An Open-label, Long Term Extension Study for Treatment of Pulmonary Arterial Hypertension in Paediatric Patients Aged 8 Years up to 18 Years Who Have Participated in AMB112529 and in Whom Continued Treatment With Ambrisentan is Desired
Phase: PHASE2
Conditions: Hypertension, Pulmonary
Sponsor: GlaxoSmithKline

T M F -1 3 3 5 9 0 3 9  
C O N FI D E N TI A L  
 
Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s  
 
A M B 1 1 4 5 8 8  
 
1  
 
Di visi o n: W orl d w i de De vel o p me nt 
Rete nti o n C ate g or y:  G R S 0 1 9  
I nf or m ati o n T y pe: Pr ot oc ol A me n d me nt  
 
Title:  
A n o pe n -la bel, l o n g ter m e xte nsi o n st u d y f or treat me nt of 
p ul m o nar y arteri al h y p ert e nsi o n i n pae diatric patie nts a ge d 8 
years u p t o 1 8 years w h o ha ve partici p ate d i n A M B 1 1 2 5 2 9 a n d 
i n w h o m c o nti n ue d treat me nt wit h a m brise nta n is desire d 
C o m p o u n d N u m ber:  G S K 1 3 2 5 7 6 0  
Effecti ve D ate:  
2 5 -M A Y -2 0 2 1  
 
Pr ot oc ol A me n d me nt N u m ber: 0 4  
T his is a n o pe n la bel, l o n g ter m e xte nsi o n t o St u d y A M B 1 1 2 5 2 9.  All s u bjects ma y 
re mai n i n t he e xte nsi o n st u d y f or a mi ni m u m of si x m o nt hs.  Be y o n d t he si x m o nt h 
peri o d, s u bjects ma y c o nti n ue i n t he e xte nsi o n st u d y u ntil o ne of t he f oll o wi n g c o n diti o ns 
is met: 
•  
t he s u bject t ur ns 1 8 years of a ge ( w he n t he s u bject ca n recei ve m ar kete d pr o d uct) or  
t he s u bject has  reac h e d p u bertal mat urit y bef ore 1 8 years of a ge a n d a m brise nta n ca n 
be s u p plie d t hr o u g h a na me d patie nt  or e x pa n de d access  pr o gra m u ntil t he s u bject 
reac hes 1 8 years of a ge  
•  
t he pr o d uct is a p pr o ve d a n d a vaila ble f or use i n t he s u bject’s a ge gr o u p, 
•  
de vel o p me nt f or use i n t h e pae diatri c p o p ulati o n is disc o nti n ue d.  
•  
t he s u bject deci des h e/s he n o l o n ger wa nts t o partici pate i n t he st u d y, 
•  
t he i n vesti gat or c o nsi ders it is i n t he best i nterest of t he s u bject t o disc o nti n ue 
a m brise nta n (e. g. f or safet y reas o ns).  
T he pri mar y o bje cti ve is t he l o n g -ter m safet y a n d t olera bilit y of a m brise nta n i n t he 
pae diatric P A H p o p ulati o n.  Sec o n dar y o bjecti ves are all ca use m ortalit y a n d c ha n ge 
fr o m baseli ne i n St u d y A M B 1 1 2 5 2 9 o n efficac y p ara meters. 
S u bject:  P ul m o nar y Arterial H y p erte nsi o n, L o n g Ter m E xte nsi o n, Pae diatrics  
A ut h or:
 
 
C o p yri g ht 2 0 2 1  t he Gla x o S mit h Kli ne gr o u p of c o m pa nies.  All ri g hts r eser ve d.  
U na ut h orise d c o p yi n g or use of t his i nf or mati o n is pr o hi bite d  
P P D
P P D

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Revision Chronology: 
 
 
RM2010/00282/00 
2010-AUG-17 
Original 
RM2010/00282/01 
2010-OCT-26 
Amendment No.: 01 
Clarify that alkaline phosphatase is a 
clinical chemistry parameter that will 
be assessed every three months. 
Clarify that vital signs, body weight, 
and height will be assessed every three 
months. 
Clarify that for the duration of Study 
AMB112529, data from AMB114588 
will be reviewed by the IDMC at the 
same times as data from AMB112529 
are being reviewed. 
Clarify the definition of the analysis 
populations to reflect the fact that this 
is not a randomized trial. 
RM2010/00282/02 
2011-FEB-02 
Amendment No.: 02 
Created in error – never implemented 
RM2010/00282/03 
2011-FEB-08 
Amendment No.: 02 
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. 
RM2010/00282/04 
2020-JUN-10 
Amendment No.: 03 
Update the Medical Monitor, Sponsor 
Address and Sponsor Signatory 

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Remove the requirement for monthly 
liver function tests unless clinically 
indicated or occurring at the time of a 
3-month visit. 
Modify the requirement for monthly 
pregnancy tests to reflect that they may 
be performed by the subject at home 
using urine test kits provided by the 
site or occurring at the time of a 3-
month visit 
Modify the requirement for 6MW 
testing at 6-month visits to make 
optional.  
Clarify the language in Section 5.7 that 
the 30-day follow-up described after 
the completion of treatment 
specifically refers to adverse events. 
Update Section 8.3.1, Section 8.3.5.1 
and Section 8.3.5.2 to reflect that for 
analyses of the ITT population subjects 
will be considered as belonging to their 
treatment group at the time of entering 
the study, and that analyses using the 
Safety Population will consider 
subjects as belonging to the treatment 
group according to the highest dose 
received.  
 
TMF-13359039 
2021-MAY-25 
Amendment No.: 04 
Update to the Sponsor Signatory 
Updates to Summary page 1, Protocol 
summary, Section 2.1.1, Section 3.1, 
Section 5.7, Section 6.2.4 and Table 1 
footnotes to include changes to when 
subjects can leave the study and the 
timing of the pubertal development 
assessment.  
New wording to account for the 
different end of study scenarios for any 
remaining subjects who are either still 

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active or in follow-up in the study: 
Subjects who reached pubertal maturity 
before 18 years of age and ambrisentan 
can be supplied through a named 
patient or expanded access program 
until the subject reaches 18 years of 
age will complete their end of study 
visit at the investigator site. Subjects 
who have reached the age of 18 and 
who have reached pubertal maturity at 
a previous visit will complete their 
final study visits in the form of a 
telephone follow-up. Subjects who 
have reached the age of 18 and who 
have not reached pubertal maturity in 
previous visits will complete their final 
study visit at the investigator site to 
have their pubertal development 
assessed. 
Clarify that pubertal development 
assessments do not need to be repeated 
if pubertal maturity has been reached in 
a previous visit. 

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SPONSOR SIGNATORY: 
Protocol Title: An open-label, long term extension study for treatment of pulmonary 
arterial hypertension in paediatric patients aged 8 years up to 18 years who have 
participated in AMB112529 and in whom continued treatment with ambrisentan is 
desired 
Protocol Number: AMB114588/Amendment 04 
Compound Number 
or Name: 
GSK1325760 
 
 
 
 
Kaivan Khavandi, MBChB, MRes, MBA, PhD, MCRP 
Future Disease Area Lead  
Clinical Sciences, Specialty 
 Date 
 
 
 
 
The signed page is a separate document. 
 
Medical Monitor Name and Contact Information will be provided separately 
 

T M F -1 3 3 5 9 0 3 9  
C O N FI D E N TI A L  
 
 
 
A M B 1 1 4 5 8 8  
 
6  
 
S P O N S O R I N F O R M A TI O N P A G E  
Cli nical St u d y I d e ntifier:  
A M B 1 1 4 5 8 8  
 
Gla x o S mit h Kli ne Researc h & D e vel o p me nt Li mite d  
9 8 0 Great W est R oa d  
Bre ntf or d  
Mi d dlese x T W 8 9 G S  
U nite d Ki n g d o m  
Tele p h o ne:  + 4 4 ( 0) 2 0 8 9 9 0 9 0 0 0  
I n s o me c o u ntries, t he cli nical trial s p o ns or ma y b e t he l ocal Gla x o S mit h Kli ne affiliate 
c o m pa n y ( or d esi g n ee).  W here a p plica ble, t h e det ai ls of t he S p o ns or a n d c o ntact pers o n 
will be pr o vi de d t o t he rele va nt re g ulat or y a ut h orit y as p art of t he cli nical trial 
s u b missi o n. 
S p o ns or Me dical M o nit or a n d Seri o us A d verse E v e nts ( S A E) C o ntact I nf or mati o n:  
 
 M D F A C C 
Cl i nical Scie nces, Res pir at or y a n d S pecialt y 
Gla x o S mit h Kli ne  
C olle ge ville, Pe n ns yl v a nia 
 
Re g ulat or y A ge nc y I de ntif yi n g N u m ber(s):  E u dra C T 2 0 1 0 -0 2 1 5 7 2 -2 9  
 
 
 
 
 
 
U S I N D 6 4, 9 1 5  
P P D

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INVESTIGATOR AGREEMENT PAGE 
For protocol AMB114588 
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 
SPONSOR SIGNATORY: ............................................................................................... 5 
TABLE OF CONTENTS .................................................................................................. 8 
LIST OF ABBREVIATIONS ........................................................................................... 11 
PROTOCOL SUMMARY ............................................................................................... 13 
1. 
INTRODUCTION .................................................................................................... 16 
1.1. 
Rationale .................................................................................................... 17 
2. 
OBJECTIVE(S) ...................................................................................................... 18 
2.1. 
Primary ....................................................................................................... 18 
2.1.1. 
Safety .......................................................................................... 18 
2.2. 
Secondary .................................................................................................. 18 
2.2.1. 
Efficacy ........................................................................................ 18 
2.2.2. 
Exploratory .................................................................................. 19 
2.2.3. 
Other ........................................................................................... 19 
3. 
INVESTIGATIONAL PLAN ..................................................................................... 19 
3.1. 
Study 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 ..................................................................................... 21 
5. 
STUDY TREATMENTS .......................................................................................... 22 
5.1. 
Investigational Product and Other Study Treatment .................................... 22 
5.2. 
Treatment Assignment ................................................................................ 23 
5.3. 
Blinding ....................................................................................................... 23 
5.4. 
Product Accountability ................................................................................ 23 
5.5. 
Treatment Compliance ................................................................................ 23 
5.6. 
Concomitant Medications and Non-Drug Therapies .................................... 24 
5.6.1. 
Permitted Medications and Non-Drug Therapies .......................... 24 
5.6.2. 
Addition of Other Targeted PAH Therapeutic Agents ................... 24 
5.6.3. 
Prohibited Medications and Non-Drug Therapies ......................... 24 
5.7. 
Treatment after the End of the Study .......................................................... 24 
5.8. 
Treatment of Study Treatment Overdose .................................................... 25 
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. 
Time to Change in Dose .............................................................. 30 

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6.2.6. 
Clinical Laboratory Tests ............................................................. 30 
6.2.6.1. 
Safety Tests ............................................................... 30 
6.2.6.2. 
NT-Pro BNP ............................................................... 31 
6.2.7. 
Liver chemistry stopping and follow up criteria ............................. 31 
6.2.8. 
Adverse Events............................................................................ 34 
6.2.8.1. 
Definition of an AE ...................................................... 34 
6.2.8.2. 
Definition of a SAE ..................................................... 35 
6.2.9. 
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs ......................................................... 36 
6.2.10. 
Pregnancy ................................................................................... 36 
6.2.11. 
Time Period and Frequency of Detecting AEs and SAEs ............. 37 
6.2.12. 
Prompt Reporting of Serious Adverse Events and Other 
Events to GSK ............................................................................. 37 
6.2.12.1. Regulatory reporting requirements for SAEs .............. 39 
6.3. 
Efficacy ....................................................................................................... 39 
6.3.1. 
All cause mortality ........................................................................ 39 
6.3.2. 
Change from Study AMB112529 baseline in the 6 minute 
walking distance (6MWD) test. ..................................................... 39 
6.3.3. 
Time to worsening of PAH ........................................................... 39 
6.3.4. 
Time to Addition of Other Targeted PAH Therapeutic 
Agents ......................................................................................... 40 
6.3.5. 
Time to Change in Dose .............................................................. 40 
6.3.6. 
Change from Study AMB112529 baseline in Subject 
Global Assessment. ..................................................................... 40 
6.3.7. 
Change from Study AMB112529 baseline in WHO 
functional class. ........................................................................... 40 
6.3.8. 
Change from Study AMB112529 baseline plasma N-
terminal pro-B type natriuretic peptide (NT-Pro BNP). .................. 40 
6.3.9. 
Change from Study AMB112529 baseline in major 
prognostic factors. ....................................................................... 41 
6.3.10. 
Change from Study AMB112529 baseline in 
cardiopulmonary hemodynamics. ................................................ 41 
6.4. 
Health Outcomes ........................................................................................ 41 
7. 
DATA MANAGEMENT ........................................................................................... 42 
8. 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS ................................... 42 
8.1. 
Hypotheses ................................................................................................. 42 
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 ....................................................................... 43 
8.3.3. 
Treatment Comparisons .............................................................. 43 
8.3.3.1. 
Primary Comparisons of Interest ................................ 43 
8.3.3.2. 
Other Comparisons of Interest .................................... 43 
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. 
Efficacy Analyses ....................................................... 45 

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8.3.5.3. 
Health Outcomes Analyses ........................................ 46 
8.3.5.4. 
Pharmacodynamic Analyses ...................................... 46 
8.3.5.5. 
Pharmacokinetic/Pharmacodynamic Analyses ........... 46 
9. 
STUDY CONDUCT CONSIDERATIONS ............................................................... 46 
9.1. 
Posting of Information on Clinicaltrials.gov .................................................. 46 
9.2. 
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................ 46 
9.3. 
Quality Control (Study Monitoring) .............................................................. 47 
9.4. 
Quality Assurance ....................................................................................... 47 
9.5. 
Study and Site Closure ............................................................................... 47 
9.6. 
Records Retention ...................................................................................... 48 
9.7. 
Provision of Study Results to Investigators, Posting to the Clinical 
Trials Register and Publication ................................................................... 48 
9.8. 
Independent Data Monitoring Committee (IDMC) ....................................... 49 
10. REFERENCES ....................................................................................................... 50 
11. APPENDICES ........................................................................................................ 52 
11.1. 
Appendix 1: Cardiopulmonary Hemodynamic Sub-study ............................ 52 
11.2. 
Appendix 2: List of Highly Effective Methods for Avoidance of 
Pregnancy in Women of Childbearing Potential .......................................... 53 
11.3. 
Appendix 3: Country Specific Requirements ............................................... 54 
11.4. 
Appendix 4: Protocol Amendment 01 .......................................................... 55 
11.5. 
Appendix 5: Protocol Amendment 02 .......................................................... 59 
11.6. 
Appendix 6: Protocol Amendment 03 .......................................................... 61 
11.7. 
Appendix 7: Protocol Amendment 04 .......................................................... 67 
 

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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 binging 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 
 
Letairis 
 
 
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 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 long term paediatric study is to provide clinically relevant 
information on the long term safety of ambrisentan in children with the most common 
causes of PAH in this age group.  This study is only open to patients who have 
participated in Study AMB112529, 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, and in whom continued treatment with ambrisentan is warranted. 
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 long term safety and tolerability of 
ambrisentan in the paediatric (aged 8 years up to 18 years) PAH population.  The 
secondary objective is to obtain supportive efficacy data (change from baseline in 
efficacy parameters) on the paediatric use of ambrisentan in PAH.  Because patient 
recruitment in Study AMB112529 was limited by the low prevalence of the disease in 
children, powered clinical hypotheses testing cannot be performed. 

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Study Design 
This is an open label, long term extension to Study AMB112529.  All subjects may 
remain in the extension study for a minimum of six months.  Beyond the six month 
period, subjects may continue in the extension study until one of the following conditions 
is met: 
• 
The subject turns 18 years of age (when the subject can receive marketed product) or 
the subject has reached pubertal maturity before 18 years of age and ambrisentan can 
be supplied through a named patient or expanded access program until the subject 
reaches 18 years of age 
• 
The product is approved and available for use in the subject’s age group; 
• 
Development for use in the paediatric population is discontinued; 
• 
The subject decides he/she no longer wants to participate in the study; 
• 
The investigator considers it is in the best interest of the subject to discontinue 
ambrisentan (e.g. for safety reasons). 
Study Endpoints/Assessments 
Primary 
The primary objective is the long-term 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 Study AMB112529 baseline in endocrinology 
assessments every six months and at 20 years of age unless pubertal maturity has 
been reached in previous visits); 
• 
The time to change in dose of ambrisentan or other targeted PAH therapeutic agents 
(prostanoids, PDE-5 inhibitors) due to tolerability issues (e.g. adverse events). 

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Secondary 
Efficacy 
• 
All cause mortality; 
• 
The change from Study AMB112529 baseline in the 6 minute walking distance 
(6MWD) test evaluated every six months; 
• 
The time to clinical worsening of PAH; 
• 
The time to addition of another targeted PAH therapeutic agents (prostanoids, PDE-5 
inhibitors) due to the following reasons: 
• 
Deterioration of clinical condition; 
• 
Lack of beneficial effect with previous therapy (not reaching set treatment 
goals); 
• 
The time to change in dose of ambrisentan or other targeted PAH therapeutic agents 
(prostanoids, PDE-5 inhibitors) due to deterioration of clinical condition; 
• 
The change from Study AMB112529 baseline in Subject Global Assessment every 
three months using the SF-10 health survey for children; 
• 
The change from Study AMB112529 baseline in WHO functional class every six 
months; 
• 
Change from Study AMB112529 baseline in N-terminal pro-B-type natriuretic 
peptide (NT-Pro BNP) concentration every six months. 
Exploratory 
• 
The change from Study AMB 112529 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 every six 
months. 
Other 
• 
The change from Study AMB112529 baseline cardiopulmonary hemodynamic 
assessments data in subjects in whom hemodynamic data is considered part of the 
standard of care (see Appendix 1). 

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1. 
INTRODUCTION 
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]). 
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 paediatric population. 

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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. 
1.1. 
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 long term safety of ambrisentan in children with the most common causes of PAH 
in this age group.  This study is only open to patients who have participated in Study 
AMB112529, 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, and in 
whom continued treatment with ambrisentan is warranted. 
                                                 
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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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 long term safety and tolerability of 
ambrisentan in the paediatric (aged 8 years up to 18 years) PAH population.  The 
secondary objective is to obtain supportive efficacy data (change from baseline in 
efficacy parameters) on the paediatric use of ambrisentan in PAH.  Because patient 
recruitment in Study AMB112529 was 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 long-term 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 Study AMB112529 baseline in endocrinology 
assessments every six months and at 20 years of age unless pubertal maturity has 
been reached in previous visits); 
• 
The time to change in dose of ambrisentan or other targeted PAH therapeutic agents 
(prostanoids, PDE-5 inhibitors) due to tolerability issues (e.g. adverse events). 
2.2. 
Secondary 
2.2.1. 
Efficacy 
• 
All cause mortality; 
• 
The change from Study AMB112529 baseline in the 6 minute walking distance 
(6MWD) test evaluated every six months; 
• 
The time to clinical worsening of PAH (Section 6.3.3); 
• 
The time to addition of another targeted PAH therapeutic agents (prostanoids, PDE-5 
inhibitors) due to the following reasons: 

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• 
Deterioration of clinical condition; 
• 
Lack of beneficial effect with previous therapy (not reaching set treatment 
goals); 
• 
The time to change in dose of ambrisentan or other targeted PAH therapeutic agents 
(prostanoids, PDE-5 inhibitors) due to deterioration of clinical condition; 
• 
The change from Study AMB112529 baseline in Subject Global Assessment every 
three months using the SF-10 health survey for children; 
• 
The change from Study AMB112529 baseline in WHO functional class every six 
months; 
• 
Change from Study AMB112529 baseline in N-terminal pro-B-type natriuretic 
peptide (NT-Pro BNP) concentration every six months. 
2.2.2. 
Exploratory 
• 
The change from Study AMB112529 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 at every 6 
months. 
2.2.3. 
Other 
• 
The change from Study AMB112529 baseline in cardiopulmonary hemodynamic 
assessments data in subjects in whom hemodynamic data is considered part of the 
standard of care (see Appendix 1). 
3. 
INVESTIGATIONAL PLAN 
3.1. 
Study Design 
This is an open label, long term extension to Study AMB112529.  All subjects may 
remain in the extension study for a minimum of six months.  Beyond the six month 
period, subjects may continue in the extension study until one of the following conditions 
is met: 
• 
The subject turns 18 years of age (when the subject can receive marketed product) or 
the subject has reached pubertal maturity before 18 years of age and ambrisentan can 
be supplied through a named patient or expanded access program until the subject 
reaches 18 years of age; 
• 
The product is approved and available for use in the subject’s age group; 
• 
Development for use in the paediatric population is discontinued; 
• 
The subject decides he/she no longer wants to participate in the study; 

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• 
The investigator considers it is in the best interest of the subject to discontinue 
ambrisentan (e.g. for safety reasons). 
Protocol waivers or exemptions are not allowed. Therefore, adherence to the study design 
requirements, including those specified in the Time and Events Table, are essential.  
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 that does not 
impact subject safety. 
4. 
SUBJECT SELECTION AND WITHDRAWAL CRITERIA 
4.1. 
Number of Subjects 
As this study is only open to subjects who have participated in AMB112529, no more 
than 66 subjects will be enrolled into this extension study. 
4.2. 
Inclusion Criteria 
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the Investigators Brochure and 
product label. 
Deviations from inclusion criteria are not allowed because they can potentially jeopardize 
the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential.    
Subjects eligible for enrolment in the study must meet all of the following criteria: 
1. Have participated in and complied, to the best of their ability, with the protocol for 
AMB112529 and have met one of the following: 
a. 
Completed the Week 24 visit in AMB112529; 
b. Required additional targeted treatment for PAH due to inadequate response to 
the current treatment or worsening of their clinical condition prior to week 24 in 
AMB112529; 
c. 
Required reduction in dose of baseline targeted treatment for PAH after 
ambrisentan was added to the treatment regimen; 
d. In the opinion of the investigator, continued treatment with ambrisentan is 
warranted. 
2. 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, 

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b. Child-bearing potential - has a negative pregnancy test and is not lactating and, 
if sexually active, agrees to continue to use 2 reliable methods of contraception 
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). 
3. 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. 
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 
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. 
Therefore, adherence to the criteria as specified in the protocol is essential.  
Subjects meeting any of the following criteria must not be enrolled in the study: 
1. Subjects who were withdrawn from ambrisentan in Study AMB112529; 
2. Subjects who did not comply with the protocol in Study AMB112529; 
3. Female subjects who are pregnant or breastfeeding; 
4. Subjects with severe renal impairment (estimated creatinine clearance <30 mL/min 
assessed within the previous 45 days) at the point of transition from Study 
AMB112529 into this study; 
5. Subject with clinically significant fluid retention in the opinion of the investigator; 
6. Subject with clinically significant anaemia in the opinion of the investigator; 
7. Subjects who are to enter another clinical trial or be treated with another 
investigational product after exiting Study AMB112529. 
4.4. 
Withdrawal Criteria 
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] data (see Section 9.8). 
A subject may also be discontinued from the study for the following reasons: 
• 
Liver chemistry values exceeding the threshold criteria (as outlined in Section 6.2.7); 
• 
Adverse event which in the opinion of the investigator requires withdrawal; 
• 
Pregnancy; 

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• 
Consent withdrawn; 
• 
Lost to follow-up; 
• 
Protocol violation; 
• 
Termination of study by sponsor; 
• 
Investigator’s discretion (document reason in eCRF). 
5. 
STUDY TREATMENTS 
5.1. 
Investigational Product and Other Study Treatment 
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.  Subjects may receive 2.5, 5, 7.5, or 10 mg of 
ambrisentan per day, as long as the dose does not exceed 0.25 mg/kg/day. 
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 below 30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 
This is an open label study.  All subjects will receive ambrisentan at a dose individually 
tailored for each subject.  At the time the subject exits Study AMB112529, the 
investigator will be told the dose of ambrisentan that the subject was receiving.  Based on 
the investigator’s best judgement, the subject may continue on the same dose, the dose 
may be adjusted downward in 2.5 mg increments to not less than 2.5 mg per day or the 
dose may be adjusted upward in 2.5 mg increments to not more than the lesser of 10 mg 
per day or 0.25 mg/kg per day.  Whenever the dose of ambrisentan is changed, one of the 
following reasons for the change will be recorded:  
• 
Change in body weight; 
• 
Deterioration of clinical condition; 
• 
Tolerability issues (e.g. adverse events); 
• 
Other. 
5.3. 
Blinding 
This is an open label study. 
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 
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 every three months 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. 

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5.6. 
Concomitant Medications and Non-Drug Therapies 
5.6.1. 
Permitted Medications and Non-Drug Therapies 
Standard medical treatment(s), other than those that are explicitly excluded below, that 
are required by the subject may be added or changed at any time.  All prescribed 
treatments and changes in doses will be recorded in the eCRF.  Whenever the dose of 
other targeted PAH therapeutic agents (e.g. prostanoid or PDE-5 inhibitor) is changed, 
one of the following reasons will be recorded: 
• 
Change in body weight; 
• 
Deterioration of clinical condition; 
• 
Tolerability issues (e.g. adverse events); 
• Other. 
Subjects may begin oral contraceptive therapy as per the prescribing information. 
5.6.2. 
Addition of Other Targeted PAH Therapeutic Agents  
Other targeted PAH therapeutic agents (e.g., prostanoid or PDE-5 inhibitor) may be 
added at the discretion of the investigator.  Whenever a new treatment is added, one of 
the following reasons will be recorded:  
• 
Deterioration of clinical condition; 
• 
Lack of beneficial effect with previous therapy (not reaching set treatment goals); 
• 
Electively (preset treatment strategy independent of effects with previous therapies). 
5.6.3. 
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. 
5.7. 
Treatment after the End of the Study 
Subjects can remain in this study until one of the following conditions is met: 
• 
The subject turns 18 years of age (when the subject can receive marketed product) or 
the subject has reached pubertal maturity before 18 years of age and ambrisentan can 
be supplied through a named patient or expanded access program until the subject 
reaches 18 years of age; 
• 
The product is approved and available for use in the subject’s age group; 
• 
Development for use in the paediatric population is discontinued; 
• 
The subject decides he/she no longer wants to participate in the study; 

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• 
The investigator considers it is in the best interest of the subject to discontinue 
ambrisentan (e.g. for safety reasons). 
The Investigator should then treat the subjects according to best standard of care 
available to the investigator. Subjects will be followed for 30 days post their last dose of 
study medication for monitoring of AEs/SAEs.   
 Subjects will only be asked to return for a pubertal development assessment following 
their 18th birthday if pubertal maturity had not been reached in a previous visit. 
All subjects who reached pubertal maturity before 18 years of age and ambrisentan can 
be supplied through a named patient or expanded access program until the subject 
reaches 18 years of age will complete their end of study visit at the investigator site for 
their end of study assessments as outlined in Table 1. As these subjects had already 
reached pubertal maturity, no further pubertal development assessments are required. 
All subjects who have reached the age of 18 and who have reached pubertal maturity at a 
previous visit will complete their final study visits in the form of a telephone follow-up. 
This is to notify the subjects of the end of the study and that no further study visits and 
assessments will take place. 
All subjects who have reached the age of 18 and who have not reached pubertal maturity 
in previous visits will complete their final study visit at the investigator site to have their 
pubertal development assessed. These patients may return at any point and do not need to 
wait until 20 years of age to have their pubertal maturity evaluated. 
GSK will continue to provide post-study medication only to subjects in territories where 
the medication is not available through normal distribution channels.   
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the patient’s medical condition whether or not GSK is providing specific 
post study treatment.  
 
5.8. 
Treatment of Study Treatment 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. 

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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 
At Entry into 
the Study1 
Monthly2 
Every 
Three 
Months 
Every 
Six 
Months 
End of 
Study 
Follow-
up3 
At 20 
years of 
age14 
Written informed 
consent and assent 
X 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
Adverse Events 
X 
 
X 
 
X 
X 
 
Serious Adverse 
Events 
X 
 
X 
 
X 
X 
 
Liver Function Tests4 
X 
X 
 
 
X 
X 
 
Clinical Chemistry5 
 
 
X 
 
X 
 
 
Haematology6 
 
 
X 
 
X 
 
 
Physical 
Examination 
 
 
 
X 
X 
X 
 
Vital Signs7 
 
 
X 
 
X 
X 
 
12-lead ECG 
 
 
 
X 
X 
X 
 
Concomitant 
Medication 
 
 
X 
 
X 
X 
 
6 Minute Walk 
Distance8 
 
 
 
X 
X 
X 
 
WHO Functional 
Class 
 
 
 
X 
X 
X 
 
Health Outcome 
Assessments9  
 
 
X 
 
X 
X 
 
Echocardiogram 
 
 
 
X 
X 
X 
 
Plasma NT-Pro BNP 
concentration 
 
 
 
X 
X 
X 
 
Hemodynamic 
assessment10 
 
 
 
 
 
 
 
Pregnancy Test11 
X 
X 
 
 
X 
X 
 
Pubertal 
Development 
Assessment12 
 
 
 
X 
X 
X 
X 
Dispense 
Investigational 
Product13 
X 
 
X 
 
 
 
 
Assess 
Investigational 
Product Compliance 
 
 
X 
 
X 
 
 
 

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Table 1 
Time and Events Table (Continued) 
1. These are transcribed from the End of Therapy (Week 24) visit in Study AMB112529 
2. For months that do not correspond to the every three month visits LFTs need not be performed unless clinically 
indicated, and, these assessments may be performed by the subject’s local physician and laboratory. From the 
time of Amendment 03, urine pregnancy tests may be performed at the subject’s home using kits supplied by 
the site. 
3. Only assessed in patients who are withdrawn from ambrisentan; assessment should be conducted within 4 to 6 
weeks after last dose of ambrisentan. 
4. Includes ALT (SGPT), AST (SGOT), GGT, and total bilirubin 
5. Includes sodium, magnesium, potassium, calcium, glucose, chloride, bicarbonate (CO2,) phosphorus-
inorganic, creatinine, total protein, albumin, LDH, creatine phosphokinase (CPK), blood urea nitrogen (BUN), 
uric acid, and alkaline phosphatase 
6. 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) 
7. Includes height, weight, supine blood pressure, and heart rate 
8. From the time of Amendment 03, this test is optional at the every six month visits. Subjects with a 20% 
decrease in 6MWD will need to return in 1 week to repeat the test, to confirm PAH deterioration. 
9. SF 10 and a record of school days scheduled and missed.  A diary card will be given to the subject at each 
3-monthly visit 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.  The diary cards will be returned at the next visit.  Data 
from all diary cards will be transcribed into the eCRF. 
10. Collected only if the assessment is being done as part of the subject’s standard care.  This is not scheduled 
per protocol, but if the assessment is being done at any time during the study, the following data will be 
transcribed into the eCRF: 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). 
11. Either Urine or blood monthly pregnancy tests for females of childbearing potential for the duration of the study: 
From the time of Amendment 03, urine pregnancy tests may be performed at the subject’s home using kits 
supplied by the site. 
12. 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. 
13. Doses may be adjusted upward or downward by 2.5 mg increments.  The minimum dose may not be less than 
2.5 mg, and the maximum dose may not be greater than the lower of 10 mg per day or 0.25 mg/kg/day. 
14. In subjects where pubertal maturity has been reached prior to 20 years of age, the 20-year pubertal 
development assessment will not be required. All subjects who are over the age of 18 and who have not 
reached pubertal maturity in previous visits will complete their final study visit at the investigator site and will 
have their pubertal development assessed.  These patients may return at any point and do not need to wait 
until 20 years of age to have their pubertal maturity evaluated. 
 

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6.1. 
Critical Baseline Assessments 
The subject’s clinical response in study AMB112529 will be assessed upon exiting Study 
AMB112529.  Only those subjects for whom, in the opinion of the investigator, 
continued treatment with ambrisentan is in the best interest of the subject will continue 
into this study. 
6.2. 
Safety 
6.2.1. 
Physical examination 
Physical examinations will be performed every six months while the subject is in the 
study, at the time he subject exits the study, and 4 to 6 weeks after discontinuing 
ambrisentan for those subjects who do not remain on ambrisentan (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 every six months while the subject is in the study, at 
the time the subject exits the study, and 4 to 6 weeks after discontinuing ambrisentan for 
those subjects who do not remain on ambrisentan.  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 every six months while the subject is in the study, 
at the time the subject exits the study, and 4 to 6 weeks after discontinuing ambrisentan 
for those subjects who do not remain on ambrisentan. 
6.2.3. 
Vital Signs, Body Weight and Height 
Vital signs (including heart rate and supine blood pressure), height, and weight will be 
collected every three months. 
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 every six months 
while the subject is in the study, at the time the subject exits the study, 4 to 6 weeks after 
discontinuing ambrisentan for those subjects who do not remain on ambrisentan, and at 
20 years of age, unless pubertal maturity has been reached in previous visits. using the 
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 every six months while the 
subject is in the study, at the time the subject exits the study, and 4 to 6 weeks after 
discontinuing ambrisentan for those subjects who do not remain on ambrisentan. 
6.2.5. 
Time to Change in Dose 
The time to change in dose of ambrisentan or other targeted PAH therapeutic agents 
(prostanoids, PDE-5 inhibitors) is defined as the time from randomization to the first 
occurrence of a tolerability issue (e.g. adverse events). 
6.2.6. 
Clinical Laboratory Tests 
A central laboratory (Quest Diagnostics) will be used for the three and six monthly 
laboratory assessments.  Results from local laboratories can be used for the monthly 
assessments that do not correspond with a three- or six-month clinic visit.  If local 
laboratories are used, the results will be forwarded to the study site, where they will be 
entered into the eCRF. 
6.2.6.1. 
Safety Tests 
The following tests are required at the time the subject exits the study, four to six weeks 
after discontinuing ambrisentan for those subjects who do not remain on ambrisentan and 
at intervals listed below. 
• 
Liver Function:  serum alanine aminotransferase (ALT/SGPT), aspartate 
aminotransferase (AST/SGOT), gamma glutamyl transferase (GGT), and total 
bilirubin at the site visits that take place every 3 months, and otherwise as clinically 
indicated. 
• 
Chemistry:  alkaline phosphatase, lactate dehydrogenase (LDH), creatine 
phosphokinase (CPK), creatinine, sodium, magnesium, potassium, chloride, 
bicarbonate (CO2), phosphorus-inorganic, calcium, blood urea nitrogen (BUN), uric 
acid, glucose, total protein, and albumin every three months. 

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• 
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 every three months. 
• 
Pregnancy:  Either urine or blood pregnancy tests for female subjects of child 
bearing potential at the site visits that take place every 3 months. At the intervening 
monthly intervals, a urine pregnancy test will be performed by the subject at home 
using a test kit supplied by the site. 
6.2.6.2. 
NT-Pro BNP 
• 
Blood samples for NT-Pro BNP concentration will be collected every six months 
while the subject is in the study, at the time the subject exits the study, and 4 to 6 
weeks after discontinuing ambrisentan for those subjects who do not remain on 
ambrisentan.  Assays for plasma concentrations will be performed in the central 
laboratory. 
Collection, processing, labelling, and shipping of the NT-pro BNP samples to central 
laboratory are detailed in the SPM. 
6.2.7. 
Liver chemistry stopping and follow up 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. 

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• 
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. 
• 
Complete the liver imaging and/or liver biopsy CRFs if these tests are performed. 
• 
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  

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• 
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);  
• 
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. 

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• 
Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to 
evaluate liver disease. 
6.2.8. 
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. 
6.2.8.1. 
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. 
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. 

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6.2.8.2. 
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. 
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). 

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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. 
6.2.9. 
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. 
6.2.10. 
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. 

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6.2.11. 
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 6.2.12. 
6.2.12. 
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. 

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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. 
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. 

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6.2.12.1. 
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. 
Efficacy 
6.3.1. 
All cause mortality 
All-cause mortality will be assessed. 
6.3.2. 
Change from Study AMB112529 baseline in the 6 minute walking 
distance (6MWD) test. 
The 6MWD will be assessed every six months while the subject is in the study but will be 
considered optional to perform at visits that take place after the approval of Protocol 
Amendment 03. The 6MWD will also be assessed at the time the subject exits the study, 
and 4 to 6 weeks after discontinuing ambrisentan for those subjects who do not remain on 
ambrisentan.  Subjects with a 20% decrease in 6MWD will need to return in 1 week to 
repeat the test, to confirm PAH deterioration. 
6.3.3. 
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), placed on active list for lung transplant, and/or atrial septostomy; 
• 
Hospitalisation due to PAH deterioration; 
• 
Addition of another targeted PAH therapeutic agents (prostanoids, PDE-5 inhibitors) 
due to deterioration of clinical condition; 
• 
Change in dose of ambrisentan or other targeted PAH therapeutic agents 
(prostanoids, PDE-5 inhibitors) due to deterioration of clinical condition; 

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• 
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).  
6.3.4. 
Time to Addition of Other Targeted PAH Therapeutic Agents 
Time to addition of another targeted PAH therapeutics agents are defined as the time 
from randomization to the first occurrence of: 
• 
Deterioration of clinical condition; 
• 
Lack of beneficial effect with previous therapy (not reaching set treatment goals). 
6.3.5. 
Time to Change in Dose 
Time to change in dose of ambrisentan or other targeted PAH therapeutic agents 
(prostanoids, PDE-5 inhibitors) is defined as the time from randomization to the first 
occurrence of a dose change due to deterioration of clinical condition. 
6.3.6. 
Change from Study AMB112529 baseline in Subject Global 
Assessment. 
Global assessments will be performed every three months while the subject is in the 
study, at the time the subject exits the study, and 4 to 6 weeks after discontinuing 
ambrisentan for those subjects who do not remain on ambrisentan. 
6.3.7. 
Change from Study AMB112529 baseline in WHO functional 
class. 
WHO functional class will be determined every six months while the subject is in the 
study, at the time the subject exits the study, and 4 to 6 weeks after discontinuing 
ambrisentan for those subjects who do not remain on ambrisentan. 
6.3.8. 
Change from Study AMB112529 baseline plasma N-terminal pro-
B type natriuretic peptide (NT-Pro BNP). 
Blood samples for determination of N-Terminal pro-B-type Natriuretic Peptide plasma 
concentrations will be determined every six months or early withdrawal.  A central lab 
(Quest Diagnostics) will analyze all samples. 

T M F -1 3 3 5 9 0 3 9  
C O N FI D E N TI A L  
 
 
 
A M B 1 1 4 5 8 8  
 
4 1  
 
6. 3. 9.  
C h a n g e fr o m St u d y A M B 1 1 2 5 2 9 b a s eli n e i n m aj or pr o g n o sti c 
f a ct or s. 
Ec h ocar di o gra ms will be perf or me d e ver y si x m o nt hs w hile t he s u bject is i n t he st u d y, at 
t he ti me t he s u bject e xits t he st u d y, a n d 4 t o 6 w ee ks after disc o nti n ui n g a m brise nta n f or 
t h ose s u bjects w h o d o n ot re mai n o n a m brise nta n.  
Pr o g n ostic fact ors i ncl u d e d pericar dial eff usi o n, R A pre ss ure, tric us pi d a n n ular pla ne 
s yst olic e x c ursi o n ( T A P S E), ecce ntricit y i n de x (s yst olic a n d diast olic), a n d ri g ht 
ve ntric ular ( R V) press ure b y tric us pi d re g ur gita nt j et ( T RJ) vel ocit y.  T hese e val uati o ns 
were c o nsi dere d e x pl orat or y i n t his st u d y.  
6. 3. 1 0.  
C h a n g e f r o m St u d y A M B 1 1 2 5 2 9 b a s eli n e i n c ar di o p ul m o n ar y 
h e m o d y n a mi c s.  
Car di o p ul m o nar y h e m o d y n a mic assess me nts data will be c ollecte d i n s u bjects i n w h o m 
he m o d y n a mic data is c o nsi dere d part of t he sta n dar d of care (see A p pe n di x 1 ). 
6. 4.  
H e alt h O ut c o m e s  
Patie nt gl o bal assess me nts will be perf or me d e ver y t hree m o nt hs w hile t he s u bject is i n 
t he st u d y, at t he ti me t he s u bject e xits t he st u d y, a n d 4 t o 6 wee ks aft er disc o nti n ui ng 
a m brise nta n f or t h ose s u bjects w h o d o n ot re mai n o n a m brise nta n.  Healt h o utc o mes will 
be rec or de d usi n g t he pare nt -c o m plete d S h ort F or m 1 0 ( S F -1 0) Healt h S ur ve y f or 
c hil dre n.  
T he s h ort -f or m 1 0 ( S F-1 0) Healt h S ur ve y f or C hil dre n is a 1 0 -ite m, 4-wee k reca ll, 
pare nt -c o m plete d healt h assess me nt t hat meas ures p h ysical a n d ps yc h os oci al f u ncti o ni n g 
f or c hil dre n a ges fi ve a n d o ver.  S pecific d o m ai ns i ncl u de P h ysic al F u ncti o ni n g ( 2 ite ms), 
R ole/ S ocial E m oti o nal -Be ha vi oral ( 1 ite m), R ole/ S ocial P h ysical ( 1 ite m), B o dil y Pai n ( 1 
ite m), Ge neral Be ha vi or ( 1 ite m), Me ntal Healt h ( 1 ite m), Self Estee m ( 2 ite ms), a n d 
Ge neral Healt h Perce pti o ns ( 1 ite m).  T his i nstr u me nt pr o vi des a brief, relia ble, a n d 
scie ntificall y vali d healt h stat us meas ure me nt t hat is eas y t o a d mi nister a n d i nter pret. 
I n a d diti o n t o t he S F-1 0, s pecific q uesti o ns will be as ke d re gar di n g sc h o ol d a ys as 
f oll o ws: 
1.  
2.  
3.  
S u bjects will rec or d t he d a ys of sc h o ol sc he d ul e d a n d misse d o n a patie nt diar y car d, 
w hic h will be ret ur n e d t o t he cli nic at t he sc he d ul e d visits.  
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e 
pr ot e ct e d b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.

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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. 
Hypotheses 
No formal hypothesis testing is planned for the study 
8.2. 
Study Design Considerations 
Study design considerations are described below. 
8.2.1. 
Sample Size Assumptions 
Sample size is based on feasibility. Due to low prevalence of the disease, no more than 66 
will be enrolled in the study. 
8.2.2. 
Sample Size Sensitivity 
No sample size sensitivity calculations were performed. 
8.2.3. 
Sample Size Re-estimation 
No sample size re-estimation is planned 
8.3. 
Data Analysis Considerations 
8.3.1. 
Analysis Populations 
The Intention-to-Treat (ITT) Population will consist of all subjects who received at least 
1 dose of study drug.  For the ITT population, subjects were considered as belonging to 
their treatment group corresponding to the dose being received at the time the subject 

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transitioned into the study from Protocol AMB112529. .  The ITT population will be used 
in all population and efficacy summaries. 
The Safety Population is defined as all subjects who received at least 1 dose of study 
drug.  Subjects were considered as belonging to the treatment group according to the 
highest dose received.  The safety population will be used in all safety summaries. 
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. 
8.3.3. 
Treatment Comparisons 
8.3.3.1. 
Primary Comparisons of Interest 
There are no formal comparisons planned for this study.  Doses of Ambrisentan will be 
summarized descriptively based on available data for: 
• 
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 Study AMB112529 baseline in endocrinology 
assessments every six months); 
• 
The time to change in dose of ambrisentan or other targeted PAH therapeutic agents 
(prostanoids, PDE-5 inhibitors) due to tolerability issues (e.g. adverse events). 
8.3.3.2. 
Other Comparisons of Interest 
The following data will also be presented descriptively and graphically by dose levels: 
• 
All cause mortality; 
• 
The change from Study AMB112529 baseline in the 6 minute walking distance 
(6MWD) test evaluated every six months; 
• 
The time to clinical worsening of PAH; 
• 
The time to addition of another targeted PAH therapeutic agents (prostanoids, PDE-5 
inhibitors) due to the following reasons: 
• 
Deterioration of clinical condition; 

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• 
Lack of beneficial effect with previous therapy (not reaching set treatment 
goals); 
• 
The time to change in dose of ambrisentan or other targeted PAH therapeutic agents 
(prostanoids, PDE-5 inhibitors) due to deterioration of clinical condition; 
• 
The change from Study AMB112529 baseline in Subject Global Assessment every 
three months using the SF-10 health survey for children; 
• 
The change from Study AMB112529 baseline in WHO functional class every six 
months; 
• 
Change from Study AMB112529 baseline in N-terminal pro-B-type natriuretic 
peptide (NT-Pro BNP) concentration every six months; 
• 
The change from Study AMB112529 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 at every 6 
months; 
• 
Change from Study AMB112529 baseline in cardiopulmonary hemodynamic 
assessments data in subjects in whom hemodynamic data is considered part of the 
standard of care (see Appendix 1). 
8.3.4. 
Interim Analysis 
No interim analysis have been planned for the 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, physical examination, and pubertal development.  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 according to the highest dose received 
and overall.  Where data are available, it will be summarised by visit. 

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8.3.5.2. 
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 summarized by treatment group 
corresponding to the dose being received at the time the subject transitioned into the 
study from Protocol AMB112529, and overall. 
The summary analysis will include:  
• 
All cause mortality; 
• 
Mean change from Study AMB112529 baseline in the 6MWD at every 6 months; 
• 
Mean time to clinical worsening of PAH; 
• 
Mean time to addition of another targeted PAH therapeutic agents (prostanoids, 
PDE-5 inhibitors) due to the following reasons: 
• 
Deterioration of clinical condition; 
• 
Lack of beneficial effect with previous therapy (not reaching set treatment 
goals); 
• 
Mean time to change in dose of ambrisentan or other targeted PAH therapeutic 
agents (prostanoids, PDE-5 inhibitors) due to deterioration of clinical condition; 
• 
Change from Study AMB112529 baseline in Subject Global Assessment at every 3 
months; 
• 
Change from Study AMB112529 baseline in WHO functional class at every 6 
months; 
• 
Change from Study AMB112529 baseline in NT-Pro BNP concentration at every 6 
months; 
• 
The change from Study AMB112529 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 at every 6 
months; 
• 
The change from Study AMB112529 baseline in cardiopulmonary hemodynamic 
assessments data in subjects in whom hemodynamic data is considered part of the 
standard of care (see Appendix 1). 
Time to clinical worsening will be also presented graphically by Kaplan-Meier curve. 
More details of the statistical analysis will be presented in the Research and Analysis 
Plan (RAP). 

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8.3.5.3. 
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 6.4): 
• 
Physical Health Summary (PHS-10); and 
• 
Psychosocial Summary (PSS-10). 
The mean change from Study AMB112529 baseline in SF-10 scores will be calculated 
every three months. 
8.3.5.4. 
Pharmacodynamic Analyses 
Not planned 
8.3.5.5. 
Pharmacokinetic/Pharmacodynamic Analyses 
Not planned 
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. 
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. 

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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. 
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 

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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. 
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. 

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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) 
The IDMC from Study AMB112529 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.  For the duration of Study AMB112529, the IDMC will review the data from 
AMB114588 at the same time the IDMC reviews the data from AMB112529.  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, 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. 
Galiè N, Manes A, Branzi A. The endothelin system in pulmonary arterial hypertension. 
Cardiovasc Res. 2004;61:227–37. 
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 

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11. 
APPENDICES 
11.1. 
Appendix 1: Cardiopulmonary Hemodynamic Sub-study 
Hemodynamic assessments are neither scheduled nor required as a part of this study; 
however, any time that hemodynamic data are being collected as a part of the standard of 
care for a subject enrolled in this study, the following data will be transcribed to the 
eCRF:   
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: Country Specific Requirements 
Not Applicable. 

T M F -1 3 3 5 9 0 3 9  
C O N FI D E N TI A L  
 
 
 
A M B 1 1 4 5 8 8  
 
5 5  
 
1 1. 4.  
A p p e n di x 4: Pr ot o c ol A m e n d m e nt 0 1  
St ate me nt of I nte nt  
T he i nte nts of t his a me n d me nt are t o clarif y pr oce d ural iss ues t o i ns ure a b etter gl o bal 
u n dersta n di n g of i nte nt of t he pr ot oc ol a n d t o c orrectl y cate g orize al kali ne p h os p hatase as 
a cli nical c he mistr y para meter rat h er t ha n a li ver f u ncti o n test..  
A me n de d Secti o ns of t he Pr ot oc ol  
Deleti o ns are n ot e d i n It alics 
I ns erti o ns are n ote d i n b ol d f ace . 
S p o ns or I nf or m ati o n P a ge  
Was  
S p o ns or Me dical M o nit or C o ntact I nf or mati o n:  
 
 F R C S 
Cli nical De vel o p me nt P h ysicia n  
M D C Cli nical Meta b olic E U  
Gla x o S mi nt h Kli ne  
St oc kle y Par k  
S p o ns or Seri o us A dverse Eve nts ( S A E) C o nt act I nf or m ati o n:  
 M D 
S afety Ev al u ati o n & Risk M a n a g e me nt  
G C S P C ar di o & Met a b olic S E R M  
Gl ax o S mit h Kli ne  
1 2 5 0 S o ut h C olle geville R o a d  
C olle geville, P A 1 9 4 2 6 -2 9 9 0  
U nite d St ates  
Is 
S p o ns or Me dical M o nit or a n d Seri o us A d verse E v e nts ( S A E)  C o ntact I nf or mati o n:  
 
 F R C S 
Cli nical De vel o p me nt P h ysicia n  
M D C Cli nical Meta b olic E U  
Gla x o S mi nt h Kli ne  
St oc kle y Par k  
Secti o n 4. 3 Wit h dr a w al Criteri a  
Was  
P P D
P P D
P P D
P P D

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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] data every three months. 
Is 
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] data (see Section 9.8). 
Rationale 
Depending on the patient accrual rate in study AMB112529 and the rate of occurrence of 
serious adverse experiences, the IDMC review may be sooner or later than every three 
months. 
Table 1 footnote 3 
Was 
3.  Only for patients who are withdrawn from ambrisentan; within 4 to 6 weeks after last 
dose of investigational drug 
Is 
3.  Only assessed in patients who are withdrawn from ambrisentan; assessment should 
be conducted within 4 to 6 weeks after last dose of ambrisentan 
Rationale 
To make the statement more clear. 
Section 6.2.3 Vital Signs, Body Weight and Height 
Was 
Vital signs (including heart rate and supine blood pressure), height, and weight will be 
collected at each study visit. 
Is 
Vital signs (including heart rate and supine blood pressure), height, and weight will be 
collected every three months. 
Rationale 
The original intent was that the study visits would be every three months and liver 
function tests and pregnancy tests (where applicable) would be conducted locally (i.e., 
outside of a scheduled “study visit”); however, for some patients, the liver function tests 

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and pregnancy tests will be conducted at the study centre.  This makes the term “at each 
study visit” ambiguous. 
Section 6.2.6.1 Safety Tests 
Was 
The following tests are required at the time the subject exits the study, four to six weeks 
after discontinuing ambrisentan for those subjects who do not remain on ambrisentan and 
at intervals listed below. 
• 
Liver Function:  serum alanine aminotransferase (ALT/SGPT), aspartate 
aminotransferase (AST/SGOT), alkaline phosphatase, gamma glutamyl transferase 
(GGT), and total bilirubin monthly. 
• 
Chemistry:  lactate dehydrogenase (LDH), creatine phosphokinase (CPK), 
creatinine, sodium, magnesium, potassium, chloride, bicarbonate (CO2), 
phosphorus-inorganic, calcium, blood urea nitrogen (BUN), uric acid, glucose, total 
protein, and albumin every three months. 
Is 
The following tests are required at the time the subject exits the study, four to six weeks 
after discontinuing ambrisentan for those subjects who do not remain on ambrisentan and 
at intervals listed below. 
• 
Liver Function:  serum alanine aminotransferase (ALT/SGPT), aspartate 
aminotransferase (AST/SGOT),  gamma glutamyl transferase (GGT), and total 
bilirubin monthly. 
• 
Chemistry:  alkaline phosphatase, lactate dehydrogenase (LDH), creatine 
phosphokinase (CPK), creatinine, sodium, magnesium, potassium, chloride, 
bicarbonate (CO2), phosphorus-inorganic, calcium, blood urea nitrogen (BUN), uric 
acid, glucose, total protein, and albumin every three months. 
Rationale 
To correct a mistake in the original protocol.  The time and events table of the original 
protocol correctly listed alkaline phosphatase under chemistry, but the text incorrectly 
listed alkaline phosphatase as a liver function test. 
Section 8.3.1  Analysis Populations 
Was 
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. 

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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. 
Is 
The Intention-to-Treat (ITT) Population will consist of all subjects who received at least 
1 dose of study drug.  For the ITT population, subjects were considered as belonging to 
their treatment group at the time of the visit/event, regardless of the baseline dose of 
ambrisentan.  The ITT population will be used in all efficacy summaries. 
The Safety Population is defined as all subjects who received at least 1 dose of study 
drug.  Subjects were considered as belonging to the treatment group according to the 
highest dose received.  The safety population will be used in all safety summaries. 
Rationale 
From the time a patient enters AMB114388, doses may be adjusted based on the clinical 
judgment of the investigator; thus, the randomization that existed in AMB112529 is no 
longer applicable. 
Section 9.8  Independent Data Monitoring Committee (IDMC) 
Was 
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. 
Is 
The IDMC from Study AMB112529 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.  For the duration of Study AMB112529, the IDMC will review the data 
from AMB114588 at the same time the IDMC reviews the data from AMB112529.  
The schedule of any planned interim analysis and the analysis plan for IDMC review is 
described in the charter, which is available upon request. 
Rationale 
To clarify that the data from the two studies that are being conducted in the same patient 
population will be reviewed together. 

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11.5. 
Appendix 5: Protocol Amendment 02 
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 12 
Was: 
12. 
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. 

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Is: 
12. 
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. 
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 every six 
months while the subject is in the study, at the time the subject exits the study, and 4 to 6 
weeks after discontinuing ambrisentan for those subjects who do not remain on 
ambrisentan. 
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 every six months while the 
subject is in the study, at the time the subject exits the study, and 4 to 6 weeks after 
discontinuing ambrisentan for those subjects who do not remain on ambrisentan. 

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11.6. 
Appendix 6: Protocol Amendment 03 
Statement of Intent 
The intents of this amendment are primarily to modify the testing schedule for liver 
functions tests and to modify the locale for performing monthly pregnancy tests that do 
not occur at the quarterly visits, in light of the COVID-19 pandemic to minimize the 
subjects need to travel to the site while maintaining appropriate monitoring to ensure 
subject safety. In addition, the amendment seeks to clarify protocol language on the 30-
day follow-up and on the dose groups to which the subjects will be considered to belong 
for the analysis displays, as well as updating the Medical Monitor and Sponsor Signatory. 
Amended Sections of the Protocol 
Deletions are noted in Italics 
Insertions are noted in bold face. 
Sponsor Signatory Page 
Was 
Rose G. Snipes, M.D. 
Vice President 
Metabolic Pathways and Cardiovascular Therapy Area Unit 
Is 
Raj Saini, M.D. 
Vice President 
Disease Area Lead, Specialty (Clinical Sciences) 
 
Sponsor Information Page 
Was 
GlaxoSmithKline 
Iron Bridge Road  
Stockley Park West, Uxbridge, Middlesex, UB11 1BU, UK 
Is 
GlaxoSmithKline Research & Development Limited 
980 Great West Road 
Brentford 
Middlesex TW8 9GS 
United Kingdom 
Was 

T M F -1 3 3 5 9 0 3 9  
C O N FI D E N TI A L  
 
 
 
A M B 1 1 4 5 8 8  
 
6 2  
 
S p o ns or Me dical M o nit or a n d Seri o us A d verse E v e nts ( S A E) C o ntact I nf or mati o n:  
 
 F R C S 
Cli nic al Devel o p me nt P h ysici a n  
M D C Cli nic al Met a b olic E U  
Gl ax o S mi nt h Kli ne  
St ockley P ar k  
Is 
 M D F A C C 
Cli nic al Scie nces, Res pir at or y a n d S peci alt y  
Gl a x o S mit h Kli ne  
C olle ge ville, Pe n ns yl v a ni a  
 
I n S e cti o n 5. 7 Tr e at m e nt aft er t h e E n d of t h e St u d y  
Was  
T he I n vesti gat or s h o ul d t he n treat t he s u bjects acc or di n g t o best sta n dar d of care 
a vaila ble t o t he i n vesti gat or. S u bjects will be f oll o we d f or 3 0 d a ys p ost t heir last d ose of 
st u d y me dicati o n.  I n a d diti o n, s u bjects will be as ke d t o ret ur n f or a p u bertal de vel o p me nt 
assess me nt at 2 0 years of a ge.   
Is 
T he I n vesti gat or s h o ul d t he n treat t he s u bjects acc or di n g t o best sta n dar d of care 
a vaila ble t o t he i n vesti gat or. S u bjects will be f oll o we d f or 3 0 d a ys p ost t heir last d ose of 
st u d y me dicati o n f or m o nit ori n g of A Es/ S A Es .  I n a d diti o n, s u bjects will be as ke d t o 
ret ur n f or a p u bert al de vel o p me nt assess me nt at 2 0 years of a ge.   
Rati o nale  
T o ma ke t he secti o n w or di n g cle arer as t o t he i nte nt of t he 3 0 -da y f oll o w -u p.  
I n S e cti o n 6 St u d y A s s e s s m e nt s a n d Pr o c e d ur e s  
T a bl e 1 F o ot n ot e 2  
Was  
2. F or m o nt hs t h at do n ot c orres p on d to t he every t hr ee mo nt h visits, t h es e ass ess m ents m ay b e 
p erf or me d by th e su bj ect’s loc al physici a n a n d la b or at ory.  
 
Is 
P P D
P P D

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2. For months that do not correspond to the every three month visits, LFTs need not be 
performed unless clinically indicated, and these assessments may be performed by the 
subject’s local physician and laboratory. From the time of Amendment 03, urine pregnancy 
tests may be performed at the subject’s home using kits supplied by the site. 
 
Table 1 Footnote 8 
Was 
8. Subjects with a 20% decrease in 6MWD will need to return in 1 week to repeat 
the test, to confirm PAH deterioration. 
 
Is 
8. From the time of Amendment 03, this test is optional at the every six month 
visits. Subjects with a 20% decrease in 6MWD will need to return in 1 week to repeat 
the test, to confirm PAH deterioration. 
 
Table 1 Footnote 11 
Was 
11.  
Either Urine or blood monthly pregnancy tests for females of childbearing 
potential for the duration of the study 
Is 
11.  
Either Urine or blood monthly pregnancy tests for females of childbearing 
potential for the duration of the study. From the time of Amendment 03, urine 
pregnancy tests may be performed at the subject’s home using kits supplied by the 
site. 
Rationale 
To align the Time and Events table (Table 1) with the intended modification to the study 
procedures in light of travel restrictions due to the COVID-19 pandemic, 
In Section 6.2.6.1 Safety Tests 
Was 
• 
Liver Function:  serum alanine aminotransferase (ALT/SGPT), aspartate 
aminotransferase (AST/SGOT), gamma glutamyl transferase (GGT), and total 
bilirubin monthly. 
• 
Pregnancy:  Either urine or blood monthly pregnancy tests for female subjects of 
child bearing potential.  
Is 

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• 
Liver Function: serum alanine aminotransferase (ALT/SGPT), aspartate 
aminotransferase (AST/SGOT), gamma glutamyl transferase (GGT), and total 
bilirubin at the site visits that take place every 3 months, and otherwise as 
clinically indicated. 
• 
Pregnancy: Either urine or blood pregnancy tests for female subjects of child 
bearing potential at the site visits that take place every 3 months. At the 
intervening monthly intervals, a urine pregnancy test will be performed by the 
subject at home using a test kit supplied by the site. 
 
Rationale 
To simplify the required procedures for the remainder of the protocol in light of travel 
risks associated with the COVID-10 pandemic. 
In Section 6.3.2 Change from Study AMB112529 baseline in the 6 
minute walking distance (6MWD) test. 
Was 
The 6MWD will be assessed every six months while the subject is in the study, at the 
time he subject exits the study, and 4 to 6 weeks after discontinuing ambrisentan for those 
subjects who do not remain on ambrisentan.  Subjects with a 20% decrease in 6MWD 
will need to return in 1 week to repeat the test, to confirm PAH deterioration. 
Is 
The 6MWD will be assessed every six months while the subject is in the study but will 
be considered optional to perform at visits that take place after the approval of 
Protocol Amendment 03. The 6MWD will also be assessed at the time the subject exits 
the study, and 4 to 6 weeks after discontinuing ambrisentan for those subjects who do not 
remain on ambrisentan.  Subjects with a 20% decrease in 6MWD will need to return in 1 
week to repeat the test, to confirm PAH deterioration. 
Rationale 
To simplify the required procedures for the remainder of the protocol in light of travel 
risks associated with the COVID-10 pandemic. 
In Section 8.3.1 Analysis Populations 
Was 
The Intention-to-Treat (ITT) Population will consist of all subjects who received at least 
1 dose of study drug.  For the ITT population, subjects were considered as belonging to 
their treatment group at the time of the visit/event, regardless of the baseline dose of 
ambrisentan.  The ITT population will be used in all efficacy summaries. 
Is 

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The Intention-to-Treat (ITT) Population will consist of all subjects who received at least 
1 dose of study drug.  For the ITT population, subjects were considered as belonging to 
their treatment group corresponding to the dose being received at the time the subject 
transitioned into the study from Protocol AMB112529.  The ITT population will be 
used in all population and efficacy summaries. 
Rationale 
The previous wording carried the risk that the analysis results could be difficult to 
interpret if a subject had multiple dose changes throughout the study. 
In Section 8.3.5.1 Safety Analyses 
Was 
No formal statistical analysis is planned for safety parameters.  All data will be presented 
descriptively or graphically, by treatment group at the time of the visit/event and overall.  
Where data are available, it will be summarised by visit. 
Is 
No formal statistical analysis is planned for safety parameters.  All data will be presented 
descriptively or graphically, by treatment group according to the highest dose received 
and overall.  Where data are available, it will be summarised by visit. 
Rationale 
To correct a mistake in the protocol and make this section consistent with the wording in 
Section 8.3.1. 
In Section 8.3.5.2 Efficacy Analyses 
Was 
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 summarized by treatment group at the 
time of the visit, and overall. 
Is 
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 summarized by treatment group 
corresponding to the dose being received at the time the subject transitioned into the 
study from Protocol AMB112529, and overall. 
Rationale 

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The previous wording carried the risk that the analysis results could be difficult to 
interpret if a subject had multiple dose changes throughout the study. 
 

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11.7. 
Appendix 7: Protocol Amendment 04 
Statement of Intent 
The primary intent of this amendment is to include changes to when subjects can leave 
the study and the timing of the pubertal development assessment. Specifically, the 
amendment seeks to clarify that any subjects who reached pubertal maturity before 18 
years of age and ambrisentan can be supplied through a named patient or expanded 
access program until the subject reaches 18 years of age will complete their end of study 
visit at the investigator site. No further pubertal development assessments will be 
required for these subjects. All subjects who have reached the age of 18 and who have 
reached pubertal maturity at a previous visit will complete their final study visit in the 
form of a telephone follow-up in order to notify the subjects of the end of the study and 
that no further study visits and assessments will take place. All subjects who have 
reached the age of 18 and who have not reached pubertal maturity in previous visits will 
complete their final study visit at the investigator site and will have their pubertal 
development assessed. These patients may return at any point and do not need to wait 
until 20 years of age to have their pubertal maturity evaluated. 
 
Amended Sections of the Protocol 
Deletions are noted in Italics 
Insertions are noted in bold face. 
 
Sponsor Signatory Page 
Was 
Raj Saini, M.D. 
Vice President 
Disease Area Lead, Specialty (Clinical Sciences) 
 
Is 
Kaivan Khavandi, MBChB, MRes, MBA, PhD, MCRP 
Future Disease Area Lead 
Clinical Sciences, Specialty 
 
Rationale 
Updated to sponsor signatory page 
 

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In Section – Page 1 Summary Page 
Was 
This is an open label, long term extension to Study AMB112529.  All subjects may 
remain in the extension study for a minimum of six months.  Beyond the six month 
period, subjects may continue in the extension study until one of the following conditions 
is met: 
• 
the subject turns 18 years of age (when the subject can receive marketed product)  
 
Is 
This is an open label, long term extension to Study AMB112529.  All subjects may 
remain in the extension study for a minimum of six months.  Beyond the six month 
period, subjects may continue in the extension study until one of the following conditions 
is met: 
• 
the subject turns 18 years of age (when the subject can receive marketed product) or 
the subject has reached pubertal maturity before 18 years of age and 
ambrisentan can be supplied through a named patient or expanded access 
program until the subject reaches 18 years of age 
 
Rationale 
Updated wording to allow mature under 18 year old subjects to leave the study and 
continue drug supply through a named patient or expanded access program until the 
subject reaches 18 years of age when the marketed product will become available. 
 
In Section – Protocol Summary – Study Design 
Was 
This is an open label, long term extension to Study AMB112529.  All subjects may 
remain in the extension study for a minimum of six months.  Beyond the six month 
period, subjects may continue in the extension study until one of the following conditions 
is met: 
• 
The subject turns 18 years of age (when the subject can receive marketed product)  
 
Is 
This is an open label, long term extension to Study AMB112529.  All subjects may 
remain in the extension study for a minimum of six months.  Beyond the six month 

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period, subjects may continue in the extension study until one of the following conditions 
is met: 
• 
The subject turns 18 years of age (when the subject can receive marketed product) or 
the subject has reached pubertal maturity before 18 years of age and 
ambrisentan can be supplied through a named patient or expanded access 
program until the subject reaches 18 years of age 
 
Rationale 
Updated wording to allow mature under 18 year old subjects to leave the study and 
continue drug supply through a named patient or expanded access program until the 
subject reaches 18 years of age when the marketed product will become available. 
 
 
In Section – Protocol Summary – Study Endpoints/Assessments - 
Safety 
Was 
• 
Pubertal development (change from Study AMB112529 baseline in endocrinology 
assessments every six months and at 20 years of age); 
 
Is 
• 
Pubertal development (change from Study AMB112529 baseline in endocrinology 
assessments every six months and at 20 years of age unless pubertal maturity has 
been reached in previous visits); 
 
Rationale 
Updated wording to clarify that pubertal development assessments do not need to be 
repeated if pubertal maturity has been reached in a previous visit. 
 
In Section – 2.1.1 Safety 
Was 
• 
Pubertal development (change from Study AMB112529 baseline in endocrinology 
assessments every six months and at 20 years of age); 

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Is 
• 
Pubertal development (change from Study AMB112529 baseline in endocrinology 
assessments every six months and at 20 years of age unless pubertal maturity has 
been reached in previous visits); 
 
Rationale 
Updated wording to clarify that pubertal development assessments do not need to be 
repeated if pubertal maturity has been reached in a previous visit. 
 
In Section – 3.1 Study Design 
Was 
This is an open label, long term extension to Study AMB112529.  All subjects may 
remain in the extension study for a minimum of six months.  Beyond the six month 
period, subjects may continue in the extension study until one of the following conditions 
is met: 
• 
The subject turns 18 years of age (when the subject can receive marketed product) 
 
Is 
This is an open label, long term extension to Study AMB112529.  All subjects may 
remain in the extension study for a minimum of six months.  Beyond the six month 
period, subjects may continue in the extension study until one of the following conditions 
is met: 
• 
The subject turns 18 years of age (when the subject can receive marketed product) or 
the subject has reached pubertal maturity before 18 years of age and 
ambrisentan can be supplied through a named patient or expanded access 
program until the subject reaches 18 years of age; 
 
Rationale 
Updated wording to allow mature under 18 year old subjects to leave the study and 
continue drug supply through a named patient or expanded access program until the 
subject reaches 18 years of age when the marketed product will become available. 
 

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In Section – 5.7 Treatment after the end of the study 
Was 
Subjects can remain in this study until one of the following conditions is met: 
• 
The subject turns 18 years of age (when the subject can receive marketed product); 
• 
The product is approved and available for use in the subject’s age group; 
• 
Development for use in the paediatric population is discontinued; 
• 
The subject decides he/she no longer wants to participate in the study; 
• 
The investigator considers it is in the best interest of the subject to discontinue 
ambrisentan (e.g. for safety reasons). 
The Investigator should then treat the subjects according to best standard of care 
available to the investigator. Subjects will be followed for 30 days post their last dose of 
study medication for monitoring of AEs/SAEs.   
In addition, subjects will be asked to return for a pubertal development assessment at 20 
years of age. 
 
Is 
Subjects can remain in this study until one of the following conditions is met: 
• 
The subject turns 18 years of age (when the subject can receive marketed product) or 
the subject has reached pubertal maturity before 18 years of age and 
ambrisentan can be supplied through a named patient or expanded access 
program until the subject reaches 18 years of age; 
• 
The product is approved and available for use in the subject’s age group; 
• 
Development for use in the paediatric population is discontinued; 
• 
The subject decides he/she no longer wants to participate in the study; 
• 
The investigator considers it is in the best interest of the subject to discontinue 
ambrisentan (e.g. for safety reasons). 
The Investigator should then treat the subjects according to best standard of care 
available to the investigator. Subjects will be followed for 30 days post their last dose of 
study medication for monitoring of AEs/SAEs.   
In addition, subjects will be asked to return for a pubertal development assessment at 20 
years of age. 
Subjects will only be asked to return for a pubertal development assessment 
following their 18th birthday if pubertal maturity had not been reached in a 
previous visit. 

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All subjects who reached pubertal maturity before 18 years of age and ambrisentan 
can be supplied through a named patient or expanded access program until the 
subject reaches 18 years of age will complete their end of study visit at the 
investigator site for their end of study assessments as outlined in Table 1. As these 
subjects had already reached pubertal maturity, no further pubertal development 
assessments are required. 
All subjects who have reached the age of 18 and who have reached pubertal 
maturity at a previous visit will complete their final study visits in the form of a 
telephone follow-up. This is to notify the subjects of the end of the study and that no 
further study visits and assessments will take place. 
All subjects who have reached the age of 18 and who have not reached pubertal 
maturity in previous visits will complete their final study visit at the investigator site 
and will have their pubertal development assessed. These patients may return at any 
point and do not need to wait until 20 years of age to have their pubertal maturity 
evaluated. 
 
Rationale 
Added new wording to account for the different end of study scenarios for any remaining 
subjects who are either still active or in follow-up in the study. Updated wording to 
clarify that pubertal development assessments do not need to be repeated if pubertal 
maturity has been reached in a previous visit. 
 
In Section – Table 1 – Footnote 14 
Was 
- 
Footnote 14 did not exist 
 
Is 
14. In subjects where pubertal maturity has been reached prior to 20 years of age, 
the 20-year pubertal development assessment will not be required. All subjects who 
are over the age of 18 and who have not reached pubertal maturity in previous visits 
will complete their final study visit at the investigator site and will have their 
pubertal development assessed.  These patients may return at any point and do not 
need to wait until 20 years of age to have their pubertal maturity evaluated. 
 
Rationale 
Added new footnote 14 to clarify that the 20 year pubertal development assessments do 
not need to be repeated if pubertal maturity has been reached in a previous visit. In 

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addition, added additional wording to clarify that immature over 18 year olds can have 
their pubertal development assessed at any time after their 18th birthday and do not need 
to wait until they are 20 years of age.  
 
In Section – 6.2.4 Pubertal Development Assessment 
Was 
Pubertal development in male and female subjects will be assessed every six months 
while the subject is in the study, at the time the subject exits the study, 4 to 6 weeks after 
discontinuing ambrisentan for those subjects who do not remain on ambrisentan, and at 
20 years of age. using the 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. 
 
Is 
Pubertal development in male and female subjects will be assessed every six months 
while the subject is in the study, at the time the subject exits the study, 4 to 6 weeks after 
discontinuing ambrisentan for those subjects who do not remain on ambrisentan, and at 
20 years of age, unless pubertal maturity has been reached in previous visits. using 
the 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 
Updated wording to clarify that pubertal development assessments do not need to be 
repeated if pubertal maturity has been reached in a previous visit.