not Specified]

7.Secondary Outcome


Title	Change From Baseline to Week 16 in Borg Dyspnea Index
Description	The Borg dyspnea index was evaluated immediately after the 6MWT to obt...
Description	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').
Time Frame	Baseline to Week 16

Outcome Measure Data

Analysis Population Description

All randomized set


Arm/Group Title	Bosentan	Placebo
Arm/Group Description:	Bosentan ...	Placebo ...
Arm/Group Description:	Bosentan bosentan: bosentan/62.5 mg tablet/b.i.d. for 4 weeks then bosentan/125 mg tablet/b.i.d.	Placebo placebo: Matching bosentan placebo/b.i.d.
Overall Number of Participants Analyzed	159	175
Mean (Standard Deviation) Unit of Measure: units on a scale
Baseline	3.5 (1.99)	3.7 (2.18)
Week 16	3.4 (2.12)	3.6 (2.24)
Change from baseline	-0.09 (1.693)	-0.08 (2.035)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bosentan, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.9566
	Comments	[Not Specified]
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.01
	Confidence Interval	(2-Sided) 95% -0.42 to 0.39
	Estimation Comments	[Not Specified]

8.Secondary Outcome


Title	Change From Baseline to Week 16 in the EuroQol 5 Dimensions (EQ-5D) Questionnaire Calculated Score
Description	The EQ-5D questionnaire is a patient-reported outcome consisting of a ...
Description	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).
Time Frame	From baseline to Week 16

Outcome Measure Data

Analysis Population Description

All randomized set


Arm/Group Title	Bosentan	Placebo
Arm/Group Description:	Bosentan ...	Placebo ...
Arm/Group Description:	Bosentan bosentan: bosentan/62.5 mg tablet/b.i.d. for 4 weeks then bosentan/125 mg tablet/b.i.d.	Placebo placebo: Matching bosentan placebo/b.i.d.
Overall Number of Participants Analyzed	159	175
Mean (Standard Deviation) Unit of Measure: units on a scale
Baseline	0.678 (0.2172)	0.681 (0.2138)
Week 16	0.662 (0.2807)	0.645 (0.3062)
Change from Baseline	-0.0161 (0.25232)	-0.0361 (0.26671)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bosentan, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.5571
	Comments	[Not Specified]
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.020
	Confidence Interval	(2-Sided) 95% -0.036 to 0.076
	Estimation Comments	[Not Specified]

9.Secondary Outcome


Title	Change From Baseline to Week 16 in the EuroQol 5 Dimensions (EQ-5D) Visual Analogue Scale Score
Description	The EQ-5D questionnaire is a patient-reported outcome consisting of a ...
Description	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.
Time Frame	Baseline to Week 16

Outcome Measure Data

Analysis Population Description

All randomized set


Arm/Group Title	Bosentan	Placebo
Arm/Group Description:	Bosentan ...	Placebo ...
Arm/Group Description:	Bosentan bosentan: bosentan/62.5 mg tablet/b.i.d. for 4 weeks then bosentan/125 mg tablet/b.i.d.	Placebo placebo: Matching bosentan placebo/b.i.d.
Overall Number of Participants Analyzed	159	175
Mean (Standard Deviation) Unit of Measure: units on a scale
Baseline	67 (17.4)	64 (17.5)
Week 16	69 (19.9)	66 (19.9)
Change from Baseline	2.1 (18.83)	2.0 (17.01)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bosentan, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.4086
	Comments	[Not Specified]
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.2
	Confidence Interval	(2-Sided) 95% -3.7 to 4.0
	Estimation Comments	[Not Specified]

10.Secondary Outcome


Title	Patient Global Self Assessment (PGSA) Status at Week 16
Description	The PGSA is a questionnaire that allows the patient to compare his/her...
Description	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.
Time Frame	Week 16

Outcome Measure Data

Analysis Population Description

All randomized set, patients who completed the assessment


Arm/Group Title	Bosentan	Placebo
Arm/Group Description:	Bosentan ...	Placebo ...
Arm/Group Description:	Bosentan bosentan: bosentan/62.5 mg tablet/b.i.d. for 4 weeks then bosentan/125 mg tablet/b.i.d.	Placebo placebo: Matching bosentan placebo/b.i.d.
Overall Number of Participants Analyzed	150	162
Measure Type: Number Unit of Measure: participants
Markedly better	24	13
Moderately better	23	30
Mildly better	32	36
No change	50	59
Mildly worse	16	15
Moderately worse	3	5
Markedly worse	2	4

Adverse Events

Time Frame	Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks
Adverse Event Reporting Description	All treated patients. Treatment emergent adverse events.

Arm/Group Title	Bosentan	Placebo
Arm/Group Description	Bosentan ...	Placebo ...
Arm/Group Description	Bosentan bosentan: bosentan/62.5 mg tablet/b.i.d. for 4 weeks then bosentan/125 mg tablet/b.i.d.	Placebo placebo: Matching bosentan placebo/b.i.d.
All-Cause Mortality
	Bosentan	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--
Serious Adverse Events Serious Adverse Events
	Bosentan	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)
Total	73/159 (45.91%)	102/174 (58.62%)
Blood and lymphatic system disorders
ANAEMIA ^† 1	3/159 (1.89%)	2/174 (1.15%)
ANAEMIA HAEMOLYTIC AUTOIMMUNE ^† 1	1/159 (0.63%)	0/174 (0.00%)
SPLENOMEGALY ^† 1	1/159 (0.63%)	0/174 (0.00%)
HYPERSPLENISM ^† 1	0/159 (0.00%)	1/174 (0.57%)
THROMBOCYTOPENIA ^† 1	0/159 (0.00%)	1/174 (0.57%)
THROMBOTIC THROMBOCYTOPENIC PURPURA ^† 1	0/159 (0.00%)	1/174 (0.57%)
Cardiac disorders
RIGHT VENTRICULAR FAILURE ^† 1	6/159 (3.77%)	8/174 (4.60%)
ATRIAL FIBRILLATION ^† 1	4/159 (2.52%)	3/174 (1.72%)
ATRIAL FLUTTER ^† 1	2/159 (1.26%)	1/174 (0.57%)
CARDIAC FAILURE CONGESTIVE ^† 1	2/159 (1.26%)	1/174 (0.57%)
BRADYCARDIA ^† 1	2/159 (1.26%)	0/174 (0.00%)
MYOCARDIAL INFARCTION ^† 1	1/159 (0.63%)	2/174 (1.15%)
COR PULMONALE ^† 1	1/159 (0.63%)	1/174 (0.57%)
CORONARY ARTERY DISEASE ^† 1	1/159 (0.63%)	1/174 (0.57%)
SUPRAVENTRICULAR TACHYCARDIA ^† 1	1/159 (0.63%)	1/174 (0.57%)
ACUTE MYOCARDIAL INFARCTION ^† 1	1/159 (0.63%)	0/174 (0.00%)
ACUTE RIGHT VENTRICULAR FAILURE ^† 1	1/159 (0.63%)	0/174 (0.00%)
CARDIAC FAILURE ^† 1	1/159 (0.63%)	0/174 (0.00%)
TRIFASCICULAR BLOCK ^† 1	1/159 (0.63%)	0/174 (0.00%)
CARDIAC ARREST ^† 1	0/159 (0.00%)	3/174 (1.72%)
ACUTE CORONARY SYNDROME ^† 1	0/159 (0.00%)	1/174 (0.57%)
ANGINA PECTORIS ^† 1	0/159 (0.00%)	1/174 (0.57%)
BRADYARRHYTHMIA ^† 1	0/159 (0.00%)	1/174 (0.57%)
INTRACARDIAC THROMBUS ^† 1	0/159 (0.00%)	1/174 (0.57%)
SICK SINUS SYNDROME ^† 1	0/159 (0.00%)	1/174 (0.57%)
Ear and labyrinth disorders
SUDDEN HEARING LOSS ^† 1	0/159 (0.00%)	1/174 (0.57%)
Eye disorders
RETINAL DETACHMENT ^† 1	1/159 (0.63%)	0/174 (0.00%)
EYE SWELLING ^† 1	0/159 (0.00%)	1/174 (0.57%)
Gastrointestinal disorders
GASTROINTESTINAL HAEMORRHAGE ^† 1	2/159 (1.26%)	1/174 (0.57%)
SMALL INTESTINAL OBSTRUCTION ^† 1	2/159 (1.26%)	0/174 (0.00%)
ABDOMINAL PAIN UPPER ^† 1	1/159 (0.63%)	1/174 (0.57%)
UPPER GASTROINTESTINAL HAEMORRHAGE ^† 1	1/159 (0.63%)	1/174 (0.57%)
ASCITES ^† 1	1/159 (0.63%)	0/174 (0.00%)
DYSPHAGIA ^† 1	1/159 (0.63%)	0/174 (0.00%)
GASTROINTESTINAL DISORDER ^† 1	1/159 (0.63%)	0/174 (0.00%)
GASTROOESOPHAGEAL REFLUX DISEASE ^† 1	1/159 (0.63%)	0/174 (0.00%)
HAEMATOCHEZIA ^† 1	1/159 (0.63%)	0/174 (0.00%)
PANCREATITIS ^† 1	1/159 (0.63%)	0/174 (0.00%)
RECTAL HAEMORRHAGE ^† 1	1/159 (0.63%)	0/174 (0.00%)
ABDOMINAL PAIN ^† 1	0/159 (0.00%)	3/174 (1.72%)
CONSTIPATION ^† 1	0/159 (0.00%)	1/174 (0.57%)
DIVERTICULUM ^† 1	0/159 (0.00%)	1/174 (0.57%)
GASTRITIS ^† 1	0/159 (0.00%)	1/174 (0.57%)
HAEMATEMESIS ^† 1	0/159 (0.00%)	1/174 (0.57%)
LARGE INTESTINE POLYP ^† 1	0/159 (0.00%)	1/174 (0.57%)
OESOPHAGEAL VARICES HAEMORRHAGE ^† 1	0/159 (0.00%)	1/174 (0.57%)
General disorders
CHEST PAIN ^† 1	5/159 (3.14%)	7/174 (4.02%)
GENERAL PHYSICAL HEALTH DETERIORATION ^† 1	1/159 (0.63%)	1/174 (0.57%)
SUDDEN DEATH ^† 1	1/159 (0.63%)	1/174 (0.57%)
GENERALISED OEDEMA ^† 1	0/159 (0.00%)	3/174 (1.72%)
OEDEMA PERIPHERAL ^† 1	0/159 (0.00%)	2/174 (1.15%)
ADVERSE DRUG REACTION ^† 1	0/159 (0.00%)	1/174 (0.57%)
ASTHENIA ^† 1	0/159 (0.00%)	1/174 (0.57%)
DEATH ^† 1	0/159 (0.00%)	1/174 (0.57%)
FATIGUE ^† 1	0/159 (0.00%)	1/174 (0.57%)
MULTI-ORGAN FAILURE ^† 1	0/159 (0.00%)	1/174 (0.57%)
Hepatobiliary disorders
HEPATIC CIRRHOSIS ^† 1	1/159 (0.63%)	1/174 (0.57%)
BILIARY DYSKINESIA ^† 1	0/159 (0.00%)	1/174 (0.57%)
CHOLECYSTITIS ^† 1	0/159 (0.00%)	1/174 (0.57%)
CHOLECYSTITIS ACUTE ^† 1	0/159 (0.00%)	1/174 (0.57%)
CHOLESTASIS ^† 1	0/159 (0.00%)	1/174 (0.57%)
PORTAL HYPERTENSION ^† 1	0/159 (0.00%)	1/174 (0.57%)
Immune system disorders
DRUG HYPERSENSITIVITY ^† 1	1/159 (0.63%)	1/174 (0.57%)
HYPERSENSITIVITY ^† 1	0/159 (0.00%)	1/174 (0.57%)
Infections and infestations
PNEUMONIA ^† 1	11/159 (6.92%)	6/174 (3.45%)
BRONCHITIS ^† 1	6/159 (3.77%)	3/174 (1.72%)
GASTROENTERITIS ^† 1	3/159 (1.89%)	5/174 (2.87%)
CELLULITIS ^† 1	3/159 (1.89%)	0/174 (0.00%)
CLOSTRIDIUM DIFFICILE COLITIS ^† 1	2/159 (1.26%)	0/174 (0.00%)
DIVERTICULITIS ^† 1	2/159 (1.26%)	0/174 (0.00%)
SEPTIC SHOCK ^† 1	1/159 (0.63%)	2/174 (1.15%)
URINARY TRACT INFECTION ^† 1	1/159 (0.63%)	2/174 (1.15%)
BRONCHOPNEUMONIA ^† 1	1/159 (0.63%)	1/174 (0.57%)
PYELONEPHRITIS ^† 1	1/159 (0.63%)	1/174 (0.57%)
SEPSIS ^† 1	1/159 (0.63%)	1/174 (0.57%)
UPPER RESPIRATORY TRACT INFECTION ^† 1	1/159 (0.63%)	1/174 (0.57%)
ABDOMINAL ABSCESS ^† 1	1/159 (0.63%)	0/174 (0.00%)
APPENDICITIS ^† 1	1/159 (0.63%)	0/174 (0.00%)
CLOSTRIDIUM DIFFICILE INFECTION ^† 1	1/159 (0.63%)	0/174 (0.00%)
DENGUE FEVER ^† 1	1/159 (0.63%)	0/174 (0.00%)
DEVICE RELATED SEPSIS ^† 1	1/159 (0.63%)	0/174 (0.00%)
GASTROENTERITIS SALMONELLA ^† 1	1/159 (0.63%)	0/174 (0.00%)
HAEMATOMA INFECTION ^† 1	1/159 (0.63%)	0/174 (0.00%)
LOWER RESPIRATORY TRACT INFECTION ^† 1	1/159 (0.63%)	0/174 (0.00%)
LUNG INFECTION ^† 1	1/159 (0.63%)	0/174 (0.00%)
PNEUMOCOCCAL SEPSIS ^† 1	1/159 (0.63%)	0/174 (0.00%)
PNEUMONIA STAPHYLOCOCCAL ^† 1	1/159 (0.63%)	0/174 (0.00%)
POSTOPERATIVE WOUND INFECTION ^† 1	1/159 (0.63%)	0/174 (0.00%)
VIRAL UPPER RESPIRATORY TRACT INFECTION ^† 1	0/159 (0.00%)	2/174 (1.15%)
BACTERAEMIA ^† 1	0/159 (0.00%)	1/174 (0.57%)
BRONCHITIS VIRAL ^† 1	0/159 (0.00%)	1/174 (0.57%)
ERYSIPELAS ^† 1	0/159 (0.00%)	1/174 (0.57%)
GASTROENTERITIS CALICIVIRAL ^† 1	0/159 (0.00%)	1/174 (0.57%)
H1N1 INFLUENZA ^† 1	0/159 (0.00%)	1/174 (0.57%)
INFECTED DERMAL CYST ^† 1	0/159 (0.00%)	1/174 (0.57%)
INFECTIVE EXACERBATION OF CHRONIC OBSTRUCTIVE AIRWAYS DISEASE ^† 1	0/159 (0.00%)	1/174 (0.57%)
KLEBSIELLA BACTERAEMIA ^† 1	0/159 (0.00%)	1/174 (0.57%)
RESPIRATORY TRACT INFECTION ^† 1	0/159 (0.00%)	1/174 (0.57%)
SEPSIS SYNDROME ^† 1	0/159 (0.00%)	1/174 (0.57%)
SINUSITIS ^† 1	0/159 (0.00%)	1/174 (0.57%)
TUBERCULOSIS ^† 1	0/159 (0.00%)	1/174 (0.57%)
UROSEPSIS ^† 1	0/159 (0.00%)	1/174 (0.57%)
WOUND INFECTION ^† 1	0/159 (0.00%)	1/174 (0.57%)
Injury, poisoning and procedural complications
HUMERUS FRACTURE ^† 1	2/159 (1.26%)	0/174 (0.00%)
FALL ^† 1	1/159 (0.63%)	2/174 (1.15%)
HIP FRACTURE ^† 1	1/159 (0.63%)	2/174 (1.15%)
LACERATION ^† 1	1/159 (0.63%)	1/174 (0.57%)
RIB FRACTURE ^† 1	1/159 (0.63%)	1/174 (0.57%)
FOOT FRACTURE ^† 1	1/159 (0.63%)	0/174 (0.00%)
POST PROCEDURAL COMPLICATION ^† 1	1/159 (0.63%)	0/174 (0.00%)
RENAL HAEMATOMA ^† 1	1/159 (0.63%)	0/174 (0.00%)
TRANSFUSION-RELATED ACUTE LUNG INJURY ^† 1	1/159 (0.63%)	0/174 (0.00%)
FEMORAL NECK FRACTURE ^† 1	0/159 (0.00%)	1/174 (0.57%)
FRACTURED SACRUM ^† 1	0/159 (0.00%)	1/174 (0.57%)
INCISIONAL HERNIA ^† 1	0/159 (0.00%)	1/174 (0.57%)
LOWER LIMB FRACTURE ^† 1	0/159 (0.00%)	1/174 (0.57%)
PELVIC FRACTURE ^† 1	0/159 (0.00%)	1/174 (0.57%)
SUBDURAL HAEMATOMA ^† 1	0/159 (0.00%)	1/174 (0.57%)
TOXICITY TO VARIOUS AGENTS ^† 1	0/159 (0.00%)	1/174 (0.57%)
Investigations
LIVER FUNCTION TEST ABNORMAL ^† 1	2/159 (1.26%)	0/174 (0.00%)
ALANINE AMINOTRANSFERASE INCREASED ^† 1	1/159 (0.63%)	1/174 (0.57%)
ASPARTATE AMINOTRANSFERASE INCREASED ^† 1	1/159 (0.63%)	1/174 (0.57%)
ELECTROCARDIOGRAM QT PROLONGED ^† 1	1/159 (0.63%)	0/174 (0.00%)
HEPATIC ENZYME INCREASED ^† 1	1/159 (0.63%)	0/174 (0.00%)
VASCULAR RESISTANCE PULMONARY INCREASED ^† 1	1/159 (0.63%)	0/174 (0.00%)
BLOOD BILIRUBIN INCREASED ^† 1	0/159 (0.00%)	1/174 (0.57%)
WEIGHT DECREASED ^† 1	0/159 (0.00%)	1/174 (0.57%)
Metabolism and nutrition disorders
DEHYDRATION ^† 1	3/159 (1.89%)	0/174 (0.00%)
FLUID OVERLOAD ^† 1	3/159 (1.89%)	0/174 (0.00%)
HYPERKALAEMIA ^† 1	2/159 (1.26%)	0/174 (0.00%)
FLUID RETENTION ^† 1	1/159 (0.63%)	1/174 (0.57%)
HYPERVOLAEMIA ^† 1	1/159 (0.63%)	0/174 (0.00%)
HYPOKALAEMIA ^† 1	1/159 (0.63%)	0/174 (0.00%)
DECREASED APPETITE ^† 1	0/159 (0.00%)	1/174 (0.57%)
GOUT ^† 1	0/159 (0.00%)	1/174 (0.57%)
Musculoskeletal and connective tissue disorders
INTERVERTEBRAL DISC PROTRUSION ^† 1	1/159 (0.63%)	0/174 (0.00%)
PAIN IN EXTREMITY ^† 1	0/159 (0.00%)	2/174 (1.15%)
ARTHRALGIA ^† 1	0/159 (0.00%)	1/174 (0.57%)
BACK PAIN ^† 1	0/159 (0.00%)	1/174 (0.57%)
COLLAGEN DISORDER ^† 1	0/159 (0.00%)	1/174 (0.57%)
CREST SYNDROME ^† 1	0/159 (0.00%)	1/174 (0.57%)
DUPUYTREN'S CONTRACTURE ^† 1	0/159 (0.00%)	1/174 (0.57%)
HAEMARTHROSIS ^† 1	0/159 (0.00%)	1/174 (0.57%)
MUSCULOSKELETAL CHEST PAIN ^† 1	0/159 (0.00%)	1/174 (0.57%)
OSTEONECROSIS ^† 1	0/159 (0.00%)	1/174 (0.57%)
ROTATOR CUFF SYNDROME ^† 1	0/159 (0.00%)	1/174 (0.57%)
SYSTEMIC LUPUS ERYTHEMATOSUS ^† 1	0/159 (0.00%)	1/174 (0.57%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
BRONCHIOLOALVEOLAR CARCINOMA ^† 1	1/159 (0.63%)	0/174 (0.00%)
DIFFUSE LARGE B-CELL LYMPHOMA ^† 1	1/159 (0.63%)	0/174 (0.00%)
UTERINE LEIOMYOMA ^† 1	1/159 (0.63%)	0/174 (0.00%)
ACOUSTIC NEUROMA ^† 1	0/159 (0.00%)	1/174 (0.57%)
BRONCHIAL CARCINOMA ^† 1	0/159 (0.00%)	1/174 (0.57%)
CERVIX CARCINOMA ^† 1	0/159 (0.00%)	1/174 (0.57%)
INFLAMMATORY CARCINOMA OF THE BREAST ^† 1	0/159 (0.00%)	1/174 (0.57%)
MALIGNANT MELANOMA IN SITU ^† 1	0/159 (0.00%)	1/174 (0.57%)
MENINGIOMA BENIGN ^† 1	0/159 (0.00%)	1/174 (0.57%)
METASTATIC MALIGNANT MELANOMA ^† 1	0/159 (0.00%)	1/174 (0.57%)
RECTAL CANCER ^† 1	0/159 (0.00%)	1/174 (0.57%)
Nervous system disorders
SYNCOPE ^† 1	3/159 (1.89%)	6/174 (3.45%)
TRANSIENT ISCHAEMIC ATTACK ^† 1	1/159 (0.63%)	3/174 (1.72%)
NEUROPATHY PERIPHERAL ^† 1	1/159 (0.63%)	0/174 (0.00%)
SCIATICA ^† 1	1/159 (0.63%)	0/174 (0.00%)
CEREBROVASCULAR ACCIDENT ^† 1	0/159 (0.00%)	2/174 (1.15%)
CONVULSION ^† 1	0/159 (0.00%)	2/174 (1.15%)
HYPOAESTHESIA ^† 1	0/159 (0.00%)	2/174 (1.15%)
BRAIN STEM STROKE ^† 1	0/159 (0.00%)	1/174 (0.57%)
DIZZINESS ^† 1	0/159 (0.00%)	1/174 (0.57%)
HEADACHE ^† 1	0/159 (0.00%)	1/174 (0.57%)
HEMIPARESIS ^† 1	0/159 (0.00%)	1/174 (0.57%)
LUMBAR RADICULOPATHY ^† 1	0/159 (0.00%)	1/174 (0.57%)
MYASTHENIA GRAVIS ^† 1	0/159 (0.00%)	1/174 (0.57%)
PRESYNCOPE ^† 1	0/159 (0.00%)	1/174 (0.57%)
Pregnancy, puerperium and perinatal conditions
PREGNANCY ^† 1	0/159 (0.00%)	3/174 (1.72%)
Psychiatric disorders
BIPOLAR I DISORDER ^† 1	1/159 (0.63%)	0/174 (0.00%)
DEPRESSION ^† 1	1/159 (0.63%)	0/174 (0.00%)
MENTAL STATUS CHANGES ^† 1	1/159 (0.63%)	0/174 (0.00%)
SUICIDE ATTEMPT ^† 1	1/159 (0.63%)	0/174 (0.00%)
SUICIDAL IDEATION ^† 1	0/159 (0.00%)	1/174 (0.57%)
Renal and urinary disorders
RENAL FAILURE ACUTE ^† 1	1/159 (0.63%)	4/174 (2.30%)
BLADDER NECK OBSTRUCTION ^† 1	0/159 (0.00%)	1/174 (0.57%)
HAEMATURIA ^† 1	0/159 (0.00%)	1/174 (0.57%)
NEPHROLITHIASIS ^† 1	0/159 (0.00%)	1/174 (0.57%)
RENAL FAILURE ^† 1	0/159 (0.00%)	1/174 (0.57%)
RENAL IMPAIRMENT ^† 1	0/159 (0.00%)	1/174 (0.57%)
RENAL TUBULAR NECROSIS ^† 1	0/159 (0.00%)	1/174 (0.57%)
Reproductive system and breast disorders
MENORRHAGIA ^† 1	1/159 (0.63%)	0/174 (0.00%)
UTERINE HAEMORRHAGE ^† 1	1/159 (0.63%)	0/174 (0.00%)
DYSMENORRHOEA ^† 1	0/159 (0.00%)	1/174 (0.57%)
OVARIAN MASS ^† 1	0/159 (0.00%)	1/174 (0.57%)
UTERINE PROLAPSE ^† 1	0/159 (0.00%)	1/174 (0.57%)
VAGINAL HAEMORRHAGE ^† 1	0/159 (0.00%)	1/174 (0.57%)
Respiratory, thoracic and mediastinal disorders
PULMONARY ARTERIAL HYPERTENSION ^† 1	25/159 (15.72%)	28/174 (16.09%)
RESPIRATORY FAILURE ^† 1	6/159 (3.77%)	3/174 (1.72%)
DYSPNOEA ^† 1	5/159 (3.14%)	8/174 (4.60%)
CHRONIC OBSTRUCTIVE PULMONARY DISEASE ^† 1	4/159 (2.52%)	2/174 (1.15%)
ACUTE RESPIRATORY FAILURE ^† 1	4/159 (2.52%)	1/174 (0.57%)
PULMONARY EMBOLISM ^† 1	3/159 (1.89%)	1/174 (0.57%)
HYPOXIA ^† 1	3/159 (1.89%)	0/174 (0.00%)
PULMONARY OEDEMA ^† 1	2/159 (1.26%)	1/174 (0.57%)
CHRONIC RESPIRATORY FAILURE ^† 1	2/159 (1.26%)	0/174 (0.00%)
HAEMOPTYSIS ^† 1	2/159 (1.26%)	0/174 (0.00%)
PNEUMOTHORAX ^† 1	2/159 (1.26%)	0/174 (0.00%)
EPISTAXIS ^† 1	1/159 (0.63%)	2/174 (1.15%)
ASTHMA ^† 1	1/159 (0.63%)	1/174 (0.57%)
PLEURISY ^† 1	1/159 (0.63%)	1/174 (0.57%)
ACUTE PULMONARY OEDEMA ^† 1	1/159 (0.63%)	0/174 (0.00%)
BRONCHIAL HYPERREACTIVITY ^† 1	1/159 (0.63%)	0/174 (0.00%)
OBLITERATIVE BRONCHIOLITIS ^† 1	1/159 (0.63%)	0/174 (0.00%)
ATELECTASIS ^† 1	0/159 (0.00%)	1/174 (0.57%)
BRONCHIAL HAEMORRHAGE ^† 1	0/159 (0.00%)	1/174 (0.57%)
ORTHOPNOEA ^† 1	0/159 (0.00%)	1/174 (0.57%)
RESPIRATORY DISTRESS ^† 1	0/159 (0.00%)	1/174 (0.57%)
Skin and subcutaneous tissue disorders
SKIN ULCER ^† 1	1/159 (0.63%)	1/174 (0.57%)
URTICARIA ^† 1	0/159 (0.00%)	1/174 (0.57%)
Surgical and medical procedures
CORONARY ARTERY BYPASS ^† 1	1/159 (0.63%)	0/174 (0.00%)
DIURETIC THERAPY ^† 1	1/159 (0.63%)	0/174 (0.00%)
FINGER AMPUTATION ^† 1	1/159 (0.63%)	0/174 (0.00%)
INCISIONAL HERNIA REPAIR ^† 1	1/159 (0.63%)	0/174 (0.00%)
KNEE ARTHROPLASTY ^† 1	0/159 (0.00%)	2/174 (1.15%)
CHEMOTHERAPY ^† 1	0/159 (0.00%)	1/174 (0.57%)
RADIOTHERAPY ^† 1	0/159 (0.00%)	1/174 (0.57%)
SKIN CYST EXCISION ^† 1	0/159 (0.00%)	1/174 (0.57%)
SKIN NEOPLASM EXCISION ^† 1	0/159 (0.00%)	1/174 (0.57%)
THYMECTOMY ^† 1	0/159 (0.00%)	1/174 (0.57%)
Vascular disorders
HYPERTENSION ^† 1	1/159 (0.63%)	2/174 (1.15%)
EXTREMITY NECROSIS ^† 1	1/159 (0.63%)	0/174 (0.00%)
DEEP VEIN THROMBOSIS ^† 1	0/159 (0.00%)	1/174 (0.57%)
FEMORAL ARTERY OCCLUSION ^† 1	0/159 (0.00%)	1/174 (0.57%)
HAEMATOMA ^† 1	0/159 (0.00%)	1/174 (0.57%)
HYPOTENSION ^† 1	0/159 (0.00%)	1/174 (0.57%)
PERIPHERAL ARTERIAL OCCLUSIVE DISEASE ^† 1	0/159 (0.00%)	1/174 (0.57%)
SHOCK HAEMORRHAGIC ^† 1	0/159 (0.00%)	1/174 (0.57%)
† Indicates events were collected by systematic assessment 1 Term from vocabulary, MedDRA version 16.0
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Bosentan	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)
Total	135/159 (84.91%)	147/174 (84.48%)
Blood and lymphatic system disorders
ANAEMIA ^† 1	15/159 (9.43%)	10/174 (5.75%)
Gastrointestinal disorders
DIARRHOEA ^† 1	19/159 (11.95%)	19/174 (10.92%)
NAUSEA ^† 1	16/159 (10.06%)	22/174 (12.64%)
ABDOMINAL PAIN ^† 1	11/159 (6.92%)	12/174 (6.90%)
VOMITING ^† 1	8/159 (5.03%)	12/174 (6.90%)
General disorders
OEDEMA PERIPHERAL ^† 1	30/159 (18.87%)	26/174 (14.94%)
CHEST PAIN ^† 1	18/159 (11.32%)	10/174 (5.75%)
FATIGUE ^† 1	13/159 (8.18%)	19/174 (10.92%)
Infections and infestations
UPPER RESPIRATORY TRACT INFECTION ^† 1	21/159 (13.21%)	29/174 (16.67%)
URINARY TRACT INFECTION ^† 1	16/159 (10.06%)	13/174 (7.47%)
BRONCHITIS ^† 1	14/159 (8.81%)	18/174 (10.34%)
NASOPHARYNGITIS ^† 1	11/159 (6.92%)	15/174 (8.62%)
SINUSITIS ^† 1	11/159 (6.92%)	12/174 (6.90%)
PNEUMONIA ^† 1	8/159 (5.03%)	8/174 (4.60%)
Injury, poisoning and procedural complications
FALL ^† 1	8/159 (5.03%)	6/174 (3.45%)
Investigations
ALANINE AMINOTRANSFERASE INCREASED ^† 1	16/159 (10.06%)	7/174 (4.02%)
ASPARTATE AMINOTRANSFERASE INCREASED ^† 1	13/159 (8.18%)	8/174 (4.60%)
LIVER FUNCTION TEST ABNORMAL ^† 1	11/159 (6.92%)	4/174 (2.30%)
HEPATIC ENZYME INCREASED ^† 1	9/159 (5.66%)	3/174 (1.72%)
Musculoskeletal and connective tissue disorders
BACK PAIN ^† 1	15/159 (9.43%)	22/174 (12.64%)
ARTHRALGIA ^† 1	13/159 (8.18%)	20/174 (11.49%)
PAIN IN EXTREMITY ^† 1	9/159 (5.66%)	15/174 (8.62%)
MUSCLE SPASMS ^† 1	8/159 (5.03%)	6/174 (3.45%)
Nervous system disorders
HEADACHE ^† 1	24/159 (15.09%)	24/174 (13.79%)
DIZZINESS ^† 1	17/159 (10.69%)	17/174 (9.77%)
Psychiatric disorders
ANXIETY ^† 1	9/159 (5.66%)	11/174 (6.32%)
INSOMNIA ^† 1	8/159 (5.03%)	11/174 (6.32%)
Respiratory, thoracic and mediastinal disorders
COUGH ^† 1	22/159 (13.84%)	21/174 (12.07%)
DYSPNOEA ^† 1	21/159 (13.21%)	19/174 (10.92%)
PULMONARY ARTERIAL HYPERTENSION ^† 1	15/159 (9.43%)	35/174 (20.11%)
EPISTAXIS ^† 1	12/159 (7.55%)	6/174 (3.45%)
NASAL CONGESTION ^† 1	8/159 (5.03%)	0/174 (0.00%)
Skin and subcutaneous tissue disorders
RASH ^† 1	10/159 (6.29%)	6/174 (3.45%)
† Indicates events were collected by systematic assessment 1 Term from vocabulary, MedDRA version 16.0

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	Jonathan Tolson
Organization:	Actelion Pharmaceuticals Ltd
Phone:	+41 61 565 56 04
EMail:	jonathon.tolson@actelion.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

McLaughlin V, Channick RN, Ghofrani HA, Lemarie JC, Naeije R, Packer M, Souza R, Tapson VF, Tolson J, Al Hiti H, Meyer G, Hoeper MM. Bosentan added to sildenafil therapy in patients with pulmonary arterial hypertension. Eur Respir J. 2015 Aug;46(2):405-13. doi: 10.1183/13993003.02044-2014. Epub 2015 Jun 25.

Layout table for additonal information

Responsible Party:	Actelion
ClinicalTrials.gov Identifier:	NCT00303459
Other Study ID Numbers:	AC-052-414 COMPASS-2 ( Other Identifier: Actelion Pharmaceuticals Ltd )
First Submitted:	March 16, 2006
First Posted:	March 17, 2006
Results First Submitted:	January 2, 2015
Results First Posted:	January 26, 2015
Last Update Posted:	November 11, 2015

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