Conditions: Pulmonary Hypertension
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 140
Healthy volunteers: no

Brief summary:
The primary objective of this study is to monitor the long-term safety of ambrisentan in adult participants with pulmonary hypertension. The available ambrisentan doses for this study are 2.5, 5, or 10 mg administered orally once daily. Investigators will be able to adjust ambrisentan dose as clinically indicated. A minimum of 4 weeks between dose adjustments is required. Participants receiving other therapies for pulmonary hypertension that are not contraindicated for concomitant use with ambrisentan are permitted to enroll in this study and continue to receive such therapies. Participants enrolled in this study will receive treatment with ambrisentan until such time as the investigator or participant chooses to stop ambrisentan treatment, ambrisentan becomes commercially available, or the sponsor stops the study.

Detailed description:

Arms:
arm 1: Participants will receive ambrisentan 2.5 mg, 5 mg or 10 mg tablet orally once daily until such time as the investigator or participant chooses to stop ambrisentan treatment, ambrisentan becomes commercially available, or the sponsor stops the study.

Interventions: intervention 1: Ambrisentan
Intervention descriptions: intervention 1: Tablet administered orally once daily

Protocol document:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL
Study Title:
ABS-LT: A Phase 3, Long-Term, Open Label, Multicenter 
Safety Study of Ambrisentan in Subjects with Pulmonary 
Hypertension
Sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
IND No.:
EudraCT Number
Indication:
Pulmonary Hypertension
Protocol ID:
GS-US-300-0124
Protocol Version/Date:
Version 2.0 Rest of World
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Amendment 1.0 ROW
CONFIDENTIALITY STATEMENT
The information contained in this document, particularly unpublished data, is the property or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an 
investigator, potential investigator, or consultant, for review by you, your staff, and an 
applicable Institutional Review Board or Independent Ethics Committee. The information is 
only to be used by you in connection with authorized clinical studies of the investigational 
drug described in the protocol. You will not disclose any of the information to others without 
written authorization from Gilead Sciences, Inc., except to the extent necessary to obtain 
informed consent from those persons to whom the drug may be administered.
(r) GILEAU 


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TABLE OF CONTENTS
TABLE OF CONTENTS .......................................................................................................................................2
LIST OF IN-TEXT TABLES.................................................................................................................................4
PROTOCOL SYNOPSIS .......................................................................................................................................5
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS ..............................................................8
1.
INTRODUCTION .......................................................................................................................................11
1.1.
Background.....................................................................................................................................11
1.1.1.
Pulmonary Hypertension...............................................................................................11
1.1.2.
Current Treatment Options............................................................................................11
1.2.
Ambrisentan....................................................................................................................................13
1.2.1.
Pharmacokinetics and Metabolism................................................................................13
1.2.2.
Preclinical Pharmacology and Toxicology....................................................................14
1.2.3.
Potential for Drug-Drug Interactions ............................................................................15
1.2.4.
Clinical Studies .............................................................................................................17
1.3.
Rationale for the Current Study ......................................................................................................23
2.
OBJECTIVES..............................................................................................................................................25
3.
STUDY DESIGN ........................................................................................................................................26
3.1.
Treatment Plan and Regimen..........................................................................................................26
3.2.
Study Schematic..............................................................................................................................27
4.
SUBJECT POPULATION...........................................................................................................................28
4.1.
Number of Subjects and Subject Selection .....................................................................................28
4.2.
Inclusion Criteria ............................................................................................................................28
4.3.
Exclusion Criteria ...........................................................................................................................29
4.4.
Study Specific Tolerance for Inclusion/Exclusion Criteria.............................................................29
5.
STUDY DRUGS..........................................................................................................................................30
5.1.
Randomization and Blinding...........................................................................................................30
5.2.
Description and Handling of Ambrisentan......................................................................................30
5.2.1.
Formulation...................................................................................................................30
5.2.2.
Packaging and Labeling ................................................................................................30
5.2.3.
Storage and Handling....................................................................................................30
5.3.
Dosage and Administration of Ambrisentan...................................................................................30
5.4.
Concomitant and Prohibited Medications.......................................................................................31
6.
STUDY PROCEDURES .............................................................................................................................32
6.1.
General Instructions ........................................................................................................................32
6.2.
Monitoring of Liver Function Test Abnormalities..........................................................................32
6.3.
Schedule of Assessments ................................................................................................................34
6.4.
Study Procedures By Time Point ....................................................................................................35
6.4.1.
Screening/Enrollment Visit (Week 0)...........................................................................35
6.4.2.
Laboratory Visits (Every 4 Weeks)...............................................................................35
6.4.3.
Clinic Visits (Every 24 Weeks).....................................................................................36
6.5.
Premature Discontinuation/End of Study........................................................................................37
6.6.
Criteria for Discontinuation of Study Treatment ............................................................................37
7.
DESCRIPTION OF STUDY PROCEDURES ............................................................................................39
7.1.
Medical History ..............................................................................................................................39


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7.2.
Concomitant Medications ...............................................................................................................39
7.3.
Vital Signs and Body Weight..........................................................................................................39
7.4.
Clinical Laboratory Tests................................................................................................................39
7.5.
Protocol Deviations.........................................................................................................................40
8.
ADVERSE EVENTS AND TOXICITY MANAGEMENT........................................................................41
8.1.
Adverse Events ...............................................................................................................................41
8.2.
Assessment of Adverse Events .......................................................................................................42
8.2.1.
Assessment of Causality................................................................................................42
8.2.2.
Assessment of Intensity.................................................................................................43
8.3.
Serious Adverse Events ..................................................................................................................43
8.4.
Special Situations Reports ..............................................................................................................45
8.4.1.
Definitions of Special Situations...................................................................................45
8.4.2.
Instructions for Reporting Special Situations................................................................45
8.5.
Serious Adverse Event Reporting Requirements ............................................................................46
8.5.1.
All Serious Adverse Events...........................................................................................46
8.5.2.
Investigator and Sponsor Reporting Requirements for SAEs .......................................47
8.5.3.
Post-Study Reporting Requirements .............................................................................47
8.6.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events 
or Serious Adverse Events ..............................................................................................................47
8.7.
Pregnancy........................................................................................................................................48
8.7.1.
Reliable Forms of Contraception ..................................................................................48
8.7.2.
Definition of Childbearing Potential and Post-Menopausal..........................................49
9.
STATISTICAL CONSIDERATIONS.........................................................................................................50
9.1.
Primary Endpoint............................................................................................................................50
9.2.
Measures of Interest........................................................................................................................50
9.3.
Methods of Analysis .......................................................................................................................50
9.3.1.
Analysis Sets.................................................................................................................50
9.3.2.
General Methodology....................................................................................................50
9.3.3.
Data Handling Conventions ..........................................................................................50
9.3.4.
Timing of Analyses.......................................................................................................50
9.4.
Demographic Data and Baseline Characteristics ............................................................................51
9.5.
Efficacy Analysis............................................................................................................................51
9.6.
Safety Analysis ...............................................................................................................................51
9.6.1.
Extent of Exposure........................................................................................................51
9.6.2.
Dose Migration..............................................................................................................51
9.6.3.
Adverse Events..............................................................................................................51
9.6.4.
Laboratory Evaluations .................................................................................................52
9.6.5.
Other Safety Evaluations...............................................................................................52
9.7.
Pharmacokinetic Analysis...............................................................................................................52
9.8.
Sample Size.....................................................................................................................................52
10.
RESPONSIBILITIES ..................................................................................................................................53
10.1.
Investigator Responsibilities ...........................................................................................................53
10.1.1.
Good Clinical Practice ..................................................................................................53
10.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) Approval..............................................................................................................53
10.1.3.
Informed Consent..........................................................................................................54
10.1.4.
Confidentiality ..............................................................................................................54
10.1.5.
Study Files and Retention of Records...........................................................................54
10.1.6.
Case Report Forms........................................................................................................55
10.1.7.
Drug Accountability......................................................................................................56
10.1.8.
Inspections ....................................................................................................................56


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10.1.9.
Protocol Compliance.....................................................................................................56
10.2.
Sponsor Responsibilities.................................................................................................................56
10.2.1.
Protocol Modifications..................................................................................................56
10.2.2.
Study Report and Publications ......................................................................................57
10.3.
Joint Investigator/Sponsor Responsibilities ....................................................................................57
10.3.1.
Access to Information for Monitoring...........................................................................57
10.3.2.
Access to Information for Auditing or Inspections .......................................................58
10.3.3.
Study Discontinuation...................................................................................................58
11.
REFERENCES ............................................................................................................................................59
12.
APPENDICES .............................................................................................................................................64
Appendix 1.
Investigator Signature Page...........................................................................................65
LIST OF IN-TEXT TABLES
Table 1-1.
Adverse Events in >3% of Ambrisentan-Treated Subjects and 
More Frequent than Placebo (AMB-320/321 Population: Safety)................................20
Table 6-1.
Dose Adjustment and Monitoring of Subjects Experiencing 
Serum Aminotransferase Elevations .............................................................................33


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title: 
ABS-LT: A Phase 3, Long-Term, Open Label, Multicenter Safety 
Study of Ambrisentan in Subjects with Pulmonary Hypertension 
IND Number:
EudraCT Number:
64,915 
2008-001838-27
Study Centers 
Planned:
Up to 80 investigational sites worldwide
Objectives:
The objective of this study is to monitor the long-term safety of 
ambrisentan in subjects with pulmonary hypertension (PH).
Number of Subjects 
Planned:
Approximately 300 subjects
Target Population:
Men and women who are discontinuing a clinical study of 
ambrisentan in PH due to study closure by the Sponsor and for 
whom ambrisentan is not yet commercially available.
Duration of 
Treatment:
Long-term 
Diagnosis and Main
Eligibility Criteria:
Men and women with PH who are discontinuing a clinical study 
of ambrisentan due to study closure by the Sponsor. Eligible 
subjects are those participating in countries where ambrisentan is 
not yet commercially available. Subjects participating in countries 
where ambrisentan is commercially available may be eligible if 
they do not qualify for treatment per the current prescribing 
information of that country.
Subjects who have discontinued an ambrisentan clinical study for 
any other reason than Sponsor-initiated study closure are not 
eligible.


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Study 
Design/Procedures
This Phase 3, international, multicenter, open-label study will 
monitor the long-term safety of ambrisentan in subjects with PH. 
The available ambrisentan doses for this study are 5 or 10 mg 
once daily (qd); these are the approved doses in the United States, 
Canada, and the European Union. Investigators will be able to 
adjust ambrisentan dose as clinically indicated. A minimum of 4 
weeks between dose adjustments is required. Subjects receiving 
other therapies for PH that are not contraindicated for concomitant 
use with ambrisentan are permitted to enroll in this study and 
continue to receive such therapies.
Subjects enrolled in this study will receive treatment with 
ambrisentan until such time as the Investigator or subject chooses 
to stop ambrisentan treatment, ambrisentan becomes 
commercially available, or the Sponsor stops the study.
Subjects will be followed by the Investigator according to clinical 
practice, with formal (per protocol) safety assessments conducted 
at the Screening/Enrollment Visit and at Clinic Visits every 
24 weeks thereafter. These safety assessments will include 
adverse events (AEs), clinical laboratory tests, vital signs, and 
concomitant medications. In addition, serum liver function tests 
(LFTs) will be monitored at Laboratory Visits every 4 weeks 
throughout the study. These LFTs will be performed at a local 
phlebotomy laboratory or at the Investigator clinic. A central 
laboratory will not be used for this study.
In animals, ambrisentan and other ERAs have been shown to be 
teratogenic. Therefore, female subjects of childbearing potential 
will undergo pregnancy testing every 4 weeks and will be 
required to use 2 reliable methods of contraception to reduce the 
risk of pregnancy during the course of the study and for at least 
30 days following the last dose of ambrisentan. If a subject has 
undergone tubal sterilization or has had a Copper T 380A 
intrauterine device (IUD) inserted, no other contraception is 
needed.
A Data Monitoring Committee (DMC) will monitor the safety and 
welfare of the study subjects. The DMC will meet at designated 
intervals to review the accumulated data.
Test Product, Dose, 
and Mode of 
Administration:
Ambrisentan tablets: 5 mg and 10 mg
Doses: 5 mg and 10 mg qd
Administration: oral tablet


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Reference Therapy, 
Dose, and Mode of 
Administration:
None
Criteria for 
Evaluation:
Safety:
The primary endpoint of this study is the incidence and severity of 
AEs associated with long-term exposure to ambrisentan in 
subjects with PH.
Additional safety endpoints of interest include:

Shift from baseline (low/normal/high) over time in clinical 
laboratory values 

Change from baseline over time in vital signs
Efficacy:
Efficacy will not be examined in this study.
Statistical Methods:
Interim analyses for this study will be performed periodically to 
generate safety data for regulatory submissions and for review by 
the DMC.
Safety data will be summarized by treatment group and all 
subjects combined for cumulative 24-week intervals. Most 
continuous data will be summarized using the following 
descriptive statistics: number of observations, mean, standard 
deviation, standard error, median, minimum and maximum. 
Categorical data will be summarized using frequencies and 
percentages. Changes from baseline will be calculated as the later 
value minus the baseline value. Baseline will be defined for all 
endpoints as the time of enrollment into this study.
This study will be conducted in accordance with the guidelines of Good Clinical Practices 
(GCPs) including archiving of essential documents.


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GLOSSARY OF ABBREVIA
D D
TIONS AN
EFINITION
M
OF TER S
ADME
absorption, distribution, metabolism, and elimination
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
bid
twice daily
BDI
Borg dyspnea index
BMI
body mass index
BNP
B-type natriuretic peptide
BSEP
bile salt export pump
BUN
blood urea nitrogen
CCB
calcium channel blockers 
Cmax
maximum plasma concentration
CONMED
concomitant medication
CRF
case report form
CRO
clinical research organization
CTD
connective tissue disease
CYP
cytochrome P450
DMC
Data Monitoring Committee
DSPH
Drug Safety and Public Health
E2
estradiol
ECE-1
endothelin converting enzyme
ECG
electrocardiogram
EEG
electroencephalogram
ERA
endothelin receptor antagonist
ET-1
endothelin-1
ETA
endothelin receptor type A
ETB
endothelin receptor type B
EU
European Union
FAS
full analysis set
FDA
Food and Drug Administration
FPAH
familial pulmonary arterial hypertension
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
GGT
gamma glutamyl transferase
hCG
human chorionic gonadotropin
HIV
Human Immunodeficiency Virus
ICF
Informed Consent Form


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
INR
international normalized ratio
IPAH
idiopathic pulmonary arterial hypertension
IUD
intrauterine device
IVRS
Interactive Voice Response System
IRB
Institutional Review Board
iv
intravenous
LFT
liver function test
MedDRA
Medical Dictionary for Regulatory Activities
m
meter
mg
milligram
mmHg
millimeters mercury
mPAP
mean pulmonary artery pressure
MRP2
multidrug resistance-associated protein 2
NDA
New Drug Application
NO
nitric oxide
NTCP
sodium-taurocholate co-transporter protein
OATP
organic anion transporter polypeptide
PAH
pulmonary arterial hypertension
PAH-CTD
pulmonary arterial hypertension associated with connective tissue disease
PAP
pulmonary artery pressure
PCWP
pulmonary capillary wedge pressure
PDE-5
phosphodiesterase type 5
PGI2
prostacyclin
P-gp
P-glycoprotein
PH
pulmonary hypertension
po
by mouth, orally
PT
prothrombin time
PVR
pulmonary vascular resistance
qd
once daily
RAP
right atrial pressure
ROW
Rest of World
SAE
serious adverse event
SOC
System Organ Class
SUSAR
Suspected Unexpected Serious Adverse Reaction
tid
three times daily


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
UGT
uridine glucuronosyltransferase
ULN
upper limit of normal
US
United States
WHO
World Health Organization
6MWD
6-minute walk distance


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1.
INTRODUCTION
1.1.
Background
1.1.1.
Pulmonary Hypertension
Pulmonary hypertension (PH) is a serious and life-threatening disease of the pulmonary 
vasculature, characterized by profound vasoconstriction and an abnormal proliferation of 
smooth muscle cells in the walls of the pulmonary arteries [1,2]. PH develops in response to 
various pathological conditions, which are categorized as: 1) pulmonary arterial hypertension 
(PAH); 2) PH associated with left heart disease; 3) PH associated with lung diseases and/or 
hypoxia; 4) PH due to chronic thrombolic and/or embolic disease and; 5) PH associated with 
miscellaneous pathologies affecting the pulmonary vasculature such as sarcoidosis, 
histiocytosis X, lymphangiomatosis, or the compression of pulmonary vessels by 
adenopathy, tumors or fibrosing mediastinitis [3].
PAH consists of a group of diseases characterized by a progressive increase of pulmonary 
vascular resistance (PVR) and pulmonary artery pressure (PAP). PAH includes idiopathic 
pulmonary arterial hypertension (IPAH), familial pulmonary arterial hypertension (FPAH), 
and PAH associated with various conditions such as connective tissue disease (CTD), 
congenital systemic-to-pulmonary shunts, portal hypertension, drug and toxin use, and 
human immunodeficiency virus (HIV) infection [4]. All of these disorders share similar 
proliferative and obstructive changes of the pulmonary microcirculation, including plexiform 
lesions [5].
The vascular damage that defines PAH is characterized by a mean pulmonary artery pressure 
(mPAP) 25 mmHg at rest or >30 mmHg with exertion and a pulmonary capillary wedge 
pressure (PCWP) 15 mmHg. Patients with PAH typically develop significant increases in 
PVR and sustained elevations in PAP, which ultimately lead to right ventricular failure and 
death [2,6]. Patients diagnosed with PAH have a poor prognosis and equally compromised 
quality of life, with a mean life expectancy of 2 to 5 years from the time of diagnosis if 
untreated [7]. Drugs that block or reduce the vasoconstriction and hypertrophy associated 
with the narrowing of the pulmonary arteries may ameliorate the cycle of constriction and 
improve pulmonary vascular blood flow.
1.1.2.
Current Treatment Options
Diuretics and anticoagulants have been widely used in the management of PH, yet treatment 
response varies [8]. Calcium channel blockers (CCBs) have shown improved survival in 
vasoreactive IPAH patients, yet the relatively low incidence of vasoreactivity make CCBs 
useful only in a minority of the population with PAH [8,9].
Three signaling pathways involved in the pathogenesis of PAH have been targeted for 
therapeutic intervention: the cAMP-dependent prostacyclin (PGI2) pathway [8], the 
cGMP-dependent nitric oxide (NO) pathway, and the phospholipase-C-dependent endothelin 


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pathway. These pathways are targeted by the following classes of drugs: PGI2 derivatives, 
phosphodiesterase type-5 (PDE-5) inhibitors, and endothelin receptor antagonists (ERAs).
The following summary is provided for illustration only, as not all treatments are available in 
all markets.
Intravenous (iv) epoprostenol (Flolan), subcutaneous, iv, and inhaled treprostinil 
(Remodulin), and inhaled iloprost (Ventavis) are PGI2 derivatives targeting the 
cAMP-dependent PGI2 pathway. These medicinal products mimic the effects of PGI2, an 
endogenous prostaglandin produced by the vascular endothelium, to stimulate cAMP-
dependent vasodilation of the pulmonary arterial bed and inhibit platelet aggregation [10]. 
Epoprostenol, a potent vasodilator, is a treatment option for patients with IPAH and PAH 
associated with connective tissue disease (PAH-CTD). There are several adverse events 
(AEs) associated with the drug including jaw pain, headache, nausea, and vomiting. The 
continuous infusion of epoprostenol requires the use of cold packs and a battery-operated 
ambulatory pump for 24-hour uninterrupted iv infusion, thereby necessitating a substantial 
commitment from patients for successful administration [11,12]. Treprostinil was originally 
given marketing authorization for administration as a continuous, subcutaneous infusion; 
however, use of this chronic prostanoid therapy has been associated with pain at the site of 
administration [13], prompting the development of iv and inhaled formulations [14]. Inhaled 
iloprost was approved for the treatment of PAH based on demonstrated improvement 
compared to placebo in 6-minute walk distance (6MWD) and World Health Organization 
(WHO) functional class after 12 weeks of therapy. This drug has a half-life of 20-25 minutes 
that requires 6-9 nebulization sessions per day and often requires patients to wake from sleep 
to administer iloprost at night [15]. 
Sildenafil citrate (Revatio), the first PDE-5 inhibitor approved for the treatment of PAH,
targets the NO pathway. Through inhibition of PDE-5, sildenafil increases cytoplasmic 
cGMP concentrations and enhances NO-mediated vasodilation of the vasculature [16]. 
Sildenafil demonstrated significant exercise capacity benefit compared with placebo over 
12 weeks of treatment [17]; however, the long-term effect of the approved dose of sildenafil 
(20 mg three times daily [tid]) as monotherapy has not been established.
The third targeted pathway is the phospholipase-C-dependent endothelin pathway. 
Endothelin-1 (ET-1) is the primary member of a family of potent vasoconstrictor peptides, 
which are known to play an essential role in mammalian cardiovascular physiology [18]. 
ET-1 is synthesized de novo and released from endothelial cells in response to a variety of 
factors, including angiotensin II, catecholamines, cytokines, hypoxia, and shear stress 
[19-22]. Two receptor subtypes, endothelin receptor type A (ETA) and endothelin receptor 
type B (ETB), mediate the effects of ET-1. In humans, the ETA receptor is preferentially 
expressed in vascular smooth muscle cells and is primarily responsible for the 
vasoconstrictive and mitogenic effects of ET-1 [23,24]. In contrast, ETB receptors are found 
mainly in the vascular endothelium, and their activation results in vasodilation via the 
production of NO and prostacyclin [25,26]. The ETB receptor is also involved in the 
regulation of circulating concentrations of ET-1, through effects on endothelin converting 
enzyme (ECE-1) expression, and the synthesis and reuptake of ET-1 by endothelial cells 
[27,28].


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ET-1 is rapidly cleared from the systemic circulation primarily by the lungs [29]. In healthy 
subjects, circulating plasma concentrations of ET-1 are normally quite low [30]; however, in 
patients with PAH, plasma ET-1 levels are elevated by as much as 10-fold [30,31]. Such 
elevations in plasma ET-1 also appear to correlate well with increased mean right atrial 
pressure (RAP) in this patient population [31]. ETA and ETB receptor mRNAs are abundantly 
expressed in human lung tissue [32]. Similarly, expression of ET-1 and ET-1 mRNA may be 
increased as much as 9-fold in the lung tissue of patients with PAH, primarily in the 
endothelium of pulmonary arteries [1]. Based on these findings, it has been suggested that 
ET-1 plays a critical role in the pathogenesis and progression of PAH.
Bosentan (Tracleer®), a non-selective, sulfonamide-class ERA, is approved globally for the 
treatment of PAH in patients with WHO functional class III or IV symptoms. Bosentan was 
demonstrated to increase exercise capacity in subjects with PAH, and reduce dyspnea during 
exercise [33-35].
1.2.
Ambrisentan
Ambrisentan [(+)-(2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-
diphenylpropanoic acid] is an orally active ERA that is selective for the ETA receptor. 
Ambrisentan (trade name: Letairis™) is approved by the United States (US) Food and Drug 
Administration (FDA) for the treatment of PAH (WHO Group 1) in patients with WHO class 
II or III symptoms to improve exercise capacity and delay clinical worsening. Ambrisentan 
has also been granted marketing authorization (under the tradename of Volibris™) by the 
European Commission and Health Canada for the treatment of patients with PAH classified 
as WHO functional class II and III. Additional marketing applications for ambrisentan have 
been filed or are planned in many countries world-wide.
1.2.1.
Pharmacokinetics and Metabolism
Clinical studies in healthy volunteers have demonstrated that ambrisentan is rapidly 
absorbed, with maximum plasma concentrations (Cmax) typically observed around 1.5 hours
after oral dosing, under both fasted and fed conditions; therefore, absorption is unaffected by 
food. In subjects with PAH, ambrisentan was rapidly absorbed following oral administration 
with Cmax typically occurring between 2 and 3 hours after dose. For both healthy volunteers 
and PAH patients, Cmax and area under the plasma concentration-time curve (AUC) increased 
dose proportionally over the therapeutic dose range, and steady-state was generally achieved 
following 4 days of repeat dosing. Steady-state plasma elimination half-life ranged from 13.6 
to 16.5 hours in healthy volunteers and from 12.9 to 17.9 hours in patients with PAH. 
Ambrisentan plasma concentrations were consistently higher (AUCss,0-24 2-3 fold) in subjects 
with PAH compared to healthy subjects. A similar difference was observed in bosentan 
clinical studies [36]. Reduction in the metabolic capacity of the liver as a consequence of 
PAH-related hepatic congestion or hypoperfusion may alter the systemic clearance of 
ambrisentan (as well as other ERAs) in patients with PAH.


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Ambrisentan is highly plasma protein bound, and the distribution of ambrisentan into red 
blood cells is low. Ambrisentan is primarily metabolized in the liver by glucuronidation and 
to a lesser extent by oxidative metabolism. Ambrisentan is glucuronidated by several uridine 
glucuronosyltransferase (UGT) enzymes (UGT1A9S, UGT2B7S and UGT1A3S) to form 
ambrisentan glucuronide. Ambrisentan glucuronide is rapidly excreted into the bile and 
partially converted back to ambrisentan by deconjugation in the gut. Ambrisentan undergoes
oxidative metabolism to form 4-hydroxymethyl ambrisentan; however, the AUC of this 
metabolite is approximately 4% of parent ambrisentan in plasma, which indicates that it is a 
minor metabolite. The 4-hydroxymethyl metabolite is generated primarily by cytochrome 
P450 (CYP) 3A4 and to a lesser extent by CYP3A5 and CYP2C19. The hydroxylated 
metabolite is further glucuronidated to 4-hydroxymethyl ambrisentan glucuronide. The 
binding affinity of 4-hydroxymethyl ambrisentan for the human ETA receptor is at least
100-fold less than that of ambrisentan. Therefore at concentrations observed in the plasma 
(~4%), 4-hydroxymethyl ambrisentan is not expected to contribute to pharmacological 
activity of ambrisentan. 
Ambrisentan and its metabolites are primarily excreted in the bile following hepatic and/or 
extra-hepatic metabolism and eliminated in the feces (65%). Approximately 22% of the 
administered dose is recovered in the urine following oral administration, with 3.3% being 
unchanged ambrisentan. 
Additional details regarding the pharmacokinetic and ADME (absorption, distribution, 
metabolism, and excretion) properties of ambrisentan, as determined in the ambrisentan 
nonclinical and clinical studies, are provided in the Investigator’s Brochure (IB) [37].
1.2.2.
Preclinical Pharmacology and Toxicology
The nonclinical pharmacology of ambrisentan has been studied in vitro and in vivo. In vitro 
nonclinical studies with ambrisentan have demonstrated that it is a potent and selective 
inhibitor of the ETA receptor. In studies using endogenously expressed, native ETA and ETB
receptors obtained from human ventricular myocardial membranes, ambrisentan
demonstrated a Ki (dissociation constant for the inhibitor) of approximately 0.011 nM for the 
ETA receptor and a Ki of 40.9 nM for the ETB receptor, resulting in a 4000-fold selectivity 
for the ETA versus the ETB receptor.
The vasodilatory and antiproliferative effects of endothelin receptor antagonism with 
ambrisentan have been established in several in vivo studies. Ambrisentan has a depressor 
action in the systemic circulation of rats and dogs and a vascular antiproliferative effect in
the injured coronary artery of the pig. Numerous studies have also been conducted in animals
to evaluate the safety of ambrisentan on the nervous, cardiovascular, respiratory, 
gastrointestinal, musculoskeletal, and genitourinary systems. Ambrisentan elicited only 
minor effects in most of these assays, even at high concentrations or doses. 
The toxicological profile of ambrisentan has been evaluated in single dose, repeat dose, 
carcinogenicity, and reproductive/developmental studies in mice, rats, rabbits and dogs, and 


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in genotoxicity studies in vitro (mammalian and bacterial cells) and in vivo (rats). In single 
and repeat dose toxicity studies in mice, rats, and dogs, few significant systemic or organ 
toxicities were observed. The target organs identified in mice, rats, and dogs with chronic 
ambrisentan administration were the gastrointestinal tract, kidneys, heart, nasal cavity, and 
testes. In rats only, chronic dosing of ambrisentan was also associated with an increase in 
osseous hyperplasia of the nasal cavities, which in turn led to suffocation and premature 
death in a portion of these obligate nose breathers. 
Teratogenicity is a class effect of ERAs, and exposure of animals to ERAs has been shown to 
cause a specific and potentially lethal combination of embryonic defects including 
craniofacial, cardiac, and thyroid abnormalities. Oral administration of ambrisentan to 
pregnant rats or rabbits on gestation days 6 to 17 resulted in abnormalities of the lower jaw, 
tongue, and/or palate at all doses evaluated. For humans, this means that the potential 
teratogenic effect of ambrisentan could occur before a patient knows she is pregnant.
The development of testicular tubular atrophy and impaired fertility has been linked to the 
chronic administration of ERAs, although the potential for human injury has not been 
determined. Ambrisentan administration was associated with the development of testicular
lesions in rats, but there was no consistent effect of these lesions on fertility and/or sperm 
morphology or motility. In clinical studies, the analysis of male fertility hormones in 
combination with the limited number of subjects providing serial semen samples did not 
suggest that long-term ambrisentan treatment was associated with an adverse effect on male 
reproductive potential.
The genotoxicity of ambrisentan was assessed in a comprehensive battery of in vitro and in 
vivo studies. Ambrisentan was clastogenic (structural chromosome damage) when tested at 
high concentrations in mammalian cells in vitro. Ambrisentan was not mutagenic to bacteria, 
and produced minimal evidence of carcinogenic potential in two 104-week rodent studies.
1.2.3.
Potential for Drug-Drug Interactions
The management of PH often requires multi-drug regimens; therefore, the risk of adverse 
drug-drug interactions should be carefully considered. Concomitant medications for the 
treatment of PAH include anticoagulants, diuretics, CCBs, and digoxin. Subjects may also 
require concomitant therapy for co-morbidities, such as immunosuppressants for CTD and 
protease inhibitors for HIV infection. In addition, the strategy of administering more than one
PAH medication to target different pathological mechanisms is increasingly being 
implemented.
Ambrisentan parent is the predominant ambrisentan-related species circulating in the plasma, 
and the minor ambrisentan metabolism that occurs is mediated by a variety of CYP and UGT 
enzymes, rather than by one predominant enzyme (Section 1.2.1). Therefore, the 
pharmacokinetics of ambrisentan are unlikely to be affected by coadministered drugs that 
induce or inhibit specific phase I or phase II enzymes. 


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Likewise, in vivo and in vitro studies have demonstrated that ambrisentan does not inhibit 
(Section 1.2.3.1) or induce (Section 1.2.3.2) CYP or UGT metabolic pathways at clinically 
relevant doses or concentrations. Therefore, administration of ambrisentan is unlikely to alter 
the pharmacokinetics of other drugs that may be metabolized by these pathways.
In vitro studies using rat and human hepatocyte cultures have demonstrated that ambrisentan 
does not inhibit the organic anion transporter polypeptide (OATP), sodium-taurocholate 
co-transporter protein (NTCP), multidrug resistance-associated protein 2 (MRP2), or the bile 
salt export pump (BSEP). Rat hepatocyte assays have demonstrated that ambrisentan does 
not induce protein levels of BSEP and P-glycoprotein (P-gp). Ambrisentan is a possible 
substrate for the hepatic influx transporter OATP and for the efflux transporter P-gp, but not 
for the hepatic influx or efflux transporters NTCP or BSEP, respectively.
Cyclosporine A is a strong inhibitor of P-gp; therefore, caution should be used when 
ambrisentan is coadministered with cyclosporine A [38].
1.2.3.1.
In Vitro Enzyme Inhibition Studies
The ability of ambrisentan to inhibit hepatic phase I and II metabolizing enzymes has been 
evaluated in microsomes prepared from a human lymphoblastoid cell line or baculovirus-
infected insect cells. Inhibition did not exceed 50% for any enzyme at the highest 
concentration (300 μM) of ambrisentan tested. These results suggest a low potential for 
ambrisentan to inhibit hepatic phase I and phase II metabolism at clinically relevant 
concentrations.
1.2.3.2.
In Vitro Enzyme Induction Studies
The activity of ambrisentan as a modulator of hepatic phase I and II enzyme induction was 
examined in rats and dogs. No induction of CYP, glutathione-S-transferase (GST), or uridine 
diphospho-glucuronosyltransferase (UDP-GT) enzyme concentrations or activities were 
observed at clinically relevant doses. Enzyme induction that was observed in these studies 
generally occurred at the highest doses, corresponding to an equivalent human 
pharmacokinetic exposure that is 50- to 200-fold higher than that determined in clinical 
development. Results suggest that ambrisentan should not possess clinically significant 
hepatic phase I or II metabolizing enzyme induction potential.
1.2.3.3.
Clinical Drug-Drug Interaction Studies
Several clinical studies have been conducted with ambrisentan to examine the potential for 
adverse drug-drug interactions. In EE-002, daily dosing of ambrisentan (5, 7.5, or 10 mg by 
mouth [po] once daily [qd]) did not increase 6-hydroxycortisol excretion, indicating a lack 
of CYP3A4 induction.
In healthy subjects receiving a single dose of sildenafil (20 mg), daily doses of ambrisentan 
(10 mg qd) did not have a clinically relevant effect on the pharmacokinetics of sildenafil (a 
CYP3A4 and CYP2C9 substrate) or the active metabolite, n-desmethyl sildenafil. Similarly, 


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daily doses of sildenafil (20 mg tid) did not have a clinically relevant effect on the 
pharmacokinetics of a single-dose of ambrisentan (10 mg). Therefore, no dose-adjustments 
of sildenafil or ambrisentan are required when co-administered.
Ambrisentan (10 mg qd) did not have a clinically relevant effect on the pharmacokinetics of 
S-warfarin (CYP2C9 substrate) or R-warfarin (CYP3A4 substrate) in healthy subjects 
receiving a single 25 mg dose of racemic warfarin. Similarly, warfarin had no clinically 
significant effects on the pharmacokinetics of ambrisentan. In addition, daily doses of 
ambrisentan (10 mg qd) did not have a clinically significant effect on prothrombin time (PT) 
or International Normalized Ratio (INR). Consistent with this result, no clinically relevant 
changes in PT, INR or warfarin-type anticoagulant dose were observed with ambrisentan 
treatment in the clinical studies of patients with PAH. Therefore, no dose adjustments for 
warfarin or ambrisentan are required when co-administered.
The effect of daily doses of ambrisentan (10 mg qd) on the pharmacokinetics of a single 
0.5 mg dose of digoxin, a substrate for P-gp, was evaluated in healthy subjects. Slight 
increases in the plasma concentrations of digoxin were observed in the presence of daily 
ambrisentan dosing, however, these increases were not considered to be clinically relevant. 
Based on the results of this study, no dose adjustment of digoxin is recommended with 
ambrisentan co-administration.
Finally, the effects of ketoconazole, a potent CYP3A4 inhibitor, on the pharmacokinetics of 
ambrisentan were also assessed in healthy subjects. Daily doses of ketoconazole (400 mg qd) 
did not have a clinically relevant effect on the single-dose pharmacokinetics of ambrisentan. 
Therefore, no ambrisentan dose adjustment is recommended when co-administered with 
ketoconazole.
These clinical data are consistent with the in vitro and in vivo nonclinical studies and support 
the conclusion that ambrisentan has a low risk of adverse drug-drug interactions. 
1.2.4.
Clinical Studies 
The safety, tolerability, pharmacokinetics, and pharmacodynamics of ambrisentan have been 
evaluated in ten Phase 1 studies in healthy subjects: EE-001 (single ascending dose study), 
EE-002 (multiple ascending dose study), AMB-103 (bioequivalence study), AMB-104 
(thorough QTc prolongation study), AMB-105 (sildenafil drug-drug interaction study), 
AMB-106 (warfarin drug-drug interaction study), AMB-107 (ADME/mass balance study), 
AMB-108 (metabolite/chirality study), ABS-109 (digoxin drug-drug interaction) and 
ABS-1010 (ketoconazole drug-drug interaction study).
In subjects with PAH, ambrisentan (2.5, 5, and 10 mg qd) has been evaluated in two pivotal 
randomized, placebo-controlled Phase 3 studies (AMB-320 and AMB-321), two Phase 2 
studies (AMB-220 and AMB-222), and two long-term safety and efficacy studies 
(AMB-220-E and AMB-320/321-E). Furthermore, ambrisentan is currently being evaluated 
in a Phase 3 open-label study in subjects with pulmonary hypertension of various etiologies 
(AMB-323). 


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Further information on all clinical studies of ambrisentan in healthy volunteers and subjects 
with PAH is provided in the IB [37].
1.2.4.1.
Clinical Efficacy
In two Phase 3, placebo-controlled studies (AMB-320 [ARIES-1] and AMB-321 
[ARIES-2]), ambrisentan demonstrated statistically significant improvement in 6MWD. An 
increase in 6MWD was observed after 4 weeks of treatment with ambrisentan, with a 
dose-response observed after 12 weeks of treatment. Results from AMB-321 demonstrated 
that 5 mg and 2.5 mg po qd of ambrisentan improved the placebo-corrected 6MWD by 
59.4 meters (p <0.001) and 32.3 meters (p = 0.022), respectively. Similarly, results from 
AMB-320 demonstrated that 10 mg and 5 mg po qd of ambrisentan improved the 
placebo-corrected 6MWD by 51.4 meters (p 0.001) and 30.6 meters (p = 0.008), 
respectively. 
Time to clinical worsening, an indicator of disease progression, was a key secondary 
endpoint in the two Phase 3, placebo-controlled studies. The individual studies were not 
statistically powered to examine secondary endpoints such as time to clinical worsening; 
therefore, to increase the power to observe a treatment effect, a combined analysis of the 
two Phase 3 studies was prespecified to examine secondary endpoints. The log-rank test for 
the comparison of the combined ambrisentan group versus placebo demonstrated that a 
significant delay in the time to clinical worsening of PAH was observed for subjects 
receiving ambrisentan (p <0.001). Furthermore, the hazard ratio was 0.29 (95% CI: 0.14 to 
0.59), indicating a 71% reduction in the probability of clinical worsening over the 12-week 
treatment period for subjects receiving ambrisentan compared to placebo. 
The conclusions of the combined analysis were supported by similar trends in the individual 
studies. In AMB-320, a 2-fold increase in the number of subjects with an event of clinical 
worsening was observed in the placebo group compared to each of the ambrisentan dose 
groups; however, the log-rank comparison of the combined ambrisentan group versus 
placebo did not demonstrate a statistically significant difference in the time to clinical 
worsening of PAH (p = 0.214). In AMB-321, a 4-fold increase in the number of subjects with 
an event of clinical worsening was observed in the placebo group compared to each of the 
ambrisentan dose groups. The log-rank test demonstrated a significant delay in time to 
clinical worsening of PAH for the comparison of the combined ambrisentan group versus 
placebo (p <0.001). The adjudication and analysis of clinical worsening events in the Phase 3 
placebo-controlled studies were prespecified; however, during the FDA review of the New
Drug Application (NDA), the agency performed a separate analysis of time to clinical 
worsening that included re-adjudication of some clinical worsening events. Per this analysis, 
both studies demonstrated a significant improvement in time to clinical worsening for the 
combined ambrisentan group compared to placebo (AMB-320, p = 0.030; AMB-321, 
p = 0.005), which is consistent with the results of the prespecified integrated analysis of the 
2 studies. Therefore, ambrisentan has been indicated in the US to delay clinical worsening in 
patients with PAH.


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Clinically relevant or statistically significant improvements were observed in the individual 
studies for the secondary endpoints of WHO functional class, the SF-36™ health survey, and 
Borg dyspnea index (BDI). In the prespecified combined analysis, all secondary endpoints 
were statistically significant. 
In addition, statistically significant improvements from baseline with ambrisentan treatment 
were observed for several hemodynamics parameters (cardiac index, mPAP, and PVR) in a 
Phase 2 dose-controlled study (AMB-220), consistent with an overall improvement in disease 
state. 
Plasma B-type natriuretic peptide (BNP), a hormone secreted primarily from the cardiac 
ventricles, has been proposed as a prognostic factor of mortality in patients with PAH 
[39-41]. Reductions in BNP have been shown to parallel improvements in hemodynamics, 
6MWD, and WHO functional class in patients with PAH [42]. Substantial (p <0.05) and 
clinically relevant decreases (29% to 45%) in BNP compared to placebo were observed in the 
Phase 3 pivotal studies, and decreases in BNP correlated with and were predictive of 
improvements in 6MWD.
The long-term follow-up of the subjects who were treated with ambrisentan in the Phase 3, 
placebo-controlled studies and their open-label extension (N = 383) shows a 95% probability 
of survival at 1 year (Kaplan-Meyer analysis) and of those with 48 weeks of data, 94% were 
still receiving monotherapy. The improvements in 6MWD, WHO functional class, and BDI 
were maintained for at least 48 weeks with ambrisentan treatment in the Phase 3 studies and 
were generally maintained for up to 3 years in the Phase 2 study (AMB-220-E).
1.2.4.2.
Clinical Adverse Event Profile
Safety data for ambrisentan were obtained from the two Phase 3, placebo-controlled studies 
and four non-placebo-controlled studies in a total of 483 patients with PAH who were treated 
with doses of 1, 2.5, 5, or 10 mg qd. As of 30 November 2006, the mean exposure to 
ambrisentan was 79.5 50.28 weeks (1.5 years) with a range of 1 day to 4 years. The 
majority of these subjects had drug exposures of at least 6 months (418, 86.5%). More than 
two-thirds of subjects had drug exposure of at least 1 year (343, 71.0%), approximately 
one-fourth for 2 or more years (120, 24.8%), and 42 (8.7%) subjects had drug exposures of 3 
or more years. 
In AMB-320 and AMB-321, a total of 261 subjects received ambrisentan at doses of 2.5, 5, 
or 10 mg qd and 132 subjects received placebo. Given that PAH is a serious and life-
threatening condition, certain types of AEs are expected. In the combined analysis of the 
Phase 3, placebo-controlled studies, the most frequent AEs experienced by the placebo group 
were headache (14%), right ventricular failure (12%), peripheral edema (11%), dizziness 
(10%), and nausea (9%). The most notable AEs that occurred more often in the subjects 
receiving placebo compared to ambrisentan were right ventricular failure and nausea.
To evaluate the effects of ambrisentan beyond the disease process that defined the study 
population, placebo-adjusted incidences were calculated for the common AEs from the 


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combined analysis of the pivotal studies by subtracting the placebo incidence from the 
ambrisentan incidence (Table 1-1).
Table 1-1.
Adverse Events in >3% of Ambrisentan-Treated Subjects and 
More Frequent than Placebo (AMB-320/321 Population: Safety)
Adverse Event
Placebo
(N = 132)
Combined ambrisentan
(N = 261)
n (%)
n (%)
Placebo-adjusted (%)
Peripheral edema
14 (11)
45 (17)
6
Nasal congestion
2 (2)
15 (6)
4
Sinusitis
0 (0)
8 (3)
3
Flushing
1 (1)
10 (4)
3
Palpitations
3 (2)
12 (5)
3
Nasopharyngitis
1 (1)
9 (3)
2
Abdominal pain
1 (1)
8 (3)
2
Constipation
2 (2)
10 (4)
2
Dyspnea
4 (3)
11 (4)
1
Headache
18 (14)
38 (15)
1
Note: This table includes all AEs >3% incidence in combined ambrisentan treatment group and greater than in the placebo 
group with a difference of ≥1% between the ambrisentan and placebo groups.
Peripheral edema is a known class effect of ERAs, and is also a clinical consequence of PAH 
and worsening PAH [43,44]. In the placebo-controlled studies, there was an increased 
incidence of peripheral edema in subjects treated with doses of 5 or 10 mg ambrisentan 
compared to placebo (Table 1-1). Most edema was mild to moderate in severity. Peripheral 
edema was similar in younger patients (<65 years) receiving ambrisentan (14%; 29/205) or 
placebo (13%; 13/104), and was greater in elderly patients (>65 years) receiving ambrisentan 
(29%; 16/56) compared to placebo (4%; 1/28).
Of the AEs shown in Table 1-1, only nasal congestion consistently displayed trends of 
increasing frequency with higher dose. However, the majority of these events were mild, and 
none were considered severe, serious, or led to premature discontinuation from the study.
AE profiles following long-term ambrisentan therapy continued to be consistent with that 
observed in the 12-week, placebo-controlled studies. In general, ambrisentan is well-tolerated 
and associated with a manageable safety profile in subjects with PAH.
To date, postmarketing surveillance of commercial ambrisentan (Letairis) safety has shown
that the nature and severity of AEs observed with commercial therapy were generally
consistent with the known safety of ambrisentan, or were attributable to concurrent disease 


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processes or other concomitant medications. Of note, postmarketing reports of fluid retention 
occurring within weeks after starting Letairis have been received and, in some cases, have 
required intervention with a diuretic or hospitalization for fluid management. 
AEs that have been associated with ERA administration include headache, nasopharyngitis, 
flushing, peripheral edema, and nasal congestion [43,44]. Other safety signals associated 
with ERAs include dose-dependent abnormalities in liver function tests (LFTs, 
Section 1.2.4.2.1) [44-46], the potential adverse effects to fetal development 
(Section1.2.4.2.3), the potential for adverse effects on male fertility (Section 1.2.4.2.2), and 
decreases in hemoglobin and hematocrit (Section 1.2.4.2.4) [33,35,43,47].
1.2.4.2.1.
Elevations in Liver Function Tests
Previous clinical studies with ERAs for the treatment of PAH have demonstrated 
dose-dependent increases in serum aminotransferase concentrations, specifically alanine 
aminotransferase (ALT) and aspartate aminotransferase (AST), which may be associated 
with liver injury. The incidence of serum aminotransferases >3x upper limit of normal (ULN) 
in the pivotal studies of bosentan was 12% and 14% for 125 mg and 250 mg twice daily (bid) 
bosentan, respectively [44]. LFT abnormalities have led to dose reduction and 
discontinuation of bosentan therapy in a significant number of patients.
Sitaxsentan has also been associated with dose-dependent LFT abnormalities, including 1 
fatal case of acute hepatitis and 1 case of acute hepatitis requiring subsequent liver 
transplantation [48,49]. In the Phase 3 PAH study (STRIDE-1), the incidence of serum 
aminotransferases >3xULN was 0% and 10% after 100 mg and 300 mg qd po dosing of 
sitaxsentan, respectively [43]. When results were combined with an extension study with a 
median exposure of 26 weeks, the incidence increased to 5% and 21% for the 100 mg and 
300 mg groups, respectively. This phase of the study was terminated prematurely due to 
concerns regarding the risk of possible liver injury [46]. STRIDE-2 was an 18-week, 
placebo-controlled study of PAH patients treated with placebo, sitaxsentan (50 mg or 100 mg 
qd), or bosentan (125 mg bid). In this study, the incidence of serum aminotransferases 
>3xULN was 6% for placebo, 5% for 50 mg sitaxsentan, 3% for 100 mg sitaxsentan, and 
11% for bosentan [50]. Sitaxsentan was withdrawn from the worldwide market in December 
2010 due to two cases of fatal liver injury causally related to the drug [51].
LFTs were closely monitored in all clinical studies with ambrisentan. In the 12-week 
placebo-controlled studies, the incidence of serum aminotransferase elevations >3xULN was 
0% for subjects receiving ambrisentan (N = 261), compared to 2.3% for subjects receiving 
placebo (N = 132). For all ambrisentan-treated subjects (N = 483), the 12-week incidence of 
aminotransferases >3xULN was 0.8% and >8xULN was 0.2%. The 1-year rate of 
aminotransferase elevations >3xULN with ambrisentan was 2.8% and >8xULN was 0.5%. 
Most aminotransferase events were generally mild (5xULN), transient, and did not require 
any action. Only 1 case of aminotransferase elevations >3xULN has been accompanied by 
bilirubin elevations >2xULN. The subject had these elevations while being hospitalized due 
to acute pneumonia. These LFT abnormalities resolved shortly after resolution of the 


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pneumonia, and the subject received 10 mg ambrisentan for an additional 177 days without 
incidence. The subject subsequently died due to a new event of viral pneumonia and acute 
respiratory failure.
Given the literature on aminotransferase abnormalities in subjects with PAH who received 
placebo in controlled studies, the accumulated clinical experience with ambrisentan suggests 
that the incidence of aminotransferase abnormalities was not greater than the background 
incidence expected in subjects with PAH [35,43].
In an uncontrolled, open label study, 36 subjects with PAH who had previously discontinued 
either bosentan, sitaxsentan, or both due to aminotransferase elevations >3xULN were 
treated with ambrisentan (AMB-222). Prior elevations were predominantly moderate, with 
64%. of the ALT elevations <5xULN; however, 9 subjects had ALT or AST elevations 
>8xULN. Eight subjects had been rechallenged with bosentan and/or sitaxsentan and all eight 
had a recurrence of aminotransferase abnormalities that required discontinuation of ERA 
therapy. All subjects had to have normal aminotransferase levels on entry to this ambrisentan 
study. Twenty five of the 36 subjects were also receiving prostanoid and/or PDE-5 inhibitor 
therapy. Two subjects discontinued early (including one of the subjects with a prior 8xULN 
elevation) for reasons other than elevated aminotransferase levels. Of the remaining 34 
subjects, one subject experienced a mild aminotransferase elevation at 12 weeks on 
ambrisentan 5 mg that resolved with decreased dosage to 2.5 mg, and that did not recur with 
later dose escalations to 10 mg. With a median follow up of 13 months and with 50% of 
subjects increasing the dose of ambrisentan to 10 mg, no subjects were discontinued for 
aminotransferase elevations.
1.2.4.2.2.
Potential Risk of Testicular Injury
It is not known if the testicular lesions seen in animals (Section 1.2.2) correspond to any 
measurable effect in humans. Data from the literature indicates that endothelin receptors are 
localized to different cell types in the rat and human testes [52-54], suggesting the potential 
for a different response in man. In the Phase 2 and Phase 3 studies of ambrisentan, male 
subjects underwent semen and male fertility hormone analyses to assess fertility before and 
after treatment with ambrisentan. These analyses did not suggest that long-term ambrisentan 
treatment is associated with a substantial adverse effect on male reproductive potential.
This clinical study includes clear informed consent regarding the potential development of 
testicular injury and infertility. The ambrisentan IB should be reviewed for additional 
information.
1.2.4.2.3.
Potential Risk to Fetal Development
Teratogenicity is a class effect of ERAs (Section 1.2.2). There are no data on the use of 
ambrisentan in pregnant women. 
Ambrisentan is contraindicated in women who are or may become pregnant while taking this 
drug. Pregnant women will be excluded from participation in the current study, and female 


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subjects of childbearing potential will be required to use at least 2 reliable methods of 
contraception throughout their participation in the study and 30 days after discontinuation of 
study drug unless the subject has undergone tubal sterilization or has had a Copper T 380A 
intrauterine device (IUD) or LNg 20 IUD inserted, in which case no other contraception is 
needed. In addition, monthly pregnancy tests will be required for subjects of childbearing 
potential.
1.2.4.2.4.
Hematological Changes
The development of drug-related reductions in hemoglobin concentration and hematocrit 
have been associated with ERA administration in subjects with PAH, including ambrisentan, 
and there have been cases where this has resulted in anemia [33,35,38,43,47]. Reversible 
hemodilution has been proposed as the mechanism of action for this ERA class effect [34]. 
In the placebo-controlled ambrisentan studies, the mean decrease in hemoglobin 
concentration was 0.8 g/dL [38], which was comparable to the decrease observed with 
bosentan treatment (0.9 g/dL) [44]. Mean hemoglobin concentration decreased over the first 
4 weeks for subjects receiving ambrisentan but stabilized by 412 weeks of treatment. There 
appeared to be no clear relationship between the decrease in hemoglobin and ambrisentan 
dose. Similar findings were observed for mean hematocrit. 
In the placebo-controlled studies, marked decreases in hemoglobin (≥15% decrease resulting 
in a value below the lower limit of normal) were observed in 7% of subjects receiving 
ambrisentan compared to 4% of subjects receiving placebo. 
No other notable hematology findings were observed with ambrisentan treatment. The cause 
of the decrease in hemoglobin is unknown, but it does not appear to result from hemorrhage 
or hemolysis.
1.3.
Rationale for the Current Study
Ambrisentan was approved in the US on 15 June 2007 and was made commercially available 
to US patients soon thereafter. Ambrisentan also received marketing authorization from 
Health Canada on 20 March 2008 and the European Commission on 21 April 2008. 
Additional marketing applications have been filed or are planned in many countries 
world-wide. Subjects who participated in the pivotal studies supporting the marketing
applications for ambrisentan in PH are currently receiving long-term therapy in several open-
label extension studies. The objectives of these original extension studies have been met and 
the studies are being closed by the Sponsor as patients transition to commercial ambrisentan 
therapy. The purpose of this protocol is to provide continuous, uninterrupted access to 
ambrisentan therapy to subjects who are discontinuing an ambrisentan PH study due to study 
closure by the Sponsor and for whom ambrisentan is not yet commercially available.
For subjects participating in the ongoing clinical studies of ambrisentan, commercial 
availability does not guarantee immediate access to ambrisentan treatment. For example, 
ambrisentan may be commercially available, but the subject may not qualify for treatment if 


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their diagnosis is not consistent with the current approved indication. To ensure 
uninterrupted, continued access to ambrisentan, subjects meeting these criteria in countries 
where ambrisentan is commercially available are eligible for enrollment in this study.
This study provides a mechanism for collecting ongoing safety data to supplement the 
existing ambrisentan safety database. The safety of subjects receiving long-term ambrisentan 
treatment will be monitored with monthly (every 4 weeks) LFT assessments and bi-annual 
(every 24 weeks) Clinic Visits.  The Screening/Enrollment visit for this study will coincide 
with the final study visit of the previous ambrisentan study. Baseline will be defined as the 
time of enrollment into this study.
Elevations in serum aminotransferase (ALT and/or AST) values may be detected at the 
Screening/Enrollment visit. Per the treatment guidelines for the review and management of 
elevated serum aminotransferases, which are included in all ambrisentan clinical protocols
(see Section 6.2 of this protocol), subjects with an increase in ALT or AST concentrations 
>8xULN must immediately stop ambrisentan treatment. These subjects may not re-initiate 
ambrisentan even after serum aminotransferase concentrations have decreased below 3xULN 
and therefore will not be allowed to enroll in this study. Subjects with ALT/or AST 
concentrations >3xULN but 8xULN will be allowed to enroll, and must treated and 
monitored per the guidelines provided in Section 6.2. 


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2.
OBJECTIVES
The objective of this study is to monitor the long-term safety of ambrisentan in subjects with 
PH.


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3.
STUDY DESIGN
3.1.
Treatment Plan and Regimen
This Phase 3, international, multicenter, open-label study will monitor the long-term safety of 
ambrisentan in subjects with PH. The available ambrisentan doses for this study are 5 or 
10 mg qd; these are the approved doses in US, Canada, and EU.
Investigators will be able to adjust ambrisentan dose as clinically indicated. A minimum of 4 
weeks between dose adjustments is required. Subjects receiving other therapies for PH that 
are not contraindicated for concomitant use with ambrisentan are permitted to enroll in this 
study and continue to receive such therapies.
Subjects enrolled in this study will receive treatment with ambrisentan until such time as the 
Investigator or subject chooses to stop ambrisentan treatment, ambrisentan becomes 
commercially available, or the Sponsor stops the study.
Subjects will be followed by the Investigator according to clinical practice, with formal (per 
protocol) safety assessments conducted at the Screening/Enrollment Visit and at Clinic Visits 
every 24 weeks thereafter. These safety assessments will include AEs, clinical laboratory 
tests, vital signs, and concomitant medications. In addition, serum LFTs will be monitored at 
Laboratory Visits every 4 weeks throughout the study. These LFTs will be performed at a 
local phlebotomy laboratory or at the Investigator clinic. A central laboratory will not be 
used for this study.
In animals, ambrisentan and other ERAs have been shown to be teratogenic. Therefore, 
female subjects of childbearing potential will undergo pregnancy testing every 4 weeks and 
will be required to use 2 reliable methods of contraception to reduce the risk of pregnancy 
during the course of the study and for at least 30 days following the last dose of ambrisentan. 
If a subject has undergone tubal sterilization or has had a Copper T 380A IUD or LNg 20 
IUD inserted, no other contraception is needed.
An internal Data Monitoring Committee (DMC) will monitor the safety and welfare of the 
study subjects. The ABS-LT study is an open label study, thus the data monitoring committee 
consists of internal employees of the Sponsor rather than external members.  The committee 
chair is a physician with extensive pulmonary hypertension experience. The remaining 
committee members include a second physician, a clinical scientist, and a biostatistician. The 
internal DMC will meet at designated intervals to review the accumulated data.


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3.2.
Study Schematic
Weeks
0
8
4
12
12
16
16
20
20
24
24
previous ABS study
2.5, 5, or 10 mg
ambrisentan 
Laboratory Visi s 
Every 4 weeks
(Local Lab or Investiga or Clinic)
Clinic Visit 
Every 24 weeks
 
 
 
 
 
Screening/Enrollment 
(End of previous ABS study)
ABS-LT
5 or 10 mg
ambrisentan
I 
I 
............... _____.,.____..,_____,.______.. - - -
~-II~-


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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
This study is designed to provide continuous, uninterrupted access to ambrisentan therapy to 
subjects who are discontinuing an ambrisentan PH study due to study closure by the Sponsor 
and for whom ambrisentan is not yet currently available. It is estimated that approximately
300 subjects will be eligible for this study at the time of its inception. This number will vary
as subjects discontinue this study, or as additional clinical studies of ambrisentan in PH are 
completed and subjects participating in these studies become eligible per the inclusion and 
exclusion criteria specified in Sections 4.2 and 4.3.
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in 
this study.
1. Subject must be discontinuing a clinical study of ambrisentan in PH due to study closure 
by the Sponsor.
2. Subject must be discontinuing a clinical study of ambrisentan in PH in a country where:
a.
Ambrisentan is not yet commercially available; or
b. Ambrisentan is commercially available, but the subject does not qualify for 
commercial therapy per the current prescribing information of that country
3. Subject must have completed study assessments and procedures for the previous 
ambrisentan study to the best of their ability.
4. Female subject of childbearing potential must have a negative serum or urine pregnancy 
test at the Screening/Enrollment Visit. A female subject of childbearing potential is 
defined in Section 8.7.
5. Female subject of childbearing potential must agree to use 2 reliable methods of 
contraception until study completion and for at least 30 days following the last dose of 
ambrisentan (reliable methods of contraception are described in Section 8.7). 
6. Subject must agree not to participate in a clinical study involving another investigational 
drug or device for PH throughout this study (does not include registry or observational 
studies)
7. Subject must be competent to understand the information given in the Institutional 
Review Board (IRB) or Independent Ethics Committee (IEC) approved Informed 
Consent Form (ICF) and must sign the form prior to the initiation of any study 
procedures.


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4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1. Subject who is discontinuing a clinical study of ambrisentan for any other reason than 
Sponsor-initiated study closure.
2. Subject who has a confirmed serum ALT and/or AST lab value >8xULN.  
3. Female subject who is pregnant or breastfeeding.
4. Subject who has demonstrated noncompliance with previous medical regimens.
5. Subject who has a recent history of abusing alcohol or illicit drugs.
6. Subject who is receiving bosentan (Tracleer), sitaxsentan (Thelin), or any 
investigational drug for PH.
7. Subject with a known hypersensitivity to ambrisentan, the metabolites, or formulation 
excipients.
4.4.
Study Specific Tolerance for Inclusion/Exclusion Criteria
Subjects with deviations to inclusion and exclusion criteria will not be permitted to enroll.


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5.
STUDY DRUGS 
5.1.
Randomization and Blinding
This is a non-randomized, open-label study. 
5.2.
Description and Handling of Ambrisentan
5.2.1.
Formulation
Gilead will provide study drug in the form of film-coated, immediate-release tablets, 
containing either 5 mg or 10 mg ambrisentan.
5.2.2.
Packaging and Labeling
All study drug will be packaged in containers with 30 study drug tablets. The study drug 
distributor will send the initial shipment of study drug to sites as soon as Gilead or a 
specified designee approves the site. Study drug resupply will occur as needed.
5.2.3.
Storage and Handling
Gilead will provide ambrisentan. Upon initial receipt of study drug, the Investigator and/or 
site staff will acknowledge receipt of the material, indicating shipment content and condition. 
The study site must maintain a dated inventory record of all study drug received and 
dispensed to subjects along with all study drug returned. A copy of the inventory log for 
study drug will be sent to Gilead or a specified designee after the study is complete.
Store at controlled room temperature (25C or 77F). Brief excursions are permitted 
between 15C and 30C (59-86F). Excursions outside of this range or those lasting longer 
than 3 days must be reported to Gilead or designee.
5.3.
Dosage and Administration of Ambrisentan
Ambrisentan is provided in oral tablets. Subjects are instructed to take ambrisentan with or 
without food once daily in the morning throughout the course of the study. Investigators will 
be able to adjust the ambrisentan dose as clinically indicated (available doses are 5 or 10 mg 
ambrisentan qd). A minimum of 4 weeks between dose adjustments is required.


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5.4.
Concomitant and Prohibited Medications 
Standard medical treatment(s) being taken by the subject upon study entry may be 
maintained throughout the study. Subjects receiving other approved therapies for PH that are 
not contraindicated for concomitant use with ambrisentan are permitted to enroll in this study 
and continue to receive such therapies.
Drugs prohibited prior to the study and throughout the treatment period are:

Bosentan (Tracleer)

Sitaxsentan (Thelin)

Any other investigational drug for PH.


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6.
STUDY PROCEDURES
6.1.
General Instructions

Ambrisentan should be taken with or without food once daily in the morning throughout 
the study unless otherwise instructed.

Subjects should be instructed to bring their used and unused ambrisentan containers with 
them to every Clinic Visit to assess compliance and drug accountability. 

All study visits will be determined from the date of first dose of ambrisentan in this 
study, and all study visit windows are 4 days.

Study compliance will be assessed via a telephone call on the day (± 2 days) of a 
Laboratory Visit 
6.2.
Monitoring of Liver Function Test Abnormalities
All subjects will have blood drawn every 4 weeks for LFTs. LFTs include serum ALT, AST, 
alkaline phosphatase, gamma glutamyl transferase (GGT), and total bilirubin concentrations. 
In order to ensure the safety of all subjects, the results of these tests must be reviewed by the 
Investigator immediately upon receipt. An increase in serum ALT or AST concentration 
>3xULN must be confirmed by a second test (>3xULN) that is collected no more than 7 days 
after receipt of the initial lab report. All events of ALT/AST (confirmed and unconfirmed) 
will be included in the assessment of aminotransferase abnormalities >3xULN; however, 
confirmed serum ALT or AST concentration >3xULN must also be immediately reported as 
a serious adverse event (SAE).
The requirements presented in Table 6-1 must be applied to the review and management of 
elevated serum aminotransferases in subjects throughout the study:


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Table 6-1.
Dose Adjustment and Monitoring of Subjects Experiencing Serum 
Aminotransferase Elevations
ALT/AST 
Concentrations
Treatment and Monitoring Requirements
>3x and 5xULN
Notify Gilead or specified designee immediately. Confirm by another serum 
aminotransferase test within 7 days. If confirmed, report as a SAE and consider dose 
reduction or discontinuation of ambrisentan. Continue to monitor serum 
aminotransferase concentrations every 2 weeks or more frequently if clinically 
indicated. If the serum aminotransferase concentrations decrease below 3xULN, 
continue at the reduced dose or reintroduce ambrisentan at a reduced dose as 
appropriate.
>5x and 8xULN
Stop ambrisentan treatment immediately and notify Gilead or specified designee. 
Confirm by another serum aminotransferase test within 7 days. If confirmed, report as 
a SAE. Continue to monitor serum aminotransferase concentrations every 2 weeks, or 
more frequently if clinically indicated. If the serum aminotransferase concentrations 
decrease below 3xULN, reintroduction of ambrisentan treatment requires consultation 
and approval from Gilead or a specified designee.
>8xULN
Stop ambrisentan treatment immediately and notify Gilead or specified designee. 
Confirm by another serum aminotransferase test within 7 days. If confirmed, report as 
a SAE. After discontinuation of ambrisentan, continue to monitor serum 
aminotransferase concentrations every 2 weeks, or more frequently if clinically 
indicated. The subject should be followed until the serum aminotransferase 
concentrations decrease below 3xULN. Ambrisentan may not be reintroduced.
If ambrisentan is reintroduced, serum aminotransferase concentrations should be checked within 3 days and then every 2 
weeks or more frequently if clinically indicated. If the serum aminotransferase elevations are accompanied by clinical 
symptoms of liver injury (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or 
increases in total bilirubin 2xULN, treatment should be stopped. Continue to monitor serum aminotransferase 
concentrations at least every 2 weeks, or more frequently if clinically indicated.


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6.3.
Schedule of Assessments
Week
Screening/Enrollment 
Visit
Laboratory Visitsa
Clinic Visitsb
0
Every 4 Weeks
Every 24 Weeks
Assessments
Informed consent
X
Medical history
X
Vital signs/body weight
X
X
Clinical laboratory testsc
Xd
Xc,e
Xd
Serum or urine pregnancy 
testf
X
X
X
CONMED assessment
X
X
Adverse events
X
X
Return unused ambrisentan
X
X
Dispense study drugg
X
X
                                                
a Laboratory Visits will be required every 4 weeks and will be completed at a local phlebotomy lab or at the 
Investigator clinic.
b Clinic Visits will be required every 24 weeks.
c Completion of the Laboratory Visit will be documented via telephone contact (within 2 days) if the 
Laboratory Visit occurs at a local phlebotomy lab.
d Clinical laboratory tests at the Screening/Enrollment Visit and Clinic Visits will include chemistry (including 
LFTs), hematology, and coagulation. Coagulation labs (PT, PTT, and INR) will only be completed for subjects 
who are receiving warfarin or any other warfarin-like anticoagulants.
e Clinical laboratory tests at the Laboratory Visits will be limited to LFTs, specifically ALT, AST, alkaline 
phosphatase, GGT, and total bilirubin. Please refer to Section 6.2 for specific guidance on dose adjustment and 
monitoring of subjects who develop aminotransferase elevations.
f Pregnancy testing required for women of childbearing potential.
g As necessary, a 3-month supply of study drug will be dispensed.


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6.4.
Study Procedures By Time Point
6.4.1.
Screening/Enrollment Visit (Week 0)
Subjects will complete the Screening/Enrollment Visit for this study (GS-US-300-0124) on 
the same day as their final visit for the previous ambrisentan study. 
The following procedures will be completed as part of the final visit for the previous 
ambrisentan study, and will be used for the Screening/Enrollment Visit of this study 
(GS-US-300-0124):

Record vital signs, including sitting blood pressure and heart rate, and body weight
(Section 7.3) 

Collect chemistry, hematology, and coagulation (Section 7.4)

Collect serum or urine pregnancy test for female subjects of childbearing potential 
(Section 7.4)

Record all concomitant medications (CONMEDS, Section 7.2)

Record all AEs since last visit
The following procedures will be completed for enrollment in this study:

Obtain written informed consent

Review all inclusion/exclusion criteria (See Sections 4.2 and 4.3)

Assess medical history (Section 7.1)

Complete the Interactive Voice Response System (IVRS) Screening Module

Dispense study drug and instruct the subject to return all used and unused ambrisentan 
containers at the next Clinical Visit 

Instruct the subject to call the clinic or return promptly should an AE occur
6.4.2.
Laboratory Visits (Every 4 Weeks)
Subjects will be required to provide blood samples for LFTs every 4 weeks at Laboratory 
Visits. Females of childbearing potential will also provide a blood or urine sample for 
pregnancy testing at these visits. The Laboratory Visits will be completed at a local 
phlebotomy laboratory or at the Investigator clinic. Completion of the Laboratory Visit will 
be documented via telephone contact (within 2 days) if the Laboratory Visit occurs at a 
local phlebotomy lab. Any local phlebotomy laboratory utilized for Laboratory Visits must 


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be added to Section 4 of the FDA Form 1572. Applicable lab certifications and normal 
ranges must be collected.
The following procedures will be completed at each Laboratory Visit:

Collect LFTs (Section 7.4)

Collect serum or urine pregnancy test for female subjects of childbearing potential 
(Section 7.4)

Assess study compliance via a telephone call on the day (±2 days) of a Laboratory Visit 

If the next visit is a Clinic Visit, remind the subject to return all used and unused 
ambrisentan containers with them at the Clinic Visit
6.4.3.
Clinic Visits (Every 24 Weeks)
Subjects will be required to visit the Investigator Clinic every 24 weeks to be evaluated for 
safety. 
The following procedures will be completed at each Clinic Visit:

Record vital signs (including sitting blood pressure and heart rate) and body weight
(Section 7.3) 

Collect chemistry, hematology, and coagulation (Section 7.4)

Collect serum or urine pregnancy test for female subjects of childbearing potential 
(Section 7.4)

Record all concomitant medications (CONMEDS, Section 7.2)

Record all AEs 

Collect all used and unused ambrisentan drug containers

Complete the IVRS Subject Subsequent Assignment Module to receive the new 
ambrisentan container number

Dispense study drug and instruct the subject to return all used and unused ambrisentan 
containers with them at the next Clinic Visit


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6.5.
Premature Discontinuation/End of Study
All subjects have the right to withdraw formal consent without prejudice at any time during 
the study. If a subject withdraws formal consent, the Investigator should make a reasonable 
effort to determine the cause for withdrawal of consent.
If, for whatever reason, a subject discontinues study participation prematurely, the following 
procedures should be completed:

Record vital signs (including sitting blood pressure and heart rate) and body weight
(Section 7.3) 

Collect chemistry, hematology, and coagulation (Section 7.4)

Collect serum or urine pregnancy test for female subjects of childbearing potential 
(Section 7.4)

Record all concomitant medications (CONMEDS, Section 7.2)

Record all AEs 

Collect all used and unused ambrisentan drug containers

Call IVRS and complete the Premature Discontinuation Module

Contact the subject by telephone 72 hours following discontinuation of study to check on 
their health status, and document the telephone contact. If the subject has experienced 
any AEs or changes to medications (including PH therapy), collect all pertinent 
information and record on the appropriate case report form CRF(s).
6.6.
Criteria for Discontinuation of Study Treatment
The subject’s participation in this clinical study may be prematurely discontinued due to:

Development of an AE where continuation of the subject’s participation in the study is 
thought by the Investigator to be inappropriate

Clinical status did not improve or deteriorated

Subject begins treatment with a prohibited concomitant therapy

Subject requests to discontinue for any reason

Noncompliance to any of the protocol procedures


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
Positive pregnancy test (every attempt should be made to follow the subject through the 
term of the pregnancy for safety)

Discretion of the Investigator

Lost to follow-up

Discontinuation of the study at the request of Gilead, a regulatory agency, or an IRB/IEC

Ambrisentan treatment may also be discontinued when ambrisentan becomes 
commercially available in the country where the subject is participating and the subject 
qualifies for commercial therapy per the current prescribing information of that country.


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7.
DESCRIPTION OF STUDY PROCEDURES
7.1.
Medical History
All ongoing conditions and relevant/significant medical history (including all major 
hospitalizations and surgeries) will be recorded at the Screening/Enrollment Visit. Symptoms 
and signs related to PH and/or the underlying etiology of the disease need not be listed on the 
medical history form; however, worsening of any symptoms or signs during the course of 
this study must be captured as an AE. 
Current medical status, subject demographics, height, and weight will be recorded at the 
Screening/Enrollment Visit. Body weight will be recorded at all subsequent Clinic Visits.
7.2.
Concomitant Medications
At the Screening/Enrollment Visit, review all medications taken 30 days prior to screening;
document and capture on the appropriate CRF. 
At each study visit, all medications will be reviewed and any changes will be captured on the 
appropriate CRF. Document any changes in concomitant medication (including PAH 
therapy) via a telephone call 72 hours following discontinuation of study.
7.3.
Vital Signs and Body Weight
Vital signs (including heart rate and blood pressure) will be collected at each Clinic Visit. 
One measurement of blood pressure and heart rate after the subject has been sitting quietly 
for at least 5 minutes should be taken. This same procedure should be followed throughout 
the study.
Vital signs must be assessed prior to, or at least 1 hour after, a blood draw. All measures of 
blood pressure will be performed using standard sphygmomanometry. If possible, the same 
sphygmomanometer and arm should be used.
In addition, body weight will be collected at each Clinic Visit.
7.4.
Clinical Laboratory Tests
Chemistry (including LFTs), hematology, and coagulation will be collected every 24 weeks 
at the Clinic Visits. Additionally, LFTs will be collected every 4 weeks at the Laboratory 
Visits. Serum or urine pregnancy tests will also be collected at all Clinic and Laboratory 
Visits for female subjects of childbearing potential.
A central laboratory will not be used for this study. Local laboratories will analyze all 
protocol-specified laboratory tests at the Laboratory Visits. Additional laboratory tests will
be performed by a local laboratory if clinically relevant abnormal values are obtained at any 


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time during the course of the study. Local lab reports must be immediately reviewed by the 
Investigator. Laboratory values that are not within normal limits will be captured on the CRF, 
along with the normal ranges.
Chemistry: The following chemistry tests are required at Clinic Visits: serum ALT, AST, 
alkaline phosphatase, GGT, total bilirubin, creatinine, amylase, blood urea nitrogen (BUN), 
sodium, potassium, chloride, bicarbonate, calcium, total cholesterol, uric acid, glucose, total 
protein and albumin.
The following chemistry tests are required at Laboratory Visits: serum ALT, AST, alkaline 
phosphatase, GGT, and total bilirubin.
Hematology: The following hematology tests are required at Clinic Visits: hemoglobin, 
hematocrit, red cell count, red cell indices, white blood cell count (total and differential) and 
platelet count.
Coagulation: At Clinic Visits, INR will be evaluated for subjects who are receiving warfarin 
(Coumadin®) or any other warfarin-like anticoagulants. 
Pregnancy Test: Serum or urine pregnancy tests will be performed for all female subjects of 
childbearing potential at the Screening/Enrollment Visit, at each subsequent study visit, 
including Laboratory Visits, and premature discontinuation, if applicable. 
7.5.
Protocol Deviations
This study will be conducted as described in this protocol except for emergency situations in 
which the protection, safety, and well being of the subject requires immediate intervention 
based upon the judgment of the Investigator (or a responsible, appropriately trained and 
credentialed professional(s) designated by the Investigator). In the event of any deviation 
from the protocol, the Investigator or a specified designee must notify Gilead and/or 
specified designee immediately. This will allow an early joint decision to be made as to 
whether or not the subject should continue in the study. Both the Investigator and Gilead or 
specified designee will document this decision.


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8.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
8.1.
Adverse Events
An adverse event (AE) is any untoward medical occurrence in a clinical investigation subject 
administered a medicinal product and which does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, 
or disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product. 
AEs may also include the following:

Pre- or post-treatment complications that occur as a result of a protocol-associated 
procedure (e.g., invasive procedures such as venipuncture, biopsy) during or after 
screening (before the administration of study drug)

Any pre-existing condition that increases in severity or changes in nature during or as a 
consequence of the study drug phase of this clinical study 

Complication and termination of pregnancy (see Section 8.7 for additional information)

All AEs that occur from the time the subject consents to participate in the study and 
throughout the duration of the study, including the follow-up off study medication period
should be recorded as an AE. For Post-Study Reporting Requirements, see Section 8.5.3.
An AE does not include the following:

Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, transfusion)
performed; the condition that leads to the procedure is an AE

Pre-existing diseases or conditions or laboratory abnormalities present or detected before
the screening visit that do not worsen

Situations where an untoward medical occurrence has not occurred (e.g., hospitalization 
for elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae; however, all overdoses, asymptomatic and 
symptomatic, must be reported using the overdose form.
Any medical condition or clinically significant laboratory abnormality with an onset date 
before the screening visit and not related to a protocol-associated procedure is not an AE. It 
is considered to be pre-existing and should be documented on the Medical History CRF.
Anticipated day-to-day fluctuations of pre-existing conditions that do not represent a 
clinically significant exacerbation or worsening need not be considered AEs. Any 


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pre-existing conditions or signs and/or symptoms not related to PH or underlying etiology 
present in a subject prior to the start of the study should be recorded on the Medical History 
CRF.
8.2.
Assessment of Adverse Events
All AEs will be assessed by the Investigator and recorded on the AE CRF page. The AE 
entry should indicate whether or not the AE was serious, the start date (AE onset), the stop 
date (date of AE resolution), whether or not the AE was related to study drug, or to a study 
procedure, the action taken with study drug due to the AE, the severity of the AE, and the 
outcome of the AE. 
AEs already documented in the CRF (i.e., at a previous assessment) and designated as 
“ongoing” should be reviewed at subsequent visits as necessary. Upon resolution, the date 
and time (if applicable) of resolution should be recorded in the CRF. If an AE increases in 
frequency or severity during a study period, a new record of the event should be started.
AEs should be documented in terms of a medical diagnosis. When this is not possible, the 
AE should be documented in terms of signs and/or symptoms observed by the Investigator or 
reported by the subject at each study visit.
For AEs associated with laboratory abnormalities, the AE should be assessed on the basis of 
the clinical severity in the context of the underlying conditions. Collection of changes in 
laboratory values as AEs should be restricted to those considered clinically significant by the 
Investigator that result in a change, interruption, or discontinuation of study drug, are 
considered an SAE, or require medical intervention or treatment. Laboratory values 
associated with clinical signs and symptoms should be reported as an AE based on the 
clinical signs and symptoms not as the laboratory value.
8.2.1.
Assessment of Causality
The relationship to study drug (ambrisentan/placebo) therapy should be assessed using 
clinical judgment and the following definitions:

No: Evidence exists that the AE has an etiology other than the study drug. For SAEs, an 
alternative causality must be provided (e.g., pre-existing condition, underlying disease, 
intercurrent illness, or concomitant medication).

Yes: A temporal relationship exists between the AE onset and administration of the study 
drug that cannot be readily explained by the subject’s clinical state or concomitant 
therapies. Furthermore, the AE appears with some degree of certainty to be related, based 
on the known therapeutic and pharmacologic actions or AE profile of the study drug. In 
case of cessation or reduction of the dose, the AE abates or resolves and reappears upon 
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It should be emphasized that ineffective treatment should not be considered as causally 
related in the context of AE reporting. 
The relationship to study procedures (e.g., invasive procedures such as venipuncture) should 
be assessed using the following definitions:

No: Evidence exists that the AE has an etiology other than the study procedure.

Yes: The AE occurred as a result of protocol-mandated procedures such as venipuncture.
8.2.2.
Assessment of Intensity
Adverse events will be graded on a 3-point scale, and reported as indicated on the CRF. 
Maximum intensity should be assigned to 1 of the following categories:
Mild: The AE does not interfere with routine activities. The subject may experience slight 
discomfort.
Moderate: The AE interferes with routine activities. The subject may experience significant 
discomfort.
Severe: The AE makes it impossible to perform routine activities. The subject may 
experience intolerable discomfort or pain.
8.3.
Serious Adverse Events
A serious adverse event (SAE) is defined as follows: 
Any adverse drug experience occurring at any dose that results in any of the following 
outcomes: 

Death

Life-threatening situation (subject is at immediate risk of death)

In-patient hospitalization or prolongation of existing hospitalization (excluding those for 
study therapy or placement of an indwelling catheter, unless associated with other SAEs)

Persistent or significant disability/incapacity

Congenital anomaly/birth defect in the offspring of a subject who received study drug

Other: medically significant events that may not be immediately life-threatening or result 
in death or hospitalization, but based upon appropriate medical and scientific judgment, 
may jeopardize the subject or may require medical or surgical intervention to prevent one 
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Examples of such events are as follows:
— Intensive treatment in an emergency room or at home for allergic bronchospasm
— Blood dyscrasias or convulsions that do not result in hospitalization
— Development of drug dependency or drug abuse
— Infections resulting from contaminated Gilead medicinal product

Study specific:

Pregnancies (Section 8.7)

Elevated serum aminotransferase concentrations (Section 6.2)
Clarification of Serious Adverse Events

Death is an outcome of an AE, and not an AE in itself. In reports of death due to “Disease 
Progression,” where no other information is provided, the death will be assumed to have 
resulted from progression of the disease being treated with the study drug(s).

“Occurring at any dose” does not imply that the subject is receiving study drug at the 
time of the event. Dosing may have been given as treatment cycles or interrupted 
temporarily before the onset of the SAE, but may have contributed to the event.

“Life-threatening” means that the subject was at immediate risk of death from the event 
as it occurred. This does not include an event that might have led to death if it had 
occurred with greater severity.

Complications that occur during hospitalizations are AEs. If a complication prolongs the 
hospitalization, it is a SAE.

“In-patient hospitalization” means the subject has been formally admitted to a hospital for 
medical reasons, for any length of time. This may or may not be overnight. It does not 
include presentation and care within an emergency department.

The Investigator should attempt to establish a diagnosis of the event on the basis of signs, 
symptoms and/or other clinical information. In such cases, the diagnosis should be 
documented as the AE and/or SAE and not the individual signs/symptoms.
A distinction should be drawn between seriousness and severity of AEs. An AE that is 
assessed as severe should not be confused with a SAE. Severity is a category utilized for 
rating the intensity of an event; and both AEs and SAEs can be assessed as severe. An event 
is defined as "serious" when it meets one of the predefined outcomes described above.


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8.4.
Special Situations Reports
8.4.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, and 
pregnancy reports regardless of an associated AE.  Also includes reports of adverse reactions 
associated with product complaints and reports arising from occupational exposure.
A pregnancy report is used to report any pregnancy following maternal exposure to the 
medicinal product (see Section 8.7).
Medication error is any unintentional error in the prescribing, dispensing, or administration 
of a medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by 
a subject.
Misuse is defined as any intentional or inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a 
medicinal product given per administration or cumulatively which is above the maximum 
recommended dose as per protocol or in the product labelling (as it applies to the daily dose 
of the subject in question). In cases of a discrepancy in drug accountability, overdose will be 
established only when it is clear that the subject has taken the excess dose(s). Overdose 
cannot be established when the subject cannot account for the discrepancy except in cases in 
which the investigator has reason to suspect that the subject has taken the additional dose(s).
Product complaint is defined as complaints arising from potential deviations in the 
manufacture, packaging, or distribution of the medicinal product.  
8.4.2.
Instructions for Reporting Special Situations
8.4.2.1.
Instructions for Reporting Pregnancies (see Section 8.7)
8.4.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to designated Pharmcovigilance Officeror Gilead DSPH within 24 hours of the 
investigator becoming aware of the situation. These reports must consist of situations that 
involve study IMP, but do not apply to concomitant medications. Except for situations that 
result in AEs, special situations involving concomitant medications will not be reported. Any 
inappropriate use of medications prohibited by this protocol should not be reported as 
“misuse,” but may be more appropriately documented as a protocol deviation.


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Special Situations should be reported to the designated Pharmacovigilance Officer using the 
Special Situations Report form. If the special situation occurs after the study has been 
completed, the special situations report should be reported directly to Gilead DSPH. Gilead 
DSPH contact information is as follows: Email: 
and Fax: 
All clinical sequelae in relation to these special situation reports will be reported as AEs or 
SAEs at the same time using the AE CRF/eCRF and/or the SAE report form. Details of the 
symptoms and signs, clinical management, and outcome will be reported, when available.
8.5.
Serious Adverse Event Reporting Requirements
8.5.1.
All Serious Adverse Events
Gilead is required to expedite reports of SAEs, Serious Adverse Drug Reactions, or 
Suspected Unexpected Serious Adverse Reactions (SUSAR) in line with relevant legislation, 
including the European Commission Clinical Trial Directive (2001/20/EC) to worldwide 
regulatory authorities; therefore, Gilead (or the Clinical Research Organization [CRO] on the 
behalf of Gilead) must be notified immediately regarding the occurrence of any SAE that
occurs after the subject consents to participate in the study, including SAEs resulting from 
protocol-associated procedures as defined in relevant legislation including 2001/20/EC, 
performed from screening onwards. The procedures for reporting all SAEs, regardless of 
causal relationship, are as follows:

Record the SAE on the AE CRF and complete the “Serious Adverse Event Report” form. 

Fax or e-mail the SAE form to the attention of designated Pharmacovigilance Officer
within 24 hours of the Investigator’s knowledge of the event. For fatal or life-threatening 
events, also fax copies of hospital case reports, autopsy reports, and other documents 
when requested and applicable. 
Gilead may request additional information from the Investigator to ensure the timely 
completion of accurate safety reports. Any subject data sent to Gilead must be made 
anonymous (while remaining traceable by the sender) before sending.
The Investigator must take all therapeutic measures necessary for resolution of the SAE. Any 
medications necessary for treatment of the SAE must be recorded onto the CONMED
Section of the subject’s CRF.
Follow-up of AEs/SAEs will continue through the last day on study and/or until the 
Investigator and/or Gilead determine that the subject’s condition is stable. Gilead may 
request that certain AEs/SAEs be followed until resolution.
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8.5.2.
Investigator and Sponsor Reporting Requirements for SAEs
An SAE may qualify for expedited reporting to worldwide regulatory authorities if it is a
SAE, Serious Adverse Event, or SUSAR in line with relevant legislation, including the 
European Commission Clinical Trials Directive (2001/20/EC). Expectedness of SAEs will be 
determined by Gilead using reference safety information specified in the IB.
All Investigators will receive a safety letter notifying them of relevant SUSAR reports. The 
Investigator should notify the IRB or IEC as soon as is practical, of serious events in writing 
where this is required by local regulatory authorities, and in accordance with the local 
institutional policy. 
In accordance with the EU Clinical Trials Directive (2001/20/EC), Gilead will notify 
worldwide regulatory authorities and the relevant Ethics Committees in concerned Member 
States of applicable SUSARs as individual notifications or through a period line listing.
8.5.3.
Post-Study Reporting Requirements
All AEs and SAEs, including deaths, regardless of cause or relationship, must be reported for 
subjects on study. Any SAEs that occur within 30 days of last study drug dose, regardless of 
causality, should also be reported.
Investigators are not obligated to actively seek out SAEs beyond the follow-up period for 
subjects. However, if the Investigator learns of an AE or SAE occurring after the 
completion/termination visit and the event is deemed by the Investigator to be relevant to the 
use of study drug (ambrisentan), he/she should promptly document and report the event to 
the designated Pharmacovigilance Officer or, if the study has been completed, to Gilead 
DSPH. Gilead DSPH contact information is as follows: Email: 
and 
Fax: 
8.6.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities are usually not recorded as AEs or SAEs. However, laboratory 
abnormalities (e.g. clinical chemistry, hematology, urinalysis) independent of the underlying 
medical condition that require medical or surgical intervention or lead to study drug 
interruption or discontinuation must be recorded as an AE, as well as an SAE, if applicable. 
In addition, laboratory or other abnormal assessments (e.g., vital signs) that are associated 
with signs and/or symptoms must be recorded as an AE or SAE if they meet the definition of 
an AE (or SAE) as described in Section 8.1 (or 8.3). If the laboratory abnormality is part of a 
syndrome, record the syndrome or diagnosis.
If the changes are mild and in the opinion of the Investigator not clinically significant, the 
Investigator should continue to carefully monitor the values. Laboratory tests may be 
repeated, as clinically indicated, without prior approval by Gilead or specified designee.
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Special attention must be paid to the results of LFTs for all subjects enrolled into this study. 
Section 6.2 Monitoring of Liver Function Test Abnormalities, provides specific guidance for 
dose adjustment and monitoring of subjects who develop serum aminotransferase elevations. 
Investigators are required to follow these guidelines. All confirmed elevations in serum 
aminotransferase concentrations >3xULN must be immediately reported as a SAE.
8.7.
Pregnancy
Subjects who become pregnant during the study must discontinue study drug immediately, 
and the pregnancy must be reported as an SAE. The Investigator should report all 
pregnancies to the designated Pharmacovigilance Officer within 24 hours of becoming aware 
of the pregnancy. The Investigator should counsel the subject regarding the possible effects 
of prior study drug exposure on the fetus (see Section 1.2.4.2.3 and the IB) and the need to 
inform the study site of the outcome of the pregnancy. The SAE reporting process, as 
identified in Section 8.5 must be followed.
Subjects should be instructed to notify the Investigator if they become pregnant at any time 
during the study, or if they become pregnant within 30 days of last study drug dose. 
Whenever possible, a pregnancy should be followed by the study site to term, and the status 
of the mother and child should be reported to the designated Pharmacovigilance Officer after 
delivery. Any premature terminations of pregnancy must be reported.
All pregnancies that occur during the study should be reported using the SAE and Pregnancy 
Report forms and faxed to the designated Pharmacovigilance Officer. Monitoring of the 
subject should continue until the conclusion of the pregnancy. The outcome should be 
reported to the designated Pharmacovigilance Officer (Section 8.5) using the Pregnancy 
Outcome Report form. If the end of the pregnancy occurs after the study has been completed, 
the outcome should be reported directly to Gilead DSPH. Gilead DSPH contact information 
is as follows: Email: 
and Fax: 
Of note, the effects of ambrisentan on pregnancy in female partners have not been evaluated; 
please refer to the IB for additional information.
8.7.1.
Reliable Forms of Contraception
Female subjects of childbearing potential (see definition below) must agree to utilize 
TWO reliable methods of contraception from the Screening/Enrollment Visit throughout the 
study period and for 30 days following the last dose of study drug. Reliable methods of 
contraception are: birth control pills/implants/injections, intrauterine devices (IUDs), 
spermicide, diaphragms, or condoms. If a subject has undergone tubal sterilization or has had 
a Copper T 380A IUD or LNg 20 IUD inserted, no other contraception is needed. The 
Investigator should counsel subjects on the most effective method(s) for avoiding pregnancy 
during the study.
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8.7.2.
Definition of Childbearing Potential and Post-Menopausal
A female patient of childbearing potential is a nonmenopausal female who has not had a 
hysterectomy, bilateral oophorectomy, or medically documented ovarian failure. This 
definition includes a young woman who has not yet started menstruating. A woman who has 
had a tubal sterilization is considered to be of childbearing potential.
Menopause can be assumed to have occurred in a woman when there is either:

Appropriate medical documentation of prior complete bilateral oophorectomy (i.e., 
surgical removal of the ovaries, resulting in “surgical menopause” and occurring at the 
age at which the procedure was performed) or

Permanent cessation of previously occurring menses as a result of ovarian failure with 
documentation of hormonal deficiency by a certified healthcare provider (i.e., 
“spontaneous menopause,” which occurs in the United States at a mean age of 
51.5 years).

A hormonal deficiency should be properly documented in the case of suspected 
spontaneous menopause as follows:

If age 54 years and with the absence of normal menses: serum follicle stimulating 
hormone (FSH) level elevated to within the post-menopausal range based on the 
laboratory reference range where the hormonal assay is performed;

If age <54 years and with the absence of normal menses: negative serum or urine human 
chorionic gonadotropin (hCG) with concurrently elevated serum FSH level in the post-
menopausal range, depressed estradiol (E2) level in the post-menopausal range, and 
absent serum progesterone level, based on the laboratory reference ranges where the 
hormonal assays are performed.
Female subjects who were determined to be post-menopausal (i.e., not of childbearing 
potential) at the time enrollment in the previous ambrisentan study will be considered post-
menopausal for this study. Female subjects who were of childbearing potential at the time of 
enrollment in the previous study must meet the criteria outlined above in order to be 
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9.
STATISTICAL CONSIDERATIONS
9.1.
Primary Endpoint
The primary endpoint of this study is the incidence and severity of AEs associated with long-
term exposure to ambrisentan in subjects with PH.
9.2.
Measures of Interest
Additional safety measures of interest include:

Shift from baseline (low/normal/high) over time in clinical laboratory values 

Change from baseline over time in vital signs
9.3.
Methods of Analysis
9.3.1.
Analysis Sets
The primary analysis set for safety analyses will include all enrolled subjects who received at 
least one dose of ambrisentan in this study (referred to hereafter as the safety full analysis set 
[FAS]). 
9.3.2.
General Methodology
Most continuous data will be summarized using the following descriptive statistics: number 
of observations, mean, standard deviation, standard error, median, minimum and maximum. 
Categorical data will be summarized using frequencies and percentages. Changes from 
baseline will be calculated as the later value minus the baseline value. Baseline will be 
defined for all endpoints as the time of enrollment into this study.
9.3.3.
Data Handling Conventions
Safety data will be used according to availability, with no imputation for missing data.
9.3.4.
Timing of Analyses
Interim analyses for this study will be performed periodically to generate safety data. This 
data may be used for regulatory submissions and publications.
The data from this study will also be reviewed on a regular basis by an unblinded DMC 
charged with protecting the safety of the study subjects. This committee will have the 
authority to recommend stopping the study early or modifying the study design for safety 
concerns.


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9.4.
Demographic Data and Baseline Characteristics
Demographic and baseline characteristics will be summarized by treatment group for the 
FAS using descriptive statistics. 
Data to be included in this summary are gender, race, region, age, height, weight, body mass 
index (BMI), childbearing potential, smoking status, PH etiology, years PH present, and 
previous ambrisentan study.
9.5.
Efficacy Analysis
Efficacy will not be examined in this study.
9.6.
Safety Analysis
All safety data collected on or after the date that ambrisentan was first administered in this 
study up to the date of last dose of ambrisentan (including any SAEs occurring as specified in 
Section 8.5.3) will be summarized by treatment group and all subjects combined. Subjects 
will be assigned to a treatment group by 2 different methods: by ambrisentan dose at 
enrollment and by maximum ambrisentan dose received at any time in the study. A data 
listing of all information relating to AEs will be provided.
In general, safety data will be summarized by treatment group and all subjects combined for 
cumulative 24-week intervals (weeks 124, weeks 148, etc…) and for the entire study.
9.6.1.
Extent of Exposure
Exposure data will be summarized by ambrisentan dose at enrollment and by maximum 
ambrisentan dose received at any time in the study. 
9.6.2.
Dose Migration
Dose migration will be summarized using shift tables of the subjects’ doses at baseline versus 
doses at 24-week intervals throughout the study.
9.6.3.
Adverse Events
Clinical and laboratory AEs will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). Events will be summarized on the basis of the date of onset for the 
event. A treatment-emergent AE will be defined as any AE that begins on or after the date of 
first dose of ambrisentan in this study up to the date of last dose of ambrisentan (including 
any SAEs occurring as specified in Section 8.5.3).
AEs reported during the study will be summarized by tabulating, for each treatment group, 
the number and percentage of subjects having AEs by System Organ Class [SOC] and 
Preferred Term. Incidence of AEs will also be summarized by severity and by relationship to 


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the study drug. AEs which led to treatment discontinuation, death, or that were considered 
serious will be tabulated separately by treatment group.
9.6.4.
Laboratory Evaluations
Laboratory data will be summarized using shift from baseline (low/normal/high) over time.
The percentage of subjects with serum aminotransferase concentrations ≤1xULN, >1xULN 
and ≤3xULN, >3xULN and ≤5x ULN, >5xULN and ≤8xULN, and >8xULN and the 
percentage of subjects with alkaline phosphatase or bilirubin ≥2xULN will be summarized 
for cumulative 24-week intervals and for the entire study.
9.6.5.
Other Safety Evaluations
Vital sign data collected at Clinic Visits will be summarized with descriptive statistics of raw 
values and of change from baseline across time.
9.7.
Pharmacokinetic Analysis
Pharmacokinetic data are not being collected in this study.
9.8.
Sample Size
This is a study of the safety of long-term ambrisentan administration to subjects with PH. 
Only subjects who are discontinuing an ambrisentan PH study due to study closure by the 
Sponsor and for whom ambrisentan is not yet currently available may enroll in this study. It 
is estimated that approximately 300 subjects will be eligible to enroll in this study at its 
inception. This number will vary as subjects discontinue this study, or as additional clinical 
studies of ambrisentan in PH are completed and subjects participating in these studies 
become eligible per the inclusion and exclusion criteria specified in Sections 4.2 and 4.3.


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10.
RESPONSIBILITIES
10.1.
Investigator Responsibilities
10.1.1.
Good Clinical Practice
The Investigator will ensure that this study is conducted in accordance with the principles of 
the “Declaration of Helsinki” (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), International Conference on Harmonisation (ICH) guidelines, or with the laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the study subject. 
Gilead and Investigators will follow requirements as set forth in the U.S. Code of Federal 
Regulations, 21 CFR Parts 50, 54, 56, and 312 and the ICH E6 Good Clinical Practice (GCP) 
Consolidated Guidance (ICH 1996). Investigator responsibilities are set out in Section 4 of 
the E6 Guideline (as published in the Federal Register May 1997). Sponsor responsibilities 
are set out in Section 5 of the E6 ICH Guideline (as published in the Federal Register May 
1997).
Since this is a “covered” clinical trial, the Investigator will ensure that 21 CFR Part 54, 1998, 
is adhered to; a “covered” clinical trial is any “study of a drug or device in humans submitted 
in a marketing application or reclassification petition subject to this part that the applicant or 
FDA relies on to establish that the product is effective (including studies that show 
equivalence to an effective product) or that make a significant contribution to the 
demonstration of safety.” This requires that Investigators and all sub-investigators must 
provide documentation of their financial interest or arrangements with Gilead, or proprietary 
interests in the drug being studied. This documentation must be provided before participation 
of the Investigator and any sub-investigator. The Investigator and sub-investigator agree to 
notify Gilead of any change in reportable interests during the study and for one year 
following completion of the study. Study completion is defined as the date that the last 
subject has completed the protocol defined activities.
This study is also subject to and will be conducted in accordance with 21 CFR Part 320, 
1993, “Retention of Bioavailability and Bioequivalence Testing Samples.”
10.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Approval
This protocol and any accompanying material to be provided to the subject (such as 
advertisements, subject information sheets, or descriptions of the study used to obtain 
informed consent) will be submitted by the Investigator to an IRB/IBC. Approval from the 
IRB/IEC must be obtained before starting the study and should be documented in a letter to 
the Investigator specifying the protocol number, protocol version, protocol date, documents 
reviewed, and date on which the committee met and granted the approval.


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All documents subject to review during the study, including, but not limited to, any 
modifications made to the protocol after receipt of IRB/IEC approval and SAE safety reports 
must also be submitted to the Committee for review and/or approval prior to implementation 
(if applicable).
As part of the written application to the IRB/IEC, the Investigator should provide the 
Committee with a current copy of the IB. If the IB is updated during the study, the 
Investigator should supply an updated copy to the Committee.
10.1.3.
Informed Consent
The Investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and before undertaking any study-related procedures. The 
Investigator must utilize an IRB/IEC-approved consent form for documenting written 
informed consent. Each informed consent will be appropriately signed and dated by the 
subject or the subject’s legally authorized representative and the person obtaining consent.
10.1.4.
Confidentiality
The Investigator must assure that subjects’ anonymity will be strictly maintained and that 
their identities are protected from unauthorized parties. Only subject initials, date of birth and 
an identification code (i.e., not names) should be recorded on any form or biological sample 
submitted to the sponsor, IRB/IEC, or laboratory. The Investigator must keep a screening log 
showing codes, names, and addresses for all subjects screened and for all subjects enrolled in 
the trial.
The Investigator agrees that all information received from Gilead, including but not limited 
to the IB, this protocol, CRFs, the study drug, and any other study information, remain the 
sole and exclusive property of Gilead during the conduct of the study and thereafter. This 
information is not to be disclosed to any third party (except employees or agents directly 
involved in the conduct of the study or as required by law) without prior written consent from 
Gilead. The Investigator further agrees to take all reasonable precautions to prevent the 
disclosure by any employee or agent of the study site to any third party or otherwise into the 
public domain.
10.1.5.
Study Files and Retention of Records
The Investigator must maintain adequate and accurate records to enable the conduct of the 
study to be fully documented and the study data to be subsequently verified. These 
documents should be classified into at least the following two categories: (1) Investigator’s 
study file, and (2) subject clinical source documents.
The Investigator’s study file will contain the protocol/amendments, CRF and query forms, 
IRB/IEC and governmental approval with correspondence, informed consent, drug records, 


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staff cuniculum vitae and authorization fonns, and other appropriate documents and 
con espondence. 
Subject clinical source documents (usually defined by the project in advance to record key 
efficacy/safety parameters independent of the CRFs) would include (although not be limited 
to) the following: subject hospital/clinic records, physician's and nurse's notes, appointment 
book, original laborato1y repo1is, electrocardiogram (ECG), electroencephalogram (EEG), 
X-ray, pathology and special assessment repo1is, consultant letters, screening and emollment 
log, etc. 
All clinical study documents must be retained by the Investigator until at least 2 years after 
the last approval of a marketing application in an ICH region (i.e., United States, Europe, or 
Japan) and until there are no pending or contemplated marketing applications in an ICH 
region; or, if no application is filed or if the application is not approved for such indication, 
until 2 years after the investigation is discontinued and regulato1y authorities have been 
notified. Investigators may be required to retain documents longer if required by applicable 
regulato1y requirements or an agreement with Gilead. The Investigator must notify Gilead 
before destroying any clinical study records. 
Should the Investigator wish to assign the study records to another paiiy or move them to 
another location, Gilead must be notified in advance. 
If the Investigator cannot guarantee this ai·chiving requirement at the study site for any or all 
of the documents, special aiTangements must be made between the Investigator and Gilead to 
store these in sealed containers outside of the site so that they can be returned sealed to the 
Investigator in case of a regulato1y audit. When source documents are required for the 
continued cai·e of the subject, appropriate copies should be made for storage outside of the 
site. 
10.1.6. 
Case Report Forms 
For each subject emolled, a CRF must be completed and signed by the Principal Investigator 
or sub-investigator within a reasonable time period after data collection. This also applies to 
records for those subjects who fail to complete the study (even during a prerandoinization 
screening period if a CRF was initiated). If a subject withdraws from the study, the reason 
must be noted on the CRF. If a subject is withdrawn from the study because of a treatment-
limiting AE, thorough effo1is should be made to clearly document the outcome. 
All protocol required data will be collected in a CRF or via electronic means. A list of 
systems used to create, modify, maintain, ai·chive, retrieve, or transinit data will be 
maintained by the sponsor or their designee. 
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10.1.7.
Drug Accountability
The Investigator or designee (i.e., pharmacist) is responsible for ensuring adequate 
accountability of all used and unused study drug. This includes acknowledgment of receipt of 
each shipment of study product (quantity and condition) and subject dispensing records and 
returned or destroyed study product. Dispensing records will document quantities received 
from Gilead and quantities dispensed to subjects, including lot number, date dispensed, 
subject identifier number, subject initials, and the initials of the person dispensing the 
medication.
At study initiation, the monitor will evaluate the site’s standard operating procedure for study 
drug disposal/destruction in order to ensure that it complies with Gilead requirements. Drug 
may be returned or destroyed on an ongoing basis during the study if appropriate. At the end 
of the study, following final drug inventory reconciliation by the monitor, the study site will 
dispose of and/or destroy all unused study drug supplies, including empty containers, 
according these procedures. If the site cannot meet Gilead’s requirements for disposal, 
arrangements will be made between the site and Gilead or its representative for destruction or 
return of unused study drug supplies.
All drug supplies and associated documentation will be periodically reviewed and verified by 
the study monitor over the course of the study.
10.1.8.
Inspections
The Investigator should understand that source documents for this trial should be made 
available to appropriately qualified personnel from Gilead or its representatives, to the 
IRB/IEC, or to regulatory authority or health authority inspectors.
10.1.9.
Protocol Compliance
The Investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
10.2.
Sponsor Responsibilities
10.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, 
may be made only by Gilead. All protocol modifications must be submitted to the IRB/IEC
in accordance with local requirements. Approval must be obtained before changes can be 
implemented.
A protocol change intended to eliminate an apparent immediate hazard to subjects may be 
implemented immediately, provided the IRB/IEC is notified within 5 days.


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Any permanent change to the protocol must be handled as a protocol amendment. The 
written amendment must be submitted to the IRB/IEC and the Investigator must await 
approval before implementing the changes. Gilead will submit protocol amendments to the 
appropriate regulatory authorities for approval.
If in the judgment of the IRB/IEC, the Investigator, and/or Gilead, the amendment to the 
protocol substantially changes the study design and/or increases the potential risk to the 
subject and/or has an impact on the subject's involvement as a study participant, the currently 
approved written ICF will require similar modification. In such cases, informed consent will 
be renewed for subjects enrolled in the study before implementing protocol changes.
10.2.2.
Study Report and Publications
A clinical study report will be prepared and provided to the regulatory agency(ies). Gilead 
will ensure that the report meets the standards set out in the ICH Guideline for Structure and 
Content of Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared 
in certain cases.
After conclusion of the study and without prior written approval from Gilead, Investigators in 
this study may communicate, orally present, or publish in scientific journals or other 
scholarly media only after the following conditions have been met:

the results of the study in their entirety have been publicly disclosed by or with the 
consent of Gilead in an abstract, manuscript, or presentation form; or

the study has been completed at all study sites for at least 2 years.
No such communication, presentation, or publication will include Gilead’s confidential 
information (see Section 10.1.4). 
The Investigator will submit any proposed publication or presentation along with the 
respective scientific journal or presentation forum at least 30 days before submission of the 
publication or presentation. The Investigator will comply with Gilead’s request to delete 
references to its confidential information (other than the study results) in any paper or 
presentation and agrees to withhold publication or presentation for an additional 60 days in 
order to obtain patent protection if deemed necessary.
10.3.
Joint Investigator/Sponsor Responsibilities
10.3.1.
Access to Information for Monitoring
In accordance with ICH Good Clinical Practice (ICH GCP) guidelines, the study monitor 
must have direct access to the Investigator’s source documentation in order to verify the data 
recorded in the CRFs for consistency.


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The monitor is responsible for routine review of the CRFs at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of 
the data being entered on them. The monitor should have access to any subject records 
needed to verify the entries on the CRFs. The Investigator agrees to cooperate with the 
monitor to ensure that any problems detected in the course of these monitoring visits are 
resolved.
10.3.2.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead may conduct inspections or audits of 
the clinical study. If the Investigator is notified of an inspection by a regulatory authority, the 
Investigator agrees to notify the designated Gilead representative immediately. The 
Investigator agrees to provide to representatives of a regulatory agency or Gilead access to 
records, facilities, and personnel for the effective conduct of any inspection or audit.
10.3.3.
Study Discontinuation
Both the Sponsor and the Investigator reserve the right to terminate the study at any time. 
Should this be necessary, both parties will arrange discontinuation procedures and notify the 
appropriate regulatory authority(ies), IRBs, and IECs. In terminating the study, Gilead and 
the Investigator will assure that adequate consideration is given to the protection of the 
subjects’ interests.


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11.
REFERENCES
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Survival in patients with primary pulmonary hypertension. Results from a national 
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11. Barst RJ, Rubin LJ, McGoon MD, Caldwell EJ, Long WA, Levy PS. Survival in primary 
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12. Rubin LJ, Mendoza J, Hood M, McGoon M, Barst R, Williams WB et al. Treatment of 
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13. Horn EM, Barst RJ. Treprostinil therapy for pulmonary artery hypertension. Expert Opin 
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15. Olschewski H, Simonneau G, Galie N, Higenbottam T, Naeije R, Rubin LJ et al. Inhaled 
iloprost for severe pulmonary hypertension. N Engl J Med 2002; 347(5):322-329.
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17. Galie N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D et al. Sildenafil citrate 
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18. Rubanyi GM, Polokoff MA. Endothelins: molecular biology, biochemistry, 
pharmacology, physiology, and pathophysiology. Pharmacol Rev 1994; 46(3):325-415.
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by angiotensin II: effects on growth and synthetic activity of vascular smooth muscle 
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20. Kaddoura S, Firth JD, Boheler KR, Sugden PH, Poole-Wilson PA. Endothelin-1 is 
involved in norepinephrine-induced ventricular hypertrophy in vivo. Acute effects of 
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Circulation 1996; 93(11):2068-2079.
21. Golden CL, Kohler JP, Nick HS, Visner GA. Effects of vasoactive and inflammatory 
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22. Harrison VJ, Ziegler T, Bouzourene K, Suciu A, Silacci P, Hayoz D. Endothelin-1 and 
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23. Davenport AP, O'Reilly G, Kuc RE. Endothelin ETA and ETB mRNA and receptors 
expressed by smooth muscle in the human vasculature: majority of the ETA sub-type. Br 
J Pharmacol 1995; 114(6):1110-1116.
24. Kirchengast M, Munter K. Endothelin-1 and endothelin receptor antagonists in 
cardiovascular remodeling. Proc Soc Exp Biol Med 1999; 221(4):312-325.


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25. Verhaar MC, Strachan FE, Newby DE, Cruden NL, Koomans HA, Rabelink TJ et al. 
Endothelin-A receptor antagonist-mediated vasodilatation is attenuated by inhibition of 
nitric oxide synthesis and by endothelin-B receptor blockade. Circulation 1998; 
97(8):752-756.
26. Hirata Y, Emori T, Eguchi S, Kanno K, Imai T, Ohta K et al. Endothelin receptor subtype 
B mediates synthesis of nitric oxide by cultured bovine endothelial cells. J Clin Invest 
1993; 91(4):1367-1373.
27. Fukuroda T, Fujikawa T, Ozaki S, Ishikawa K, Yano M, Nishikibe M. Clearance of 
circulating endothelin-1 by ETB receptors in rats. Biochem Biophys Res Commun 1994; 
199(3):1461-1465.
28. Ozaki S, Ohwaki K, Ihara M, Fukuroda T, Ishikawa K, Yano M. ETB-mediated 
regulation of extracellular levels of endothelin-1 in cultured human endothelial cells. 
Biochem Biophys Res Commun 1995; 209(2):483-489.
29. de Nucci G, Thomas R, d'Orleans-Juste P, Antunes E, Walder C, Warner TD et al. 
Pressor effects of circulating endothelin are limited by its removal in the pulmonary 
circulation and by the release of prostacyclin and endothelium-derived relaxing factor. 
Proc Natl Acad Sci U S A 1988; 85(24):9797-9800.
30. Stewart DJ, Levy RD, Cernacek P, Langleben D. Increased plasma endothelin-1 in 
pulmonary hypertension: marker or mediator of disease? Ann Intern Med 1991; 
114(6):464-469.
31. Nootens M, Kaufmann E, Rector T, Toher C, Judd D, Francis GS et al. Neurohormonal 
activation in patients with right ventricular failure from pulmonary hypertension: relation 
to hemodynamic variables and endothelin levels. J Am Coll Cardiol 1995; 26(7):1581-
1585.
32. Hosoda K, Nakao K, Hiroshi A, Suga S, Ogawa Y, Mukoyama M et al. Cloning and 
expression of human endothelin-1 receptor cDNA. FEBS Lett 1991; 287(1-2):23-26.
33. Channick RN, Simonneau G, Sitbon O, Robbins IM, Frost A, Tapson VF et al. Effects of 
the dual endothelin-receptor antagonist bosentan in patients with pulmonary 
hypertension: a randomised placebo-controlled study. Lancet 2001; 358(9288):1119-
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34. Actelion Pharmaceuticals Ltd. Briefing Document Concerning TracleerTM (bosentan) in 
Pulmonary Arterial Hypertension. Submission to the FDA Cardiovascular and Renal 
Drugs Advisory Committee August 10, 2001.  2001. 
35. Rubin LJ, Badesch DB, Barst RJ, Galie N, Black CM, Keogh A et al. Bosentan therapy 
for pulmonary arterial hypertension. N Engl J Med 2002; 346(12):896-903.


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36. Dingemanse J, Van Giersbergen PL. Clinical pharmacology of bosentan, a dual 
endothelin receptor antagonist. Clin Pharmacokinet 2004; 43(15):1089-1115.
37. Ambrisentan Investigator's Brochure version 008.  Gilead Sciences, Inc. Westminster, 
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38. Gilead Sciences I. Letairis (ambrisentan) tablets for oral use.  United States Food and 
Drug Administration Drug Product Label.  6-15-2007. 
39. Leuchte HH, Holzapfel M, Baumgartner RA, Neurohr C, Vogeser M, Behr J. 
Characterization of brain natriuretic peptide in long-term follow-up of pulmonary arterial 
hypertension. Chest 2005; 128(4):2368-2374.
40. Nagaya N, Nishikimi T, Uematsu M, Satoh T, Kyotani S, Sakamaki F et al. Plasma brain 
natriuretic peptide as a prognostic indicator in patients with primary pulmonary 
hypertension. Circulation 2000; 102(8):865-870.
41. Park MH, Scott RL, Uber PA, Ventura HO, Mehra MR. Usefulness of B-type natriuretic 
peptide as a predictor of treatment outcome in pulmonary arterial hypertension. Congest 
Heart Fail 2004; 10(5):221-225.
42. Leuchte HH, Holzapfel M, Baumgartner RA, Ding I, Neurohr C, Vogeser M et al. 
Clinical significance of brain natriuretic peptide in primary pulmonary hypertension. J 
Am Coll Cardiol 2004; 43(5):764-770.
43. Barst RJ, Langleben D, Frost A, Horn EM, Oudiz R, Shapiro S et al. Sitaxsentan therapy 
for pulmonary arterial hypertension. Am J Respir Crit Care Med 2004; 169(4):441-447.
44. Actelion Pharmaceuticals Ltd. Tracleer (bosentan) tablets.  United States Food and Drug 
Administration Drug Product Label.  2006. 
45. McLaughlin VV, Sitbon O, Badesch DB, Barst RJ, Black C, Galie N et al. Survival with 
first-line bosentan in patients with primary pulmonary hypertension. Eur Respir J 2005; 
25:244-249.
46. Osborne R. ICOS, Texas Biotechnology Stop Phase IIb/III Extension. BioWorld Today 
2002; 13(140):1-4.
47. Carducci MA, Padley RJ, Breul J, Vogelzang NJ, Zonnenberg BA, Daliani DD et al. 
Effect of endothelin-A receptor blockade with atrasentan on tumor progression in men 
with hormone-refractory prostate cancer: a randomized, phase II, placebo-controlled trial. 
J Clin Oncol 2003; 21(4):679-689.
48. Barst RJ, Rich S, Widlitz A, Horn EM, McLaughlin V, McFarlin J. Clinical efficacy of 
sitaxsentan, an endothelin-a receptor antagonist, in patients with pulmonary arterial 
hypertension(*) : open-label pilot study. Chest 2002; 121(6):1860-1868.


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49. Barst R, Langleben D, Frost A, Horn E, Oudiz R, Shapiro S et al. Sitaxsentan Therapy for 
Pulmonary Arterial Hypertension (Running head:  Sitaxsentan and PAH).  2003. 
50. Barst RJ, Langleben D, Badesch D, Frost A, Lawrence EC, Shapiro S et al. Treatment of 
pulmonary arterial hypertension with the selective endothelin-a receptor antagonist 
sitaxsentan. J Am Coll Cardiol 2006; 47(10):2049-2056.
51. European Medicines Agency. Thelin (sitaxentan): Withdrawal of the marketing 
authorisation in the European Union.  2-22-2011.
52. Fantoni G, Morris PL, Forti G, Vannelli GB, Orlando C, Barni T et al. Endothelin-1: a 
new autocrine/paracrine factor in rat testis. Am J Physiol 1993; 265(2 Pt 1):E267-E274.
53. Harneit S, Paust HJ, Mukhopadhyay AK, Ergun S. Localization of endothelin-1 and 
endothelin-receptors A and B in human epididymis. Mol Hum Reprod 1997; 3(7):579-
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54. Maggi M, Barni T, Orlando C, Fantoni G, Finetti G, Vannelli GB et al. Endothelin-1 and 
its receptors in human testis. J Androl 1995; 16(3):213-224.


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12.
APPENDICES
Appendix 1.
Investigator Signature Page


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Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
GS-US-300-0124: ABS-LT: A Phase 3, Long-Term, Open Label, Multicenter Safety 
Study of Ambrisentan in Subjects with Pulmonary Hypertension 
Version 2.0 Rest of World 
12 June 2013 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
[PPD 
PPD 
Date 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to 
all information provided by Gilead Sciences, lnc. J will discuss this material with them to 
ensure that they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
Page 65 
12 June 2013 

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
ABS-LT: A Phase 3, Long-Term, Open Label, Multicenter 
Safety Study of Ambrisentan in Subjects with Pulmonary 
Hypertension
Name of Test Drug:
Ambrisentan
Study Number:
GS-US-300-0124
Protocol Version:
Version 2 Rest of World; 
Version 3 US
Protocol Date:
12 June 2013
Analysis Type:
End of Study
Analysis Plan Version:
Version 1.0
Analysis Plan Date:
13 July 2020
Analysis Plan Author:
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD
(rJ GILEAU 


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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF ABBREVIATIONS........................................................................................................................................4
1.
INTRODUCTION ................................................................................................................................................5
1.1.
Study Objectives ......................................................................................................................................5
1.2.
Study Design............................................................................................................................................5
1.3.
Sample Size and Power............................................................................................................................7
2.
TYPE OF PLANNED ANALYSIS ......................................................................................................................8
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES..............................................................................9
3.1.
Analysis Sets............................................................................................................................................9
3.1.1.
Safety Analysis Set.................................................................................................................9
3.2.
Subject Groups.........................................................................................................................................9
3.3.
Strata and Covariates................................................................................................................................9
3.4.
Examination of Subject Subsets...............................................................................................................9
3.5.
Multiple Comparisons..............................................................................................................................9
3.6.
Missing Data and Outliers........................................................................................................................9
3.7.
Data Handling Conventions and Transformations .................................................................................10
3.8.
Visit Windows........................................................................................................................................10
3.8.1.
Definition of Study Day 1 ....................................................................................................10
3.8.2.
Analysis Windows................................................................................................................10
4.
SUBJECT DISPOSITION ..................................................................................................................................12
4.1.
Subject Enrollment.................................................................................................................................12
4.2.
Disposition of Subjects ..........................................................................................................................12
4.3.
Extent of Exposure.................................................................................................................................12
4.3.1.
Duration of Exposure to Study Drug....................................................................................12
4.4.
Protocol Deviations................................................................................................................................12
5.
BASELINE DATA .............................................................................................................................................13
5.1.
Demographics and Baseline Characteristics ..........................................................................................13
5.2.
Medical History......................................................................................................................................13
6.
EFFICACY ANALYSES ...................................................................................................................................14
7.
SAFETY ANALYSES........................................................................................................................................15
7.1.
Adverse Events and Deaths....................................................................................................................15
7.1.1.
Adverse Event Dictionary ....................................................................................................15
7.1.2.
Adverse Event Severity........................................................................................................15
7.1.3.
Relationship of Adverse Events to Study Drug....................................................................15
7.1.4.
Serious Adverse Events........................................................................................................15
7.1.5.
Treatment-Emergent Adverse Events...................................................................................15
7.1.5.1.
Definition of Treatment-Emergent .................................................................15
7.1.5.2.
Incomplete Dates ............................................................................................16
7.1.6.
Summaries of Adverse Events and Deaths...........................................................................16
7.1.7.
Additional Analysis of Adverse Events ...............................................................................17
7.2.
Laboratory Evaluations ..........................................................................................................................17
7.2.1.
Summaries of Numeric Laboratory Results .........................................................................17
7.2.2.
Shifts Relative to the Normal Range....................................................................................17
7.3.
Transformation of Numeric Laboratory Data.........................................................................................18
7.4.
Body Weight and Vital Signs.................................................................................................................18
7.5.
Prior and Concomitant Medications.......................................................................................................18


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7.6.
Changes From Protocol-Specified Safety Analyses...............................................................................18
8.
SOFTWARE.......................................................................................................................................................20
9.
SAP REVISION..................................................................................................................................................21


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LIST OF ABBREVIATIONS
AE
adverse event
BMI
body mass index
BPM
beats per minute
CI
confidence interval
CRF
case report form
DMC
data monitoring committee
ECG
electrocardiogram
FAS
full analysis set
HLGT
high level group term
ICH
International Conference on Harmonisation
LLT
low level term
MedDRA
medical dictionary for regulatory activities
PAH
pulmonary arterial hypertension
PK
pharmacokinetics
PT
preferred term
Q1
first quartile
Q3
third quartile
ROW
Rest of World
SAP
statistical analysis plan
SOC
system organ class
TFLs
tables, figures, and listings
ULN
upper limit of normal
US
United States
WHO
World Health Organization


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1.
INTRODUCTION
1.1.
Study Objectives
Primary Study Objectives

The objective of this study is to monitor the long-term 
safety of ambrisentan in subjects with pulmonary 
hypertension (PH)
Secondary Study Objectives
N/A
1.2.
Study Design
Design Configuration and 
Subject Population
This Phase 3, international, multicenter, open-label study will 
monitor the long-term safety of ambrisentan in subjects with 
PH.  The target population is those men and women who are 
discontinuing a clinical study of ambrisentan in PH due to 
study closure by the Sponsor and for whom ambrisentan is 
not yet commercially available.
Treatment Groups
Available doses are 2.5 (Protocol Version 1 only), 5, or 
10 mg once daily (qd).  Investigators may adjust the
ambrisentan dose as clinically indicated.
Key Eligibility Criteria
Men and women with PH who are discontinuing a clinical 
study of ambrisentan due to study closure by the Sponsor.  
Eligible subjects are those participating in countries where 
ambrisentan is not yet commercially available.  Subjects 
participating in countries where ambrisentan is commercially 
available may be eligible if they do not qualify for treatment 
per the current prescribing information of that country.
Subjects who have discontinued an ambrisentan clinical 
study for any other reason than Sponsor-initiated study 
closure are not eligible.
Study Periods/Phases
There is one study period: treatment. Treatment will continue 
until such time as the Investigator or subject chooses to stop 
ambrisentan treatment, ambrisentan becomes commercially 
available, or the Sponsor stops the study.


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Schedule of Assessments
Screening/Enrollment 
Visit
Laboratory 
Visitsa
Laboratory Visitsb -
Pregnancy Test 
Only
Clinic Visitsc
Week
0
Every 
12 Weeks
Every 
4 Weeks
Every 
24 Weeks
Assessments
Informed consent
X
Medical history
X
Vital signs/body weight
X
X
Clinical laboratory testsd
Xe
Xd,f
Xc
Serum or urine pregnancy 
testg
X
Xd
Xd
X
CONMED assessment
X
X
Adverse events
X
X
Return unused 
ambrisentan
X
X
Dispense study drugh
X
X
a
Laboratory Visits will be required every 12 weeks for United States (US) and every 4 weeks for Rest of World (ROW) and 
will be completed at a local phlebotomy lab or at the Investigator clinic.
b
Laboratory Visits Pregnancy Test Only will be required every 4 weeks and will be completed at a local phlebotomy lab or 
at the Investigator clinic.
c
Clinic Visits will be required every 24 weeks.
d
Completion of the Laboratory Visit will be documented via telephone contact (within 2 days) if the Laboratory Visit 
occurs at a local phlebotomy lab.
e
Clinical laboratory tests at the Screening/Enrollment Visit and Clinic Visits will include chemistry (including LFTs), 
hematology, and coagulation. Coagulation labs (PT, PTT, and INR) will only be completed for subjects who are receiving 
warfarin or any other warfarin like anticoagulants.
f
Clinical laboratory tests at the Laboratory Visits will be limited to LFTs, specifically ALT, AST, alkaline phosphatase, 
GGT, and total bilirubin.
g
Pregnancy testing required for women of childbearing potential.
h
As necessary, a 3 month supply of study drug will be dispensed.


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Randomization
This is an open-label study in up to 80 investigational sites 
worldwide.  No randomization is planned.
Site and/or Stratum 
Enrollment Limits
NA
Study Duration
Subjects will receive treatment with ambrisentan until such time as 
the investigator or subject chooses to stop ambrisentan treatment, 
ambrisentan becomes commercially available, or the Sponsor stops 
the study.
1.3.
Sample Size and Power
Planned Sample Size
Approximately 300 subjects will be eligible to enroll in this study 
at its inception
Power Statement
NA
Actual Enrollment 
and Impact on Power
NA


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2.
TYPE OF PLANNED ANALYSIS
The primary endpoint for this study is the incidence and severity of AEs associated with 
long-term exposure to ambrisentan in subjects with PH.  When all subjects have completed the 
study, the database will be locked, the final analyses will be run, and data collected will be 
analyzed.
In addition, the data from this study will be reviewed on a regular basis by an internal Data 
Monitoring Committee (DMC) charged with protecting the safety of the study subjects. This 
committee will have the authority to recommend stopping the study early or modifying the study 
design for safety concerns. No adjustments for these interim summaries of safety data will be 
made to the final analysis.
This statistical analysis plan (SAP) covers the final analysis.


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3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
3.1.
Analysis Sets
Analysis sets define which subjects are included in an analysis. Because there are no efficacy 
analyses for this study, and because all subjects received at least one dose of study drug, only 
one analysis set will be defined.
3.1.1.
Safety Analysis Set
The safety analysis set includes subjects who were enrolled into the study and received at least 
one dose of study drug and will be used for all analyses.
3.2.
Subject Groups
Subjects were enrolled at 2.5 mg, 5 mg, and 10 mg ambrisentan, but adjustments to dose were 
allowed during the course of the study. Therefore, all subjects will be combined into one 
group: Ambrisentan.
3.3.
Strata and Covariates
Analyses will not be stratified.
3.4.
Examination of Subject Subsets
There are no planned analyses of subject subsets.
3.5.
Multiple Comparisons
No adjustments for multiple comparisons will be performed.
3.6.
Missing Data and Outliers
Missing Data
A missing data point for a given study visit may be due to any of the following reasons:

A visit occurred in the window but data were not collected or were unusable

A visit did not occur in the window

A subject permanently discontinued from the study before reaching the window.
Values for missing data will not be imputed unless otherwise specified.


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Outliers
No adjustments for outliers will be performed.
3.7.
Data Handling Conventions and Transformations
Safety data will be used according to availability, with no imputation for missing data.
Some laboratory data will need to be transformed in order to utilize it. These transformations are 
presented in Section 7.3.
3.8.
Visit Windows
3.8.1.
Definition of Study Day 1
Study Day 1 (baseline) is defined as the day of first dose of study drug in this study.
3.8.2.
Analysis Windows
Subject visits might not occur on protocol-specified days. Therefore, for the purpose of analysis, 
selected observations will be assigned to visits based on the windows presented in Table 1. 
Day 1 is the day of first dose of study drug in this study and is expected to be the day after the 
Enrollment visit, however, the Enrollment visit and Day 1 may also be the same day.
Table 1.
Visit Windows for Vital Signs
Visit
Target Day
Visit Window in Days
Comment
Baseline
N/A
N/A
Value at Enrollment visit will be used 
(expected to be the day prior to Day 1, 
but may be on Day 1)
Week 24
168
1-252
Week 48
336
253-420
Week X
X*7
[(X*7)-83] - [(X*7) + 84]
Week X is for 24-week periods 
through the end of study.
Depending on the statistical analysis method, single values may be required for each analysis 
window. If multiple valid, nonmissing measurements exist in an analysis window, records will 
be chosen based on the following rules if a single value is needed:

For baseline, the value at the Enrollment visit will be selected. If there is not an Enrollment 
visit value, the last nonmissing value on or prior to the first dosing date of study drug will be 
selected. If there are multiple records with the same time or no time recorded on the same 
day, the baseline value will be the average of the measurements for continuous data, or the 
measurement with the lowest severity (e.g., normal will be selected over abnormal) for 
categorical data.


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
For postbaseline values:
The record closest to the nominal day for that visit will be selected.
If there are 2 records that are equidistant from the nominal day, the later record will be 
selected.
If there is more than 1 record on the selected day, the average will be taken for 
continuous data and the worse severity will be taken for categorical data, unless 
otherwise specified.


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4.
SUBJECT DISPOSITION
4.1.
Subject Enrollment
The number and percentage of subjects enrolled in each country and by each investigator within 
a country will be summarized. The denominator for this calculation will be the total number of 
enrolled subjects. 
4.2.
Disposition of Subjects
A summary of subject disposition will be provided.  This summary will present the number of 
subjects enrolled, included in the safety analysis set, and the number and percentage of subjects
who permanently discontinued study with reasons for permanent discontinuation.
The denominator for the percentages of subjects in each category will be the number of subjects 
in the safety analysis set. 
No inferential statistics will be generated. A data listing of reasons for study discontinuation will 
be provided.
4.3.
Extent of Exposure
4.3.1.
Duration of Exposure to Study Drug
Duration of exposure to study drug will be defined as (last dose date first dose date + 1), 
regardless of temporary interruptions in study drug administration, and will be expressed in 
weeks (recorded to one decimal place, e.g., 4.5 weeks). Partial last dose dates with missing 
month and/or day will be estimated using the month and/or day of permanent discontinuation, or 
if that date is unavailable, the month and/or day of the last available visit date (including 
laboratory visits). Duration of exposure to study drug will be summarized using descriptive 
statistics (sample size, mean, standard deviation, median, first quartile (Q1), third quartile (Q3), 
minimum and maximum) and as the number and percentage of subjects exposed for specific 
periods (ie, through 12 weeks, through 24 weeks, etc).
The summary will be provided for subjects in the safety analysis set.
4.4.
Protocol Deviations
A listing will be provided of subjects in the safety analysis set who violated at least one inclusion 
or exclusion criteria.  The listing will include the criteria not met and related comments.


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5.
BASELINE DATA
5.1.
Demographics and Baseline Characteristics
Demographic and baseline characteristics will be summarized for the safety analysis set using 
descriptive statistics (sample size, mean, standard deviation, median, Q1, Q3, minimum and 
maximum) for continuous data and using the number and percent of subjects for categorical data.
Data to be included in this summary are gender, race, region, age, height, weight, body mass 
index (BMI), childbearing potential, PH etiology, years PH present, WHO functional class and 
previous ambrisentan study.
Years PH present will be calculated as the time from diagnosis date to first dose of study drug in 
this study. Partial dates will be estimated using “June 15” for missing month and day and “15” 
for missing day only.
5.2.
Medical History
General medical history (i.e., conditions not specific to the disease being studied) data will be 
listed only. General medical history data will not be coded.


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6.
EFFICACY ANALYSES
No efficacy analyses will be performed.


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7.
SAFETY ANALYSES
7.1.
Adverse Events and Deaths
The safety analysis set will be the primary analysis set for evaluation of adverse events and 
deaths.
7.1.1.
Adverse Event Dictionary
Clinical and laboratory adverse events (AEs) will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). System organ class (SOC), high level group term (HLGT), 
high level term (HLT), preferred term (PT), and lower level term (LLT) will be attached to the 
clinical database.
7.1.2.
Adverse Event Severity
AEs are graded by the investigator as mild, moderate, or severe. The severity grade of events for 
which the investigator did not record severity will be categorized as “missing” for tabular 
summaries and data listings, and will be considered the least severe for the purposes of sorting 
for data presentation.
7.1.3.
Relationship of Adverse Events to Study Drug
Related AEs are those for which the investigator answers “Yes” to the question “Related to 
Ambrisentan?”. Events for which the investigator did not record relationship to study drug will 
be considered related to study drug. Data listings will show relationship as missing.
7.1.4.
Serious Adverse Events
Serious adverse events (SAEs) are those identified as serious in the clinical database. The 
clinical database will be reconciled with the SAE database from the Gilead Pharmacovigilance & 
Epidemiology Department before database finalization.
7.1.5.
Treatment-Emergent Adverse Events
7.1.5.1.
Definition of Treatment-Emergent
Since all subjects received treatment with ambrisentan in a previous study, treatment-emergent 
AEs for this study are defined as all events that meet one of the following criteria:

Began on or before the date of the last dose of study drug plus 30 days.

Resulted in study drug discontinuation.


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7.1.5.2.
Incomplete Dates
If the date of onset is incomplete, then the month and year (or year alone if month is not 
recorded) of onset determine treatment emergent as follows. The event is treatment emergent if 
the month and year of onset (or year of onset) of the event meets the following criteria:

The same as or before the month and year (or year) of the date of the last dose of study drug 
7.1.6.
Summaries of Adverse Events and Deaths
A brief summary of AEs will show the number and percentage of subjects who (1) had any 
treatment-emergent AE, (2) had any severe treatment-emergent AE, (3) had any moderate or 
severe AE, (4) had any treatment-emergent treatment-related AE, (5) had any severe treatment-
emergent treatment-related AE, (6) had any moderate or severe treatment-emergent treatment-
related AE, (7) had any treatment-emergent SAE, (8) had any treatment-emergent treatment-
related SAE, (9) permanently discontinued from study drug or withdrew from the study due to an 
AE, and (10) died during study.
Summaries (number and percentage of subjects) of adverse events (by SOC and PT) will be 
provided using the safety analysis set as follows:

All treatment-emergent AEs

Treatment-emergent AEs by severity

Treatment-emergent AEs related to study drug

Treatment-emergent AEs related to study drug by severity

All treatment-emergent AEs that caused permanent discontinuation from study drug

All treatment-emergent AEs that caused study withdrawal

All treatment-emergent AEs with an outcome of death

All treatment-emergent SAEs

Treatment-emergent SAEs by severity

All treatment-emergent SAEs related to study drug
An additional summary will be provided for all treatment-emergent AEs by PT.
Multiple events will be counted once only per subject in each summary. For data presentation,
SOC will be ordered alphabetically, with PT sorted by decreasing total frequency. For 
summaries by severity grade, the most severe event will be selected.


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For each of the AE summaries, data will be summarized for all subjects combined, for all 
treatment-emergent AEs during the study.
In addition to the summaries, data listings will be provided for the following:

All AEs (with a variable indicating whether the event is treatment-emergent)

SAEs

Deaths

AEs leading to discontinuation of study drug or study withdrawal
7.1.7.
Additional Analysis of Adverse Events
No additional analyses of adverse events are planned.
7.2.
Laboratory Evaluations
7.2.1.
Summaries of Numeric Laboratory Results
Laboratory tests were analyzed by local laboratories. Laboratory values that were not within the 
normal range limits of the local laboratory were captured on the CRF, along with the normal 
ranges. If the result was within the normal limits, the results and associated normal ranges were 
not captured and the CRF only captured the result of “Normal”. Therefore, descriptive statistics 
will not be presented for laboratory measurements.
7.2.2.
Shifts Relative to the Normal Range
The following summaries (number and percentage of subjects) relative to the respective 
laboratory test normal ranges will be provided.

The number and percentage of subjects with ALT or AST within the following categories at 
any time during the study:
>3xULN
>5xULN
>10xULN
>20xULN

The number and percentage of subjects with alkaline phosphatase >1.5xULN or total 
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
Additionally, the number and percentage of subjects with ALT >3xULN or AST >3xULN,
and total bilirubin >2xULN with or without alkaline phosphatase <2xULN simultaneously at 
any time during the study will be summarized
7.3.
Transformation of Numeric Laboratory Data
Certain numeric laboratory data need to be transformed for the summary tables, although in the 
listings original inputted values will be presented.  The following rules will be used for the data 
transformation.

For values with a comma, treat the comma as a decimal.  For example, treat “23,2” as 23.2.

For values with units, remove the units.  For example, treat “47 U/L” as 47.

For values ending with symbol “`” or “%”, remove the symbol.  For example, treat “31`” as 
31, and treat “14.7%” as 14.7.

For values containing “NCS” or “ABNORMAL”, remove the word and any associated 
punctuation.  For example, treat “NCS 3.44” as 3.44 and “ABNORMAL, 11.2” as 11.2.

For values starting with symbol “<”, remove the symbol and subtract 0.01 from the number.  
For example, treat “<30” as 29.99.

For postbaseline values reported as normal or values indicating the test was not performed, 
remove from summaries.
7.4.
Body Weight and Vital Signs
Body weight and vital signs (systolic and diastolic blood pressure and heart rate) and change 
from baseline in body weight and vital signs will be summarized using descriptive statistics 
(sample size, mean, standard deviation, median, Q1, Q3, minimum and maximum) for each post-
baseline clinic visit where 4 or more subjects have measurements. The target days and windows 
presented in Section 3.8.2 will be applied here to select the value at each visit.
7.5.
Prior and Concomitant Medications
Prior and concomitant medications will be coded using the World Health Organization (WHO) 
Drug Dictionary. The WHO preferred name and drug code will be attached to the clinical 
database. Prior and concomitant medications will be listed by subject.  
7.6.
Changes From Protocol-Specified Safety Analyses
The protocol specifies that safety data would be summarized by ambrisentan dose at enrollment 
and by maximum ambrisentan dose received at any time during the study. Instead, because most 
subjects were on 5 mg or 10 mg (approved doses) at some time during the study, safety data will 
be summarized using all ambrisentan doses combined as one group.


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The protocol specifies that dose migrations will be summarized by a shift table.  These data will 
be listed as part of the study drug administration listing instead due to multiple shifts per subject 
which cannot be appropriately characterized by a shift table.
The protocol specifies treatment-emergent AEs as those starting on or after the first dose of study 
drug up to the date of last dose of study drug.  For the purposes of this SAP, treatment-emergent 
AEs are defined as those starting on or after the first dose of study drug up to the date of last 
dose of study drug plus 30 days.
The protocol specifies that safety data will be summarized for cumulative 24-week periods. This 
will not be done and only the cumulative study period will be summarized.
The protocol-specified shifts from baseline value (low, normal, or high) to postbaseline value 
(low, normal, or high) at each postbaseline clinical visit will not be provided for laboratory tests.


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8.
SOFTWARE
SAS® Software Version 9.4. SAS Institute Inc., Cary, NC, USA.


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9.
SAP REVISION
Revision Date
(dd month, yyyy)
Section
Summary of Revision
Reason for Revision


GS-US-300-0124-SAP
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Clinical Research eSigned
14-Jul-2020
19:57:46
Biostatistics eSigned
16-Jul-2020
22:54:13
PPD
PPD