BUILD 3: Bosentan Use in Interstitial Lung Disease

• Sponsor: Actelion (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00391443
• Collaborator: (none)
• Enrollment: 616
• Locations: 117
• Arms: 2
• Duration (Months): 40.9
• Patients Per Site: 5.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

BUILD 3 is a prospective, multicenter, randomized, double-blind, parallel group, placebo-controlled, event-driven, group sequential, phase III superiority study. The primary objective is to demonstrate that bosentan delays disease worsening or death in patients with Idiopathic Pulmonary Fibrosis.

Condition or Disease	Intervention/Treatment	Phase
Idiopathic Pulmonary Fibrosis	Drug: Bosentan; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 616 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Effects of Bosentan on Morbidity and Mortality in Patients With Idiopathic Pulmonary Fibrosis - a Multicenter, Double-blind, Randomized, Placebo-controlled, Parallel Group, Event-driven, Group Sequential, Phase III Study.
• Study Start Date: Feb 1, 2007
• Actual Primary Completion Date: Feb 1, 2010
• Actual Study Completion Date: Jul 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Bosentan Subjects receive bosentan 62.5 mg twice daily (b.i.d.) for 4 weeks followed by bosentan 125 mg b.i.d (if body weight > 40 kg) or bosentan 62.5 mg b.i.d. (if body weight < 40 kg)	Drug: Bosentan; Bosentan 62.5 mg tablets twice daily (b.i.d.) for 4 weeks followed by bosentan 125 mg tablets b.i.d (if body weight > 40 kg) or bosentan 62.5 mg tablets b.i.d. (if body weight < 40 kg); Other Names: Ro 47-0203 ACT-050088
Placebo Comparator: Placebo Subjects receive placebo matching the bosentan treatment regimen	Drug: Placebo; Placebo matching bosentan 62.5 mg tablets and 125 mg tablets

Outcome Measures

Primary Outcome Measures

1. Time to Occurrence of Disease Worsening or Death up to End of Study. [36 months]

   Disease worsening was defined as an event of worsening of pulmonary function tests (PFT) or acute exacerbation of idiopathic pulmonary fibrosis (IPF).

Secondary Outcome Measures

1. Percentage of Patients Who Experienced Either Disease Worsening or Death at 1 Year. [12 months]

   Disease worsening was defined as an event of worsening of pulmonary function tests (PFT) or acute exacerbation of idiopathic pulmonary fibrosis (IPF).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Signed informed consent

• Male or female aged 18 years or older (females of child-bearing potential must have been surgically sterilized or use a reliable method of contraception.)

• Proven diagnosis of IPF according to American Thoracic Society / European Respiratory Society (ATS-ERS) statement, of <3 years, with surgical lung biopsy (SLB)

Exclusion Criteria:

• Interstitial lung disease due to conditions other than IPF.

• Presence of extensive honeycombing (HC) on baseline high-resolution computed tomography (HRCT) scan.

• Severe concomitant illness limiting life expectancy (<1 year).

• Severe restrictive lung disease.

• Obstructive lung disease.

• Diffusing capacity of the lung for carbon monoxide <30% predicted.

• Residual volume > or = 120% predicted.

• Documented sustained improvement of patient's IPF condition up to 12 months prior to randomization with or without IPF-specific therapy.

• Recent pulmonary or upper respiratory tract infection (up to 4 weeks prior to randomization).

• Acute or chronic impairment (other than dyspnea) limiting the ability to comply with study requirements.

• Chronic heart failure with New York Heart Association (NYHA) class III/IV or known left ventricular ejection fraction <25%.

• Alanine aminotransferase (ALT/SGPT) and/or aspartate aminotransferase (AST/SGOT) > 1.5 times the upper limit of the normal ranges.

• Moderate to severe hepatic impairment.

• Serum creatinine > or = 2.5 mg/dl or chronic dialysis.

• Hemoglobin concentration <75% the lower limit of the normal ranges.

• Systolic blood pressure <85 mmHg.

• Pregnancy or breast-feeding.

• Current drug or alcohol dependence.

• Chronic treatment with the following drugs prescribed for IPF (within 4 weeks of randomization):oral corticosteroids (>20 mg/day of prednisone or equivalent), immunosuppressive or cytotoxic drugs, antifibrotic drugs, chronic use of N-acetylcysteine (prescribed for IPF).

• Oral anticoagulants other than those indicated for a venous or arterial thrombotic disease.

• Treatment with glibenclamide (glyburide) and calcineurin inhibitors (cyclosporine A, tacrolimus) up to 1 week prior to randomization.

• Treatment with an endothelin receptor antagonist up to 3 months prior to randomization.

• Participation in the BUILD 1 trial.

• Treatment with another investigational drug up to 3 months prior to randomization or planned treatment.

• Known hypersensitivity to bosentan or any of the excipients.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UAB Division of Pulmonary	Birmingham	Alabama	United States	35294
2	Pulmonary Associates	Phoenix	Arizona	United States	85006
3	Mayo Clinic	Scottsdale	Arizona	United States	85259
4	USC University Hospital	Los Angeles	California	United States	90033
5	UCLA-Division of Pulmonary & Critical Care	Los Angeles	California	United States	90095
6	UC Davis University of California	Sacramento	California	United States	95817
7	UCSD Medical Center	San Diego	California	United States	92103
8	UCSF-Interstitial Lung Disease Center	San Francisco	California	United States	94143
9	Pulmonary and Critical Care Medicine-Stanford University Medical Center	Stanford	California	United States	94305
10	National Jewish Medical & Research Center	Denver	Colorado	United States	80206
11	Yale University School of Medicine-Dept of Internal Med-Pulmonary & Critical Care	New Haven	Connecticut	United States	06520
12	PAB Clinical Research	Brandon	Florida	United States	33511
13	Emory University	Atlanta	Georgia	United States	30322
14	University of Chicago - Section of Pulmonary, Dept of Medicine, Respiratory Clinical Research	Chicago	Illinois	United States	60637
15	Consultants in Pulmonary Medicine	Olathe	Kansas	United States	66061
16	Wichita Clinic, P.A.	Wichita	Kansas	United States	67208
17	Boston University School of Medicine	Boston	Massachusetts	United States	02118
18	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
19	University of Minnesota	Minneapolis	Minnesota	United States	55455
20	Mayo Clinic	Rochester	Minnesota	United States	55905
21	St. Luke's Medical Group, Cardio-Pulmonary Research	Chesterfield	Missouri	United States	63017
22	Pulmonary & Allergy Associates, P.A.	Summit	New Jersey	United States	07901
23	Mount Sinai School of Medicine	New York	New York	United States	10029-6574
24	Highland Hospital - Pulmonary Department	Rochester	New York	United States	14620
25	Duke University Medical Center	Durham	North Carolina	United States	27710
26	University of Cincinnati	Cincinnati	Ohio	United States	45267
27	The Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
28	University of Pennsylvania Medical Center	Philadelphia	Pennsylvania	United States	19104
29	Temple University Hospital	Philadelphia	Pennsylvania	United States	19140
30	Medical University of South Carolina	Charleston	South Carolina	United States	29425
31	Vanderbilt Medical Center - IPF Center	Nashville	Tennessee	United States	37232-5735
32	University of Texas-Southwestern Dallas-Div. of Pulm & Critical Care Unit	Dallas	Texas	United States	75390
33	Baylor College of Medicine	Houston	Texas	United States	77030
34	University of Utah	Salt Lake City	Utah	United States	84108
35	Vermont Lung Center	Colchester	Vermont	United States	05446
36	University of Virginia - Div. of Pulmonary & Critical Care	Charlottesville	Virginia	United States	22908
37	Inova Heart and Vascular Institute	Falls Church	Virginia	United States	22042
38	University of Washington Medical Center	Seattle	Washington	United States	98195
39	University of Wisconsin-Madison	Madison	Wisconsin	United States	53792-3240
40	St. Vincent's Public Hospital, Lung Transplantation & Respiratory Medicine	Darlinghurst	New South Wales	Australia	2010
41	Prince Charles Hospital - Lung Transplant, Thoraic Dept.	Chermside	Queensland	Australia	4032
42	Royal Adelaide Hospital-Respiratory Clinical Trials Unit	Adelaide	South Australia	Australia	5000
43	Royal Perth Hospital; Advanced Lung Disease Unit	Perth	Western Australia	Australia	6000
44	Medizinische Universität Graz-Klinische Abteilung für Pulmonologie	Graz		Austria	8036
45	Landesklinikum Thermenregion Hochegg	Grimmenstein		Austria	2840
46	Medical University of Innsbruck-Div. of Clinical & Internal Medicine	Innsbruck		Austria	6020
47	Medical University of Vienna and AKH-Div of Pulmonology	Wien		Austria	1090
48	Otto-Wagner Spital Wien	Wien		Austria	1140
49	UZ Gasthuisberg	Leuven		Belgium	3000
50	Walter C. Mackenzie Health Sciences Centre-Univeristy of Alberta	Edmonton	Alberta	Canada	T6G 2B7
51	The Health Care Corporation of St. John's-Eastern Health	St. John's	Newfoundland and Labrador	Canada	A1B 3V6
52	St. Joseph's Healthcare	Hamilton	Ontario	Canada	L8N 4A6
53	Lawson Health Research Institute	London	Ontario	Canada	N6A 4G5
54	Toronto General Hospital-Rosedale Medical Center PFT Lab	Toronto	Ontario	Canada	M4X 1W4
55	Hopital Notre Dame - Centre Hospitalier de L'Universit de Montreal	Montreal	Quebec	Canada	H2L 4M1
56	Institut de Cardiologie et de Pneumologie de l'Universite Laval	Ste-Foy	Quebec	Canada	G1V 4G5
57	University Hospital for Lung Disease "Jordanovac"	Zagreb		Croatia	10000
58	University Hospital Olomouc - Dept of Respiratory Disease-IP Pavlova	Olomouc		Czech Republic	775 20
59	Thomayer Faculty Hospital Prague-Dept of Respiratory Disease	Praha 4		Czech Republic	140 59
60	University Hospital Na Bulovce	Praha 8		Czech Republic	180 81
61	Hopital Avicenne	Bobigny		France	93009
62	Hopital Louis Pradel	Bron		France	69677
63	HYLAB, Clinique du Mail	Grenoble		France	38100
64	CHRU de Lille-Hopital Albert Calmette	Lille Cedex		France	59037
65	CHU Hôpital Arnaud de Villeneuve	Montpellier		France	34295
66	Hôpital Bichat	Paris		France	75877
67	HELIOS Klinikum Emil von Behring	Berlin		Germany	D-14165
68	Fachkrankenhaus Coswig; Centre for Pulmonology and Thoracic Surgery	Coswig		Germany
69	Klinik Donaustauf-Zentrum für Pneumologie	Donaustauf		Germany	93093
70	Ruhrlandklinik, Pneumologie/Allergologie	Essen		Germany	45239
71	Medizinische Universitätsklinik, Abteilung Pneumologie	Freiburg		Germany	79106
72	Justus-Liebig-Universitat Giessen-Zentrum für Innere Medizin	Giessen		Germany	35392
73	Thoraxklinik Heidelberg GmbH	Heidelberg		Germany	01640
74	Fachklinik fur Lungenerkrankungen	Immenhausen		Germany
75	Klinik Löwenstein GmbH-Medizinische Klinik 1 Pneumologie-Kardiologie	Löwenstein		Germany	74245
76	Klinikum der Universität München Medizinische Klinik und Poliklinik 1 - Grosshadern	Munich		Germany	81377
77	Mater Misicordiae Hospital	Dublin 7		Ireland
78	Rambam Medical Centre-Div. for Pulmonary Disease	Haifa		Israel	31096
79	Hadassah Medical Organization: Ein Karem-Institute of Pulmonology	Jerusalem		Israel	91120
80	Pulmonary Istitute-Rabin Medical Centre: Beilinson Campus	Petach Tikvah		Israel
81	Kaplan Medical Centre-Pulmoary Istitute	Rehovot		Israel	76100
82	Tel-Aviv Sourasky Medical Centre-Institute of Pulmonary & Allergic Diseases	Tel-Aviv		Israel	64239
83	Chaim Sheba Medical Centre	Tel-Hashomer		Israel	52621
84	Azienda Sanitaria di Forli-Presidio Ospedaliero Stabilimento	Forli		Italy	47100
85	Ospedale San Giuseppe Milanocuore, Unita Operativa di Pneumologia	Milan		Italy	20123
86	Azienda Ospedaliero-Universitaria San Luigi Gonzaga	Orbassano (Torino)		Italy	10043
87	Azienda Ospedaliera di Padova - Immunologia Clinica	Padova		Italy	35128
88	Pneumologia ISMETT	Palermo		Italy	90127
89	University degli Studi Siena, Policlinico le Scotte	Siena		Italy	53100
90	Tosei General Hospital	Seto	Aichi	Japan	489-8642
91	Himeji medical center	Himeji	Hyogo	Japan	670-8520
92	Kanagawa Cardiovascular Respiratory Center	Yokohama	Kanagawa	Japan	236-0051
93	Tenri Hospital	Tenri	Nara	Japan	632-8552
94	Kinki - Chuo Chest Medical Center	Sakai	Osaka	Japan	591-8555
95	Gil Medical Centre, Gachon University	Incheon		Korea, Republic of	405-760
96	Seoul National University Hospital	Seoul		Korea, Republic of	110-744
97	Samsung Medical Centre	Seoul		Korea, Republic of	135-710
98	Asan Medical Center	Seoul		Korea, Republic of	138-736
99	SoonChunHyang University Bucheon Hospital	Seoul		Korea, Republic of	420-767
100	Academisch Medisch Centrum Amsterdam	Amsterdam		Netherlands	1105 AZ
101	Institut za Plucne bolest l TBC Klinickog Centra Srbije	Belgrade		Serbia	11000
102	Institut za Plucne bolesti Vojvodine, Sremska Kamenica	Sremska Kamenica		Serbia	21204
103	Hospital Vall d'Hebron-Neumologia	Barcelona		Spain	08035
104	Hospital Clinic Barcelona (Pneumology Service)	Barcelona		Spain	08036
105	Hospital La Princesa	Madrid		Spain	28006
106	Hospital Universitario Ramon y Cajal	Madrid		Spain	28034
107	Hospital Clinico San Carlos	Madrid		Spain	28040
108	Hospital General de Valencia	Valencia		Spain	46014
109	Hospital Universitario Dr. Peset	Valencia		Spain	46017
110	University Hospital Basel-Div of Pneumology	Basel		Switzerland	4031
111	Inselspital Bern-Div of Pulmonary Medicine	Bern		Switzerland	3010
112	University Hopital Zurich-Clinic for Pneumology & Lung Transplant Program	Zurich		Switzerland	8091
113	Aberdeen Royal Infirmary	Aberdeen		United Kingdom	AB25 2ZN
114	Southmead Hospital	Bristol		United Kingdom	BS10 5NB
115	Papworth Hospital	Cambridge		United Kingdom	CB23 3RE
116	Royal Brompton Hospital	London		United Kingdom	SW3 6NP
117	NWLC, Wythenshawe Hospital	Manchester		United Kingdom	M23 9LT

Sponsors and Collaborators

• Actelion

Investigators

• Study Director: Isabelle Leconte, Actelion

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Actelion
• ClinicalTrials.gov Identifier: NCT00391443
• Other Study ID Numbers: AC-052-321
• First Posted: Oct 24, 2006
• Last Update Posted: Sep 28, 2015
• Last Verified: Aug 1, 2015

• Keywords provided by Actelion: BUILD 3; Idiopathic Pulmonary Fibrosis; Tracleer; Interstitial Lung Disease; bosentan; Actelion
• Additional relevant MeSH terms: Pulmonary Fibrosis; Idiopathic Pulmonary Fibrosis; Fibrosis; Bosentan

Study Results

Participant Flow

Arm/Group Title	Placebo	Bosentan
Arm/Group Description	Initial dose: 62.5 mg twice daily (b.i.d.) for 4 weeks. Target dose: - body weight > 40 kg (90 lb): 125 mg b.i.d., (if the initial dose is well tolerated); - body weight < 40 kg (90 lb): 62.5 mg b.i.d.	Initial dose: 62.5 mg twice daily (b.i.d.) for 4 weeks. Target dose: - body weight > 40 kg (90 lb): 125 mg b.i.d., (if the initial dose is well tolerated); - body weight < 40 kg (90 lb): 62.5 mg b.i.d.
Period Title: Overall Study
STARTED	209	407
COMPLETED	209	407
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Placebo	Bosentan	Total
Arm/Group Description	Initial dose: 62.5 mg twice daily (b.i.d.) for 4 weeks. Target dose: - body weight > 40 kg (90 lb): 125 mg b.i.d., (if the initial dose is well tolerated); - body weight < 40 kg (90 lb): 62.5 mg b.i.d.	Initial dose: 62.5 mg twice daily (b.i.d.) for 4 weeks. Target dose: - body weight > 40 kg (90 lb): 125 mg b.i.d., (if the initial dose is well tolerated); - body weight < 40 kg (90 lb): 62.5 mg b.i.d.	Total of all reporting groups
Overall Participants	209	407	616
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63.2 (9.1)	63.8 (8.4)	63.6 (8.6)
Age, Customized (participants) [Number]
Between 18 and 40 years	4 1.9%	5 1.2%	9 1.5%
Between 41 and 60 years	74 35.4%	119 29.2%	193 31.3%
Between 61 and 70 years	87 41.6%	195 47.9%	282 45.8%
> 70 years	44 21.1%	88 21.6%	132 21.4%
Sex: Female, Male (Count of Participants)
Female	76 36.4%	111 27.3%	187 30.4%
Male	133 63.6%	296 72.7%	429 69.6%
Region of Enrollment (participants) [Number]
United States	99 47.4%	185 45.5%	284 46.1%
Serbia	2 1%	0 0%	2 0.3%
Spain	7 3.3%	15 3.7%	22 3.6%
Ireland	2 1%	2 0.5%	4 0.6%
Austria	3 1.4%	4 1%	7 1.1%
Israel	7 3.3%	16 3.9%	23 3.7%
Switzerland	5 2.4%	8 2%	13 2.1%
Italy	8 3.8%	14 3.4%	22 3.6%
United Kingdom	3 1.4%	7 1.7%	10 1.6%
France	9 4.3%	14 3.4%	23 3.7%
Czech Republic	5 2.4%	9 2.2%	14 2.3%
Canada	14 6.7%	30 7.4%	44 7.1%
Belgium	1 0.5%	2 0.5%	3 0.5%
Croatia	0 0%	2 0.5%	2 0.3%
Australia	11 5.3%	22 5.4%	33 5.4%
Germany	10 4.8%	26 6.4%	36 5.8%
Netherlands	0 0%	2 0.5%	2 0.3%
Japan	14 6.7%	26 6.4%	40 6.5%
Korea, Republic of	9 4.3%	23 5.7%	32 5.2%

Outcome Measures

1. Primary Outcome

Title	Time to Occurrence of Disease Worsening or Death up to End of Study.
Description	Disease worsening was defined as an event of worsening of pulmonary function tests (PFT) or acute exacerbation of idiopathic pulmonary fibrosis (IPF).
Time Frame	36 months

Outcome Measure Data

Analysis Population Description

The primary analysis was performed on the Intent To Treat (ITT) population.

Arm/Group Title	Placebo	Bosentan
Arm/Group Description	Initial dose: 62.5 mg twice daily (b.i.d.) for 4 weeks. Target dose: - body weight > 40 kg (90 lb): 125 mg b.i.d., (if the initial dose is well tolerated); - body weight < 40 kg (90 lb): 62.5 mg b.i.d.	Initial dose: 62.5 mg twice daily (b.i.d.) for 4 weeks. Target dose: - body weight > 40 kg (90 lb): 125 mg b.i.d., (if the initial dose is well tolerated); - body weight < 40 kg (90 lb): 62.5 mg b.i.d.
Measure Participants	209	407
month 4 (122 days)	10 4.8%	18 4.4%
month 8 (244 days)	22 10.5%	40 9.8%
month12 (366 days)	43 20.6%	74 18.2%
month 18 (549 days)	74 35.4%	117 28.7%
month 24 (732 days)	88 42.1%	145 35.6%
month 30 (915 days)	94 45%	156 38.3%
month 36 (1098 days)	94 45%	158 38.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Bosentan
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2110
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.850
	Confidence Interval	(2-Sided) 95%; 0.658 to 1.097
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Percentage of Patients Who Experienced Either Disease Worsening or Death at 1 Year.
Description	Disease worsening was defined as an event of worsening of pulmonary function tests (PFT) or acute exacerbation of idiopathic pulmonary fibrosis (IPF).
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Placebo	Bosentan
Arm/Group Description	Initial dose: 62.5 mg twice daily (b.i.d.) for 4 weeks. Target dose: - body weight > 40 kg (90 lb): 125 mg b.i.d., (if the initial dose is well tolerated); - body weight < 40 kg (90 lb): 62.5 mg b.i.d.	Initial dose: 62.5 mg twice daily (b.i.d.) for 4 weeks. Target dose: - body weight > 40 kg (90 lb): 125 mg b.i.d., (if the initial dose is well tolerated); - body weight < 40 kg (90 lb): 62.5 mg b.i.d.
Measure Participants	209	407
Number (95% Confidence Interval) [percentage of participants with event]	23.9 11.4%	19.9 4.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Bosentan
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2542
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Relative risk reduction
	Estimated Value	0.17
	Confidence Interval	(2-Sided) 95%; -0.13 to 0.39
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	All treatment-emergent adverse events occurring after the start of study treatment and within 24 hours after the end of study treatment
Adverse Event Reporting Description	One subject who did not receive study treatment (bosentan) was excluded from the safety population. Events listed as idiopathic pulmonary fibrosis were reported as worsening of idiopathic pulmonary fibrosis.
Arm/Group Title	Placebo		Bosentan
Arm/Group Description	Initial dose: 62.5 mg twice daily (b.i.d.) for 4 weeks. Target dose: - body weight > 40 kg (90 lb): 125 mg b.i.d., (if the initial dose is well tolerated); - body weight < 40 kg (90 lb): 62.5 mg b.i.d.		Initial dose: 62.5 mg twice daily (b.i.d.) for 4 weeks. Target dose: - body weight > 40 kg (90 lb): 125 mg b.i.d., (if the initial dose is well tolerated); - body weight < 40 kg (90 lb): 62.5 mg b.i.d.
All Cause Mortality
	Placebo		Bosentan
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Bosentan
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	74/209 (35.4%)		129/406 (31.8%)
Blood and lymphatic system disorders
ANAEMIA	0/209 (0%)		1/406 (0.2%)
LYMPHADENOPATHY	0/209 (0%)		1/406 (0.2%)
Cardiac disorders
CORONARY ARTERY DISEASE	1/209 (0.5%)		6/406 (1.5%)
MYOCARDIAL INFARCTION	1/209 (0.5%)		4/406 (1%)
ATRIAL FIBRILLATION	0/209 (0%)		3/406 (0.7%)
ANGINA UNSTABLE	0/209 (0%)		2/406 (0.5%)
CARDIAC FAILURE CONGESTIVE	3/209 (1.4%)		1/406 (0.2%)
CORONARY ARTERY STENOSIS	1/209 (0.5%)		1/406 (0.2%)
ACUTE CORONARY SYNDROME	0/209 (0%)		1/406 (0.2%)
ATRIAL FLUTTER	0/209 (0%)		1/406 (0.2%)
CARDIAC ARREST	0/209 (0%)		1/406 (0.2%)
SUPRAVENTRICULAR TACHYCARDIA	0/209 (0%)		1/406 (0.2%)
ANGINA PECTORIS	4/209 (1.9%)		0/406 (0%)
CARDIAC FAILURE	1/209 (0.5%)		0/406 (0%)
VENTRICULAR HYPOKINESIA	1/209 (0.5%)		0/406 (0%)
Ear and labyrinth disorders
MENIERE'S DISEASE	0/209 (0%)		1/406 (0.2%)
VERTIGO	0/209 (0%)		1/406 (0.2%)
Endocrine disorders
GOITRE	1/209 (0.5%)		0/406 (0%)
Gastrointestinal disorders
COLITIS	0/209 (0%)		1/406 (0.2%)
COLONIC POLYP	0/209 (0%)		1/406 (0.2%)
GASTRITIS	0/209 (0%)		1/406 (0.2%)
VOMITING	0/209 (0%)		1/406 (0.2%)
ANAL HAEMORRHAGE	1/209 (0.5%)		0/406 (0%)
DIVERTICULUM INTESTINAL HAEMORRHAGIC	1/209 (0.5%)		0/406 (0%)
DYSKINESIA OESOPHAGEAL	1/209 (0.5%)		0/406 (0%)
INGUINAL HERNIA	1/209 (0.5%)		0/406 (0%)
INTESTINAL OBSTRUCTION	1/209 (0.5%)		0/406 (0%)
LOWER GASTROINTESTINAL HAEMORRHAGE	1/209 (0.5%)		0/406 (0%)
MESENTERIC ARTERIOSCLEROSIS	1/209 (0.5%)		0/406 (0%)
PERITONITIS	1/209 (0.5%)		0/406 (0%)
General disorders
CHEST PAIN	2/209 (1%)		2/406 (0.5%)
PYREXIA	1/209 (0.5%)		2/406 (0.5%)
GENERAL PHYSICAL HEALTH DETERIORATION	0/209 (0%)		1/406 (0.2%)
IMPAIRED HEALING	0/209 (0%)		1/406 (0.2%)
CHEST DISCOMFORT	1/209 (0.5%)		0/406 (0%)
INFLUENZA LIKE ILLNESS	1/209 (0.5%)		0/406 (0%)
Hepatobiliary disorders
BILE DUCT STONE	0/209 (0%)		1/406 (0.2%)
CHOLELITHIASIS	0/209 (0%)		1/406 (0.2%)
HEPATITIS ACUTE	0/209 (0%)		1/406 (0.2%)
CHOLECYSTITIS	2/209 (1%)		0/406 (0%)
CHOLECYSTITIS ACUTE	1/209 (0.5%)		0/406 (0%)
Immune system disorders
ALLERGIC OEDEMA	0/209 (0%)		1/406 (0.2%)
DRUG HYPERSENSITIVITY	0/209 (0%)		1/406 (0.2%)
Infections and infestations
PNEUMONIA	10/209 (4.8%)		16/406 (3.9%)
LOWER RESPIRATORY TRACT INFECTION	5/209 (2.4%)		7/406 (1.7%)
BRONCHITIS	3/209 (1.4%)		2/406 (0.5%)
CLOSTRIDIUM DIFFICILE COLITIS	1/209 (0.5%)		2/406 (0.5%)
APPENDICITIS	2/209 (1%)		1/406 (0.2%)
DEVICE RELATED INFECTION	0/209 (0%)		1/406 (0.2%)
DIVERTICULITIS	0/209 (0%)		1/406 (0.2%)
HERPES ZOSTER OPHTHALMIC	0/209 (0%)		1/406 (0.2%)
PILONIDAL CYST	0/209 (0%)		1/406 (0.2%)
PYELONEPHRITIS	0/209 (0%)		1/406 (0.2%)
UROSEPSIS	0/209 (0%)		1/406 (0.2%)
VIRAL UPPER RESPIRATORY TRACT INFECTION	0/209 (0%)		1/406 (0.2%)
UPPER RESPIRATORY TRACT INFECTION	3/209 (1.4%)		0/406 (0%)
LOBAR PNEUMONIA	2/209 (1%)		0/406 (0%)
ANAL ABSCESS	1/209 (0.5%)		0/406 (0%)
ARTHRITIS BACTERIAL	1/209 (0.5%)		0/406 (0%)
CELLULITIS	1/209 (0.5%)		0/406 (0%)
HERPES ZOSTER OTICUS	1/209 (0.5%)		0/406 (0%)
TRACHEOBRONCHITIS	1/209 (0.5%)		0/406 (0%)
URINARY TRACT INFECTION	1/209 (0.5%)		0/406 (0%)
VIRAL LABYRINTHITIS	1/209 (0.5%)		0/406 (0%)
Injury, poisoning and procedural complications
ROAD TRAFFIC ACCIDENT	0/209 (0%)		2/406 (0.5%)
FALL	1/209 (0.5%)		1/406 (0.2%)
ANKLE FRACTURE	0/209 (0%)		1/406 (0.2%)
EXCORIATION	0/209 (0%)		1/406 (0.2%)
LUMBAR VERTEBRAL FRACTURE	0/209 (0%)		1/406 (0.2%)
RIB FRACTURE	0/209 (0%)		1/406 (0.2%)
TENDON RUPTURE	0/209 (0%)		1/406 (0.2%)
UPPER LIMB FRACTURE	0/209 (0%)		1/406 (0.2%)
CONTUSION	1/209 (0.5%)		0/406 (0%)
HIP FRACTURE	1/209 (0.5%)		0/406 (0%)
Investigations
LIVER FUNCTION TEST ABNORMAL	0/209 (0%)		4/406 (1%)
PULMONARY FUNCTION TEST DECREASED	0/209 (0%)		2/406 (0.5%)
Metabolism and nutrition disorders
DEHYDRATION	1/209 (0.5%)		1/406 (0.2%)
HYPOVOLAEMIA	0/209 (0%)		1/406 (0.2%)
Musculoskeletal and connective tissue disorders
BACK PAIN	3/209 (1.4%)		3/406 (0.7%)
OSTEOARTHRITIS	1/209 (0.5%)		2/406 (0.5%)
ARTHRALGIA	0/209 (0%)		1/406 (0.2%)
ROTATOR CUFF SYNDROME	0/209 (0%)		1/406 (0.2%)
SJOGREN'S SYNDROME	0/209 (0%)		1/406 (0.2%)
BURSITIS	1/209 (0.5%)		0/406 (0%)
COSTOCHONDRITIS	1/209 (0.5%)		0/406 (0%)
FRACTURE NONUNION	1/209 (0.5%)		0/406 (0%)
JOINT EFFUSION	1/209 (0.5%)		0/406 (0%)
POLYARTHRITIS	1/209 (0.5%)		0/406 (0%)
SPINAL COLUMN STENOSIS	1/209 (0.5%)		0/406 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
PROSTATE CANCER	0/209 (0%)		4/406 (1%)
BLADDER CANCER	0/209 (0%)		2/406 (0.5%)
COLON CANCER	0/209 (0%)		1/406 (0.2%)
LUNG ADENOCARCINOMA	0/209 (0%)		1/406 (0.2%)
LUNG NEOPLASM	0/209 (0%)		1/406 (0.2%)
NON-HODGKIN'S LYMPHOMA	0/209 (0%)		1/406 (0.2%)
SQUAMOUS CELL CARCINOMA OF SKIN	0/209 (0%)		1/406 (0.2%)
LUNG NEOPLASM MALIGNANT	1/209 (0.5%)		0/406 (0%)
Nervous system disorders
SYNCOPE	2/209 (1%)		1/406 (0.2%)
DIZZINESS	1/209 (0.5%)		1/406 (0.2%)
CEREBRAL HAEMORRHAGE	0/209 (0%)		1/406 (0.2%)
TRANSIENT ISCHAEMIC ATTACK	0/209 (0%)		1/406 (0.2%)
CAROTID ARTERY OCCLUSION	1/209 (0.5%)		0/406 (0%)
DEMENTIA	1/209 (0.5%)		0/406 (0%)
HAEMORRHAGIC STROKE	1/209 (0.5%)		0/406 (0%)
NEUROPATHY PERIPHERAL	1/209 (0.5%)		0/406 (0%)
SOMNOLENCE	1/209 (0.5%)		0/406 (0%)
Psychiatric disorders
ANXIETY	0/209 (0%)		1/406 (0.2%)
DEPRESSION	0/209 (0%)		1/406 (0.2%)
PANIC DISORDER	0/209 (0%)		1/406 (0.2%)
Renal and urinary disorders
HAEMATURIA	0/209 (0%)		3/406 (0.7%)
RENAL MASS	0/209 (0%)		1/406 (0.2%)
RENAL FAILURE ACUTE	1/209 (0.5%)		0/406 (0%)
Reproductive system and breast disorders
BENIGN PROSTATIC HYPERPLASIA	0/209 (0%)		1/406 (0.2%)
PROSTATISM	1/209 (0.5%)		0/406 (0%)
Respiratory, thoracic and mediastinal disorders
IDIOPATHIC PULMONARY FIBROSIS	17/209 (8.1%)		41/406 (10.1%)
DYSPNOEA	0/209 (0%)		6/406 (1.5%)
PULMONARY EMBOLISM	1/209 (0.5%)		4/406 (1%)
RESPIRATORY FAILURE	1/209 (0.5%)		4/406 (1%)
ACUTE RESPIRATORY FAILURE	0/209 (0%)		2/406 (0.5%)
PULMONARY HYPERTENSION	0/209 (0%)		2/406 (0.5%)
ACUTE RESPIRATORY DISTRESS SYNDROME	1/209 (0.5%)		1/406 (0.2%)
COUGH	1/209 (0.5%)		1/406 (0.2%)
ACUTE INTERSTITIAL PNEUMONITIS	0/209 (0%)		1/406 (0.2%)
BRONCHOSPASM	0/209 (0%)		1/406 (0.2%)
DYSPNOEA EXERTIONAL	0/209 (0%)		1/406 (0.2%)
HAEMOPTYSIS	0/209 (0%)		1/406 (0.2%)
NASAL CONGESTION	0/209 (0%)		1/406 (0.2%)
PLEURAL EFFUSION	0/209 (0%)		1/406 (0.2%)
PULMONARY OEDEMA	0/209 (0%)		1/406 (0.2%)
PNEUMOTHORAX	2/209 (1%)		0/406 (0%)
HYPOXIA	1/209 (0.5%)		0/406 (0%)
Skin and subcutaneous tissue disorders
PRURITUS ALLERGIC	0/209 (0%)		1/406 (0.2%)
Surgical and medical procedures
CHOLECYSTECTOMY	0/209 (0%)		1/406 (0.2%)
TRANSURETHRAL PROSTATECTOMY	0/209 (0%)		1/406 (0.2%)
LUNG TRANSPLANT	1/209 (0.5%)		0/406 (0%)
Vascular disorders
DEEP VEIN THROMBOSIS	1/209 (0.5%)		2/406 (0.5%)
HYPOTENSION	1/209 (0.5%)		1/406 (0.2%)
INTERMITTENT CLAUDICATION	0/209 (0%)		1/406 (0.2%)
ORTHOSTATIC HYPOTENSION	0/209 (0%)		1/406 (0.2%)
HYPERTENSION	1/209 (0.5%)		0/406 (0%)
TEMPORAL ARTERITIS	1/209 (0.5%)		0/406 (0%)
VASCULITIS	1/209 (0.5%)		0/406 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Bosentan
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	200/209 (95.7%)		386/406 (95.1%)
Gastrointestinal disorders
NAUSEA	15/209 (7.2%)		27/406 (6.7%)
General disorders
FATIGUE	15/209 (7.2%)		46/406 (11.3%)
OEDEMA PERIPHERAL	23/209 (11%)		37/406 (9.1%)
CHEST PAIN	12/209 (5.7%)		24/406 (5.9%)
Infections and infestations
UPPER RESPIRATORY TRACT INFECTION	59/209 (28.2%)		114/406 (28.1%)
BRONCHITIS	28/209 (13.4%)		44/406 (10.8%)
NASOPHARYNGITIS	22/209 (10.5%)		40/406 (9.9%)
SINUSITIS	18/209 (8.6%)		38/406 (9.4%)
LOWER RESPIRATORY TRACT INFECTION	18/209 (8.6%)		26/406 (6.4%)
Investigations
ALANINE AMINOTRANSFERASE INCREASED	7/209 (3.3%)		27/406 (6.7%)
LIVER FUNCTION TEST ABNORMAL	0/209 (0%)		26/406 (6.4%)
ASPARTATE AMINOTRANSFERASE INCREASED	6/209 (2.9%)		23/406 (5.7%)
Musculoskeletal and connective tissue disorders
ARTHRALGIA	17/209 (8.1%)		30/406 (7.4%)
BACK PAIN	16/209 (7.7%)		24/406 (5.9%)
Nervous system disorders
HEADACHE	22/209 (10.5%)		44/406 (10.8%)
DIZZINESS	17/209 (8.1%)		24/406 (5.9%)
Respiratory, thoracic and mediastinal disorders
IDIOPATHIC PULMONARY FIBROSIS	59/209 (28.2%)		92/406 (22.7%)
COUGH	51/209 (24.4%)		78/406 (19.2%)
DYSPNOEA	24/209 (11.5%)		57/406 (14%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

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

Actelion, with steering committee, shall complete the review and provide any modifications required to protect Actelion's patent rights and confidential information within sixty (60) days of receipt of the proposed publication. During this period, Investigator shall not permit publication. If Actelion reasonably anticipates filing a patent application claiming an invention arising out of the Study, such publication shall be delayed until after the application is filed.