Clinical trial NCT01342952
Conditions: Hypertension, Pulmonary
Keywords: pulmonary arterial hypertension pediatrics
Sponsor: GlaxoSmithKline
Start date: 2011-06-21; Completion date: 2022-06-09
Enrollment: 38 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
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) 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 primary objective is the long-term safety and tolerability of ambrisentan in the paediatric PAH population. Secondary objectives are all cause mortality and change from baseline in Study AMB112529 on efficacy parameters.

Detailed description:
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. If left untreated, PAH ultimately leads to right ventricular failure and death; adult subjects have a median survival of 2.8 years without treatment. Epidemiological estimates vary but prevalence in Europe is thought to be of the order of 15 cases per million. 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. 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.

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).

Arms: arm 1: Open label, flexible dosing from 2.5 mg to 10 mg (not to exceed 0.25 mg/kg) per day
Interventions: intervention 1: Ambrisentan
Intervention descriptions: intervention 1: open label, flexible dosing from 2.5 to 10 mg (not to exceed 10 mg/kg) per day

Protocol documents:
Prot_000.pdf: 
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 
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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) 
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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. 
 
 

SAP_001.pdf: 
R A P  
C O N F I D E N T I A L  
A M B 1 1 4 5 8 8  
 
1  
Di visi o n: W orl d Wi 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: Re p orti n g a n d A nal ysis Pla n  
Title:  
Re p orti n g a n d A nal ysis Pla n f or A M B 1 1 4 5 8 8:  
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:  
0 3 J u n 2 0 2 2  
 
Descri pti o n : T his d oc u me nt o utli nes t he safet y a n d efficac y re p orti n g pla n ne d f or 
pr ot oc ol A M B 1 1 4 5 8 8 b y Gla x o S mit h Kli ne ( G S K).  
I de ntifier/ Versi o n N u m ber:  Versi o n 2 . 0 
S u bject:  G S K 1 3 2 5 7 6 0, P ul m o nar y Art erial H y perte nsi o n, L o n g T er m E xte nsi o n, 
Pae diatrics; Re p orti n g; Ta bles, Fi g ures, Listi n gs ( T F Ls)  
A ut h or’s N a me, Title a n d F u ncti o n al Are a:
,
 
Harti n gt o n Statistics a n d Data Ma na ge me nt Lt d.  
U p dat es b y 
A p pr o ve d b y:  
 
Se ni or Ma na ger -Statistics  
De vel o p me nt Statistics  
 
 
 
 
 
 
 
C o p yri g ht 2 0 2 2  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
P P D
P P D


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CONFIDENTIAL 
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2 
TABLE OF CONTENTS 
PAGE 
ABBREVIATIONS ........................................................................................................... 5 
1. 
INTRODUCTION ...................................................................................................... 7 
2. 
STUDY OBJECTIVE(S) AND ENDPOINT(S) ........................................................... 7 
2.1. 
Study Objective(s) ........................................................................................ 7 
2.1.1. 
Primary Objective .......................................................................... 7 
2.1.2. 
Secondary Objectives .................................................................... 7 
2.2. 
Study Endpoint(s) ......................................................................................... 7 
2.2.1. 
Primary Endpoints ......................................................................... 7 
2.2.2. 
Secondary Endpoints ..................................................................... 8 
2.2.2.1. 
Pharmacokinetics ......................................................... 8 
2.2.2.2. 
Efficacy ......................................................................... 8 
2.2.2.3. 
Exploratory ................................................................... 8 
2.2.2.4. 
Other ............................................................................ 8 
2.3. 
Statistical Hypotheses................................................................................... 8 
2.4. 
Pharmacokinetic (PK) and PK/Pharmacodynamic (PD) hypotheses ............. 9 
3. 
STUDY DESIGN ...................................................................................................... 9 
4. 
PLANNED ANALYSES ............................................................................................ 9 
4.1. 
Interim Analyses ........................................................................................... 9 
4.2. 
Final Analysis ............................................................................................... 9 
5. 
SAMPLE SIZE CONSIDERATIONS ......................................................................... 9 
6. 
ANALYSIS POPULATIONS ................................................................................... 10 
7. 
TREATMENT COMPARISONS .............................................................................. 10 
7.1. 
Data Display Treatment and Other Sub-group Descriptors ......................... 10 
8. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES ....................................... 10 
8.1. 
Examination of Subgroups .......................................................................... 10 
9. 
DATA HANDLING CONVENTIONS ....................................................................... 10 
9.1. 
Premature Withdrawal and Missing Data .................................................... 11 
9.1.1. 
Missing Efficacy Outcomes Data ................................................. 11 
9.1.2. 
Missing AE data ........................................................................... 11 
9.1.3. 
Missing Dates (other than for AEs) .............................................. 11 
9.1.4. 
Missing Items on SF-10 ............................................................... 11 
9.2. 
Derived and Transformed Data ................................................................... 12 
9.2.1. 
Baseline ....................................................................................... 12 
9.2.2. 
Change from baseline and percentage change from 
baseline ....................................................................................... 12 
9.2.3. 
WHO FC change from baseline categorisation 1 ......................... 12 
9.2.4. 
WHO FC class change from baseline categorisation 2 ................ 13 
9.2.5. 
Study Day .................................................................................... 13 
9.2.6. 
Age Calculation............................................................................ 13 


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9.2.7. 
Duration of Exposure ................................................................... 13 
9.2.8. 
Transformations for Efficacy Outcomes ....................................... 13 
9.2.9. 
Treatment Compliance Rates ...................................................... 14 
9.3. 
Assessment Windows ................................................................................. 14 
9.4. 
Values of Clinical Concern .......................................................................... 14 
9.4.1. 
Laboratory Parameters ................................................................ 14 
9.4.2. 
Vital Signs .................................................................................... 16 
10. STUDY POPULATION ........................................................................................... 16 
10.1. 
Disposition of Subjects ................................................................................ 16 
10.2. 
Protocol Deviations ..................................................................................... 16 
10.3. 
Medical Conditions ..................................................................................... 17 
10.4. 
Prior and Concomitant Medications ............................................................ 17 
10.5. 
Treatment Compliance ................................................................................ 17 
11. SAFETY ANALYSES ............................................................................................. 18 
11.1. 
Extent of Exposure ..................................................................................... 18 
11.2. 
Adverse Events........................................................................................... 18 
11.3. 
Adverse Events Leading to Discontinuation of Investigational 
Product and/or Withdrawal from the Study and Other Significant 
Adverse Events........................................................................................... 19 
11.4. 
Deaths and Serious Adverse Events ........................................................... 19 
11.5. 
Adverse Events of Special Interest ............................................................. 19 
11.6. 
Non-serious Adverse Events ....................................................................... 19 
11.7. 
Laboratory Evaluations ............................................................................... 19 
11.7.1. 
Liver Events ................................................................................. 20 
11.7.2. 
Vital Signs .................................................................................... 20 
11.7.3. 
Physical Examination ................................................................... 20 
11.8. 
12-Lead ECG .............................................................................................. 20 
11.9. 
Endocrinology ............................................................................................. 20 
11.10. Change in dose due to tolerability issues .................................................... 21 
11.11. Pregnancies (as applicable) ........................................................................ 21 
12. EFFICACY ANALYSES .......................................................................................... 21 
12.1. 
Exploratory analyses .................................................................................. 22 
12.2. 
Other analyses ........................................................................................... 22 
13. ADDITIONAL ANALYSES DUE TO THE COVID-19 PANDEMIC ........................... 23 
13.1 
Study Population ......................................................................................... 23 
13.2 
Subject Disposition and Protocol Deviations ................................ 23 
13.3 
Protocol Deviations ...................................................................... 23 
13.4 
Additional Displays for Participants with a COVID-19 
Infection ....................................................................................... 23 
13.5 
Additional Analyses Due to the COVID-19 Pandemic .................. 23 
13.6 
Assessment of COVID-19 AEs .................................................... 24 
14. CLINICAL PHARMACOLOGY DATA ANALYSES .................................................. 24 
14.1. 
Pharmacokinetic Analyses .......................................................................... 24 
14.2. 
Pharmacodynamic Analyses ....................................................................... 24 
14.3. 
Pharmacokinetic/Pharmacodynamic Analyses ............................................ 24 
15. BIOMARKER DATA ANALYSIS ............................................................................. 24 


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4 
16. PHARMACOGENETIC DATA ANALYSES ............................................................. 24 
17. VIRAL GENOTYPING/PHENOTYPING ................................................................. 24 
18. REFERENCES ....................................................................................................... 24 
19. ATTACHMENTS .................................................................................................... 25 
19.1. 
Table of Contents for Data Display Specifications ....................................... 25 
19.1.1. 
Tables .......................................................................................... 25 
19.1.2. 
Listings ........................................................................................ 31 
19.1.3. 
Figures ........................................................................................ 34 
19.2. 
Data Display Specifications ........................................................................ 36 
20. APPENDICES ...................................................................................................... 165 
20.1. 
Appendix 1 – IDSL Age Calculation .......................................................... 165 
 


RAP 
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5 
ABBREVIATIONS 
6MWD 
6 minute walking distance test 
AE 
Adverse Event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body mass index 
BSA 
Body surface area 
DBF 
Database Freeze 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
FC 
Functional Class 
GGT 
gamma glutamyl transferase 
GSK 
GlaxoSmithKline 
IDSL 
Integrated Data Standards Library 
IP 
Investigational Product 
ITT 
Intent-to-Treat 
kg 
Kilogram 
m 
Meter 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg  
milligram 
NT-Pro BNP 
N-Terminal pro-B-type Natriuretic Peptide 
PAH 
Pulmonary Arterial Hypertension  
PD 
Pharmacodynamic 
PDE-5 
Phosphodiesterase type 5 
PHS 
Physical Summary 
PK 
Pharmacokinetic 
PSS 
Psychosocial Summary 
PT 
Preferred Term 
RA 
Right atrial 
RV 
Right ventricle  
SAE 
Serious Adverse Event 
SAS 
Statistical Analysis Ststem 
SD 
Standard Deviation 
SF 
Short Form 
SOC 
System Organ Class 
TAPSE 
Tricuspid annular plane systolic excursion 
TEAE 
Treatment-emergent adverse events 
TRJ 
Tricuspid regurgitant jet 
ULN 
Upper limit of normal 
WHO 
World Health Organization 


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6 
Trademark Information 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
AMBRISENTAN 
 
Adcirca 
FLOLAN 
 
C RIBA 
 
 
Letairis 
 
 
NONMEM 
 
 
Remodulin 
 
 
Revatio 
 
 
Thelin 
 
 
Tracleer 
 
 
Ventavis 
 
 
Viagra 
 


RAP 
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7 
1. 
INTRODUCTION 
This Reporting and Analysis Plan (RAP) outlines the safety and efficacy reporting 
planned for protocol AMB114588 for provision to GSK.  
In this RAP, reference is made to the protocol AMB114588 dated 8th February 2011, and 
subsequent amendments. 
2. 
STUDY OBJECTIVE(S) AND ENDPOINT(S) 
2.1. 
Study Objective(s) 
This final RAP was updated following Protocol Amendment 4, in which the study was 
brought to early closure prior to the remaining active subjects either completing 18 years 
of treatment (1 subject) and/or having a pubertal assessment at 20 years of age. 
2.1.1. 
Primary Objective 
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. 
2.1.2. 
Secondary Objectives 
The secondary objective is to obtain supportive efficacy data (change from baseline in 
efficacy parameters) on the paediatric use of ambrisentan in PAH.  
2.2. 
Study Endpoint(s) 
2.2.1. 
Primary Endpoints 
• 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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8 
2.2.2. 
Secondary Endpoints 
2.2.2.1. 
Pharmacokinetics 
Not applicable. 
2.2.2.2. 
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. 
• School days missed due to PAH.   
2.2.2.3. 
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. 
2.2.2.4. 
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. 
2.3. 
Statistical Hypotheses 
No formal hypothesis is planned. 


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AMB114588 
 
9 
2.4. 
Pharmacokinetic (PK) and PK/Pharmacodynamic (PD) 
hypotheses 
Not applicable. 
3. 
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). 
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.  
For further details regarding the study design, please refer to the protocol. 
4. 
PLANNED ANALYSES 
4.1. 
Interim Analyses 
An interim analysis was added post the finalization of the study protocol, in order to 
provide analyses in support of regulatory interactions.  All data collected by a pre-
determined clinical cut-off date will be analyzed as per this RAP for the interim analysis 
report.  
4.2. 
Final Analysis 
This analysis plan outlines the final analysis that will be performed on the safety and 
efficacy endpoints of this study, once Database Freeze (DBF) has taken place.   
5. 
SAMPLE SIZE CONSIDERATIONS 
Sample size is based on feasibility. Due to low prevalence of the disease, no more than 66 
subjects will be enrolled in the study. No sample size sensitivity calculations were 
performed. No sample size re-estimation is planned. 


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10 
6. 
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 at the start of study AMB114588.  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. 
 
The Idiopathic Group Population is defined as subjects having an Idiopathic Aetiology of 
PAH (IPAH) at start of study treatment in AMB112529. 
 
7. 
TREATMENT COMPARISONS 
There are no formal comparisons planned for this study.  Doses of ambrisentan will be 
summarized descriptively based on available data. 
7.1. 
Data Display Treatment and Other Sub-group Descriptors 
Refer to the data display specification in Section 19 for examples showing how treatment 
groups will be displayed in the study report data displays. 
8. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES 
All programming of tables, figures and listings will be performed using Statistical 
Analysis System (SAS®) version 8.2 or higher. 
8.1. 
Examination of Subgroups 
Selected safety and efficacy outputs will be produced by age strata (8-11, 12-18 years). 
Selected outputs will also be produced for patients enrolled at centres in Japan to support 
registration activities. 
9. 
DATA HANDLING CONVENTIONS 
All data displays will be presented according to the GSK’s Integrated Data Standards 
Library (IDSL) statistical display principles. The file extension used for landscape tables 
and listings will be L10, with point size of 10, line size of 108 and 43 lines per page.  
Where data are sparse, empty tables may be produced with the “Data too sparse for table 
to be produced” or “No Data to Report” or similar. 
 
All data collected on the electronic case report form (eCRF) will be listed. Data collected 
outside of the eCRFs (eg. labs, SF10) will also be listed. All listings will be presented by 
treatment group and subject identification number. 


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9.1. 
Premature Withdrawal and Missing Data 
Subjects who withdraw from the study will not be replaced and all information obtained 
from them will be included in the summaries. 
9.1.1. 
Missing Efficacy Outcomes Data  
No imputation will be made for any missing numerical data, unless otherwise specified. 
 
Missing data will generally not be considered in the calculation of percentages (i.e., the 
denominator will not include subjects who have missing data at a given time point). 
9.1.2. 
Missing AE data  
Where a start date for an adverse event (AE) is partial or missing, the following 
imputation rules will be applied:  
• 
If day portion is missing, set day to 1. 
• 
If month portion is missing, set month to January. 
• 
If the date is completely missing, or if the date imputed using the above rules is prior 
to the first dose date, set the date to first dose date. 
Where an end date for an AE is partial or missing, the following imputation rules will be 
applied.  These will only be applied to AEs that are resolved; if they are not resolved then 
nothing will be imputed.  
• 
If day portion is missing, set day to the last day of the month. 
• 
If month portion is missing, set month to December.  
• 
If the date is completely missing, or if the date imputed using the above rules is after 
the treatment end date, set the date to the treatment end date or if the treatment end 
date is missing then set to date of discontinuation.  
No further imputation will be performed for missing data. 
 
9.1.3. 
Missing Dates (other than for AEs) 
For any data type that collects partial dates, impute missing day as 01 and missing month 
as January.  If date is completely missing then date should remain missing.  
Where the start date of study medication is missing, the date of randomisation will be 
used.  Where end date of study medication is partial or missing, the last complete non-
missing date of dosing will be used as the last date for determining duration of exposure. 
9.1.4. 
Missing Items on SF-10 
The SF-10 will be scored in accordance with the developer’s guidelines. Out-of-range 
values are converted to missing values and no algorithm is used to estimate missing 
values.  The Physical and Psychosocial summary scores are not calculated if any 
component scores are missing.   


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9.2. 
Derived and Transformed Data 
All listings will include all subjects that have the relevant data for each listing. 
The number of subjects (N) in each treatment group and overall for the population being 
summarised, will be displayed in each table unless specified otherwise.  
For continuous data, the following summary statistics will be presented: n, mean, 
standard deviation (SD), median, upper and lower quartiles, minimum and maximum.   
Mean and median values will be reported to one decimal place greater than the original 
data they were collected from while the SD will be reported to two decimal places greater 
than the original data however, if this results in a value of 0.00 being presented then a 
zero (0) will be presented.  Minimum and maximum values will be reported with the 
same precision as they were collected. 
All text fields must be left justified.  Numeric or numeric with some text specification 
(e.g., not done, unknown, <4.5, …) must be right justified. 
The format for dates will be DDMMMYYYY. 
All tables and listings will have the protocol number and population in the top left-hand 
corner and the page number in the form of page x of n will be presented in the top right-
hand corner.  In the bottom left-hand corner of tables and listings the name of the person 
who created the output followed by a colon, the output filepath and the date and time of 
the production of the output, in the form DDMMMYYYY HH:MM, will be displayed.   
If a count in a table summary is zero (0) then a percentage will not be presented.  
To determine whether an adverse event is on-treatment and a medication is prior or 
concomitant, imputation of missing or partial start and stop dates is required (see RAP 
Section 9.1.2 and Section 9.1.3). Imputed dates will not be listed and adverse event 
duration will not be calculated if the start date or stop date had to be imputed. 
9.2.1. 
Baseline 
Baseline values are those collected prior to the first dose (from Study AMB112529).  
Therefore, if a subject has no data for a parameter on Day 1 (prior to first dose) then the 
data from their last pre-treatment assessment will be used. 
9.2.2. 
Change from baseline and percentage change from baseline 
For untransformed data change from baseline at Week X will be calculated as Week X 
value minus baseline value. The percentage change from baseline at Week X will be 
calculated as: 100  (Week X value – baseline value) / baseline value. 
For log-transformed data (see Section 9.2.8), ratio to baseline expressed as percentage 
change will be calculated by taking the mean change on the log scale, exponentiating, 
subtracting 1 and multiplying by 100. 
 (Exp(mean of (Log x - Log baseline)) -1)*100 
9.2.3. 
WHO FC change from baseline categorisation 1 
Note that based on the study inclusion criteria subjects must have a WHO FC of II or III 
at baseline.  Change from baseline at Week X will be calculated as Week X value minus 
baseline value, thus categories may be -2, -1, 0, +1, +2.  
 


R A P  
C O N F I D E N T I A L  
A M B 1 1 4 5 8 8  
 
1 3  
 
 
P ost B aseli ne W H O F C  
 
B aseli ne W H O 
F C  
9. 2. 4.  
W H O F C cl a s s c h a n g e fr o m b a s eli n e c at e g ori s ati o n 2  
i n C ha n ge fr o m Bas eli ne Cate g orisati o n 
i n C ha n ge fr o m Bas eli ne Cate g oris ati o n 
i n C ha n ge fr o m Baseli ne Cate g orisati o n 
9. 2. 5.  
St u d y D a y  
St u d y Da y 1 is defi n e d as t he da y of t he first d ose of st u d y dr u g  i n A MB 1 1 2 5 2 9.  
Rel ati ve D a y t o st art of st u d y me dic ati o n f or a n E ve nt is defi ne d as: 
Date of e v e nt - D ate of first st u d y me dicati o n + 1, if t he e ve nt is o n or after t he first d ose 
date.  
Date of e v e nt - D ate of first st u d y me dicati o n, if t he e ve nt is pri or t o t he  first d ose date. 
Rel ati ve D a y t o e n d of me dic ati o n  f or a n E v e nt is defi ne d as: 
Date of e v e nt - D ate of last st u d y m e dicati o n + 1, if t he e ve nt is o n or after t he last d ose 
date.  
Date of e v e nt - D ate of last st u d y m e dicati o n, if t h e e ve nt is pri or t o t he l ast d ose date.  
9. 2. 6.  
A g e C al c ul ati o n  
A ge i n years at baseli ne will be deri ve d as a w h ol e n u m ber acc or di n g t o t h e I D S L 
sta n dar d al g orit h m (see A p pe n di x 1 ). 
9. 2. 7.  
D ur ati o n of E x p o s ur e  
D urati o n of e x p os ure will be calc ulate d i n d a ys as ( Treat me nt st o p dat e –  Treat me nt start 
date  i n A M B 1 1 2 5 2 9) + 1. 
9. 2. 8.  
Tr a n sf or m ati o n s f or Effi c a c y O ut c o m e s  
A l o g tra nsf or mati o n  will be a p plie d t o N T -pr o B N P data.  
S u m maries of t he relati v e c ha n ges fr o m bas eli ne base d o n a nal ysis of l o g -tra nsf or me d 
data will i ncl u de t he ge o metric mea n a n d c oeffici e nt of variati o n (calc ulat e d as bel o w 
base d o n t he l o g ge d val u es) a n d t he ge o metric me a n of t he rati o of t he val u e of t he 
e n d p oi nt at t he ti me p oi nt of i nterest t o t he baseli n e val ue (s ee Secti o n 9. 2. 2 ) . 
Ge o metric mea n = e x p( µ)  
C oefficie nt of v aria ti o n =s 1 0 0 x √ [e x p( σ 2) –  1]  
C CI
C CI
C CI
C CI


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9.2.9. 
Treatment Compliance Rates 
Compliance to study medication is recorded at each visit in one of the following 
categorical groups: 
• 0% compliant (subject did not take any doses) 
• >0% and < 80% compliant (subject missed a number of doses) 
• >=80% and <=120%, (number of doses taken was within compliance range) 
• >120% compliant (number of doses taken exceeds compliance limits) 
 
At the subject level compliance rate is calculated as  
100*(the number of visits at which the subject was compliant (i.e. ≥80% and ≤120%) / 
(the sum of all study visits for the subject).   
 
At a treatment group level compliance rate is calculated as  
100*(the total number of visits at which all subjects in that group were compliant (i.e. ≥ 
80% and ≤ 120%)) / (the sum of all study visits for all subjects in that group). 
  
9.3. 
Assessment Windows 
All data will be reported for the whole study period. 
Unscheduled assessments will not be slotted to a particular time point, but will remain as 
unscheduled unless otherwise specified. 
Time points relating to nominal visits will be used in tables, figures and listings. 
Time to clinical worsening of PAH and time to liver event will be calculated using the 
date of assessment.  
9.4. 
Values of Clinical Concern 
9.4.1. 
Laboratory Parameters 
The following values of potential clinical concern will be considered: 
Values of potential 
clinical concern 
values will be 
defined for 
laboratory 
parameters as 
follows: 
Parameter 
Code 
Units  
Low 
Concern 
Value (SI 
units) 
High 
Concern 
Value (SI 
units) 
Worse case 
direction 
Hematology 
 
 
 
 
 
Hemoglobin 
HGB 
G/L 
Males:     
< 98 
Females: 
< 91 
Males:   > 
180.0 
Females:  
> 161.0 
Low 


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Values of potential 
clinical concern 
values will be 
defined for 
laboratory 
parameters as 
follows: 
Parameter 
Code 
Units  
Low 
Concern 
Value (SI 
units) 
High 
Concern 
Value (SI 
units) 
Worse case 
direction 
Hematocrit 
HCT  
% 
(1) 
Males:     
< 32.0 
(<0.32) 
Females:  
<29.0 
(<0.29) 
Males:     
> 54.0 
(>0.54) 
Females:  
> 50.6 
(>0.506) 
Low 
Platelets 
PLATE 
10^9/L 
(same as 
GI/L) 
< 100 
> 500 
Low 
Chemistry 
 
 
 
 
 
Total bilirubin 
BILTOT UMOL/L 
None 
>= 34.2   
High 
AST 
ASAT 
IU/L 
None 
>= 3 x 
ULN 
High 
ALT 
ALAT 
IU/L 
None 
>= 3 x 
ULN 
High 
GGT 
GGT 
IU/L 
None 
>= 3 x 
ULN 
High 
Creatinine 
CREAT 
UMOL/L 
None 
>= 176.8 
High 
 


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9.4.2. 
Vital Signs  
The following criteria will be used to determine whether a subject’s vital signs (blood 
pressure and heart rate) lie outside a pre-determined range of clinical concern: 
Parameter 
Code 
Units  
Low Concern 
Value 
High Concern Value 
Heart Rate 
PUL 
Bpm 
< 50 
> 120 
Systolic 
SYS 
mm Hg 
< 80 
> 160 mm Hg  
> 30 mm Hg  change from 
Baseline 
Diastolic 
DIA 
mm Hg 
< 40 
> 110 mm Hg 
> 20 mm Hg change from 
Baseline 
Body weight 
WT 
Kg 
< 20 
 
10. 
STUDY POPULATION 
Study population data will be presented for the Intent-to-Treat Population unless 
otherwise specified. 
10.1. 
Disposition of Subjects 
The number of subjects eligible for each of the analysis populations will be summarised 
by treatment group and overall, and by country and centre.   
The number of subjects completing/withdrawing from the study along with the reasons 
for withdrawal will be summarised by treatment group and overall. 
10.2. 
Protocol Deviations 
The number of subjects with important protocol deviations will be summarised by 
treatment group and overall. 
 
A summary of subjects who did not satisfy all inclusion and exclusion criteria will be 
provided by treatment group. 
 
The protocol deviations will be reviewed by the clinical team after the database release 
and prior to the database freeze, to determine which ones are considered to be important 
Demographic and Baseline Characteristics. 
The number and percentage of subjects in each category for categorical variables or 
summary statistics for continuous variables will be summarised by treatment group and 
overall. These include age, age strata, sex, child-bearing potential, ethnicity and 
geographic ancestry, aetiology of PAH strata, duration of PAH, PAH therapy use, WHO 
FC score and 6 minute walk distance. 


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10.3. 
Medical Conditions 
The number and percentage of subjects with past or current medical conditions will be 
summarised by treatment group and overall, for any condition and by condition 
classification. 
10.4. 
Prior and Concomitant Medications 
The GSKdrug dictionary will be used to code drug names. 
Prior medications are those that started and stopped prior to the date of first study 
treatment.  Ongoing medications at baseline are those started before first dose date of 
study drug, which were continued during the treatment phase. 
Lab  medications are defined as: 
▪ Medications that start prior to or on the date of first study treatment and that 
stopped prior to the date of last study treatment, 
▪ Medications that start prior to or on the date of first study treatment and continued 
after the date of last study treatment, 
▪ Medications that start after the date of first study treatment and that stopped prior 
to the date of the last study treatment, 
▪ Medications that start after the date of first study treatment and continued after the 
date of last study treatment. 
Any medications that started after the last study treatment are classed as post-treatment 
medications.  
Note that it will be assumed that the medication has been taken by the medication start 
and stop dates recorded in the eCRF. 
The number and percentage of subjects with concomitant medications will be 
summarised by Anatomical Therapeutic Chemical (ATC) Classification System code and 
drug name Preferred term by treatment group and overall.  
The number and percentage of subjects with ongoing (at entry to AMB114588) and 
concomitant PAH therapy (at 6 months after entry into AMB114588 and then annually as 
well as the final visit) will be summarised by preferred term, by treatment group and 
overall. The ATC codes from the GSKDrug dictionary for the groupings of PAH therapy 
will be agreed with the Clinical Safety Group and provided in a separate file.  This 
includes: 
• 
PDE5i 
• 
Prostanoid 
10.5. 
 Treatment Compliance 
Every three months, treatment compliance will be recorded as 0%, >0% - <80%, =>80% 
- <=120% and >120%.  
The number and percentage of subjects in each compliance category will be summarised 
at each visit by treatment group and overall. 


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11. 
SAFETY ANALYSES 
Safety data will be presented for the Safety Population unless otherwise specified. 
11.1. 
Extent of Exposure 
The number of days of exposure to study drug will be summarised by treatment group 
and overall. 
This number of days of exposure will be categorised in 30 day intervals as follows: <=30 
days, 31-60 days, 61-90 days etc.   
The number and percentage of subjects in each of these categories will be summarised by 
treatment group and overall.  
11.2. 
Adverse Events 
All AEs will be categorised into Preferred Term (PT) and associated System Organ Class 
(SOC) using the Medical Dictionary for Regulatory Activities (MedDRA) coding 
dictionary. 
Only treatment-emergent adverse events (TEAEs) will be included in summary tables. 
TEAEs are defined as those events that start on or after first dose date of study treatment. 
Any subject with at least one reported TEAE will be classified as a subject with: 
▪ A TEAE, 
▪ A TEAE leading to study treatment discontinuation (definitive or temporary), 
▪ A TEAE leading to study withdrawal, 
▪ At least one serious TEAE. 
The numbers and percentages of subjects with at least one reported TEAE will be 
summarised by treatment group and overall according to: 
▪ PT, 
▪ SOC and PT, 
▪ SOC and PT by intensity, 
▪ SOC and PT by relationship to study treatment, 
▪ PT by action taken with investigational product (IP). 
 
Recurring TEAEs (i.e. successive TEAEs classified with the same PT) for a given subject 
will only be counted once and only their most severe intensity will be tabulated. 
The cumulative incidence of each TEAE will also be summarised by SOC and PT and the 
following categories:  <=3 months, >3 to <=6months, etc.  
TEAEs will be listed by SOC and PT, by treatment with the number of subjects who 
experienced the event and their subject numbers presented.  A more detailed listing will 
also be produced for all subjects who experienced an AE.   


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11.3. 
Adverse Events Leading to Discontinuation of 
Investigational Product and/or Withdrawal from the Study 
and Other Significant Adverse Events 
The numbers and percentages of subjects with at least one reported TEAE leading to 
discontinuation of the investigational product or withdrawal from the study will be 
summarised by SOC and PT for each treatment group and overall.  Covid-19 adverse 
event data will be shown here if any exist. 
11.4. 
Deaths and Serious Adverse Events 
Summary tables detailed in sections 11.2 and Section 11.3 (with the exception of 
cumulative incidence) will be repeated for serious TEAEs. 
Summary tables will also be presented for serious TEAEs by PT and outcome for each 
treatment group and overall. 
A summary of serious TEAEs displaying the number of subjects and occurrences will 
also be presented. 
In addition, the number of subjects with fatal TEAEs and fatal TEAEs related to IP will 
be summarised by SOC and PT for each treatment group and overall. 
11.5. 
Adverse Events of Special Interest 
Summary tables detailed in sections 11.2 and Section 11.3 (with the exception of tables 
by maximum intensity/grade, action taken and relation to IP) will be repeated for AEs of 
special interest.  MedDRA preferred terms and codes for AEs of special interest will be 
agreed with Clinical Safety Group and provided in a separate file. 
The adverse events of special interest are: 
• 
Anaemia 
• 
Hepatoxicity  
• 
Hypersensitivity 
• 
Hypotension 
• 
Male infertility 
• 
Oedema 
• 
Fluid retention 
11.6. 
Non-serious Adverse Events 
A summary of the most common (>=5%) non-serious TEAEs displaying the number of 
subjects and occurrences will also be presented. 
11.7. 
Laboratory Evaluations 
Absolute values and changes from baseline of laboratory data will be summarised for 
each visit, by treatment group and overall. 


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20 
Separate tables will be presented for haematology data, clinical chemistry data and 
endocrine data (females only). 
The number and percentages of subjects with laboratory values above and below 
reference ranges for potential clinical concern described in Section 9.4.1 will be 
summarised for each visit, by treatment group and overall. 
11.7.1. 
Liver Events 
The number and percentage of subjects reporting a liver event will be summarised: 
overall, during and post study treatment. 
 
The following will be listed by treatment group, for subjects with liver events: 
▪ liver chemistry result involved in the event. 
▪ Time from first and last dose to start of event  
▪ Patient specific information for liver events  
▪ Medical conditions. 
▪ Liver biopsy details. 
▪ Liver imaging details. 
 
11.7.2. 
Vital Signs 
Absolute values and changes from baseline of vital signs data will be summarised for 
each visit, by treatment group and overall. 
The number and percentages of subjects with vital signs values or change from baseline 
values above and below reference ranges for potential clinical concern described in 
Section 9.4.2 will be summarised for each visit, by treatment group and overall.  
11.7.3. 
Physical Examination 
Physical examination at each visit will be summarised by treatment group and overall. 
11.8. 
12-Lead ECG 
The number and percentages of subjects with electrocardiogram (ECG) abnormalities 
(clinically significant and not clinically significant) will be summarised for each visit, by 
treatment group and overall. 
11.9. 
Endocrinology 
The following will be summarised for each visit (as appropriate) by treatment group and 
overall. 
▪ Female breast development and pubic hair development. 
▪ Male testicular volume, genital development and pubic hair development. 
▪ Change from baseline in male testicular volume. 
▪ Change from baseline in plasma endocrine parameters (Follicle Stimulating 
Hormone, Luteinizing Hormone, Sex Hormone Binding Globulin, Total 
Testosterone and Inhibin B) by gender. 
 
The above tables will also be summarised by pubertal status at baseline defined as 
follows: 


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21 
Male:  Pre-pubertal: testicular volume < 4 ml, Post-pubertal: testicular volume ≥ 4 ml. 
Female: Pre-pubertal: Stage 1 breast development, Post-pubertal: Stage ≥ 2 breast 
development. 
 
11.10. 
Change in dose due to tolerability issues 
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) will be 
summarised by treatment group and overall. 
11.11. 
Pregnancies (as applicable) 
A listing of pregnancy events will be provided, as necessary.  
 
12. 
EFFICACY ANALYSES 
Efficacy data will be presented for the Intent-to-Treat Population unless otherwise 
specified. 
The following will be summarised for observed case data for each visit (as appropriate) 
by treatment group and overall. 
▪ All cause mortality. 
▪ The absolute value, change from Study AMB112529 baseline and % change from 
baseline in the 6 minute walking distance (6MWD) test, overall and by oxygen 
use.   
▪ The walking duration for subjects who walked less than six minutes. 
▪ The use of oxygen during the 6MWD test. 
▪ The time to clinical worsening of PAH. 
▪ The criteria for clinical worsening of PAH. 
▪ The time to addition of another targeted PAH therapeutic agent (prostanoids, 
PDE-5 inhibitors) due to the following reasons: 
o Deterioration of clinical condition; 
o 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. 
▪ WHO Functional Class and change from Study AMB112529 baseline in WHO 
Functional Class.  
▪ The absolute value and percent change from Study AMB112529 baseline, using 
log-transformed data, in N-terminal pro-B-type natriuretic peptide (NT-Pro BNP) 
concentration. 
▪ The absolute value and change from baseline in the number of school days, 
missed school days and missed school days due to PAH. 
▪ The absolute value and change from Study AMB112529 baseline in Subject 
Global Assessment as measured by the SF-10 health survey for children and 
summarised for the physical summary score (PHS-10) and the psychosocial 
summary score (PSS-10).    


R A P  
C O N F I D E N T I A L  
A M B 1 1 4 5 8 8  
 
2 2  
F urt her t a ble will be pr o d uce d s u m marizi n g c h a n ge i n W H O F C sc ores cate g orize d i n 
ter ms of 
a n d i n ter ms of 
(see 
Secti o n 9. 2. 3  a n d Secti o n 9. 2. 4 ). 
1 2. 1.  
E x pl or at or y a n al y s e s  
T he f oll o wi n g will be s u m marise d f or eac h visit, b y treat me nt gr o u p a n d o verall.  
•  
T he a bs ol ute val ue a n d c ha n ge fr o m St u d y A M B 1 1 2 5 2 9 baseli ne i n e x pl orat or y 
ec h ocar di o gra m: pericar dial eff usi o n, ri g ht atrial press ure, tric us pi d a n n ular pla ne 
s yst olic e x c ursi o n, ecce ntricit y i n de x (s yst olic a n d diast olic), tric us pi d re g ur gita nt jet 
vel ocit y a n d ri g ht ve ntric ular press ur e.  
1 2. 2.  
Ot h er a n al y s e s  
T he f oll o wi n g will be liste d f or eac h visit, b y treat me nt gr o u p. 
▪ T he a bs ol ute val ue a n d c ha n ge fr o m St u d y A M B 1 1 2 5 2 9 baseli ne i n 
car di o p ul m o nar y h e m o d y n a mics  (at ce nt res w h ere t he c ollecti o n of 
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): - h eart rate, m ea n 
arterial bl o o d press ure, m ea n p ul m o nar y arterial press ure, mea n ri g ht atrial 
press ure, left ve ntric ular e n d diast olic press ure or p ul m o nar y ca pillar y we d ge 
press ure, p ul m o nar y vasc ular resista nce, car diac o ut p ut, car diac i n de x (calc ulate d 
val ue), arterial o x y ge n s at urati o n a n d mi x e d ve n o us o x y ge n s at urati o n.  
C CI
C CI


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13. 
ADDITIONAL ANALYSES DUE TO THE COVID-19 
PANDEMIC 
13.1 
Study Population 
No changes required as enrollment was completed at time of COVID-19 restrictions. 
13.2 
Subject Disposition and Protocol Deviations 
A country level listing of the dates of the COVID-19 Pandemic measures will be 
produced, as well as a listing of visits impacted by the COVID-19 Pandemic.  
Phases of COVID-19 Pandemic Measures 
Pandemic measures began in different countries at different times. A dataset containing 
the date when pandemic measures began, as determined by the GSK country Issue 
Management Teams (IMT), will be used to determine the start date of pandemic 
measures within each country. A copy of this dataset will be taken at the time of database 
freeze (DBF). 
 
The ‘Summary of Subject Status and Subject Disposition for the Study Conclusion 
Record’ and the ‘Summary of Treatment Status and Reasons for Discontinuation of Study 
Treatment’ will be repeated, with the reason for withdrawal/discontinuation categorised 
as due to the COVID-19 pandemic, or non-due to the COVID-19 pandemic based on 
information collected on the COVID-19 Pandemic Study Impact form.  
 
13.3 
Protocol Deviations 
In addition to the overall summary of important protocol deviations, a separate summary 
will be produced of important protocol deviations related to COVID-19.  
13.4 
Additional Displays for Participants with a COVID-19 Infection 
A participant is defined as having a suspected, probable or confirmed COVID-19 
infection during the study if the answer is “Confirmed”, “Probable” or “Suspected” to the 
case diagnosis question from the COVID-19 coronavirus infection assessment eCRF. 
Summaries and/or listings of the numbers of participants with a suspected, probable or 
confirmed COVID-19 infection, and of COVID-19 test results will be presented. 
 
13.5 
Additional Analyses Due to the COVID-19 Pandemic 
Visits and assessments missed due to the COVID-19 pandemic, together with visits 
conducted remotely, will be summarised in a table and listed by subject. The summaries 
will be based on GSK Core Data Standards, and details are provided in Section 4: List of 
Data Displays. 


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24 
13.6 
Assessment of COVID-19 AEs 
A terms of interest list, list code 319259, created by the GSK dictionaries group, will be 
used to identify all COVID-19 AEs. 
 
The incidence of AEs and SAEs (Fatal and Non-Fatal) of COVID-19, COVID-19 AEs 
leading to study drug discontinuation, and COVID-19 AEs leading to study withdrawal, 
and COVID-19 AEs by severity, will be obtained from standard AE and SAE summaries 
if data exist to meet the criteria.  A listing of relevant data will be created. 
14. 
CLINICAL PHARMACOLOGY DATA ANALYSES 
14.1. 
Pharmacokinetic Analyses 
Not applicable. 
14.2. 
Pharmacodynamic Analyses 
Not applicable. 
14.3. 
Pharmacokinetic/Pharmacodynamic Analyses 
Not applicable. 
15. 
BIOMARKER DATA ANALYSIS 
Not applicable. 
16. 
PHARMACOGENETIC DATA ANALYSES 
Not applicable. 
17. 
VIRAL GENOTYPING/PHENOTYPING 
Not applicable. 
18. 
REFERENCES 
 


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25 
19. 
ATTACHMENTS 
19.1. 
Table of Contents for Data Display Specifications 
19.1.1. 
Tables 
Table numbering for the Japanese subgroup will be add 001 at the end of the table number.  Thus, Table 1.1 will become 1.1001. 
Table numbering for the Age Strata subgroup will be add 002 at the end of the table number.  Thus, Table 1.5 will become 1.5002. 
 
Japanese and Age subgroup analysis will not be needed for final SAC. 
 
Population Tables 
 
Table 
Number 
Title 
Population 
Template 
Table 
Japanese 
subgroup 
analysis 
Age strata 
subgroup 
analysis 
Deliverable 
1.1 
Summary of Subject Disposition 
(See 2 additional rows added to existing table: 1) additional row 
20 year count, and 1 covid death related row) 
Prog Note:  The deaths should be mutually exclusive (ie only in 1 category) 
Intent-to-
Treat 
1.1 
X 
 
Interim, SAC 
1.2 
Summary of Study Populations   
Randomised 
1.2 
 
 
Interim, SAC 
1.3 
Summary of Subjects by Country and Centre 
Intent-to-
Treat 
1.3 
 
Disclosure Interim, SAC 
1.4 
Summary of Inclusion/Exclusion Criteria Deviations 
Intent-to-
Treat 
1.4 
 
 
Interim, SAC 
1.5 
Summary of Demographic and Baseline Characteristics 
Intent-to-
Treat 
1.5 
X 
X 
Interim, SAC 
1.6 
Summary of Past Medical Conditions 
Intent-to-
Treat 
1.6 
 
X 
Interim, SAC 
1.7 
Summary of Current Medical Conditions 
Intent-to-
Treat 
1.6 
 
X 
Interim, SAC 
1.8 
Summary of Concomitant Medications 
Intent-to-
Treat 
1.8 
X 
 
Interim, SAC 
1.9 
Summary of Ongoing Background PAH Therapy at Entry 
Visit to AMB114588 By Drug Class and Preferred Term 
Intent-to-
Treat 
1.9 
 
X 
Interim, SAC 
1.10 
Summary of Ongoing Background PAH Therapy by Drug 
Class and Preferred Term 
Intent-to-
Treat 
1.9 
 
X 
Interim, SAC 
1.11 
Summary of Compliance to Investigational Product 
since last visit 
Intent-to-
Treat 
1.11 
 
 
Interim, SAC 
1.12 
Summary of Investigational Product Compliance 
Overall 
Intent-to-
Treat 
1.12 
 
 
Interim, SAC 
1.13 
Summary of initial dose of ambrisentan at entry to 
AMB114588 and highest dose received during study 
Intent-to-
Treat 
1.13 
 
 
Interim, SAC 
1.14 
Summary of initial dose of ambrisentan at entry to 
AMB114588 and final dose at end of study or 
termination 
Intent-to-
Treat 
1.14 
 
 
Interim, SAC 
1.15 
Summary of Important Protocol Deviation 
Intent-to-
Treat 
1.15 
 
 
Interim, SAC 
1.16 
Summary of Concomitant Medications starting in 
AMB114588 
Intent-to-
treat 
1.8 
 
 
Added at 
Interim 
 
 
 
Covid-19 Tables 


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AMB114588 
 
 
26 
Table 
Number 
Title 
Population Template 
Table 
Deliverable 
Programming Notes 
1.17 
Summary of Important 
COVID-19 Related 
Protocol Deviations 
Intent-to-
Treat 
Same as protocol DV table 
except subset for COVID-19 
related 
SAC [1] 
 
1.18 
Summary of COVID-19 
Assessments for Subjects 
with Suspected, Probable 
or Confirmed COVID-19 
Case Diagnosis 
Intent-to-
Treat 
1.19 
SAC [1] 
 
1.19 
 
Summary of Visits 
impacted by COVID-19 
Pandemic 
Intent-to-
Treat 
1.20 
SAC [1] 
 
 
 
Efficacy Tables 
Table 
Number 
Title 
Population 
Template 
Table 
Japanese 
subgroup 
analysis 
Age 
strata 
subgroup 
analysis 
Deliverable 
2.1 
Summary of Time to Death (All cause) (days) 
Intent-to-
Treat 
2.1 
X 
X 
Interim, SAC 
2.2 
Summary of 6 Minute Walking Distance (meters) 
Intent-to-
Treat 
2.2 
X 
X 
Interim, SAC 
2.3 
Summary of Change from Baseline in 6 Minute Walking 
Distance (meters) 
Intent-to-
Treat 
2.2 
X 
X 
Interim, SAC 
2.4 
Summary of Percent Change from Baseline in 6 Minute 
Walking Distance (meters) 
Intent-to-
Treat 
2.2 
X 
X 
Interim, SAC 
2.5 
Summary of Walking Duration (minutes) for subjects 
who walked less than six minutes 
Intent-to-
Treat 
2.5 
X 
X 
Interim, SAC 
2.6 
Summary of use of Oxygen during 6 Minute Walking 
exercise (L/min) 
Intent-to-
Treat 
2.6 
X 
X 
Interim, SAC 
2.7 
Summary of Time to Clinical Worsening of PAH (days) 
Intent-to-
Treat 
2.7 
X 
 
Interim, SAC 
2.8 
Summary of Clinical Worsening of PAH 
Intent-to-
Treat 
2.8 
 
 
Interim, SAC 
2.9 
Summary of Time to the addition of another targeted 
PAH therapeutic agent (prostanoids, PDE-5 
inhibitors) (days) 
Intent-to-
Treat 
2.9 
X 
 
Interim, SAC 
2.10 
Summary of Time to change in dose of ambrisentan or 
other targeted PAH therapeutic agents (prostanoids, 
PDE-5 inhibitors) due to deterioration of clinical 
condition (days) 
Intent-to-
Treat 
2.10 
X 
 
 
Interim, SAC 
2.11 
Summary of WHO Functional Class 
Intent-to-
Treat 
2.11 
X 
X 
Interim, SAC 
2.12 
Summary of Change from Baseline in WHO Functional 
Class 
Intent-to-
Treat 
2.11 
X 
X 
Interim, SAC 
2.13 
Summary of WHO Functional Class Shifts from Baseline 
by Visit 
Intent-to-
Treat 
2.13 
X 
X 
Interim, SAC 
2.14 
Summary of WHO Functional Class Change from Baseline 
Categorisation 
Intent-to-
Treat 
2.14 
X 
X 
Interim, SAC 
2.15 
Summary of Plasma NT-Pro BNP concentration (ng/L) 
Intent-to-
Treat 
2.15 
X 
X 
Interim, SAC 
2.16 
Summary of Ratio to Baseline in Plasma NT-Pro BNP 
concentration (%) 
Intent-to-
Treat 
2.15 
X 
X 
Interim, SAC 


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27 
Table 
Number 
Title 
Population 
Template 
Table 
Japanese 
subgroup 
analysis 
Age 
strata 
subgroup 
analysis 
Deliverable 
2.17 
Summary of Exploratory Echocardiogram 
Intent-to-
Treat 
2.17 
X 
X 
Interim, SAC 
2.18 
Summary of Change from Baseline in Exploratory 
Echocardiogram 
Intent-to-
Treat 
2.18 
X 
X 
Interim, SAC 
2.19 
Summary of Number of Subjects with School Days 
Intent-to-
Treat 
2.19 
X 
X 
Interim, SAC 
2.20 
Summary Statistics of School Days 
Intent-to-
Treat 
2.20 
X 
X 
Interim, SAC 
2.21 
Summary Statistics of Change from Baseline in School 
Days 
Intent-to-
Treat 
2.20 
X 
X 
Interim, SAC 
2.22 
Summary of Subject Global Assessment (SF10 Health 
Survey for Children)  
Intent-to-
Treat 
2.22 
X 
X 
Interim, SAC 
2.23 
Summary of Change from Baseline in Subject Global 
Assessment (SF10 Health Survey for Children) 
Intent-to-
Treat 
2.22 
X 
X 
Interim, SAC 
2.24 
Summary of SF10 Health Survey – Number and 
Percentage of Subjects with Particular Item 
Responses 
Intent-to-
Treat 
2.24 
X 
X 
Interim, SAC 
2.25 
Number of subjects who achieved a clinically 
significant improvement (20 Meters) in 6 min 
walk 
Intent-to-
Treat 
2.25 
 
 
 
GSK SAC, 
Internal 
2.26 
Number of subjects who achieved a clinically 
significant improvement (20 Meters) in 6 min 
walk 
Idiopathic 
Group 
2.26 
 
 
GSK SAC, 
Internal 
2.27 
Number of subjects who achieved an NT-proBNP 
levels of less than 1200 ng/L 
Intent-to-
Treat 
2.27 
 
 
GSK SAC, 
Internal 
2.28 
Number of subjects who achieved an NT-proBNP 
levels of less than 1200 ng/L 
Idiopathic 
Group 
2.28 
 
 
GSK SAC, 
Internal 
2.29 
Distribution of NT-proBNP levels at baseline and 
extent of change during treatment 
Intent-to-
Treat 
2.29 
 
 
GSK SAC, 
Internal 
2.30 
Distribution of NT-proBNP levels at baseline and 
extent of change during treatment 
Idiopathic 
Group 
2.30 
 
 
GSK SAC, 
Internal 
2.31 
The Event Rate of the Clinical Worsening 
Endpoint per 100 Patient-Years 
Intent-to-
Treat 
2.31 
 
 
GSK SAC, 
Internal 
 
Safety Tables 
 
Table 
Number 
Title 
Population 
Template 
Table 
Japanese 
subgroup 
analysis 
Age strata 
subgroup 
analysis 
Deliverable 
3.1 
Summary of Exposure to Investigational Product 
New Footnote: For subjects missing their last 
exposure date at the time of study end, their last 
visit date in the study was used.    
  
Safety 
3.1 
X 
X 
Interim, SAC 
3.2 
Summary of Treatment-Emergent Adverse Events 
Safety 
3.2 
X 
X 
Interim, SAC 
3.3 
Summary of Treatment-Emergent Adverse Events by 
Preferred Term 
Safety 
3.3 
 
X 
Interim, SAC 
3.4 
Summary of Treatment-Emergent Adverse Events by 
Maximum Intensity 
Safety 
3.4 
X 
 
Interim, SAC 
3.5 
Summary of Treatment-Emergent Adverse Events by 
Action Taken with IP 
Safety 
3.5 
 
 
Interim, SAC 


RAP 
CONFIDENTIAL 
AMB114588 
 
 
28 
Table 
Number 
Title 
Population 
Template 
Table 
Japanese 
subgroup 
analysis 
Age strata 
subgroup 
analysis 
Deliverable 
3.6 
Summary of Treatment-Emergent Adverse Events 
leading to Permanent Discontinuation of IP or 
Withdrawal from the Study 
Safety 
3.2 
 
X 
Interim, SAC 
3.7 
Summary of Treatment-Emergent Adverse Events 
related to IP 
Safety 
3.2 
X 
X 
Interim, SAC 
3.8 
Summary of Cumulative Incidence of Treatment-
Emergent Adverse Events by Time to First Occurrence 
Safety 
3.8 
 
 
Interim, SAC 
3.9 
Summary of Serious Treatment-Emergent Adverse 
Events 
Safety 
3.2 
 
X  
Interim, SAC 
3.10 
Summary of Serious Treatment-Emergent Adverse 
Events – Number of Subjects and Occurrences 
Safety 
3.10 
 
Disclosure 
Interim, SAC 
3.11 
Summary of Serious Treatment-Emergent Adverse 
Events by Outcome 
Safety 
3.11 
 
 
Interim, SAC 
3.12 
Summary of Serious Treatment-Emergent Adverse 
Events by Action Taken with IP 
Safety 
3.5 
 
 
Interim, SAC 
3.13 
Summary of Serious Treatment-Emergent Adverse 
Events leading to Permanent Discontinuation of IP 
or Withdrawal from the Study 
Safety 
3.2 
 
 
Interim, SAC 
3.14 
Summary of Serious Treatment-Emergent Adverse 
Events related to IP 
Safety 
3.2 
 
Disclosure 
Interim, SAC 
3.15 
Summary of Fatal Serious Treatment-Emergent Adverse 
Events  
Safety 
3.2 
 
 
Interim, SAC 
3.16 
Summary of Fatal Serious Treatment-Emergent Adverse 
Events related to IP 
Safety 
3.2 
 
Disclosure 
Interim, SAC 
3.17 
Summary of Treatment-Emergent Adverse Events of 
Special Interest 
Safety 
3.2 
X 
 
Interim, SAC 
3.18 
Summary of Treatment-Emergent Adverse Events of 
Special Interest leading to Permanent 
Discontinuation of IP or Withdrawal from the Study 
Safety 
3.2 
 
 
Interim, SAC 
3.19 
Summary of Cumulative Incidence of Treatment-
Emergent Adverse Events of Special Interest by Time 
to First Occurrence 
Safety 
3.8 
 
 
Interim, SAC 
3.20 
Summary of Most Common (>5%) Non-Serious Treatment-
Emergent Adverse Events – Number of Subjects and 
Occurrences 
Safety 
3.10 
 
Disclosure 
Interim, SAC 
3.21 
Summary of Haematology Data 
Safety 
3.21 
X 
 
Interim, SAC 
3.22 
Summary of Change from Baseline in Haematology Data 
Safety 
3.21 
X 
 
Interim, SAC 
3.23 
Summary of Haematology Data of Potential Clinical 
Concern 
Safety 
3.23 
X 
 
Interim, SAC 
3.24 
Summary of Clinical Chemistry Data 
Safety 
3.21 
X 
 
Interim, SAC 
3.25 
Summary of Change from Baseline in Clinical 
Chemistry Data 
Safety 
3.21 
X 
 
Interim, SAC 
3.26 
Summary of Clinical Chemistry Data of Potential 
Clinical Concern 
Safety 
3.23 
X 
 
Interim, SAC 
3.27 
Summary of Endocrinology Laboratory Data (females 
only) 
Safety 
3.21 
X 
 
Interim, SAC 
3.28 
Summary of Change from Baseline in Endocrinology 
Laboratory Data (females only) 
Safety 
3.21 
X 
 
Interim, SAC 
3.29 
Summary of Liver Events Assessment 
Safety 
3.29 
 
 
Interim, SAC 


RAP 
CONFIDENTIAL 
AMB114588 
 
 
29 
Table 
Number 
Title 
Population 
Template 
Table 
Japanese 
subgroup 
analysis 
Age strata 
subgroup 
analysis 
Deliverable 
3.30 
Summary of Vital Signs 
 
Safety 
3.30 
X 
 
Interim, SAC 
3.31 
Summary of Change from Baseline in Vital Signs 
Safety 
3.30 
X 
 
Interim, SAC 
3.32 
Summary of Vital Signs Data of Potential Clinical 
Concern 
Safety 
3.32 
X 
 
Interim, SAC 
3.33 
Summary of Change from Baseline in Vital Signs Data 
of Potential Clinical Concern 
Safety 
3.32 
X 
 
Interim, SAC 
3.34 
Summary of Physical Examination by Visit 
Safety 
3.34 
X 
 
Interim, SAC 
3.35 
Summary of 12-lead ECG 
Safety 
3.35 
X 
 
Interim, SAC 
3.36 
Summary of Endocrinology assessments by Visit – 
Female   
Safety 
3.36 
X 
ADDED: 
Footnote re 
20 year 
assessments 
in all 
TLF’s 
Interim, SAC 
3.37 
Summary of Endocrinology assessments by Visit – 
Male 
Safety 
3.37 
X 
ADDED: 
Footnote 
Interim, SAC 
3.38 
Summary of Pubertal Development Shifts from 
Baseline - Female 
Safety 
3.38 
X 
ADDED: 
Footnote 
Interim, SAC 
3.39 
Summary of Pubertal Development Shifts from 
Baseline - Male 
Safety 
3.39 
X 
ADDED: 
Footnote 
Interim, SAC 
3.40 
Summary of Testicular Volume Change from Baseline – 
Male 
Safety 
3.40 
X 
ADDED: 
Footnote 
Interim, SAC 
3.41 
Summary of Change from Baseline in Plasma Endocrine 
Parameters – Female 
Safety 
3.41 
X 
ADDED: 
Footnote 
Interim, SAC 
3.42 
Summary of Change from Baseline in Plasma Endocrine 
Parameters – Male 
Safety 
3.42 
X 
ADDED: 
Footnote 
Interim, SAC 
3.43 
Summary of Time to change in dose of ambrisentan or 
other targeted PAH therapeutic agents (prostanoids, 
PDE-5 inhibitors) due to tolerability issues (days) 
Safety 
2.10 
X 
 
 
Interim, SAC 
3.44 
Summary of Treatment Emergent Adverse Events 
Starting in AMB114588 
Safety 
3.44 
 
 
SAC 
3.45 
Summary of Treatment Emergent Adverse Events 
by PAH Therapy 
Safety 
3.44 
 
 
GSK SAC, 
Internal S&P 
3.46 
Summary of Serious Treatment Emergent Adverse 
Events by PAH Therapy 
Safety 
3.44 
 
 
GSK SAC, 
Internal S&P 
3.47 
Summary of Non-Serious Treatment Emergent 
Adverse Events by PAH Therapy 
Safety 
3.44 
 
 
GSK SAC, 
Internal S&P 
3.48 
Summary of Common (>=5%) Treatment Emergent 
Adverse Events by PAH Therapy 
 
Footnote:  Note: Common adverse events (>=5%) 
were those experienced by at least 5% of 
subjects in the total population (N=38) 
irrespective of dose group and/or PAH therapy. 
Safety 
3.44 
 
 
GSK SAC, 
Internal S&P 
3.49 
Summary of Treatment Emergent Adverse Events 
by PAH Aetiology 
Safety 
3.48 
 
 
GSK SAC, 
Internal S&P 


RAP 
CONFIDENTIAL 
AMB114588 
 
 
30 
Table 
Number 
Title 
Population 
Template 
Table 
Japanese 
subgroup 
analysis 
Age strata 
subgroup 
analysis 
Deliverable 
3.50 
Summary of Serious Treatment Emergent Adverse 
Events by PAH Aetiology 
Safety 
3.48 
 
 
GSK SAC, 
Internal S&P 
3.51 
Summary of non-Serious Treatment Emergent 
Adverse Events by PAH Aetiology 
Safety 
3.48 
 
 
GSK SAC, 
Internal S&P 
3.52 
Summary of Common (>=5%)Treatment Emergent 
Adverse Events by PAH Aetiology 
Footnote:  Note: Common adverse events (>=5%) 
were those experienced by at least 5% of 
subjects in the total population (N=38) 
irrespective of dose group and/or PAH 
Aetiology. 
 
Safety 
3.48 
 
 
GSK SAC, 
Internal S&P 
3.53 
Summary of Cardiopulmonary Hemodynamics 
Safety 
3.52 
 
 
SAC-New 
 
 


RAP 
CONFIDENTIAL 
AMB114588 
 
 
31 
19.1.2. 
Listings 
Population Listings 
 
 
 
Listing 
Number 
Title 
Population 
Template 
Listing 
Japanese 
subgroup 
analysis 
Age 
strata 
subgroup 
analysis 
Deliverable 
1.1 
Listing of Reasons for Study Withdrawal 
Intent-to-
Treat 
1.1 
 
 
Interim, SAC 
1.2 
Listing of Subjects with Inclusion/Exclusion Criteria 
Deviations 
Intent-to-
Treat 
1.2 
 
 
Interim, SAC 
1.3 
Listing of Demographic Characteristics 
Intent-to-
Treat 
1.3 
 
 
Interim, SAC 
1.4 
Listing of Race 
Intent-to-
Treat 
1.4 
 
 
Interim, SAC 
1.5 
Listing of Disease History 
Intent-to-
Treat 
1.5 
 
 
Interim, SAC 
1.6 
Listing of Medical Conditions 
Intent-to-
Treat 
1.6 
 
 
Interim, SAC 
1.7 
Listing of Medications 
Intent-to-
Treat 
1.7 
 
 
Interim, SAC 
1.8 
Listing of PAH Therapy 
Intent-to-
Treat 
1.8 
 
 
Interim, SAC 
1.9 
Relationship between ATC Level 1, Ingredient and 
Verbatim Text 
Intent-to-
Treat 
1.9 
 
 
Interim, SAC 
1.10 
Listing of Compliance Data 
Intent-to-
Treat 
1.10 
 
 
Interim, SAC 
1.11 
Listing of initial, highest and final dose of 
ambrisentan  
 
Intent-to-
Treat 
1.11 
 
 
 
1.12 
Listing of Protocol Deviation 
Intent-to-
Treat 
1.12 
 
 
Interim, SAC 
 
 

 


RAP 
CONFIDENTIAL 
AMB114588 
 
 
32 
Efficacy Listings 
Listing 
Number 
Title 
Population 
Template 
Listing 
Japanese 
subgroup 
analysis 
Age 
strata 
subgroup 
analysis 
Deliverable 
2.1 
Listing of Time to Death (All cause) 
Intent-to-
Treat 
2.1 
 
 
Interim, SAC 
2.2 
Listing of 6 Minute Walking Distance Data 
Intent-to-
Treat 
2.2 
 
 
Interim, SAC 
2.3 
Listing of Clinical Worsening of PAH 
Intent-to-
Treat 
2.3 
 
 
Interim, SAC 
2.4 
Listing of Time to the addition of another targeted 
PAH therapeutic agent (prostanoids, PDE-5 inhibitors) 
Intent-to-
Treat 
2.1 
 
 
Interim, SAC 
2.5 
Listing of Time to change in dose of ambrisentan or 
other targeted PAH therapeutic agents (prostanoids, 
PDE-5 inhibitors) due to deterioration of clinical 
condition  
Intent-to-
Treat 
2.1 
 
 
Interim, SAC 
2.6 
Listing of WHO Functional Class Data 
Intent-to-
Treat 
2.6 
 
 
Interim, SAC 
2.7 
Listing of Plasma NT-Pro BNP Concentration (ng/L) 
Intent-to-
Treat 
2.7 
 
 
Interim, SAC 
2.8 
Listing of Exploratory Echocardiogram 
Intent-to-
Treat 
2.8 
 
 
Interim, SAC 
2.9 
Listing of Cardiopulmonary Hemodynamics 
Intent-to-
Treat 
2.9 
 
 
Interim, SAC 
2.10 
Listing of School Days 
Intent-to-
Treat 
2.10 
 
 
Interim, SAC 
2.11 
Listing of Subject Global Assessment (SF10 Health 
Survey for Children) 
Intent-to-
Treat 
2.11 
 
 
Interim, SAC 
 
Safety Listings 
 
Listing 
Number 
Title 
Population 
Template 
Listing 
Japanese 
subgroup 
analysis 
Age 
strata 
subgroup 
analysis 
Deliverable 
3.1 
Listing of Exposure and Compliance to 
Investigational Product 
Safety 
3.1 
 
 
Interim, SAC 
3.2 
Listing of All Adverse Events 
Safety 
3.2 
 
 
Interim, SAC 
3.3 
Listing of Relationship between Adverse Event System 
Organ Class, Preferred Term and Verbatim Text 
Safety 
3.3 
 
 
Interim, SAC 
3.4 
Listing of Subject Numbers for Specified Adverse 
Events 
Safety 
3.4 
 
 
Interim, SAC 
3.5 
Listing of Serious Adverse Events 
Safety 
3.2 
 
 
Interim, SAC 
3.6 
Listing of Fatal Serious Adverse Events 
Safety 
3.2 
 
 
Interim, SAC 
3.7 
Listing of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal 
from Study  
Safety 
3.2 
 
 
Interim, SAC 
3.8 
Listing of Haematology 
 
Safety 
3.8 
 
 
Interim, SAC 
3.9 
Listing of Haematology Data for Subjects with 
Abnormalities of Potential Clinical Concern 
Safety 
3.9 
 
 
Interim, SAC 


RAP 
CONFIDENTIAL 
AMB114588 
 
 
33 
Listing 
Number 
Title 
Population 
Template 
Listing 
Japanese 
subgroup 
analysis 
Age 
strata 
subgroup 
analysis 
Deliverable 
3.10 
Listing of Clinical Chemistry 
 
Safety 
3.8 
 
 
Interim, SAC 
3.11 
Listing of Clinical Chemistry Data for Subjects with 
Abnormalities of Potential Clinical Concern 
Safety 
3.9 
 
 
Interim, SAC 
3.12 
Listing of Endocrinology Laboratory Data - Females 
only 
Safety 
3.8 
 
ADDED: 
Footnote 
(See 
listing 
3.22) 
Interim, SAC 
3.13 
Listing of Liver Event Results and Time of Event 
Relative to Treatment 
Safety 
3.13 
 
 
Interim, SAC 
3.14 
Listing of patient specific information for liver 
events 
Safety 
3.14 
 
 
Interim, SAC 
3.15 
Listing of Medical Conditions for Subjects with 
Liver Events on Treatment 
Safety 
3.15 
 
 
Interim, SAC 
3.16 
Listing of Liver Biopsy Details 
Safety 
3.16 
 
 
Interim, SAC 
3.17 
Listing of Liver Imaging Details 
Safety 
3.17 
 
 
Interim, SAC 
3.18 
Listing of Vital Signs 
 
Safety 
3.18 
 
 
Interim, SAC 
3.19 
Listing of Vital Signs Data for Subjects with 
Abnormalities of Potential Clinical Concern 
Safety 
3.9 
 
 
Interim, SAC 
3.20 
Listing of Physical Examination 
Safety 
3.20 
 
 
Interim, SAC 
3.21 
Listing of 12-Lead ECG Findings 
Safety 
3.21 
 
 
Interim, SAC 
3.22 
Listing of Endocrinology Assessments 
Safety 
3.22 
 
ADDED: 
Footnote 
Interim, SAC 
3.23 
Listing of Time to change in dose of ambrisentan or 
other targeted PAH therapeutic agents (prostanoids, 
PDE-5 inhibitors) due to tolerability issues 
Safety 
2.1 
 
 
Interim, SAC 
3.24 
Listing of Pregnancy Results 
Safety 
3.24 
 
 
Interim, SAC 
3.25 
Listing of Endocrinology Parameters - 20 Year Visit 
Safety 
3.25 
 
ADDED: 
Footnote 
New Listing 
for SAC 
Covid-19 Listings 
3.26 
Listing of Country Level Start Dates of COVID-19 
Pandemic Measures   
Intent-to-
Treat 
3.26 
 
 
SAC 
3.27 
Listing of Visits and Assessments Impacted by COVID-
19 Pandemic 
Intent-to-
Treat 
3.27 
 
 
SAC 
3.28 
Listing of COVID-19 Assessments for Subjects with 
COVID-19 Adverse Events 
 
Safety 
 
 
 
SAC 
 
 
 
 


RAP 
CONFIDENTIAL 
AMB114588 
 
 
34 
19.1.3. 
Figures 
Efficacy Figures 
Figure 
Number 
Title 
Population 
Template 
Figure 
Japanese 
subgroup 
analysis 
Age strata 
subgroup 
analysis 
Deliverable 
2.1 
Kaplan-Meier Survival Curves with 95% Confidence Bands of Time to Death 
(All Cause) 
Intent-to-Treat 
3.1 
 
 
Interim, SAC 
2.2 
Box plots of 6 Minute Walking Distance (meters) by Visit  
 
Intent-to-Treat 
3.4 
 
 
Interim, SAC 
2.3 
Box plots of Change from Baseline in 6 Minute Walking Distance (meters) 
by Visit  
 
Intent-to-Treat 
3.4 
 
 
Interim, SAC 
2.4 
Kaplan-Meier Survival Curves with 95% Confidence Bands of Time to First 
Clinical Worsening of PAH 
Intent-to-Treat 
3.1 
 
 
Interim, SAC 
2.5 
Kaplan-Meier Survival Curves with 95% Confidence Bands of Time to the 
addition of another targeted PAH therapeutic agent (prostanoids, PDE-5 
inhibitors) 
Intent-to-Treat 
3.1 
 
 
Interim, SAC 
2.6 
Kaplan-Meier Survival Curves with 95% Confidence Bands of Time to change 
in dose of ambrisentan or other targeted PAH therapeutic agents 
(prostanoids, PDE-5 inhibitors) due to deterioration of clinical 
condition  
Intent-to-Treat 
3.1 
 
 
Interim, SAC 
2.7 
Box plots of Plasma NT-Pro BNP concentration by Visit  
 
Intent-to-Treat 
3.4 
 
 
Interim, SAC 
2.8 
Box plots of Change from Baseline in Plasma NT-Pro BNP concentration by 
Visit 
Intent-to-Treat 
3.4 
 
 
Interim, SAC 
2.9 
Box plots of Exploratory Echocardiogram Data by Visit  
 
Intent-to-Treat 
3.4 
X 
(Line plots 
of 
Exploratory 
Echocardiogra
m Data by 
Subject) see 
template 
3.11) 
 
Interim, SAC 
2.10 
Box plots of Change from Baseline in Exploratory Echocardiogram Data by 
Visit 
Intent-to-Treat 
3.4 
 
 
Interim, SAC 
 
Safety Figures 
Figure 
Number 
Title 
Population 
Template 
Figure 
Japanese 
subgroup 
analysis 
Age strata 
subgroup 
analysis 
Deliverable 
3.1 
Kaplan-Meier Survival Curves with 95% Confidence Bands of Time to First 
Treatment-Emergent Adverse Event  
Safety 
3.1 
 
 
Interim, SAC 
3.2 
Kaplan-Meier Survival Curves with 95% Confidence Bands of Time to First 
Serious Adverse Event 
Safety 
3.1 
 
 
Interim, SAC 
3.3 
Bar Chart of Treatment-Emergent Adverse Events Occurring in Two or More 
Subjects in any Treatment Group  
Safety 
3.3 
 
 
Interim, SAC 
3.4 
Box plots of Haematology Data by Visit (Selected Parameters) 
Safety 
3.4 
 
 
Interim, SAC 


RAP 
CONFIDENTIAL 
AMB114588 
 
 
35 
Figure 
Number 
Title 
Population 
Template 
Figure 
Japanese 
subgroup 
analysis 
Age strata 
subgroup 
analysis 
Deliverable 
3.5 
Box plots of Change from Baseline in Haematology Data by Visit (Selected 
Parameters) 
Safety 
3.4 
 
 
Interim, SAC 
3.6 
Box plots of Chemistry Data by Visit (Selected Parameters) 
Safety 
3.4 
 
 
Interim, SAC 
3.7 
Box plots of Change from Baseline in Chemistry Data by Visit (Selected 
Parameters) 
Safety 
3.4 
 
 
Interim, SAC 
3.8 
Patient Profiles of Liver Function Tests  
 
Safety 
3.8 
 
 
Interim, SAC 
3.9 
Box plots of Vital Signs Data by Visit 
Safety 
3.4 
 
 
Interim, SAC 
3.10 
Box plots of Change from Baseline in Vital Signs Data by Visit 
Safety 
3.4 
 
 
Interim, SAC 
3.11 
Line plots of Endocrinology Assessments by subject 
Safety 
3.11 
 
ADDED: 
Footnote 
Interim, SAC 
3.12 
Kaplan-Meier Survival Curves with 95% Confidence Bands of Time to change 
in dose of ambrisentan or other targeted PAH therapeutic agents 
(prostanoids, PDE-5 inhibitors) due to tolerability issues 
Safety 
3.1 
 
 
Interim, SAC 
 
 
 

 


RAP 
CONFIDENTIAL 
AMB114588 
 
 
36 
19.2. 
Data Display Specifications 
Protocol: AMB114588                                                                                                Page 1 of n 
Population: Intent-to-Treat 
Table 1.1:  Summary of Subject Disposition 
 
 
Ambrisentan 
2.5mg 
(N=XXX) 
Ambrisentan 
5mg 
(N=XXX) 
Ambrisentan 
7.5mg 
(N=XXX) 
Ambrisentan 
10mg 
(N=XXX) 
Total 
(N=XXX) 
 
 
 
 
 
 
Subject status 
 
 
 
 
 
  Completed 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Withdrawn 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Died 
  Died due to Covid-19 Complications 
 
 
 
 
 
 
Primary reason for study withdrawal * 
 
 
 
 
 
  Adverse event 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Lack of Efficacy 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Protocol Deviation 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Subject reached protocol defined stopping criteria 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Study closed/terminated 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Lost to Follow-up 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Investigator discretion 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Withdrew consent 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
   Number of subjects who returned for a pubertal assessment  
   at 20-years of age      
 
 
 
 
 
   xx    (%) 
        xx    (%)                     xx    (%)                    xx    (%)                     xx    (%) 
 
 
 
 
 
 
 
Note:  * Percentages are based on the number of subjects in the treatment group. 
 
 Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
 
USER ID: Directory/Program.sas Date Time 
Programming notes: Denominator for each primary reason for withdrawal is number of subjects in the Intent-to-Treat population per treatment group. 


RAP 
CONFIDENTIAL 
AMB114588 
 
 
37 
Protocol: AMB114588                                                                                                Page 1 of n 
Population: Randomised 
Table 1.2:  Summary of Study Populations 
 
 
Ambrisentan 
2.5mg 
(N=XXX) 
Ambrisentan 
5mg 
(N=XXX) 
Ambrisentan 
7.5mg 
(N=XXX) 
Ambrisentan 
10mg 
(N=XXX) 
Total 
(N=XXX) 
 
 
 
 
 
 
Randomised 
   XXX   
   XXX   
   XXX   
   XXX   
   XXX  
 
 
 
 
 
 
Safety Population 
   XXX (%) 
   XXX (%) 
   XXX (%) 
   XXX (%) 
   XXX (%) 
 
 
 
 
 
 
Intention-to-Treat population 
   XXX (%) 
   XXX (%) 
   XXX (%) 
   XXX (%) 
   XXX (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  The Safety Population is defined as all subjects who received at least 1 dose of study drug.  
 
 Subjects are considered as belonging to the treatment group according to the highest dose received.    
  
 
  
 
 The Intention-to-Treat (ITT) Population will consist of all subjects who received at least 1 dose of study drug.  
  
 Subjects are considered as 
belonging to their treatment group at the start of study AMB114588. 
 
USER ID: Directory/Program.sas Date Time 
 
Programming notes: See notes above relating to denominators for percentages. 
 
 


RAP 
CONFIDENTIAL 
AMB114588 
 
 
38 
Protocol: AMB114588                                                                                                Page 1 of n   
Population: Intent-to-treat                                                                                  
Table 1.3: Summary of Subjects by Country and Centre 
 
 
Country 
Centre ID 
Ambrisentan 
2.5mg 
(N=XXX) 
Ambrisentan 
5mg 
(N=XXX) 
Ambrisentan 
7.5mg 
(N=XXX) 
Ambrisentan 
10mg 
(N=XXX) 
Total 
(N=XXX) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
XXXXXXXXX 
All 
    XX (%)   
    XX (%) 
    XX (%)   
    XX (%) 
    XX (%) 
 
XXXXXX 
    XX (%)   
    XX (%) 
    XX (%)   
    XX (%) 
    XX (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
XXXXXXXXX 
All 
    XX (%)   
    XX (%) 
    XX (%)   
    XX (%) 
    XX (%) 
 
XXXXXX 
    XX (%)   
    XX (%) 
    XX (%)   
    XX (%) 
    XX (%) 
 
 
 
 
 
 
 
XXXXXXXXX 
All 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
XXXXXX 
    XX (%)   
    XX (%) 
    XX (%)   
    XX (%) 
    XX (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
 
USER ID: Directory/Program.sas Date Time 
 
 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Intent-to-Treat 
Table 1.4:  Summary of Inclusion/Exclusion Criteria Deviations 
 
 
Ambrisentan 
2.5mg 
(N=XXX) 
Ambrisentan 
5mg 
(N=XXX) 
Ambrisentan 
7.5mg 
(N=XXX) 
Ambrisentan 
10mg 
(N=XXX) 
Total 
(N=XXX) 
 
 
 
 
 
 
Any criteria deviations 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
 
 
 
 
 
Inclusion 
 
 
 
 
 
  I1 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  I2 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Etc.. 
 
 
 
 
 
 
 
 
 
 
 
Exclusion 
 
 
 
 
 
  E1 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  E2 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  Please refer to numbering of inclusion and exclusion criteria in protocol. 
       Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
 
USER ID: Directory/Program.sas Date Time 
 
Programming notes: Only present criteria where there is at least one (total) deviation.  “Any criteria deviations” is the number of subjects who had at least one 
deviation. 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Intent-to-Treat 
Table 1.5:  Summary of Demographic and Baseline Characteristics 
 
 
Ambrisentan 
2.5mg 
(N=XXX) 
Ambrisentan 
5mg 
(N=XXX) 
Ambrisentan 
7.5mg 
(N=XXX) 
Ambrisentan 
10mg 
(N=XXX) 
Total 
(N=XXX) 
 
 
 
 
 
 
Age (yrs)** 
 
 
 
 
 
  N 
     XXX          XXX 
     XXX          XXX 
     XXX 
  Mean 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  SD 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
  Q1 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  Median 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  Q3 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  Min. 
      XX 
      XX 
      XX 
      XX 
      XX 
  Max. 
      XX 
      XX 
      XX 
      XX 
      XX 
 
 
 
 
 
 
Age (yrs)** 
 
 
 
 
 
  N 
      XXX  
      XXX 
      XXX  
      XXX 
      XX (%) 
  <8 years 
      XX (%)       XX (%)       XX (%)       XX (%)       XX (%) 
  8 – 11 years 
      XX (%)       XX (%)       XX (%)       XX (%)       XX (%) 
  12 - <18 years  
      XX (%)       XX (%)       XX (%)       XX (%)       XX (%) 
  >=18 years 
      XX (%)       XX (%)       XX (%)       XX (%)       XX (%) 
 
 
 
 
 
 
Sex 
 
 
 
 
 
  N 
      XXX  
      XXX 
      XXX  
      XXX 
      XX (%) 
  Female 
      XX (%)       XX (%)       XX (%)       XX (%)       XX (%) 
  Male 
      XX (%)       XX (%)       XX (%)       XX (%)       XX (%) 
 
 
 
 
 
 
 
 
 
 
 
Note:  ** At start of study treatment in AMB112529 
 
 * At entry to AMB114588 
       $ A subject may be represented in more than one geographic ancestry group. 
        Q1 = 1st quartile, Q3 = 3rd quartile. 
       Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
          
USER ID: Directory/Program.sas Date Time 


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Protocol: AMB114588                                                                                                Page 2 of n 
Population: Intent-to-Treat 
Table 1.5:  Summary of Demographic and Baseline Characteristics 
 
 
Ambrisentan 
2.5mg 
(N=XXX) 
Ambrisentan 
5mg 
(N=XXX) 
Ambrisentan 
7.5mg 
(N=XXX) 
Ambrisentan 
10mg 
(N=XXX) 
Total 
(N=XXX) 
 
 
 
 
 
 
Child Bearing Potential (Females only) * 
 
 
 
 
 
  N 
     XXX 
     XXX 
     XXX 
     XXX 
     XXX 
  Pre-menarcheal 
      XX (%)       XX (%)       XX (%)       XX (%)       XX (%) 
  Sterile (of child bearing age) 
      XX (%)       XX (%)       XX (%)       XX (%)       XX (%) 
  Potentially able to bear children 
      XX (%)       XX (%)       XX (%)       XX (%)       XX (%) 
 
 
 
 
 
 
Ethnicity ** 
 
 
 
 
 
  N 
     XXX 
     XXX 
     XXX 
     XXX 
     XXX 
  Hispanic/Latino 
      XX (%)       XX (%)       XX (%)       XX (%)       XX (%) 
  Not Hispanic/Latino 
      XX (%)       XX (%)       XX (%)       XX (%)       XX (%) 
 
 
 
 
 
 
Geographic Ancestry **$ 
 
 
 
 
 
  n 
     XXX 
     XXX 
     XXX 
     XXX 
     XXX 
  African American/African Heritage 
      XX (%)       XX (%)       XX (%)       XX (%)       XX (%) 
  American Indian or Alaskan Native 
      XX (%)       XX (%)       XX (%)       XX (%)       XX (%) 
  Asian - Central/South Asian Heritage 
      XX (%)       XX (%)       XX (%)       XX (%)       XX (%) 
  Asian - East Asian Heritage 
      XX (%)       XX (%)       XX (%)       XX (%)       XX (%) 
  Asian - Japanese Heritage 
      XX (%)       XX (%)       XX (%)       XX (%)       XX (%) 
  Asian - South East Asian Heritage 
      XX (%)       XX (%)       XX (%)       XX (%)       XX (%) 
  Native Hawaiian or Other Pacific Islander 
      XX (%)       XX (%)       XX (%)       XX (%)       XX (%) 
  White - Arabic/North African Heritage 
      XX (%)       XX (%)       XX (%)       XX (%)       XX (%) 
  White - White/Caucasian/European Heritage 
      XX (%)       XX (%)       XX (%)       XX (%)       XX (%) 
 
 
 
 
 
Note:  ** At start of study treatment in AMB112529 
 
 * At entry to AMB114588 
       $ A subject may be represented in more than one geographic ancestry group. 
        Q1 = 1st quartile, Q3 = 3rd quartile. 
       Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
          
USER ID: Directory/Program.sas Date Time 


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Protocol: AMB114588                                                                                                Page 3 of n 
Population: Intent-to-Treat 
Table 1.5:  Summary of Demographic and Baseline Characteristics 
 
 
Ambrisentan 
2.5mg 
(N=XXX) 
Ambrisentan 
5mg 
(N=XXX) 
Ambrisentan 
7.5mg 
(N=XXX) 
Ambrisentan 
10mg 
(N=XXX) 
Total 
(N=XXX) 
 
 
 
 
 
 
Weight (kg)* 
 
 
 
 
 
  N 
     XXX          XXX 
     XXX          XXX 
     XXX 
  Mean 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  SD 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
  Q1 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  Median 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  Q3 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  Min. 
      XX 
      XX 
      XX 
      XX 
      XX 
  Max. 
      XX 
      XX 
      XX 
      XX 
      XX 
 
 
 
 
 
 
Weight (kg)* 
 
 
 
 
 
  N 
      XXX  
      XXX 
      XXX  
      XXX 
      XX (%) 
  <20 kg 
      XX (%)       XX (%)       XX (%)       XX (%)       XX (%) 
  20 – <35 kg 
      XX (%)       XX (%)       XX (%)       XX (%)       XX (%) 
  35 - <50 kg  
      XX (%)       XX (%)       XX (%)       XX (%)       XX (%) 
  >=50 kg 
      XX (%)       XX (%)       XX (%)       XX (%)       XX (%) 
 
 
 
 
 
 
Aetiology of PAH Randomised Strata ** 
 
 
 
 
 
  n 
      XXX  
      XXX 
      XXX  
      XXX 
      XX (%) 
  Idiopathic (IPAH) 
      XX (%)       XX (%)       XX (%)       XX (%)       XX (%) 
  Familial (FPAH) 
      XX (%)       XX (%)       XX (%)       XX (%)       XX (%) 
  Persistent PAH despite surgical repair 
      XX (%)       XX (%)       XX (%)       XX (%)       XX (%) 
  Secondary to connective tissue disease 
      XX (%)       XX (%)       XX (%)       XX (%)       XX (%) 
 
 
 
 
Note:  ** At start of study treatment in AMB112529 
 
 * At entry to AMB114588 
       $ A subject may be represented in more than one geographic ancestry group. 
        Q1 = 1st quartile, Q3 = 3rd quartile. 
       Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
          
USER ID: Directory/Program.sas Date Time 
 
 


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Protocol: AMB114588                                                                                                Page 4 of n 
Population: Intent-to-Treat 
Table 1.5:  Summary of Demographic and Baseline Characteristics 
 
 
Ambrisentan 
2.5mg 
(N=XXX) 
Ambrisentan 
5mg 
(N=XXX) 
Ambrisentan 
7.5mg 
(N=XXX) 
Ambrisentan 
10mg 
(N=XXX) 
Total 
(N=XXX) 
 
 
 
 
 
 
Duration of PAH (days)** 
 
 
 
 
 
  N 
     XXX          XXX 
     XXX          XXX 
     XXX 
  Mean 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  SD 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
  Q1 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  Median 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  Q3 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  Min. 
      XX 
      XX 
      XX 
      XX 
      XX 
  Max. 
      XX 
      XX 
      XX 
      XX 
      XX 
 
 
 
 
 
 
PAH Therapy Use ** 
 
 
 
 
 
  n 
      XXX  
      XXX 
      XXX  
      XXX 
      XX (%) 
  Ongoing PAH therapy at baseline 
      XX (%)       XX (%)       XX (%)       XX (%)       XX (%) 
  Prior PAH therapy, not ongoing at baseline 
      XX (%)       XX (%)       XX (%)       XX (%)       XX (%) 
  No PAH therapy recorded 
      XX (%)       XX (%)       XX (%)       XX (%)       XX (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  ** At start of study treatment in AMB112529 
 
 * At entry to AMB114588 
       $ A subject may be represented in more than one geographic ancestry group. 
        Q1 = 1st quartile, Q3 = 3rd quartile. 
       Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
          
USER ID: Directory/Program.sas Date Time 


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Protocol: AMB114588                                                                                                Page 5 of n 
Population: Intent-to-Treat 
Table 1.5:  Summary of Demographic and Baseline Characteristics 
 
Ambrisentan 
2.5mg 
(N=XXX) 
Ambrisentan 
5mg 
(N=XXX) 
Ambrisentan 
7.5mg 
(N=XXX) 
Ambrisentan 
10mg 
(N=XXX) 
Total 
(N=XXX) 
WHO Functional Class ** 
 
 
 
 
 
  N 
      XXX  
      XXX 
      XXX  
      XXX 
      XX (%) 
  Class II 
      XX (%)       XX (%)       XX (%)       XX (%)       XX (%) 
  Class III 
      XX (%)       XX (%)       XX (%)       XX (%)       XX (%) 
 
 
 
 
 
 
WHO Functional Class * 
 
 
 
 
 
  N 
      XXX  
      XXX 
      XXX  
      XXX 
      XX (%) 
  Class II 
      XX (%)       XX (%)       XX (%)       XX (%)       XX (%) 
  Class III 
      XX (%)       XX (%)       XX (%)       XX (%)       XX (%) 
 
 
 
 
 
 
6 minute walk data (m)** 
 
 
 
 
 
  N 
     XXX          XXX 
     XXX          XXX 
     XXX 
  Mean 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  SD 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
  Q1 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  Median 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  Q3 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  Min. 
      XX 
      XX 
      XX 
      XX 
      XX 
  Max. 
      XX 
      XX 
      XX 
      XX 
      XX 
 
 
 
 
 
 
6 minute walk data (m)* 
 
 
 
 
 
  N 
     XXX          XXX 
     XXX          XXX 
     XXX 
  Mean 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  SD 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
  Q1 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  Median 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  Q3 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  Min. 
      XX 
      XX 
      XX 
      XX 
      XX 
  Max. 
      XX 
      XX 
      XX 
      XX 
      XX 
 
 
 
 
 
 
Note:  ** At start of study treatment in AMB112529 
 
 * At entry to AMB114588 
       $ A subject may be represented in more than one geographic ancestry group. 
        Q1 = 1st quartile, Q3 = 3rd quartile. 
       Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
USER ID: Directory/Program.sas Date Time 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Intent-to-Treat 
Table 1.6:  Summary of Past Medical Conditions 
 
 
Classification 
Ambrisentan 
2.5mg 
(N=XXX) 
Ambrisentan 
5mg 
(N=XXX) 
Ambrisentan 
7.5mg 
(N=XXX) 
Ambrisentan 
10mg 
(N=XXX) 
Total 
(N=XXX) 
 
 
 
 
 
 
Any condition 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
 
 
 
 
 
Classification 1 
 
 
 
 
 
  Any condition 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Preferred Term 1 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Preferred Term 2 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
etc 
 
 
 
 
 
 
 
 
 
 
 
Classification 2 
 
 
 
 
 
  Any condition 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Preferred Term 1 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Preferred Term 2 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
etc 
 
 
 
 
 
 
 
 
 
 
 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
 
USER ID: Directory/Program.sas Date Time 
 
Programming notes: “Any condition” relates to the number and percentage of subjects who had at least one condition.  Subjects may be counted more than once across 
classifications. 
Produce table for data collected in AMB112529 for the subset of subjects who entered AMB114588. 
 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Intent-to-Treat 
Table 1.8:  Summary of Concomitant Medications 
 
ATC Level 1 
  Preferred Term 
Ambrisentan 
2.5mg 
(N=XXX) 
Ambrisentan 
5mg 
(N=XXX) 
Ambrisentan 
7.5mg 
(N=XXX) 
Ambrisentan 
10mg 
(N=XXX) 
Total 
(N=XXX) 
 
 
 
 
 
 
Any medication 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
 
 
 
 
 
Endocrine & Metabolic 
 
 
 
 
 
  Any medication 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Fluticasone propionate 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Beclomethasone dipropionate 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
 
 
 
 
 
Anti-infectives & immunologicals 
 
 
 
 
 
  Any medication 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Amoxycillin 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Amoxycillin trihydrate 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Clamoxyl 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Cefaclor 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Cefproxil 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
 
 
 
 
 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: A medication may be included in more than one ATC level category and appear more than once. 
      Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
 
USER ID: Directory/Program.sas Date Time 
 
Programming notes: Medications will be sorted in descending order of total incidence across treatment groups for the ATC level 1 and in descending order of total 
incidence for the preferred term within each ATC level. If the total incidence for any two or more preferred terms is equal, they will be presented in alphabetical 
order.   
 
 


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AMB114588 
 
 
47 
Protocol: AMB114588                                                                                                Page 1 of n 
Population: Intent-to-Treat 
Table 1.9:  Summary of Ongoing Background PAH Therapy at Entry Visit to AMB114588 
By Drug Class and Preferred Term  
 
PAH Therapy 
Ambrisentan 
2.5mg 
(N=XXX) 
Ambrisentan 
5mg 
(N=XXX) 
Ambrisentan 
7.5mg 
(N=XXX) 
Ambrisentan 
10mg 
(N=XXX) 
Total 
(N=XXX) 
 
 
 
 
 
 
Any medication 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
 
 
 
 
 
PDE5i (monotherapy) 
 
 
 
 
 
  Any medication 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Preferred Term 1 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Preferred Term 1 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
Prostanoid (monotherapy) 
 
 
 
 
 
  Any medication 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Preferred Term 1 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Preferred Term 1 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
PDE5i and prostanoid in combination 
 
 
 
 
 
  Any medication 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Preferred Term 1 + Preferred Term 2 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Preferred Term 3 + Preferred Term 4 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
Etc..  
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
 
USER ID: Directory/Program.sas Date Time 
 
Programming notes: For Table 1.10, data will be presented at 6 months after entry into AMB114588 and then annually as well as the final visit.  
 
 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Intent-to-Treat 
Table 1.11:  Summary of Compliance to Investigational Product since last visit 
 
 
 
Ambrisentan 
2.5mg 
Ambrisentan 
5mg 
Ambrisentan 
7.5mg 
Ambrisentan 
10mg 
Total 
Planned Relative Time 
Compliance assessment 
(N=XXX) 
(N=XXX) 
(N=XXX) 
(N=XXX) 
(N=XXX) 
 
 
 
 
 
 
 
Month 3 
   n 
   XXX 
   XXX 
   XXX 
   XXX 
   XXX 
 
   0% compliant 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
   >0% and < 80% 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
   >= 80% and <= 120% 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
   >120% compliant 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
 
 
 
 
 
 
Month 6 
   n 
   XXX 
   XXX 
   XXX 
   XXX 
   XXX 
 
   0% compliant 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
   >0% and < 80% 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
   >= 80% and <= 120% 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
   >120% compliant 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
 
 
 
 
 
 
Etc.. 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
Note:  Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
 
USER ID: Directory/Program.sas Date Time 
 
Programming notes: Present available visits and End of Study. 
 
 


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Protocol: AMB114588                                                                                                Page 1 of n   
Population: Intent-to-treat                                                                                  
                             Table  1.12: Summary of Investigational Product Compliance Overall 
 
 
 
Ambrisentan 
2.5mg 
(N=XXX) 
Ambrisentan 
5mg 
(N=XXX) 
Ambrisentan 
7.5mg 
(N=XXX) 
Ambrisentan 
10mg 
(N=XXX) 
Total 
(N=XXX) 
 
 
 
 
 
 
Overall % of visits at which subject is compliant 
  XX  
  XX  
  XX  
  XX  
  XX  
 
 
 
 
 
 
  N 
  XX 
  XX 
  XX 
  XX 
  XX 
  Mean 
  XX.X    
  XX.X    
  XX.X    
  XX.X    
  XX.X    
  SD 
  XX.XX   
  XX.XX   
  XX.XX   
  XX.XX   
  XX.XX   
  Q1 
  XX.X    
  XX.X    
  XX.X    
  XX.X    
  XX.X    
  Median 
  XX.X    
  XX.X    
  XX.X    
  XX.X    
  XX.X    
  Q3 
  XX.X    
  XX.X    
  XX.X    
  XX.X    
  XX.X    
  Min. 
  XX 
  XX 
  XX 
  XX 
  XX 
  Max. 
  XX 
  XX 
  XX 
  XX 
  XX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Q1 = 1st quartile, Q3 = 3rd quartile. 
      Compliant visits are those at which subjects are ≥80% and ≤120% compliant. Compliance is determined 
      by the site. 
      At a subject level compliance = 100*(the number of visits at which the subject was compliant)/(the sum 
      of all study visits for the subject). At a treatment group level the overall compliance = 100*(the 
      total number of visits at which all subjects in that group were compliant)/(the sum of all study  
      visits for all subjects in that group). 
      Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
 
USER ID: Directory/Program.sas Date Time 
 
 


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50 
Protocol: AMB114588                                                                                                Page 1 of n   
Population: Intent-to-treat                                                                                  
Table  1.13: Summary of initial dose of ambrisentan at entry to AMB114588 and highest dose received during study 
 
 
 
Highest Dose 
 
Initial Dose 
 
2.5mg 
 
 
5mg 
 
 
7.5mg 
 
 
10mg 
 
 
Total 
 
 
 
 
 
 
 
  2.5 mg 
XX 
XX 
XX 
XX 
XX 
  5 mg 
XX 
XX 
XX 
XX 
XX 
  7.5 mg 
XX 
XX 
XX 
XX 
XX 
  10 mg 
XX 
XX 
XX 
XX 
XX 
  Total 
XX 
XX 
XX 
XX 
XX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
USER ID: Directory/Program.sas Date Time 
 
 


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Protocol: AMB114588                                                                                                Page 1 of n   
Population: Intent-to-treat                                                                                  
Table  1.14: Summary of initial dose of ambrisentan at entry to AMB114588 and final dose at end of study or termination 
 
 
 
Final Dose 
 
Initial Dose 
 
2.5mg 
 
 
5mg 
 
 
7.5mg 
 
 
10mg 
 
 
Total 
 
 
 
 
 
 
 
  2.5 mg 
XX 
XX 
XX 
XX 
XX 
  5 mg 
XX 
XX 
XX 
XX 
XX 
  7.5 mg 
XX 
XX 
XX 
XX 
XX 
  10 mg 
XX 
XX 
XX 
XX 
XX 
  Total 
XX 
XX 
XX 
XX 
XX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
USER ID: Directory/Program.sas Date Time
 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Intent-to-Treat 
Table 1.15:  Summary of Important Protocol Deviation 
 
Ambrisentan 
2.5mg 
Ambrisentan 5mg 
Ambrisentan 
7.5mg 
Ambrisentan 10mg 
Total 
Protocol Deviation Category 
(N=XXX) 
(N=XXX) 
(N=XXX) 
(N=XXX) 
(N=XXX) 
 
 
 
 
 
Any Deviation 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
 
 
 
 
Eligibility criteria not met 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
Not withdrawn after developing withdrawal criteria 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
Prohibited medication or device 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
Visit window 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
Informed consent procedure 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
Administer/dispense study medication 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
Failure to report SAE, Pregnancy, or liver function abnormalities per 
protocol
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
Study blind/ unblind procedures 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
Study treatment supply procedures 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
Biological specimen sample procedures 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
Assessment procedures 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
Diary Card procedures 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
Equipment procedures 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
Randomization procedures 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
IP taken inappropriately 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
Procedures/Assessments not performed per protocol 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
Other
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
 
 
 
 
 
 
 
 
 
 
Note:  Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
 
USER ID: Directory/Program.sas Date Time 
 
 


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Protocol: AMB114588                                                                              
Page 1 of 1 
Population: Intent-to-Treat 
 
Table 1.19 
 
Summary of COVID-19 Assessments for Subjects with 
Suspected, Probable or Confirmed COVID-19 Case 
Diagnosis 
 
 
 
 
Assessments 
Treatment A 
(N=300) 
Treatment B 
(N=300) 
 
 
 
 
COVID-19 Case Diagnosis [1] 
     100 (33%) 
     100 (33%) 
 
Confirmed 
      29 (10%) 
      29 (10%) 
Probable 
      50 (17%) 
      50 (17%) 
Suspected 
      21  (7%) 
      21  (7%) 
 
COVID-19 Test Performed [2] 
n 
     100 
     100 
 
No 
      50  (50%) 
      50  (50%) 
Yes 
      50  (50%) 
      50  (50%) 
 
 
 
Result of the COVID-19 Test 
n 
      50 
      50 
Negative 
      10  (20%) 
      10  (20%) 
Positive 
      30  (60%) 
      30  (60%) 
 
Indeterminate 
      10  (20%) 
      10  (20%) 
 
[1] COVID-19 Case Diagnosis is based on WHO Definition as of dd-mmm-yyyy. 
  
[2] COVID-19 Test Performed is only captured for subjects with a COVID-19 Case Diagnosis. 
Programmer Notes: For COVID-19 Test Performed, the small n is based on the number of subjects 
with a COVID-19 Case Diagnosis. 
For Result of the COVID-19 Test, the small n is based on the COVID-19 Test Performed=Yes. 
There are multiple collection forms, select the appropriate display format, PAN1 or PAN1A, 
depending on the form used in the study.  Use PAN1 when the COVID-19 assessments can only be 
captured once during the study and use PAN1A if the COVID-19 assessments are captured using 
repeating form design.  
    
  
 
 


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Protocol: AMB114588                                                                             
Page 1 of 1 
Population: Intent-to-Treat 
 
Table 1.20 
 
 
Summary of Visits impacted by COVID-19 Pandemic 
 
Treatment A 
Treatment B 
Total 
 
  
(N=100) 
(N=100) 
(N=200) 
Any Visit Impacted 
 
 
 
Number of subjects with visits impacted 
80 (80%) 
80 (80%) 
160 (80%) 
 
Impact [4] 
MISSED VISIT 
25 (25%) 
25 (25%) 
50 (25%) 
 
Primary Reason for Impact [4] 
SUBJECT ACQUIRED COVID-19 INFECTION [1] 
15 (15%) 
15 (15%) 
30 (15%) 
SUBJECT RELATED IMPACT [2] 
15 (15%) 
15 (15%) 
30 (15%) 
SITE RELATED IMPACT [3] 
15 (15%) 
15 (15%) 
30 (15%) 
 
SITE VISIT WITH ONE OR MORE ASSESSMENTS MISSED  
45 (45%) 
45 (45%) 
90 (45%) 
Primary Reason for Impact [4] 
SUBJECT ACQUIRED COVID-19 INFECTION [1] 
25 (25%) 
25 (25%) 
50 (25%) 
SUBJECT RELATED IMPACT [2] 
15 (15%) 
15 (15%) 
30 (15%) 
 
SITE RELATED IMPACT [3] 
15 (15%) 
15 (15%) 
30 (15%) 
REMOTE VISIT WITH NO ASSESSMENTS MISSED 
15 (15%) 
15 (15%) 
30 (15%) 
Primary Reason for Impact [4] 
 
 
 
 
SUBJECT ACQUIRED COVID-19 INFECTION [1] 
10 (10%) 
10 (10%) 
20 (10%) 
SUBJECT RELATED IMPACT [2] 
10 (10%) 
10 (10%) 
20 (10%) 
SITE RELATED IMPACT [3] 
10 (10%) 
10 (10%) 
20 (10%) 
 
 
 
 
 
REMOTE VISIT WITH ONE OR MORE ASSESSMENTS MISSED 
15 (15%) 
15 (15%) 
30 (15%) 
Primary Reason for Impact [4] 
SUBJECT ACQUIRED COVID-19 INFECTION [1] 
10 (10%) 
10 (10%) 
20 (10%) 
SUBJECT RELATED IMPACT [2] 
10 (10%) 
10 (10%) 
20 (10%) 
 
SITE RELATED IMPACT [3] 
10 (10%) 
10 (10%) 
20 (10%) 
Visit #
 
 
 
 
Number of impacted subjects at the visit (n) 
60 
60 
120 
Impact 
MISSED VISIT 
6 (10%) 
6 (10%) 
12 (10%) 
 
Primary Reason for Impact 
SUBJECT ACQUIRED COVID-19 INFECTION [1] 
3  (5%) 
3  (5%) 
 6  (5%) 
SUBJECT RELATED IMPACT [2] 
0 
0 
 0 
SITE RELATED IMPACT [3] 
3  (5%) 
3  (5%) 
 6  (5%) 
 
 
 
 
 
 
SITE VISIT WITH ONE OR MORE ASSESSMENTS MISSED  
36 (60%) 
36 (60%) 
72 (60%) 
Primary Reason for Impact 
 
 
 
 
SUBJECT ACQUIRED COVID-19 INFECTION [1] 
0 
0 
 0 


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CONFIDENTIAL 
AMB114588 
 
 
55 
SUBJECT RELATED IMPACT [2] 
6 (10%) 
6 (10%) 
12 (10%) 
 
SITE RELATED IMPACT [3] 
30 (50%) 
30 (50%) 
 60 (50%) 
 
 
 
 
 
 
Visit … 
 
 
 
 
  
[1] Subject acquired COVID-19 includes suspected, probable and confirmed. 
  
[2] Subject related impact include subject discretion and travel restrictions. 
  
[3] Site related impacts include site temporarily closed, site staff unavailable, and study drug unavailable. 
  
[4] Subjects may be counted in more than one category. 
  
/Directory/program.sas  01JAN2002 12:01 
  
  
  
  
 
 
 
 
 
 
 
 
Programmer notes: After the overall summary of any impacted visits, the summary is then produced by visit starting with the first impacted visit.  
This is represented in the mock-up as # for the first impacted visits and #+1 for each visit thereafter. 
  
 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Intent-to-Treat 
 
Table 2.1:  Summary of Time to Death (All cause) (days) 
 
 
Ambrisentan 
2.5mg 
(N=XXX) 
Ambrisentan 
5mg 
(N=XXX) 
Ambrisentan 
7.5mg 
(N=XXX) 
Ambrisentan 
10mg 
(N=XXX) 
Total 
(N=XXX) 
 
 
 
 
 
 
  N 
XXX (XX%) 
XXX (XX%) 
XXX (XX%) 
XXX (XX%) 
XXX (XX%) 
  Mean 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  SD 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
  Q1 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  Median 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  Q3 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  Min. 
      XX 
      XX 
      XX 
      XX 
      XX 
  Max. 
      XX 
      XX 
      XX 
      XX 
      XX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  Q1 = 1st quartile, Q3 = 3rd quartile. 
       Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
 
USER ID: Directory/Program.sas Date Time 

 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Intent-to-Treat 
Table 2.2:  Summary of 6 Minute Walking Distance (meters) 
 
Treatment 
Planned  
Relative Time 
n 
Mean 
SD 
Q1 
Median 
Q3 
Min. 
Max. 
 
 
 
 
 
 
 
 
 
 
Ambrisentan  
2.5mg 
Baseline** 
Overall 
With oxygen use 
Without oxygen use 
 
XXX 
XXX 
XXX 
  
 XX.X 
 XX.X 
 XX.X 
  
 XX.XX 
 XX.XX 
 XX.XX 
  
 XX.X 
 XX.X 
 XX.X 
  
 XX.X 
 XX.X 
 XX.X 
  
 XX.X 
 XX.X 
 XX.X 
  
 XX 
 XX 
 XX 
  
 XX 
 XX 
 XX 
(N=XXX) 
Entry Visit* 
Overall 
With oxygen use 
Without oxygen use 
 
 
XXX 
XXX 
XXX 
  
 XX.X 
 XX.X 
 XX.X 
  
 XX.XX 
 XX.XX 
 XX.XX 
  
 XX.X 
 XX.X 
 XX.X 
  
 XX.X 
 XX.X 
 XX.X 
  
 XX.X 
 XX.X 
 XX.X 
  
 XX 
 XX 
 XX 
  
 XX 
 XX 
 XX 
 
Month 6 
 
 
 
 
 
 
 
 
 
Etc..  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ambrisentan  
5mg 
Etc.. 
 
 
 
 
 
 
 
 
(N=XXX) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ambrisentan  
7.5mg 
Etc.. 
 
 
 
 
 
 
 
 
(N=XXX) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ambrisentan  
10mg 
Etc.. 
 
 
 
 
 
 
 
 
(N=XXX) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total 
Etc.. 
 
 
 
 
 
 
 
 
(N=XXX) 
 
 
 
 
 
 
 
 
 
Note:  ** Baseline is the last value recorded prior to start of study treatment from AMB112529. 
       * Entry Visit is at entry to AMB114588. 
    
 Q1 = 1st quartile, Q3 = 3rd quartile. 
       Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
 
USER ID: Directory/Program.sas Date Time 
 
Programming notes: Present available visits, End of Study and Follow-Up. 
 
 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Intent-to-Treat 
 
Table 2.5:  Summary of Walking Duration (minutes) for subjects who walked less than six minutes 
 
Treatment 
Number of subjects who 
attempted the 6 minute 
walk 
Planned  
Relative Time 
n 
Mean 
SD 
Q1 
Median 
Q3 
Min. 
Max. 
 
 
 
 
 
 
 
 
 
 
 
Ambrisentan 
2.5mg 
XX 
Baseline** 
XX (%)  XX.X 
 XX.XX 
 XX.X 
 XX.X 
 XX.X 
 XX 
 XX 
(N=XXX) 
XX 
Entry Visit* 
XX (%)  XX.X 
 XX.XX 
 XX.X 
 XX.X 
 XX.X 
 XX 
 XX 
 
XX 
Month 6 
XX (%)  XX.X 
 XX.XX 
 XX.X 
 XX.X 
 XX.X 
 XX 
 XX 
 
XX 
Etc.. 
XX (%)  XX.X 
 XX.XX 
 XX.X 
 XX.X 
 XX.X 
 XX 
 XX 
 
 
 
 
 
 
 
 
 
 
 
Ambrisentan 
5mg 
 
Etc.. 
 
 
 
 
 
 
 
 
(N=XXX) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ambrisentan 
7.5mg 
 
Etc.. 
 
 
 
 
 
 
 
 
(N=XXX) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ambrisentan 
10mg 
 
Etc.. 
 
 
 
 
 
 
 
 
(N=XXX) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total 
 
Etc.. 
 
 
 
 
 
 
 
 
(N=XXX) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  ** Baseline is the last value recorded prior to start of study treatment from AMB112529. 
       * Entry Visit is at entry to AMB114588. 
    
 Q1 = 1st quartile, Q3 = 3rd quartile. 
       Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
 
USER ID: Directory/Program.sas Date Time 
 
Programming notes: Present available visits, End of Study and Follow-Up. 
 
 


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CONFIDENTIAL 
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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Intent-to-Treat 
Table 2.6:  Summary of use of Oxygen during 6 Minute Walking exercise (L/min) 
 
Treatment 
Number of subjects 
who attempted the 6 
minute walk 
Planned  
Relative Time 
n 
Mean 
SD 
Q1 
Median 
Q3 
Min. 
Max. 
 
 
 
 
 
 
 
 
 
 
 
Ambrisentan  
2.5mg 
XX 
Baseline** 
XX (%)  XX.X 
 XX.XX 
 XX.X 
 XX.X 
 XX.X 
 XX 
 XX 
(N=XXX) 
XX 
Entry Visit* 
XX (%)  XX.X 
 XX.XX 
 XX.X 
 XX.X 
 XX.X 
 XX 
 XX 
 
XX 
Month 6 
XX (%)  XX.X 
 XX.XX 
 XX.X 
 XX.X 
 XX.X 
 XX 
 XX 
 
XX 
Etc.. 
XX (%)  XX.X 
 XX.XX 
 XX.X 
 XX.X 
 XX.X 
 XX 
 XX 
 
 
 
 
 
 
 
 
 
 
 
Ambrisentan  
5mg 
 
Etc.. 
 
 
 
 
 
 
 
 
(N=XXX) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ambrisentan  
7.5mg 
 
Etc.. 
 
 
 
 
 
 
 
 
(N=XXX) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ambrisentan  
10mg 
 
Etc.. 
 
 
 
 
 
 
 
 
(N=XXX) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total 
 
Etc.. 
 
 
 
 
 
 
 
 
(N=XXX) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  ** Baseline is the last value recorded prior to start of study treatment from AMB112529. 
       * Entry Visit is at entry to AMB114588. 
    
 Q1 = 1st quartile, Q3 = 3rd quartile. 
       Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
 
USER ID: Directory/Program.sas Date Time 
 
Programming notes: Present available visits, End of Study and Follow-Up. 
 
 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Intent-to-Treat 
 
Table 2.7:  Summary of Time to the first Clinical Worsening of PAH (days) 
 
 
Ambrisentan 
2.5mg 
(N=XXX) 
Ambrisentan 
5mg 
(N=XXX) 
Ambrisentan 
7.5mg 
(N=XXX) 
Ambrisentan 
10mg 
(N=XXX) 
Total 
(N=XXX) 
 
 
 
 
 
 
  N 
XXX (XX%) 
XXX (XX%) 
XXX (XX%) 
XXX (XX%) 
XXX (XX%) 
  Mean 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  SD 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
  Q1 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  Median 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  Q3 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  Min. 
      XX 
      XX 
      XX 
      XX 
      XX 
  Max. 
      XX 
      XX 
      XX 
      XX 
      XX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  Q1 = 1st quartile, Q3 = 3rd quartile. 
       Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
 
USER ID: Directory/Program.sas Date Time 
 
 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Intent-to-Treat 
Table 2.8:  Summary of Clinical Worsening of PAH 
 
Ambrisentan 
2.5mg 
(N=XXX) 
Ambrisentan 
5mg 
(N=XXX) 
Ambrisentan 
7.5mg 
(N=XXX) 
Ambrisentan 
10mg 
(N=XXX) 
Total 
(N=XXX) 
 
 
 
 
 
Subjects with at least one criteria 
XX (%)  
XX (%) 
XX (%)  
XX (%) 
XX (%) 
 
 
 
 
 
Death (all cause) or placed on active list for lung transplant 
XX (%)  
XX (%) 
XX (%)  
XX (%) 
XX (%) 
Hospitalisation for worsening of PAH 
XX (%)  
XX (%) 
XX (%)  
XX (%) 
XX (%) 
Addition/increased dose of other targeted PAH therapetic agents and/or atrial 
septostomy 
XX (%)  
XX (%) 
XX (%)  
XX (%) 
XX (%) 
PAH related deterioration 
XX (%)  
XX (%) 
XX (%)  
XX (%) 
XX (%) 
 
 
 
 
 
PAH related deterioration:- 
 
 
 
 
 
Increase from baseline in WHO functional class 
XX (%)  
XX (%) 
XX (%)  
XX (%) 
XX (%) 
Deterioration in exercise testing  
XX (%)  
XX (%) 
XX (%)  
XX (%) 
XX (%) 
Clinical signs or symptoms of right sided heart failure 
XX (%)  
XX (%) 
XX (%)  
XX (%) 
XX (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
 
USER ID: Directory/Program.sas Date Time 
 
 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Intent-to-Treat 
 
Table 2.9:  Summary of Time to the addition of another targeted PAH therapeutic agent (prostanoids, PDE-5 inhibitors) (days) 
 
 
Ambrisentan 
2.5mg 
(N=XXX) 
Ambrisentan 
5mg 
(N=XXX) 
Ambrisentan 
7.5mg 
(N=XXX) 
Ambrisentan 
10mg 
(N=XXX) 
Total 
(N=XXX) 
Due to Deterioration of Clinical 
Condition 
 
 
 
 
 
  N 
XXX (XX%) 
XXX (XX%) 
XXX (XX%) 
XXX (XX%) 
XXX (XX%) 
  Mean 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  SD 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
  Q1 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  Median 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  Q3 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  Min. 
      XX 
      XX 
      XX 
      XX 
      XX 
  Max. 
      XX 
      XX 
      XX 
      XX 
      XX 
 
 
 
 
 
 
Due to Lack of beneficial effect with 
previous therapy 
 
 
 
 
 
  N 
XXX (XX%) 
XXX (XX%) 
XXX (XX%) 
XXX (XX%) 
XXX (XX%) 
  Mean 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  SD 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
  Q1 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  Median 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  Q3 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  Min. 
      XX 
      XX 
      XX 
      XX 
      XX 
  Max. 
      XX 
      XX 
      XX 
      XX 
      XX 
 
 
 
 
 
 
Overall 
 
 
 
 
 
  N 
 
 
 
 
 
  Mean 
 
 
 
 
 
  Etc.. 
 
 
 
 
 
 
Note:  Q1 = 1st quartile, Q3 = 3rd quartile. 
       Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
USER ID: Directory/Program.sas Date Time 
Programming notes: Use CONMEDS dataset where CMTYPCD is 84(PAH Therapy) and CMSTRSCD = 46 (Deterioration of clinical condition) or = 47 (Lack of beneficial effect 
with previous therapy). 
 
 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Intent-to-Treat 
 
Table 2.10:  Summary of Time to change in dose of ambrisentan or other targeted PAH therapeutic agents (prostanoids, PDE-5 inhibitors) due to deterioration of 
clinical condition (days) 
 
 
Ambrisentan 
2.5mg 
(N=XXX) 
Ambrisentan 
5mg 
(N=XXX) 
Ambrisentan 
7.5mg 
(N=XXX) 
Ambrisentan 
10mg 
(N=XXX) 
Total 
(N=XXX) 
 
 
 
 
 
 
  N 
XXX (XX%) 
XXX (XX%) 
XXX (XX%) 
XXX (XX%) 
XXX (XX%) 
  Mean 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  SD 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
  Q1 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  Median 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  Q3 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  Min. 
      XX 
      XX 
      XX 
      XX 
      XX 
  Max. 
      XX 
      XX 
      XX 
      XX 
      XX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  Q1 = 1st quartile, Q3 = 3rd quartile. 
       Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
 
USER ID: Directory/Program.sas Date Time 
Programming notes: Use CONMEDS dataset where CMTYPCD is 84(PAH Therapy) and CMSTRSCD = 46 (Deterioration of clinical condition) or EXPOSURE dataset where EXCHRSCD 
=58 (Deterioration of clinical condition). 
 
 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Intent-to-Treat 
Table 2.11:  Summary of WHO Functional Class 
 
Treatment 
Planned  
Relative Time 
n 
Mean 
SD 
Q1 
Median 
Q3 
Min. 
Max. 
 
 
 
 
 
 
 
 
 
 
Ambrisentan 
2.5mg 
Baseline** 
XX  
 XX.X 
 XX.XX 
 XX.X 
 XX.X 
 XX.X 
 XX 
 XX 
(N=XXX) 
Entry Visit* 
XX  
 XX.X 
 XX.XX 
 XX.X 
 XX.X 
 XX.X 
 XX 
 XX 
 
Month 6 
XX  
 XX.X 
 XX.XX 
 XX.X 
 XX.X 
 XX.X 
 XX 
 XX 
 
Etc.. 
XX  
 XX.X 
 XX.XX 
 XX.X 
 XX.X 
 XX.X 
 XX 
 XX 
 
 
 
 
 
 
 
 
 
 
Ambrisentan 
5mg 
Etc.. 
 
 
 
 
 
 
 
 
(N=XXX) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ambrisentan 
7.5mg 
Etc.. 
 
 
 
 
 
 
 
 
(N=XXX) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ambrisentan 
10mg 
Etc.. 
 
 
 
 
 
 
 
 
(N=XXX) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total 
Etc.. 
 
 
 
 
 
 
 
 
(N=XXX) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  ** Baseline is the last value recorded prior to start of study treatment from AMB112529. 
       * Entry Visit is at entry to AMB114588. 
       There are 4 grades of WHO FC based on symptom severity (
). 
       Grades mapped to numeric scale 1-4 (i.e. Class IV=4).  
    
 Q1 = 1st quartile, Q3 = 3rd quartile. 
       Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
USER ID: Directory/Program.sas Date Time 
 
Programming notes: Present available visits, End of Study and Follow-Up. 
 
 
CCI


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CONFIDENTIAL 
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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Intent-to-Treat 
Table 2.13:  Summary of WHO Functional Class Shifts from Baseline by Visit 
 
 
 
Treatment 
Planned  
Relative 
Time 
WHO 
Functional 
Class 
Baseline**  
WHO Functional Class 
 
II 
III 
 
 
 
 
 
Ambrisentan 2.5mg (N=XXX) 
Entry Visit* 
I 
  XX (%) 
 XX (%) 
 
 
II 
  XX (%) 
 XX (%) 
 
 
III 
    XX (%) 
    XX (%) 
 
 
IV 
    XX (%) 
    XX (%) 
 
 
Unknown/ 
Not Recorded 
    XX   
    XX   
 
 
 
 
 
Month 6 
I 
  XX (%) 
 XX (%) 
 
 
II 
  XX (%) 
 XX (%) 
 
 
III 
    XX (%) 
    XX (%) 
 
 
IV 
    XX (%) 
    XX (%) 
 
 
Unknown/ 
Not Recorded 
    XX   
    XX   
 
Etc.. 
 
 
 
 
 
 
 
 
Ambrisentan 5mg (N=XXX) 
Etc.. 
 
 
 
 
 
 
 
 
Ambrisentan 7.5mg (N=XXX) 
Etc.. 
 
 
 
 
 
 
 
 
Ambrisentan 10mg (N=XXX) 
Etc.. 
 
 
 
 
 
 
 
 
Total (N=XXX) 
Etc.. 
 
 
 
 
Note:  ** Baseline is the last value recorded prior to start of study treatment from AMB112529. 
       * Entry Visit is at entry to AMB114588. 
       There are 4 grades of WHO FC based on symptom severity (
). 
       Grades mapped to numeric scale 1-4 (i.e. Class IV=4).  
    
 Baseline WHO functional class not shown for III and IV because no subjects met the criteria for these categories at baseline. 
       Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
USER ID: Directory/Program.sas Date Time 
 
Programming notes: Present available visits, End of Study and Follow-Up. 
 
 
CCI


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Intent-to-Treat 
Table 2.14:  Summary of WHO Functional Class Change from Baseline Categorisation 
 
 
 
Ambrisentan 
2.5mg 
Ambrisentan 
5mg 
Ambrisentan 
7.5mg 
Ambrisentan 
10mg 
Total 
Planned Relative Time 
WHO Category 
(N=XXX) 
(N=XXX) 
(N=XXX) 
(N=XXX) 
(N=XXX) 
 
 
 
 
 
 
 
Entry Visit* 
 N 
   XXX  
   XXX  
   XXX  
   XXX  
   XXX  
 
 Improved 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
 No Change 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
 Deteriorated 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
 
 
 
 
 
 
 
-2 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
-1 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
 0 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
+1 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
+2 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
 
 
 
 
 
 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  * Entry Visit is at entry to AMB114588. 
       Baseline is the last value recorded prior to start of study treatment from AMB112529. 
       There are 4 grades of WHO FC based on symptom severity (
). 
       Grades mapped to numeric scale 1-4 (i.e. Class IV=4).  
       Change categorisation (based on -2, -1, 0, +1, +2); 
, 
       
.     
  
       Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
 
USER ID: Directory/Program.sas Date Time 
 
Programming notes: Present available visits, End of Study and Follow-Up. 
 
 
CCI
CCI
CCI


RAP 
CONFIDENTIAL 
AMB114588 
 
 
67 
Protocol: AMB114588                                                                                                Page 1 of n 
Population: Intent-to-Treat 
Table 2.15:  Summary of plasma NT-Pro BNP concentration (ng/L) 
 
Treatment 
Planned  
Relative Time 
n 
Geometric 
Mean 
SD 
[logs] 
Q1 
Median 
Q3 
Min. 
Max. 
 
 
 
 
 
 
 
 
 
 
Ambrisentan 
2.5mg 
Baseline** 
XXX 
 XX.X 
 XX.XX 
 XX.X 
 XX.X 
 XX.X 
 XX 
 XX 
(N=XXX) 
Entry Visit* 
XXX 
 XX.X 
 XX.XX 
 XX.X 
 XX.X 
 XX.X 
 XX 
 XX 
  
Month 6 
XXX 
 XX.X 
 XX.XX 
 XX.X 
 XX.X 
 XX.X 
 XX 
 XX 
 
Etc..  
XXX 
 XX.X 
 XX.XX 
 XX.X 
 XX.X 
 XX.X 
 XX 
 XX 
 
 
 
 
 
 
 
 
 
 
Ambrisentan 
5mg 
Etc.. 
 
 
 
 
 
 
 
 
(N=XXX) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ambrisentan 
7.5mg 
Etc..  
 
 
 
 
 
 
 
 
(N=XXX) 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
Ambrisentan 
10mg 
Etc.. 
 
 
 
 
 
 
 
 
(N=XXX) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total 
Etc.. 
 
 
 
 
 
 
 
 
(N=XXX) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  ** Baseline is the last value recorded prior to start of study treatment from AMB112529. 
       * Entry Visit is at entry to AMB114588. 
    
 Q1 = 1st quartile, Q3 = 3rd quartile. 
       Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
USER ID: Directory/Program.sas Date Time 
 
Programming notes: Present available visits, End of Study and Follow-Up. 
 
 


RAP 
CONFIDENTIAL 
AMB114588 
 
 
68 
Protocol: AMB114588                                                                                                Page 1 of n 
Population: Intent-to-Treat 
Table 2.17:  Summary of Exploratory Echocardiogram 
 
Planned 
Relative Time 
 
Ambrisentan 
2.5mg 
Ambrisentan 
5mg 
Ambrisentan 
7.5mg 
Ambrisentan 
10mg 
Total 
Baseline** 
 
(N=XXX) 
(N=XXX) 
(N=XXX) 
(N=XXX) 
(N=XXX) 
 
 
 
 
 
 
Pericardial 
N 
   XXX     
   XXX     
   XXX     
   XXX     
   XXX     
Effusion
Absent 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
Trace: separation of pericardial layers in both systole 
and diastole 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
Small: diastolic separation equals 1cm 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
Moderate: diastolic separation of 1 to 2cm 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
Large: diastolic separation equals 2cm 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
 
 
 
 
 
Mean right 
N 
    XXX     
    XXX     
    XXX     
    XXX     
    XXX     
Atrial
Mean 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
Pressure
SD 
     XX.XX 
     XX.XX 
     XX.XX 
     XX.XX 
     XX.XX 
(mmHg)
Q1 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
Median 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
Q3 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
Min. 
     XX 
     XX 
     XX 
     XX 
     XX 
Max. 
     XX 
     XX 
     XX 
     XX 
     XX 
 
 
 
 
 
 
Tricuspid 
N 
    XXX     
    XXX     
    XXX     
    XXX     
    XXX     
Annular
Mean 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
Plane
SD 
     XX.XX 
     XX.XX 
     XX.XX 
     XX.XX 
     XX.XX 
Systolic
Q1 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
Excursion  
Median 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
(cm)
Q3 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
Min. 
     XX 
     XX 
     XX 
     XX 
     XX 
Max. 
     XX 
     XX 
     XX 
     XX 
     XX 
Note:  ** Baseline is the last value recorded prior to start of study treatment from AMB112529. 
       * Entry Visit is at entry to AMB114588. 
       Q1 = 1st quartile, Q3 = 3rd quartile. 
       Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
 
USER ID: Directory/Program.sas Date Time 
 
Programming notes: Present available visits (including Entry Visit), End of Study and Follow-Up. 
 
 


RAP 
CONFIDENTIAL 
AMB114588 
 
 
69 
Protocol: AMB114588                                                                                                Page 2 of n 
Population: Intent-to-Treat 
Table 2.17:  Summary of Exploratory Echocardiogram 
 
Planned 
Relative Time 
 
Ambrisentan 
2.5mg 
Ambrisentan 
5mg 
Ambrisentan 
7.5mg 
Ambrisentan 
10mg 
Total 
Baseline** 
 
(N=XXX) 
(N=XXX) 
(N=XXX) 
(N=XXX) 
(N=XXX) 
 
 
 
 
 
 
Eccentricity 
N 
    XXX     
    XXX     
    XXX     
    XXX     
    XXX     
Index
Mean 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
Systolic
SD 
     XX.XX 
     XX.XX 
     XX.XX 
     XX.XX 
     XX.XX 
Q1 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
Median 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
Q3 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
Min. 
     XX 
     XX 
     XX 
     XX 
     XX 
Max. 
     XX 
     XX 
     XX 
     XX 
     XX 
 
 
 
 
 
 
Eccentricity 
N 
    XXX     
    XXX     
    XXX     
    XXX     
    XXX     
Index
Mean 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
Diastolic 
SD 
     XX.XX 
     XX.XX 
     XX.XX 
     XX.XX 
     XX.XX 
Q1 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
Median 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
Q3 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
Min. 
     XX 
     XX 
     XX 
     XX 
     XX 
Max. 
     XX 
     XX 
     XX 
     XX 
     XX 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  ** Baseline is the last value recorded prior to start of study treatment from AMB112529. 
       * Entry Visit is at entry to AMB114588. 
       Q1 = 1st quartile, Q3 = 3rd quartile. 
       Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
 
USER ID: Directory/Program.sas Date Time 
 
Programming notes: Present available visits (including Entry Visit), End of Study and Follow-Up. 
 
 


RAP 
CONFIDENTIAL 
AMB114588 
 
 
70 
Protocol: AMB114588                                                                                                Page 3 of n 
Population: Intent-to-Treat 
Table 2.17:  Summary of Exploratory Echocardiogram 
 
Planned 
Relative Time 
 
Ambrisentan 
2.5mg 
Ambrisentan 
5mg 
Ambrisentan 
7.5mg 
Ambrisentan 
10mg 
Total 
Baseline** 
 
(N=XXX) 
(N=XXX) 
(N=XXX) 
(N=XXX) 
(N=XXX) 
 
 
 
 
 
 
Tricuspid 
N 
    XXX     
    XXX     
    XXX     
    XXX     
    XXX     
Regurgitant 
Mean 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
Jet Velocity 
SD 
     XX.XX 
     XX.XX 
     XX.XX 
     XX.XX 
     XX.XX 
(m/s)
Q1 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
Median 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
Q3 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
Min. 
     XX 
     XX 
     XX 
     XX 
     XX 
Max. 
     XX 
     XX 
     XX 
     XX 
     XX 
 
 
 
 
 
 
Right
N 
    XXX     
    XXX     
    XXX     
    XXX     
    XXX     
Ventricular 
Mean 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
Pressure
SD 
     XX.XX 
     XX.XX 
     XX.XX 
     XX.XX 
     XX.XX 
(mmHg)
Q1 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
Median 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
Q3 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
Min. 
     XX 
     XX 
     XX 
     XX 
     XX 
Max. 
     XX 
     XX 
     XX 
     XX 
     XX 
 
 
 
 
 
 
 
Note:  ** Baseline is the last value recorded prior to start of study treatment from AMB112529. 
       * Entry Visit is at entry to AMB114588. 
       Q1 = 1st quartile, Q3 = 3rd quartile. 
       Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
 
USER ID: Directory/Program.sas Date Time 
 
Programming notes: Present available visits (including Entry Visit), End of Study and Follow-Up. 
 
 


RAP 
CONFIDENTIAL 
AMB114588 
 
 
71 
Protocol: AMB114588                                                                                                Page 1 of n 
Population: Intent-to-Treat 
 
Table 2.18:  Summary of Change from Baseline in Exploratory Echocardiogram 
 
Planned Relative 
Time
 
Ambrisentan 
2.5mg 
Ambrisentan 
5mg 
Ambrisentan 
7.5mg 
Ambrisentan 
10mg 
Total 
Entry Visit* 
 
(N=XXX) 
(N=XXX) 
(N=XXX) 
(N=XXX) 
(N=XXX) 
 
 
 
 
 
 
Pericardial 
n 
   XXX     
   XXX     
   XXX     
   XXX     
   XXX     
Effusion
No Change 
  Absent 
 
    XX (%) 
     XX (%) 
    XX (%) 
     XX (%) 
    XX (%) 
     XX (%) 
    XX (%) 
     XX (%) 
    XX (%) 
     XX (%) 
Improved 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
Worsened 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
 
 
 
 
 
Mean right 
n 
    XXX     
    XXX     
    XXX     
    XXX     
    XXX     
Atrial
Mean 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
Pressure
SD 
     XX.XX 
     XX.XX 
     XX.XX 
     XX.XX 
     XX.XX 
(mmHg)
Q1 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
Median 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
Q3 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
Min. 
     XX 
     XX 
     XX 
     XX 
     XX 
Max. 
     XX 
     XX 
     XX 
     XX 
     XX 
 
 
 
 
 
 
Tricuspid 
n 
    XXX     
    XXX     
    XXX     
    XXX     
    XXX     
Annular
Mean 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
Plane
SD 
     XX.XX 
     XX.XX 
     XX.XX 
     XX.XX 
     XX.XX 
Systolic
Q1 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
Excursion  
Median 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
(cm)
Q3 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
Min. 
     XX 
     XX 
     XX 
     XX 
     XX 
Max. 
     XX 
     XX 
     XX 
     XX 
     XX 
 
Note:  * Entry Visit is at entry to AMB114588. 
       Baseline is the last value recorded prior to start of study treatment from AMB112529. 
       Q1 = 1st quartile, Q3 = 3rd quartile. 
       Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
 
USER ID: Directory/Program.sas Date Time 
Programming notes: Present available visits, End of Study and Follow-Up. 
 
 


RAP 
CONFIDENTIAL 
AMB114588 
 
 
72 
Protocol: AMB114588                                                                                                Page 2 of n 
Population: Intent-to-Treat 
 
Table 2.18:  Summary of Change from Baseline in Exploratory Echocardiogram 
 
Planned 
Relative Time 
 
Ambrisentan 
2.5mg 
Ambrisentan 
5mg 
Ambrisentan 
7.5mg 
Ambrisentan 
10mg 
Total 
Entry Visit* 
 
(N=XXX) 
(N=XXX) 
(N=XXX) 
(N=XXX) 
(N=XXX) 
 
 
 
 
 
 
Eccentricity 
n 
    XXX     
    XXX     
    XXX     
    XXX     
    XXX     
Index
Mean 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
Systolic
SD 
     XX.XX 
     XX.XX 
     XX.XX 
     XX.XX 
     XX.XX 
Q1 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
Median 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
Q3 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
Min. 
     XX 
     XX 
     XX 
     XX 
     XX 
Max. 
     XX 
     XX 
     XX 
     XX 
     XX 
 
 
 
 
 
 
Eccentricity 
N 
    XXX     
    XXX     
    XXX     
    XXX     
    XXX     
Index
Mean 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
Diastolic 
SD 
     XX.XX 
     XX.XX 
     XX.XX 
     XX.XX 
     XX.XX 
Q1 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
Median 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
Q3 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
Min. 
     XX 
     XX 
     XX 
     XX 
     XX 
Max. 
     XX 
     XX 
     XX 
     XX 
     XX 
 
 
 
 
 
 
 
 
 
 
 
Note:  * Entry Visit is at entry to AMB114588. 
       Baseline is the last value recorded prior to start of study treatment from AMB112529. 
       Q1 = 1st quartile, Q3 = 3rd quartile. 
       Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
 
USER ID: Directory/Program.sas Date Time 
 
Programming notes: Present available visits, End of Study and Follow-Up. 
 
 


RAP 
CONFIDENTIAL 
AMB114588 
 
 
73 
Protocol: AMB114588                                                                                                Page 3 of n 
Population: Intent-to-Treat 
 
Table 2.18:  Summary of Change from Baseline in Exploratory Echocardiogram 
 
Planned Relative 
Time
 
Ambrisentan 
2.5mg 
Ambrisentan 
5mg 
Ambrisentan 
7.5mg 
Ambrisentan 
10mg 
Total 
Entry Visit* 
 
(N=XXX) 
(N=XXX) 
(N=XXX) 
(N=XXX) 
(N=XXX) 
 
 
 
 
 
 
Tricuspid 
N 
    XXX     
    XXX     
    XXX     
    XXX     
    XXX     
Regurgitant 
Mean 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
Jet Velocity 
SD 
     XX.XX 
     XX.XX 
     XX.XX 
     XX.XX 
     XX.XX 
(m/s)
Q1 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
Median 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
Q3 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
Min. 
     XX 
     XX 
     XX 
     XX 
     XX 
Max. 
     XX 
     XX 
     XX 
     XX 
     XX 
 
 
 
 
 
 
Right
N 
    XXX     
    XXX     
    XXX     
    XXX     
    XXX     
Ventricular 
Mean 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
Pressure
SD 
     XX.XX 
     XX.XX 
     XX.XX 
     XX.XX 
     XX.XX 
(mmHg)
Q1 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
Median 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
Q3 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
     XX.X 
Min. 
     XX 
     XX 
     XX 
     XX 
     XX 
Max. 
     XX 
     XX 
     XX 
     XX 
     XX 
 
 
 
 
 
Note:  * Entry Visit is at entry to AMB114588. 
       Baseline is the last value recorded prior to start of study treatment from AMB112529. 
       Q1 = 1st quartile, Q3 = 3rd quartile. 
       Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
 
USER ID: Directory/Program.sas Date Time 
 
Programming notes: Present available visits, End of Study and Follow-Up. 


RAP 
CONFIDENTIAL 
AMB114588 
 
 
74 
Protocol: AMB114588                                                                                                Page 1 of n   
Population: Intent-to-treat                                                                                 
                                                
Table  2.19: Summary of Number of Subjects with School Days 
 
 
Planned Relative Time 
Ambrisentan 
2.5mg 
Ambrisentan 
5mg 
Ambrisentan 
7.5mg 
Ambrisentan 
10mg 
Total 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
Baseline** 
 
 
 
 
 
Subjects with scheduled days 
xx     (xx%) 
xx     (xx%) 
xx     (xx%) 
xx     (xx%) 
xx     (xx%) 
Subjects with at least one scheduled day missed 
xx     (xx%) 
xx     (xx%) 
xx     (xx%) 
xx     (xx%) 
xx     (xx%) 
Number of scheduled days missed / 
xx/xxx (xx%) 
xx/xxx (xx%) 
xx/xxx (xx%) 
xx/xxx (xx%) 
xx/xxx (xx%) 
Number of scheduled days 
 
 
 
 
 
 
 
 
 
 
Subjects with at least one scheduled day missed due to PAH 
xx     (xx%) 
xx     (xx%) 
xx     (xx%) 
xx     (xx%) 
xx     (xx%) 
Number of scheduled days missed due to PAH / 
xx     (xx%) 
xx     (xx%) 
xx     (xx%) 
xx     (xx%) 
xx     (xx%) 
Number of scheduled days 
xx/xxx (xx%) 
xx/xxx (xx%) 
xx/xxx (xx%) 
xx/xxx (xx%) 
xx/xxx (xx%) 
 
 
 
 
 
Entry Visit* 
 
 
 
 
 
Subjects with scheduled days 
xx     (xx%) 
xx     (xx%) 
xx     (xx%) 
xx     (xx%) 
xx     (xx%) 
Subjects with at least one scheduled day missed 
xx     (xx%) 
xx     (xx%) 
xx     (xx%) 
xx     (xx%) 
xx     (xx%) 
Number of scheduled days missed / 
xx/xxx (xx%) 
xx/xxx (xx%) 
xx/xxx (xx%) 
xx/xxx (xx%) 
xx/xxx (xx%) 
Number of scheduled days 
 
 
 
 
 
 
 
 
 
 
Subjects with at least one scheduled day missed due to PAH 
xx     (xx%) 
xx     (xx%) 
xx     (xx%) 
xx     (xx%) 
xx     (xx%) 
Number of scheduled days missed due to PAH / 
xx     (xx%) 
xx     (xx%) 
xx     (xx%) 
xx     (xx%) 
xx     (xx%) 
Number of scheduled days 
xx/xxx (xx%) 
xx/xxx (xx%) 
xx/xxx (xx%) 
xx/xxx (xx%) 
xx/xxx (xx%) 
 
 
 
 
 
Etc..
 
 
 
 
 
 
 
Note:  ** Baseline is the last value recorded prior to start of study treatment from AMB112529. 
       * Entry Visit is at entry to AMB114588. 
       This summary excludes subjects with 0 scheduled days of school for the given period. 
       Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
 
USER ID: Directory/Program.sas Date Time  
 
Programming notes: Present available visits, End of Study and Follow-Up. 
 
 


RAP 
CONFIDENTIAL 
AMB114588 
 
 
75 
Protocol: AMB114588                                                                                                Page 1 of n 
Population: Intent-to-Treat 
Table 2.20:  Summary Statistics of School Days 
 
Planned Relative Time 
 
Ambrisentan 
2.5mg 
Ambrisentan 
5mg 
Ambrisentan 
7.5mg 
Ambrisentan 
10mg 
Total 
Baseline** 
 
(N=XXX) 
(N=XXX) 
(N=XXX) 
(N=XXX) 
(N=XXX) 
Number 
N 
     XXX          XXX          XXX          XXX     
     XXX     
of scheduled days 
Mean 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
 
SD 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
 
Q1 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
 
Median 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
 
Q3 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
 
Min. 
      XX 
      XX 
      XX 
      XX 
      XX 
 
Max. 
      XX 
      XX 
      XX 
      XX 
      XX 
 
 
 
 
 
 
 
Number 
N 
     XXX          XXX          XXX          XXX     
     XXX     
of missed days 
Mean 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
 
SD 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
 
Q1 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
 
Median 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
 
Q3 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
 
Min. 
      XX 
      XX 
      XX 
      XX 
      XX 
 
Max. 
      XX 
      XX 
      XX 
      XX 
      XX 
 
 
 
 
 
 
 
Number 
N 
     XXX          XXX          XXX          XXX     
     XXX     
of missed days 
Mean 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
due to PAH 
SD 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
 
Q1 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
 
Median 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
 
Q3 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
 
Min. 
      XX 
      XX 
      XX 
      XX 
      XX 
 
Max. 
      XX 
      XX 
      XX 
      XX 
      XX 
Note:  ** Baseline is the last value recorded prior to start of study treatment from AMB112529. 
       * Entry Visit is at entry to AMB114588. 
       This summary excludes subjects with 0 scheduled days of school for the given period. 
       Q1 = 1st quartile, Q3 = 3rd quartile. 
       Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
 
USER ID: Directory/Program.sas Date Time  
 
Programming notes: Present available visits (including Entry Visit), End of Study and Follow-Up. 
 
 


RAP 
CONFIDENTIAL 
AMB114588 
 
 
76 
Protocol: AMB114588                                                                                                Page 2 of n 
Population: Intent-to-Treat 
Table 2.20:  Summary Statistics of School Days 
 
Planned Relative Time 
 
Ambrisentan 
2.5mg 
Ambrisentan 
5mg 
Ambrisentan 
7.5mg 
Ambrisentan 
10mg 
Total 
Entry Visit 
 
(N=XXX) 
(N=XXX) 
(N=XXX) 
(N=XXX) 
(N=XXX) 
 
 
 
 
 
 
 
Proportion of days 
n 
     XXX          XXX          XXX          XXX     
     XXX     
missed (%) 
Mean 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
 
SD 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
 
Q1 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
 
Median 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
 
Q3 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
 
Min. 
      XX 
      XX 
      XX 
      XX 
      XX 
 
Max. 
      XX 
      XX 
      XX 
      XX 
      XX 
 
 
 
 
 
 
 
Proportion of days 
N 
     XXX          XXX          XXX          XXX     
     XXX     
missed due to PAH(%) 
Mean 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
 
SD 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
 
Q1 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
 
Median 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
 
Q3 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
 
Min. 
      XX 
      XX 
      XX 
      XX 
      XX 
 
Max. 
      XX 
      XX 
      XX 
      XX 
      XX 
 
 
 
 
 
 
 
 
Note:  ** Baseline is the last value recorded prior to start of study treatment from AMB112529. 
       * Entry Visit is at entry to AMB114588. 
       This summary excludes subjects with 0 scheduled days of school for the given period. 
       Q1 = 1st quartile, Q3 = 3rd quartile. 
       Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
 
USER ID: Directory/Program.sas Date Time  
 
Programming notes: Present available visits (including Entry Visit), End of Study and Follow-Up. 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Intent-to-Treat 
Table 2.22:  Summary of Subject Global Assessment (SF10 Health Survey for Children) 
 
Planned Relative Time 
 
Ambrisentan 
2.5mg 
Ambrisentan 
5mg 
Ambrisentan 
7.5mg 
Ambrisentan 
10mg 
Total 
Baseline** 
 
(N=XXX) 
(N=XXX) 
(N=XXX) 
(N=XXX) 
(N=XXX) 
 
 
 
 
 
 
 
Physical Health Summary 
n 
     XXX          XXX          XXX          XXX     
     XXX     
 
Mean 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
 
SD 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
 
Q1 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
 
Median 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
 
Q3 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
 
Min. 
      XX 
      XX 
      XX 
      XX 
      XX 
 
Max. 
      XX 
      XX 
      XX 
      XX 
      XX 
 
 
 
 
 
 
 
Psychosocial Summary 
N 
     XXX          XXX          XXX          XXX     
     XXX     
 
Mean 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
 
SD 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
 
Q1 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
 
Median 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
 
Q3 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
 
Min. 
      XX 
      XX 
      XX 
      XX 
      XX 
 
Max. 
      XX 
      XX 
      XX 
      XX 
      XX 
 
 
 
 
 
 
 
 
 
Note:  ** Baseline is the last value recorded prior to start of study treatment from AMB112529. 
       * Entry Visit is at entry to AMB114588. 
       Q1 = 1st quartile, Q3 = 3rd quartile. 
       Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
 
USER ID: Directory/Program.sas Date Time  
 
Programming notes: Present available visits (including Entry Visit), End of Study and Follow-Up. 
 
 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Intent-to-Treat 
Table 2.24:  Summary of SF10 Health Survey – Number and Percentage of Subjects with Particular Item Responses 
 
Planned Relative Time 
Ambrisentan 
2.5mg 
Ambrisentan 
5mg 
Ambrisentan 
7.5mg 
Ambrisentan 
10mg 
Total 
Baseline** 
(N=XXX) 
(N=XXX) 
(N=XXX) 
(N=XXX) 
(N=XXX) 
Completed SF-10 ^ 
    XX (%)  
    XX (%)  
    XX (%)  
    XX (%)  
    XX (%)  
In general, would you say your child’s health is 
 
 
 
 
 
  N 
    XX 
    XX 
    XX 
    XX 
    XX 
  Excellent 
    XX (%)  
    XX (%)  
    XX (%)  
    XX (%)  
    XX (%)  
  Very Good 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Good 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Fair 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Poor 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
 
 
 
 
 
During the past 4 weeks, has your child been limited 
doing things that take some energy such as riding a 
bike or skating due to HEALTH problems? 
 
 
 
 
 
  N 
    XX 
    XX 
    XX 
    XX 
    XX 
  Yes, limited a lot 
    XX (%)  
    XX (%)  
    XX (%)  
    XX (%)  
    XX (%)  
  Yes, limited some 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Yes, limited a little 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  No, not limited 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
 
 
 
 
 
During the past 4 weeks, has your child been limited 
during bending, lifting or stooping due to HEALTH 
problems? 
 
 
 
 
 
  N 
    XX 
    XX 
    XX 
    XX 
    XX 
  Yes, limited a lot 
    XX (%)  
    XX (%)  
    XX (%)  
    XX (%)  
    XX (%)  
  Yes, limited some 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Yes, limited a little 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  No, not limited 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
etc... 
 
 
 
 
 
Note:  ** Baseline is the last value recorded prior to start of study treatment from AMB112529. 
       * Entry Visit is at entry to AMB114588. 
       ^ Completed at least one of the 10 items of SF-10 
       Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
 
USER ID: Directory/Program.sas Date Time  
 
Programming notes: Present available visits (including Entry Visit), End of Study and Follow-Up. 
 
 


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Protocol: AMB114588                                                                              Page 1 of 1 
Population: Intent-to-treat 
                                                 Table 2.25 
                      Number of subjects who achieved an increase in 6MWD >=20 metres 
 
                                                                                          N=xx 
       --------------------------------------------------------------------------------------------- 
       >/= 20 meters increase from baseline (LOCF) at 12 months                           xx (xx%) 
       >/= 20 meters increase from baseline at last observation                           xx (xx%) 
 
 
 
Note: Baseline is the last value recorded prior to the start of study treatment from AMB112529. 
USER ID: Directory/Program.sas Date Time 


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Protocol: AMB114588                                                                              Page 1 of 1 
Population: Intent-to-treat 
                                                 Table 2.26 
                      Number of subjects who achieved an increase in 6MWD >=20 metres by Idiopathic group 
 
     Idiopathic group                                                                      
 
 
 
        N=100 
     ------------------------------------------------------------------------------------------------------------------------------------------------------------- 
     Idiopathic group                                                               
 
 
 
 
          xx 
                               
 >/= 20 meters increase from baseline at 12 months (LOCF)      
            
    xx (xx%) 
                               
 >/= 20 meters increase from baseline at last observation                
          xx (xx%) 
 
     Non-idiopathic group                                                                  
 
 
       
    xx 
                               
>/= 20 meters increase from baseline at 12 months (LOCF)     
   
       
    xx (xx%) 
                               
>/= 20 meters increase from baseline at last observation       
 
    
 
    xx (xx%) 
 
 
 
 
 
 
Note: Baseline is the last value recorded prior to the start of study treatment from AMB112529. 
'Idiopathic group' refers to those with an idiopathic aetiology of PAH in 112529, and ‘non-idiopathic’ refers to those classified as having: an aetiology of 
familial, persistent PAH despite surgical repair, or secondary to connective tissue disease. 
For subjects with missing data at 12 months, the post-baseline last observation was carried forward (LOCF) to the 12 month visit. 
 
USER ID: Directory/Program.sas Date Time 
 
 
 
 


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Protocol: AMB114588                                                                              Page 1 of 1 
Population: Intent-to-treat 
                                                 Table 2.27 
                 Number of subjects who achieved an NT-proBNP level of less than 1200 ng/L  
 
                                                                                          N=xx 
       --------------------------------------------------------------------------------------------- 
       NT-proBNP level of less than 1200 ng/L at 12 months (LOCF)                         xx (xx%) 
       NT-proBNP level of less than 1200 ng/L at last observation                         xx (xx%) 
 
 
 
Note:  For subjects with missing data at 12 months, the post-baseline last observation was carried forward (LOCF) to the 12 month visit. 
 
USER ID: Directory/Program.sas Date Time 
 
 


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Protocol: AMB114588                                                                              Page 1 of 1 
Population: Intent-to-treat 
                                                 Table 2.28 
                 Number of subjects who achieved an NT-proBNP level of less than 1200 ng/L by Idiopathic group 
 
     Idiopathic group                                                                        N=xx 
     -------------------------------------------------------------------------------------------------- 
     Idiopathic group                                                                        xx 
                              NT-proBNP level of less than 1200 ng/L at 12 months (LOCF)     xx (xx%) 
                              NT-proBNP level of less than 1200 ng/L at last observation     xx (xx%) 
 
     Non-idiopathic group                                                                    xx 
                              NT-proBNP level of less than 1200 ng/L at 12 months (LOCF)     xx (xx%) 
                              NT-proBNP level of less than 1200 ng/L at last observation     xx (xx%) 
 
 
 
 
Note: 'Idiopathic group' refers to those with an idiopathic aetiology of PAH in 112529, and ‘non-idiopathic’ refers to those classified as having: an aetiology of 
familial, persistent PAH despite surgical repair, or secondary to connective tissue disease. 
For subjects with missing data at 12 months, the post-baseline last observation was carried forward (LOCF) to the 12 month visit.        
 
USER ID: Directory/Program.sas Date Time 


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Protocol: AMB114588                                                                              Page 1 of 1 
Population: Intent-to-treat 
                                                 Table 2.29 
             Distribution of NT-proBNP levels at baseline and extent of change during treatment 
 
                                                                                     N=xx 
            ----------------------------------------------------------------------------------- 
            NT-proBNP value above 1200 ng/L at baseline                               x (18%) 
              How many stayed over 1200                                               x (3%) 
              How many had at least 1 value < 1200                                    x (13%) 
              How many had value <1200 as last value                                  x (13%) 
              Other (a)                                                               x (3%) 
 
            NT-proBNP value above 1200 ng/L at any time during the study             xx (29%) 
 
            NT-proBNP value between 500 ng/L and 1200 ng/L at baseline                x (8%) 
              How many had at least 1 value >1200?                                    x (3%) 
                and how many of these stayed over 1200?                               x (3%) 
              How many stayed between 500 and 1200?                                   x (3%) 
              How many fell below 500                                                 x (5%) 
                Of those how many were <500 as last value?                            x (3%) 
                Other (b)                                                             x (3%) 
 
            NT-proBNP value < 500 ng/L at baseline                                   xx (71%) 
              How many had at least 1 value > 1200                                    x (8%) 
                and of these how many stayed over 1200?                               x (5%) 
                Other (c)                                                             x (3%) 
              How many rose to between 500 and 1200?                                  x (13%) 
                how many stayed there?                                                x (5%) 
                Other (d)                                                             x (8%) 
              How many stayed below 500?                                             xx (55%) 
 
 
 
 
Note:   
(a) Subject
did not have a baseline visit in AMB112529. 
(b) Subject
only had a baseline value. 
(c) Subject
went up to>1200, back down to 500-1200 
(d) Subject
fell below 500 then up above 1200 
(e) Subject
went up to 500-1200 but ended above 1200 
(f) Subject
 fell below 500 then back up to 500-1200 
 
 
USER ID: Directory/Program.sas Date Time 
 
 
PPD


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Protocol: AMB114588                                                                              Page 1 of 2 
Population: Intent-to-treat 
                                                 Table 2.30 
             Distribution of NT-proBNP levels at baseline and extent of change during treatment - by Idiopathic group 
 
Group: Idiopathic group 
 
                                                                                     N=xx 
            ----------------------------------------------------------------------------------- 
            Idiopathic group                                                         xx 
 
            NT-proBNP value above 1200 ng/L at baseline                               xx (xx%) 
              How many stayed over 1200                                               x (x%) 
              How many had at least 1 value < 1200                                    xx (xx%) 
              How many had value <1200 as last value                                  xx (xx%) 
              Other (a)                                                               xx (x%) 
 
            NT-proBNP value above 1200 ng/L at any time during the study             xx (xx%) 
 
            NT-proBNP value between 500 ng/L and 1200 ng/L at baseline                x (xx%) 
              How many had at least 1 value >1200?                                    0 
                and how many of these stayed over 1200?                               X (x%) 
              How many stayed between 500 and 1200?                                   x (x%) 
              How many fell below 500                                                 x (x%) 
                Of those how many were <500 as last value?                            X (x%) 
 
            NT-proBNP value < 500 ng/L at baseline                                   xx (63%) 
              How many had at least 1 value > 1200                                    x (x%) 
                and of these how many stayed over 1200?                               x (x%) 
                Other (b)                                                             x (x%) 
              How many rose to between 500 and 1200?                                  x (x%) 
                how many stayed there?                                                x (x%) 
                Other (c)                                                             x (x%) 
              How many stayed below 500?                                             xx (x%) 
 
 
 
Group: Non-idiopathic group-all other categories 
 
                                                                                     N=xx 
            ----------------------------------------------------------------------------------- 
            Number in non-idiopathic group                                           xx 
 
            NT-proBNP value above 1200 ng/L at baseline                               0 
              How many stayed over 1200                                               0 
              How many had at least 1 value < 1200                                    0 
              How many had value <1200 as last value                                  0 
 
            NT-proBNP value above 1200 ng/L at any time during the study              x (xx%) 
 
            NT-proBNP value between 500 ng/L and 1200 ng/L at baseline                x (xx%) 
              How many had at least 1 value >1200?                                    x (xx%) 
                and how many of these stayed over 1200?                               X (xx%) 
              How many stayed between 500 and 1200?                                   x 
              How many fell below 500                                                 x (xx%) 
                Of those how many were <500 as last value?                            x (xx%) 
                Other (d)                                                             x (xx%) 
 
            NT-proBNP value < 500 ng/L at baseline                                   xx (xx%) 
              How many had at least 1 value > 1200                                    0 


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85 
                and of these how many stayed over 1200?                               0 
              How many rose to between 500 and 1200?                                  x (xx%) 
                how many stayed there?                                                x (xx%) 
                Other (e)                                                             x (xx%) 
              How many stayed below 500?                                              0 (xx%) 
 
 
 
Note:   
(a) Subject 
did not have a baseline visit in AMB112529. 
(b) Subject 
only had a baseline value. 
(c) Subject 
went up to>1200, back down to 500-1200 
(d) Subject 
fell below 500 then up above 1200 
(e) Subject 
went up to 500-1200 but ended above 1200 
(f) Subject 
 fell below 500 then back up to 500-1200 
 
 
USER ID: Directory/Program.sas Date Time 
 
 
PPD


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Protocol: AMB114588                                                                              Page 1 of 1 
Population: Intent-to-Treat 
                                                 Table 2.31 
                  The Event Rate of the Clinical Worsening Endpoint per 100 Patient-Years 
 
                             The number of subjects with at   Total exposure time   Event rate per 100 
     Treatment   N           least one clinical worsening     (year)                patient-years 
     -------------------------------------------------------------------------------------------------- 
     Total       xx          xx                              xxxx.x                 x.x 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Total Exposure time in years is calculated by the sum for all subjects of (last exposure date - first exposure date + 1) / 
365.25. If the last exposure date is missing, the last study visit date is used. 
For the subjects with at least one clinical worsening, the first event date should be used instead of the last 
exposure date. 
Event rate per 100 patient-years: The number of subjects with at least one clinical worsening / Total 
exposure time (year) * 100; 
 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Safety 
Table 3.1:  Summary of Exposure to Investigational Product 
 
 
 
Ambrisentan 
2.5mg 
Ambrisentan 
5mg 
Ambrisentan 
7.5mg 
Ambrisentan 
10mg 
Total 
 
 
(N=XXX) 
(N=XXX) 
(N=XXX) 
(N=XXX) 
(N=XXX) 
 
 
 
 
 
 
 
Number of days 
n 
     XXX        XXX     
     XXX     
   XXX     
   XXX     
of exposure 
Mean 
      XX.X 
    XX.X 
      XX.X 
    XX.X 
    XX.X 
 
SD 
      XX.XX     XX.XX 
      XX.XX 
    XX.XX 
    XX.XX 
 
Q1 
      XX.X 
    XX.X 
      XX.X 
    XX.X 
    XX.X 
 
Median 
      XX.X 
    XX.X 
      XX.X 
    XX.X 
    XX.X 
 
Q3 
      XX.X 
    XX.X 
      XX.X 
    XX.X 
    XX.X 
 
Min. 
      XX 
    XX 
      XX 
    XX 
    XX 
 
Max. 
      XX 
    XX 
      XX 
    XX 
    XX 
 
 
 
 
 
 
 
Interval of days 
n 
   XXX 
   XXX 
   XXX 
   XXX 
   XXX 
of exposure 
<=1 month 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
>1 month to <=2 months     XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
>2 month to <=3 months     XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
Etc.. 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
 
 
 
 
 
 
 
 
 
 
Note: For each patient, exposure (days) = date of last dose of study drug – first dose date + 1 day. 
      Q1 = 1st quartile, Q3 = 3rd quartile. 
      Subjects are considered as belonging to the treatment group according to the highest dose received. 
      For subjects missing their last exposure date at the time of study end, their last visit date in the study was used.      
 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Safety 
Table 3.2:  Summary of Treatment-Emergent Adverse Events 
 
System Organ Class 
  Preferred term 
Ambrisentan 
2.5mg 
(N=XXX) 
Ambrisentan 
5mg 
(N=XXX) 
Ambrisentan 
7.5mg 
(N=XXX) 
Ambrisentan 
10mg 
(N=XXX) 
Total 
(N=XXX) 
 
 
 
 
 
 
Any event 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
 
 
 
 
 
Gastrointestinal disorders 
 
 
 
 
 
  Any event 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Dyspepsia 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Nausea 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
 
 
 
 
 
Nervous system disorders 
 
 
 
 
 
  Any event 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Headache 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Dizziness 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Somnolence 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Tremor 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Sedation 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
 
 
 
 
 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  Subjects are considered as belonging to the treatment group according to the highest dose received.    
  
 
USER ID: Directory/Program.sas Date Time 
 
Programming notes: Events will be sorted in descending order of total incidence across treatment groups for the System Organ Class and in descending order of total 
incidence for the preferred term within each System Organ Class. If the total incidence for any two or more preferred terms is equal, they will be presented in 
alphabetical order.


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Safety 
Table 3.3:  Summary of Treatment-Emergent Adverse Events by Preferred Term 
 
 
  Preferred term 
Ambrisentan 
2.5mg 
(N=XXX) 
Ambrisentan 
5mg 
(N=XXX) 
Ambrisentan 
7.5mg 
(N=XXX) 
Ambrisentan 
10mg 
(N=XXX) 
Total 
(N=XXX) 
 
 
 
 
 
 
Any event 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
 
 
 
 
 
  Dyspepsia 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Nausea 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Headache 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Dizziness 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Somnolence 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Tremor 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Sedation 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
 
 
 
 
 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  Subjects are considered as belonging to the treatment group according to the highest dose received.    
  
 
USER ID: Directory/Program.sas Date Time 
 
Programming notes: Events will be sorted in descending order of total incidence across treatment groups for the preferred term.  If the total incidence for any two 
or more preferred terms is equal, they will be presented in alphabetical order.


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Safety 
Table 3.4:  Summary of Treatment-Emergent Adverse Events by Maximum Intensity 
 
 
Ambrisentan 
2.5mg 
(N=XXX) 
Ambrisentan 
5mg 
(N=XXX) 
Ambrisentan 
7.5mg 
(N=XXX) 
Ambrisentan 
10mg 
(N=XXX) 
 
System Organ 
Class 
  Preferred Term 
Mild 
Moderate Severe Mild 
Moderate 
Severe Mild 
Moderate 
Severe Mild 
Moderate 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
 
Any Event 
XX (%) XX (%) 
XX (%) XX (%) XX (%) 
XX (%) XX (%) XX (%) 
XX (%) XX (%) XX (%) 
XX (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiovascular 
disorders 
XX (%) XX (%) 
XX (%) XX (%) XX (%) 
XX (%) XX (%) XX (%) 
XX (%) XX (%) XX (%) 
XX (%) 
  Any Event 
XX (%) XX (%) 
XX (%) XX (%) XX (%) 
XX (%) XX (%) XX (%) 
XX (%) XX (%) XX (%) 
XX (%) 
  Hypertension 
XX (%) XX (%) 
XX (%) XX (%) XX (%) 
XX (%) XX (%) XX (%) 
XX (%) XX (%) XX (%) 
XX (%) 
  Syncope 
XX (%) XX (%) 
XX (%) XX (%) XX (%) 
XX (%) XX (%) XX (%) 
XX (%) XX (%) XX (%) 
XX (%) 
  Aneurysms 
XX (%) XX (%) 
XX (%) XX (%) XX (%) 
XX (%) XX (%) XX (%) 
XX (%) XX (%) XX (%) 
XX (%) 
  Hypotension 
XX (%) XX (%) 
XX (%) XX (%) XX (%) 
XX (%) XX (%) XX (%) 
XX (%) XX (%) XX (%) 
XX (%) 
  Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
Note:  Subjects are considered as belonging to the treatment group according to the highest dose received.    
  
 
USER ID: Directory/Program.sas Date Time 
 
Programming notes: Repeat display for Total group on following page.  Subjects who experience the same event several times, with different intensities/grades, will 
only be counted with the maximum intensity/grade. For example, a subject who had three headaches, two severe and one mild, is counted only once, under the preferred 
term "Headache" in the "Severe" column of the table. Likewise, each subject is counted only once, at the maximum severity/grade, within each SOC even though they 
may have several different PT events at different intensities/grades within that SOC. Events will be sorted in descending order of total incidence across treatment 
groups for the System Organ Class and in descending order of total incidence for the preferred term within each System Organ Class. If the total incidence for any 
two or more preferred terms is equal, they will be presented in alphabetical order.


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Safety 
Table 3.5:  Summary of Treatment-Emergent Adverse Events by Action Taken with IP 
 
System Organ Class 
  Preferred term 
    Action Taken 
Ambrisentan 
2.5mg 
(N=XXX) 
Ambrisentan 
5mg 
(N=XXX) 
Ambrisentan 
7.5mg 
(N=XXX) 
Ambrisentan 
10mg 
(N=XXX) 
Total 
(N=XXX) 
 
 
 
 
 
 
Any event 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
 
 
 
 
 
<System Organ Class 1> 
 
 
 
 
 
<Any event> 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  IP withdrawn 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Dose interrupted 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Dose reduced 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Dose not changed 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Dose increased 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Not applicable 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
 
 
 
 
 
<Preferred Term 1> 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  IP withdrawn 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Dose interrupted 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Dose reduced 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Dose not changed 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Dose increased 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Not applicable 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
 
 
 
 
 
Etc.. 
 
 
 
 
 
  
 
 
 
 
 
Note:  Subjects are considered as belonging to the treatment group according to the highest dose received.    
  
 
USER ID: Directory/Program.sas Date Time 
 
Programming notes: Subjects who experience the same event several times, with different Action Taken, will only be counted once for the overall and Preferred Term 
category, but more than once in the Action Taken categories. Events will be sorted in descending order of total incidence across treatment groups for the preferred 
term.  If the total incidence for any two or more preferred terms is equal, they will be presented in alphabetical order.


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Safety 
 
Table 3.8:  Summary of Cumulative Incidence of Treatment-Emergent Adverse Events by Time to First Occurrence 
 
Treatment: Ambrisentan 2.5mg (N=XXX) 
 
 
Time Since Start of Study Medication in AMB114588 
System Organ Class 
  Preferred term 
<=3  
months 
>3 to <=6 
months 
>6 to <=9 
months 
Etc.. 
Etc.. 
Etc.. 
Etc.. 
Overall 
 
 
 
 
 
 
 
 
 
Any event 
  XX (%) 
  XX (%) 
  XX (%) 
  XX (%) 
  XX (%) 
  XX (%) 
  XX (%) 
  XX (%) 
 
 
 
 
 
 
 
 
 
Gastrointestinal 
disorders 
 
 
 
 
 
 
 
 
  Any event 
  XX (%) 
  XX (%) 
  XX (%) 
  XX (%) 
  XX (%) 
  XX (%) 
  XX (%) 
  XX (%) 
  Dyspepsia 
  XX (%) 
  XX (%) 
  XX (%) 
  XX (%) 
  XX (%) 
  XX (%) 
  XX (%) 
  XX (%) 
  Nausea 
  XX (%) 
  XX (%) 
  XX (%) 
  XX (%) 
  XX (%) 
  XX (%) 
  XX (%) 
  XX (%) 
 
 
 
 
 
 
 
 
 
Nervous system disorders  
 
 
 
 
 
 
 
  Any event 
  XX (%) 
  XX (%) 
  XX (%) 
  XX (%) 
  XX (%) 
  XX (%) 
  XX (%) 
  XX (%) 
  Headache 
  XX (%) 
  XX (%) 
  XX (%) 
  XX (%) 
  XX (%) 
  XX (%) 
  XX (%) 
  XX (%) 
  Dizziness 
  XX (%) 
  XX (%) 
  XX (%) 
  XX (%) 
  XX (%) 
  XX (%) 
  XX (%) 
  XX (%) 
  Somnolence 
  XX (%) 
  XX (%) 
  XX (%) 
  XX (%) 
  XX (%) 
  XX (%) 
  XX (%) 
  XX (%) 
  Tremor 
  XX (%) 
  XX (%) 
  XX (%) 
  XX (%) 
  XX (%) 
  XX (%) 
  XX (%) 
  XX (%) 
  Sedation 
  XX (%) 
  XX (%) 
  XX (%) 
  XX (%) 
  XX (%) 
  XX (%) 
  XX (%) 
  XX (%) 
 
 
 
 
 
 
 
 
 
 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  Subjects are considered as belonging to the treatment group according to the highest dose received.    
  
 
USER ID: Directory/Program.sas Date Time 
 
Programming notes: Events will be sorted in descending order of total incidence across treatment groups for the preferred term.  If the total incidence for any two 
or more preferred terms is equal, they will be presented in alphabetical order. Repeat for all Ambrisentan and Total groups.


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Safety 
 
Table 3.10:  Summary of Serious Treatment-Emergent Adverse Events – Number of Subjects and Occurrences 
 
____________________________________________________________________________________________________________ 
                                                                                                  Fatalities 
                                                                         Occurrences              Causally   
                                                                         Causally                 Related    
                                       Subjects   Subjects               Related to               to         
System Organ Class         Treatment   Affected,  Exposed,  Occurrences  Treatment,  Fatalities,  Treatment, 
Preferred Term             Group       Number     Number    All, Number  Number*     Number       Number*    
____________________________________________________________________________________________________________ 
 
CARDIAC DISORDERS                                                                                            
 
Atrial fibrillation        Ambrisentan    x          x         x            x           x            x       
 
 
 
 
   2.5mg   
 
                           Ambrisentan    x          x         x            x           x            x       
                           5mg                                                                               
 
                           Ambrisentan    x          x         x            x           x            x       
                           7.5mg                                                                               
 
                           Ambrisentan    x          x         x            x           x            x       
                           10mg                                                                               
 
                           Total          x          x         x            x           x            x       
 
Bradyarrhythmia             
etc 
   
 
 
 
 
 
Note: * Drug-related as determined by the investigator.                                                      
      Subjects are considered as belonging to the treatment group according to the highest dose received.    
  
 
USER ID: Directory/Program.sas Date Time 
 
 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Safety 
Table 3.11:  Summary of Serious Treatment-Emergent Adverse Events by Outcome 
 
System Organ Class 
  Preferred term 
    Outcome 
Ambrisentan 
2.5mg 
(N=XXX) 
Ambrisentan 
5mg 
(N=XXX) 
Ambrisentan 
7.5mg 
(N=XXX) 
Ambrisentan 
10mg 
(N=XXX) 
Total 
(N=XXX) 
 
 
 
 
 
 
Any event 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
 
 
 
 
 
<System Organ Class 1> 
 
 
 
 
 
<Any event> 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Recovered/Resolved 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Recovering/Resolving 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Recovered/Resolved with sequelae 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Not Recovered/ Not Resolved 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
 
 
 
 
 
<Preferred Term 1> 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Recovered/Resolved 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Recovering/Resolving 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Recovered/Resolved with sequelae 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
  Not Recovered/ Not Resolved 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
 
 
 
 
 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  Subjects are considered as belonging to the treatment group according to the highest dose received.    
  
 
USER ID: Directory/Program.sas Date Time 
 
Programming notes: Subjects who experience the same event several times, with different Outcome, will only be counted once for the overall and Preferred Term 
category, but more than once in the Outcome categories. Events will be sorted in descending order of total incidence across treatment groups for the preferred term.  
If the total incidence for any two or more preferred terms is equal, they will be presented in alphabetical order. 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Safety 
Table 3.21:  Summary of Haematology Data 
Central/Local Laboratory 
Parameter: <Parameter (units)> 
 
Treatment 
Planned  
Relative Time 
N 
Mean 
SD 
Q1 
Median 
Q3 
Min. 
Max. 
 
 
 
 
 
 
 
 
 
 
Ambrisentan 
2.5mg 
Baseline** 
XXX 
 XX.X 
 XX.XX 
 XX.X 
 XX.X 
 XX.X 
 XX 
 XX 
(N=XXX) 
Entry Visit* 
XXX 
 XX.X 
 XX.XX 
 XX.X 
 XX.X 
 XX.X 
 XX 
 XX 
 
Month 1 
XXX 
 XX.X 
 XX.XX 
 XX.X 
 XX.X 
 XX.X 
 XX 
 XX 
 
Month 2 
XXX 
 XX.X 
 XX.XX 
 XX.X 
 XX.X 
 XX.X 
 XX 
 XX 
 
Month 3 
XXX 
 XX.X 
 XX.XX 
 XX.X 
 XX.X 
 XX.X 
 XX 
 XX 
 
Month 4 
XXX 
 XX.X 
 XX.XX 
 XX.X 
 XX.X 
 XX.X 
 XX 
 XX 
 
Month 5 
XXX 
 XX.X 
 XX.XX 
 XX.X 
 XX.X 
 XX.X 
 XX 
 XX 
 
Month 6 
XXX 
 XX.X 
 XX.XX 
 XX.X 
 XX.X 
 XX.X 
 XX 
 XX 
 
Etc..  
XXX 
 XX.X 
 XX.XX 
 XX.X 
 XX.X 
 XX.X 
 XX 
 XX 
 
 
 
 
 
 
 
 
 
 
Ambrisentan 
5mg 
Etc.. 
 
 
 
 
 
 
 
 
(N=XXX) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ambrisentan 
7.5mg 
Etc.. 
 
 
 
 
 
 
 
 
(N=XXX) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ambrisentan 
10mg 
Etc.. 
 
 
 
 
 
 
 
 
(N=XXX) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total 
Etc.. 
 
 
 
 
 
 
 
 
(N=XXX) 
 
 
 
 
 
 
 
 
 
 
Note:  ** Baseline is the last value recorded prior to start of study treatment from AMB112529. 
       * Entry Visit is at entry to AMB114588. 
    
 Q1 = 1st quartile, Q3 = 3rd quartile. 
       Subjects are considered as belonging to the treatment group according to the highest dose received.    
  
USER ID: Directory/Program.sas Date Time 
Programming notes: Present available visits, End of Study and Follow-Up. Absolute value tables done separately for central and local labs. Change from baseline 
required only for the subset of subjects who have QUEST Central labs throughout. 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Safety 
Table 3.23:  Summary of Haematology Data of Potential Clinical Concern 
 
Central/Local Laboratory 
Parameter: <Parameter (units) [Reference range = xx.x to xx.x ]> 
 
Planned  
Relative Time 
 
Category 
Ambrisentan 
2.5mg 
(N=XXX) 
Ambrisentan 
5mg 
(N=XXX) 
Ambrisentan 
7.5mg 
(N=XXX) 
Ambrisentan 
10mg 
(N=XXX) 
Total 
(N=XXX) 
 
 
 
 
 
 
 
Baseline** 
N 
   XXX 
   XXX 
   XXX 
   XXX 
   XXX 
 
> reference range high 
    XX (%)  
    XX (%)  
    XX (%)  
    XX (%)  
    XX (%)  
 
< reference range low 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
 
 
 
 
 
 
Entry Visit* 
N 
   XXX 
   XXX 
   XXX 
   XXX 
   XXX 
 
> reference range high 
    XX (%) 
    XX (%)  
    XX (%) 
    XX (%)  
    XX (%)  
 
< reference range low 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
 
 
 
 
 
 
Month 1 
N 
   XXX 
   XXX 
   XXX 
   XXX 
   XXX 
 
> reference range high 
    XX (%)  
    XX (%)  
    XX (%)  
    XX (%)  
    XX (%)  
 
< reference range low 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
 
 
 
 
 
 
Month 2 
N 
   XXX 
   XXX 
   XXX 
   XXX 
   XXX 
 
> reference range high 
    XX (%)  
    XX (%)  
    XX (%)  
    XX (%)  
    XX (%)  
 
< reference range low 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
 
 
 
 
 
 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Any time  
post-baseline 
N 
   XXX 
   XXX 
   XXX 
   XXX 
   XXX 
 
> reference range high 
    XX (%)  
    XX (%)  
    XX (%)  
    XX (%)  
    XX (%)  
 
< reference range low 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
Note:  ** Baseline is the last value recorded prior to start of study treatment from AMB112529. 
       * Entry Visit is at entry to AMB114588. 
       For ‘Any time in AMB114588 (Entry to End of Study)':-  
       Subjects with both Normal and Low values are counted once under their worst case (Low).                        
       Subjects with both Normal and High values are counted once under their worst case (High).              
       Subjects with both High and Low values are counted under both categories.                              
       Subjects are considered as belonging to the treatment group according to the highest dose received.    
USER ID: Directory/Program.sas Date Time 
Programming notes: Present available visits, End of Study and Follow-Up. 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Safety 
Table 3.29:  Summary of Liver Events Assessment 
 
  
Ambrisentan 
2.5mg 
Ambrisentan 
5mg 
Ambrisentan 
7.5mg 
Ambrisentan 
10mg 
Total 
 
(N=XXX) 
(N=XXX) 
(N=XXX) 
(N=XXX) 
(N=XXX) 
  
 
 
 
 
 
Subjects reporting a significant liver chemistry result * 
 XX  (XX%)  XX  (XX%)  XX  (XX%)  XX  (XX%)  XX  (XX%) 
Subjects with event occurring while receiving study treatment 
 XX  (XX%)  XX  (XX%)  XX  (XX%)  XX  (XX%)  XX  (XX%) 
Subjects with event occurring after stopping study treatment 
 
 XX  (XX%)  XX  (XX%)  XX  (XX%)  XX  (XX%)  XX  (XX%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  * A significant liver chemistry result is any result which meets the stopping criteria defined in the protocol. 
Detailed information on liver events assessment can be found in related listings. 
      Subjects are considered as belonging to the treatment group according to the highest dose received.    
  
 
USER ID: Directory/Program.sas Date Time
 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Safety 
Table 3.30  Summary of Vital Signs 
 
Parameter 
Treatment 
Planned  
Relative Time 
n 
Mean 
SD 
Q1 
Median 
Q3 
Min. 
Max. 
 
 
 
 
 
 
 
 
 
 
 
<Parameter (units)> 
Ambrisentan 
2.5mg 
Baseline** 
XXX 
 XX.X 
 XX.XX 
 XX.X 
 XX.X 
 XX.X 
 XX 
 XX 
 
(N=XXX) 
Entry Visit 
XXX 
 XX.X 
 XX.XX 
 XX.X 
 XX.X 
 XX.X 
 XX 
 XX 
 
 
Month 3 
XXX 
 XX.X 
 XX.XX 
 XX.X 
 XX.X 
 XX.X 
 XX 
 XX 
 
 
Month 6 
XXX 
 XX.X 
 XX.XX 
 XX.X 
 XX.X 
 XX.X 
 XX 
 XX 
 
 
Month 9 
XXX 
 XX.X 
 XX.XX 
 XX.X 
 XX.X 
 XX.X 
 XX 
 XX 
 
 
Month 12 
XXX 
 XX.X 
 XX.XX 
 XX.X 
 XX.X 
 XX.X 
 XX 
 XX 
 
 
Etc.. 
XXX 
 XX.X 
 XX.XX 
 XX.X 
 XX.X 
 XX.X 
 XX 
 XX 
 
 
 
 
 
 
 
 
 
 
 
 
Ambrisentan 
5mg 
Etc.. 
 
 
 
 
 
 
 
 
 
(N=XXX) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ambrisentan 
5mg 
Etc.. 
 
 
 
 
 
 
 
 
 
(N=XXX) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ambrisentan 
5mg 
Etc.. 
 
 
 
 
 
 
 
 
 
(N=XXX) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total 
Etc.. 
 
 
 
 
 
 
 
 
 
(N=XXX) 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  ** Baseline is the last value recorded prior to start of study treatment from AMB112529. 
       * Entry Visit is at entry to AMB114588. 
       Q1 = 1st quartile, Q3 = 3rd quartile. 
       Subjects are considered as belonging to the treatment group according to the highest dose received.    
  
 
USER ID: Directory/Program.sas Date Time 
 
Programming notes: Present available visits, End of Study and Follow-Up. Include Height, Weight, Systolic BP, Diastolic BP, Heart Rate, BSA and BMI. 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Safety 
Table 3.32:  Summary of Vital Signs Data of Potential Clinical Concern 
 
Parameter: <Parameter (units) [Reference range = xx.x to xx.x ]> 
 
Planned  
Relative Time 
 
Category 
Ambrisentan 
2.5mg 
(N=XXX) 
Ambrisentan 
5mg 
(N=XXX) 
Ambrisentan 
7.5mg 
(N=XXX) 
Ambrisentan 
10mg 
(N=XXX) 
Total 
(N=XXX) 
 
 
 
 
 
 
 
Baseline** 
n 
   XXX 
   XXX 
   XXX 
   XXX 
   XXX 
 
> reference range high 
    XX (%)  
    XX (%)  
    XX (%)  
    XX (%)  
    XX (%)  
 
< reference range low 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
 
 
 
 
 
 
Entry Visit* 
n 
   XXX 
   XXX 
   XXX 
   XXX 
   XXX 
 
> reference range high 
    XX (%) 
    XX (%)  
    XX (%) 
    XX (%)  
    XX (%)  
 
< reference range low 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
 
 
 
 
 
 
Month 3 
n 
   XXX 
   XXX 
   XXX 
   XXX 
   XXX 
 
> reference range high 
    XX (%)  
    XX (%)  
    XX (%)  
    XX (%)  
    XX (%)  
 
< reference range low 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
 
 
 
 
 
 
Month 6 
n 
   XXX 
   XXX 
   XXX 
   XXX 
   XXX 
 
> reference range high 
    XX (%)  
    XX (%)  
    XX (%)  
    XX (%)  
    XX (%)  
 
< reference range low 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
 
 
 
 
 
 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Any time 
Post-baseline 
n 
   XXX 
   XXX 
   XXX 
   XXX 
   XXX 
 
> reference range high 
    XX (%)  
    XX (%)  
    XX (%)  
    XX (%)  
    XX (%)  
 
< reference range low 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
Note:  ** Baseline is the last value recorded prior to start of study treatment from AMB112529. 
       * Entry Visit is at entry to AMB114588. 
       For ‘Any time in AMB114588 (Entry to End of Study)':- 
       Subjects with both Normal and Low values are counted once under their worst case (Low).                        
       Subjects with both Normal and High values are counted once under their worst case (High).              
       Subjects with both High and Low values are counted under both categories.                              
       Subjects are considered as belonging to the treatment group according to the highest dose received.    
  
USER ID: Directory/Program.sas Date Time 
Programming notes: Present available visits, End of Study and Follow-Up. Include Systolic BP, Diastolic BP and Heart Rate. 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Safety 
Table 3.34:  Summary of Physical Examination by Visit 
 
Planned Relative Time: Entry Visit* 
Ambrisentan 
2.5mg 
(N=XXX) 
Ambrisentan 
5mg 
(N=XXX) 
Ambrisentan 
7.5mg 
(N=XXX) 
Ambrisentan 
10mg 
(N=XXX) 
Total 
(N=XXX) 
 
 
 
 
 
 
Liver Size 
 
 
 
 
 
  Normal 
      XX (%) 
      XX (%) 
      XX (%) 
      XX (%) 
      XX (%) 
  Abnormal 
      XX (%) 
      XX (%) 
      XX (%) 
      XX (%) 
      XX (%) 
 
 
 
 
 
 
Jugular Venous Pressure 
 
 
 
 
 
  Normal 
      XX (%) 
      XX (%) 
      XX (%) 
      XX (%) 
      XX (%) 
  Abnormal 
      XX (%) 
      XX (%) 
      XX (%) 
      XX (%) 
      XX (%) 
 
 
 
 
 
 
Ascites 
 
 
 
 
 
  Absent 
      XX (%) 
      XX (%) 
      XX (%) 
      XX (%) 
      XX (%) 
  Present 
      XX (%) 
      XX (%) 
      XX (%) 
      XX (%) 
      XX (%) 
 
 
 
 
 
 
Peripheral Oedema 
 
 
 
 
 
  Absent 
      XX (%) 
      XX (%) 
      XX (%) 
      XX (%) 
      XX (%) 
  Present 
      XX (%) 
      XX (%) 
      XX (%) 
      XX (%) 
      XX (%) 
 
 
 
 
 
 
Saturated Oxygen (units) 
 
 
 
 
 
  n 
     XXX     
     XXX     
     XXX     
     XXX     
     XXX     
  Mean 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  SD 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
  Q1 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  Median 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  Q3 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  Min. 
      XX 
      XX 
      XX 
      XX 
      XX 
  Max. 
      XX 
      XX 
      XX 
      XX 
      XX 
 
 
Note:  * Entry Visit is at entry to AMB114588. 
       Q1 = 1st quartile, Q3 = 3rd quartile. 
       Subjects are considered as belonging to the treatment group according to the highest dose received.    
  
 
USER ID: Directory/Program.sas Date Time 
 
Programming notes: Present for available visits, Follow-Up and End of Study. 
 
 


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Protocol: AMB114588                                                                                                Page 2 of n 
Population: Safety 
Table 3.34:  Summary of Physical Examination by Visit 
 
Planned Relative Time: Month 6 
Ambrisentan 
2.5mg 
(N=XXX) 
Ambrisentan 
5mg 
(N=XXX) 
Ambrisentan 
7.5mg 
(N=XXX) 
Ambrisentan 
10mg 
(N=XXX) 
Total 
(N=XXX) 
Liver Size 
 
 
 
 
 
  N 
      XX 
     XX 
      XX 
     XX 
     XX 
  Normal 
      XX (%) 
      XX (%) 
      XX (%) 
      XX (%) 
      XX (%) 
  Abnormal:Improved 
      XX (%) 
      XX (%) 
      XX (%) 
      XX (%) 
      XX (%) 
  Abnormal:Unchanged  
      XX (%) 
      XX (%) 
      XX (%) 
      XX (%) 
      XX (%) 
  Abnormal:Worsened  
      XX (%) 
      XX (%) 
      XX (%) 
      XX (%) 
      XX (%) 
 
 
 
 
 
 
Jugular Venous Pressure 
 
 
 
 
 
  N 
      XX 
     XX 
      XX 
     XX 
     XX 
  Normal 
      XX (%) 
      XX (%) 
      XX (%) 
      XX (%) 
      XX (%) 
  Abnormal:Improved 
      XX (%) 
      XX (%) 
      XX (%) 
      XX (%) 
      XX (%) 
  Abnormal:Unchanged  
      XX (%) 
      XX (%) 
      XX (%) 
      XX (%) 
      XX (%) 
  Abnormal:Worsened  
      XX (%) 
      XX (%) 
      XX (%) 
      XX (%) 
      XX (%) 
 
 
 
 
 
 
Ascites 
 
 
 
 
 
  n 
      XX 
     XX 
      XX 
     XX 
     XX 
  Absent 
      XX (%) 
      XX (%) 
      XX (%) 
      XX (%) 
      XX (%) 
  Present:Improved 
      XX (%) 
      XX (%) 
      XX (%) 
      XX (%) 
      XX (%) 
  Present:Unchanged  
      XX (%) 
      XX (%) 
      XX (%) 
      XX (%) 
      XX (%) 
  Present:Worsened  
      XX (%) 
      XX (%) 
      XX (%) 
      XX (%) 
      XX (%) 
 
 
 
 
 
 
Peripheral Oedema  
 
 
 
 
 
  n 
      XX 
     XX 
      XX 
     XX 
     XX 
  Absent 
      XX (%) 
      XX (%) 
      XX (%) 
      XX (%) 
      XX (%) 
  Present:Improved 
      XX (%) 
      XX (%) 
      XX (%) 
      XX (%) 
      XX (%) 
  Abnormal:Worsened  
      XX (%) 
      XX (%) 
      XX (%) 
      XX (%) 
      XX (%) 
  Abnormal:Unchanged 
      XX (%) 
      XX (%) 
      XX (%) 
      XX (%) 
      XX (%) 
 
 
 
 
 
 
Note:  * Entry Visit is at entry to AMB114588. 
       Q1 = 1st quartile, Q3 = 3rd quartile. 
       Subjects are considered as belonging to the treatment group according to the highest dose received.    
  
 
USER ID: Directory/Program.sas Date Time 
 
Programming notes: Present for available visits, Follow-Up and End of Study.
 


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Population: Safety 
Table 3.34:  Summary of Physical Examination by Visit 
 
Planned Relative Time: Month 6 
Ambrisentan 
2.5mg 
(N=XXX) 
Ambrisentan 
5mg 
(N=XXX) 
Ambrisentan 
7.5mg 
(N=XXX) 
Ambrisentan 
10mg 
(N=XXX) 
Total 
(N=XXX) 
Saturated Oxygen (units) 
 
 
 
 
 
  n 
     XXX     
     XXX     
     XXX     
     XXX     
     XXX     
  Mean 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  SD 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
  Q1 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  Median 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  Q3 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  Min. 
      XX 
      XX 
      XX 
      XX 
      XX 
  Max. 
      XX 
      XX 
      XX 
      XX 
      XX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  * Entry Visit is at entry to AMB114588. 
       Q1 = 1st quartile, Q3 = 3rd quartile. 
       Subjects are considered as belonging to the treatment group according to the highest dose received.    
  
 
USER ID: Directory/Program.sas Date Time 
 
Programming notes: Present for available visits, Follow-Up and End of Study. 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Safety 
Table 3.35:  Summary of 12-lead ECG 
 
Planned  
Relative Time 
 
Category 
Ambrisentan 
2.5mg 
(N=XXX) 
Ambrisentan 
5mg 
(N=XXX) 
Ambrisentan 
7.5mg 
(N=XXX) 
Ambrisentan 
10mg 
(N=XXX) 
Total 
(N=XXX) 
 
 
 
 
 
 
 
Baseline** 
n 
   XXX 
   XXX 
   XXX 
   XXX 
   XXX 
 
Normal 
    XX (%)  
    XX (%)  
    XX (%)  
    XX (%)  
    XX (%)  
 
Abnormal, not clinically significant 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
Abnormal, clinically significant 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
 
 
 
 
 
 
Entry Visit* 
n 
   XXX 
   XXX 
   XXX 
   XXX 
   XXX 
 
Normal 
    XX (%)  
    XX (%)  
    XX (%)  
    XX (%)  
    XX (%)  
 
Abnormal, not clinically significant 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
Abnormal, clinically significant 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
 
 
 
 
 
 
Month 6 
n 
   XXX 
   XXX 
   XXX 
   XXX 
   XXX 
 
Normal 
    XX (%)  
    XX (%)  
    XX (%)  
    XX (%)  
    XX (%)  
 
Abnormal, not clinically significant 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
Abnormal, clinically significant 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
 
 
 
 
 
 
Month 12 
n 
   XXX 
   XXX 
   XXX 
   XXX 
   XXX 
 
Normal 
    XX (%)  
    XX (%)  
    XX (%)  
    XX (%)  
    XX (%)  
 
Abnormal, not clinically significant 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
Abnormal, clinically significant 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
 
 
 
 
 
 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Any time post-study entry 
n 
   XXX 
   XXX 
   XXX 
   XXX 
   XXX 
 
Normal 
    XX (%)  
    XX (%)  
    XX (%)  
    XX (%)  
    XX (%)  
 
Abnormal, not clinically significant 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
Abnormal, clinically significant 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
Note:  ** Baseline is the last value recorded prior to start of study treatment from AMB112529. 
       * Entry Visit is at entry to AMB114588. 
       For ‘Any time in AMB114588 (Entry to End of Study)' if a subject had more than one ECG result, the worst case will 
       be chosen for a conservative approach.   
       Subjects are considered as belonging to the treatment group according to the highest dose received.    
  
USER ID: Directory/Program.sas Date Time 
Programming notes: Present for available visits, Follow-Up and End of Study. 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Safety 
Table 3.36:  Summary of Endocrinology assessments – Female 
 
Overall 
 
Planned Relative Time 
Ambrisentan 
2.5mg 
Ambrisentan 
5mg 
Ambrisentan 
7.5mg 
Ambrisentan 
10mg 
Total 
Baseline** 
(N=XXX) 
(N=XXX) 
(N=XXX) 
(N=XXX) 
(N=XXX) 
 
 
 
 
 
 
Female breast development 
  
 
  
 
 
   N 
   XXX 
   XXX 
   XXX 
   XXX 
   XXX 
   Pre-adolescent 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
   Breast bud stage 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
   Etc.. 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
 
 
 
 
 
 
 
 
 
 
 
Female pubic hair development  
 
 
 
 
 
   N 
   XXX 
   XXX 
   XXX 
   XXX 
   XXX 
   Pre-adolescent 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
   Sparse growth 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
   Etc..  
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
 
 
 
 
 
 
 
 
Note:  ** Baseline is the last value recorded prior to start of study treatment from AMB112529. 
       * Entry Visit is at entry to AMB114588. 
       Subjects are considered as belonging to the treatment group according to the highest dose received.    
  
 
 Pre-pubertal at baseline: Stage 1 breast development, Post-pubertal at baseline: Stage ≥ 2 breast development. 
  
 For some patients, pubertal development assessments were not repeated at 20 years of age if pubertal maturity had been    reached in a previous visit.  
 
USER ID: Directory/Program.sas Date Time 
 
Programming notes: Present for Baseline, Entry Visit, all available visits, End of Study and Follow Up. Present Overall and by Pubertal Status (Pre-pubertal, Post 
Pubertal). 
 
 
 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Safety 
Table 3.37:  Summary of Endocrinology assessments – Male 
Overall 
 
Planned Relative Time 
Ambrisentan 
2.5mg 
Ambrisentan 
5mg 
Ambrisentan 
7.5mg 
Ambrisentan 
10mg 
Total 
Baseline** 
(N=XXX) 
(N=XXX) 
(N=XXX) 
(N=XXX) 
(N=XXX) 
 
 
 
 
 
 
Right Testicular volume 
(units) 
 
 
 
 
 
  N 
     XXX          XXX          XXX          XXX          XXX     
  Mean 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  SD 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
  Q1 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  Median 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  Q3 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  Min. 
      XX 
      XX 
      XX 
      XX 
      XX 
  Max. 
      XX 
      XX 
      XX 
      XX 
      XX 
 
 
 
 
 
 
Left Testicular volume 
(units) 
 
 
 
 
 
  N 
     XXX          XXX          XXX          XXX          XXX     
  Mean 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  SD 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
  Q1 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  Median 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  Q3 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
  Min. 
      XX 
      XX 
      XX 
      XX 
      XX 
  Max. 
      XX 
      XX 
      XX 
      XX 
      XX 
 
Note:  ** Baseline is the last value recorded prior to start of study treatment from AMB112529. 
       * Entry Visit is at entry to AMB114588. 
       Q1 = 1st quartile, Q3 = 3rd quartile. 
       Subjects are considered as belonging to the treatment group according to the highest dose received.    
  
 
 Pre-pubertal at baseline: testicular volume < 4 ml, Post-pubertal at baseline: testicular volume ≥ 4 ml 
For some patients, pubertal development assessments were not repeated at 20 years of age if pubertal maturity had been      reached in a previous visit.  
 
USER ID: Directory/Program.sas Date Time 
 
Programming notes: Present for Baseline, Entry Visit, all available visits, End of Study and Follow Up. Present Overall and by Pubertal Status (Pre-pubertal, Post 
Pubertal). 
 
 


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Protocol: AMB114588                                                                                                Page 2 of n 
Population: Safety 
Table 3.37:  Summary of Endocrinology assessments – Male 
Overall 
 
Planned Relative Time 
Ambrisentan 
2.5mg 
Ambrisentan 
5mg 
Ambrisentan 
7.5mg 
Ambrisentan 
10mg 
Total 
Baseline** 
(N=XXX) 
(N=XXX) 
(N=XXX) 
(N=XXX) 
(N=XXX) 
 
 
 
 
 
 
Male genital development 
  
 
  
 
 
   N 
   XXX 
   XXX 
   XXX 
   XXX 
   XXX 
   Pre-adolescent 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
   Etc.. 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
 
 
 
 
 
 
 
 
 
 
 
Male pubic hair development 
 
 
 
 
 
   N 
   XXX 
   XXX 
   XXX 
   XXX 
   XXX 
   Pre-adolescent 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
   Sparse growth 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
   Etc.  
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
    XX (%) 
 
 
 
 
 
 
 
 
 
Note:  ** Baseline is the last value recorded prior to start of study treatment from AMB112529. 
       * Entry Visit is at entry to AMB114588. 
       Q1 = 1st quartile, Q3 = 3rd quartile. 
       Subjects are considered as belonging to the treatment group according to the highest dose received.    
  
 
 Pre-pubertal at baseline: testicular volume < 4 ml, Post-pubertal at baseline: testicular volume ≥ 4 ml 
For some patients, pubertal development assessments were not repeated at 20 years of age if pubertal maturity had been reached in a previous visit.  
USER ID: Directory/Program.sas Date Time 
 
Programming notes: Present for Baseline, Entry Visit, all available visits, End of Study and Follow Up. Present Overall and by Pubertal Status (Pre-pubertal, Post 
Pubertal). 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Safety 
Table 3.38:  Summary of Pubertal Development Shifts from Baseline – Female 
Overall 
Female Breast Development 
 
 
 
Treatment 
Planned  
Relative 
Time 
Code 
 
Baseline** Code 
 
1 
2 
3 
4 
5 
 
 
 
 
 
 
 
 
Ambrisentan 2.5mg (N=XXX) 
Entry 
Visit* 
1 
XX (%) 
XX (%) 
XX (%) 
XX (%) 
XX (%) 
  
2 
XX (%) 
XX (%) 
XX (%) 
XX (%) 
XX (%) 
 
 
3 
XX (%) 
XX (%) 
XX (%) 
XX (%) 
XX (%) 
 
 
4 
XX (%) 
XX (%) 
XX (%) 
XX (%) 
XX (%) 
 
 
5 
XX (%)  
XX (%)  
XX (%)  
XX (%)  
XX   
 
 
Unknown/ 
Not Recorded 
XX   
XX   
XX   
XX   
XX   
 
 
 
 
 
 
 
 
Etc.. 
1 
XX (%) 
XX (%) 
XX (%) 
XX (%) 
XX (%) 
 
 
2 
XX (%) 
XX (%) 
XX (%) 
XX (%) 
XX (%) 
 
 
3 
XX (%) 
XX (%) 
XX (%) 
XX (%) 
XX (%) 
 
 
4 
XX (%) 
XX (%) 
XX (%) 
XX (%) 
XX (%) 
 
 
5 
XX (%)  
XX (%)  
XX (%)  
XX (%)  
XX   
 
 
Unknown/ 
Not Recorded 
XX   
XX   
XX   
XX   
XX   
Etc.. 
 
 
 
 
 
 
 
 
Note:  ** Baseline is the last value recorded prior to start of study treatment from AMB112529. 
       * Entry Visit is at entry to AMB114588. 
       Subjects are considered as belonging to the treatment group according to the highest dose received.    
  
 
 Pre-pubertal at Baseline: Stage 1 breast development, Post-pubertal at Baseline: Stage ≥ 2 breast development. 
  For some patients, pubertal development assessments were not repeated at 20 years of age if pubertal maturity had been reached in a previous visit. 
USER ID: Directory/Program.sas Date Time 
Programming notes: Present for Female Breast Development and Female Pubic Hair Development, for each treatment group, overall and by Pubertal Status (Pre-pubertal, 
Post Pubertal), at all available visits. Put coding below on first page on listing:- 
       Female Breast Development:- 
       1=Pre-adolescent; elevation of papilla only, 2=etc… 
       Female Pubic Hair Development:- 
       1=Pre-adolescent; vellus over pubes not developed over anterior abdominal wall, 2=etc… 
 
 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Safety 
Table 3.39:  Summary of Pubertal Development Shifts from Baseline - Male 
Overall 
Male Genital Development 
 
 
 
Treatment 
Planned  
Relative 
Time 
Code 
 
Baseline** Code 
 
1 
2 
3 
4 
5 
 
 
 
 
 
 
 
 
Ambrisentan 2.5mg N=XXX) 
Entry 
Visit* 
1 
XX (%) 
XX (%) 
XX (%) 
XX (%) 
XX (%) 
 
 
2 
XX (%) 
XX (%) 
XX (%) 
XX (%) 
XX (%) 
 
 
3 
XX (%) 
XX (%) 
XX (%) 
XX (%) 
XX (%) 
 
 
4 
XX (%) 
XX (%) 
XX (%) 
XX (%) 
XX (%) 
 
 
5 
XX (%)  
XX (%)  
XX (%)  
XX (%)  
XX   
 
 
Unknown/ 
Not Recorded 
XX   
XX   
XX   
XX   
XX   
 
 
 
 
 
 
 
 
Etc.. 
1 
XX (%) 
XX (%) 
XX (%) 
XX (%) 
XX (%) 
 
 
2 
XX (%) 
XX (%) 
XX (%) 
XX (%) 
XX (%) 
 
 
3 
XX (%) 
XX (%) 
XX (%) 
XX (%) 
XX (%) 
 
 
4 
XX (%) 
XX (%) 
XX (%) 
XX (%) 
XX (%) 
 
 
5 
XX (%)  
XX (%)  
XX (%)  
XX (%)  
XX   
 
 
Unknown/ 
Not Recorded 
XX   
XX   
XX   
XX   
XX   
Etc.. 
 
 
 
 
 
 
 
 
Note:  ** Baseline is the last value recorded prior to start of study treatment from AMB112529. 
       * Entry Visit is at entry to AMB114588. 
       Subjects are considered as belonging to the treatment group according to the highest dose received.    
  
 
 Pre-pubertal at Baseline: testicular volume < 4 ml, Post-pubertal at Baseline: testicular volume ≥ 4 ml 
For some patients, pubertal development assessments were not repeated at 20 years of age if pubertal maturity had been reached in a previous visit. 
USER ID: Directory/Program.sas Date Time 
Programming notes: Present for Male Genital Development and Male Pubic Hair Development, for each treatment group, overall and by Pubertal Status (Pre-pubertal, 
Post Pubertal), at all available visits. Put coding below on first page on listing:- 
       Male Genital Development:- 
       1=Pre-adolescent; testes, scrotum and penis same size and proportion, 2=etc… 
       Male Pubic Hair Development:- 
       1=Pre-adolescent; velus over pubes no further developed than over abdominal wall, 2=etc… 
 
 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Safety 
Table 3.40:  Summary of Testicular Volume Change from Baseline - Male 
Overall 
 
Planned Relative Time 
 
Ambrisentan 
2.5mg 
Ambrisentan 
5mg 
Ambrisentan 
7.5mg 
Ambrisentan 
10mg 
Total 
 
 
(N=XXX) 
(N=XXX) 
(N=XXX) 
(N=XXX) 
(N=XXX) 
 
 
 
 
 
 
 
Entry Visit* 
  N 
     XXX          XXX          XXX          XXX          XXX    
 
  Mean 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
 
  SD 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
 
  Q1 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
 
  Median 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
 
  Q3 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
 
  Min. 
      XX 
      XX 
      XX 
      XX 
      XX 
 
  Max. 
      XX 
      XX 
      XX 
      XX 
      XX 
 
 
 
 
 
 
 
Etc.. 
  N 
     XXX          XXX          XXX          XXX          XXX    
 
  Mean 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
 
  SD 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
 
  Q1 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
 
  Median 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
 
  Q3 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
 
  Min. 
      XX 
      XX 
      XX 
      XX 
      XX 
 
  Max. 
      XX 
      XX 
      XX 
      XX 
      XX 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  * Entry Visit is at entry to AMB114588. 
       Baseline is the last value recorded prior to start of study treatment from AMB112529. 
       Q1 = 1st quartile, Q3 = 3rd quartile. 
       Subjects are considered as belonging to the treatment group according to the highest dose received.    
  
 
 Pre-pubertal at Baseline: testicular volume < 4 ml, Post-pubertal at Baseline: testicular volume ≥ 4 ml 
For some patients, pubertal development assessments were not repeated at 20 years of age if pubertal maturity had been reached in a previous visit. 
USER ID: Directory/Program.sas Date Time 
Programming notes: Present overall and by Pubertal Status (Pre-pubertal, Post Pubertal), at all available visits.  
 
 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Safety 
Table 3.41:  Summary of Change from Baseline in Plasma Endocrine Parameters – Female 
Overall 
Central Laboratory 
Parameter: <Parameter (units)> 
 
Planned Relative Time 
 
Ambrisentan 
2.5mg 
Ambrisentan 
5mg 
Ambrisentan 
7.5mg 
Ambrisentan 
10mg 
Total 
 
 
(N=XXX) 
(N=XXX) 
(N=XXX) 
(N=XXX) 
(N=XXX) 
 
 
 
 
 
 
 
Entry Visit* 
  N 
     XXX          XXX          XXX          XXX          XXX    
 
  Mean 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
 
  SD 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
 
  Q1 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
 
  Median 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
 
  Q3 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
 
  Min. 
      XX 
      XX 
      XX 
      XX 
      XX 
 
  Max. 
      XX 
      XX 
      XX 
      XX 
      XX 
 
 
 
 
 
 
 
Etc.. 
  N 
     XXX          XXX          XXX          XXX          XXX    
 
  Mean 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
 
  SD 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
 
  Q1 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
 
  Median 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
 
  Q3 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
 
  Min. 
      XX 
      XX 
      XX 
      XX 
      XX 
 
  Max. 
      XX 
      XX 
      XX 
      XX 
      XX 
Etc.. 
 
 
 
 
 
 
 
Note:  * Entry Visit is at entry to AMB114588. 
       Baseline is the last value recorded prior to start of study treatment from AMB112529. 
       Q1 = 1st quartile, Q3 = 3rd quartile. 
       Subjects are considered as belonging to the treatment group according to the highest dose received.    
  
 
 Pre-pubertal at Baseline: Stage 1 breast development, Post-pubertal at Baseline: Stage ≥ 2 breast development. 
  For some patients, pubertal development assessments were not repeated at 20 years of age if pubertal maturity had been reached in a previous visit. 
USER ID: Directory/Program.sas Date Time 
 
Programming notes: Present overall and by Pubertal Status (Pre-pubertal, Post Pubertal), at available visits, for Follicle Stimulating Hormone, Luteinizing Hormone, 
Sex Hormone Binding Globulin, Total Testosterone and Inhibin B. Change from baseline presented only for the subset of subjects who have QUEST Central labs 
throughout. 
 
 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Safety 
Table 3.42:  Summary of Change from Baseline in Plasma Endocrine Parameters – Male 
Overall 
Central Laboratory 
Parameter: <Parameter (units)> 
 
Planned Relative Time 
 
Ambrisentan 
2.5mg 
Ambrisentan 
5mg 
Ambrisentan 
7.5mg 
Ambrisentan 
10mg 
Total 
 
 
(N=XXX) 
(N=XXX) 
(N=XXX) 
(N=XXX) 
(N=XXX) 
 
 
 
 
 
 
 
Entry Visit* 
  N 
     XXX          XXX          XXX          XXX          XXX    
 
  Mean 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
 
  SD 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
 
  Q1 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
 
  Median 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
 
  Q3 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
 
  Min. 
      XX 
      XX 
      XX 
      XX 
      XX 
 
  Max. 
      XX 
      XX 
      XX 
      XX 
      XX 
 
 
 
 
 
 
 
Etc.. 
  N 
     XXX          XXX          XXX          XXX          XXX    
 
  Mean 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
 
  SD 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
      XX.XX 
 
  Q1 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
 
  Median 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
 
  Q3 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
      XX.X 
 
  Min. 
      XX 
      XX 
      XX 
      XX 
      XX 
 
  Max. 
      XX 
      XX 
      XX 
      XX 
      XX 
Etc.. 
 
 
 
 
 
 
 
Note:  * Entry Visit is at entry to AMB114588. 
       Baseline is the last value recorded prior to start of study treatment from AMB112529. 
       Q1 = 1st quartile, Q3 = 3rd quartile. 
       Subjects are considered as belonging to the treatment group according to the highest dose received.    
  
 
 Pre-pubertal at Baseline: testicular volume < 4 ml, Post-pubertal at Baseline: testicular volume ≥ 4 ml 
For some patients, pubertal development assessments were not repeated at 20 years of age if pubertal maturity had been reached in a previous visit. 
USER ID: Directory/Program.sas Date Time 
 
Programming notes: Present overall and by Pubertal Status (Pre-pubertal, Post Pubertal), at available visits, for Follicle Stimulating Hormone, Luteinizing Hormone, 
Sex Hormone Binding Globulin, Total Testosterone and Inhibin B. Change from baseline presented only for the subset of subjects who have QUEST Central labs 
throughout. 
 
 


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Protocol: AMB114588                                                                            Page 1 of 1   
Population: Intent-to-Treat                                                                                  
                                                Table  3.43 
         Summary of Time to change in dose of ambrisentan or other targeted PAH therapeutic agents 
                     (prostanoids, PDE-5 inhibitors) due to tolerability issues (days) 
 
 _________________________________________________________________________________________________________ 
                                                  Ambrisentan Dose Group                                   
                                __________________________________________________________                 
                                2.5mg           5mg             7.5mg           10mg              Total    
                                (N=x)           (N=xx)          (N=x)           (N=xx)            (N=xx)   
 _________________________________________________________________________________________________________ 
 
 n                                 x               x               x               x               x       
 Mean                            xxx.x           xxx.x           xxx.x           xxx.x           xxx.x     
 SD                                               xx.xx                          xxx.xx4          xxx.xx    
 Q1                              xxx.x           xxx.x           xxx.x           xxx.x           xxx.x     
 Median                          xxx.x           xxx.x           xxx.x          xxxx.x           xxx.x     
 Q3                              xxx.x           xxx.x           xxx.x          xxxx.x           xxx.x     
 Min.                            xxx             xxx             xxx             xxx             xxx       
 Max.                            xxx             xxx             xxx            xxxx            xxxx       
 
 
 
 


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Protocol: AMB114588                                                                                                        Page 1 of 36 
Population: Safety 
                                                              Table 3.44 
                                      Summary of Treatment-Emergent Adverse Events by PAH Therapy 
______________________________________________________________________________________________________________________________________ 
                                        Treatment A (N=100)                                 Treatment B (N=100) 
                         ______________________________________________________ ______________________________________________________ 
                                               PDE5i      Prost.                                      PDE5i      Prost. 
System Organ Class       None       Any        Only       Only       Both       None       Any        Only       Only       Both 
  Preferred Term         N=x        N=x       N=x        N=x        N=x        N=x        N=x        N=x        N=x        N=x 
-------------------------------------------------------------------------------------------------------------------------------------- 
ANY EVENT                  x (100%)   x (100%)   x (100%)    0          0         x (57%)    x (100%)   x (100%)    0          0 
Infections and 
infestations 
  Any event                x (100%)   x  (67%)   x  (67%)    0          0         x (29%)    x  (67%)   x (67%)     0          0 
  Upper respiratory        x (100%)   x  (33%)   x  (33%)    0          0         x  (14%)   x  (22%)   x  (22%)    0          0 
  tract infection 
  Nasopharyngitis          0          0          0           0          0         x (14%)    x  (44%)   x  (44%)    0          0 
  Pharyngitis              0          x  (33%)   x  (33%)    0          0         0          x  (33%)   x  (33%)    0          0 
  Gastroenteritis          0          x  (33%)   x  (33%)    0          0         0          x  (22%)   x  (22%)    0          0 
  Influenza                0          0          0           0          0         0          x  (33%)   x (33%)     0          0 
  Pneumonia                0          x  (33%)   1  (33%)    0          0         0          x  (11%)   x  (11%)    0          0 
  Bronchitis               0          0          0           0          0         0          x  (11%)   x  (11%)    0          0 
  Gastroenteritis viral    0          0          0           0          0         0          x  (22%)   x  (22%)    0          0 
  Hordeolum                0          0          0           0          0         0          x  (11%)   x  (11%)    0          0 
  Otitis externa           0          0          0           0          0         0          x  (22%)   x  (22%)    0          0 
  Otitis media             0          1  (33%)   x  (33%)    0          0         0          0          0           0          0 
  Otitis media chronic     0          1  (33%)   x  (33%)    0          0         0          0          0           0          0 
  Pharyngotonsillitis      0          0          0           0          0         0          0          0           0          0 
  Respiratory tract        0          0          0           0          0         0          0          0           0          0 
  infection 
  Rhinitis                 0          0          0           0          0         0          x  (11%)   x  (11%)    0          0 
  Sinusitis                0          0          0           0          0         0          1  (11%)   x  (11%)    0          0 
 
 
Note:  Prost.=Prostanoids. 
 
USER ID: Directory/Program.sas Date Time 
 
Programming Notes: 
Repeat for  
 
 
 
 
 
3.45 
Summary of Serious Treatment Emergent Adverse Events by PAH Therapy 
3.46 
Summary of Non-Serious Treatment Emergent Adverse Events by PAH Therapy 
3.47 
Summary of Common (>=5%) Treatment Emergent Adverse Events by PAH Therapy 
Footnote:  Note: Common adverse events (>=5%) were those 
experienced by at least 5% of subjects in the total 
population (N=38) irrespective of dose group and/or PAH 
therapy 


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Protocol: AMB114588                                                                                                        Page 1 of xx 
Population: Safety 
                                                              Table 3.48 
                               Summary of Treatment Emergent Adverse Events by PAH Aetiology  
___________________________________________________________________________________________________________________________________ 
                                           Treatment A (N=100)         Treatment B (N=100)                Treatment C (N=6) 
                                        _____________________________   _____________________________   _____________________________ 
                                                        Non-                             Non-                          Non- 
  System Organ Class                    Idiopathic      Idiopathic      Idiopathic      Idiopathic    Idiopathic      Idiopathic   
    Preferred Term                       N=xx             N=xx             N=xx            N=xx            N=xx             N=xx 
  ----------------------------------------------------------------------------------------------------------------------------------- 
  ANY EVENT                                0              x (xx%)         x  (xx%)        x (xx%)        x  (xx%)        x (xx%) 
  Infections and infestations   
    Any event                              0              x (xx%)         x  (xx%)        x (xx%)        x (xx%)         x  (xx%) 
    Upper respiratory tract infection      0              x (xx%)         x  (xx%)        x (xx%)        x  (xx%)        x  (xx%) 
    Nasopharyngitis                        0              0               x  (xx%)        x  (xx%)       x  (xx%)        0 
    Pharyngitis                            0              x (xx%)         x   (x%)        x (xx%)         0               0 
    Gastroenteritis                        0              x (xx%)         0              xx  (xx%)        0               0 
    Influenza                              0              0               x  (xx%)        x  (xx%)        0               0 
    Bronchitis                             0              0               0               1  (xx%)        x  (xx%)        0 
    Gastroenteritis viral                  0              0               x   (x%)        1  (xx%)        0               0 
    Hordeolum                              0              0               0               1  (xx%)        1  (xx%)        0 
    Otitis externa                         0              0               0               2  (xx%)        0               0 
    Otitis media                           0              x  (xx%)        0               0               0               0 
 
 
 
Note:  Idiopathic group refers to those with an idiopathic aetiology of PAH at baseline in study AMB112529 and non-idiopathic refers to those classified as 
having an aetiology of familial, persistent PAH despite surgical repair, or secondary to connective tissue disease.     
 
USER ID: Directory/Program.sas Date Time 
 
Programming Notes: 
Repeat for  
3.49 
Summary of Serious Treatment Emergent Adverse Events by PAH Aetiology 
3.50 
Summary of non-Serious Treatment Emergent Adverse Events by PAH Aetiology 
3.51 
Summary of Common (>=5%)Treatment Emergent Adverse Events by PAH Aetiology 
Footnote:  Note: Common adverse events (>=5%) were those 
experienced by at least 5% of subjects in the total 
population (N=38) irrespective of dose group and/or PAH 
Aetiology. 
 

 


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115 
Protocol: AMB114588    
Population: Safety 
Table 3.52  Summary of Cardiopulmonary Hemodynamics 
  
Parameter 
Treatment 
Planned  
Relative Time 
n 
Mean 
SD 
Q1 
Median 
Q3 
Min. 
Max. 
  
  
  
  
  
  
  
  
  
  
  
<Parameter (units)> 
Ambrisentan 
2.5mg 
Baseline** 
XXX 
XX.X 
XX.XX 
XX.X 
XX.X 
XX.X 
XX 
XX 
  
(N=XXX) 
Entry Visit 
XXX 
XX.X 
XX.XX 
XX.X 
XX.X 
XX.X 
XX 
XX 
  
  
Month 3 
XXX 
XX.X 
XX.XX 
XX.X 
XX.X 
XX.X 
XX 
XX 
  
  
Month 6 
XXX 
XX.X 
XX.XX 
XX.X 
XX.X 
XX.X 
XX 
XX 
  
  
Month 9 
XXX 
XX.X 
XX.XX 
XX.X 
XX.X 
XX.X 
XX 
XX 
  
  
Month 12 
XXX 
XX.X 
XX.XX 
XX.X 
XX.X 
XX.X 
XX 
XX 
  
  
Etc.. 
XXX 
XX.X 
XX.XX 
XX.X 
XX.X 
XX.X 
XX 
XX 
  
  
  
  
  
  
  
  
  
  
  
  
Ambrisentan 
5mg 
Etc.. 
  
  
  
  
  
  
  
  
  
(N=XXX) 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Ambrisentan 
5mg 
Etc.. 
  
  
  
  
  
  
  
  
  
(N=XXX) 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Ambrisentan 
5mg 
Etc.. 
  
  
  
  
  
  
  
  
  
Note:  ** Baseline is the last value recorded prior to start of study treatment from AMB112529. 
       * Entry Visit is at entry to AMB114588. 
       Q1 = 1st quartile, Q3 = 3rd quartile. 
       Subjects are considered as belonging to the treatment group according to the highest dose received.    
  
 
USER ID: Directory/Program.sas Date Time 
 
Programming notes: Present available visits, End of Study and Follow-Up. Include all the available parameters. 
 
 
 
 
 
 
 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Intent-to-Treat 
 
Listing 1.1:  Listing of Reasons for Study Withdrawal 
 
Treatment: Ambrisentan 2.5mg 
 
Centre ID/ 
Subject ID 
Date of 
Withdrawal 
Study 
Day 
Reason for 
Withdrawal 
 
 
 
 
XXXXXX/ 
XXXXXX 
DDMMMYYYY 
 XX 
XXXXXXXXXXXXX 
XXXXXX/ 
XXXXXX 
DDMMMYYYY 
 XX 
XXXXXXXXXXXXX 
XXXXXX/ 
XXXXXX 
DDMMMYYYY 
 XX 
XXXXXXXXXXXXX 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
 
USER ID: Directory/Program.sas Date Time  
 
Programming notes: Present each treatment group and Centre/Subject ID. Sort by treatment group, Centre ID, Subject ID. 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Intent-to-Treat 
 
Listing 1.2:  Listing of Subjects with Inclusion/Exclusion Criteria Deviations 
 
Treatment: Ambrisentan 2.5mg 
 
Centre ID/ 
Subject ID 
Type 
Criterion 
 
 
 
XXXXXX/ 
XXXXXX 
Inclusion 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
 
 
 
 
Exclusion 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
 
 
 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
 
USER ID: Directory/Program.sas Date Time 
 
Programming notes: Present each treatment group and Centre/Subject ID. Sort by treatment group, Centre ID, Subject ID. 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Intent-to-Treat 
 
Listing 1.3:  Listing of Demographic Characteristics 
 
Treatment: Ambrisentan 2.5mg 
   
Centre ID/ 
Subject ID 
 
Partial 
Date of Birth 
 
Age (years)* 
 
Sex 
 
Child Bearing 
Potential 
Has Child 
Bearing 
Potential 
Changed? 
Date of Child 
Bearing 
Potential 
Change 
 
Ethnicity 
 
 
 
 
 
 
 
 
XXXXXX/ 
XXXXXX 
YYYY 
XX 
Female 
Pre-menarcheal 
Yes 
DDMMMYYYY ^ 
Hispanic/Latino 
 
 
 
 
 
 
 
 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  * Age at start of study treatment in AMB112529 
       ^ Date of first menses 
       # Date of final menses 
       ~ Date became sterile 
       Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
 
USER ID: Directory/Program.sas Date Time  
 
Programming notes: Present each treatment group and Centre/Subject ID. Sort by treatment group, Centre ID, Subject ID. 


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119 
Protocol: AMB114588                                                                                                Page 1 of n 
Population: Intent-to-Treat 
 
Listing 1.4:  Listing of Race 
 
 
Treatment: Ambrisentan 2.5mg 
   
Centre ID/ 
Subject ID 
 
Race 
 
 
XXXXXX/ 
XXXXXX 
Asian – East Asian Heritage 
 
 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
 
USER ID: Directory/Program.sas Date Time  
 
Programming notes: Present each treatment group and Centre/Subject ID. Sort by treatment group, Centre ID, Subject ID. 


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120 
Protocol: AMB114588                                                                                                Page 1 of n   
Population: Intent-to-treat                                                                                  
Listing  1.5:  Listing of Disease History 
 
 
Treatment: Ambrisentan 2.5mg 
 
 
 
 
 
 
 
 
 
 
Duration  
Centre ID / 
 
 
Date of 
of PAH 
Baseline 
Subject ID 
Diagnosis 
Sub category 
Diagnosis (yrs) 
WHO FC 
 
 
 
 
 
XXXXXX /
Idiopathic PAH 
 
DDMMMYYYY X.X 
I 
XXXXXX
 
 
 
 
 
 
 
 
 
 
XXXXXX /
XXXXXX
Persistent PAH despite surgical 
repair 
Atrio-ventricular septal 
defects 
DDMMMYYYY X.X 
II 
 
 
 
 
 
Etc..
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
 
USER ID: Directory/Program.sas Date Time  
 
Programming notes: Present each treatment group and Centre/Subject ID. Sort by treatment group, Centre ID, Subject ID.  
Produce listing for data collected in AMB112529 for the subset of subjects who entered AMB114588. 
 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Intent-to-Treat 
 
Listing 1.6:  Listing of Medical Conditions 
 
Treatment: Ambrisentan 2.5mg 
 
Centre ID/ 
Subject ID 
Age (y)/ 
Sex/ 
 
Classification 
Preferred Term 
Condition 
Status 
 
 
 
 
 
 
XXXXXX/ 
XXXXXX 
XX/ 
XXXXXX 
 
Hepatobiliary disorders 
XXXXXXXXXXXXXXX 
HEPATITIS A 
Current 
 
 
Psychiatric disorders 
XXXXXXXXXXXXXXXX 
PARANOIA COMBINED WITH MANIA. 
Past 
 
 
 
 
 
 
XXXXXX/ 
XXXXXX 
XX/ 
XXXXXX 
Eye disorders 
XXXXXXXXXXXXXXXX 
ASTIGMATISM 
Current 
 
 
 
 
 
 
XXXXXX/ 
XXXXXX 
XX/ 
XXXXXX 
Metabolism and nutrition 
disorders 
XXXXXXXXXXXX 
RICKETS 
Current 
 
 
 
 
 
 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
 
USER ID: Directory/Program.sas Date Time  
 
Programming notes: Present each treatment group and Centre/Subject ID. Sort by treatment group, Centre ID, Subject ID.  
Produce listing for data collected in AMB112529 for the subset of subjects who entered AMB114588. 
 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Intent-to-Treat 
 
Listing 1.7:  Listing of Medications 
 
Treatment: Ambrisentan 2.5mg 
 
Centre ID/ 
Subject ID 
 
 
ATC Level 1/  
Ingredient/ 
Verbatim Text 
Total 
Daily 
Dose/    
Units/ 
Freq/    
Route 
 
 
Date 
Started/ 
Study Day 
 
 
Date 
Stopped/ 
Study Day 
 
 
Reason 
For 
Medication 
 
 
 
 
 
 
XXXXXX/ 
XXXXXX 
Endocrine & metabolic/  
Fluticasone propionate/ 
FLIXOTIDE # 
2/  
MG/ 
2XD/ 
IH 
27SEP1999/ 
15 
02OCT1999 
xxxxxxxxxx 
 
 
 
 
 
 
 
Endocrine & metabolic/  
Fluticasone propionate/ 
FLIXOTIDE # 
4/  
MG/ 
2XD/ 
IH 
03OCT1999/ 
21 
Ongoing 
 
 
 
 
 
 
 
 
Etc.. 
 
 
 
 
 
 
 
 
 
 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  * Prior, # Concomitant, $ Post-treatment. 
       PAH Therapies are not included within this listing, for PAH Therapy please see Listing 1.7 
       Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
 
USER ID: Directory/Program.sas Date Time  
 
Programming notes: Present each treatment group and Centre/Subject ID. Sort by treatment group, Centre ID, Subject ID. 


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123 
Protocol: AMB114588                                                                                                Page 1 of n 
Population: Intent-to-Treat 
 
Listing 1.8:  Listing of PAH Therapy 
Treatment: Ambrisentan 2.5mg 
 
Centre ID/ 
Subject ID 
Drug Class/ 
ATC Level 1/  
Ingredient/ 
Verbatim Text/ 
Total 
Daily 
Dose/    
Units 
Date 
Started/ 
Study Day 
Date 
Stopped/ 
Study Day 
Reason the 
medication 
started? 
 
 
 
 
 
 
XXXXXX/ 
XXXXXX 
XXXXXXXXXXXXXXXXX/ 
XXXXXXXXXXXXXXXXXXXXXXXXX/  
XXXXXXXXXXXXXXXXX/ 
XXXXXXXXXXX #@ 
X/  
XX 
DDMMMYYYY/ 
XX 
DDMMMYYYY XXXXXXXXXXXXXXX 
 
 
 
 
 
 
XXXXXX/ 
XXXXXX 
XXXXXXXXXXXXXXXXX/ 
XXXXXXXXXXXXXXXXXXXXXXXXX/  
XXXXXXXXXXXXXXXXX/ 
XXXXXXXXXXX # 
X/  
XX 
DDMMMYYYY/ 
XX 
Ongoing 
XXXXXXXXXXXXXX 
 
 
 
 
 
 
 
Etc.. 
 
 
 
 
 
 
 
 
 
 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  * Prior, # Concomitant, $ Post-treatment. 
       @ Ongoing background PAH therapy at baseline 
       Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
 
USER ID: Directory/Program.sas Date Time  
 
Programming notes: Present each treatment group and Centre/Subject ID. Sort by treatment group, Centre ID, Subject ID. 


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124 
Protocol: AMB114588                                                                                                Page 1 of n 
Population: Intent-to-Treat 
 
Listing 1.9:  Relationship between ATC Level 1, Ingredient and Verbatim Text 
 
ATC Level 1 
Ingredient 
Verbatim Text 
 
 
 
Endocrine & metabolic 
Fluticasone Propionate 
FLIXOTIDE 
 
Prednisolone 
PREDNISOLONE 
 
 
 
 
 
 
Drugs acting via the nervous 
system 
Paracetamol 
PANADOL  
CHILDREN'S PANADOL 1-5YERS 
 
 
 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
USER ID: Directory/Program.sas Date Time  
 
Programming notes: Sort by ATC level 1treatment group, Ingredient. 


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125 
Protocol: AMB114588                                                                                                Page 1 of n 
Population: Intent-to-Treat 
 
Listing 1.10:  Listing of Compliance Data 
 
Treatment: Ambrisentan 2.5mg 
 
 
Centre ID/ 
Subject ID 
% of 
compliant 
visits 
 
 
 
Visit 
 
Visit Date/ 
Study Day 
 
Compliance since 
the last visit 
 
 
 
 
 
XXXXXX/ 
XXXXXX 
100 
XXXXXXXXX 
DDMMMYYYY/ 
XX 
  
 
 
XXXXXXXXX 
DDMMMYYYY/ 
XX 
>=80% and <=120% 
 
 
XXXXXXXXX 
DDMMMYYYY/ 
XX 
>=80% and <=120% 
 
 
XXXXXXXXX 
DDMMMYYYY/ 
XX 
>=80% and <=120% 
 
 
XXXXXXXXX 
DDMMMYYYY/ 
XX 
>=80% and <=120% 
 
 
XXXXXXXXX 
DDMMMYYYY/ 
XX 
>=80% and <=120% 
 
 
XXXXXXXXX 
DDMMMYYYY/ 
XX 
>=80% and <=120% 
 
 
 
 
 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  Compliant visits are those at which subjects are >=80% and <=120% compliant. 
       Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
 
USER ID: Directory/Program.sas Date Time  
 
Programming notes: Present each treatment group, Centre/Subject ID and time-point. Sort by treatment group, Centre ID, Subject ID and time-point. 
 


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126 
Protocol: AMB114588                                                                                                Page 1 of n 
Population: Intent-to-Treat 
 
Listing 1.11:  Listing of initial, highest and final dose of ambrisentan  
 
Treatment: Ambrisentan 2.5mg 
 
Centre ID/ 
Subject ID 
Initial dose mg/kg 
Highest dose 
mg/kg 
Final dose mg/kg 
 
 
 
 
XXXXXX/ 
XXXXXX 
X.X 
X.X 
X.X 
 
 
 
 
XXXXXX/ 
XXXXXX 
X.X 
X.X 
X.X 
 
 
 
 
 
Etc.. 
 
 
 
 
 
 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
 
USER ID: Directory/Program.sas Date Time  
 
 


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127 
Protocol: AMB114588                                                                                                Page 1 of n 
Population: Intent-to-Treat 
 
Listing 1.12:  Listing of Protocol Deviation 
Treatment: Ambrisentan 2.5mg 
 
Centre ID/ 
Subject ID 
Important 
Protocol 
Deviations 
Protocol Deviation Category 
Protocol Deviation 
Description 
 
Protocol 
Deviation Date/ 
Study Day 
Visit 
Phase 
Action 
taken 
Escalated 
for 
Medical 
Oversight
? 
 
 
 
 
 
 
 
 
XXXXXX/ 
XXXXXX 
Y 
Biological specimen sample 
procedures 
XXXXXXXXXXXXXXXXXXXX
XXX * 
DDMMMYYYY/ 
XX 
XXXXXXXX 
XXXXXXXXX
XXXXXXXXX
XXXXX 
 
 
 
 
 
 
 
 
 
XXXXXX/ 
XXXXXX 
N 
Other: 
XXXXXXXXXXXXXXXXXXXXXXX 
XXXXXXXXXXXXXXXXXXXX
XXX 
DDMMMYYYY/ 
XX 
XXXXXXXX 
XXXXXXXXX
XXXXXXXXX
XXXXX 
 
 
 
 
 
 
 
 
 
 
 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  * Important Deviation 
       Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
 
USER ID: Directory/Program.sas Date Time  
 
Programming notes: Present each treatment group and Centre/Subject ID. Sort by treatment group, Centre ID, Subject ID. 


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128 
Protocol: AMB114588                                                                                                Page 1 of n 
Population: Intent-to-Treat 
 
Listing 2.1:  Listing of Time to Death (All cause) 
 
Treatment: Ambrisentan 2.5mg 
 
Centre ID/ 
Subject ID 
Death Date/ 
Study Day 
Details 
 
 
 
XXXXXX/ 
XXXXXX 
DDMMMYYYY/ 
XX 
 
 
DDMMMYYYY/ 
XX 
 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
 
USER ID: Directory/Program.sas Date Time  
 
Programming notes: Present each treatment group and Centre/Subject ID. Sort by treatment group, Centre ID, Subject ID. 
 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Intent-to-Treat 
 
Listing 2.2:  Listing of 6 Minute Walking Distance Data 
 
Treatment: Ambrisentan 2.5mg 
 
Centre 
ID/ 
Subject 
ID 
 
 
 
 
 
 
 
 
Visit 
 
 
 
 
 
Visit Date/ 
Time/ 
Study Day 
Distance Walked (m) 
Did subject 
walk less 
than 6 
minutes?/ 
Reason for 
stopping 
prematurely 
Duration 
walked 
(seconds) 
Did subject 
use 
supplemental 
oxygen 
Oxygen 
flow 
rate 
(L/min) 
Actual 
 
 
 
Change 
from 
Baseline 
Percentage 
Change 
from 
Baseline 
 
 
 
 
 
 
 
 
 
 
XXXXXX/ 
XXXXXX 
Baseline ** 
DDMMMYYYY/ 
HH:MM/ 
XX 
XXX 
 
 
Y/ 
XXXXXXXXXXXX 
XXX 
Y 
XXXX 
 
Entry Visit * 
DDMMMYYYY/ 
HH:MM/ 
XX 
XXX 
XXX 
XXX 
Y/ 
XXXXXXXXXXXX 
XXX 
Y 
XXXX 
 
XXXXXXX 
DDMMMYYYY/ 
HH:MM/ 
XX 
XXX 
XXX 
XXX 
N 
 
N 
 
 
XXXXXXX 
DDMMMYYYY/ 
HH:MM/ 
XX 
XXX 
XXX 
XXX 
N 
 
N 
 
 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
Note:  ** Baseline is the last value recorded prior to start of study treatment from AMB112529. 
       *  Entry Visit is at entry to AMB114588. 
       Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
 
USER ID: Directory/Program.sas Date Time  
 
Programming notes: Present each treatment group, Centre/Subject ID and time-point. Sort by treatment group, Centre ID, Subject ID and time-point. 
 


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130 
Protocol: AMB114588                                                                                                Page 1 of n 
Population: Intent-to-Treat 
 
Listing 2.3:  Listing of Clinical Worsening of PAH 
 
Treatment: Ambrisentan 2.5mg 
 
Centre ID/ 
Subject ID 
Event Date/ 
Study Day 
Clinical worsening criteria 
 
 
 
XXXXXX/ 
XXXXXX 
DDMMMYYYY/ 
XX 
Hospitalisation for worsening of PAH 
 
DDMMMYYYY/ 
XX 
PAH related deterioration: Clinical signs or symptoms of right sided heart failure 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
 
USER ID: Directory/Program.sas Date Time  
 
Programming notes: Present each treatment group and Centre/Subject ID. Sort by treatment group, Centre ID, Subject ID. 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Intent-to-Treat 
 
Listing 2.6:  Listing of WHO Functional Class Data 
 
Treatment: Ambrisentan 2.5mg 
 
Centre ID/ 
Subject ID 
 
 
 
Visit 
 
Visit 
Date/ 
Study Day 
WHO pulmonary 
hypertension 
functional 
classification 
Actual $ 
Change 
from 
Baseline 
 
 
Change 
Categorisatio
n 
 
 
 
 
 
 
 
XXXXXX/ 
XXXXXX 
Baseline ** 
DDMMMYYYY/ 
XX 
Class II 
2 
 
 
 
Entry Visit * 
DDMMMYYYY/ 
XX 
Class II 
2 
0 
NC 
 
XXXXXXX 
DDMMMYYYY/ 
XX 
Class IV 
4 
2 
Det 
 
XXXXXXX 
DDMMMYYYY/ 
XX 
Class I 
1 
-1 
Imp 
 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  ** Baseline is the last value recorded prior to start of study treatment from AMB112529. 
       * Entry Visit is at entry to AMB114588. 
       There are 4 grades for WHO FC based on severity of symptoms (
). 
       $ Grades mapped to numeric scale 1-4 (i.e. Class IV = 4).  
       Change categorisation (based on -2, -1, 0, +1, +2); 
, 
      
. 
       Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
 
USER ID: Directory/Program.sas Date Time  
 
Programming notes: Present each treatment group, Centre/Subject ID and time-point. Sort by treatment group, Centre ID, Subject ID and time-point. 
 
CCI
CCI
CCI


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132 
Protocol: AMB114588                                                                                                Page 1 of n 
Population: Intent-to-Treat 
 
Listing 2.7:  Listing of Plasma NT-Pro BNP Concentration (ng/L) 
 
Treatment: Ambrisentan 2.5mg 
 
Centre ID/ 
Subject ID 
 
 
 
Visit 
 
Visit 
Date/ 
Study Day 
 
 
 
Visit Value 
 
 
 
Change from Baseline 
 
Raw  
 
Log 
Raw 
Log$ 
 
 
 
 
 
 
 
XXXXXX/ 
XXXXXX 
Baseline ** 
DDMMMYYYY/ 
XX 
XXX.X 
X.XX 
 
 
 
Entry Visit * 
DDMMMYYYY/ 
XX 
XXX.X 
X.XX 
XXX.X 
X.XX 
 
XXXXXXX 
DDMMMYYYY/ 
XX 
XXX.X 
X.XX 
XXX.X 
X.XX 
 
XXXXXXX 
DDMMMYYYY/ 
XX 
XXX.X 
X.XX 
XXX.X 
X.XX 
 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  ** Baseline is the last value recorded prior to start of study treatment from AMB112529. 
       * Entry Visit is at entry to AMB114588. 
       $ Log (change from baseline) = Log (Visit) – Log (Baseline). 
       Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
 
USER ID: Directory/Program.sas Date Time  
 
Programming notes: Present each treatment group, Centre/Subject ID and time-point. Sort by treatment group, Centre ID, Subject ID and time-point.  
 
 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Intent-to-Treat 
 
Listing 2.8:  Listing of Exploratory Echocardiogram 
 
Treatment: Ambrisentan 2.5mg 
 
Centre 
ID/ 
Subject 
ID 
 
 
 
 
 
 
Visit 
 
 
 
 
Visit 
Date/ 
Study Day 
Pericardial 
effusion/ 
Change from 
Baseline 
Mean right 
atrial 
pressure 
(mmHg)/ 
Change from 
Baseline 
Tricuspid 
annular plane 
systolic 
excursion (cm)/ 
Change from 
Baseline 
Systolic 
Eccentricity 
Index/ 
Change from 
Baseline 
Diastolic 
Eccentricity 
Index/ 
Change from 
Baseline 
Tricuspid 
regurgitant 
jet (m/s)/ 
Change from 
Baseline 
Right 
Ventricular 
Pressure 
(mmHg)/ 
Change from 
Baseline 
 
 
 
 
 
 
 
 
 
 
XXXXXX/ 
XXXXXX 
Baseline 
** 
DDMMMYYYY/ 
XX 
Absent 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
Entry 
Visit * 
DDMMMYYYY/ 
XX 
Trace/ 
Worsened 
XXX/ 
XXX 
XXX/ 
XXX 
XXX/ 
XXX 
XXX/ 
XXX 
XXX/ 
XXX 
XXX/ 
XXX 
 
XXXXXXX 
DDMMMYYYY/ 
XX 
Small/ 
Worsened 
XXX/ 
XXX 
XXX/ 
XXX 
XXX/ 
XXX 
XXX/ 
XXX 
XXX/ 
XXX 
XXX/ 
XXX 
 
XXXXXXX 
DDMMMYYYY/ 
XX 
Trace/ 
Worsened 
XXX/ 
XXX 
XXX/ 
XXX 
XXX/ 
XXX 
XXX/ 
XXX 
XXX/ 
XXX 
XXX/ 
XXX 
 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
 
USER ID: Directory/Program.sas Date Time  
 
Programming notes: Present each treatment group, Centre/Subject ID and time-point. Sort by treatment group, Centre ID, Subject ID and time-point. 
 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Intent-to-Treat 
 
Listing 2.9:  Listing of Cardiopulmonary Hemodynamics 
 
Treatment: Ambrisentan 2.5mg 
 
Centre ID/ 
Subject ID 
 
Right Heart 
Catheterization 
Date / 
Time/ 
Study Day 
Heart 
Rate(bpm)/ 
Change from 
Baseline 
Mean Pulmonary 
Arterial 
Pressure (mmHg)/ 
Change from 
Baseline 
Mean Right 
Atrial 
Pressure (mmHg)/ 
Change from 
Baseline 
Pulmonary 
Capillary Wedge 
Pressure (mmHg)/ 
Change from 
Baseline 
 
 
 
 
 
 
XXXXXX/ 
XXXXXX 
DDMMMYYYY/ 
HH:MM/ 
XX 
XXX 
XXX 
XXX 
XXX 
 
DDMMMYYYY/ 
HH:MM/ 
XX 
XXX/ 
XXX 
XXX/ 
XXX 
XXX/ 
XXX 
XXX/ 
XXX 
 
DDMMMYYYY/ 
HH:MM/ 
XX 
XXX/ 
XXX 
XXX/ 
XXX 
XXX/ 
XXX 
XXX/ 
XXX 
 
DDMMMYYYY/ 
HH:MM/ 
XX 
XXX/ 
XXX 
XXX/ 
XXX 
XXX/ 
XXX 
XXX/ 
XXX 
 
 
 
 
 
 
 
 
 
 
 
 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
 
USER ID: Directory/Program.sas Date Time  
 
Programming notes: Present each treatment group, Centre/Subject ID and time-point. Sort by treatment group, Centre ID, Subject ID and time-point. 
 


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Protocol: AMB114588                                                                                                Page 2 of n 
Population: Intent-to-Treat 
 
Listing 2.9:  Listing of Cardiopulmonary Hemodynamics 
 
Treatment: Ambrisentan 2.5mg 
 
Centre ID/ 
Subject ID 
Right Heart 
Catheterization 
Date / 
Time/ 
Study Day 
Method used to 
Calculate 
Cardiac Output/ 
Oxygen 
Consumption 
Cardiac Output 
(Litres/minute)/ 
Change from 
Baseline 
Cardiac index 
(L/min/meters/ 
square)/ 
Change from 
Baseline 
Pulmonary Vascular 
Resistance 
(mmHg/L/min)/ 
Change from 
Baseline 
 
 
 
 
 
 
XXXXXX/ 
XXXXXX 
DDMMMYYYY/ 
HH:MM/ 
XX 
XXXXXXXXXXXX/ 
XXXXXXXXXXX 
XXX 
XXX 
XXX 
 
DDMMMYYYY/ 
HH:MM/ 
XX 
XXXXXXXXXXXX/ 
XXXXXXXXXXX 
XXX/ 
XXX 
XXX/ 
XXX 
XXX/ 
XXX 
 
DDMMMYYYY/ 
HH:MM/ 
XX 
XXXXXXXXXXXX/ 
XXXXXXXXXXX 
XXX/ 
XXX 
XXX/ 
XXX 
XXX/ 
XXX 
 
DDMMMYYYY/ 
HH:MM/ 
XX 
XXXXXXXXXXXX/ 
XXXXXXXXXXX 
XXX/ 
XXX 
XXX/ 
XXX 
XXX/ 
XXX 
 
 
 
 
 
 
 
 
 
 
 
 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
 
 
USER ID: Directory/Program.sas Date Time  
 
Programming notes: Present each treatment group, Centre/Subject ID and time-point. Sort by treatment group, Centre ID, Subject ID and time-point. 
 


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Protocol: AMB114588                                                                                                Page 3 of n 
Population: Intent-to-Treat 
 
Listing 2.9:  Listing of Cardiopulmonary Hemodynamics 
 
Treatment: Ambrisentan 2.5mg 
 
Centre ID/ 
Subject ID 
Right Heart 
Catheterization 
Date / 
Time/ 
Study Day 
Left Ventricle 
End Diastolic 
Pressure (mmHg)/ 
Change from 
Baseline 
Arterial 
Oxygen 
Saturation 
Percentage/ 
Change from 
Baseline 
Venous 
Oxygen 
Saturation/ 
Change from 
Baseline 
Mean Arterial 
Pressure (mmHg)/ 
Change from 
Baseline 
 
 
 
 
 
 
XXXXXX/ 
XXXXXX 
DDMMMYYYY **/ 
HH:MM/ 
XX 
XXX 
XXX 
XXX 
XXX 
 
DDMMMYYYY/ 
HH:MM/ 
XX 
XXX/ 
XXX 
XXX/ 
XXX 
XXX/ 
XXX 
XXX/ 
XXX 
 
DDMMMYYYY/ 
HH:MM/ 
XX 
XXX/ 
XXX 
XXX/ 
XXX 
XXX/ 
XXX 
XXX/ 
XXX 
 
DDMMMYYYY/ 
HH:MM/ 
XX 
XXX/ 
XXX 
XXX/ 
XXX 
XXX/ 
XXX 
XXX/ 
XXX 
 
 
 
 
 
 
 
 
 
 
 
 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
Note:  ** Baseline - the last value recorded prior to start of study treatment from AMB112529. 
       Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
 
USER ID: Directory/Program.sas Date Time  
 
Programming notes: Present each treatment group, Centre/Subject ID and time-point. Sort by treatment group, Centre ID, Subject ID and time-point. 
 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Intent-to-Treat 
 
Listing 2.10:  Listing of School Days 
 
Treatment: Ambrisentan 2.5mg 
 
Centre ID/ 
Subject ID 
 
Age(y)/ 
Sex/ 
Race 
 
 
 
 
 
Visit 
 
 
 
 
Visit Date 
/ 
Study Day 
School Days 
Scheduled/ 
Change from 
Baseline 
School Days 
missed/ 
Change from 
Baseline 
School Days  
missed due 
to PAH/ 
Change from 
Baseline 
Proportion of 
days missed 
(%)/ 
Change from 
Baseline 
Proportion of 
days missed due 
to PAH (%)/ 
Change from 
Baseline 
 
 
 
 
 
 
 
 
 
XXXXXX/ 
XXXXXX 
XX/ 
Male/ 
XXXXXX 
Baseline ** DDMMMYYYY/ 
XX 
XX 
XX 
XX 
XX 
XX 
 
 
Entry  
Visit * 
DDMMMYYYY/ 
XX 
XX/ 
XX 
 
XX/ 
XX 
XX/ 
XX 
XX/ 
XX 
XX/ 
XX 
 
 
XXXXXXX 
DDMMMYYYY/ 
XX 
XX/ 
XX 
 
XX/ 
XX 
XX/ 
XX 
XX/ 
XX 
XX/ 
XX 
 
 
XXXXXXX 
DDMMMYYYY/ 
XX 
XX/ 
XX 
 
XX/ 
XX 
XX/ 
XX 
XX/ 
XX 
XX/ 
XX 
 
 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  ** Baseline is the last value recorded prior to start of study treatment from AMB112529. 
       * Entry Visit is at entry to AMB114588. 
       Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
 
USER ID: Directory/Program.sas Date Time 
 
Programming notes: Present each treatment group, Centre/Subject ID and time-point. Sort by treatment group, Centre ID, Subject ID and time-point. 
 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Intent-to-Treat 
 
Listing 2.11:  Listing of Subject Global Assessment (SF10 Health Survey for Children) 
 
Treatment: Ambrisentan 2.5mg 
 
Centre ID/ 
Subject ID 
 
 
 
 
 
Visit 
 
 
 
 
Visit Date / 
Study Day 
1.Childs General 
Health 
2a.Limited Riding 
and Skating 
2b.Limited 
Bending 
3.Physical 
Problems Limit 
Schoolwork 
4.Emotional 
Problems Limit 
Schoolwork 
5.Bodily pain 
 
 
 
 
 
 
 
 
XXXXXX/
XXXXXX
Baseline 
** 
DDMMMYYYY/ 
XX 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
Entry 
Visit * 
DDMMMYYYY/ 
XX 
XXXXXXXX 
 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
XXXXXXX 
DDMMMYYYY/ 
XX 
XXXXXXXX 
 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
XXXXXXX 
DDMMMYYYY/ 
XX 
XXXXXXXX 
 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Etc..
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  ** Baseline is the last value recorded prior to start of study treatment from AMB112529. 
       * Entry Visit is at entry to AMB114588. 
       The Physical Summary Score (aggregate of item responses 1, 2a, 2b, 3 and 5) and Psychosocial Summary Score (aggregate             
       of item responses 4, 6, 7, 8 and 9) were calculated by QualityMetrics Health Outcomes software.   
       Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
 
USER ID: Directory/Program.sas Date Time 
 
Programming notes: Present each treatment group, Centre/Subject ID and time-point. Sort by treatment group, Centre ID, Subject ID and time-point. 
 


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Protocol: AMB114588                                                                                                Page 2 of n 
Population: Intent-to-Treat 
 
Listing 2.11:  Listing of Subject Global Assessment (SF10 Health Survey for Children) 
 
Treatment: Ambrisentan 2.5mg 
 
Centre ID/ 
Subject ID 
 
 
 
 
 
Visit 
 
 
 
 
Visit Date 
/ 
Study Day 
6.Satisfied with 
friendships 
7.Satisfied with life 
overall 
8.Time bothered or 
upset 
9.General 
behaviour 
Physical 
Health 
Summary/ 
Change 
from 
Baseline 
Psychosocial 
Summary/ 
Change from 
Baseline 
 
 
 
 
 
 
 
 
XXXXXX/
XXXXXX
Baseline ** 
DDMMMYYYY/ 
XX 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
XX 
XX 
Entry Visit 
* 
DDMMMYYYY/ 
XX 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
XX/ 
XX 
XX/ 
XX 
XXXXXXX 
DDMMMYYYY/ 
XX 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
XX/ 
XX 
XX/ 
XX 
XXXXXXX 
DDMMMYYYY/ 
XX 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
XX/ 
XX 
XX/ 
XX 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Etc..
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  ** Baseline is the last value recorded prior to start of study treatment from AMB112529. 
       * Entry Visit is at entry to AMB114588. 
       The Physical Summary Score (aggregate of item responses 1, 2a, 2b, 3 and 5) and Psychosocial Summary Score (aggregate             
       of item responses 4, 6, 7, 8 and 9) were calculated by QualityMetrics Health Outcomes software.   
       Subjects are considered as belonging to their treatment group at the start of study AMB114588. 
 
USER ID: Directory/Program.sas Date Time 
 
Programming notes: Present each treatment group, Centre/Subject ID and time-point. Sort by treatment group, Centre ID, Subject ID and time-point. 
 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Safety 
 
Listing 3.1:  Listing of Exposure Investigational Product 
 
Treatment: Ambrisentan 2.5mg 
 
 
Subject 
ID 
IP 
Start 
Date 
IP 
Stop 
Date 
Duration 
(Months) 
Start Date 
of Dose/ 
Study Day 
End Date 
of Dose / 
Study Day 
Dose 
Dose 
Unit Primary reason for change 
 
 
 
 
 
 
 
 
 
XXXXXX 
DDMMMYYYY 
DDMMMYYYY 
XXX 
DDMMMYYYY/ 
XX 
DDMMMYYYY/ 
XX 
X^ 
XX 
 
 
 
 
 
DDMMMYYYY/ 
XX 
DDMMMYYYY/ 
XX 
X^ 
XX 
XXXXXXXXXXXX 
 
 
 
 
DDMMMYYYY/ 
XX 
DDMMMYYYY/ 
XX 
Xv 
XX 
XXXXXXXXXXXX 
 
 
 
 
 
 
 
 
 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: ^ Up titration, v Down titration, # Restart of investigational product. 
 
USER ID: Directory/Program.sas Date Time  
 
Programming notes: Present each treatment group, subject and time-point. 
 
 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Safety 
Listing 3.2:  Listing of All Adverse Events 
Treatment: Ambrisentan 2.5mg 
Centre ID/ 
Subject ID 
 
Age (y)/ 
Sex/ 
Race/ 
Weight 
(kg) 
 
 
 
Preferred Term/ 
Verbatim Text 
Outcome/ 
Onset Date/ 
Resolution Date/ 
Frequency 
 
Time Since  
First Dose/ 
Last Dose/ 
Duration (days) 
 
Maximum  
Intensity/ 
Serious/ 
Withdrawal 
 
Action 
Taken/ 
Relation to 
Study Drug 
 
Further Details if 
Serious Event 
 
 
 
 
 
 
 
 
XXXXXX/ 
XXXXXX 
XX/ 
XXXXXX/ 
XXXXXX/ 
XX 
XXXXXXXXXXX/ 
XXXXXXXXXXX * 
XXXXXXXXX/ 
DDMMMYYYY/ 
DDMMMYYYY/ 
XXXXXXXXX 
XX/ 
XX/ 
XX 
 
XXXX/ 
XXX/ 
XXX 
XXXXXXXX/ 
XX 
e.g. 
Results in death, 
Results in disability/ 
Incapacity, 
Congential anomaly/ 
birth defect, 
Possible drug induced 
liver injury, 
Life threatening, 
Requires prolonged 
hospitalisation, 
Caused by activity 
related to study, 
Etc.. 
 
 
XXXXXXXXXXX/ 
XXXXXXXXXXX # 
XXXXXXXXX/ 
DDMMMYYYY/ 
DDMMMYYYY/ 
XXXXXXXXX 
XX/ 
XX/ 
XX 
 
XXXX/ 
XXX/ 
XXX 
XXXXXXXX/ 
XX 
 
 
 
 
 
 
 
 
 
XXXXXX/ 
XXXXXX 
XX/ 
XXXXXX/ 
XXXXXX/ 
XX 
XXXXXXXXXXX/ 
XXXXXXXXXXX $ 
XXXXXXXXX/ 
DDMMMYYYY/ 
DDMMMYYYY/ 
XXXXXXXXX 
XX/ 
XX/ 
XX 
 
XXXX/ 
XXX/ 
XXX 
XXXXXXXX/ 
XX 
 
 
 
 
 
 
 
 
 
Etc.. 
 
 
 
 
 
 
 
Note:  * Prior, # Treatment-emergent, $ Post-treatment, ~ AE started pre extension study. 
       Subjects are considered as belonging to the treatment group according to the highest dose received. 
 
USER ID: Directory/Program.sas Date Time 
Programming notes: Present each treatment group and Centre/Subject ID. Sort by treatment group, Centre ID, Subject ID and Onset date. 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Safety 
 
Listing 3.3:  Listing of Relationship between Adverse Event System Organ Class, Preferred Term and Verbatim Text 
 
System Order Class 
Preferred Term 
Verbatim Text 
 
 
 
Blood and lymphatic system 
disorder 
Lymphadenopathy 
Enlarged lymph node 
 
 
 
Cardiac disorder 
Palpitations 
Heart palpitation 
 
Tachycardia nos 
Tachycardia 
 
 
 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
USER ID: Directory/Program.sas Date Time 
 
Programming notes: Continue for all combinations.  Sort in order of SOC, PT, and verbatim text. 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Safety 
 
Listing 3.4:  Listing of Subject Numbers for Specified Adverse Events 
 
Treatment: Ambrisentan 2.5mg 
 
System Organ Class 
  Preferred term 
No. with 
Event 
Centre ID/Subject ID 
Gastrointestinal disorders 
 
 
  Dyspepsia 
  9 
XXXXXX/XXXXXX, XXXXXX/XXXXXX, 
XXXXXX/XXXXXX, XXXXXX/XXXXXX, 
XXXXXX/XXXXXX, XXXXXX/XXXXXX, 
XXXXXX/XXXXXX, XXXXXX/XXXXXX, 
XXXXXX/XXXXXX,  
  Nausea 
  1 
XXXXXX/XXXXXX 
  Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  Subjects are considered as belonging to the treatment group according to the highest dose received. 
 
USER ID: Directory/Program.sas Date Time 
 
Programming notes: Present each treatment group. Sort by treatment group, SOC, PT. 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Safety 
 
Listing 3.8:  Listing of Haematology 
 
Central / Local Laboratory 
Treatment: Ambrisentan 2.5mg 
 
Centre ID/ 
Subject ID 
 
Age(y)/ 
Sex/ 
Race/ 
Baseline 
Weight(kg) 
 
 
 
 
Lab test (units) 
 
 
Planned 
Relative 
Time 
 
 
 
 
Date 
 
 
 
Study 
Day 
 
 
 
Converted Data 
 
 
 
Flag $ 
NR CC BL 
Value 
Normal Range 
 
 
 
 
 
 
 
 
 
XXXXXX/ 
XXXXXX 
XX/ 
<Parameter (units)> 
Baseline ** 
DDMMMYYYY 
 XX     XXX  
 XXX – XXX  
 
 
XXXXXX/ 
 
Entry Visit* 
DDMMMYYYY 
 XX     XXX  
 XXX – XXX 
 
 
XXXXXX/ 
 
XXXXXXXXX 
DDMMMYYYY 
 XX     XXX  
 XXX – XXX 
H  H   H 
 
XX 
 
XXXXXXXXX 
DDMMMYYYY 
 XX     XXX  
 XXX – XXX 
H      H  
 
 
 
XXXXXXXXX 
DDMMMYYYY 
 XX     XXX  
 XXX – XXX 
 
 
 
 
XXXXXXXXX 
DDMMMYYYY 
 XX     XXX  
 XXX – XXX 
 
 
 
 
XXXXXXXXX 
DDMMMYYYY 
 XX     XXX  
 XXX – XXX 
 
 
 
 
XXXXXXXXX 
DDMMMYYYY 
 XX     XXX 
 XXX – XXX 
L  L   L 
 
 
 
XXXXXXXXX 
DDMMMYYYY 
 XX     XXX  
 XXX – XXX 
 
 
 
 
XXXXXXXXX 
DDMMMYYYY 
 XX     XXX  
 XXX - XXX 
L 
 
 
 
 
 
 
 
 
 
 
 
<Parameter (units)> 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  ** Baseline is the last value recorded prior to start of study treatment from AMB112529. 
       * Entry Visit is at entry to AMB114588. 
       $ NR for Normal Range flag, CC for Clinical Concern flag; BL for Change from Baseline  
       H=Above range, L=Below range 
       Subjects are considered as belonging to the treatment group according to the highest dose received. 
 
USER ID: Directory/Program.sas Date Time  
 
Programming notes: Present each treatment group, Centre/Subject ID and time-point. Sort by treatment group, Centre ID, Subject ID and time-point. Continue for all 
parameters. 
 
 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Safety 
 
Listing 3.9  Listing of Haematology Data for Subjects with Abnormalities of Potential Clinical Concern 
 
Central /Local Laboratory 
Treatment: Ambrisentan 2.5mg 
 
Centre ID/ 
Subject ID 
 
Age(y)/ 
Sex/ 
Race/ 
Baseline 
Weight(kg) 
 
 
 
 
Lab test (units) 
 
 
Planned 
Relative 
Time 
 
 
 
 
Date 
 
 
 
Study 
Day 
 
 
 
Converted Data 
 
 
 
Flag $ 
NR CC BL 
Value Normal 
Range 
Low 
Concern 
High 
Concern 
 
 
 
 
 
 
 
 
 
 
 
XXXXXX/ 
XXXXXX 
XX/ 
<Parameter (units)> 
Baseline 
** 
DDMMMYYYY 
 XX     XXX  XXX – XXX   XXX  
 XXX  
 
 
XXXXXX/ 
 
Entry 
Visit* 
DDMMMYYYY 
 XX     XXX  XXX – XXX  XXX  
 XXX  
 
 
XXXXXX/ 
 
XXXXXXXXX DDMMMYYYY 
 XX     XXX  XXX – XXX  XXX  
 XXX  
H  H   H 
 
XX 
 
XXXXXXXXX DDMMMYYYY 
 XX     XXX  XXX – XXX  XXX  
 XXX  
H      H  
 
 
 
XXXXXXXXX DDMMMYYYY 
 XX     XXX  XXX – XXX  XXX  
 XXX  
 
 
 
 
XXXXXXXXX DDMMMYYYY 
 XX     XXX  XXX – XXX  XXX  
 XXX  
 
 
 
 
XXXXXXXXX DDMMMYYYY 
 XX     XXX  XXX – XXX  XXX  
 XXX  
 
 
 
 
XXXXXXXXX DDMMMYYYY 
 XX     XXX 
XXX – XXX  XXX 
 XXX 
L  L   L 
 
 
 
XXXXXXXXX DDMMMYYYY 
 XX     XXX  XXX – XXX  XXX  
 XXX  
 
 
 
 
XXXXXXXXX DDMMMYYYY 
 XX     XXX  XXX - XXX  XXX  
 XXX  
L 
 
 
 
 
 
 
 
 
 
 
 
<Parameter (units)> 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  ** Baseline is the last value recorded prior to start of study treatment from AMB112529. 
       * Entry Visit is at entry to AMB114588. 
       $ NR for Normal Range flag, CC for Clinical Concern flag; BL for Change from Baseline  
       H=Above range, L=Below range 
       Subjects are considered as belonging to the treatment group according to the highest dose received. 
 
USER ID: Directory/Program.sas Date Time 
Programming notes: Present each treatment group, Centre/Subject ID and time-point. Sort by treatment group, Centre ID, Subject ID and time-point. Continue for all 
parameters. 
 
 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Safety 
 
Listing 3.13:  Listing of Liver Event Results and Time of Event Relative to Treatment 
 
Treatment: Ambrisentan 2.5mg 
 
Centre ID/ 
Subject ID 
 
 
Age (y)/ 
Sex/ 
Race/ 
 
 
Event Date/ 
Study Day 
Days from  
first dose to 
start of  
event 
Days from 
last dose to 
start of 
event 
 
 
Event that reached or exceeded protocol 
defined criteria 
 
 
 
 
 
 
XXXXXX/ 
XXXXXX 
XX/ 
DDMMMYYYY/ 
X 
X 
ALT (alanine aminotransferase) 
 
XXXXXX/ 
XX 
 
 
 
 
XXXXXX/ 
 
 
 
 
 
XX 
 
 
 
 
 
 
 
 
 
 
Etc.. 
 
 
 
 
 
 
     
     
     
     
   
 
 
 
 
 
 
 
 
 
 
 
 
Note:  Subjects are considered as belonging to the treatment group according to the highest dose received. 
 
USER ID: Directory/Program.sas Date Time  
 
Programming notes: Present each treatment group and Centre/Subject ID. Sort by treatment group, Centre ID, Subject ID. 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Safety 
 
Listing 3.14:  Listing of patient specific information for liver events 
 
Treatment: Ambrisentan 2.5mg 
 
Centre ID/ 
Subject ID 
 
 
 
 
Age (y)/ 
Sex/ 
Race/ 
 
 
Event that 
reached or 
exceeded protocol 
defined criteria 
 
 
 
 
 
Event Date/ 
Study Day 
Days 
from 
last 
dose 
to 
start 
of 
event 
 
 
 
 
 
 
 
Assessment 
 
 
 
 
 
 
 
Result 
 
 
 
 
 
 
 
XXXXXX/ 
XXXXXX 
XX/ 
XXXXXXXXXXXXX 
DDMMMYYYY/ 
X 
Subject become pregnant? 
No 
 
XXXXXX/ 
 
XX 
 
Was a biopsy taken? 
Yes 
 
XXXXXX/ 
 
 
 
Any unconventional medications 
No 
 
XX 
 
 
 
Fasting or significant dietary change 
No 
 
 
 
 
 
Is this event serious? 
Yes 
 
 
 
 
 
Evaluation interval 
During the treatment 
period 
 
 
 
 
 
 
 
 
 
 
 
 
Does the subject consume alcohol? 
Yes 
 
 
 
 
 
Average number of units of alcohol consumed per week 
XX 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  Subjects are considered as belonging to the treatment group according to the highest dose received. 
 
USER ID: Directory/Program.sas Date Time  
 
Programming notes: Present each treatment group and Centre/Subject ID. Sort by treatment group, Centre ID, Subject ID. 
 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Safety 
 
Listing 3.15: Listing of Medical Conditions for Subjects with Liver Events on Treatment 
 
 
Treatment 
Centre 
ID/ 
Subject 
ID 
Age (y)/ 
Sex/ 
Race/ 
Classification 
Condition 
Status 
 
 
 
 
 
 
Ambrisentan 
2.5mg 
XXXXXX/ 
XXXXXX 
XX/ 
XXXXXXX/ 
XXXXXX 
 
Hepatobiliary 
HEPATITIS A 
Current 
 
 
 
Psychiatric 
PARANOIA COMBINED WITH MANIA. 
Past 
 
 
 
 
 
 
 
XXXXXX/ 
XXXXXX 
XX/ 
XXXXXXX/ 
XXXXXX 
 
Eye 
ASTIGMATISM 
Current 
 
 
 
 
 
 
Ambrisentan 
5mg 
XXXXXX/ 
XXXXXX 
XX/ 
XXXXXXX/ 
XXXXXX 
 
Metabolism and 
nutrition 
RICKETS 
Current 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  Subjects are considered as belonging to the treatment group according to the highest dose received. 
 
USER ID: Directory/Program.sas Date Time  
 
 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Safety 
 
Listing 3.16:  Listing of Liver Biopsy Details 
 
Treatment: Ambrisentan 2.5mg 
 
Centre ID/ 
Subject ID 
 
 
 
Age (y)/ 
Sex/ 
Race/ 
 
Event that 
reached or 
exceeded protocol 
defined criteria 
 
 
 
 
Biopsy Date/ 
Study Day 
 
 
 
 
Biopsy 
Size 
(mm) 
 
 
 
 
 
 
Liver biopsy test 
 
 
 
 
 
 
Liver biopsy result 
 
 
 
 
 
 
 
XXXXXX/ 
XXXXXX 
XX/ 
XXXXXXXXXXXXX 
DDMMMYYYY/ 
X 
Bile ducts 
Other: Bile ducts blocked 
 
XXXXXX/ 
 
XX 
 
Final diagnosis 
Alcoholic hepatic cirrhosis 
 
XXXXXX/ 
 
 
 
Description of liver cells/hepatocytes 
Normal 
 
XX 
 
 
 
Liver cell/hepatocyte inclusion/vacuole 
No inclusions 
 
 
 
 
 
Hepatocyte/liver cell nuclear abnorm 
None 
 
 
 
 
 
Etc.. 
 
 
 
 
 
 
 
 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  Subjects are considered as belonging to the treatment group according to the highest dose received. 
 
USER ID: Directory/Program.sas Date Time  
 
Programming notes: Present each treatment group and Centre/Subject ID. Sort by treatment group, Centre ID, Subject ID.


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Safety 
 
Listing 3.17:  Listing of Liver Imaging Details 
 
Treatment: Ambrisentan 2.5mg 
 
Centre ID/ 
Subject ID 
 
 
 
Age (y)/ 
Sex/ 
Race/ 
 
Event that 
reached or 
exceeded protocol 
defined criteria 
 
 
 
 
Imaging Date/ 
Study Day 
 
 
 
 
Liver 
imaging 
method 
 
 
 
 
Are images 
technically 
adequate? 
 
 
 
 
 
 
Liver imaging test 
 
 
 
 
 
 
Liver imaging result 
 
 
 
 
 
 
 
 
XXXXXX/ 
XXXXXX 
XX/ 
XXXXXXXXXXXXX 
DDMMMYYYY/ 
X 
XX 
Liver Size 
Hypertrophy (or enlarged) 
 
XXXXXX/ 
 
XX 
 
 
Liver Texture 
Normal 
 
XXXXXX/ 
 
 
 
 
Liver fatty infiltrate grade 
Not applicable – No fatty 
infiltration 
 
XX 
 
 
 
 
Ascites present 
None present 
 
 
 
 
 
 
Focal hepatic lesions character 
Not applicable – no hepatic 
lesions 
 
 
 
 
 
 
Gallstones or gallbladder lesions 
None 
 
 
 
 
 
 
Biliary ductal lesions 
None 
 
 
 
 
 
 
Portal/Hepatic vein abnormalities 
None 
 
 
 
 
 
 
 
 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  Subjects are considered as belonging to the treatment group according to the highest dose received. 
 
USER ID: Directory/Program.sas Date Time  
 
Programming notes: Present each treatment group and Centre/Subject ID. Sort by treatment group, Centre ID, Subject ID. 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Safety 
 
Listing 3.18:  Listing of Vital Signs 
 
Treatment: Ambrisentan 2.5mg 
 
Centre ID/ 
Subject ID 
 
 
 
 
Age(y)/ 
Sex/ 
Race 
 
 
 
 
 
 
Visit 
 
 
 
 
Visit 
Date/ 
Study Day 
Systolic 
Blood 
Pressure 
(mmHg)/ 
Change 
from 
Baseline 
Diastolic 
Blood 
Pressure  
(mmHg)/ 
Change 
from 
Baseline 
 
Heart 
Rate 
(bpm)/  
Change 
from 
Baseline 
 
 
Height 
(units)/ 
Change 
from 
Baseline 
 
 
Weight 
(units)/ 
Change 
from 
Baseline 
 
 
BMI 
(units)/ 
Change 
from 
Baseline 
 
 
BSA 
(units)/ 
Change 
from 
Baseline 
 
 
 
 
 
 
 
 
 
 
 
XXXXXX/ 
XXXXXX 
XX/ 
XXXXXX/ 
Baseline 
** 
DDMMMYYYY/ 
XX 
XX 
XX 
XX  
XX 
XX 
XX  
XX  
 
XXXXXX Entry 
Visit * 
DDMMMYYYY/ 
XX 
XX/ 
XX 
XX/ 
XX 
XX/ 
XX 
XX/ 
XX 
XX/ 
XX 
XX/ 
XX 
XX/ 
XX 
 
 
XXXXXXX 
DDMMMYYYY/ 
XX 
XX/ 
XX 
XX/ 
XX 
XX/ 
XX 
XX/ 
XX 
XX/ 
XX 
XX/ 
XX 
XX/ 
XX 
 
 
 
 
 
 
 
 
 
 
 
 
 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  ** Baseline is the last value recorded prior to start of study treatment from AMB112529. 
       * Entry Visit is at entry to AMB114588. 
       H=Above clinical concern, L=Below clinical concern,  
       Change from Baseline HC=Above clinical concern, LC=Below clinical concern  
       Subjects are considered as belonging to the treatment group according to the highest dose received. 
 
USER ID: Directory/Program.sas Date Time  
 
Programming notes: Present each treatment group, Centre/Subject ID and time-point. Sort by treatment group, Centre ID, Subject ID and time-point. 
 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Safety 
 
Listing 3.20:  Listing of Physical Examination 
Treatment: Ambrisentan 2.5mg 
 
Centre ID/ 
Subject ID 
Age(y)/ 
Sex/ 
Race 
 
 
Visit 
Visit 
Date/ 
Study Day 
 
Liver 
Size 
Jugular 
Venous 
Pressure 
 
 
Ascites 
 
Peripheral 
Oedema 
Saturated 
Oxygen 
(units) 
 
 
 
 
 
 
 
 
 
XXXXXX/ 
XXXXXX 
XX/ 
XXXXXX/ 
Entry 
Visit * 
DDMMMYYYY/ 
XX 
XXXXXX XXXXXXXX 
XXXXXXX 
XXXXXXX 
XX.XXX 
 
XXXXXX 
XXXXXXX 
DDMMMYYYY/ 
XX 
XXXXXX XXXXXXXX (I) XXXXXXX 
XXXXXXX 
XX.XXX 
 
 
XXXXXXX 
DDMMMYYYY/ 
XX 
XXXXXX XXXXXXXX 
XXXXXXX (W) XXXXXXX 
XX.XXX 
 
 
XXXXXXX 
DDMMMYYYY/ 
XX 
XXXXXX XXXXXXXX (U) XXXXXXX 
XXXXXXX 
XX.XXX 
 
 
 
 
 
 
 
 
 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  * Entry Visit is at entry to AMB114588. 
       I=Improved, W=Worsened, U=Unchanged 
       Subjects are considered as belonging to the treatment group according to the highest dose received. 
USER ID: Directory/Program.sas Date Time  
 
Programming notes: Present each treatment group, Centre/Subject ID and time-point. Sort by treatment group, Centre ID, Subject ID and time-point. 
 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Safety 
 
Listing 3.21:  Listing of 12-Lead ECG Findings 
 
Treatment: Ambrisentan 2.5mg 
 
Centre ID/ 
Subject ID 
 
Age(y)/ 
Sex/ 
Race 
 
 
 
Visit 
 
 
Visit Date/ 
Study Day 
 
 
 
Result 
 
 
 
 
 
XXXXXX/ 
XXXXXX 
XX/ 
XXXXXX/ 
Baseline 
** 
DDMMMYYYY/ 
XX 
XXXXXXXXXXXXX 
 
XXXXXX 
Entry 
Visit * 
DDMMMYYYY/ 
XX 
XXXXXXXXXXXXX 
 
 
XXXXXXX 
DDMMMYYYY/ 
XX 
XXXXXXXXXXXXX 
 
 
 
 
 
 
 
Etc.. 
 
 
 
 
 
 
 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  ** Baseline is the last value recorded prior to start of study treatment from AMB112529. 
       * Entry Visit is at entry to AMB114588. 
      Subjects are considered as belonging to the treatment group according to the highest dose received. 
 
USER ID: Directory/Program.sas Date Time  
 
Programming notes: Present each treatment group, Centre/Subject ID and time-point. Sort by treatment group, Centre ID, Subject ID and time-point. 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Safety 
 
Listing 3.22:  Listing of Endocrinology Assessments 
 
Treatment: Ambrisentan 2.5mg 
 
Centre ID/ 
Subject ID 
 
Age(y)/ 
Sex/ 
Race 
 
 
 
Visit 
Endocrinology 
Assessment 
Date/ 
Study Day 
 
 
 
Assessment Type 
 
 
Assessment 
Result 
 
 
 
 
 
 
XXXXXX/ 
XXXXXX 
XX/ 
Male/ 
Baseline 
** 
DDMMMYYYY/ 
XX 
Testicular volume 
Right/Left (units) 
XXX / XXX 
 
XXXXXX 
 
 
Male genital 
development  
XXXXXXXXXX
XXX 
 
 
 
 
Male pubic hair 
development  
XXXXXXXXXX
XXX 
 
 
 
 
 
 
 
 
Entry 
Visit * 
DDMMMYYYY/ 
XX 
Testicular volume 
Right/Left (units) 
XXX / XXX 
 
 
 
 
Male genital 
development  
XXXXXXXXXX
XXX 
 
 
 
 
Male pubic hair 
development  
XXXXXXXXXX
XXX 
 
 
Etc.. 
 
 
 
 
 
 
 
 
 
XXXXXX/ 
XXXXXX 
XX/ 
Female/ 
XXXXXXX 
DDMMMYYYY/ 
XX 
Female breast 
development 
XXXXXXXXXX
XXX 
 
XXXXXX 
 
 
Female pubic hair 
development 
XXXXXXXXXX
XXX 
 
 
Etc.. 
 
 
 
Etc.. 
 
 
 
 
 
 
Note:  ** Baseline is the last value recorded prior to start of study treatment from AMB112529. 
       * Entry Visit is at entry to AMB114588. 
       Subjects are considered as belonging to the treatment group according to the highest dose received. 
For some patients, pubertal development assessments were not repeated at 20 years of age if pubertal maturity had been reached in a previous visit. 
 
 
USER ID: Directory/Program.sas Date Time  
 
Programming notes: Present each treatment group, Centre/Subject ID and time-point. Sort by treatment group, Centre ID, Subject ID and time-point. 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Safety 
 
Listing 3.24:  Listing of Pregnancy Results 
 
Treatment: Ambrisentan 2.5mg 
 
Centre ID/ 
Subject ID 
 
 
Age(y)/ 
Race 
 
 
 
Visit 
 
 
Visit Date/ 
Study Day 
 
 
 
Result 
 
 
Subject became 
pregnant? 
 
 
 
 
 
 
XXXXXX/ 
XXXXXX 
XX/ 
XXXXXX/ 
XXXXXXX 
DDMMMYYYY/ 
XX 
XXXXXXXXXXXXX 
No 
 
XXXXXX 
XXXXXXX 
DDMMMYYYY/ 
XX 
XXXXXXXXXXXXX 
 
 
 
XXXXXXX 
DDMMMYYYY/ 
XX 
XXXXXXXXXXXXX 
 
 
 
 
 
 
 
 
 
Etc.. 
 
 
 
 
 
 
 
 
 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  Subjects are considered as belonging to the treatment group according to the highest dose received. 
 
USER ID: Directory/Program.sas Date Time  
 
Programming notes: Present each treatment group, Centre/Subject ID and time-point. Sort by treatment group, Centre ID, Subject ID and time-point.  


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Safety 
 
Listing 3.25:  Listing of Endocrinology Parameters - 20 Year Visit 
 
Treatment: Ambrisentan 2.5mg 
 
Centre 
ID/ 
Subject 
ID 
Age(y)/ 
Sex/ 
Race 
20 Year Visit 
Date/ 
20 Year Visit  
Endocrine   Assessment Type 
Assessment 
Date/Day      
Assessment 
Result 
 
 
 
Converted Data 
 
 
 
 
 
Value 
Normal Range 
XXXXXX/ 
XXXXXX 
XX/ 
XXXXXX/ 
DDMMMYYYY/ 
20 Years Old 
DDMMMYYYY/  Total Testosterone 
XX 
XXXXXXXXXXXXX 
 
 
 
XXXXXX 
 
DDMMMYYYY/  Luteinizing Hormone 
XX 
XXXXXXXXXXXXX 
 XXX  
 XXX – XXX  
 
 
 
DDMMMYYYY/  etc. 
XX 
XXXXXXXXXXXXX 
 XXX  
 XXX – XXX 
 
 
 
 
 
 XXX  
 XXX – XXX 
XXXXXX/ 
XXXXXX 
XX/ 
XXXXXX/ 
DDMMMYYYY/ 
20 Years Old 
DDMMMYYYY/  Total Testosterone 
XX 
XXXXXXXXXXXXX 
 XXX  
 XXX – XXX 
 
XXXXXX 
 
DDMMMYYYY/  Luteinizing Hormone 
XX 
XXXXXXXXXXXXX 
 XXX  
 XXX – XXX 
 
 
 
 
 
 
Note:  Endocrinology assessments are only displayed for subjects who completed their 20-year visit and for which endocrinology parameters are available. 
 
USER ID: Directory/Program.sas Date Time  
 
Programming notes: a listing that only include those subjects with a 20 Year Old Visit have the columns below i.e the ID/Sex/Last Visit Date/Last Visit/last Visit with Endo labs and the date, and then all 
the endo labs on that date.   
Listing of and all Endo labs on that date - endocrine parameters (Follicle Stimulating Hormone, Luteinizing Hormone, Sex Hormone Binding Globulin, Total Testosterone and Inhibin B)  
 
 
 
 


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Population: Intent-to-Treat 
 
Listing 3.26 
Country Level Listing of Start Dates of COVID-19 Pandemic Measures   
Country  
Pandemic Measures  
Start Date 
 
 
Overall [1] 
2020-01-01 
 
 
Italy 
2020-01-01 
Germany 
2020-02-12 
 
etc 
2020-03-12 
 
 
 
[1] The Overall row reflects the earliest pandemic measures start date. 
  
/Directory/program.sas  01JAN2002 12:01 
Programming Note:  Please list participating countries only 
  
 
 
 


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Protocol: AMB114588                                                                              
Page 1 of 1 
Population: Intent-to-Treat 
 
Listing 3.27 
 
Listing of Visits and Assessments Impacted by COVID-19 Pandemic 
Site Id.: 
Country: Brazil 
Treatment 
Unique Subject 
Id./ 
Subject Id. 
Impacted 
Visit 
Impact 
Primary Reason for Impact 
 
 
 
 
Trt A
Visit 6 
MISSED VISIT 
SUBJECT RELATED IMPACT [2] 
Visit 7 
REMOTE VISIT WITH NO ASSESSMENTS MISSED 
SITE RELATED IMPACT [3] 
 
 
 
 
Trt B
Visit 4 
SITE VISIT WITH ONE OR MORE ASSESSMENTS 
MISSED 
SITE RELATED IMPACT [3] 
 
Visit 5 
MISSED VISIT 
SUBJECT ACQUIRED COVID-19 INFECTION [1] 
 
 
 
 
 
 
[1] Subject acquired COVID-19 includes suspected, probable and confirmed. 
  
[2] Subject related impact include subject discretion and travel restrictions. 
  
[3] Site related impacts include site temporarily closed, site staff unavailable, and study drug unavailable. 
  
/Directory/program.sas  01JAN2002 12:01   
  
  
 
 
 
PPD
PPD


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Protocol: AMB114588                                                                              
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Population: Safety 
Listing 3.28 
Listing of COVID-19 Assessments and Symptom Assessments for Subjects with COVID-19 Adverse Events 
Treatment: xxxxx 
 
 
Centre ID/ 
Subject ID 
Adverse Event 
AE Start Date 
COVID-19 
Case 
Diagnosis 
[1] 
COVID-19 Test Performed/ Test 
Date/ 
Results 
Assessments and Symptom Assessments 
Result 
xxxxxxx/ 
xxxx 
Coronavirus 
infection 
2020-04-16 
Suspected 
Yes/ 
2020-04-17/ 
Indeterminate 
Travel to Location with Community 
Transmission [2] 
No 
Visited Health Care Facility [2] 
No 
 
 
 
 
 
Contact with COVID-19 Confirmed/Probable 
Case [2] 
Unknown 
Medication Taken to Treat COVID-19  
Yes 
 
 
 
 
 
Fever 
Yes 
 
 
 
 
 
Home Quarantined/Isolated 
Unknown 
COVID-19 pneumonia 
2020-05-20 
Confirmed 
Yes/ 
2020-05-22 
Positive 
Travel to Location with Community 
Transmission [2] 
Yes 
 
 
 
 
 
Visited Health Care Facility [2] 
No 
 
 
 
 
 
Contact with COVID-19 Confirmed/Probable 
Case [2] 
Yes 
 
 
 
 
 
Medication Taken to Treat COVID-19  
No 
Sore Throat  
No 
 
 
 
 
 
Loss of Smell 
Unknown 
Loss of Taste 
No 
Coronavirus infection 
2020-04-16 
Probable 
Yes/ 
2020-04-17/ 
Indeterminate 
Travel to Location with Community 
Transmission [2] 
Yes 
Visited Health Care Facility [2] 
No 
Contact with COVID-19 Confirmed/Probable 
Case [2] 
Yes 
 
 
 
 
 
Medication Taken to Treat COVID-19  
No 
Fever 
Yes 
Cough 
Yes 
Asymptomatic 
No 
Home Quarantined/Isolated 
Yes 
[1] COVID-19 Case Diagnosis is based on WHO Definition as of dd-mmm-yyyy 
[2] Within 14 days prior to symptom onset. 
 
 
/Directory/program.sas  01JAN2002 12:01 
  
  
 
 
Programming Note:  The COVID-19 AE terms include: Asymptomatic COVID-19, Coronavirus infection, COVID-19, COVID-19 pneumonia, Suspected COVID-19.  
Note that the number of COVID-19 AE terms may change  
 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Safety 
 
Figure 3.1:  Kaplan-Meier Survival Curves with 95% Confidence Bands of Time to First Treatment-Emergent Adverse Event 
 
 
 
 
 
 
 
 
 
Note:  Subjects are considered as belonging to the treatment group according to the highest dose received. 
 
USER ID: Directory/Program.sas Date Time 
 
Programming notes: Change Treatment Labels. Also present Total group. Annotate to display number of events in each group also. 
 
 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Safety 
 
Figure 3.3:  Bar Chart of Treatment-Emergent Adverse Events Occurring in Two or More Subjects in any Treatment Group 
 
 
 
 
 
 
 
 
Note:  Subjects are considered as belonging to the treatment group according to the highest dose received. 
 
USER ID: Directory/Program.sas Date Time 
 
Programming notes: Change Treatment Labels. Also present Total group. Continue for each preferred term. 
 
 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Safety 
          
 
 
Figure 3.4: Box plots of Haematology Data by Visit (Selected Parameters) 
Parameter = <Parameter (units)> 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  Subjects are considered as belonging to the treatment group according to the highest dose received. 
 
USER ID: Directory/Program.sas Date Time 
 
Programming notes: Change Treatment Labels. Also present Total group. Label vertical axes with parameter name and units. Label horizontal axis with appropriate 
visit structure. Repeat for each parameter. Haematology parameters (haemoglobin, hematocrit, platelets), Chemistry parameters (Total bilirubin, AST, ALT, GGT, 
Creatinine). Use log scale for Plasma NT-Pro BNP (Figures 2.7 and 2.8). 
 
 


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Safety 
 
Figure 3.8:  Patient Profiles of Liver Function Tests 
 
 
 
 
Note:  Subjects are considered as belonging to the treatment group according to the highest dose received. 
 
USER ID: Directory/Program.sas Date Time 
 
Programming notes: Change Treatment Labels. Also present Total group. Present parameters ALT, AST, Alk. Phos, Total Bilirubin. Present one patient per page only, 
not grid of 4 patients.  


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Protocol: AMB114588                                                                                                Page 1 of n 
Population: Safety 
 
Figure 3.11:  Line plots of Endocrinology Assessments by Subject 
 
 
Note:  Subjects are considered as belonging to the treatment group according to the highest dose received. 
 
USER ID: Directory/Program.sas Date Time 
 
Programming notes: Only one patient on a page, with a grid of plots on each page for each parameter. For Figure 3.11, plot female breast development and pubic hair 
development; male testicular volume, genital development and pubic hair development and change from baseline in male testicular volume (left and right separately). 
For Figure 2.9 (Japanese subset) plot echocardiogram parameters. For coded data, plot the numeric code and present codes on first page of the plot. 


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20. 
APPENDICES 
20.1. 
Appendix 1 – IDSL Age Calculation 
IDSL standard/GSK standard of the derivation of AGE: 
AGE = intck(‘year’,DEMO.BIRTHDT, AGEREFDT) –  
            (month(AGEREFDT) < month(DEMO.BIRTHDT) or        
               (month(AGEREFDT)=month(DEMO.BIRTHDT) and  
                    day(AGEREFDT) <  day(DEMO.BIRTHDT) 
               )); 
 
For this study, it was decided that the AGE is calculated based on the date of the baseline visit ie. 
AGEREFDT = Date of record with VISITNUM=20 in the VISIT dataset. 
BIRTHDT = derived by DM in DEMO dataset which contains imputed date for 
date of birth (ie. 30JUNYYYY) .