A Randomized, Open Label Study Comparing Safety and Efficacy Parameters for a High and a Low Dose of Ambrisentan (Adjusted for Body Weight) for the Treatment of Pulmonary Arterial Hypertension in Paediatric Patients Aged 8 Years up to 18 Years
Phase: PHASE2
Conditions: Hypertension, Pulmonary
Sponsor: GlaxoSmithKline

RM2010/00053/03 
CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
AMB112529 
 
1 
 
Division: Worldwide Development 
Retention Category: GRS019 
Information Type: Protocol Amendment 
 
Title: 
A randomized, open label study comparing safety and efficacy 
parameters for a high and a low dose of ambrisentan (adjusted 
for body weight) for the treatment of pulmonary arterial 
hypertension in paediatric patients aged 8 years up to 18 years. 
Compound Number: GSK1325760 
Effective Date: 
02-FEB-2011 
Protocol Amendment Number:  03 
Description: 
A 6-month (24-week), randomized, open label evaluation of the safety, tolerability, and 
efficacy of a high and low dose ambrisentan (adjusted for body weight) treatment group 
in subjects aged 8 years up to 18 years with pulmonary arterial hypertension (PAH).  An 
additional objective is to determine the ambrisentan population pharmacokinetics in the 
paediatric population.  The study will include a screening/baseline period and a treatment 
period.  The treatment period will be 24 weeks or until the subject’s clinical condition 
deteriorates to the point that alternative/additional treatment is necessary.  Patients who 
participate in the study and in whom continued treatment with ambrisentan is desired will 
be eligible to enrol into a long term follow-up study.  The primary comparison will be the 
safety and tolerability of the two ambrisentan dose groups (Low vs. High) in the 
paediatric PAH population  The secondary comparison will be the change from baseline 
for the efficacy parameters between the two treatment groups. 
 
Subject: Pulmonary Arterial Hypertension 
Author: 
 
 
 
 
 
 
 
Copyright 2011 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited 
PPD

RM2010/00053/03 
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The GlaxoSmithKline group of companies 
 
AMB112529 
 
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Revision Chronology: 
 
 
RM2010/00053/00 
2010-MAY-07 
Original 
RM2010/00053/01 
2010-JUN-09 
Amendment No.: 01 
Clarify the inclusion criteria that 
existing drug treatment for PAH would 
continue unchanged throughout the 
study. 
Clarify that two forms of contraception 
is required only for female subjects of 
child bearing potential who are 
sexually active 
Expand the eligibility for the 
continuation study to all patients who 
participate in this study and in whom 
continued treatment with ambrisentan 
is desired. 
Specify that patients will be given a 
diary card to collect information about 
dosing and days missed from school. 
Remove references to “brain natriuretic 
peptide” and clarify that it is N-
Terminal pro-B-type Natriuretic 
Peptide that is being assessed. 
Add more specific references for the 
Tanner development criteria. 
Change the wording of the questions 
regarding days missed from school to 
make it clear that the total number of 
days  missed includes the days missed 
because of PAH and that the days 
missed because of PAH are due to 
symptoms of PAH and do not include 
clinic visits. 
Remove the requirement for an 
unblinded person to enter compliance 
data into InForm. 
Allow the investigator to be unblinded 
to treatment for an individual patient 
once that patient has completed the 
study. 

RM2010/00053/03 
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The GlaxoSmithKline group of companies 
 
AMB112529 
 
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RM2010/00053/02 
2010-OCT-26 
Amendment No.: 02 
To clarify that it is hepatitis B surface 
antigen, and not hepatitis B surface 
antibody, that is being assessed as part 
of the exclusion criteria. 
Add the US IND number to the 
Sponsor Information Page and clarify 
that the medical monitor and Serious 
Adverse Events contact are the same 
person. 
RM2010/00053/03 
2011-FEB-02 
Amendment No.: 03 
Add oestrogen to the laboratory tests 
being performed on female subjects at 
all times that pubertal development 
assessments are performed. 
Remove testosterone from the 
laboratory tests being performed on 
female subjects at all times that the 
pubertal development assessments are 
performed. 
Change the storage requirements for 
the study medication to store below 
30°C. 
 

P P D

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SPONSOR INFORMATION PAGE 
Clinical Study Identifier:   AMB112529 
 
GlaxoSmithKline 
Iron Bridge Road  
Stockley Park West, Uxbridge, Middlesex, UB11 1BU, UK 
Telephone:  
  
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline affiliate 
company (or designee).  Where applicable, the details of the Sponsor and contact person 
will be provided to the relevant regulatory authority as part of the clinical trial 
submission. 
Sponsor Medical Monitor and Serious Adverse Events (SAE) Contact Information: 
 
 FRCS 
Clinical Development Physician 
MDC Clinical Metabolic EU 
GlaxoSminthKline  
Stockley Park 
Sponsor Serious Adverse Events (SAE) Contact Information:  
Regulatory Agency Identifying Number(s):  EudraCT 2010-019547-19 
 
 
 
 
 
 
US IND 64,915 
 
PPD
PPD

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INVESTIGATOR AGREEMENT PAGE 
For protocol AMB112529 
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment. 
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described clinical study. 
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study.  
Investigator Name:  _____________________________ 
 
 
 
 
Investigator Signature 
 
Date 
 

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TABLE OF CONTENTS 
PAGE 
LIST OF ABBREVIATIONS ............................................................................................. 10 
PROTOCOL SUMMARY ................................................................................................. 12 
1. 
INTRODUCTION ..................................................................................................... 15 
1.1. 
Background .................................................................................................. 15 
1.2. 
Rationale ...................................................................................................... 16 
2. 
OBJECTIVE(S) ........................................................................................................ 17 
2.1. 
Primary ......................................................................................................... 17 
2.1.1. 
Safety ............................................................................................ 17 
2.1.2. 
Secondary ..................................................................................... 17 
2.1.2.1. 
Pharmcokinetics: ......................................................... 17 
2.1.2.2. 
Efficacy ........................................................................ 18 
2.1.2.3. 
Exploratory .................................................................. 18 
2.1.2.4. 
Other ........................................................................... 18 
3. 
INVESTIGATIONAL PLAN ...................................................................................... 18 
3.1. 
Study Design ................................................................................................ 18 
3.2. 
Discussion of Design .................................................................................... 19 
4. 
SUBJECT SELECTION AND WITHDRAWAL CRITERIA ....................................... 20 
4.1. 
Number of Subjects ...................................................................................... 20 
4.2. 
Inclusion Criteria .......................................................................................... 20 
4.3. 
Exclusion Criteria ......................................................................................... 21 
4.4. 
Withdrawal Criteria ....................................................................................... 22 
5. 
STUDY TREATMENTS ........................................................................................... 23 
5.1. 
Investigational Product and Reference Therapy .......................................... 23 
5.2. 
Treatment Assignment ................................................................................. 24 
5.3. 
Blinding ........................................................................................................ 24 
5.4. 
Product Accountability .................................................................................. 25 
5.5. 
Treatment Compliance ................................................................................. 25 
5.6. 
Concomitant Medications and Non-Drug Therapies .................................... 25 
5.6.1. 
Permitted Medications and Non-Drug Therapies .......................... 25 
5.6.2. 
Prohibited Medications and Non-Drug Therapies ......................... 25 
5.7. 
Treatment after the End of the Study ........................................................... 26 
5.8. 
Treatment of Investigational Product Overdose ........................................... 26 
6. 
STUDY ASSESSMENTS AND PROCEDURES ...................................................... 26 
6.1. 
Critical Baseline Assessments ..................................................................... 29 
6.2. 
Safety ........................................................................................................... 29 
6.2.1. 
Physical examination .................................................................... 29 
6.2.2. 
Electrocardiogram / Echocardiogram ............................................ 29 
6.2.3. 
Vital Signs, Body Weight and Height ............................................ 29 
6.2.4. 
Pubertal Development Assessment .............................................. 30 
6.2.5. 
Clinical Laboratory Tests .............................................................. 30 
6.2.5.1. 
Safety Tests ................................................................ 30 

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6.2.5.2. 
Pharmacogenetics and NT-Pro BNP ........................... 30 
6.2.6. 
Liver chemistry stopping and followup criteria .............................. 31 
6.2.7. 
Adverse Events ............................................................................. 33 
6.2.7.1. 
Definition of an AE ....................................................... 33 
6.2.7.2. 
Definition of a SAE ...................................................... 34 
6.2.8. 
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs .......................................................... 36 
6.2.9. 
Pregnancy ..................................................................................... 36 
6.2.10. 
Time Period and Frequency of Detecting AEs and SAEs ............. 36 
6.2.11. 
Prompt Reporting of Serious Adverse Events and Other 
Events to GSK .............................................................................. 37 
6.2.11.1.  Regulatory reporting requirements for SAEs ............... 38 
6.3. 
Pharmacokinetics ......................................................................................... 38 
6.4. 
Efficacy ......................................................................................................... 39 
6.4.1. 
Change from baseline in the 6 minute walking distance 
(6MWD) test. ................................................................................. 39 
6.4.2. 
Time to worsening of PAH ............................................................ 39 
6.4.3. 
Change from baseline (Week 0) in Subject Global 
Assessment to Week 24. .............................................................. 39 
6.4.4. 
Change from baseline in WHO functional class to Week 
24. ................................................................................................. 39 
6.4.5. 
Change from baseline plasma N-terminal pro-B type 
natriuretic peptide (NT-Pro BNP) at Week 24 ............................... 40 
6.4.6. 
Change from baseline in major prognostic factors to Week 
24. ................................................................................................. 40 
6.4.7. 
Change from baseline in cardiopulmonary hemodynamics 
at Week 24 .................................................................................... 40 
6.5. 
Health Outcomes.......................................................................................... 40 
6.6. 
Pharmacogenetics........................................................................................ 41 
7. 
DATA MANAGEMENT ............................................................................................. 41 
8. 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS ................................... 41 
8.1. 
Study Objectives .......................................................................................... 41 
8.2. 
Study Design Considerations ....................................................................... 42 
8.2.1. 
Sample Size Assumptions ............................................................ 42 
8.2.2. 
Sample Size Sensitivity ................................................................. 42 
8.2.3. 
Sample Size Re-estimation ........................................................... 42 
8.3. 
Data Analysis Considerations ...................................................................... 42 
8.3.1. 
Analysis Populations ..................................................................... 42 
8.3.2. 
Analysis Data Sets ........................................................................ 42 
8.3.3. 
Treatment Comparisons ............................................................... 43 
8.3.3.1. 
Primary Comparisons of Interest ................................. 43 
8.3.3.2. 
Secondary Comparisons of Interest ............................ 43 
8.3.3.3. 
Exploratory Comparisons of Interest ........................... 44 
8.3.3.4. 
Other Comparisons of Interest .................................... 44 
8.3.4. 
Interim Analysis ............................................................................. 44 
8.3.5. 
Key Elements of Analysis Plan ..................................................... 44 
8.3.5.1. 
Safety Analyses ........................................................... 44 
8.3.5.2. 
Pharmacokinetic Analyses .......................................... 44 
8.3.5.3. 
Pharmacokinetic/Pharmacodynamic Analyses ........... 45 
8.3.5.4. 
Efficacy Analyses ........................................................ 45 

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8.3.5.5. 
Health Outcomes Analyses ......................................... 46 
8.3.5.6. 
Pharmacogenetic Analyses ......................................... 47 
8.3.5.7. 
Novel Biomarker(s) Analyses ...................................... 47 
8.3.5.7.1. 
RNA Transcriptome Analysis .................. 47 
8.3.5.7.2. 
RNA Expression Analysis of a 
Subset of RNA Species ........................... 47 
9. 
STUDY CONDUCT CONSIDERATIONS ................................................................. 47 
9.1. 
Posting of Information on Clinicaltrials.gov .................................................. 47 
9.2. 
Regulatory and Ethical Considerations, Including the Informed 
Consent Process .......................................................................................... 47 
9.3. 
Quality Control (Study Monitoring) ............................................................... 48 
9.4. 
Quality Assurance ........................................................................................ 48 
9.5. 
Study and Site Closure................................................................................. 49 
9.6. 
Records Retention........................................................................................ 49 
9.7. 
Provision of Study Results to Investigators, Posting to the Clinical 
Trials Register and Publication ..................................................................... 50 
9.8. 
Independent Data Monitoring Committee (IDMC) ........................................ 50 
10.  REFERENCES ........................................................................................................ 51 
11.  APPENDICES .......................................................................................................... 53 
11.1. 
Appendix 1: Cardiopulmonary Hemodynamic Sub-study ............................. 53 
11.2. 
Appendix 2: List of Highly Effective Methods for Avoidance of 
Pregnancy in Women of Childbearing Potential ........................................... 54 
11.3. 
Appendix 3: Pharmacogenetic Research ..................................................... 55 
11.4. 
Appendix 4: Country Specific Requirements ................................................ 60 
11.5. 
Appendix 5: Protocol Amendment 01 ........................................................... 61 
11.6. 
Appendix 6: Protocol Amendment 02 ........................................................... 70 
11.7. 
Appendix 7: Protocol Amendment 03 ........................................................... 72 
 

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LIST OF ABBREVIATIONS 
6MWD 
6 minute walking distance test 
ACE 
Angiotensin-converting enzymes 
AE 
Adverse Event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BMI 
Body mass index 
BSA 
Body surface area 
BUN 
Blood urea nitrogen 
CCBs 
Calcium Channel Blockers 
cGMP 
Cyclic guanosine monophosphate  
CHD 
Congenital heart defects 
COPD 
Congestive obstructive pulmonary disease 
CPK 
Creatine phosphokinase 
CTD 
Connective tissue disease 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ERA 
Endothelin receptor antagonist  
ET 
endothelin 
EU 
European Union 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyl transferase 
GGT 
gamma glutamyl transferase 
GSK 
GlaxoSmithKline 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
INR 
International Normalized Ratio 
IPAH 
Idiopathic Pulmonary Arterial Hypertension 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IVRS 
Central interactive voice recognition system 
IVRS 
Interactive Voice Response System 
kg 
kilogram 
LDH 
Lactate dehydrogenase 
LEVDP 
Left ventricular end diastolic pressure 
LFT 
Liver function test 
LH 
Luteinizing hormone  
m 
meter 
MCH 
mean corpuscular haemoglobin 
MCHC 
mean corpuscular haemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg  
milligram 
mPAP 
mean pulmonary arterial pressure 
MSDS 
Material Safety Data Sheet 

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NT-Pro BNP 
N-Terminal pro-B-type Natriuretic Peptide 
PAH 
Pulmonary Arterial Hypertension  
PAH-CTD 
pulmonary arterial hypertension associated with connective 
tissue disease 
PCWP 
Pulmonary capillary wedge pressure 
PDCO 
EMA Paediatric Committee 
PDE-5 
Phosphodiesterase type 5 
PGx 
Pharmacogenetic 
PIP 
Paediatric Investigational Plan 
Pk 
pharmacokinetic 
PVR 
Pulmonary vascular resistance 
RA 
Right atrial 
RHC 
Right heart catheterisation 
RV 
Right ventricle  
RVF 
Right ventricular failure 
SAE 
Serious Adverse Event 
SEM 
Standard error of the mean 
SHBG 
Sex hormone binding globulin 
SPC 
Summary of Product Characteristics 
SPM 
Study Procedures Manual 
TAPSE 
Tricuspid annular plane systolic excursion 
TRAX 
Tracleer excellence database 
TRJ 
Tricuspid regurgitant jet 
ULN 
Upper limit of normal 
V/Q 
Ventilation/perfusion 
WHO 
World Health Organization 
 
Trademark Information 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
FLOLAN 
 
Adcirca 
VOLIBRIS 
 
C RIBA 
 
 
Letairis 
 
 
NONMEM 
 
 
Remodulin 
 
 
Revatio 
 
 
Thelin 
 
 
Tracleer 
 
 
Ventavis 
 
 
Viagra 
 

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PROTOCOL SUMMARY 
Rationale 
Pulmonary arterial hypertension (PAH) is a rare, progressive, highly debilitating disease  
characterized by vascular obstruction and the variable presence of vasoconstriction, 
leading to increased pulmonary vascular resistance and right-sided heart failure 
[Moledina, 2010; Newman, 2004].  If left untreated, PAH ultimately leads to right 
ventricular failure and death; adult subjects have a median survival of 2.8 years without 
treatment [Krum, 2000].  Epidemiological estimates vary but prevalence in Europe is 
thought to be of the order of 15 cases per million [Humbert, 2006].  Large scale 
epidemiology studies of PAH in children have not been conducted and there is no or 
limited outcome data in pediatric PAH patients.  A register in France (1995-1996) 
estimates the prevalence in children is as low as 3.7 cases per million [Fraisse, 2010].  In 
a national, comprehensive country wide survey of the epidemiology of idiopathic PAH 
(IPAH) management and survival in the United Kingdom (UK) the incidence was 0.48 
cases per million children per year and the prevalence was 2.1 cases per million children 
[Moledina, 2010]. 
Ambrisentan (VOLIBRIS™ tablets) is an endothelin receptor antagonist (ERA) marketed 
in the European Union (EU) and some other countries by GlaxoSmithKline (GSK) and in 
the United States as Letairis by Gilead Sciences Inc.  Ambrisentan is indicated for the 
treatment of adult patients with PAH to improve exercise capacity, decrease the 
symptoms of PAH, and delay clinical worsening. 
The primary purpose of this paediatric study is to provide clinically relevant information 
on the safety and pharmacokinetic profile of ambrisentan in children with the most 
common causes of PAH in this age group.  The design of the study is also intended to 
provide information to guide dose selection and supportive efficacy data in this age 
group.  Despite the fact that none of the currently available adult treatments are licensed 
for use in children <12 yrs, (with the exception of bosentan which was recently approved 
for use in paediatric population from 2 years of age) they are widely used off label.  This 
study will provide useful prescribing information to the medical community for treating 
this orphan disease in children in this environment of rapidly changing medical practice.  
This study is part of a Paediatric Investigational Plan (PIP; EMEA-000434-PIP01-08) 
agreed with the European Medicines Agency’s Paediatric Committee (PDCO). 
Objective(s) 
The primary objective of this study is to evaluate the safety and tolerability of 
ambrisentan in the paediatric (aged 8 years up to 18 years) PAH population.  Other 
objectives are to obtain supportive efficacy data (change from baseline in efficacy 
parameters) on the paediatric use of ambrisentan in PAH and to determine the 
ambrisentan population pharmacokinetics in the paediatric population.  Because patient 
recruitment is limited by the low prevalence of the disease in children, powered clinical 
hypotheses testing cannot be performed. 

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Study Design 
A 6-month (24-week), randomized, open label evaluation of the safety, tolerability, and 
efficacy of a high and low dose ambrisentan (adjusted for body weight) treatment group 
in 66 subjects (33 per treatment group) aged 8 years up to 18 years with PAH.  The study 
will include a screening/baseline period and a treatment period.  The treatment period 
will be 24 weeks or until the subject’s clinical condition deteriorates to the point that 
alternative/additional treatment is necessary.  Patients who participate in this study and in 
whom continued treatment with ambrisentan is desired will be eligible to enrol into a 
long term follow-up study.  The primary comparison will be the safety and tolerability of 
the two ambrisentan dose groups (Low vs. High) in the paediatric PAH population  The 
secondary comparison will be the change from baseline of the efficacy parameters 
between the two treatment groups.  Because patient recruitment is limited by the low 
prevalence of the disease in children, powered clinical hypotheses testing cannot be 
performed.  Sixty-six (66) subjects were chosen on the predicted recruitment rate based 
on historic data so that the study can be completed in a reasonable time frame (2 years) 
for it to be useful and informative to the medical community.  A 10% drop out rate will 
leave 60 evaluable subjects. 
Study Endpoints/Assessments 
Primary 
The safety and tolerability of ambrisentan in the paediatric PAH population (see Safety): 
Safety 
• 
Adverse Events. 
• 
Serious Adverse Events. 
• 
Clinical laboratory parameters. 
• 
Physical examination (Including  height, weight, body mass index / body surface 
area, oxygen saturation, jugular venous pressure, liver size, and presence of 
peripheral oedema and/or ascites.) 
• 
Vital Signs. 
• 
Pubertal development (change from baseline in endocrinology assessments at Weeks 
12 and 24). 
Secondary 
Pharmcokinetics: 
• 
Population pharmacokinetic assessment based on one plasma sample per subject at 
Weeks 4 (trough), 8 (0.5 to 4 hours post-dose), 12 (trough), 16 (0.5 to 4 hours post-
dose), 20 (4 to 22 hours post-dose), and 24 (trough). 
• 
Pharmacokinetic/pharmacodynamic modelling. 

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Efficacy 
• 
The change from baseline in the 6 minute walking distance (6MWD) test evaluated 
after 24 weeks of therapy. 
• 
Mean changes from baseline in the 6MWD test at Weeks 4, 8, 12, 16, and 20. 
• 
The time to clinical worsening of PAH. 
• 
The change from baseline in Subject Global Assessment to Week 24 using the SF-10 
health survey for children. 
• 
The change from baseline in WHO functional class to Week 24. 
• 
Change from baseline in plasma N-Terminal pro-B-type Natriuretic Peptide (NT-Pro 
BNP) concentration at Week 24. 
Exploratory 
• 
The change from baseline in major prognostic factors based on echocardiogram: 
pericardial effusion, right atrial (RA) pressure, tricuspid annular plane systolic 
excursion (TAPSE), eccentricity index (systolic and diastolic), and right ventricular 
(RV) pressure by tricuspid regurgitant jet (TRJ) velocity to Week 24. 
Other 
• 
Change from baseline in cardiopulmonary hemodynamics at Week 24 (a sub-study in 
subjects enrolled at centres where the collection of hemodynamic data is considered 
part of the standard of care); see Appendix 1. 

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1. 
INTRODUCTION 
1.1. 
Background 
Pulmonary arterial hypertension (PAH) is a group of diseases characterised by a 
progressive increase of pulmonary vascular resistance (PVR) leading to right ventricular 
failure (RVF) and premature death. A recent meta-analysis estimates survival for 
untreated idiopathic PAH (IPAH) in adults to be only 79% at 1 year and 66% at 2 years 
[McLaughlin, 2006].  In the UK, survival in treated children with IPAH at 1, 3 and 5 
years was 89%, 84%, and 75% respectively; whilst transplant free survival was 89%, 
76%, and 57% respectively [Moledina, 2010]. 
Detailed, consensus, evidence-based guidelines for the treatment of PAH have been 
published [Badesch, 2004; Galiè, 2009].  Pharmacological approaches are divided into 
those that are supportive or background treatment (aimed at alleviating vasoconstriction, 
breathlessness, and thromboembolic complications) and those (such as endothelium 
receptor antagonist [ERAs]) that target the underlying pathophysiology.  
Diuretics and anticoagulants have been widely used in the management of PAH, yet 
response varies [Humbert, 2004].  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 
[Humbert, 2004; Rich, 1992]. 
The pathophysiologic mechanisms which underpin the disease spectrum of PAH involve 
pulmonary vascular dysfunction, which produces an imbalance in vasoactive substances 
as well as proliferation signals that lead to structural remodelling and pulmonary 
vasoconstriction.  Although its role is not fully understood, endothelin (ET) is considered 
to be an important mediator of pathology in PAH.  Almost all components of the 
endothelin system are upregulated in PAH [Giaid, 1993; Galiè, 2004].  There appears to 
be a significant correlation between serum endothelin 1 (ET-1) levels and disease 
severity, reflected by elevations in PVR, mean pulmonary artery pressure (mPAP) and 
right atrial pressure [Nootens, 1995].  Endothelin-1 (ET-1) receptor antagonists are a 
targeted pharmacological approach that limit both the vasoconstrictor and proliferative 
action of endothelin [Dingemanse, 2004], and in this way ameliorate the clinical 
manifestations of the disease.  
Three signalling pathways involved in the pathogenesis of PAH have been targeted for 
therapeutic intervention [Humbert, 2004]: the cAMP-dependent prostacyclin (PGI2) 
pathway, the cGMP-dependent nitric oxide (NO) pathway, and the 
phospholipase-C-dependent endothelin pathway.  These pathways are targeted by the 
following classes of PAH medicines: prostanoids (FLOLAN™ [epoprostenol], Ventavis 
[iloprost] and Remodulin [terprostinil]); phosphodiesterase type-5 (PDE-5) inhibitors 
(Revatio [EU]/Viagra [sildenafil] and Adcirca [tadalafil])); and ERAs (VOLIBRIS 
[EU]/Letairis [US] (ambrisentan), Tracleer [bosentan] and Thelin [sitaxentan]). 

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There is evidence that prostanoid therapies are effective in children, but in common to 
their use in adults, the pharmacokinetic properties of these drugs and routes of 
administration (e.g., intravenous, subcutaneous injection, and multiple inhalations) 
present substantial challenges to their successful use in a pediatric population. 
The clinical profile of ambrisentan (an ERA selective for the ETA receptor) in adults is 
that it has an efficacy profile broadly comparable with other targeted oral treatments, but 
that it has potentially important advantages.  Ambrisentan has been associated with a 
favourable liver safety profile and a low risk of drug-drug interactions.  It is noted that 
data from the TRAX1 database indicates that the risk of elevated aminotransferases with 
bosentan is lower in children than adults [Beghetti, 2008].  Nevertheless the liver safety 
profile of ambrisentan in adults has been favourable and if replicated in children would 
provide a clinically useful option.  Children, like adults with PAH, commonly require 
many concomitant medications.  The low risk of drug-drug interactions and convenient 
once a day dosing associated with ambrisentan may provide a therapeutic option that 
simplifies treatment in this complex disease. 
1.2. 
Rationale 
Pulmonary arterial hypertension (PAH) is a rare, progressive, highly debilitating disease 
characterized by vascular obstruction and the variable presence of vasoconstriction, 
leading to increased pulmonary vascular resistance and right-sided heart failure 
[Moledina, 2010; Newman, 2004].  If left untreated, PAH ultimately leads to right 
ventricular failure and death; adult subjects have a median survival of 2.8 years without 
treatment [Krum, 2000].  Epidemiological estimates vary but prevalence in Europe is 
thought to be of the order of 15 cases per million [Humbert, 2006].  Large scale 
epidemiology studies of PAH in children have not been conducted and there is no or 
limited outcome data in paediatric PAH patients.  A register in France (1995-1996) 
estimates the prevalence in children is as low as 3.7 cases per million [Fraisse, 2010].  In 
a national, comprehensive country wide survey of the epidemiology of idiopathic PAH 
(IPAH) management and survival in the United Kingdom (UK) the incidence was 0.48 
cases per million children per year and the prevalence was 2.1 cases per million children 
[Moledina, 2010].  
Ambrisentan (VOLIBRIS tablets) is an endothelin receptor antagonist (ERA) marketed in 
the European Union (EU) and some other countries by GlaxoSmithKline (GSK) and in 
the United States as Letairis by Gilead Sciences Inc.  Ambrisentan is indicated for the 
treatment of adult patients with PAH to improve exercise capacity, decrease the 
symptoms of PAH, and delay clinical worsening. 
The primary purpose of this paediatric study is to provide clinically relevant information 
on the safety and pharmacokinetic profile of ambrisentan in children with the most 
common causes of PAH in this age group.  The design of the study is also intended to 
                                                 
1  TRAX - the Tracleer Excellence database is a non-interventional, prospective, internet-based surveillance 
system initiated by the manufacturer in cooperation with Regulatory agencies to collect potential safety 
signals associated with bosentan use including adverse events, elevations of liver aminotransferase 
levels, other abnormal laboratory values, deaths, and hospitalisation [Segal, 2005]. 

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provide information to guide dose selection and supportive efficacy data in this age 
group.  Despite the fact that none of the currently available adult treatments are licensed 
for use in children <12 yrs, (with the exception of bosentan which was recently approved 
for use in paediatric population from 2 years of age) they are widely used off label.  This 
study will provide useful prescribing information to the medical community for treating 
this orphan disease in children in this environment of rapidly changing medical practice.  
This study is part of a Paediatric Investigational Plan (PIP; EMEA-000434-PIP01-08) 
agreed with the European Medicines Agency’s Paediatric Committee (PDCO).  
2. 
OBJECTIVE(S) 
The primary objective of this study is to evaluate the safety and tolerability of 
ambrisentan in the paediatric (aged 8 years up to 18 years) PAH population.  Other 
objectives are to obtain supportive efficacy data (change from baseline in efficacy 
parameters) on the paediatric use of ambrisentan in PAH and to determine the 
ambrisentan population pharmacokinetics in the paediatric population.  Because patient 
recruitment is limited by the low prevalence of the disease in children, powered clinical 
hypotheses testing cannot be performed. 
2.1. 
Primary 
The primary objective is the safety and tolerability of ambrisentan in the paediatric PAH 
population (see Safety). 
2.1.1. 
Safety 
• 
Adverse Events. 
• 
Serious Adverse Events. 
• 
Clinical laboratory parameters. 
• 
Physical examination (Including  height, weight, body mass index / body surface 
area, oxygen saturation, jugular venous pressure, liver size, and presence of 
peripheral oedema and/or ascites.) 
• 
Vital Signs. 
• 
Pubertal development (change from baseline in endocrinology assessments at Weeks 
12 and 24). 
2.1.2. 
Secondary 
2.1.2.1. 
Pharmcokinetics: 
• 
Population pharmacokinetic assessment based on one plasma sample per subject at 
Weeks 4 (trough), 8 (0.5 to 4 hours post-dose), 12 (trough), 16 (0.5 to 4 hours post-
dose), 20 (4 to 22 hours post-dose), and 24 (trough). 

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• 
Pharmacokinetic/pharmacodynamic modelling. 
2.1.2.2. 
Efficacy 
• 
The change from baseline in the 6 minute walking distance (6MWD) test evaluated 
after 24 weeks of therapy. 
• 
Mean changes from baseline in the 6MWD test at Weeks 4, 8, 12, 16, and 20. 
• 
The time to clinical worsening of PAH. 
• 
The change from baseline in Subject Global Assessment to Week 24 using the SF-10 
health survey for children. 
• 
The change from baseline in WHO functional class to Week 24. 
• 
Change from baseline in N-terminal pro-B-type natriuretic peptide (NT-Pro BNP) 
concentration at Week 24. 
2.1.2.3. 
Exploratory 
• 
The change from baseline in major prognostic factors based on echocardiograms: 
pericardial effusion, right atrial (RA) pressure, tricuspid annular plane systolic 
excursion (TAPSE), eccentricity index (systolic and diastolic), and right ventricular 
(RV) pressure by tricuspid regurgitant jet (TRJ) velocity to Week 24. 
2.1.2.4. 
Other 
• 
Change from baseline in cardiopulmonary hemodynamics at Week 24 (a sub-study in 
subjects enrolled at centres where the collection of hemodynamic data is considered 
part of the standard of care); see Appendix 1. 
3. 
INVESTIGATIONAL PLAN 
3.1. 
Study Design 
A 6-month (24-week), randomized, open label evaluation of the safety, tolerability, and 
efficacy of a high and low dose ambrisentan (adjusted for body weight) in 66 subjects (33 
per treatment group) aged 8 years up to 18 years with PAH.  The study will include a 
screening/baseline period and a treatment period.  The treatment period will be 24 weeks 
or until the subject’s clinical condition deteriorates to the point that alternative/additional 
treatment is necessary.  Subjects who participate in the study will be eligible to enrol into 
a long term follow-up study.  The primary comparison will be the safety and tolerability 
of the two ambrisentan dose groups (Low vs. High) in the paediatric PAH population.  
The secondary comparison will be the change from baseline of the efficacy parameters 
between the two treatment groups.  Because subject recruitment is limited by the low 
prevalence of the disease in children, powered clinical hypotheses testing cannot be 
performed.  Sixty-six (66) subjects were chosen on the predicted recruitment rate based 
on historic data so that the study can be completed in a reasonable time frame (2 years) 

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for it to be useful and informative to the medical community.  A 10% drop out rate will 
leave 60 evaluable subjects. 
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Procedures Manual (SPM).  The SPM will provide 
the site personnel with administrative and detailed technical information on study 
conduct. 
3.2. 
Discussion of Design 
PAH is a serious and rapidly progressive disease in children.  Despite the fact that none 
of the currently available adult treatments are licensed for use in children <12 yrs, (with 
the exception of bosentan which was recently approved for use in paediatric population 
from 2 years of age) they are widely used off label.  In this context it is not considered 
appropriate to have a placebo control.  This has been confirmed by discussion with expert 
clinicians in the treatment of PAH in children.  The lack of robust data in children for the 
currently available treatments also means that there is little consistency regarding 
treatment selection.  As a result there is no international consensus on what represents 
current standard of care.  This makes a study comparing ambrisentan with ‘standard of 
care’ impractical across the number of sites required to conduct a study in children. 
Recruitment into studies in children with PAH has been difficult and slow as evidenced 
by the 4 years the sildenafil study took to recruit [ClinicalTrials.gov identifier: 
NCT00159913].  A study with this duration of recruitment may be confounded by 
changes in routine management.  This GSK study will be more tightly controlled in that it 
proposes to include patients with IPAH, PAH associated with connective tissue disease, 
and cases of sustained PAH following intracardiac repair.  PAH associated with 
congenital heart disease, which is more common, will not be included because of the 
wide variation in causation and complexity.  GSK has therefore based the size of the 
proposed study (in 8 up to 18 year-olds) on what is considered to be a feasible number of 
patients to recruit within a reasonable timeframe (18 months to 2 years).  The estimate is 
based on the number of incident cases reported by a panel of clinical PAH experts at their 
centres.  All patients will receive ambrisentan.  On this basis the estimated sample size is 
60 evaluable subjects.  It is not possible to power the study for inferential analyses of 
between-group differences. 
This is an open label study since there is no feasible method of blinding the study.  All 
subjects will be randomised to one of two dose groups of ambrisentan.  The risks and 
inconveniences associated with blinding the study as to dose outweigh any benefit of 
conducting the study in a blinded fashion.  All patients will be receiving ambrisentan and, 
although the dose group assignment could be blinded the unsuitability of the resulting 
dosage form precludes blinding.  The 2.5 mg, 5 mg, and 10 mg ambrisentan tablets differ 
in size and colour.  Over-encapsulating the tablets so that all dose strengths appear the 
same would create a dosage form that would be more difficult for the younger children to 
swallow.  Using all 2.5 mg tablets (with matching placebo) to disguise the dose would 
require every subject to take four tablets at each dose (which would be very difficult for 
the younger children) and could lead to an unacceptable risk of patients receiving the 
wrong dose (i.e., the wrong mix of active and placebo tablets). 

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However, to minimise bias, a person who is not involved in subject assessments will be 
designated at each investigation site to dispense the investigational product and to 
perform the subsequent compliance checks (i.e., pill counts).  Subjects and their parents 
or legal guardian will be asked not to comment on the treatment (e.g., no. of tablets 
taken) with the individual making the assessments.  Therefore, the individual making the 
subjects assessments would be unbiased. 
4. 
SUBJECT SELECTION AND WITHDRAWAL CRITERIA 
4.1. 
Number of Subjects 
Approximately 80 subjects will enter the study to achieve 66 randomized subjects (33 per 
treatment group).  It is anticipated that approximately 60 randomized subjects will 
complete the study and/or provide some evaluable data for the primary endpoint.   
4.2. 
Inclusion Criteria 
Subjects eligible for enrolment in the study must meet all of the following criteria: 
1. Male or female at least 8 years of age and not yet 18 years of age at the time of 
randomization. 
2. A current diagnosis of PAH (WHO Group 1) with WHO class II or III symptoms in 
one of the following categories: 
• 
Idiopathic 
• 
Heritable [familial] 
• 
Secondary to connective tissue disease (e.g., limited scleroderma, diffuse 
scleroderma, mixed connective tissue disease (CTD), systemic lupus 
erythematosus, or overlap syndrome). 
• 
Persistent PAH despite surgical repair (at least 6 months prior to the screening 
visit) of atrial septal defects, ventricular septal defects, atrio-ventricular septal 
defects, and persistent patent ductus. 
3. Have met the following hemodynamic criteria for subjects with right heart 
catheterization (RHC) when performed as part of the diagnosis or routine care (see 
Appendix 1): 
• 
mean pulmonary arterial pressure (mPAP) of ≥25 mmHg 
• 
pulmonary vascular resistance (PVR) of ≥240 dyne⋅sec/cm5 
• 
left ventricular end diastolic pressure (LEVDP) or pulmonary capillary wedge 
pressure (PCWP) of ≤15 mmHg. 

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4. Subjects must either be treatment naïve, have discontinued treatment with another 
ERA (e.g., bosentan) at least 1 month previously because of elevated liver function 
tests (LFTs), or have been on a stable dose of drug therapy for PAH (e.g., sildenafil 
or prostacyclin) for at least one month prior to the Screening Visit.  The baseline 
drug therapy for PAH, if any, should not change from the Screening Visit until the 
end of all Treatment Period assessments. 
5. Subjects who discontinued ERA treatment due to elevated LFTs, must have LFTs of 
<3 x Upper Limit of Normal (ULN). 
6. A female is eligible to participate in this study, as assessed by the investigator, if she 
is of: 
a. 
Non-childbearing potential (i.e., physiologically incapable of becoming pregnant); 
or, 
b. Child-bearing potential - has a negative pregnancy test and is not lactating at the 
Screening and Baseline/Randomisation Visits and, if sexually active, agrees to use 2 
reliable methods of contraception from the Screening Visit until study completion 
and for at least 30 days following the last dose of study drug (reliable methods of 
contraception are listed in Appendix 2). 
7. Subject or subject’s legal guardian is able and willing to give written informed 
consent.  As part of the consent, female subjects of childbearing potential will be 
informed of the risk of teratogenicity and will need to be counselled in a 
developmentally appropriate manner on the importance of pregnancy prevention; and 
male subjects will need to be informed of potential risk of testicular tubular atrophy 
and aspermia. 
Complete information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the investigational product that may impact subject 
eligibility is provided in the Investigators Brochure and product label. 
French subjects: In France, a subject will be eligible for inclusion in this study only if 
either affiliated to or a beneficiary of a social security category. 
4.3. 
Exclusion Criteria 
Subjects meeting any of the following criteria must not be enrolled in the study: 
1. Subjects currently taking an ERA. 
2. Subjects currently taking cyclosporine A. 
3. Subjects whose body weight is less than 20 Kg. 
4. Subjects who have not tolerated PAH therapy due to adverse effects which may be 
related to their mechanism of action (e.g., prostanoids, ERA, PDE-5 inhibitors) with 
the exception of liver abnormalities for those subjects who were receiving another 
ERA. 
5. Female subjects who are pregnant or breastfeeding. 

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6. Subjects with diagnosis of active hepatitis (hepatitis B surface antigen and hepatitis 
C antibody), or clinically significant hepatic enzyme elevation (i.e., ALT, AST or AP 
>3xULN) at Screening. 
7. Subjects with severe renal impairment (creatinine clearance <30 mL/min) at 
Screening. 
8. Subject has clinically significant fluid retention in the opinion of the investigator. 
9. Subject has clinically significant anaemia in the opinion of the investigator. 
10. Subject has a known hypersensitivity to the study drug, the metabolites, or 
formulation excipients. 
11. Subjects who have participated in another trial or have taken another investigational 
product during the previous 30 days. 
12. Alcohol abuse, illicit drug use within 1 year. 
13. Any concurrent condition or concurrent use of medication that would affect subject 
safety in the opinion of the investigator. 
4.4. 
Withdrawal Criteria 
Subjects who do not tolerate treatment or whose baseline drug therapy for PAH (i.e., 
PDE-5 or prostanoid) is changed will be withdrawn from the study.  Treatment for 
subjects withdrawn from the study will be implemented at the Investigator’s discretion 
and PAH guidelines. 
Subjects whose clinical condition deteriorates to the point that additional drug treatment 
is indicated (including increasing the baseline doses of targeted PAH therapy) prior to 
Week 24 will be considered as having completed the study at that point. 
The Independent Data Monitoring Committee (IDMC) may stop the study at any time if 
they consider that the potential risks outweigh the potential benefits (based on review of 
safety [adverse experiences] and exposure [plasma concentration] data after 20 subjects 
have completed Week 12 of the study and again after 40 subjects have completed 
Week 12). 
A subject may also be discontinued prior to completion of the study for the following 
reasons: 
• 
Liver chemistry values exceeding the threshold criteria (as outlined in Section 6.2.6). 
• 
Adverse event which in the opinion of the investigator requires withdrawal. 
• 
Pregnancy. 
• 
Consent withdrawn. 
• 
Lost to follow-up. 
• 
Protocol violation. 
• 
Termination of study by sponsor. 

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• 
Investigator’s discretion (document reason in eCRF). 
5. 
STUDY TREATMENTS 
5.1. 
Investigational Product and Reference Therapy 
The sponsor will provide commercially available ambrisentan 5 mg, and 10 mg tablets, as 
well as 2.5 mg tablets of equivalent quality.  For centres in Japan, one or more 2.5 mg 
tablets will be used to achieve the appropriate dose.  Subjects will be dosed orally (tablet 
must be swallowed whole) once daily for 24 weeks after randomization to either a high 
dose or a low dose group as shown below.  Within each body weight group, subjects will 
start at the lower dose for that group and then, at Week 2 those randomized to the high 
dose group will receive the higher dose. 
Body Weight 
Low Dose 
High Dose 
≥ 50 kg 
5 mg 
10 mg 
≥ 35 kg and < 50 kg 
5 mg 
7.5 mg 
≥ 20 kg and <35 kg 
2.5 mg 
5 mg 
 
The 7.5 mg dose will consist of one 2.5 mg tablet and one 5 mg tablet (three 2.5 mg 
tablets in Japan).   
The contents of the label will be in accordance with all applicable regulatory 
requirements. 
Under normal conditions of handling and administration, investigational product is not 
expected to pose significant safety risks to site staff.  A Material Safety Data Sheet 
(MSDS) describing the occupational hazards and recommended handling precautions will 
be provided to site staff if required by local laws or will otherwise be available from GSK 
upon request. 
Investigational product must be stored in a secure area under the appropriate physical 
conditions for the product.  The Investigator, the hospital pharmacist, or other personnel 
allowed to store and dispense the investigational products will be responsible for ensuring 
that the investigational product used in the study will be securely maintained as specified 
by the Sponsor and in accordance with applicable regulatory requirements. 
Study medication will be stored in secure (locked) areas at a temperature below30°C and 
dispensed according to the protocol under the supervision of the Investigator or his/her 
designee.  Investigational product must be dispensed or administered only to subjects 
enrolled in the study and in accordance with the protocol.  Subjects will be instructed to 
keep dispensed treatment in a secure place, out of reach of children, and at room 
temperature.   
Subjects will be instructed to return unused medication to the Investigator.  Any unused 
product will be returned by the Investigator to GSK or destroyed at the site based on local 
regulations. 

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5.2. 
Treatment Assignment 
All subjects who meet the inclusion and exclusion criteria will be randomized to one of 
two dose groups (Low dose or High dose, based on body weight, see Section 5.1) of 
ambrisentan according to a computer-generated randomisation schedule.  To ensure 
balance with respect to the number of patients assigned to each treatment group, the 
allocation schedule will be generated in blocks.  Each subject will be assigned to a pack 
number according to the predefined randomisation list.  A central Interactive Voice 
Response System (IVRS) will be used for treatment assignment. 
Once a randomisation number has been assigned, the patient will be considered as 
definitely included and the number will not be re-assigned.  The assigned study treatment 
should be initiated as soon as possible after randomisation.  
Randomization will be stratified by the age groups 8 years up to 11 years and 12 years up 
to 18 years and by aetiology of PAH as follows: 
• 
idiopathic; 
• 
heritable [familial]; 
• 
secondary to connective tissue disease; and  
• 
persistent despite surgical repair of atrial septal defects, ventricular septal 
defects, atrio-ventricular septal defects, and persistent patent ductus.  
Subjects will be assigned to study treatment in accordance with the randomization 
schedule. 
5.3. 
Blinding 
This is an open label study.  It is not feasible to blind the study in the classical sense; 
however, to minimise bias, a person who is not involved in subject assessments will be 
designated at each investigation site to dispense the investigational product and to 
perform the subsequent compliance checks (i.e., pill counts).  Subjects and their parents 
or legal guardian will be asked not to comment on the treatment (e.g., no. of tablets 
taken) with the individual making the assessments.  Therefore, the individual making the 
subjects assessments would be unbiased. 
After each subject has completed the study, the randomised treatment will be unblinded 
to the investigators to allow for informed dose adjustments and follow-up treatment as 
may be necessary 

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5.4. 
Product Accountability 
In accordance with local regulatory requirements, the investigator, designated site staff, 
or head of the medical institution (where applicable) must document the amount of GSK 
investigational product dispensed and/or administered to study subjects, the amount 
returned by study subjects, and the amount received from and returned to GSK, when 
applicable.  Product accountability records must be maintained throughout the course of 
the study. 
5.5. 
Treatment Compliance 
Compliance will be assessed by the investigator or designee as specified in the Time and 
Events Table, (Table 1), and recorded in the eCRF.  Compliance is calculated based on 
the number of tablets dispensed and the number of tablets returned, and the days between 
the date dispensed and the date returned.  Compliance should be assessed for each child 
resistant blister pack to ensure an accurate assessment.  The range of compliance at the 
appropriate visits will be recorded on the eCRF. 
5.6. 
Concomitant Medications and Non-Drug Therapies 
5.6.1. 
Permitted Medications and Non-Drug Therapies 
Standard medical treatment(s) being taken by the subject upon study entry may be 
maintained throughout the study. 
Subjects taking PAH specific medications (i.e., prostanoids [treprostinil, epoprostinol, 
iloprost ], vasodilators [e.g., Angiotensin-converting enzymes [ACE] inhibitors, Calcium 
Channel blockers, nitric oxide] or Cyclic guanosine monophosphate (cGMP) inhibitors –
specific phosphodiesterase type 5 [PDE-5; e.g., slidenafil, tadalafil]) have to have stable 
PAH therapy for 1 month before screening and the therapy has to be maintained 
throughout the study treatment period. 
If a subjects targeted PAH background therapy (i.e., PDE-5 or prostanoid) is changed or 
discontinued due to tolerability issues, the subject should be withdrawn from the study. 
Subjects may begin oral contraceptive therapy as per the prescribing information. 
5.6.2. 
Prohibited Medications and Non-Drug Therapies 
During the study, patients may not receive: 
• 
Endothelin receptor antagonists other than ambrisentan (e.g., bosentan, sitaxentan). 
• 
Cyclosporine A. 

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5.7. 
Treatment after the End of the Study 
Patients who participate in the study and in whom continued treatment with ambrisentan 
is desired will be eligible to enrol into a long term follow-up study. 
5.8. 
Treatment of Investigational Product Overdose 
There is no experience in PAH patients of ambrisentan at daily doses greater than 10 mg.  
In healthy volunteers, single doses of 50 mg and 100 mg (5 to 10 times the maximum 
recommended dose) were associated with headache, flushing, dizziness, nausea, and 
nasal congestion. 
Due to the mechanism of action, an overdose of ambrisentan could potentially result in 
hypotension.  In case of pronounced hypotension, active cardiac support may be required.  
No specific antidote is available. 
6. 
STUDY ASSESSMENTS AND PROCEDURES 
The following measurements and evaluations will be conducted during the trial.  Please 
refer to the Time and Events Table (Table 1) for additional details on the timing of the 
assessments.  Every effort must be made to adhere to the protocol defined visit schedule.  
The data collection tool for this study will be GSK defined eCRFs.  In all cases, subject 
initials will not be collected nor transmitted to GSK.  Subject data necessary for analysis 
and reporting will be entered/transmitted into a validated database or data system.  
Clinical data management will be performed in accordance with applicable GSK 
standards and data cleaning procedures.   

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Table 1 
Time and Events Table 
Procedure 
Screening/ 
Baseline1 
Treatment 
Early 
Withdrawal 
End of 
Therapy 
Follow-
up2 
 
Max. 2 Wks  
Wk 2 
±2 days 
Wk 4 
±7 days 
Wk 8 
±7 days 
Wk 12 
±7 days 
Wk 16 
±7 days 
Wk 20 
±7 days 
 
Week 
24 
 
Written informed consent and assent 
X 
 
 
 
 
 
 
 
 
 
Subject Demography 
X 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
Disease History 
X 
 
 
 
 
 
 
 
 
 
Therapy History 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serious Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Chemistry3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Haematology4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
X 
 
 
 
X 
 
 
X 
X 
X 
Vital Signs5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
 
 
 
X 
 
 
X 
X 
X 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
6 Minute Walk Distance6 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
WHO Functional Class 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Health Outcome Assessments7  
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Echocardiogram 
X 
 
 
 
X 
 
 
X 
X 
X 
Plasma NT-Pro BNP concentration 
X 
 
 
 
X 
 
 
X 
X 
 
Plasma Sample for Population 
Pharmacokinetic assessment8 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Hemodynamic assessment9 
X 
 
 
 
 
 
 
X 
X 
 
PGx Sampling 
 
 
X 
 
 
 
 
 
 
 
Pregnancy Test10 
U 
 
U 
U 
U 
U 
U 
U 
U 
U 
Pubertal Development Assessment11 
X 
 
 
 
X 
 
 
X 
X 
 
HBsAg and hepatitis C antibody12 
X 
 
 
 
 
 
 
 
 
 
Dispense Investigational Product13 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Assess Investigational Product 
Compliance 
 
X 
X 
X 
X 
X 
X 
X 
X 
 

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Table 1 
Time and Events Table (Continued) 
1. 2 weeks maximum between screening and baseline (randomization) visit; Note: screening and baseline can be the same day if local labs available to confirm eligibility.  Central 
lab blood draw must also be done at this visit. 
2. Only for subjects who are not participating in the long term follow-up study; within 4 to 6 weeks after last dose of investigational drug 
3. Includes sodium, magnesium, potassium, calcium, glucose, chloride, bicarbonate (CO2,) phosphorus-inorganic, creatinine, total protein, albumin, ALT (SGPT), AST (SGOT), 
GGT, LDH, total bilirubin, creatine phosphokinase (CPK), blood urea nitrogen (BUN), uric acid, and alkaline phosphatase 
4. Includes platelet count, RBC count, reticulocyte count, hematocrit, hemoglobin, RBC indices (mean corpuscular volume [MCV], mean corpuscular haemoglobin [MCH], and mean 
corpuscular haemoglobin concentration [MCHC]), WBC count, automated WBC differential (neutrophils-total, lymphocytes, monocytes, eosinophils, basophils) 
5. Includes height, weight, supine blood pressure, and heart rate 
6. Subjects with a 20% decrease in 6MWD will need to return in 1 week to repeat the test, to confirm PAH deterioration. 
7. SF 10 and a record of school days scheduled and missed.  Two diary cards will be given to the subject at Baseline, and one diary card will be given to the subject at Weeks 4, 8, 
12, 16, 20 and 24 on which to record the number of school days scheduled, the number missed for any reason, and the number missed because of symptoms of PAH.  One 
baseline diary card will be completed and returned during the visit.  The other baseline diary card should be returned at the Week 4 visit.  All other diary cards will be returned at 
the next visit.  Data from all diary cards will be transcribed into the eCRF. 
8. One plasma sample per visit. A diary card will be given to the subject at Baseline to record date and time of study medication dosing 2 days prior to and 1 day prior to the Week 4 
visit and at Weeks 4, 8, 12, and 20 to record date and time of study medication dosing 2 days prior to and 1 day prior to the next visit.  At Week 16, a diary card will be given to the 
subject to record the date and time of study medication dosing 2 days prior to, 1 day prior to and on the day of the Week 20 visit.  The diary card given out at Baseline should be 
returned at the Week 4 visit.  All other diary cards will be returned at the next visit.  The dates and times of study medication dosing will be transcribed into the eCRF.  Subjects will 
have the option to receive a reminder SMS message on the days they should complete the diary card and to remind them of their next visit date. 
9. Sub-study - Heart rate, mean blood pressure (systolic, diastolic), mean pulmonary artery (PA) pressure (systolic, diastolic), mean right atrium (RA) pressure, left ventricular end 
diastolic pressure (LEVDP) or pulmonary capillary wedge pressure (PCWP), cardiac output, cardiac index (calculated value), arterial oxygen saturation and mixed venous oxygen 
saturation.  Record method used to calculate cardiac output measurement (if Fick’s principle was used it must be stated if oxygen consumptions is measured or assumed).  
10. Monthly pregnancy test for females of childbearing potential for the duration of the study:  U = urine. 
11. Pubertal development in male and female subjects will be assessed using Tanner criteria.  In male subjects, testicular volume will be assessed using Prader’s orchidometer, and 
blood samples will be obtained to measure follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, sex hormone binding globulin (SHBG) and inhibin B levels.  
In female subjects, blood samples will be obtained to measure FSH, LH, oestrogen, SHBG and inhibin B levels. 
12. Hepatitis B surface antigen and hepatitis C antibody (if hepatitis C antibody positive, a hepatitis C RIBA immunoblot assay should be reflexively performed on the same sample to 
confirm the result). 
13. Within each body weight group, subjects will start at the lower dose for that group and then, at Week 2 those randomized to the high dose group will receive the higher dose. 
 

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6.1. 
Critical Baseline Assessments 
Review historical diagnostic tests, such as Right Heart Catheter (RHC); chest X-ray; 
echocardiogram; ventilation/perfusion scan, computed axial tomography (CT) or spiral 
CT, and pulmonary arteriogram (if applicable), to ensure that none of the exclusion 
criteria for PAH aetiology are met. 
Historic hemodynamic data (e.g., mPAP, RAP, PVR, and cardiac index) based on the 
most recent RHC prior to starting this study will be collected. 
Therapy history including PAH treatment and ERA discontinued due to elevated LFTs. 
6.2. 
Safety 
6.2.1. 
Physical examination 
Physical examination at Baseline and Weeks 12 and 24 (including height, weight, body 
mass index [BMI] / body surface area [BSA], oxygen saturation, jugular venous pressure, 
liver size, and presence of peripheral oedema and/or ascites) and pubertal development 
(see Section 6.2.4).   
Note: BMI and BSA to be calculated centrally using height and weight collected in the 
eCRF. 
6.2.2. 
Electrocardiogram / Echocardiogram 
A 12-lead ECG will be performed at Baseline and at Weeks 12 and 24 (or early 
withdrawal), and Follow-up.  Any changes since Baseline felt to be significant in the 
medical and scientific judgement of the investigator are to be recorded as AEs or SAEs in 
the eCRF. 
An echocardiogram will be performed at Baseline and at Weeks 12 and 24 (or early 
withdrawal), and Follow-up (if applicable).  An echocardiogram (the results of which are 
considered exploratory in this study) will also be performed if there is PAH deterioration 
or if there is a change in PAH therapy. 
6.2.3. 
Vital Signs, Body Weight and Height 
Vital signs (including heart rate and supine blood pressure), height, and weight will be 
collected at each clinic visit. 
All measures of blood pressure will be performed using standard sphygmomanometry.  If 
possible, the same sphygmomanometer and arm should be used.  Procedural details are 
provided in the study procedures manual. 

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6.2.4. 
Pubertal Development Assessment 
Pubertal development in male and female subjects will be assessed at baseline, Week 12, 
and Week 24 or early termination using Tanner criteria [Marshall, 1969; Marshall, 1970; 
Cameron, 2004].  In male subjects, testicular volume will be assessed by Prader’s 
orchidometer.  These assessments will be performed by a paediatric endocrinologist or 
another individual with comparable experience employing the Tanner criteria and 
Prader’s orchidometer.  Preferably, the same assessor will evaluate an individual subject 
at each assessment time. 
In addition, follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone 
(in male subjects only), oestrogen (in female subjects only), sex hormone binding 
globulin (SHBG), and inhibin B levels will be assessed at baseline, Week 12, and Week 
24 or early withdrawal.  
6.2.5. 
Clinical Laboratory Tests 
Central labs (Quest Diagnostics) will be used for all laboratory assessments.  However, 
results from local labs can be used if more readily available to confirm eligibility criteria 
at the Screening visit. 
6.2.5.1. Safety Tests 
The following tests are required at each clinic visits (including early withdrawal or end of 
therapy visits, and Follow-up visit [if applicable]). 
• 
Chemistry:  serum alanine aminotransferase (ALT/SGPT), aspartate 
aminotransferase (AST/SGOT), alkaline phosphatase, gamma glutamyl transferase 
(GGT), lactate dehydrogenase (LDH), creatine phosphokinase (CPK), total bilirubin, 
creatinine, sodium, magnesium, potassium, chloride, bicarbonate (CO2), 
phosphorus-inorganic, calcium, blood urea nitrogen (BUN), uric acid, glucose, total 
protein, and albumin. 
• 
Haematology:  haemoglobin, hematocrit, red cell count, red cell indices (mean 
corpuscular volume [MCV], mean corpuscular haemoglobin [MCH], and mean 
corpuscular haemoglobin concentration [MCHC]), white blood cell count (total and 
differential), reticulocyte count, and platelet count. 
• 
Pregnancy:  Urine pregnancy test at screening/baseline and end of treatment or early 
withdrawal visit and monthly urine pregnancy test for female subjects of child 
bearing potential. 
6.2.5.2. Pharmacogenetics and NT-Pro BNP 
• 
Blood samples for NT-Pro BNP concentration will be collected at 
screening/baseline, Week 12, early withdrawal or Week 24 (end of therapy) visits, 
and Follow-up visit (if applicable).  Assays for plasma concentrations will be 
performed in the central laboratory. 

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• 
The first PK sample (at Week 4) will also be used for pharmacogenetics. 
Collection, processing, labelling, and shipping of the NT-pro BNP and pharmacogenetic 
samples to central laboratory are detailed in the SPM. 
6.2.6. 
Liver chemistry stopping and followup criteria 
Phase II liver chemistry stopping and follow up criteria have been designed to assure 
subject safety and evaluate liver event aetiology. 
Phase II liver chemistry stopping criteria 1-5 are defined below: 
1. ALT ≥ 3xULN and bilirubin ≥ 2xULN (>35% direct bilirubin) (or ALT ≥ 3xULN 
and International Normalized Ratio [INR]>1.5, if INR measured). 
NOTE: if serum bilirubin fractionation is not immediately available, study drug should be 
discontinued if ALT ≥ 3xULN and bilirubin ≥ 2xULN. Serum bilirubin fractionation 
should be performed if testing is available. If testing is unavailable, record presence of 
detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations and 
suggesting liver injury. 
2. ALT ≥ 5xULN. 
3. ALT ≥ 3xULN if associated with the appearance or worsening of symptoms of 
hepatitis or hypersensitivity such as fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash or eosinophilia. 
4. ALT ≥ 3xULN persists for ≥4 weeks 
5. ALT ≥ 3xULN and cannot be monitored weekly for 4 weeks. 
When any of the liver chemistry stopping criteria 1-5 is met, do the following: 
• 
Immediately withdraw investigational product  
• 
Report the event to GSK within 24 hours of learning its occurrence 
• 
Complete the liver event CRF and SAE data collection tool if the event also meets 
the criteria for an SAE. All events of ALT ≥ 3xULN and bilirubin ≥ 2xULN (>35% 
direct bilirubin) (or ALT ≥ 3xULN and INR>1.5, if INR measured; INR 
measurement is not required and the threshold value stated will not apply to patients 
receiving anticoagulants), termed ‘Hy’s Law’, must be reported as an SAE 
(excluding studies of hepatic impairment or cirrhosis). 
NOTE: if serum bilirubin fractionation is not immediately available, study drug should be 
discontinued if ALT ≥ 3xULN and bilirubin ≥ 2xULN. Serum bilirubin fractionation 
should be performed if testing is available. If testing is unavailable, record presence of 
detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations and 
suggesting liver injury. 
• 
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• 
Perform liver event follow up assessments, and monitor the subject until liver 
chemistries resolve, stabilize, or return to baseline values as described below.  
• 
Withdraw the subject from the study (unless further safety follow up is required) 
after completion of the liver chemistry monitoring as described below. 
• 
Do not re-challenge with investigational product. 
In addition, for criterion 1:  
• 
Make every reasonable attempt to have subjects return to clinic within 24 hours for 
repeat liver chemistries, liver event follow up assessments (see below), and close 
monitoring 
• 
A specialist or hepatology consultation is recommended. 
• 
Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) resolve, stabilize or return to within baseline values. 
For criteria 2, 3, 4, and 5: 
• 
Make every reasonable attempt to have subjects return to clinic within 24-72 hrs for 
repeat liver chemistries and liver event follow up assessments (see below) 
• 
Monitor subjects weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilize or return to within baseline values; criterion 5 subjects 
should be monitored as frequently as possible. 
Subjects with ALT ≥3xULN but <5xULN and bilirubin <2xULN, without hepatitis 
symptoms or rash, and who can be monitored weekly for 4 weeks 
• 
Notify the GSK medical monitor within 24 hours of learning of the abnormality to 
discuss subject safety.  
• 
Can continue investigational product [this can be deleted for single-dose studies] 
• 
Must return weekly for repeat liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilize or return to within baseline  
• 
If at any time these subjects meet the liver chemistry stopping criteria, proceed as 
described above 
• 
If, after 4 weeks of monitoring, ALT <3xULN and bilirubin <2xULN, monitor 
subjects twice monthly until liver chemistries normalize or return to within baseline 
values.  
For criteria 1-5, make every attempt to carry out the liver event follow up assessments 
described below: 
• 
Viral hepatitis serology including: 
• 
Hepatitis A IgM antibody; 
• 
Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM);  

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• 
Hepatitis C RNA;  
• 
Cytomegalovirus IgM antibody;   
• 
Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);   
• 
Hepatitis E IgM antibody (if subject resides outside the US or Canada, or has 
travelled outside US or Canada in past 3 months); 
• 
Blood sample for pharmacokinetic (PK) analysis, obtained within 24 hours of last 
dose.  Record the date/time of the PK blood sample draw and the date/time of the last 
dose of investigational product prior to blood sample draw on the eCRF.  If the date 
or time of the last dose is unclear, provide the subject’s best approximation.  If the 
date/time of the last dose cannot be approximated OR a PK sample cannot be 
collected in the time period indicated above, do not obtain a PK sample.  Instructions 
for sample handling and shipping are in the SPM.  
• 
Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH). 
• 
Fractionate bilirubin, if total bilirubin≥2xULN. 
• 
Obtain complete blood count with differential to assess eosinophilia. 
• 
Record the appearance or worsening of clinical symptoms of hepatitis, or 
hypersensitivity, such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever rash or eosinophilia as relevant on the AE report form. 
• 
Record use of concomitant medications, acetaminophen, herbal remedies, other over 
the counter medications, or putative hepatotoxins, on the concomitant medications 
report form. 
• 
Record alcohol use on the liver event alcohol intake case report form 
The following are required for subjects with ALT ≥3xULN and bilirubin ≥2xULN (>35% 
direct) but are optional for other abnormal liver chemistries: 
• 
Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney 
microsomal antibodies. 
• 
Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to 
evaluate liver disease. 
6.2.7. 
Adverse Events 
The investigator or site staff will be responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE. 
6.2.7.1. 
Definition of an AE 
Any untoward medical occurrence in a patient or clinical investigation subject, 
temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product. 

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Note:  An AE can therefore be any unfavourable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.  For marketed medicinal products, this 
also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse. 
Events meeting the definition of an AE include: 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition 
• 
New conditions detected or diagnosed after investigational product administration 
even though it may have been present prior to the start of the study 
• 
Signs, symptoms, or the clinical sequelae of a suspected interaction 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either 
investigational product or a concomitant medication (overdose per se will not be 
reported as an AE/SAE). 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE.  However, the signs and symptoms and/or clinical sequelae 
resulting from lack of efficacy will be reported if they fulfil the definition of an AE or 
SAE.   
Events that do not meet the definition of an AE include: 
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that 
leads to the procedure is an AE 
• 
Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital) 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 
condition. 
6.2.7.2. 
Definition of a SAE 
A serious adverse event is any untoward medical occurrence that, at any dose: 
a. 
Results in death 
b. Is life-threatening 
NOTE:  The term 'life-threatening' in the definition of 'serious' refers to an event in 
which the subject was at risk of death at the time of the event.  It does not refer to an 
event, which hypothetically might have caused death, if it were more severe. 

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c. 
Requires hospitalization or prolongation of existing hospitalization 
NOTE:  In general, hospitalization signifies that the subject has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting.  Complications that occur during hospitalization are 
AEs.  If a complication prolongs hospitalization or fulfils any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
d. Results in disability/incapacity, or 
NOTE:  The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions.  This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhoea, influenza, and accidental trauma (e.g. sprained ankle) which 
may interfere or prevent everyday life functions but do not constitute a substantial 
disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Medical or scientific judgement should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition.  These should also be considered 
serious.  Examples of such events are invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse. 
g. All events of possible drug-induced liver injury with hyperbilirubinaemia defined as 
ALT ≥ 3xULN and bilirubin ≥ 2xULN (>35% direct) (or ALT ≥ 3xULN and 
INR>1.5, if INR measured) termed ‘Hy’s Law’ events (INR measurement is not 
required and the threshold value stated will not apply to patients receiving 
anticoagulants). 
NOTE: bilirubin fractionation is performed if testing is available. If testing is 
unavailable, record the presence of detectable urinary bilirubin on dipstick indicating 
direct bilirubin elevations and suggesting liver injury. If testing is unavailable and a 
subject meets the criterion of total bilirubin ≥ 2xULN, then the event is still reported 
as an SAE. If INR is obtained, include values on the SAE form. INR elevations >1.5 
suggest severe liver injury. 

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6.2.8. 
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs 
Any abnormal laboratory test results (haematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECGs, radiological scans, vital signs measurements), 
including those that worsen from baseline, and felt to be clinically significant in the 
medical and scientific judgement of the investigator are to be recorded as AEs or SAEs. 
However, any clinically significant safety assessments that are associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the subject’s condition, are not to be reported as AEs or SAEs. 
6.2.9. 
Pregnancy 
Subjects who become pregnant during the study must discontinue study drug 
immediately.  The Investigator should counsel the subject regarding the possible effects 
of prior study drug exposure on the foetus (See SmPC and USPI) and the need to inform 
the study site of the outcome of the pregnancy.  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. 
Any pregnancy that occurs during study participation must be reported using a clinical 
trial pregnancy form.  To ensure subject safety, each pregnancy must be reported to GSK 
within 2 weeks of learning of its occurrence.  The pregnancy must be followed up to 
determine outcome (including premature termination) and status of mother and child.  
Pregnancy complications and elective terminations for medical reasons must be reported 
as an AE or SAE.  Spontaneous abortions must be reported as an SAE. 
Any SAE occurring in association with a pregnancy brought to the investigator’s 
attention after the subject has completed the study and considered by the investigator as 
possibly related to the investigational product, must be promptly reported to GSK. 
6.2.10. 
Time Period and Frequency of Detecting AEs and SAEs 
The investigator or site staff is responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE. 
AEs will be collected from the start of investigational product and until 30 days after the 
last dose of investigational product.  
SAEs will be collected over the same time period as stated above for AEs.  However, any 
SAEs assessed as related to study participation (e.g., investigational product, protocol-
mandated procedures, invasive tests, or change in existing therapy) or related to a GSK 
concomitant medication, will be recorded from the time a subject consents to participate 
in the study up to and including any follow up contact. All SAEs will be reported to GSK 
within 24 hours, as indicated in Section 6.2.11.  

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6.2.11. 
Prompt Reporting of Serious Adverse Events and Other Events 
to GSK 
SAEs, pregnancies, and liver function abnormalities meeting pre-defined criteria will be 
reported promptly by the investigator to GSK as described in the following table once the 
investigator determines that the event meets the protocol definition for that event. 
 
Initial Reports 
Follow-up Information on a 
Previous Report 
Type of Event 
Time Frame 
Documents 
Time Frame 
Documents 
All SAEs 
24 hours 
“SAE” data 
collection tool 
24 hours 
Updated “SAE” 
data collection tool
Pregnancy 
2 Weeks 
Pregnancy 
Notification Form 
2 Weeks 
Pregnancy Follow 
up Form 
Liver chemistry 
abnormalities Phase 
II: 
 
 
 
 
ALT≥3xULN and 
Bilirubin≥2xULN 
(>35% direct) (or 
ALT≥3xULN and 
INR>1.5, if INR 
measured)*** 
24 hours* 
SAE data 
collection tool. 
**Liver Event 
Case Report Form 
(CRF) and liver 
imaging and/or 
biopsy CRFs if 
applicable  
24 hours 
Updated SAE data
collection tool. 
**Updated Liver 
Event CRF 
ALT≥5xULN; 
ALT≥3xULN with 
hepatitis or rash or 
3xULN ≥4 weeks 
24 hours* 
**Liver Event CRF 
24 hours 
**Updated Liver 
Event CRF 
ALT≥3xULN and 
<5xULN and biliribin 
<2xULN 
24 hours* 
**Liver Event CRF 
does not need 
completing unless 
elevations persist  
for 4 weeks or 
subject cannot be 
monitored weekly 
for 4 weeks 
 
 
*GSK to be notified at onset of liver chemistry elevations to discuss subject safety. 
** Liver event documents should be completed as soon as possible. 
*** INR measurement is not required; if measured, the threshold value stated will not apply to patients receiving 
anticoagulants. 
 
The method of detecting, recording, evaluating and follow-up of AEs and SAEs plus 
procedures for completing and transmitting SAE reports to GSK are provided in the 
SPM.  Procedures for post-study AEs/SAEs are provided in the SPM. 

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Procedures for documenting, transmitting and follow-up of medical device incidents 
along with the regulatory reporting requirements for medical devices are provided in the 
SPM. 
6.2.11.1. 
Regulatory reporting requirements for SAEs 
Prompt notification of SAEs by the investigator to GSK is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects are met. 
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators. 
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary. 
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements. 
6.3. 
Pharmacokinetics 
Blood samples for pharmacokinetic analysis of ambrisentan will be collected at the time 
points indicated in Table 2.  The actual date and time of each blood sample collection 
will be recorded in the GSK-defined eCRF.  The exact time of dosing on the day of the 
visit, 1 day prior to the visit and 2 days prior to the visit will be recorded in the eCRF by 
having the subject return a patient diary card on which this information is recorded. 
Table 2 
Pharmacokinetic Sampling 
 
Treatment 
Sample Collection Timepoint1 
Week 4 
Week 8 
Week 12 
Week 16 
Week 20 
Week 24 
Pre-dose 
 (Trough concentration) 
X2 
 
X2 
 
 
X2 
0.5-4 hours after dose  
(Absorption phase) 
 
X 
 
X 
 
 
4-22 hours after dose 
(Elimination phase) 
 
 
 
 
X 
 
1. If the subject is withdrawn early, a blood sample for PK should be collected prior to discharge, if possible. 
2. Subjects should be reminded to not take their study medication until after the PK sample is drawn. 
 
Plasma analysis will be performed under the management of Worldwide Bioanalysis, 
DMPK, GSK.  Plasma samples will be analyzed for ambrisentan only.  The main 
circulating metabolite of ambrisentan, 4-hydroxymethyl ambrisentan, represents 
approximately 4% of parent AUC in plasma and the binding affinity of this metabolite is 
approximately 64-fold less than ambrisentan.  Therefore, at concentrations observed in 

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the plasma, 4-hydroxymethyl ambrisentan is not expected to contribute to 
pharmacological activity of ambrisentan. 
Details of PK blood sample collection (including volume to be collected), processing, 
storage, and shipping procedures are provided in the Study Procedures Manual (SPM). 
6.4. 
Efficacy 
6.4.1. 
Change from baseline in the 6 minute walking distance (6MWD) 
test. 
The 6MWD will be assessed at Baseline, Weeks 4, 8, 12, 16, 20, and Week 24 or early 
withdrawal, and Follow –up (at Follow-up only for subjects who are not participating in 
the long term follow-up study).  Subjects with a 20% decrease in 6MWD will need to 
return in 1 week to repeat the test, to confirm PAH deterioration. 
6.4.2. 
Time to worsening of PAH 
Time to clinical worsening of PAH is defined as the time from randomization to the first 
occurrence of: 
• 
Death (all cause) or placed on active list for lung transplant; 
• 
Hospitalisation due to PAH deterioration; 
• 
Addition or increased dose of other targeted PAH therapeutic agents (prostanoids, 
PDE-5 inhibitors) and/or atrial septostomy; 
• 
PAH related deterioration identified by: 
• 
increase in WHO functional class;  
• 
deterioration in exercise testing (i.e., 20% decrease in 6MWD on two 
consecutive tests - 1 week apart); 
• 
clinical signs or symptoms of right sided heart failure (i.e., new peripheral 
edema, increase in liver size, ascites, increase in jugular venous pressure, 
pericardial effusion, increased dyspnea).  
6.4.3. 
Change from baseline (Week 0) in Subject Global Assessment to 
Week 24. 
Global assessments will be performed at baseline and Week 24 or early withdrawal, and 
Follow–up (if appropriate). 
6.4.4. 
Change from baseline in WHO functional class to Week 24. 
WHO functional class will be determined at baseline and Weeks 4, 8, 12, 16, 20, and 
Week 24 or early withdrawal, and Follow –up (if appropriate). 

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6.4.5. 
Change from baseline plasma N-terminal pro-B type natriuretic 
peptide (NT-Pro BNP) at Week 24 
Blood samples for determination of N-Terminal pro-B-type Natriuretic Peptide plasma 
concentrations will be determined at baseline, Week 12 and Week 24 or early 
withdrawal.  A central lab (Quest Diagnostics) will analyze all samples. 
6.4.6. 
Change from baseline in major prognostic factors to Week 24. 
Echocardiograms will be performed at baseline and Weeks 12 and 24 or early 
withdrawal.  Prognostic factors included pericardial effusion, RA pressure, tricuspid 
annular plane systolic excursion (TAPSE), eccentricity index (systolic and diastolic), and 
right ventricular (RV) pressure by tricuspid regurgitant jet (TRJ) velocity.  These 
evaluations were considered exploratory in this study.  
6.4.7. 
Change from baseline in cardiopulmonary hemodynamics at 
Week 24 
Cardiopulmonary hemodynamic assessments will be performed at baseline and Week 24 
or early withdrawal in a subgroup of subjects enrolled in centres where the collection of 
hemodynamic data is considered part of the standard of care (see Appendix 1). 
6.5. 
Health Outcomes 
Patient global assessments will be performed at Baseline, Weeks 4, 8, 12, 16, 20, and 
Week 24 or early withdrawal, and Follow-up (if appropriate).  Health outcomes will be 
recorded using the parent-completed Short Form 10 (SF10) Health Survey for children. 
The short-form 10 (SF-10) Health Survey for Children is a 10-item, 4-week recall, 
parent-completed health assessment that measures physical and psychosocial functioning 
for children ages five and over.  Specific domains include Physical Functioning (2 items), 
Role/Social Emotional-Behavioral (1 item), Role/Social Physical (1 item), Bodily Pain (1 
item), General Behavior (1 item), Mental Health (1 item), Self Esteem (2 items), and 
General Health Perceptions (1 item).  This instrument provides a brief, reliable, and 
scientifically valid health status measurement that is easy to administer and interpret. 
In addition to the SF10, specific questions will be asked regarding school days as 
follows: 
1. 
Within the past month, how many days of school were scheduled? (at Baseline 
only) 
 
or 
 
Since your baseline visit, how many days of school were scheduled? (at Week 4 
only) 
 
or 

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Since your last clinic visit, how many days of school were scheduled? (all other 
assessment times) 
2. 
How many scheduled days of school were missed for any reason? 
3. 
Of these, how many days were missed because of symptoms of pulmonary arterial 
hypertension (PAH)? 
Subjects will record the days of school scheduled and missed on a patient diary card, 
which will be returned to the clinic at the scheduled visits. 
6.6. 
Pharmacogenetics 
Information regarding pharmacogenetic research is included in Appendix 3.  The 
IEC/IRB and, where required, the applicable regulatory agency must approve the PGx 
assessments before these can be conducted at the site.  The approval(s) must be in writing 
and will clearly specify approval of the PGx assessments (i.e., approval of X).  In some 
cases, approval of the PGx assessments can occur after approval is obtained for the rest of 
the study.  If so, then the written approval will clearly indicate approval of the PGx 
assessments is being deferred and the study, except for PGx assessments, can be initiated.  
When PGx assessments will not be approved, then the approval for the rest of the study 
will clearly indicate this and therefore, PGx assessments will not be conducted. 
7. 
DATA MANAGEMENT 
For this study, subject data will be entered into GSK defined electronic case report forms 
(eCRFs), transmitted electronically to GSK, and combined with data provided from other 
sources in a validated data system.   
Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., removing 
errors and inconsistencies in the data.  Adverse events and concomitant medications 
terms will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), 
and an internal validated medication dictionary, GSKDrug.  eCRFs (including queries 
and audit trails) will be retained by GSK, and copies will be sent to the investigator to 
maintain as the investigator copy.  In all cases, subject initials will not be collected or 
transmitted to GSK according to GSK policy. 
8. 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
8.1. 
Study Objectives 
The primary objective of this study is to evaluate the safety and tolerability of 
ambrisentan in the proposed paediatric PAH population.  Secondary objectives are to 
obtain supportive efficacy data (change from baseline in efficacy parameters) on the 
paediatric use of ambrisentan in PAH.  Other objectives are to determine the ambrisentan 
population pharmacokinetics in the paediatric population. 

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8.2. 
Study Design Considerations 
8.2.1. 
Sample Size Assumptions 
Due to the low prevalence of the disease in children, sample size was based on feasibility 
rather than formal power calculations.  Recruitment of approximately 66 subjects (33 per 
treatment group with no prespecified number in each age group/aetiology stratum) is felt 
to be achievable within a reasonable period of time (~ 2 years) minimizing any impact of 
changing practice on the conduct and interpretation of the study. 
8.2.2. 
Sample Size Sensitivity 
Since the sample size is based on feasibility and no formal hypothesis testing is planned, 
no sample size sensitivity calculations were performed. 
8.2.3. 
Sample Size Re-estimation 
No sample size re-estimation is planned for this study. 
8.3. 
Data Analysis Considerations 
8.3.1. 
Analysis Populations 
The Intention-to-Treat (ITT) Population will consist of all randomized subjects who 
received at least 1 dose of study drug.  For the ITT population, subjects were considered 
as belonging to their randomized treatment group, regardless of the actual dose of 
ambrisentan received.  The ITT population will be used in all efficacy summaries. 
The Safety Population is defined as all randomized subjects who received at least 1 dose 
of study drug.  Subjects were considered as belonging to the treatment group according to 
highest dose received.  The safety population will be used in all safety summaries. 
The Pharmacokinetic Population will consist of all randomized subjects from which a PK 
blood sample is obtained. 
8.3.2. 
Analysis Data Sets 
Analysis datasets will consist of all data collected in the study and evaluated according to 
the populations described in Section 8.3.1. 
PK analysis data will contain all plasma ambrisentan concentrations with appropriate 
corresponding dosing records.  Pharmacokinetic data from this study may be enriched 
with selected adult PK data to establish a structural PK model as described in 
Section 8.3.5.2. 

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8.3.3. 
Treatment Comparisons 
8.3.3.1. 
Primary Comparisons of Interest 
The primary comparison of interest will be between Low and High dose of Ambrisentan 
in terms of safety and tolerability during the treatment period as follows: 
• 
Adverse Events. 
• 
Serious Adverse Events. 
• 
Clinical laboratory parameters. 
• 
Physical examination (Including  height, weight, body mass index / body surface 
area, oxygen saturation, jugular venous pressure, liver size, and presence of 
peripheral oedema and/or ascites.) 
• 
Vital Signs. 
• 
Pubertal development (change from baseline in endocrinology assessments at Weeks 
12 and 24). 
8.3.3.2. 
Secondary Comparisons of Interest 
Secondary comparisons of interest will be the comparison of the two treatment groups in 
respect to the following: 
Phamacokinetics: 
• 
Population pharmacokinetic assessment based on one plasma sample per subject at 
Weeks 4, 8, 12, 16, 20, and 24. 
• 
Pharmacokinetic/pharmacodynamic modelling. 
Efficacy: 
• 
The change from baseline in 6 minute walking distance (6MWD) test  after 24 weeks 
• 
Mean changes from baseline in the 6MWD test at each Weeks 4, 8, 12, 16, and 20 
• 
Time to clinical worsening of PAH 
• 
The change from baseline in Subject Global Assessment to Week 24. 
• 
The change from baseline in WHO functional class to Week 24. 
• 
Change from baseline in plasma N-Terminal pro-B-type Natriuretic Peptide 
concentration at Week 24. 

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8.3.3.3. 
Exploratory Comparisons of Interest 
• 
The change from baseline in major prognostic factors based on echocardiograms:  
pericardial effusion, RA pressure, tricuspid annular plane systolic excursion 
(TAPSE), eccentricity index (systolic and diastolic), and right ventricular (RV) 
pressure by tricuspid regurgitant jet (TRJ) velocity to Week 24. 
8.3.3.4. 
Other Comparisons of Interest 
• 
Change from baseline in cardiopulmonary hemodynamics at Week 24 (a sub-study in 
subjects enrolled at centres where the collection of hemodynamic data is considered 
part of the standard of care), see Appendix 1. 
8.3.4. 
Interim Analysis 
There is no interim analysis planned for this study. 
8.3.5. 
Key Elements of Analysis Plan 
8.3.5.1. 
Safety Analyses 
All subjects who received at least one dose of study medication will be assessed for 
clinical safety and tolerability and will be denoted as the Safety population. 
Clinical interpretation will be based upon review of displays of adverse events, laboratory 
values, vital signs, body weight, pubertal development, and concomitant medications.  
Principal considerations in this evaluation of adverse events will be time to onset and 
investigator-reported relationship of either adverse events or laboratory abnormalities to 
study medication.  . For each laboratory test, the number and percentage of subjects with 
values above the reference range will be displayed for each treatment group and overall.  
Appropriate monitoring of safety data will be conducted throughout the conduct of the 
study. 
No formal statistical analysis is planned for safety parameters.  All data will be presented 
descriptively or graphically, by treatment group (Low and High) and overall.  Where data 
are available, it will be summarised by visit. 
8.3.5.2. 
Pharmacokinetic Analyses 
The objective of the pharmacokinetic analysis is to establish a population 
pharmacokinetic model adequate to describe the time-course and variability of plasma 
ambrisentan concentrations following repeat dosing in paediatric PAH patients.  The 
specific objectives are: 
1. To define a suitable structural PK model to characterize the PK of ambrisentan in 
paediatrics following oral administration. 

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2. To estimate the population pharmacokinetic parameters (e.g., absorption rate 
constant [ka], apparent volume of distribution [V/F] and apparent clearance [CL/F] 
of ambrisentan and their associated variability and precision. 
3. To evaluate the influence of available covariates (e.g., subject demographics, 
physiological factors, patient status, ambrisentan doses and concomitant 
medications) on the population pharmacokinetic parameters and their associated 
variability. 
The paediatric PK data may be enriched with selected adult PK data to establish a 
structural PK model.  PK data will be analyzed using the nonlinear mixed effects 
modeling program (NONMEM).  During each step in the model building process, 
improvements to the model will be assessed by evaluation of the agreement between the 
observed and predicted plasma concentrations, reductions in the range of weighted 
residuals, uniformity of the distribution of the weighted residuals versus the predicted 
concentrations about the line of identity, and increases in the precision of the parameter 
estimates, as well as reduction of the terms for inter-individual variability and random 
residual variability.  Assessment of the log likelihood ratio test will also be conducted as 
a means of assessing improvement in the model. 
Population PK analysis will be the responsibility of the Department of Clinical 
Pharmacology Modeling and Simulation (CPMS), Quantitative Sciences, 
GlaxoSmithKline. 
8.3.5.3. 
Pharmacokinetic/Pharmacodynamic Analyses 
The objective of the pharmacokinetic/pharmacodynamic (PK/PD) analysis is to evaluate 
the potential relationships between ambrisentan dose/exposure versus efficacy and/or 
safety measures in the paediatric patient population. 
PK/PD data will be graphically assessed initially and maybe further analyzed with the use 
of the nonlinear mixed effects modeling program (NONMEM).  Model selection will be 
conducted using the same criteria as described above for the PK analyses. Covariates 
examined during the development of the population PK model will also be evaluated to 
assess their effects on ambrisentan PK/PD. 
Population PK/PD analysis will be the responsibility of the Department of Clinical 
Pharmacology Modeling and Simulation (CPMS), Quantitative Sciences, 
GlaxoSmithKline. 
8.3.5.4. 
Efficacy Analyses 
All subjects from the ITT population will be included in the analysis of efficacy data. 
Given the small sample size, all efficacy data will be summarized descriptively 
(including 95% CI) and graphically.  Data will be summarised by treatment group (Low 
and High) and overall.  In addition, summary analysis of the difference between the Low 
and High dose will be performed. 

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The summary analysis will include:  
• 
mean change from baseline in the 6MWD after 24 weeks of therapy; 
• 
mean changes from baseline in 6MWD for Weeks 4, 8, 12 16, and 20; 
• 
mean time to clinical worsening of PAH; 
• 
change from baseline in Subject Global Assessment to Week 24; 
• 
change from baseline in WHO functional class to Week 24; 
• 
The change from baseline in major prognostic factors: pericardial effusion, right 
atrial (RA) pressure, tricuspid annular plane systolic excursion (TAPSE), and 
eccentricity index (systolic and diastolic) to Week 24 
• 
change from baseline in cardiopulmonary hemodynamics at Week 24; and  
• 
change from baseline in plasma NT-Pro BNP concentration at Week 24. 
• 
change form baseline in endocrinology assessments in male subjects at Weeks 12 
and 24. 
Time to clinical worsening will be presented graphically by Kaplan-Meier curves.  
Results will include the estimated hazard ratio, and confidence interval.  The hazard 
ratios will express the rate of event occurrence for the high dose ambrisentan group 
relative to the low dose ambrisentan group. 
Exploratory 
• 
The change from baseline in major prognostic factors to Week 24 by 
echocardiogram:  pericardial effusion, right atrial (RA) pressure, tricuspid annular 
plane systolic excursion (TAPSE), eccentricity index (systolic and diastolic), and 
right ventricular (RV) pressure by tricuspid regurgitant jet (TRJ) velocity. 
Other 
• 
Change from baseline in cardiopulmonary hemodynamics at Week 24 (a sub-study in 
subjects enrolled at centres where the collection of hemodynamic data is considered 
part of the standard of care); see Appendix 1. 
8.3.5.5. 
Health Outcomes Analyses 
Two sets of summary scores will be calculated based on responses to each item on the 
SF-10 Health Survey for Children (see Section 6.5): 
• 
Physical Health Summary (PHS-10); and 
• 
Psychosocial Summary (PSS-10). 
The mean change from Baseline in SF10 scores will be calculated at Weeks 4, 8, 12, 16, 
20, and 24. 

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8.3.5.6. 
Pharmacogenetic Analyses 
8.3.5.7. 
Novel Biomarker(s) Analyses 
The results of these biomarker investigations will be reported separately from the main 
clinical study report.  All endpoints of interest from all comparisons will be descriptively 
and/or graphically summarised as appropriate to the data. 
8.3.5.7.1. RNA Transcriptome Analysis 
RNA transcriptome profile data will first be normalized to enable direct comparison of all 
data sets.  Uninformative data (RNA species in all samples below detectable limits or 
levels unchanged across all samples under comparison) will be removed and multivariate 
statistical analyses will be performed on the remaining data to uncover intrinsic 
differences and similarities in the levels of RNAs between the different samples, and 
groups of samples.  Statistical tools such as Principal Component Analysis, PLS-
Discriminant Analysis, and ANOVA using either standard or customized software will be 
used for the profile analysis to assist identification of patterns/profiles which may 
associate with treatment outcome or PAH and medically related conditions. 
8.3.5.7.2. RNA Expression Analysis of a Subset of RNA Species 
RNA expression profile data are first normalised to enable direct comparison of all data 
sets.  After data reduction to remove uninformative data (RNAs whose levels are below 
levels of detection for all samples, and those whose levels are unchanged across all 
samples) the remaining data will be subject to a series of multivariate statistical analyses 
to uncover intrinsic differences and similarities in the levels of RNAs between the 
different samples.  This will include application of statistical tools such as Principal 
Component Analysis, and ANOVA using standard analysis software as well as software 
packages customised for such profile analysis to assist identification of patterns/profiles 
which may associate with treatment outcome and/or PAH. 
9. 
STUDY CONDUCT CONSIDERATIONS 
9.1. 
Posting of Information on Clinicaltrials.gov 
Study information from this protocol will be posted on clinicaltrials.gov before enrolment 
of subjects begins. 
9.2. 
Regulatory and Ethical Considerations, Including the 
Informed Consent Process 
Prior to initiation of a study site, GSK will obtain approval from the appropriate 
regulatory agency to conduct the study in accordance with applicable country-specific 
regulatory requirements, including those required under a US IND. 

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The study will be conducted in accordance with all applicable regulatory requirements. 
The study will be conducted in accordance with Good Clinical Practice (GCP), all 
applicable subject privacy requirements, and the ethical principles that are outlined in the 
Declaration of Helsinki 2008, including, but not limited to: 
• 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and 
approval of study protocol and any subsequent amendments. 
• 
Subject informed consent. 
• 
Investigator reporting requirements. 
GSK will provide full details of the above procedures, either verbally, in writing, or both. 
Written informed consent must be obtained from each subject prior to participation in the 
study. 
9.3. 
Quality Control (Study Monitoring) 
In accordance with applicable regulations, GCP, and GSK procedures, GSK monitors 
will contact the site prior to the start of the study to review with the site staff the protocol, 
study requirements, and their responsibilities to satisfy regulatory, ethical, and GSK 
requirements.  When reviewing data collection procedures, the discussion will include 
identification, agreement and documentation of data items for which the CRF will serve 
as the source document. 
GSK will monitor the study to ensure that the: 
• 
Data are authentic, accurate, and complete. 
• 
Safety and rights of subjects are being protected. 
• 
Study is conducted in accordance with the currently approved protocol and any other 
study agreements, GCP, and all applicable regulatory requirements. 
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents. 
9.4. 
Quality Assurance 
To ensure compliance with GCP and all applicable regulatory requirements, GSK may 
conduct a quality assurance audit of the site records, and the regulatory agencies may 
conduct a regulatory inspection at any time during or after completion of the study. In the 
event of an audit or inspection, the investigator (and institution) must agree to grant the 
auditor(s) and inspector(s) direct access to all relevant documents and to allocate their 
time and the time of their staff to discuss any findings/relevant issues. 

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9.5. 
Study and Site Closure 
Upon completion or termination of the study, the GSK monitor will conduct site closure 
activities with the investigator or site staff (as appropriate), in accordance with applicable 
regulations, GCP, and GSK Standard Operating Procedures. 
GSK reserves the right to temporarily suspend or terminate the study at any time for 
reasons including (but not limited to) safety issues, ethical issues, or severe non-
compliance.  If GSK determines that such action is required, GSK will discuss the 
reasons for taking such action with the investigator or head of the medical institution 
(where applicable).  When feasible, GSK will provide advance notice to the investigator 
or head of the medical institution of the impending action. 
If a study is suspended or terminated for safety reasons, GSK will promptly inform all 
investigators, heads of the medical institutions (where applicable),and/or institutions 
conducting the study.  GSK will also promptly inform the relevant regulatory authorities 
of the suspension/termination along with the reasons for such action.  Where required by 
applicable regulations, the investigator or head of the medical institution must inform the 
IRB/IEC promptly and provide the reason(s) for the suspension/termination. 
9.6. 
Records Retention 
Following closure of the study, the investigator or head of the medical institution (where 
applicable) must maintain all site study records (except for those required by local 
regulations to be maintained elsewhere) in a safe and secure location.  The records must 
be easily accessible when needed (e.g., for a GSK audit or regulatory inspection) and 
must be available for review in conjunction with assessment of the facility, supporting 
systems, and relevant site staff. 
Where permitted by local laws/regulations or institutional policy, some or all of the 
records may be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution must be exercised before such action is taken.  The 
investigator must ensure that all reproductions are legible and are a true and accurate 
copy of the original.  In addition, they must meet accessibility and retrieval standards, 
including regeneration of a hard copy, if required.  The investigator must also ensure that 
an acceptable back-up of the reproductions exists and that there is an acceptable quality 
control procedure in place for creating the reproductions. 
GSK will inform the investigator of the time period for retaining the site records in order 
to comply with all applicable regulatory requirements.  The minimum retention time will 
meet the strictest standard applicable to a particular site, as dictated by local 
laws/regulations, GSK standard operating procedures, and/or institutional requirements. 
The investigator must notify GSK of any changes in the archival arrangements, including, 
but not limited to archival of records at an off-site facility or transfer of ownership of the 
records in the event that the investigator is no longer associated with the site. 

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9.7. 
Provision of Study Results to Investigators, Posting to the 
Clinical Trials Register and Publication 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location. 
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate. 
GSK will provide the investigator with the randomization codes for their site only after 
completion of the full statistical analysis. 
The results summary will be posted to the Clinical Study Register no later than 12 
months after the last subject’s last visit (LSLV) or sooner if required by legal agreement, 
local law or regulation. In addition, a manuscript will be submitted to a peer-reviewed 
journal for publication within 18 months of LSLV. When manuscript publication in a 
peer-reviewed journal is not feasible, further study information will be posted to the GSK 
Clinical Study Register to supplement the results summary.  
9.8. 
Independent Data Monitoring Committee (IDMC) 
An IDMC will be utilized in this study to ensure external objective medical and/or 
statistical review of safety and/or efficacy issues in order to protect the ethical and safety 
interests of subjects and to protect the scientific validity of the study.  The schedule of 
any planned interim analysis and the analysis plan for IDMC review is described in the 
charter, which is available upon request. 

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10. 
REFERENCES 
Badesch DB, Abman SH, Ahearn GS, Barst RJ, McCrory DC, Simonneau G, 
McLaughlin VV. Medical therapy for pulmonary arterial hypertension: ACCP evidence-
based clinical practice guidelines. Chest. 2004 Jul;126(1 Suppl):35S-62S.  
Beghetti M, Hoeper MM, Kiely DG, Carlesen J, Schwierin B, Segal ES, Humbart M. 
Safety experience with bosentan in 146 children 2-11 years with pulmonary arterial 
hypertension: results from the European post-marketing surveillance program. Pediar 
Res. 2008;64(2):200-4. 
Cameron N.  Measuring maturity.  In: Hauspie R, Cameron N, Molinari L. (eds.) 
Methods in Human Growth Research. Cambridge: Cambridge University Press 2004 
Dingemanse J, van Giersbergen P. Clinical pharmacology of bosentan, a dual endothelin 
receptor antagonist. Clin Pharmacokinet. 2004;43(15):1089-1115.  
Fraisse A, Xavier J, Schliech JM, di Flippo S, Maragnes P, Beghetti M, Gressin V, 
Voisin M, Dauphin C, Clerson, Godart F, Bonnet D. Characteristics and prospective 2-
year follow-up of children with pulmonary arterial hypertension in France. Arch 
Cardiovasc Dis (2010), doi:10.1016/j.acvd.2009.12.001; in press  
Galiè N, Manes A, Branzi A. The endothelin system in pulmonary arterial hypertension. 
Cardiovasc Res. 2004;61:227–37.  
Galiè N, Hoeper MM, Humbert M. Torbicki A, Vachiery JL, Barbera JA, Beghetti M, et. 
al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J. 
2009; 34:1219-1263.  Co-published:  Eur Heart J. 2009; 30:2493-2537. 
Giaid A, Yanagisawa M, Langleben D Michel R, Levy R, Shennib H. Expression of 
endothelin-1 in the lungs of subjects with pulmonary hypertension. N Engl J Med 
1993;328:1732–9. 
Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V, Yaici A, 
Weitzenblum E, Cordier JF, Chabot F, Dromer C, Pison C, Reynaud-Gaubert M, Haloun 
A, Laurent M, Hachulla E, Simonneau G. Pulmonary arterial hypertension in France: 
results from a national registry. Am J Respir Crit Care Med. 2006 1;173(9): 1023-30. 
Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary hypertension. N Eng J 
Med. 2004;351:1425-36. 
Krum H. New and emerging pharmacologic strategies in the management of chronic 
heart failure. Clin Cardiol 2000; 23(10): 724-730. 
Marshall WA and Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis 
Childh. 1969, 44: 291-303. 
Marshall WA and Tanner JM. Variations in pattern of pubertal changes in boys Arch Dis 
Child. 1970, 45: 13-23. 

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McLaughlin VV. Survival in subjects with pulmonary arterial hypertension treated with 
first-line bosentan. Eur J Clin Invest. 2006;36(Suppl. 3):10–15.  
Moledina S, Hislop A, Foster H, Schulze-Neick I, Haworth S. Childhood idiopathic 
pulmonary hypertension – A national cohort study. Heart 2010, in press.  
Newman JH, Fanburg BL, Archer SL, Badesch DB, Barst RJ, Garcia JGN, et al., 
Pulmonary Arterial Hypertension: Future Directions: Report of a National Heart, Lung 
and Blood Institute/Office of Rare Diseases Workshop. Circulation 2004; 109(24): 2947-
52. 
Nootens M, Kaufmann E, Rector T, Fisher C, Judd D, Francis G. Neurohormonal 
activation in subjects with right ventricular failure from pulmonary hypertension: relation 
to hemodynamic variables and endothelin levels. J Am Coll Cardiol. 1995;26:1581–5.  
Rich S and Levy PS. The effect of high doses of calcium-channel blockers on survival in 
primary pulmonary hypertension.  N Eng J Med. 1992; 327(2):76-81.  
Segal E, Valette C, Oster L, Bouley L, Edfjall C, et. al. Risk management strategies in the 
postmarketing period – Safety experience with the US and EU bosentan surveillance 
programmes. Drug Safety.2005;28(11);971-980 
Simonneau G, Galie N, Rubin LJ, Langleben D, Seeger W, Domenighetti G, et al., 
Clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2004;43(12 Suppl 
S):5S-12S.  
Sitbon O, Humbert M, Jais X, Ioos V, Hamid AM, Provencher S, et al. Long-term 
response to calcium channel blockers in idiopathic pulmonary arterial hypertension. 
Circulation. 2005;111(23):3105-11 

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11. 
APPENDICES 
11.1. 
Appendix 1: Cardiopulmonary Hemodynamic Sub-study 
Hemodynamic assessments will be performed at baseline and Week 24 or early 
withdrawal in a subgroup of subjects enrolled in centres where the collection of 
hemodynamic data is considered part of the standard of care.  A ‘diagnostic catheter’ 
must have been done within 3 months prior to randomization or re-catheterisation, and no 
change in PAH targeted medication since the most recent hemodynamic assessment. 
Hemodynamic assessments will include: 
• 
heart rate; 
• 
mean blood pressure (systolic, diastolic); 
• 
mean pulmonary arterial pressure (PA; systolic, diastolic); 
• 
mean right atrial (RA) pressure; 
• 
left ventricular end diastolic pressure (LEVDP); or 
• 
pulmonary capillary wedge pressure (PCWP); 
• 
cardiac output; 
• 
cardiac index (calculated value); 
• 
arterial and mixed venous oxygen saturation (Record method used to calculate 
cardiac output measurement, if Fick’s principle was used it must be stated if 
oxygen consumptions is measured or assumed). 

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11.2. 
Appendix 2: List of Highly Effective Methods for Avoidance 
of Pregnancy in Women of Childbearing Potential 
The following is the all inclusive list of the highly effective methods for avoiding 
pregnancy (i.e., have a failure rate of less than 1% per year).  
• Abstinence [Hatcher, 2004] 
• Combination Oral Contraceptive [Hatcher, 2004] 
• Injectable progestogen [Hatcher, 2004] 
• Implants of levonorgestrel [Hatcher, 2004] 
• Estrogenic vaginal ring [Hatcher, 2004] 
• Percutaneous contraceptive patches [Hatcher, 2004] 
• Intrauterine device (IUD) or intrauterine system (IUS) that meets the SOP 
effectiveness criteria as stated in the product label [Hatcher, 2004] 
• Male partner sterilization (vasectomy with documentation of azoospermia) prior 
to the female subject's entry into the study, and this male is the sole partner for 
that subject [Hatcher, 2004]. For this definition, “documented” refers to the 
outcome of the investigator's/designee’s medical examination of the subject or 
review of the subject's medical history for study eligibility, as obtained via a 
verbal interview with the subject or from the subject’s medical records. 
• Double barrier method: condom and an occlusive cap (diaphragm or 
cervical/vault caps) with a vaginal spermicidal agent 
(foam/gel/film/cream/suppository) [Trussell, 2003]  
Nonoxynol-9 is the critical component in most spermicides, and is regarded as an 
acceptable spermicidal agent. Concern has been raised that nonoxynol-9 damages 
the epithelial lining of the vagina, and exposure may facilitate transmission of 
viruses, particularly human immunodeficiency virus (HIV). The World Health 
Organization (WHO) conducted a technical consultation in October 2001 and 
concluded that the increased risk for such transmission was low to minimal 
[Trussell, 2003]. 
References 
Hatcher RA, Trussell J, Stewart F, Nelson AL, Cates W, Guest F, Kowal DD, editors. 
Contraceptive Technology. New York: Ardent Media, 2004: 226. Table 9-2, “% of 
Women Experiencing an Unintended Pregnancy During the First Year of Typical Use 
and the First Year of Perfect Use of Contraception and the Percentage Continuing Use at 
the End of the First Year. United States”, column entitled, “% of Women Experiencing 
an Unintended Pregnancy Within the First Year of Use. Perfect Use”. 
Trussell J. Personal communication WHO/CONRAD Technical consultation on 
nonoxynol-9. WHO, Geneva, 9-10 October 2001. Summary Report. World Health 
Organization, 2003 

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11.3. 
Appendix 3: Pharmacogenetic Research 
Pharmacogenetics – Background 
Pharmacogenetics (PGx) is the study of variability in drug response due to hereditary 
factors in different populations.  There is increasing evidence that an individual's genetic 
composition (i.e., genotype) may impact the pharmacokinetics (absorption, distribution, 
metabolism, and elimination), pharmacodynamics (relationship between concentrations 
and pharmacologic effects or the time course of pharmacologic effects) and/or clinical 
outcome (in terms of efficacy and/or safety and tolerability). Some reported examples of 
PGx analysis include: 
Drug 
Disease 
Gene 
Outcome 
Abacavir 
HIV [Hetherington, 2002; 
Mallal, 2002] 
HLA –B*5701 
Individuals with HLA-B*5701 variant 
may be at increased risk for 
experiencing hypersensitivity to 
abacavir. Clinical assays are 
available for HLA-B*5701 but none 
has been validated. HLA-B*5701 
screening would supplement but 
never replace abacavir clinical risk 
management strategies aimed at 
minimising rare but serious 
outcomes associated with abacavir 
hypersensitivity. 
Warfarin 
Cardiovascular  
[Neergard, 2006; 
Wilke, 2005] 
CYP2C9 
Serious adverse events (SAEs) 
experienced by some patients on 
warfarin may be explained by 
variations in the CYP2C9 gene that 
influences the degree of 
anticoagulation achieved.  
Irinotecan 
Cancer  
[FDA News Release, 2005] 
UGT1A1 
Variations in the UGT1A1 gene can 
influence a patient’s ability to break 
down irinotecan, which can lead to 
increased blood levels of the drug 
and a higher risk of side effects. A 
dose of irinotecan that is safe for 
one patient with a particular 
UGT1A1 gene variation, might be 
too high for another patient without 
this variation, raising the risk of 
certain side-effects.  
A genetic blood test (Invader 
UGT1A1 molecular assay) is 
available that can detect variations 
in the gene.     
 

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A key component to successful PGx research is the collection of samples during the 
conduct of clinical studies. 
Collection of whole blood samples, even when no a priori hypothesis has been identified, 
may enable PGx analysis to be conducted if at any time it appears that there is a potential 
unexpected or unexplained variation in handling or response to ambrisentan.  
Pharmacogenetic Research Objectives 
The objective of the PGx research (if there is a potential unexpected or unexplained 
variation) is to investigate a possible genetic relationship to handling or response to 
ambrisentan.  If at any time it appears there is potential variability in response in this 
clinical study or in a series of clinical studies with ambrisentan that may be attributable to 
genetic variations of subjects, the following objectives may be investigated:  
• 
Relationship between genetic variants and the pharmacokinetics and/or 
pharmacodynamics of investigational product; 
• 
Relationship between genetic variants and safety and/or tolerability of investigational 
product; and  
• 
Relationship between genetic variants and efficacy of investigational product. 
Study Population 
Any subject who has given informed consent to participate in the clinical study, has met 
all the entry criteria for the clinical study, and receives investigational product may take 
part in the PGx research.  Any subject who has received an allogeneic bone marrow 
transplant must be excluded from the PGx research. 
Subject participation in the PGx research is voluntary and refusal to participate will not 
indicate withdrawal from the clinical study.  Refusal to participate will involve no penalty 
or loss of benefits to which the subject would otherwise be entitled. 
Study Assessments and Procedures 
Blood taken for pharmacokinetics will also be used for the PGx sample.  It is 
recommended that the first PK sample (Week 4) is used to prepare the PGx sample, but 
any of the PK samples can be used.  Full details of sample preparation are provided in the 
SPM. 
The PGx sample is labelled (or “coded”) with a study specific number that can be traced 
or linked back to the subject by the investigator or site staff.  Coded samples do not carry 
personal identifiers (such as name or social security number).  The blood sample is taken 
on a single occasion unless a duplicate sample is required due to inability to utilize the 
original sample.   

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The DNA extracted from the blood sample may be subjected to sample quality control 
analysis.  This analysis will involve the genotyping of several genetic markers to confirm 
the integrity of individual samples.  If inconsistencies are noted in the analysis, then those 
samples may be destroyed. 
The need to conduct PGx analysis may be identified after a study (or a set of studies) of 
ambrisentan has been completed and the study data reviewed. 
In some cases, the samples may not be studied. e.g., no questions are raised about how 
people respond to ambrisentan. 
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study or GSK may destroy the samples sooner.  GSK or those working 
with GSK (for example, other researchers) will use samples collected from the study for 
the purpose stated in this protocol and in the informed consent form.   
Subjects can request their sample to be destroyed at any time. 
Subject Withdrawal from Study 
If a subject who has consented to participate in PGx research and has a sample taken for 
PGx research withdraws from the clinical study for any reason other than lost to follow-
up, the subject will be given the following options: 
• 
The sample is retained for PGx research 
• 
Any PGx sample is destroyed. 
If a subject withdraws consent from the PGx research or requests sample destruction for 
any reason, the investigator must complete the appropriate documentation to request 
sample destruction within the timeframe specified by GSK and maintain the 
documentation in the site study records.  If the sample has already been processed, it will 
be destroyed after all steps are complete. GSK will ensure that any data related to the 
sample will not be analysed. The sample will be destroyed after processing is complete.  
Pharmacogenetics Analyses 
Generally GSK will utilize three approaches to explore genetic variation in drug 
response. 
1. Specific sections of DNA may be selected from areas of the genome (e.g., candidate 
genes) known to encode the drug target, drug metabolizing enzymes, areas 
associated with mechanisms underlying adverse events, and those linked to study 
disease and, thus, linked to drug response.  
The candidate genes that may be investigated in this study include the following: the 
GSK Absorption, Distribution, Metabolism and Excretion genes. These play a central 
role in drug pharmacokinetics and pharmacodynamics. In addition, continuing research 
may identify other enzymes, transporters, proteins or receptors that may be involved in 
response to ambrisentan.  The genes that may code for these proteins may also be studied. 

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2. By evaluating large numbers of polymorphic markers (e.g., single nucleotide 
polymorphisms or SNPs) throughout the genome, sets of markers may be identified 
that correspond to differential drug response.  
The results of PGx investigations will be reported either as part of the main clinical study 
report or as a separate report. All endpoints of interest from all comparisons will be 
descriptively and/or graphically summarised as appropriate to the data. In all cases, 
appropriate statistical methods will be used to analyse the genetic markers in the context 
of other clinical data. Statistical methods may include, but are not limited to Hardy-
Weinberg Equilibrium testing, Comparison of Demographic and Baseline Characteristics 
by Genotype, Evaluation of Genotypic Effects, Evaluation of Treatment by Genotype and 
Gene-Gene Interaction, Linkage Disequilibrium, Multiple Comparison and Multiplicity 
and/or Power and Sample Size Considerations. Detailed description of the analyses to be 
conducted will be documented in the Pharmacogenetics Reporting and Analysis Plan.   
3. Genome-wide scans involving a large number of polymorphic markers (e.g., single 
nucleotide polymorphisms) located throughout the genome. This approach is often 
employed when potential genetic effects are not well understood. 
Informed Consent 
Subjects who do not wish to participate in the PGx research may still participate in the 
clinical study.  PGx informed consent must be obtained prior to any blood being taken for 
PGx research. 
Provision of Study Results and Confidentiality of Subject’s PGx Data 
GSK may summarize the cumulative PGx research results in the clinical study report. 
In general, GSK does not inform the investigator, subject, or anyone else (e.g., family 
members, study investigators, primary care physicians, insurers, or employers) of the 
PGx research results that are not known to be relevant to the subject’s medical care at the 
time of the study, because the information generated from PGx studies is preliminary in 
nature, and the significance and scientific validity of the results are undetermined at such 
an early stage of research, under any circumstances unless required by law. 
References 
Hetherington S, Hughes AR, Mosteller M, Shortino D, Baker KL, Spreen W, Lai E, 
Davies K, Handley A, Dow DJ, Fling ME, Stocum M, Bowman C, Thurmond LM, Roses 
AD. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. 
Lancet. 2002; 359:1121-2. 
Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, Sayer D, Castley A, Mamotte 
C, Maxwell D, James I.  Association between presence of HLA-B*5701, HLA-DR7, and 
HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir.  
Lancet. 2002; 359:727-32. 
Neergard. Reducing the risk of blood thinners. Associated press, September 2006.  

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U.S. Food and Drug Administration, FDA Clears Genetic Test That Advances 
Personalized Medicine Test Helps Determine Safety of Drug Therapy 22 August 2005, 
http://www.fda.gov/bbs/topics/NEWS/2005/NEW01220.html.    
Wilke RA, Musana AK, Weber WW. Cytochrome P450 gene-based drug prescribing, 
and factors impacting translation into routine clinical practice. Personalized Med 2005; 2: 
213-224.   

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11.4. 
Appendix 4: Country Specific Requirements 

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11.5. 
Appendix 5: Protocol Amendment 01 
Statement of Intent 
The intents of this amendment are to clarify procedural issues to insure a better global 
understanding of intent of the protocol and to open the long term extension study to those 
patients who have reached an endpoint in this study prior to week 24 but in whom 
continued treatment with ambrisentan is desirable. 
Amended Sections of the Protocol 
Deletions are noted in Italics 
Insertions are noted in bold face. 
Section 2.1.2.2 Efficacy 
Item 6 
Was: 
• 
Change from baseline in plasma brain natriuretic peptide (NT-Pro BNP) 
concentration at Week 24. 
Is: 
• 
Change from baseline in plasma N-terminal pro-B-type natriuretic peptide (NT-Pro 
BNP) concentration at Week 24. 
Section 3.1 – Study Design 
Was: 
Subjects who complete 24 weeks of treatment will be eligible to enrol into a long term 
follow-up study.   
Is: 
Subjects who participate in this study and in whom continued treatment with 
ambrisentan is desired will be eligible to enrol into a long term follow-up study.   

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Section 3.2 – Discussion of Design 
Last paragraph 
Was: 
However, to minimise bias, a person who is not involved in subject assessments will be 
designated at each investigation site to dispense the investigational product, to perform 
the subsequent compliance checks (i.e., pill counts), and to complete the InForm data 
entry.  Subjects and their parents or legal guardian will be asked not to comment on the 
treatment (e.g., no. of tablets taken) with the individual making the assessments.  
Therefore, the individual making the subjects assessments would be unbiased. 
Is: 
However, to minimise bias, a person who is not involved in subject assessments will be 
designated at each investigation site to dispense the investigational product and to 
perform the subsequent compliance checks (i.e., pill counts).  Subjects and their parents 
or legal guardian will be asked not to comment on the treatment (e.g., no. of tablets 
taken) with the individual making the assessments.  Therefore, the individual making the 
subjects assessments would be unbiased. 
Section 4.2 – Inclusion Criteria 
Item 4 
Was: 
Subjects must either be treatment naïve, have discontinued treatment with another ERA 
(e.g., bosentan) at least 1 month previously because of elevated liver function tests 
(LFTs), or have been on a stable dose of background treatment for PAH (e.g., sildenafil 
or prostacyclin) for at least one month prior to the Screening Visit.  Background 
treatment for PAH, if any, should not change from the Screening Visit until the end of all 
Treatment Period assessments. 
Is: 
Subjects must either be treatment naïve, have discontinued treatment with another ERA 
(e.g., bosentan) at least 1 month previously because of elevated liver function tests 
(LFTs), or have been on a stable dose of drug therapy for PAH (e.g., sildenafil or 
prostacyclin) for at least one month prior to the Screening Visit.  The baseline drug 
therapy for PAH, if any, should not change from the Screening Visit until the end of all 
Treatment Period assessments. 

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Rationale: 
The intent of the protocol was to ensure that subjects who were still symptomatic despite 
other PAH treatment (excluding another ERA) could enter the study, as long as the 
previous treatment was maintained throughout the study.  Some people interpreted 
“background treatment” to include only supportive therapy such as supplemental oxygen; 
therefore, the protocol is amended to make it clear that it is the baseline drug therapy 
targeted to PAH that is allowed and is not to be changed during the course of the study. 
Item 6 b 
Was: 
Child-bearing potential - has a negative pregnancy test and is not lactating at the 
Screening and Baseline/Randomisation Visits and agrees to use 2 reliable methods of 
contraception from the Screening Visit until study completion and for at least 30 days 
following the last dose of study drug (reliable methods of contraception are listed in 
Appendix 2. 
Is: 
Child-bearing potential - has a negative pregnancy test and is not lactating at the 
Screening and Baseline/Randomisation Visits and, if sexually active, agrees to use 2 
reliable methods of contraception from the Screening Visit until study completion and for 
at least 30 days following the last dose of study drug (reliable methods of contraception 
are listed in Appendix 2). 
Rationale: 
Abstinence is one of the acceptable methods of contraception listed in Appendix 2, and it 
makes no sense to require another form of contraception in subjects who are not sexually 
active. 
Section 4.4 – Withdrawal Criteria 
Was: 
Subjects who do not tolerate treatment or whose background targeted PAH therapy (i.e., 
PDE-5 or prostanoid) is changed will be withdrawn from the study.  Treatment for 
subjects withdrawn from the study will be implemented at the Investigator’s discretion 
and PAH guidelines. 
Subjects whose clinical condition deteriorates to the point that additional treatment is 
indicated prior to Week 24 will be considered as having completed the study at that point. 

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Is: 
Subjects who do not tolerate treatment or whose baseline drug therapy for PAH (i.e., 
PDE-5 or prostanoid) is changed will be withdrawn from the study.  Treatment for 
subjects withdrawn from the study will be implemented at the Investigator’s discretion 
and PAH guidelines. 
Subjects whose clinical condition deteriorates to the point that additional drug treatment 
is indicated (including increasing the baseline doses of targeted PAH therapy) prior to 
Week 24 will be considered as having completed the study at that point. 
Rationale: 
To clarify that increasing the dose from baseline of targeted PAH therapy meets the 
criteria of “additional drug treatment” and to be consistent with the amended wording in 
Section 4.2 item 4. 
Section 5.3 Blinding 
Was: 
This is an open label study.  It is not feasible to blind the study in the classical sense; 
however, to minimise bias, a person who is not involved in subject assessments will be 
designated at each investigation site to dispense the investigational product, to perform 
the subsequent compliance checks (i.e., pill counts), and to complete the InForm data 
entry.  Subjects and their parents or legal guardian will be asked not to comment on the 
treatment (e.g., no. of tablets taken) with the individual making the assessments.  
Therefore, the individual making the subjects assessments would be unbiased. 
Is: 
This is an open label study.  It is not feasible to blind the study in the classical sense; 
however, to minimise bias, a person who is not involved in subject assessments will be 
designated at each investigation site to dispense the investigational product and to 
perform the subsequent compliance checks (i.e., pill counts).  Subjects and their parents 
or legal guardian will be asked not to comment on the treatment (e.g., no. of tablets 
taken) with the individual making the assessments.  Therefore, the individual making the 
subjects assessments would be unbiased. 
After each subject has completed the study, the randomised treatment will be 
unblinded to the investigators to allow for informed dose adjustments and follow-up 
treatment as may be necessary 

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Rationale 
Since the compliance data that are entered into InForm are only categorical estimates of 
the percent compliance, there is no reason for the unblinded person to physically enter 
those data into the system.  It is important that the investigator know which dose the 
patient was receiving to manage the patient’s care properly once the patient has 
completed the study. 
Section 5.7 – Treatment after the End of the Study 
Was 
Patients who complete 24 weeks of treatment will be eligible to enrol into a long term 
follow-up study. 
Is 
Patients who participate in the study and in whom continued treatment with 
ambrisentan is desired will be eligible to enrol into a long term follow-up study. 
Rationale 
Subjects could complete the study prior to week 24 (e.g., if additional PAH treatment or 
if a dose adjustment to their baseline PAH drug therapy is necessary).  In some of these 
patients, it might be desirable to continue treatment with ambrisentan and add or change 
the dose of other targeted PAH treatment.  
Section 6.2.2 – Electrocardiogram / Echocardiogram 
Was: 
A 12-lead ECG will be performed at Baseline and at Weeks 12 and 24 (or early 
withdrawal), and Follow-up.  Any changes since the Screening Visit felt to be significant 
in the medical and scientific judgement of the investigator are to be recorded as AEs or 
SAEs in the eCRF. 
Is: 
A 12-lead ECG will be performed at Baseline and at Weeks 12 and 24 (or early 
withdrawal), and Follow-up.  Any changes since Baseline felt to be significant in the 
medical and scientific judgement of the investigator are to be recorded as AEs or SAEs in 
the eCRF. 

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Section 6.2.4 – Pubertal Development Assessment 
Was: 
Pubertal development in male and female subjects will be assessed at baseline, Week 12, 
and Week 24 or early termination by a paediatric endocrinologist using Tanner criteria 
[Cameron, 2004].  In male subjects, testicular volume will be assessed by Prader’s 
orchidometer. 
Is: 
Pubertal development in male and female subjects will be assessed at baseline, Week 12, 
and Week 24 or early termination using Tanner criteria [Marshall, 1969; 
Marshall, 1970; Cameron, 2004].  In male subjects, testicular volume will be assessed 
by Prader’s orchidometer.  These assessments will be performed by a paediatric 
endocrinologist or another individual with comparable experience employing the 
Tanner criteria and Prader’s orchidometer.  Preferably, the same assessor will 
evaluate an individual subject at each assessment time. 
Rationale: 
“Paediatric endocrinologist” is not a recognized speciality in all territories.  The intent is 
that the person performing these assessments be someone who is competent and 
experienced with using the Tanner criteria and Prader’s orchidometer.  In some centres, 
the individual who has that experience might not have the title “paediatric 
endocrinologist”. 
Section 6.3 – Pharmacokinetics 
Was 
Blood samples for pharmacokinetic analysis of ambrisentan will be collected at the time 
points indicated in Table 2.  The actual date and time of each blood sample collection 
will be recorded in the GSK-defined eCRF.  The exact time of dosing on the day of the 
visit, 1 day prior to the visit and 2 days prior to the visit will be recorded in the eCRF by 
having the subject return a medication card on which this information is recorded. 
Is 
Blood samples for pharmacokinetic analysis of ambrisentan will be collected at the time 
points indicated in Table 2.  The actual date and time of each blood sample collection 
will be recorded in the GSK-defined eCRF.  The exact time of dosing on the day of the 
visit, 1 day prior to the visit and 2 days prior to the visit will be recorded in the eCRF by 
having the subject return a patient diary card on which this information is recorded. 

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Section 6.4.5 
Heading 
Was: 
Change from baseline plasma brain natriuretic peptide (NT-Pro BNP) at Week 24 
Is: 
Change from baseline plasma N-terminal pro-B type natriuretic peptide (NT-Pro BNP) 
at Week 24 
Section 6.5 – Health Outcomes 
Was: 
In addition to the SF10, specific question will be asked regarding school days as follows: 
1. 
Within the past month, how many days of school were scheduled?  
2. 
How many days of school were missed for any reason? 
3. 
How many days of school were missed because of pulmonary arterial 
hypertension (PAH)? 
Is: 
In addition to the SF10, specific question will be asked regarding school days as follows: 
1. 
Within the past month, how many days of school were scheduled? (at Baseline 
only) 
 
or 
 
Since your baseline visit, how many days of school were scheduled? (at Week 
4 only) 
 
or 
 
Since your last clinic visit, how many days of school were scheduled? (all 
other assessment times) 
2. 
How many scheduled days of school were missed for any reason? 
3. 
Of these, how many days were missed because of symptoms of pulmonary 
arterial hypertension (PAH)? 
Subjects will record the days of school scheduled and missed on a patient diary 
card, which will be returned to the clinic at the scheduled visits. 

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Rationale: 
To clarify that the number of days missed in question 2 is inclusive of the days missed in 
question 3 and to differentiate between days missed because of clinic visits and days 
missed because of symptoms of the disease. 
Section 8.3.3.2  Secondary Comparisons of Interest 
Efficacy bullet item 6 
Was: 
• 
Change from baseline in plasma brain natriuretic peptide (BNP or N-Terminal pro-
B-type Natriuretic Peptide) concentration at Week 24. 
Is: 
• 
Change from baseline in plasma NT-Pro BNP concentration at Week 24. 
Section 8.3.5.4  Efficacy Analyses 
Item 8 
Was: 
• 
change from baseline in plasma BNP concentration at Week 24 
Is: 
• 
change from baseline in plasma NT-Pro BNP concentration at Week 24 
Table 1 – Time and Events Table 
Change “Patient Global Assessment (SF10)” to “Health Outcomes Assessments” 
Add a foot note for “Health Outcomes Assessments” as follows: “SF 10 and a record of 
school days scheduled and missed.  Two diary cards will be given to the subject at 
Baseline, and one diary card will be given to the subject at Weeks 4, 8, 12, 16, 20 and 
24 on which to record the number of school days scheduled, the number missed for 
any reason, and the number missed because of symptoms of PAH.  One baseline 
diary card will be completed and returned during the visit.  The other baseline diary 
card should be returned at the Week 4 visit.  All other diary cards will be returned 
at the next visit.  Data from all diary cards will be transcribed into the eCRF.” 
To footnote for “Plasma Sample for Population Pharmacokinetic Assessment” add “A 
diary card will be given to the subject at Baseline to record date and time of study 
medication dosing 2 days prior to and 1 day prior to the Week 4 visit and at Weeks 
4, 8, 12, and 20 to record date and time of study medication dosing 2 days prior to 
and 1 day prior to the next visit.  At Week 16, a diary card will be given to the 

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subject to record the date and time of study medication dosing 2 days prior to, 1 day 
prior to and on the day of the Week 20 visit.  The diary card given out at Baseline 
should be returned at the Week 4 visit.  All other diary cards will be returned at the 
next visit.  The dates and times of study medication dosing will be transcribed into 
the eCRF.  Subjects will have the option to receive a reminder SMS message on the 
days they should complete the diary card and to remind them of their next visit 
date.” 
Footnote for “Pubertal Development Assessment” 
Was: 
Pubertal development in male and female subjects will be assessed by a paediatric 
endocrinologist using Tanner criteria.  In male subjects, testicular volume will be 
assessed using Prader’s orchidometer.  In addition, blood samples will be obtained to 
measure follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, sex 
hormone binding globulin (SBGH) and inhibin B levels. 
Is: 
Pubertal development in male and female subjects will be using Tanner criteria.  In male 
subjects, testicular volume will be assessed using Prader’s orchidometer.  In addition, 
blood samples will be obtained to measure follicle-stimulating hormone (FSH), 
luteinizing hormone (LH), testosterone, sex hormone binding globulin (SBGH) and 
inhibin B levels. 
Rationale 
To be consistent with the text of the protocol and to clarify the use of patient diary cards. 

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11.6. 
Appendix 6: Protocol Amendment 02 
Statement of Intent 
The intents of this amendment are to clarify procedural issues to insure a better global 
understanding of intent of the protocol and to correct that it is hepatitis B surface antigen 
that is being assessed as part of the exclusion criteria. 
Amended Sections of the Protocol 
Deletions are noted in Italics 
Insertions are noted in bold face. 
Sponsor Information Page 
Was 
Sponsor Medical Monitor Contact Information: 
 
 FRCS 
Clinical Development Physician 
MDC Clinical Metabolic EU 
GlaxoSminthKline  
Stockley Park 
Sponsor Serious Adverse Events (SAE) Contact Information:  
Regulatory Agency Identifying Number(s):  EudraCT 2010-019547-19 
Is 
Sponsor Medical Monitor and Serious Adverse Events (SAE) Contact Information: 
 
 FRCS 
Clinical Development Physician 
MDC Clinical Metabolic EU 
GlaxoSminthKline  
Stockley Park 
Regulatory Agency Identifying Number(s):  EudraCT 2010-019547-19 
 
 
 
 
 
 
US IND 64,915 
Rationale 
To confirm that for the sites in the US, the study is being conducted under a US IND and 
that the Medical Monitor and SAE contact are the same person. 
PPD
PPD

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Table 1 – Time and Events Table 
Footnote 12 
Was 
12.  Hepatitis B surface antibody and hepatitis C antibody (if hepatitis C antibody 
positive, a hepatitis C RIBA immunoblot assay should be reflexively performed on the 
same sample to confirm the result). 
Is 
12.  Hepatitis B surface antigen and hepatitis C antibody (if hepatitis C antibody positive, 
a hepatitis C RIBA immunoblot assay should be reflexively performed on the same 
sample to confirm the result). 
Rationale 
Antibody was a mistake.  The intent was to assess the hepatitis B surface antigen, and the 
line item in the table to which the footnote applied correctly listed “HBsAg” 
Section 4.3  Exclusion Criteria 
Item 6 
Was 
6.  Subjects with diagnosis of active hepatitis (hepatitis B surface antibody and hepatitis 
C antibody), or clinically significant hepatic enzyme elevation (i.e., ALT, AST or AP 
>3xULN) at Screening. 
Is 
6.  Subjects with diagnosis of active hepatitis (hepatitis B surface antigen and hepatitis C 
antibody), or clinically significant hepatic enzyme elevation (i.e., ALT, AST or AP 
>3xULN) at Screening. 
Rationale 
Antibody was a mistake.  The intent was to assess the hepatitis B surface antigen, and the 
line item in the time and events table correctly listed “HBsAg”. 

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11.7. 
Appendix 7: Protocol Amendment 03 
Statement of Intent 
The intents of this amendment are to add oestrogen and remove testosterone from 
laboratory assessments being conducted on female subjects and to align the storage 
conditions requirements in the protocol with those that are printed on the study 
medication package. 
Amended Sections of the Protocol 
Deletions are noted in Italics 
Insertions are noted in bold face. 
In Section 5.1  Investigational Product and Reference Therapy 
Was: 
Study medication will be stored in secure (locked) areas at a temperature between 15° 
and 30°C and dispensed according to the protocol under the supervision of the 
Investigator or his/her designee.   
Is 
Study medication will be stored in secure (locked) areas at a temperature below 30°C and 
dispensed according to the protocol under the supervision of the Investigator or his/her 
designee.   
Table 1 – Time and Events Table 
Footnote 11 
Was 
11. 
Pubertal development in male and female subjects will be assessed using Tanner 
criteria.  In male subjects, testicular volume will be assessed using Prader’s orchidometer.  
In addition, blood samples will be obtained to measure follicle-stimulating hormone 
(FSH), luteinizing hormone (LH), testosterone, sex hormone binding globulin (SBGH) 
and inhibin B levels. 
Is 
11. 
Pubertal development in male and female subjects will be assessed using Tanner 
criteria.  In male subjects, testicular volume will be assessed using Prader’s orchidometer, 
and blood samples will be obtained to measure follicle-stimulating hormone (FSH), 
luteinizing hormone (LH), testosterone, sex hormone binding globulin (SHBG) and 

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inhibin B levels.  In female subjects, blood samples will be obtained to measure FSH, 
LH, oestrogen, SHBG and inhibin B levels. 
In Section 6.2.4  Pubertal Development Assessment 
Was: 
In addition, follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, 
sex hormone binding globulin (SHBG), and inhibin B levels will be assessed at baseline, 
Week 12, and Week 24 or early withdrawal.  
Is: 
In addition, follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone 
(in male subjects only), oestrogen (in female subjects only), sex hormone binding 
globulin (SHBG), and inhibin B levels will be assessed at baseline, Week 12, and Week 
24 or early withdrawal.