Online Appendix
Appendix A: Study Conduct, Study Sites, and Investigators
Study Conduct: The study was conducted at 65 centers in the US and Canada (Appendix A). The
study was initiated on March 27, 2006 and completed on May 01, 2008. Medical and clinical
monitoring of this study were conducted by the sponsor or its designated representatives. Study
drug was packaged, labeled, and shipped by the study sponsor. Clinical laboratory assessments
were performed by Quest Diagnostics. Echocardiographic interpretation was performed by Mayo
Clinic. Data management, data analysis, and biostatistics were completed by the sponsor. This
study was conducted in compliance with the ethical principles originating in or derived from the
Declaration of Helsinki and in compliance with all International Conference on Harmonization
(ICH) Good Clinical Practice (GCP) Guidelines. In addition, all local regulatory requirements
were followed, in particular, those affording greater protection to the safety of trial participants.
Written informed consent was obtained prior to the subject entering the study (before initiation
of protocol-specified procedures).
The study was managed initially by Encysive and then by Pfizer Global Research and
Development (the sponsor) and conducted by investigators contracted by and under the direction
of the sponsor. The investigators were responsible for adhering to the study procedures described
in the protocol, for keeping records of study drug, and for accurately completing and signing the
case report forms and data collection tools supplied by the sponsor. The authors had full access
to the data and take full responsibility for their integrity. All authors have read and agree to the
manuscript as written.
Investigator
Site
1
Adamson, Philip
Adler, Alexander
Anand, Inder
Baran, David
Benton, Robert
Brown, Christopher
Capodilupo, Robert
Chahoud, Georges
Dauber, Ira
DeNofrio, David
Eichhorn, Eric
Elkayam, Uri
Feldman, Jeremy
Gatewood, Robert
Geltman, Edward
Gilbert, Edward
Givertz, Michael
Greenberg, Barry
Heilman, K. John
Hodson, Robert
Horn, Evelyn
Jain, Anuj
Karia, Darshak
Katz, Stuart
Kfoury, Abdallah
Kim, Antony
Kitzman, Dalane
Klapholz, Marc
Kono, Alan
Kurrelmeyer, Karla
Labovitz, Arthur
LeBlanc, Marie-Hélène
Leier, Carl
LeWinter, Martin
Margulies, Kenneth
Maybaum, Simon
McGrew, Frank
McKelvie, Robert
McMillan, Edward
McNamara, Dennis
Mehta, Jawahar
Michel, Caroline
Milunski, Mark
Moe, Gordon
Murali, Srinivas
Nikolaidis, Lazaros
Oklahoma Foundation for Cardiovascular Research
Methodist Heart, Lung and Vascular Institute
Minneapolis VA Medical Center
Newark Beth Israel Medical Center
Capital Cardiology Associates
Mobile Heart Specialists
New England Heart Institute of Catholic Medical Center Research
University of Arkansas for Medical Sciences
South Denver Cardiology
Tufts-New England Medical Center
The Dallas Heart Group
University of Southern California Medical Center
Arizona Pulmonary Specialist
Buffalo Cardiology & Pulmonary Associates
Washington University School of Medicine
University of Utah
Brigham and Women's Hospital
University of California
Black Hills Clinical Research Center
The Oregon Clinic
Columbia University Medical Center
Nebraska Heart Institute
Albert Einstein Medical Center
Yale University School of Medicine
Intermountain Medical Center
The University of Chicago
Wake Forest University Health Sciences
University of Medicine and Dentistry of NJ
Dartmouth Hitchcock Medical Center
Methodist DeBakey Heart Center
St. Louis University Hospital
Hospital Laval
The Ohio State University
Fletcher Allen Health Care
University of Pennsylvania
Montefiore Medical Center
The Stern Cardiovascular Center
Hamilton Health Sciences
Mid Carolina Cardiology Research
University of Pittsburgh Medical Center
Central Arkansas Veterans HCS
SMBD Jewish General Hospital
Florida Heart Group
St Michael's Hospital
Allegheny General Hospital
Temple University Hospital
2
O’Shaughnessy, Mark
O'Brien, Terrence
Pan, David
Parrott, Charles
Peart, Brenda
Peberdy, Mary Ann
Pettyjohn, Frank
Pina, Ileana
Rahko, Peter
Randall, Otelio
Rashid, Haroonur-Ur
Safdar, Zeenat
Silver, Marc
Stillabower, Michael
Tallaj, Jose
Uszenski, Ronald
VanHamersveld, Daniel
Waxman, Aaron
Weiss, Robert
Parkview Research Center
RHJ VA Medical Center
Orange County Heart Institute
Providence Hospital
Southwest Heart
Medical College of Virginia
University of South Alabama
University Hospitals of Cleveland
University of Wisconsin
Capital City Research
Kelsey Seybold Clinic
Baylor College of Medicine
Advocate Christ Medical Center
Christiana Hospital
University of Alabama at Birmingham
Mid Carolina Cardiology
Sacramento Heart Vascular Research Center
Massachusetts General Hospital
Cardiovascular Consultants of Maine
3
Appendix B: Most Frequently (> 5%) Reported Adverse Events
System Organ Class/Preferred Term
Blood and lymphatic system disorders
Anemia
Cardiac disorders
Palpitations
Gastrointestinal disorders
Constipation
Diarrhea
Dyspepsia
Nausea
Vomiting
General disorders and administration site conditions
Chest pain
Fatigue
Non-cardiac chest pain
Edema peripheral
Infections and infestations
Nasopharyngitis
Upper respiratory tract infection
Urinary tract infection
Investigations
Weight increased
Musculoskeletal and connective tissue disorders
Arthralgia
Back pain
Muscle spasms
Pain in extremity
Nervous system disorders
Dizziness
Headache
Syncope
Psychiatric disorders
Insomnia
Respiratory, thoracic and mediastinal disorders
Cough
Dyspnea
Placebo
Sitaxsentan
p-Value
(N=64)
(N=128)
2 (3.1%)
8 (6.3%)
0.4999
8 (12.5%)
7 (5.5%)
0.1511
5 ( 7.8%)
3 (4.7%)
4 ( 6.3%)
5 ( 7.8%)
4 ( 6.3%)
2 ( 1.6%)
7 ( 5.5%)
3 ( 2.4%)
10 ( 7.9%)
5 ( 3.9%)
0.0432
1.0000
0.2262
1.0000
0.4863
5 ( 7.8%)
4 ( 6.3%)
4 ( 6.3%)
10 (
15.6%)
10 ( 7.9%)
10 ( 7.9%)
4 ( 3.1%)
1.0000
0.7768
0.4450
25 ( 19.7%)
0.5567
4 ( 6.3%)
3 ( 4.7%)
5 ( 7.8%)
6 ( 4.7%)
14 ( 11.0%)
12 ( 9.4%)
0.7343
0.1843
0.7939
4 ( 6.3%)
1 ( 0.8%)
0.0440
6(
5(
6(
3(
9.4%)
7.8%)
9.4%)
4.7%)
6 ( 4.7%)
8 ( 6.3%)
4 ( 3.1%)
10 ( 7.9%)
0.2214
0.7635
0.0878
0.5489
6 ( 9.4%)
11 (
17.2%)
4 ( 6.3%)
10 ( 7.9%)
0.7842
10 ( 7.9%)
2 ( 1.6%)
0.0836
0.0984
4 ( 6.3%)
4 ( 3.1%)
0.4450
2 ( 3.1%)
10 (
15.6%)
9 ( 7.1%)
0.3406
21 ( 16.5%)
1.0000
4
Skin and subcutaneous tissue disorders
Rash
Vascular disorders
Hypotension
4 ( 6.3%)
3 ( 2.4%)
0.2262
2 ( 3.1%)
8 ( 6.3%)
0.4999
5
Appendix C: Most Frequently (> 3%) Reported Treatment-Related Adverse Events
Placebo
Sitaxsentan
(N=64)
(N=128)
0
4 ( 3.1%)
2 ( 3.1%)
2 ( 1.6%)
Constipation
3 ( 4.7%)
0
Nausea
2 ( 3.1%)
4 ( 3.1%)
System Organ Class/Preferred Term
Blood and lymphatic system disorders
Anemia
Cardiac disorders
Palpitations
Gastrointestinal disorders
General disorders and administration site conditions
Edema peripheral
5 ( 7.8%)
11 ( 8.7%)
Injury, poisoning and procedural complications
Contusion
2 ( 3.1%)
0
Blood creatinine increased
2 ( 3.1%)
0
Weight increased
2 ( 3.1%)
1 ( 0.8%)
Dizziness
0
6 ( 4.7%)
Headache
7 ( 10.9%)
8 ( 6.3%)
2 ( 3.1%)
0
Investigations
Nervous system disorders
Psychiatric disorders
Insomnia
Respiratory, thoracic and mediastinal disorders
Dyspnea
2 ( 3.1%)
6 ( 4.7%)
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Appendix D: Serious Adverse Events
Placebo
Sitaxsentan
(N=64)
(N=128)
16 (25.0%)
25 (19.7%)
1 ( 1.6%)
1 ( 0.8%)
Angina unstable
1 ( 1.6%)
0
Atrial fibrillation
1 ( 1.6%)
0
0
1 ( 0.8%)
Cardiac failure
1 ( 1.6%)
1 ( 0.8%)
Cardiac failure congestive
2 ( 3.1%)
2 ( 1.6%)
Coronary artery disease
0
3 ( 2.4%)
Diastolic dysfunction
0
1 ( 0.8%)
Myocardial infarction
1 ( 1.6%)
0
1 ( 1.6%)
0
Gastroesophageal reflux disease
0
1 ( 0.8%)
Large intestine perforation
0
1 ( 0.8%)
1 ( 1.6%)
0
System Organ Class/Preferred Term
Subjects with at Least one SAE
Blood and lymphatic system disorders
Anemia
Cardiac disorders
Atrioventricular block second degree
Gastrointestinal disorders
Duodenitis
Peptic ulcer hemorrhage
General disorders and administration site conditions
Chest pain
2 ( 3.1%)
3 ( 2.4%)
Generalized edema
0
1 ( 0.8%)
Multi-organ failure
0
1 ( 0.8%)
2 ( 3.1%)
1 ( 0.8%)
Non-cardiac chest pain
Infections and infestations
7
Bronchitis
0
1 ( 0.8%)
Bronchitis acute
0
1 ( 0.8%)
1 ( 1.6%)
0
Gastroenteritis
0
1 ( 0.8%)
Incision site infection
0
1 ( 0.8%)
1 ( 1.6%)
3 ( 2.4%)
Sepsis
0
2 ( 1.6%)
Upper respiratory tract infection
0
1 ( 0.8%)
1 ( 1.6%)
0
0
1 ( 0.8%)
0
1 ( 0.8%)
Back pain
1 ( 1.6%)
1 ( 0.8%)
Intervertebral disc protrusion
1 ( 1.6%)
0
0
1 ( 0.8%)
Diverticulitis
Pneumonia
Injury, poisoning and procedural complications
Post procedural hemorrhage
Investigations
Ultrasound bladder abnormal
Metabolism and nutrition disorders
Fluid overload
Musculoskeletal and connective tissue disorders
Spinal osteoarthritis
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Hepatic neoplasm malignant
0
1 ( 0.8%)
Lymphoma
0
1 ( 0.8%)
1 ( 1.6%)
0
0
1 ( 0.8%)
1 ( 1.6%)
0
0
1 ( 0.8%)
Non-small cell lung cancer
Nervous system disorders
Cerebrovascular accident
Syncope
Transient ischemic attack
8
Psychiatric disorders
Confusional state
1 ( 1.6%)
0
0
1 ( 0.8%)
1 ( 1.6%)
0
0
1 ( 0.8%)
1 ( 1.6%)
0
Renal and urinary disorders
Obstructive uropathy
Renal failure acute
Renal failure chronic
Reproductive system and breast disorders
Colpocele
Respiratory, thoracic and mediastinal disorders
Asthma
0
3 ( 2.4%)
Chronic obstructive pulmonary disease
0
2 ( 1.6%)
Dyspnea
2 ( 3.1%)
1 ( 0.8%)
Hypoxia
0
1 ( 0.8%)
Pulmonary embolism
0
1 ( 0.8%)
0
1 ( 0.8%)
Surgical and medical procedures
Abdominal hernia repair
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Appendix E: Safety Results
Of 191 subjects who received study drug, 54 (28.3%) subjects prematurely discontinued from
study: 16 (25.0%) in the placebo arm and 38 (29.9%) in the sitaxsentan arm; 32 (16.8%) during
run-in phase and 22 (11.5%) during maintenance phase. Ten subjects discontinued from study
primarily due to adverse events or death: 2 (3.1%) in the placebo arm and 8 (6.3%) in sitaxsentan
arm including one death. One (1.6%) subject in the placebo arm discontinued due to requiring
additional chronic heart failure treatment. One (0.8%) subject in the sitaxsentan arm discontinued
due to elevated liver enzyme values. The discontinuation rate in the sitaxsentan arm is higher
than that in the placebo arm during run-in phase, but lower during maintenance phase.
For the Safety population of 191 subjects, the mean drug exposure was 29 weeks in placebo
arm and 28 weeks in sitaxsentan arm. The mean treatment compliance was 98% for placebo arm
and 97% for sitaxsentan arm. The number of subjects who experienced at least one adverse event
(AE) during study was 56 (88%) in the placebo arm and 110 (87%) in sitaxsentan arm. Thirty
(47%) subjects in the placebo arm and 48 (38%) subjects in sitaxsentan arm had treatmentrelated AE. The number of subjects who had serious AE was 16 (25%) in the placebo arm and
25 (20%) in sitaxsentan arm. There were 5 (8%) subjects in placebo arm and 15 (12%) in
sitaxsentan arm who had AE leading to premature discontinuation. There were 2 deaths during
the study; neither was considered to be related to study drug. One subject (female, 51 years old)
died due to severe diastolic heart dysfunction; the subject had received sitaxsentan for 180 days
at the time of death. One subject (male, 76 years old) died due to sepsis and multiorgan failure;
the subject had received sitaxsentan for 234 days at the time of death, with the last dose
administered approximately 3 weeks prior to the death of the subject. No subjects had elevated
liver function test values following placebo administration. One subject (0.8%) receiving
10
sitaxsentan had alanine aminotransferase (ALT) and aspartate aminotransferase (AST) values
that were greater than 3 x upper limit of normal (ULN): ALT values of 331 and 291 U/L (both
greater than 5 x ULN [48 U/L]) during Week M16 and early termination visits, respectively,
with AST values of 261 and 188 U/L (both greater than 3 x ULN [55 U/L]) at these visits. This
subject had bilirubin within the normal ranges at all time points. These elevations were reported
as moderate AEs that were probably related to the study drug, and dosing was discontinued.
These abnormalities were asymptomatic and resolved when drug was discontinued. One (0.8%)
subject in the sitaxsentan arm had an elevated value of international normalized ratio (INR)
above 3.5. The most frequently reported AEs in greater than 5% of subjects in either treatment
arm are summarized in Table 6. The most frequently reported treatment-related (probably or
possibly related) AEs in greater than 3% of subjects in either treatment arm are summarized in
Appendix B. All serious AEs are summarized in Appendix C.
Appendix F: Exercise-Induced Changes in Heart Rate and Blood Pressure
Placebo
Sitaxsentan
Study/Condition
Heart Rate
Systolic BP
Diastolic BP
Heart Rate
Systolic BP
Diastolic BP
Baseline/Rest
89±16
129±14
75±9
91±17
136±21
75±12
Baseline/Exercise
112±18*
153±19*
76±10
112±21*
157±27*
76±13
Week M24/Rest
86±16
122±14
72±10
89±15
131±18
73±11
Week M24/Exercise
115±20*
147±20*
74±14
115±20*
159±29*
76±14
* = p < 0.05 vs. rest, data are mean ± SD, there were no differences between baseline and Week
M24 or between placebo and sitaxsentan.
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