Compass-2: Effects of the Combination of Bosentan and Sildenafil Versus Sildenafil Monotherapy on Pulmonary Arterial Hypertension (PAH)
Sponsor
Actelion (Industry)
Overall Status
Completed
CT.gov ID
NCT00303459
Collaborator
(none)
334
68
2
91
4.9
0.1
Study Details
Study Description
Brief Summary
COMPASS-2 is a Phase 4, prospective, randomized, double-blind, placebo-controlled, event-driven study evaluating the effect of bosentan on the time to first confirmed morbidity/mortality event in patients with symptomatic PAH already receiving sildenafil therapy. Patients must have been receiving doses of sildenafil equal to or greater than 20 mg t.i.d. for at least 12 weeks prior to being randomized.
The study continued until the predefined target number of morbidity/mortality events was reached.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 4 |
Study Design
Study Type:
Interventional
Actual Enrollment
:
334 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
Effects of Combination of Bosentan and Sildenafil Versus Sildenafil Monotherapy on Morbidity and Mortality in Symptomatic Patients With Pulmonary Arterial Hypertension - A Multicenter, Double-blind, Randomized, Placebo-controlled, Parallel Group, Prospective, Event Driven Phase IV Study
Study Start Date
:
May 1, 2006
Actual Primary Completion Date
:
Dec 1, 2013
Actual Study Completion Date
:
Dec 1, 2013
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: A Bosentan |
Drug: bosentan
bosentan/62.5 mg tablet/b.i.d. for 4 weeks then bosentan/125 mg tablet/b.i.d.
|
| Placebo Comparator: B Placebo |
Drug: placebo
Matching bosentan placebo/b.i.d.
|
Outcome Measures
Primary Outcome Measures
- Time to First Confirmed Morbidity/Mortality Event up to the End of Study [From baseline to end of study, approximately 86 months]
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.
Secondary Outcome Measures
- Time to First Confirmed Death, Hospitalization for Worsening or Complication of PAH or Initiation of Intravenous Prostanoids, Atrial Septostomy, or Lung Transplantation [Baseline to end of study, approximately 86 months]
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.
- Change From Baseline to Week 16 in 6 Minute Walk Test (6MWT) [From baseline to week 16]
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.
- Number of Participants With Improved, No Change, or Worsened World Health Organisation Functional Class From Baseline to Week 16 [From baseline to Week 16]
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 to Death of All Causes From Baseline to End of Study [Baseline to End of Study, approximately 86 months]
Kaplan-Meier estimate of percentage of participants without a mortality event.Time to death due to any cause.
- Adjusted Percentage Ratio From Baseline in N-terminal Pro-B-type Natriuretic Peptide (NT-pro-BNP) [Baseline to Month 20]
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.
- Change From Baseline to Week 16 in Borg Dyspnea Index [Baseline to Week 16]
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').
- Change From Baseline to Week 16 in the EuroQol 5 Dimensions (EQ-5D) Questionnaire Calculated Score [From baseline to Week 16]
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).
- Change From Baseline to Week 16 in the EuroQol 5 Dimensions (EQ-5D) Visual Analogue Scale Score [Baseline to Week 16]
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.
- Patient Global Self Assessment (PGSA) Status at Week 16 [Week 16]
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.
Eligibility Criteria
Criteria
Ages Eligible for Study:
12 Years
and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
-
Signed informed consent prior to initiation of any study-mandated procedure
-
Males or females >=12 years of age (except for countries where this age limit is contrary to specific regulatory requirements).
- Women of childbearing potential must have a negative pretreatment pregnancy test and must use a reliable method of contraception during study treatment and for at least 3 months after study treatment termination.
·Reliable methods of contraception are:
O Barrier type devices (e.g., female condom, diaphragm, contraceptive sponge) only in combination with a spermicide.
O Intrauterine devices. O Oral, transdermal, injectable or implantable contraceptives only in combination with a barrier method.
-
Hormone-based contraceptives alone, regardless of the route of administration, are not considered as reliable methods of contraception.
-
Abstention, rhythm method, and contraception by the partner alone are not acceptable methods of contraception.
-
Women not of childbearing potential are defined as postmenopausal (i.e., amenorrhea for at least 1 year), or documented surgically or naturally sterile.
-
Patients with symptomatic PAH
-
Patients with the following types of PAH belonging to WHO Group I:
-
Idiopathic (IPAH)
-
Familial (FPAH)
-
Associated with (APAH):
- Collagen vascular disease with normal left ventricular function (ejection fraction (EF) > 50%) ii. Congenital systemic-to-pulmonary shunts at least 2 years post surgical repair iii. Drugs and toxins
- PAH diagnosed by right heart catheter showing:
-
Mean pulmonary arterial pressure (mPAP) >= 25 mm Hg AND
-
Pulmonary capillary wedge pressure (PCWP) =< 15 mm Hg or left ventricular end diastolic pressure (LVEDP) =< 15 mmHg If both PCWP and LVEDP are available then the LVEDP value is retained for inclusion.
- Treatment with a stable dose of sildenafil equal to or greater than 20 mg t.i.d. for at least 12 weeks prior to randomization (no sildenafil dosage adjustment should occur in this period) 7)150 m =< 6-minute walk test (6MWT) =< 480 m, documented by 2 tests with second 6MWT within 15% of first 6MWT distance or a third test required
Exclusion Criteria :
-
PAH belonging to WHO group II-V
-
PAH associated with portal hypertension and HIV infection
-
PAH associated with thyroid disorders, glycogen storage disease, Gaucher disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders and splenectomy
-
PAH associated with significant venous or capillary involvement (PCWP > 15 mmHg): pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis
-
Persistent pulmonary hypertension of the newborn
-
Significant valvular disease with valvular lesions to be excluded by echocardiogram within 2 years prior to randomization (i.e. patients with tricuspid or pulmonary insufficiency secondary to PAH can be included)
-
Restrictive lung disease: total lung capacity (TLC) < 60% of normal predicted value (see Appendix 3)
-
Obstructive lung disease: forced expiratory volume/forced vital capacity (FEV1/FVC) < 0.5
-
Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C
-
Known HIV infection
-
Acute or chronic impairment (other than dyspnea), limiting the ability to comply with study requirements or that may interfere with the safety or the evaluation of the study, such as chronic infection, chronic renal failure etc.
-
Psychotic, addictive or other disorder limiting the ability to provide informed consent or to comply with study requirements
-
Pregnancy or breast-feeding
-
Condition that prevents compliance with the protocol or adherence to therapy
-
Systolic blood pressure < 85 mmHg
-
Body weight < 40 kg
-
Hemoglobin <75% of the lower limit of the normal range
-
Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 1.5 times the upper limit of normal ranges
-
Known hypersensitivity or history of drug-related adverse events with bosentan (e.g. increase in liver function test results), or any of the excipients of its formulation
-
Receipt of an investigational product other than sildenafil within 3 months before start of study treatment
-
Treatment with endothelin receptor antagonists (ERAs), prostanoids or phosphodiesterase (PDE) 5 inhibitors other than sildenafil within 3 months prior to randomization
-
Concomitant systemic treatment within 1 week prior to randomization with
-
calcineurin inhibitors (e.g., cyclosporine A and tacrolimus), sirolimus and everolimus
-
glibenclamide (glyburide)
-
both cytochrome P2C9 (CYP2C9) and cytochrome P3A4 (CYP3A4) (e.g., fluconazole, amiodarone, voriconazole)
-
combination of drugs that inhibit CYP2C9 and CYP3A4
-
Treatment with nitrates and alpha-blockers at time of randomization
-
In the opinion of the investigator - patients in need for treatment with any prostanoid up to Visit 4
-
Significant left ventricular dysfunction
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | UCSD Medical Center, Thornton Hospital | La Jolla | California | United States | 92037-7381 |
| 2 | Greater Los Angeles VA Medical Center | Los Angeles | California | United States | 90073 |
| 3 | University of California (UC) Davis Health System | Sacramento | California | United States | 95817 |
| 4 | UCSF | San Francisco | California | United States | 94143 |
| 5 | University of Colorado Health Sciences Center | Denver | Colorado | United States | 80220 |
| 6 | University of Connecticut | Farmington | Connecticut | United States | 06030 |
| 7 | Yale University School of Medicine, Dept. of Internal Medicine, Pulmonary & Critical Care | New Haven | Connecticut | United States | 06520-8057 |
| 8 | Bay Area Chest Physicians | Clearwater | Florida | United States | 33756 |
| 9 | Shands Hospital at the University of Florida | Gainesville | Florida | United States | 30067 |
| 10 | University of Florida - Jacksonville | Jacksonville | Florida | United States | 32209 |
| 11 | Mayo Clinic Jacksonville | Jacksonville | Florida | United States | 32224 |
| 12 | Winthrop University Hospital | Mineola | Georgia | United States | 30067 |
| 13 | University of Iowa Pulmonary Hypertension Program | Iowa City | Iowa | United States | 52242 |
| 14 | University of Kansas Medical Center | Kansas City | Kansas | United States | 66160 |
| 15 | UK Medical Center - University of Kentucky | Lexington | Kentucky | United States | 40536-0294 |
| 16 | University of Maryland - School of Medicine | Baltimore | Maryland | United States | 21201-1595 |
| 17 | Johns Hopkins University | Baltimore | Maryland | United States | 21205 |
| 18 | Tufts - New England Medical Center | Boston | Massachusetts | United States | 02111 |
| 19 | University of Michigan Cardiology | Ann Arbor | Michigan | United States | 48109 |
| 20 | Harper University Hospital - Wayne State University | Detroit | Michigan | United States | 48201 |
| 21 | Spectrum Health Research Department | Grand Rapids | Michigan | United States | 49525 |
| 22 | University of Minnesota Department of Medicine - Cardiovascular Division | Minneapolis | Minnesota | United States | 55455 |
| 23 | Mayo Clinic | Rochester | Minnesota | United States | 55905 |
| 24 | St. Luke's Hospital | Chesterfield | Missouri | United States | 63017 |
| 25 | Washington University | St. Louis | Missouri | United States | 63110 |
| 26 | Dartmouth Hitchcock Medical Center | Lebanon | New Hampshire | United States | 03756-0001 |
| 27 | Duke University Medical Center (DUMC) | Durham | North Carolina | United States | 27710 |
| 28 | Lindner Clinical Trials Center | Cincinnati | Ohio | United States | 45219 |
| 29 | The Cleveland Clinic Foundation | Cleveland | Ohio | United States | 44195 |
| 30 | Ohio State University - Pulmonary Clinical Trials Office - Martha Morehouse Medical Plaza | Columbus | Ohio | United States | 43210 |
| 31 | The Oregon Clinic - Pulmonary and Critical Care Medicine | Portland | Oregon | United States | 97220 |
| 32 | Allegheny General Hospital | Pittsburgh | Pennsylvania | United States | 15212 |
| 33 | University of Pittsburgh Medical Center - Presbyterian Cardiovascular Institute | Pittsburgh | Pennsylvania | United States | 15213 |
| 34 | Medical University of South Carolina (MUSC) | Charleston | South Carolina | United States | 29425 |
| 35 | Mid Carolina Internal Medicine | Lexington | South Carolina | United States | 29072 |
| 36 | South Carolina Pharmaceutical Research | Spartanburg | South Carolina | United States | 29303 |
| 37 | University of Texas Medical Branch | Galveston | Texas | United States | 77555-0561 |
| 38 | Baylor Clinic | Houston | Texas | United States | 77030 |
| 39 | Inova Fairfax Hospital | Falls Church | Virginia | United States | 22042-3300 |
| 40 | Froedtert Memorial Lutheran Hospital | Milwaukee | Wisconsin | United States | 53226 |
| 41 | Hospital de Messejana | Fortaleza | CE | Brazil | 60864-190 |
| 42 | Hospital Universitário de Brasília | Brasília | DF | Brazil | 70840-050 |
| 43 | Hospital das Clínicas - UFMG | Belo Horizonte | MG | Brazil | 30130-100 |
| 44 | Hospital Madre Teresa | Belo Horizonte | Brazil | 30430-142 | |
| 45 | CHSCPA | Porto Alegre | Brazil | 90020-090 | |
| 46 | Instituto Dante Pazzanese | Sao Paulo | Brazil | 04012-909 | |
| 47 | UNIFESP - Pneumologia | Sao Paulo | Brazil | 04023-062 | |
| 48 | Hospital das Clínicas - FMUSP | Sao Paulo | Brazil | 05403-000 | |
| 49 | Vseobecna Fakultni Nemocnice | Praha | Czech Republic | 128 08 | |
| 50 | Kardiologicka klinika Videnska | Praha | Czech Republic | 140 21 | |
| 51 | Rigshospitalet | Copenhagen | Denmark | 2100 | |
| 52 | Universitätsklinikum Giessen und Marburg, Standort Giessen Zentrum für Innere Medizin | Giessen | Germany | 35392 | |
| 53 | Medizinische Hochschule Hannover | Hannover | Germany | 30625 | |
| 54 | Medizinische Klinik der Universitat Innere Medizin III | Heidelberg | Germany | 69120 | |
| 55 | Klinik Lowenstein GmbH | Loewenstein | Germany | 74245 | |
| 56 | Universitatsklinikum Regensburg | Regensburg | Germany | 93053 | |
| 57 | General Hospital Alexandra | Athens | Greece | 11528 | |
| 58 | University General Hospital "Attikon" | Athens | Greece | 12462 | |
| 59 | Rio University Hospital | Patras | Greece | ||
| 60 | Universidade de Coimbra | Coimbra | Portugal | 3000-076 | |
| 61 | Hospital de Santa Maria | Lisbon | Portugal | 1649-035 | |
| 62 | Riyadh Military Hospital | Riyadh | Saudi Arabia | 11159 | |
| 63 | NUSCH, a.s. | Bratislava | Slovakia | ||
| 64 | Vychodoslovensky ustav srdcovych a cievnych chorob, a.s. | Kosice | Slovakia | ||
| 65 | Hospital Universitario Insular de Gran Canaria | Las Palmas de Gran Canaria | Spain | 35016 | |
| 66 | Hospital Universitario 12 Octubre | Madrid | Spain | 28041 | |
| 67 | Sahlgrenska University Hospital | Gothenburg | Sweden | ||
| 68 | Royal Hallamshire Hospital | Sheffield | United Kingdom | S102JF |
Sponsors and Collaborators
- Actelion
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.Responsible Party:
Actelion
ClinicalTrials.gov Identifier:
NCT00303459
Other Study ID Numbers:
- AC-052-414
- COMPASS-2
First Posted:
Mar 17, 2006
Last Update Posted:
Nov 11, 2015
Last Verified:
Oct 1, 2015
Keywords provided by Actelion
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | First subject, first visit was17 May 2006 and last subject, last visit was 05 Dec 2013. |
|---|---|
| Pre-assignment Detail | 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 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 |
| COMPLETED | 76 | 86 |
| NOT COMPLETED | 83 | 89 |
Baseline Characteristics
| Arm/Group Title | Bosentan | Placebo | Total |
|---|---|---|---|
| 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 Participants | 159 | 175 | 334 |
| Age (years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [years] |
52.9
(15.44)
|
54.7
(15.73)
|
53.9
(15.60)
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
125
78.6%
|
128
73.1%
|
253
75.7%
|
| Male |
34
21.4%
|
47
26.9%
|
81
24.3%
|
| Race/Ethnicity, Customized (participants) [Number] | |||
| Caucasian/White |
147
92.5%
|
149
85.1%
|
296
88.6%
|
| Black |
7
4.4%
|
12
6.9%
|
19
5.7%
|
| Hispanic |
5
3.1%
|
6
3.4%
|
11
3.3%
|
| Other |
0
0%
|
8
4.6%
|
8
2.4%
|
| Region of Enrollment (participants) [Number] | |||
| Brazil |
36
22.6%
|
35
20%
|
71
21.3%
|
| Czech Republic |
12
7.5%
|
15
8.6%
|
27
8.1%
|
| Denmark |
3
1.9%
|
4
2.3%
|
7
2.1%
|
| Germany |
19
11.9%
|
22
12.6%
|
41
12.3%
|
| Greece |
4
2.5%
|
5
2.9%
|
9
2.7%
|
| Portugal |
3
1.9%
|
0
0%
|
3
0.9%
|
| Saudi Arabia |
0
0%
|
1
0.6%
|
1
0.3%
|
| Slovakia |
4
2.5%
|
3
1.7%
|
7
2.1%
|
| Spain |
1
0.6%
|
1
0.6%
|
2
0.6%
|
| Sweden |
4
2.5%
|
5
2.9%
|
9
2.7%
|
| United Kingdom |
0
0%
|
1
0.6%
|
1
0.3%
|
| United States |
73
45.9%
|
83
47.4%
|
156
46.7%
|
Outcome Measures
| Title | Time to First Confirmed Morbidity/Mortality Event up to the End of Study |
|---|---|
| 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 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. |
| Measure Participants | 159 | 175 |
| Kaplan-Meier estimate at Month 4 |
96.1
60.4%
|
90.6
51.8%
|
| Kaplan-Meier estimate at Month 8 |
90.5
56.9%
|
83.0
47.4%
|
| Kaplan-Meier estimate at Month 12 |
82.7
52%
|
74.0
42.3%
|
| Kaplan-Meier estimate at Month 16 |
74.7
47%
|
71.0
40.6%
|
| Kaplan-Meier estimate at Month 20 |
71.8
45.2%
|
66.1
37.8%
|
| Kaplan-Meier estimate at Month 24 |
66.6
41.9%
|
61.5
35.1%
|
| Kaplan-Meier estimate at Month 28 |
65.8
41.4%
|
55.0
31.4%
|
| Kaplan-Meier estimate at Month 32 |
62.4
39.2%
|
52.7
30.1%
|
| Kaplan-Meier estimate at Month 34 |
57.5
36.2%
|
48.8
27.9%
|
| Kaplan-Meier estimate at Month 40 |
56.4
35.5%
|
48.0
27.4%
|
| Kaplan-Meier estimate at Month 44 |
50.6
31.8%
|
46.2
26.4%
|
| Kaplan-Meier estimate at Month 48 |
46.7
29.4%
|
45.2
25.8%
|
| Kaplan-Meier estimate at Month 52 |
45.1
28.4%
|
45.2
25.8%
|
| Kaplan-Meier estimate at Month 56 |
45.1
28.4%
|
42.6
24.3%
|
| Kaplan-Meier estimate at Month 60 |
45.1
28.4%
|
39.7
22.7%
|
| Kaplan-Meier estimate at Month 64 |
45.1
28.4%
|
39.7
22.7%
|
| Kaplan-Meier estimate at Month 68 |
40.1
25.2%
|
39.7
22.7%
|
| Kaplan-Meier estimate at Month 72 |
40.1
25.2%
|
39.7
22.7%
|
| Kaplan-Meier estimate at Month 76 |
40.1
25.2%
|
36.1
20.6%
|
| Kaplan-Meier estimate at Month 80 |
40.1
25.2%
|
36.1
20.6%
|
| Kaplan-Meier estimate at Month 84 |
40.1
25.2%
|
36.1
20.6%
|
| Kaplan-Meier estimate at End of Study |
40.1
25.2%
|
36.1
20.6%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Bosentan, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.2508 |
| Comments | ||
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.831 | |
| Confidence Interval |
(2-Sided) 97.31% 0.582 to 1.187 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| 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 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 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. |
| Measure Participants | 159 | 175 |
| Kaplan-Meier estimate at Month 4 |
97.4
61.3%
|
95.3
54.5%
|
| Kaplan-Meier estimate at Month 8 |
94.6
59.5%
|
91.8
52.5%
|
| Kaplan-Meier estimate at Month 12 |
89.6
56.4%
|
88.8
50.7%
|
| Kaplan-Meier estimate at Month 16 |
85.3
53.6%
|
86.9
49.7%
|
| Kaplan-Meier estimate at Month 20 |
82.3
51.8%
|
83.8
47.9%
|
| Kaplan-Meier estimate at Month 24 |
76.9
48.4%
|
79.8
45.6%
|
| Kaplan-Meier estimate at Month 28 |
76.1
47.9%
|
74.7
42.7%
|
| Kaplan-Meier estimate at Month 32 |
75.2
47.3%
|
73.1
41.8%
|
| Kaplan-Meier estimate at Month 36 |
72.2
45.4%
|
64.4
36.8%
|
| Kaplan-Meier estimate at Month 40 |
72.2
45.4%
|
61.9
35.4%
|
| Kaplan-Meier estimate at Month 44 |
64.2
40.4%
|
60.1
34.3%
|
| Kaplan-Meier estimate at Month 48 |
60.3
37.9%
|
58.1
33.2%
|
| Kaplan-Meier estimate at Month 52 |
57.4
36.1%
|
56.8
32.5%
|
| Kaplan-Meier estimate at Month 56 |
53.8
33.8%
|
52.7
30.1%
|
| Kaplan-Meier estimate at Month 60 |
53.8
33.8%
|
51.3
29.3%
|
| Kaplan-Meier estimate at Month 64 |
53.8
33.8%
|
51.3
29.3%
|
| Kaplan-Meier estimate at Month 68 |
39.8
25%
|
49.2
28.1%
|
| Kaplan-Meier estimate at Month 72 |
39.8
25%
|
49.2
28.1%
|
| Kaplan-Meier estimate at Month 76 |
39.8
25%
|
45.1
25.8%
|
| Kaplan-Meier estimate at Month 80 |
39.8
25%
|
45.1
25.8%
|
| Kaplan-Meier estimate at Month 84 |
39.8
25%
|
45.1
25.8%
|
| Kaplan-Meier estimate at End of Study |
39.8
25%
|
45.1
25.8%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Bosentan, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.8385 |
| Comments | ||
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.963 | |
| Confidence Interval |
(2-Sided) 95% 0.673 to 1.380 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| 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 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 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. |
| Measure Participants | 159 | 175 |
| 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 | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0106 |
| Comments | ||
| Method | Wilcoxon (Mann-Whitney) | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Net) |
| Estimated Value | 21.8 | |
| Confidence Interval |
(2-Sided) 95% 5.9 to 37.8 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| 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 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 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. |
| Measure Participants | 159 | 175 |
| Improved |
25
15.7%
|
28
16%
|
| No change |
121
76.1%
|
130
74.3%
|
| Worsened |
13
8.2%
|
17
9.7%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Bosentan, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 1.0000 |
| Comments | ||
| Method | Fisher Exact | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Relative risk of improvement |
| Estimated Value | 0.98 | |
| Confidence Interval |
(2-Sided) 95% 0.60 to 1.61 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Time to Death of All Causes From Baseline to End of Study |
|---|---|
| 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 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. |
| Measure Participants | 159 | 175 |
| Kaplan-Meier estimate at Month 4 |
99.4
62.5%
|
98.2
56.1%
|
| Kaplan-Meier estimate at Month 8 |
98.7
62.1%
|
95.8
54.7%
|
| Kaplan-Meier estimate at Month 12 |
96.5
60.7%
|
94.0
53.7%
|
| Kaplan-Meier estimate at Month 16 |
92.8
58.4%
|
92.8
53%
|
| Kaplan-Meier estimate at Month 20 |
90.6
57%
|
89.5
51.1%
|
| Kaplan-Meier estimate at Month 24 |
89.1
56%
|
88.2
50.4%
|
| Kaplan-Meier estimate at Month 28 |
85.8
54%
|
85.9
49.1%
|
| Kaplan-Meier estimate at Month 32 |
85.8
54%
|
84.3
48.2%
|
| Kaplan-Meier estimate at Month 36 |
85.8
54%
|
78.5
44.9%
|
| Kaplan-Meier estimate at Month 40 |
85.8
54%
|
76.8
43.9%
|
| Kaplan-Meier estimate at Month 44 |
81.4
51.2%
|
74.9
42.8%
|
| Kaplan-Meier estimate at Month 48 |
77.7
48.9%
|
71.8
41%
|
| Kaplan-Meier estimate at Month 52 |
75.0
47.2%
|
70.5
40.3%
|
| Kaplan-Meier estimate at Month 56 |
70.1
44.1%
|
66.4
37.9%
|
| Kaplan-Meier estimate at Month 60 |
67.8
42.6%
|
64.9
37.1%
|
| Kaplan-Meier estimate at Month 64 |
67.8
42.6%
|
64.9
37.1%
|
| Kaplan-Meier estimate at Month 68 |
67.8
42.6%
|
64.9
37.1%
|
| Kaplan-Meier estimate at Month 72 |
67.8
42.6%
|
64.9
37.1%
|
| Kaplan-Meier estimate at Month 76 |
67.8
42.6%
|
60.3
34.5%
|
| Kaplan-Meier estimate at Month 80 |
58.1
36.5%
|
60.3
34.5%
|
| Kaplan-Meier estimate at Month 84 |
58.1
36.5%
|
60.3
34.5%
|
| Kaplan-Meier estimate at End of Study |
58.1
36.5%
|
60.3
34.5%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Bosentan, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.4974 |
| Comments | ||
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.855 | |
| Confidence Interval |
(2-Sided) 95% 0.544 to 1.344 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| 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 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 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. |
| Measure Participants | 109 | 117 |
| Month 1 to Baseline |
87.46
|
110.02
|
| Month 4 to Baseline |
92.65
|
113.20
|
| Month 8 to Baseline |
85.21
|
122.87
|
| Month 12 to Baseline |
84.48
|
132.11
|
| Month 16 to Baseline |
92.69
|
129.92
|
| Month 20 to Baseline |
98.36
|
143.17
|
| Treatment effect over 20 months |
92.54
|
121.00
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Bosentan, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0003 |
| Comments | ||
| Method | Repeated measures analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Percentage change over placebo |
| Estimated Value | -23.52 | |
| Confidence Interval |
(2-Sided) 95% -33.69 to -11.79 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Change From Baseline to Week 16 in Borg Dyspnea Index |
|---|---|
| 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 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. |
| Measure Participants | 159 | 175 |
| 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 | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.9566 |
| Comments | ||
| Method | Wilcoxon (Mann-Whitney) | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Net) |
| Estimated Value | -0.01 | |
| Confidence Interval |
(2-Sided) 95% -0.42 to 0.39 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| 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 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 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. |
| Measure Participants | 159 | 175 |
| 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 | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.5571 |
| Comments | ||
| Method | Wilcoxon (Mann-Whitney) | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Net) |
| Estimated Value | 0.020 | |
| Confidence Interval |
(2-Sided) 95% -0.036 to 0.076 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| 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 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 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. |
| Measure Participants | 159 | 175 |
| 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 | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.4086 |
| Comments | ||
| Method | Wilcoxon (Mann-Whitney) | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Net) |
| Estimated Value | 0.2 | |
| Confidence Interval |
(2-Sided) 95% -3.7 to 4.0 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Patient Global Self Assessment (PGSA) Status at Week 16 |
|---|---|
| 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 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. |
| Measure Participants | 150 | 162 |
| Markedly better |
24
15.1%
|
13
7.4%
|
| Moderately better |
23
14.5%
|
30
17.1%
|
| Mildly better |
32
20.1%
|
36
20.6%
|
| No change |
50
31.4%
|
59
33.7%
|
| Mildly worse |
16
10.1%
|
15
8.6%
|
| Moderately worse |
3
1.9%
|
5
2.9%
|
| Markedly worse |
2
1.3%
|
4
2.3%
|
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 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 (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | ||
Serious Adverse Events |
||||
| Bosentan | Placebo | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 73/159 (45.9%) | 102/174 (58.6%) | ||
| Blood and lymphatic system disorders | ||||
| ANAEMIA | 3/159 (1.9%) | 2/174 (1.1%) | ||
| ANAEMIA HAEMOLYTIC AUTOIMMUNE | 1/159 (0.6%) | 0/174 (0%) | ||
| SPLENOMEGALY | 1/159 (0.6%) | 0/174 (0%) | ||
| HYPERSPLENISM | 0/159 (0%) | 1/174 (0.6%) | ||
| THROMBOCYTOPENIA | 0/159 (0%) | 1/174 (0.6%) | ||
| THROMBOTIC THROMBOCYTOPENIC PURPURA | 0/159 (0%) | 1/174 (0.6%) | ||
| Cardiac disorders | ||||
| RIGHT VENTRICULAR FAILURE | 6/159 (3.8%) | 8/174 (4.6%) | ||
| ATRIAL FIBRILLATION | 4/159 (2.5%) | 3/174 (1.7%) | ||
| ATRIAL FLUTTER | 2/159 (1.3%) | 1/174 (0.6%) | ||
| CARDIAC FAILURE CONGESTIVE | 2/159 (1.3%) | 1/174 (0.6%) | ||
| BRADYCARDIA | 2/159 (1.3%) | 0/174 (0%) | ||
| MYOCARDIAL INFARCTION | 1/159 (0.6%) | 2/174 (1.1%) | ||
| COR PULMONALE | 1/159 (0.6%) | 1/174 (0.6%) | ||
| CORONARY ARTERY DISEASE | 1/159 (0.6%) | 1/174 (0.6%) | ||
| SUPRAVENTRICULAR TACHYCARDIA | 1/159 (0.6%) | 1/174 (0.6%) | ||
| ACUTE MYOCARDIAL INFARCTION | 1/159 (0.6%) | 0/174 (0%) | ||
| ACUTE RIGHT VENTRICULAR FAILURE | 1/159 (0.6%) | 0/174 (0%) | ||
| CARDIAC FAILURE | 1/159 (0.6%) | 0/174 (0%) | ||
| TRIFASCICULAR BLOCK | 1/159 (0.6%) | 0/174 (0%) | ||
| CARDIAC ARREST | 0/159 (0%) | 3/174 (1.7%) | ||
| ACUTE CORONARY SYNDROME | 0/159 (0%) | 1/174 (0.6%) | ||
| ANGINA PECTORIS | 0/159 (0%) | 1/174 (0.6%) | ||
| BRADYARRHYTHMIA | 0/159 (0%) | 1/174 (0.6%) | ||
| INTRACARDIAC THROMBUS | 0/159 (0%) | 1/174 (0.6%) | ||
| SICK SINUS SYNDROME | 0/159 (0%) | 1/174 (0.6%) | ||
| Ear and labyrinth disorders | ||||
| SUDDEN HEARING LOSS | 0/159 (0%) | 1/174 (0.6%) | ||
| Eye disorders | ||||
| RETINAL DETACHMENT | 1/159 (0.6%) | 0/174 (0%) | ||
| EYE SWELLING | 0/159 (0%) | 1/174 (0.6%) | ||
| Gastrointestinal disorders | ||||
| GASTROINTESTINAL HAEMORRHAGE | 2/159 (1.3%) | 1/174 (0.6%) | ||
| SMALL INTESTINAL OBSTRUCTION | 2/159 (1.3%) | 0/174 (0%) | ||
| ABDOMINAL PAIN UPPER | 1/159 (0.6%) | 1/174 (0.6%) | ||
| UPPER GASTROINTESTINAL HAEMORRHAGE | 1/159 (0.6%) | 1/174 (0.6%) | ||
| ASCITES | 1/159 (0.6%) | 0/174 (0%) | ||
| DYSPHAGIA | 1/159 (0.6%) | 0/174 (0%) | ||
| GASTROINTESTINAL DISORDER | 1/159 (0.6%) | 0/174 (0%) | ||
| GASTROOESOPHAGEAL REFLUX DISEASE | 1/159 (0.6%) | 0/174 (0%) | ||
| HAEMATOCHEZIA | 1/159 (0.6%) | 0/174 (0%) | ||
| PANCREATITIS | 1/159 (0.6%) | 0/174 (0%) | ||
| RECTAL HAEMORRHAGE | 1/159 (0.6%) | 0/174 (0%) | ||
| ABDOMINAL PAIN | 0/159 (0%) | 3/174 (1.7%) | ||
| CONSTIPATION | 0/159 (0%) | 1/174 (0.6%) | ||
| DIVERTICULUM | 0/159 (0%) | 1/174 (0.6%) | ||
| GASTRITIS | 0/159 (0%) | 1/174 (0.6%) | ||
| HAEMATEMESIS | 0/159 (0%) | 1/174 (0.6%) | ||
| LARGE INTESTINE POLYP | 0/159 (0%) | 1/174 (0.6%) | ||
| OESOPHAGEAL VARICES HAEMORRHAGE | 0/159 (0%) | 1/174 (0.6%) | ||
| General disorders | ||||
| CHEST PAIN | 5/159 (3.1%) | 7/174 (4%) | ||
| GENERAL PHYSICAL HEALTH DETERIORATION | 1/159 (0.6%) | 1/174 (0.6%) | ||
| SUDDEN DEATH | 1/159 (0.6%) | 1/174 (0.6%) | ||
| GENERALISED OEDEMA | 0/159 (0%) | 3/174 (1.7%) | ||
| OEDEMA PERIPHERAL | 0/159 (0%) | 2/174 (1.1%) | ||
| ADVERSE DRUG REACTION | 0/159 (0%) | 1/174 (0.6%) | ||
| ASTHENIA | 0/159 (0%) | 1/174 (0.6%) | ||
| DEATH | 0/159 (0%) | 1/174 (0.6%) | ||
| FATIGUE | 0/159 (0%) | 1/174 (0.6%) | ||
| MULTI-ORGAN FAILURE | 0/159 (0%) | 1/174 (0.6%) | ||
| Hepatobiliary disorders | ||||
| HEPATIC CIRRHOSIS | 1/159 (0.6%) | 1/174 (0.6%) | ||
| BILIARY DYSKINESIA | 0/159 (0%) | 1/174 (0.6%) | ||
| CHOLECYSTITIS | 0/159 (0%) | 1/174 (0.6%) | ||
| CHOLECYSTITIS ACUTE | 0/159 (0%) | 1/174 (0.6%) | ||
| CHOLESTASIS | 0/159 (0%) | 1/174 (0.6%) | ||
| PORTAL HYPERTENSION | 0/159 (0%) | 1/174 (0.6%) | ||
| Immune system disorders | ||||
| DRUG HYPERSENSITIVITY | 1/159 (0.6%) | 1/174 (0.6%) | ||
| HYPERSENSITIVITY | 0/159 (0%) | 1/174 (0.6%) | ||
| Infections and infestations | ||||
| PNEUMONIA | 11/159 (6.9%) | 6/174 (3.4%) | ||
| BRONCHITIS | 6/159 (3.8%) | 3/174 (1.7%) | ||
| GASTROENTERITIS | 3/159 (1.9%) | 5/174 (2.9%) | ||
| CELLULITIS | 3/159 (1.9%) | 0/174 (0%) | ||
| CLOSTRIDIUM DIFFICILE COLITIS | 2/159 (1.3%) | 0/174 (0%) | ||
| DIVERTICULITIS | 2/159 (1.3%) | 0/174 (0%) | ||
| SEPTIC SHOCK | 1/159 (0.6%) | 2/174 (1.1%) | ||
| URINARY TRACT INFECTION | 1/159 (0.6%) | 2/174 (1.1%) | ||
| BRONCHOPNEUMONIA | 1/159 (0.6%) | 1/174 (0.6%) | ||
| PYELONEPHRITIS | 1/159 (0.6%) | 1/174 (0.6%) | ||
| SEPSIS | 1/159 (0.6%) | 1/174 (0.6%) | ||
| UPPER RESPIRATORY TRACT INFECTION | 1/159 (0.6%) | 1/174 (0.6%) | ||
| ABDOMINAL ABSCESS | 1/159 (0.6%) | 0/174 (0%) | ||
| APPENDICITIS | 1/159 (0.6%) | 0/174 (0%) | ||
| CLOSTRIDIUM DIFFICILE INFECTION | 1/159 (0.6%) | 0/174 (0%) | ||
| DENGUE FEVER | 1/159 (0.6%) | 0/174 (0%) | ||
| DEVICE RELATED SEPSIS | 1/159 (0.6%) | 0/174 (0%) | ||
| GASTROENTERITIS SALMONELLA | 1/159 (0.6%) | 0/174 (0%) | ||
| HAEMATOMA INFECTION | 1/159 (0.6%) | 0/174 (0%) | ||
| LOWER RESPIRATORY TRACT INFECTION | 1/159 (0.6%) | 0/174 (0%) | ||
| LUNG INFECTION | 1/159 (0.6%) | 0/174 (0%) | ||
| PNEUMOCOCCAL SEPSIS | 1/159 (0.6%) | 0/174 (0%) | ||
| PNEUMONIA STAPHYLOCOCCAL | 1/159 (0.6%) | 0/174 (0%) | ||
| POSTOPERATIVE WOUND INFECTION | 1/159 (0.6%) | 0/174 (0%) | ||
| VIRAL UPPER RESPIRATORY TRACT INFECTION | 0/159 (0%) | 2/174 (1.1%) | ||
| BACTERAEMIA | 0/159 (0%) | 1/174 (0.6%) | ||
| BRONCHITIS VIRAL | 0/159 (0%) | 1/174 (0.6%) | ||
| ERYSIPELAS | 0/159 (0%) | 1/174 (0.6%) | ||
| GASTROENTERITIS CALICIVIRAL | 0/159 (0%) | 1/174 (0.6%) | ||
| H1N1 INFLUENZA | 0/159 (0%) | 1/174 (0.6%) | ||
| INFECTED DERMAL CYST | 0/159 (0%) | 1/174 (0.6%) | ||
| INFECTIVE EXACERBATION OF CHRONIC OBSTRUCTIVE AIRWAYS DISEASE | 0/159 (0%) | 1/174 (0.6%) | ||
| KLEBSIELLA BACTERAEMIA | 0/159 (0%) | 1/174 (0.6%) | ||
| RESPIRATORY TRACT INFECTION | 0/159 (0%) | 1/174 (0.6%) | ||
| SEPSIS SYNDROME | 0/159 (0%) | 1/174 (0.6%) | ||
| SINUSITIS | 0/159 (0%) | 1/174 (0.6%) | ||
| TUBERCULOSIS | 0/159 (0%) | 1/174 (0.6%) | ||
| UROSEPSIS | 0/159 (0%) | 1/174 (0.6%) | ||
| WOUND INFECTION | 0/159 (0%) | 1/174 (0.6%) | ||
| Injury, poisoning and procedural complications | ||||
| HUMERUS FRACTURE | 2/159 (1.3%) | 0/174 (0%) | ||
| FALL | 1/159 (0.6%) | 2/174 (1.1%) | ||
| HIP FRACTURE | 1/159 (0.6%) | 2/174 (1.1%) | ||
| LACERATION | 1/159 (0.6%) | 1/174 (0.6%) | ||
| RIB FRACTURE | 1/159 (0.6%) | 1/174 (0.6%) | ||
| FOOT FRACTURE | 1/159 (0.6%) | 0/174 (0%) | ||
| POST PROCEDURAL COMPLICATION | 1/159 (0.6%) | 0/174 (0%) | ||
| RENAL HAEMATOMA | 1/159 (0.6%) | 0/174 (0%) | ||
| TRANSFUSION-RELATED ACUTE LUNG INJURY | 1/159 (0.6%) | 0/174 (0%) | ||
| FEMORAL NECK FRACTURE | 0/159 (0%) | 1/174 (0.6%) | ||
| FRACTURED SACRUM | 0/159 (0%) | 1/174 (0.6%) | ||
| INCISIONAL HERNIA | 0/159 (0%) | 1/174 (0.6%) | ||
| LOWER LIMB FRACTURE | 0/159 (0%) | 1/174 (0.6%) | ||
| PELVIC FRACTURE | 0/159 (0%) | 1/174 (0.6%) | ||
| SUBDURAL HAEMATOMA | 0/159 (0%) | 1/174 (0.6%) | ||
| TOXICITY TO VARIOUS AGENTS | 0/159 (0%) | 1/174 (0.6%) | ||
| Investigations | ||||
| LIVER FUNCTION TEST ABNORMAL | 2/159 (1.3%) | 0/174 (0%) | ||
| ALANINE AMINOTRANSFERASE INCREASED | 1/159 (0.6%) | 1/174 (0.6%) | ||
| ASPARTATE AMINOTRANSFERASE INCREASED | 1/159 (0.6%) | 1/174 (0.6%) | ||
| ELECTROCARDIOGRAM QT PROLONGED | 1/159 (0.6%) | 0/174 (0%) | ||
| HEPATIC ENZYME INCREASED | 1/159 (0.6%) | 0/174 (0%) | ||
| VASCULAR RESISTANCE PULMONARY INCREASED | 1/159 (0.6%) | 0/174 (0%) | ||
| BLOOD BILIRUBIN INCREASED | 0/159 (0%) | 1/174 (0.6%) | ||
| WEIGHT DECREASED | 0/159 (0%) | 1/174 (0.6%) | ||
| Metabolism and nutrition disorders | ||||
| DEHYDRATION | 3/159 (1.9%) | 0/174 (0%) | ||
| FLUID OVERLOAD | 3/159 (1.9%) | 0/174 (0%) | ||
| HYPERKALAEMIA | 2/159 (1.3%) | 0/174 (0%) | ||
| FLUID RETENTION | 1/159 (0.6%) | 1/174 (0.6%) | ||
| HYPERVOLAEMIA | 1/159 (0.6%) | 0/174 (0%) | ||
| HYPOKALAEMIA | 1/159 (0.6%) | 0/174 (0%) | ||
| DECREASED APPETITE | 0/159 (0%) | 1/174 (0.6%) | ||
| GOUT | 0/159 (0%) | 1/174 (0.6%) | ||
| Musculoskeletal and connective tissue disorders | ||||
| INTERVERTEBRAL DISC PROTRUSION | 1/159 (0.6%) | 0/174 (0%) | ||
| PAIN IN EXTREMITY | 0/159 (0%) | 2/174 (1.1%) | ||
| ARTHRALGIA | 0/159 (0%) | 1/174 (0.6%) | ||
| BACK PAIN | 0/159 (0%) | 1/174 (0.6%) | ||
| COLLAGEN DISORDER | 0/159 (0%) | 1/174 (0.6%) | ||
| CREST SYNDROME | 0/159 (0%) | 1/174 (0.6%) | ||
| DUPUYTREN'S CONTRACTURE | 0/159 (0%) | 1/174 (0.6%) | ||
| HAEMARTHROSIS | 0/159 (0%) | 1/174 (0.6%) | ||
| MUSCULOSKELETAL CHEST PAIN | 0/159 (0%) | 1/174 (0.6%) | ||
| OSTEONECROSIS | 0/159 (0%) | 1/174 (0.6%) | ||
| ROTATOR CUFF SYNDROME | 0/159 (0%) | 1/174 (0.6%) | ||
| SYSTEMIC LUPUS ERYTHEMATOSUS | 0/159 (0%) | 1/174 (0.6%) | ||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||
| BRONCHIOLOALVEOLAR CARCINOMA | 1/159 (0.6%) | 0/174 (0%) | ||
| DIFFUSE LARGE B-CELL LYMPHOMA | 1/159 (0.6%) | 0/174 (0%) | ||
| UTERINE LEIOMYOMA | 1/159 (0.6%) | 0/174 (0%) | ||
| ACOUSTIC NEUROMA | 0/159 (0%) | 1/174 (0.6%) | ||
| BRONCHIAL CARCINOMA | 0/159 (0%) | 1/174 (0.6%) | ||
| CERVIX CARCINOMA | 0/159 (0%) | 1/174 (0.6%) | ||
| INFLAMMATORY CARCINOMA OF THE BREAST | 0/159 (0%) | 1/174 (0.6%) | ||
| MALIGNANT MELANOMA IN SITU | 0/159 (0%) | 1/174 (0.6%) | ||
| MENINGIOMA BENIGN | 0/159 (0%) | 1/174 (0.6%) | ||
| METASTATIC MALIGNANT MELANOMA | 0/159 (0%) | 1/174 (0.6%) | ||
| RECTAL CANCER | 0/159 (0%) | 1/174 (0.6%) | ||
| Nervous system disorders | ||||
| SYNCOPE | 3/159 (1.9%) | 6/174 (3.4%) | ||
| TRANSIENT ISCHAEMIC ATTACK | 1/159 (0.6%) | 3/174 (1.7%) | ||
| NEUROPATHY PERIPHERAL | 1/159 (0.6%) | 0/174 (0%) | ||
| SCIATICA | 1/159 (0.6%) | 0/174 (0%) | ||
| CEREBROVASCULAR ACCIDENT | 0/159 (0%) | 2/174 (1.1%) | ||
| CONVULSION | 0/159 (0%) | 2/174 (1.1%) | ||
| HYPOAESTHESIA | 0/159 (0%) | 2/174 (1.1%) | ||
| BRAIN STEM STROKE | 0/159 (0%) | 1/174 (0.6%) | ||
| DIZZINESS | 0/159 (0%) | 1/174 (0.6%) | ||
| HEADACHE | 0/159 (0%) | 1/174 (0.6%) | ||
| HEMIPARESIS | 0/159 (0%) | 1/174 (0.6%) | ||
| LUMBAR RADICULOPATHY | 0/159 (0%) | 1/174 (0.6%) | ||
| MYASTHENIA GRAVIS | 0/159 (0%) | 1/174 (0.6%) | ||
| PRESYNCOPE | 0/159 (0%) | 1/174 (0.6%) | ||
| Pregnancy, puerperium and perinatal conditions | ||||
| PREGNANCY | 0/159 (0%) | 3/174 (1.7%) | ||
| Psychiatric disorders | ||||
| BIPOLAR I DISORDER | 1/159 (0.6%) | 0/174 (0%) | ||
| DEPRESSION | 1/159 (0.6%) | 0/174 (0%) | ||
| MENTAL STATUS CHANGES | 1/159 (0.6%) | 0/174 (0%) | ||
| SUICIDE ATTEMPT | 1/159 (0.6%) | 0/174 (0%) | ||
| SUICIDAL IDEATION | 0/159 (0%) | 1/174 (0.6%) | ||
| Renal and urinary disorders | ||||
| RENAL FAILURE ACUTE | 1/159 (0.6%) | 4/174 (2.3%) | ||
| BLADDER NECK OBSTRUCTION | 0/159 (0%) | 1/174 (0.6%) | ||
| HAEMATURIA | 0/159 (0%) | 1/174 (0.6%) | ||
| NEPHROLITHIASIS | 0/159 (0%) | 1/174 (0.6%) | ||
| RENAL FAILURE | 0/159 (0%) | 1/174 (0.6%) | ||
| RENAL IMPAIRMENT | 0/159 (0%) | 1/174 (0.6%) | ||
| RENAL TUBULAR NECROSIS | 0/159 (0%) | 1/174 (0.6%) | ||
| Reproductive system and breast disorders | ||||
| MENORRHAGIA | 1/159 (0.6%) | 0/174 (0%) | ||
| UTERINE HAEMORRHAGE | 1/159 (0.6%) | 0/174 (0%) | ||
| DYSMENORRHOEA | 0/159 (0%) | 1/174 (0.6%) | ||
| OVARIAN MASS | 0/159 (0%) | 1/174 (0.6%) | ||
| UTERINE PROLAPSE | 0/159 (0%) | 1/174 (0.6%) | ||
| VAGINAL HAEMORRHAGE | 0/159 (0%) | 1/174 (0.6%) | ||
| Respiratory, thoracic and mediastinal disorders | ||||
| PULMONARY ARTERIAL HYPERTENSION | 25/159 (15.7%) | 28/174 (16.1%) | ||
| RESPIRATORY FAILURE | 6/159 (3.8%) | 3/174 (1.7%) | ||
| DYSPNOEA | 5/159 (3.1%) | 8/174 (4.6%) | ||
| CHRONIC OBSTRUCTIVE PULMONARY DISEASE | 4/159 (2.5%) | 2/174 (1.1%) | ||
| ACUTE RESPIRATORY FAILURE | 4/159 (2.5%) | 1/174 (0.6%) | ||
| PULMONARY EMBOLISM | 3/159 (1.9%) | 1/174 (0.6%) | ||
| HYPOXIA | 3/159 (1.9%) | 0/174 (0%) | ||
| PULMONARY OEDEMA | 2/159 (1.3%) | 1/174 (0.6%) | ||
| CHRONIC RESPIRATORY FAILURE | 2/159 (1.3%) | 0/174 (0%) | ||
| HAEMOPTYSIS | 2/159 (1.3%) | 0/174 (0%) | ||
| PNEUMOTHORAX | 2/159 (1.3%) | 0/174 (0%) | ||
| EPISTAXIS | 1/159 (0.6%) | 2/174 (1.1%) | ||
| ASTHMA | 1/159 (0.6%) | 1/174 (0.6%) | ||
| PLEURISY | 1/159 (0.6%) | 1/174 (0.6%) | ||
| ACUTE PULMONARY OEDEMA | 1/159 (0.6%) | 0/174 (0%) | ||
| BRONCHIAL HYPERREACTIVITY | 1/159 (0.6%) | 0/174 (0%) | ||
| OBLITERATIVE BRONCHIOLITIS | 1/159 (0.6%) | 0/174 (0%) | ||
| ATELECTASIS | 0/159 (0%) | 1/174 (0.6%) | ||
| BRONCHIAL HAEMORRHAGE | 0/159 (0%) | 1/174 (0.6%) | ||
| ORTHOPNOEA | 0/159 (0%) | 1/174 (0.6%) | ||
| RESPIRATORY DISTRESS | 0/159 (0%) | 1/174 (0.6%) | ||
| Skin and subcutaneous tissue disorders | ||||
| SKIN ULCER | 1/159 (0.6%) | 1/174 (0.6%) | ||
| URTICARIA | 0/159 (0%) | 1/174 (0.6%) | ||
| Surgical and medical procedures | ||||
| CORONARY ARTERY BYPASS | 1/159 (0.6%) | 0/174 (0%) | ||
| DIURETIC THERAPY | 1/159 (0.6%) | 0/174 (0%) | ||
| FINGER AMPUTATION | 1/159 (0.6%) | 0/174 (0%) | ||
| INCISIONAL HERNIA REPAIR | 1/159 (0.6%) | 0/174 (0%) | ||
| KNEE ARTHROPLASTY | 0/159 (0%) | 2/174 (1.1%) | ||
| CHEMOTHERAPY | 0/159 (0%) | 1/174 (0.6%) | ||
| RADIOTHERAPY | 0/159 (0%) | 1/174 (0.6%) | ||
| SKIN CYST EXCISION | 0/159 (0%) | 1/174 (0.6%) | ||
| SKIN NEOPLASM EXCISION | 0/159 (0%) | 1/174 (0.6%) | ||
| THYMECTOMY | 0/159 (0%) | 1/174 (0.6%) | ||
| Vascular disorders | ||||
| HYPERTENSION | 1/159 (0.6%) | 2/174 (1.1%) | ||
| EXTREMITY NECROSIS | 1/159 (0.6%) | 0/174 (0%) | ||
| DEEP VEIN THROMBOSIS | 0/159 (0%) | 1/174 (0.6%) | ||
| FEMORAL ARTERY OCCLUSION | 0/159 (0%) | 1/174 (0.6%) | ||
| HAEMATOMA | 0/159 (0%) | 1/174 (0.6%) | ||
| HYPOTENSION | 0/159 (0%) | 1/174 (0.6%) | ||
| PERIPHERAL ARTERIAL OCCLUSIVE DISEASE | 0/159 (0%) | 1/174 (0.6%) | ||
| SHOCK HAEMORRHAGIC | 0/159 (0%) | 1/174 (0.6%) | ||
Other (Not Including Serious) Adverse Events |
||||
| Bosentan | Placebo | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 135/159 (84.9%) | 147/174 (84.5%) | ||
| Blood and lymphatic system disorders | ||||
| ANAEMIA | 15/159 (9.4%) | 10/174 (5.7%) | ||
| Gastrointestinal disorders | ||||
| DIARRHOEA | 19/159 (11.9%) | 19/174 (10.9%) | ||
| NAUSEA | 16/159 (10.1%) | 22/174 (12.6%) | ||
| ABDOMINAL PAIN | 11/159 (6.9%) | 12/174 (6.9%) | ||
| VOMITING | 8/159 (5%) | 12/174 (6.9%) | ||
| General disorders | ||||
| OEDEMA PERIPHERAL | 30/159 (18.9%) | 26/174 (14.9%) | ||
| CHEST PAIN | 18/159 (11.3%) | 10/174 (5.7%) | ||
| FATIGUE | 13/159 (8.2%) | 19/174 (10.9%) | ||
| Infections and infestations | ||||
| UPPER RESPIRATORY TRACT INFECTION | 21/159 (13.2%) | 29/174 (16.7%) | ||
| URINARY TRACT INFECTION | 16/159 (10.1%) | 13/174 (7.5%) | ||
| BRONCHITIS | 14/159 (8.8%) | 18/174 (10.3%) | ||
| NASOPHARYNGITIS | 11/159 (6.9%) | 15/174 (8.6%) | ||
| SINUSITIS | 11/159 (6.9%) | 12/174 (6.9%) | ||
| PNEUMONIA | 8/159 (5%) | 8/174 (4.6%) | ||
| Injury, poisoning and procedural complications | ||||
| FALL | 8/159 (5%) | 6/174 (3.4%) | ||
| Investigations | ||||
| ALANINE AMINOTRANSFERASE INCREASED | 16/159 (10.1%) | 7/174 (4%) | ||
| ASPARTATE AMINOTRANSFERASE INCREASED | 13/159 (8.2%) | 8/174 (4.6%) | ||
| LIVER FUNCTION TEST ABNORMAL | 11/159 (6.9%) | 4/174 (2.3%) | ||
| HEPATIC ENZYME INCREASED | 9/159 (5.7%) | 3/174 (1.7%) | ||
| Musculoskeletal and connective tissue disorders | ||||
| BACK PAIN | 15/159 (9.4%) | 22/174 (12.6%) | ||
| ARTHRALGIA | 13/159 (8.2%) | 20/174 (11.5%) | ||
| PAIN IN EXTREMITY | 9/159 (5.7%) | 15/174 (8.6%) | ||
| MUSCLE SPASMS | 8/159 (5%) | 6/174 (3.4%) | ||
| Nervous system disorders | ||||
| HEADACHE | 24/159 (15.1%) | 24/174 (13.8%) | ||
| DIZZINESS | 17/159 (10.7%) | 17/174 (9.8%) | ||
| Psychiatric disorders | ||||
| ANXIETY | 9/159 (5.7%) | 11/174 (6.3%) | ||
| INSOMNIA | 8/159 (5%) | 11/174 (6.3%) | ||
| Respiratory, thoracic and mediastinal disorders | ||||
| COUGH | 22/159 (13.8%) | 21/174 (12.1%) | ||
| DYSPNOEA | 21/159 (13.2%) | 19/174 (10.9%) | ||
| PULMONARY ARTERIAL HYPERTENSION | 15/159 (9.4%) | 35/174 (20.1%) | ||
| EPISTAXIS | 12/159 (7.5%) | 6/174 (3.4%) | ||
| NASAL CONGESTION | 8/159 (5%) | 0/174 (0%) | ||
| Skin and subcutaneous tissue disorders | ||||
| RASH | 10/159 (6.3%) | 6/174 (3.4%) | ||
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
Results Point of Contact
| Name/Title | Jonathan Tolson |
|---|---|
| Organization | Actelion Pharmaceuticals Ltd |
| Phone | +41 61 565 56 04 |
| jonathon.tolson@actelion.com |
Responsible Party:
Actelion
ClinicalTrials.gov Identifier:
NCT00303459
Other Study ID Numbers:
- AC-052-414
- COMPASS-2
First Posted:
Mar 17, 2006
Last Update Posted:
Nov 11, 2015
Last Verified:
Oct 1, 2015