Clinical Study of Macitentan in Patients With Pulmonary Arterial Hypertension to Psychometrically Validate the PAH-SYMPACT Instrument

• Sponsor: Actelion (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01841762
• Collaborator: (none)
• Enrollment: 284
• Locations: 81
• Arm: 1
• Actual Duration (Months): 31
• Patients Per Site: 3.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

SYMPHONY is prospective, multi-center, open-label, single-arm, Phase 3b psychometric validation study of the PAH-SYMPACT, a new quality of life questionnaire for patients with pulmonary arterial hypertension. Patients will be in the study for 5 1/2 months, 4 months of which they will receive macitentan, 10 mg, once daily.

The primary objectives are to demonstrate the final content validity of the PAH SYMPACT instrument, to demonstrate the psychometric characteristics of reliability and construct validity of the PAH-SYMPACT instrument, and to demonstrate the ability of the PAH SYMPACT instrument to detect change. The secondary objective is to assess the safety of macitentan in patients with pulmonary arterial hypertension. The exploratory objective is to explore the effects of macitentan on PAH symptoms and their impact (as measured by the PAH-SYMPACT) in patients with pulmonary arterial hypertension.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Arterial Hypertension	Drug: Macitentan	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 284 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multi-center, Open-label, Single-arm, Phase 3b Study of Macitentan in Patients With Pulmonary Arterial Hypertension to Psychometrically Validate the PAH-SYMPACT Instrument
• Actual Study Start Date: Apr 1, 2013
• Actual Primary Completion Date: Nov 1, 2015
• Actual Study Completion Date: Nov 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Macitentan Macitentan tablet, dose of 10 mg, once daily	Drug: Macitentan; Macitentan tablet, dose of 10 mg, once daily; Other Names: Macitentan / ACT-064992

Outcome Measures

Primary Outcome Measures

1. Development and Refinement of the Patient-reported Outcome Measure of Symptoms and Their Impact in PAH (the PAH-SYMPACT) [From Screening Visit (Day -14) to End of Treatment (EOT) Visit (Visit 4, Week 16)]

   Content validity of the PAH-SYMPACT was assessed using item performance, exploratory and confirmatory factor analysis. The final item content and domain structure of PAH-SYMPACT was determined based on these analyses from the Steering Committee (expert clinicians) and findings from the qualitative research done with patients previously.

2. Validation of the Patient-reported Outcome Measure of Symptoms and Their Impact in PAH (the PAH-SYMPACT), With Reliability Assessed Via Test-retest Reliability. [From ePRO period 1 (Days -14 to -8) to ePRO period 2 (Days -7 to -1) in screening period.]

   The reliability of the PAH-SYMPACT is assessed by test-retest reliability. Intra-class correlation coefficients (ICCs) assess test-retest reliability for the symptom and impact part scores as well as domains. ICCs equal to or greater than 0.70 are considered to demonstrate good test-retest reliability for total and domain scores.

3. Validation of the Patient-reported Outcome Measure of Symptoms and Their Impact in PAH (the PAH-SYMPACT), Assessing Internal Consistency Reliability. [From ePRO period 1 (Days -14 to -8) to ePRO period 2 (Days -7 to -1) in screening period.]

   The reliability of the PAH-SYMPACT is assessed by internal consistency reliability. This was determined using Cronbach's alpha-a value on an internal level scale from 0 to 1.0 with higher scores indicating a more-reliable (precise) instrument.

Secondary Outcome Measures

1. Number of Participants With Treatment-emergent Adverse Events, Serious Adverse Events, and Adverse Events Resulting in Patient Study Drug Discontinuation Between Time Periods, BL to End of Study Visit (EoS, Week 16+30 Days for Follow-up Safety Visits) [From Day 1 (Baseline Visit) to End of Study visit (EoS).]

   Safety events are reported and documented as defined in study protocol.

Other Outcome Measures

1. Assessment of the Sensitivity to Detect Change in the Symptoms and Impacts Domain Scores of the PAH-SYMPACT From Baseline to Week 16. [From Screening period (Days -7 to -1) to Week 16 (7-day period prior to Week 16 visit).]

   Sensitivity to change is an aspect of construct validity and represents the instrument's ability to detect underlying change. Sensitivity to change was examined to compare the difference in mean score in each domain of the PAH-SYMPACT. The symptoms and impacts domains consisted of 11 items each reported on a 7-point Likert Scale (from 0=no symptom/with no difficulty at all/not at all to 6=very severe symptoms/very much/extremely/not able at all). An average symptoms domain score is determined based on the daily scores of the containing items. An average impacts domain score is determined based on the items in the domain.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Signed informed consent prior to initiation of any study mandated procedure

2. Patients with symptomatic PAH in World Health Organization (WHO) Functional Class (FC) II to IV

3. Patients with PAH belonging to one of the following subgroups of the Dana Point

Clinical Classification Group 1:

1. Idiopathic, or

2. Heritable, or

3. Drug or toxin induced, or

4. Associated with one of the following:

1. Connective tissue disease ii. Congenital heart disease with simple systemic-to-pulmonary shunt at least one year after surgical repair iii. HIV infection

1. Documented hemodynamic diagnosis of PAH by right heart catheterization - performed at any time prior to Screening showing:

2. Resting mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg and

3. Resting pulmonary vascular resistance (PVR) > 240 dyn•s•cm-5 and

4. Pulmonary capillary wedge pressure (PCWP) or left ventricular end diastolic pressure (LVEDP) ≤ 15 mmHg

5. 6-minute walk distance (6MWD) ≥ 150 m at Screening

6. Able to fluently speak and read English

7. For patients on phosphodiesterase type-5 inhibitors (PDE5i), inhaled prostacyclin analogues, or calcium channel blockers, stable doses for at least 3 months prior to Visit 2

8. For patients on oral diuretics, stable doses for at least 4 weeks prior to Visit 2

9. Men or women aged 18 or older

10. A woman is considered to be of childbearing potential unless she:

• Has not yet entered puberty, or

• Does not have a uterus, or

• Has gone through menopause (has not had a period for at least 12 months for natural reasons, or who has had their ovaries removed)

1. A women of childbearing potential is eligible only if she meets both criteria below:

• Has a negative serum pregnancy test at Screening and a negative urine pregnancy test at Baseline and agree to perform monthly urine pregnancy tests, and

• Agrees to use two methods of contraception (one method for patients with a progesterone implant or an intrauterine device or tubal sterilization) from the Screening Visit 1 until one month after study drug discontinuation

Exclusion Criteria:

1. Moderate to severe obstructive lung disease: forced expiratory volume in one second (FEV1) / forced vital capacity < 70% and FEV1 < 65% of predicted value after bronchodilator administration

2. Moderate to severe restrictive lung disease: total lung capacity < 60% of predicted value

3. Hemoglobin < 75% of the lower limit of the normal range at screening

4. Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 3 times the upper limit of normal (ULN) at screening

5. Estimated creatinine clearance < 30 mL/min at screening

6. Systolic blood pressure (SBP) < 90 mmHg at screening

7. Body weight < 40 kg at screening

8. Known concomitant life-threatening diseases with a life expectancy of < 12 months

9. Any condition that prevents compliance with the protocol or adherence to therapy

10. Treatment with endothelin receptor antagonists (ERAs) within 3 months prior to Visit 2, or scheduled to receive any of these compounds, other than macitentan, during the trial

11. Treatment with intravenous or subcutaneous prostacyclin or prostacyclin analogs within 3 months prior to Visit 2, or scheduled to receive any of these compounds during the trial

12. Treatment with riociguat within 3 months prior to Visit 2, or scheduled to receive riociguat during the trial

13. Treatment with strong cytochrome P450 (CYP) 3A4 inducers or inhibitors within 4 weeks prior to Visit 2

14. Recently started (< 8 weeks prior to Visit 2) or planned cardio-pulmonary rehabilitation program based on exercise

15. Females who are lactating or pregnant (positive Screening or Baseline pregnancy test) or plan to become pregnant during the study

16. Known hypersensitivity to macitentan or its excipients or drugs of the same class

17. Treatment with another investigational drug within 3 months prior to Visit 2

18. Any known factor or disease that might interfere with treatment compliance, study conduct or interpretation of the results such as drug or alcohol dependence or psychiatric disease

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cardiovascular Associates of the Southeast, LLC	Birmingham	Alabama	United States	35243
2	University of Alabama at Birmingham	Birmingham	Alabama	United States	35294
3	Pulmonary Associates, PA	Phoenix	Arizona	United States	85006-2611
4	Mayo Clinic Arizona	Phoenix	Arizona	United States	85054-4502
5	Cedars-Sinai Medical Center	Beverly Hills	California	United States	90211
6	UCSF Fresno	Fresno	California	United States	93701
7	UCSD Medical Center, Pulmonary Department	La Jolla	California	United States	92093
8	VAGLAHS, VA Greater LA Healthcare System	Los Angeles	California	United States	90073
9	University of California Los Angeles	Los Angeles	California	United States	90095
10	University of California San Francisco Medical Center	San Francisco	California	United States	94143
11	Stanford University	Stanford	California	United States	94305-2200
12	Los Angeles Biomedical Research Institute	Torrance	California	United States	90502
13	University of Colorado	Aurora	Colorado	United States	80045
14	MedStar Georgetown University Hospital	Washington	District of Columbia	United States	20007
15	Medstar Washington Hospital Center	Washington	District of Columbia	United States	20010
16	Bay Area Cardiology Associates, P.A.	Brandon	Florida	United States	33511
17	University of Florida Academic Health Center	Gainesville	Florida	United States	32610
18	University of Florida College of Medicine, Jacksonville	Jacksonville	Florida	United States	32209
19	Mayo Clinic	Jacksonville	Florida	United States	32224-1865
20	Cleveland Clinic Florida	Weston	Florida	United States	33331-3609
21	Georgia Regents University	Augusta	Georgia	United States	30912
22	Georgia Clinical Research	Austell	Georgia	United States	30106
23	Northwestern University	Chicago	Illinois	United States	60611
24	University of Chicago Medical	Chicago	Illinois	United States	60637
25	Advocate Health and Hospitals Corporation	Oakbrook Terrace	Illinois	United States	60181
26	Chest Infectious Diseases and Critical Care Associates, PC	Des Moines	Iowa	United States	50325-7046
27	University of Iowa Hospitals & Clinics	Iowa City	Iowa	United States	52242
28	Iowa City Heart Center	Iowa City	Iowa	United States	52245
29	University of Kansas Medical Center	Kansas City	Kansas	United States	66160-0001
30	Veritas Clinical Specialties	Topeka	Kansas	United States	66606
31	Kentuckiana Pulmonary Associates	Louisville	Kentucky	United States	40202
32	University of Louisville	Louisville	Kentucky	United States	40202
33	University of Maryland Medical Center	Baltimore	Maryland	United States	21201
34	Johns Hopkins University	Baltimore	Maryland	United States	21205
35	Tufts Medical Center	Boston	Massachusetts	United States	02111
36	Boston University Medical Center	Boston	Massachusetts	United States	02118
37	University of Michigan	Ann Arbor	Michigan	United States	48109-5644
38	Beaumont Hospital	Troy	Michigan	United States	48085
39	Mayo Clinic	Rochester	Minnesota	United States	55905
40	Midwest Pulmonary Consultants	Kansas City	Missouri	United States	64111
41	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
42	Mercy Clinic Pulmonology	Saint Louis	Missouri	United States	63141
43	Clayton Sleep Institute	Saint Louis	Missouri	United States	63143
44	Ferrell-Duncan Clinic	Springfield	Missouri	United States	65807
45	Nebraska Pulmonary Specialties	Lincoln	Nebraska	United States	68506
46	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198
47	Pulmonary and Critical Care Associates	Union	New Jersey	United States	07083
48	Montefiore Medical Center, Weiler Division	Bronx	New York	United States	10461
49	Buffalo General Medical Center	Buffalo	New York	United States	14203
50	Winthrop University Hospital	Mineola	New York	United States	11501
51	North Shore-LIJ/Advance Lung Disease Clinic	New Hyde Park	New York	United States	11040
52	Beth Israel Medical Center	New York	New York	United States	10003
53	Columbia University Medical Center	New York	New York	United States	10032
54	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina	United States	27599
55	Novant Health Pulmonary and Critical Care	Matthews	North Carolina	United States	28105
56	The Christ Hospital	Cincinnati	Ohio	United States	45219
57	UC Health/University of Cincinnati	Cincinnati	Ohio	United States	45267
58	Cleveland Clinic	Cleveland	Ohio	United States	45219
59	Davis Heart & Lung Research Institute	Columbus	Ohio	United States	43210-1252
60	The Ohio State University	Columbus	Ohio	United States	43221
61	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
62	The Oregon Clinic	Portland	Oregon	United States	97220
63	CDA for Oregon Pulmonary Associate	Portland	Oregon	United States	97225
64	Oregon Health and Science University	Portland	Oregon	United States	97239
65	Thomas Jefferson University, Division on Pulmonary and Critical Care	Philadelphia	Pennsylvania	United States	19107-5109
66	Temple Lung Center	Philadelphia	Pennsylvania	United States	19140
67	UPMC	Pittsburgh	Pennsylvania	United States	15123
68	Allegheny General Hospital	Pittsburgh	Pennsylvania	United States	15212-4756
69	Berks Schuylkill Respiratory Specialists, Ltd.	Wyomissing	Pennsylvania	United States	19610
70	Wellspan Lung, Sleep and Critical Care	York	Pennsylvania	United States	17402-8200
71	Sioux Falls Cardiovascular, PC	Sioux Falls	South Dakota	United States	57108
72	Baylor Research Institute (BRI)	Dallas	Texas	United States	75204
73	UT Southwestern Medical Center	Dallas	Texas	United States	75390-8550
74	Baylor College of Medicine	Houston	Texas	United States	77030-2348
75	The University of Texas Health Science Center at Houston	Houston	Texas	United States	77030
76	Scott & White Memorial Hospital	Temple	Texas	United States	76508
77	Inova Heart and Vascular Institue / Inova Fairfax Hospital	Falls Church	Virginia	United States	22042-3307
78	Sentara Norfolk General Hospital	Norfolk	Virginia	United States	23507
79	Pulmonary & Sleep Research	Spokane	Washington	United States	99204
80	University of Wisconsin School of Medicine and Public Health	Madison	Wisconsin	United States	53792
81	Aurora Cardiovascular Services	Milwaukee	Wisconsin	United States	53215

Sponsors and Collaborators

• Actelion

Investigators

• Study Chair: Alain Romero, PharmD, PhD, Actelion Pharmaceuticals US, Inc
• Study Chair: Gary Palmer, MD, MBA, Actelion Pharmaceuticals US, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Actelion
• ClinicalTrials.gov Identifier: NCT01841762
• Other Study ID Numbers: AC-055-401
• First Posted: Apr 29, 2013
• Last Update Posted: Feb 26, 2019
• Last Verified: Feb 1, 2019

• Keywords provided by Actelion: PAH-SYMPACT; Pulmonary Arterial Hypertension; psychometric instrument
• Additional relevant MeSH terms: Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension; Macitentan

Study Results

Participant Flow

Recruitment Details	Seventy-nine sites recruited subjects to reach a total of 284 total enrolled, with 335 subjects entered screening. Institution-based and community clinic sites, with pulmonary arterial hypertension expertise, were included in the study. The first subject, first visit occurred on 25 APR 2013 and last subject, last visit occurred on 05 OCT 2015
Pre-assignment Detail	Screen failures total 51 subjects. Six subjects were removed from the full analysis set of 284 due to exclusion. The per protocol set includes 278 subjects total (97.9% of enrollment), utilized for all validation and exploratory ePRO analyses. The safety set, encompassing all enrolled subjects receiving study treatment, includes 284 subjects.

Arm/Group Title	Macitentan
Arm/Group Description	Macitentan tablet, dose of 10 mg, once daily
Period Title: Screening Period
STARTED	335
COMPLETED	284
NOT COMPLETED	51
Period Title: Screening Period
STARTED	284
COMPLETED	252
NOT COMPLETED	32
Period Title: Screening Period
STARTED	284
COMPLETED	269
NOT COMPLETED	15

Baseline Characteristics

Arm/Group Title	Macitentan
Arm/Group Description	Macitentan tablet, dose of 10 mg, once daily
Overall Participants	284
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	167 58.8%
>=65 years	117 41.2%
Age (Years) [Mean (Inter-Quartile Range) ]
Mean (Inter-Quartile Range) [Years]	59.7
Sex: Female, Male (Count of Participants)
Female	223 78.5%
Male	61 21.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	27 9.5%
Not Hispanic or Latino	257 90.5%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	2 0.7%
Asian	8 2.8%
Native Hawaiian or Other Pacific Islander	1 0.4%
Black or African American	35 12.3%
White	228 80.3%
More than one race	10 3.5%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	Development and Refinement of the Patient-reported Outcome Measure of Symptoms and Their Impact in PAH (the PAH-SYMPACT)
Description	Content validity of the PAH-SYMPACT was assessed using item performance, exploratory and confirmatory factor analysis. The final item content and domain structure of PAH-SYMPACT was determined based on these analyses from the Steering Committee (expert clinicians) and findings from the qualitative research done with patients previously.
Time Frame	From Screening Visit (Day -14) to End of Treatment (EOT) Visit (Visit 4, Week 16)

Outcome Measure Data

Analysis Population Description

Per Protocol Set (PPS) comprised all patients included in the Full Analysis Set (FAS) who had no major protocol violations.

Arm/Group Title	Macitentan
Arm/Group Description	Macitentan tablet, dose of 10 mg, once daily
Measure Participants	278
Item number in symptoms part of baseline	16
Item number in symptoms part at Week 16	11
Item number in impacts part at baseline	25
Item number in impacts part at Week 16	11

2. Primary Outcome

Title	Validation of the Patient-reported Outcome Measure of Symptoms and Their Impact in PAH (the PAH-SYMPACT), With Reliability Assessed Via Test-retest Reliability.
Description	The reliability of the PAH-SYMPACT is assessed by test-retest reliability. Intra-class correlation coefficients (ICCs) assess test-retest reliability for the symptom and impact part scores as well as domains. ICCs equal to or greater than 0.70 are considered to demonstrate good test-retest reliability for total and domain scores.
Time Frame	From ePRO period 1 (Days -14 to -8) to ePRO period 2 (Days -7 to -1) in screening period.

Outcome Measure Data

Analysis Population Description

Per Protocol Set of 278 patients.

Arm/Group Title	Macitentan
Arm/Group Description	Macitentan tablet, dose of 10 mg, once daily
Measure Participants	278
ICCs of Cardiopulmonary Symptoms domain	0.94
ICCs of Cardiovascular Symptoms domain	0.93
ICCs of Physical Impacts domain	0.91
ICCs of Cognitive/Emotional Impacts domain	0.84

3. Primary Outcome

Title	Validation of the Patient-reported Outcome Measure of Symptoms and Their Impact in PAH (the PAH-SYMPACT), Assessing Internal Consistency Reliability.
Description	The reliability of the PAH-SYMPACT is assessed by internal consistency reliability. This was determined using Cronbach's alpha-a value on an internal level scale from 0 to 1.0 with higher scores indicating a more-reliable (precise) instrument.
Time Frame	From ePRO period 1 (Days -14 to -8) to ePRO period 2 (Days -7 to -1) in screening period.

Outcome Measure Data

Analysis Population Description

Per protocol set of 278.

Arm/Group Title	Macitentan
Arm/Group Description	Macitentan tablet, dose of 10 mg, once daily
Measure Participants	278
Cronbach's Alpha for Cardiopulmonary Symptoms	0.81
Cronbach's Alpha for Cardiovascular Symptoms	0.88
Cronbach's Alpha for Physical Impacts Domain	0.92
Cronbach's Alpha for Cognitive/Emotional Impacts	0.87

4. Secondary Outcome

Title	Number of Participants With Treatment-emergent Adverse Events, Serious Adverse Events, and Adverse Events Resulting in Patient Study Drug Discontinuation Between Time Periods, BL to End of Study Visit (EoS, Week 16+30 Days for Follow-up Safety Visits)
Description	Safety events are reported and documented as defined in study protocol.
Time Frame	From Day 1 (Baseline Visit) to End of Study visit (EoS).

Outcome Measure Data

Analysis Population Description

Safety set of 284 subjects.

Arm/Group Title	Macitentan
Arm/Group Description	Macitentan tablet, dose of 10 mg, once daily
Measure Participants	284
Participants with AEs	228 80.3%
Participants with severe intensity AEs	36 12.7%
Participants with SAEs	49 17.3%
Participants prematurely discontinued study drug	17 6%

5. Other Pre-specified Outcome

Title	Assessment of the Sensitivity to Detect Change in the Symptoms and Impacts Domain Scores of the PAH-SYMPACT From Baseline to Week 16.
Description	Sensitivity to change is an aspect of construct validity and represents the instrument's ability to detect underlying change. Sensitivity to change was examined to compare the difference in mean score in each domain of the PAH-SYMPACT. The symptoms and impacts domains consisted of 11 items each reported on a 7-point Likert Scale (from 0=no symptom/with no difficulty at all/not at all to 6=very severe symptoms/very much/extremely/not able at all). An average symptoms domain score is determined based on the daily scores of the containing items. An average impacts domain score is determined based on the items in the domain.
Time Frame	From Screening period (Days -7 to -1) to Week 16 (7-day period prior to Week 16 visit).

Outcome Measure Data

Analysis Population Description

Per Protocol Set of 278 subjects.

Arm/Group Title	Macitentan
Arm/Group Description	Macitentan tablet, dose of 10 mg, once daily
Measure Participants	278
Cardiopulmonary Symptoms domain score at baseline	1.0
Cardiopulmonary Symptoms domain score at Week 8	0.8
Cardiopulmonary Symptoms domain score at Week 16	0.7
Cardiovascular Symptoms domain score at baseline	0.4
Cardiovascular Symptoms domain score at Week 8	0.2
Cardiovascular Symptoms domain score at Week 16	0.2
Physical Impacts domain score at baseline	1.3
Physical Impacts domain score at Week 8	1.0
Physical Impacts domain score at Week 16	0.9
Cogn./Emotional Impacts domain score at baseline	0.8
Cogn./Emotional Impacts domain score at Week 8	0.8
Cogn./Emotional Impacts domain score at Week 16	0.5

Adverse Events

Time Frame	Treatment-emergent adverse events were collected from study drug initiation until Day 30 after study drug discontinuation.
Adverse Event Reporting Description	Study sites were instructed to document any adverse change from the patient's baseline condition, i.e., any unfavorable and unintended sign, including an abnormal laboratory finding, symptom, or disease that occurs during the course of the study, whether or not considered related to the study drug. Counts and percentages of subjects who experienced adverse events were tabulated by system organ class and preferred term within each system organ class, as well as by individual preferred term.
Arm/Group Title	Macitentan
Arm/Group Description	Macitentan tablet, dose of 10 mg, once daily
All Cause Mortality
	Macitentan
	Affected / at Risk (%)	# Events
Total	1/284 (0.4%)
Serious Adverse Events
	Macitentan
	Affected / at Risk (%)	# Events
Total	49/284 (17.3%)
Blood and lymphatic system disorders
Anaemia	3/284 (1.1%)
Hypoglycaemia	2/284 (0.7%)
Angina Unstable	1/284 (0.4%)
Cardiac disorders
Cardiac Failure	3/284 (1.1%)
Cardiac Failure Congestive	3/284 (1.1%)
Atrial Fibrillation	1/284 (0.4%)
Atrial Flutter	1/284 (0.4%)
Gastrointestinal disorders
Small Intestinal Obstruction	3/284 (1.1%)
Diverticulitis	2/284 (0.7%)
General disorders
Chest Pain	4/284 (1.4%)
Fluid Overload	3/284 (1.1%)
Nervous system disorders
Vertigo	2/284 (0.7%)
Cerebrovascular Accident	1/284 (0.4%)
Renal and urinary disorders
Renal Failure Acute	3/284 (1.1%)
Bladder Transitional Cell Carcinoma	1/284 (0.4%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	5/284 (1.8%)
Pneumonia	4/284 (1.4%)
Hypoxia	3/284 (1.1%)
Acute Respiratory Disorder	2/284 (0.7%)
Surgical and medical procedures
Transfusion	2/284 (0.7%)
Other (Not Including Serious) Adverse Events
	Macitentan
	Affected / at Risk (%)	# Events
Total	228/284 (80.3%)
Blood and lymphatic system disorders
Oedema peripheral	50/284 (17.6%)
Anaemia	16/284 (5.6%)
Ear and labyrinth disorders
Dizziness	19/284 (6.7%)
General disorders
Fatigue	22/284 (7.7%)
Nausea	17/284 (6%)
Nervous system disorders
Headache	36/284 (12.7%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	34/284 (12%)
Cough	26/284 (9.2%)
Nasal congestion	23/284 (8.1%)
Upper Respiratory Tract Infection	19/284 (6.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Any study-related publication written independently by investigators must be submitted to Actelion for review at least 30 days prior to submission for publication or presentation. Upon review, Actelion may provide comments, and may also request alterations and/or deletions for the sole purpose of protecting its confidential information and/or patent rights. Neither the institution nor the investigator should permit publication during such a review period.