Clinical trial NCT04095286
Conditions: Hypertension, Pulmonary
Keywords: Ambrisentan Oral dosage forms Pulmonary arterial hypertension Bioavailability
Sponsor: GlaxoSmithKline
Start date: 2019-09-30; Completion date: 2019-12-17
Enrollment: 29 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This is a single center, open-label, randomized, single-dose, three-period cross-over study in healthy participants. The aim of this study is to provide clinically relevant information on the pharmacokinetic (PK) and safety profile of a new lower dose formulation ambrisentan (AMB) tablet, which is intended for pediatric use. The study will compare the relative bioavailability of the lower dose tablet, dispersed in water and administered orally, with the reference marketed AMB tablet in healthy adults. The total study duration for each participant is expected to be approximately 9 weeks.

Detailed description:

Arms: arm 1: Eligible participants will receive a single oral dose of 5 milligram (mg) AMB tablet dispersed in water during treatment period 1 followed by a single dose of 5 mg AMB oral tablet in treatment period 2. In treatment period 3, participants will receive a single oral dose of reference 5 mg AMB tablet. There will be a washout period of 7 days between doses in each treatment period. arm 2: Eligible participants will receive single dose of 5 mg AMB oral tablet during treatment period 1 followed by single dose of reference 5 mg AMB oral tablet in treatment period 2. In treatment period 3, participants will receive single dose of 5 mg AMB tablet dispersed in water. There will be a washout period of 7 days between doses in each treatment period. arm 3: Eligible participants will receive single dose of reference 5 mg AMB oral tablet during treatment period 1 followed by single dose of 5 mg AMB tablet dispersed in water in treatment period 2. In treatment period 3 participants will receive single dose of 5 mg AMB oral tablet. There will be a washout period of 7 days between doses in each treatment period. arm 4: Eligible participants will receive single dose of 5 mg AMB tablet dispersed in water during treatment period 1 followed by single dose of reference 5 mg AMB oral tablet in treatment period 2. In treatment period 3 participants will receive single dose of 5 mg AMB oral tablet. There will be a washout period of 7 days between doses in each treatment period. arm 5: Eligible participants will receive single dose of 5 mg AMB oral tablet during treatment period 1 followed by single dose of 5 mg AMB tablet dispersed in water in treatment period 2. In treatment period 3 participants will receive single dose of reference 5 mg AMB oral tablet. There will be a washout period of 7 days between doses in each treatment period. arm 6: Eligible participants in this arm will receive single dose of reference 5 mg AMB oral tablet during treatment period 1 followed by single dose of 5 mg AMB oral tablet in treatment period 2. In treatment period 3 participants will receive single dose of 5 mg AMB tablet dispersed in water There will be a washout period of 7 days between doses in each treatment period.
Interventions: intervention 1: AMB new formulation (1 mg) intervention 2: Reference AMB (5 mg)
Intervention descriptions: intervention 1: AMB tablets will be available at a unit dose strength of 1 mg. Participants will orally administer 5 tablets of 1 mg unit dose. intervention 2: AMB reference tablet will be available as film-coated tablet at unit dose strength of 5 mg. Participants will orally administer 1 tablet of 5 mg unit dose

Protocol documents:
Prot_000.pdf: 
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TITLE PAGE
Protocol Title: An open-label, randomized three period cross-over relative 
bioavailability study to compare the pharmacokinetic parameters of a lower dose
formulation of ambrisentan (GSK1325760) with marketed ambrisentan in healthy adult 
participants
Protocol Number: 205019
Compound Number:
GSK1325760
Study Phase: Phase 1
Short Title:  Relative bioavailability study of marketed and lower dose ambrisentan in 
healthy adult participants
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Medical Monitor Name and Contact Information can be found in the Study 
Reference Manual
Regulatory Agency Identifying Number(s):
EudraCT:  2019-001699-12
Approval Date: 19-JUN-2019
Copyright 2019 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SUMMARY..........................................................................................6
1.1.
Synopsis.......................................................................................................6
1.2.
Schema ........................................................................................................8
1.3.
Schedule of Activities (SoA)..........................................................................9
1.3.1.
Screening and Follow-up Schedule of Activities.............................9
1.3.2.
Treatment Periods 1, 2 and 3 (minimum of 7 days 
washout between doses) .............................................................10
2.
INTRODUCTION....................................................................................................12
2.1.
Study Rationale ..........................................................................................12
2.2.
Background ................................................................................................12
2.3.
Benefit/Risk Assessment ............................................................................14
2.3.1.
Risk Assessment .........................................................................15
2.3.2.
Benefit Assessment.....................................................................16
2.3.3.
Overall Benefit: Risk Conclusion..................................................16
3.
OBJECTIVES AND ENDPOINTS...........................................................................16
4.
STUDY DESIGN ....................................................................................................16
4.1.
Overall Design ............................................................................................16
4.2.
Scientific Rationale for Study Design ..........................................................17
4.3.
Justification for Dose ..................................................................................17
4.4.
End of Study Definition ...............................................................................18
5.
STUDY POPULATION...........................................................................................18
5.1.
Inclusion Criteria.........................................................................................18
5.2.
Exclusion Criteria........................................................................................19
5.3.
Lifestyle Considerations..............................................................................21
5.3.1.
Meals and Dietary Restrictions ....................................................21
5.3.2.
Caffeine, Alcohol, and Tobacco ...................................................21
5.3.3.
Activity .........................................................................................22
5.4.
Screen Failures...........................................................................................22
6.
STUDY INTERVENTION........................................................................................22
6.1.
Study Intervention(s) Administered .............................................................22
6.2.
Preparation/Handling/Storage/Accountability..............................................23
6.3.
Measures to Minimize Bias: Blinding and Randomization ...........................24
6.3.1.
Blinding........................................................................................24
6.3.2.
Randomization.............................................................................24
6.3.3.
Treatment Sequences..................................................................24
6.4.
Study Intervention Compliance ...................................................................25
6.5.
Concomitant Therapy..................................................................................25
6.6.
Dose Modification .......................................................................................26
6.7.
Intervention after the End of the Study........................................................26
7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL.....................................................................26
7.1.
Discontinuation of Study Intervention..........................................................26
7.1.1.
Liver Chemistry Stopping Criteria ................................................26
 
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7.1.1.1.
Study Intervention Restart or Rechallenge after 
liver stopping criteria met............................................27
7.1.2.
QTc Stopping Criteria ..................................................................27
7.1.3.
Hypotension Stopping Criteria .....................................................28
7.1.4.
Haemoglobin Stopping Criteria ....................................................28
7.1.5.
Temporary Discontinuation ..........................................................28
7.2.
Participant Discontinuation/Withdrawal from the Study ...............................28
7.3.
Lost to Follow Up........................................................................................28
8.
STUDY ASSESSMENTS AND PROCEDURES .....................................................29
8.1.
Efficacy Assessments.................................................................................29
8.2.
Safety Assessments ...................................................................................30
8.2.1.
Physical Examinations.................................................................30
8.2.2.
Vital Signs....................................................................................30
8.2.3.
Electrocardiograms......................................................................30
8.2.4.
Clinical Safety Laboratory Assessments ......................................30
8.3.
Adverse Events and Serious Adverse Events.............................................31
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................31
8.3.2.
Method of Detecting AEs and SAEs.............................................32
8.3.3.
Follow-up of AEs and SAEs.........................................................32
8.3.4.
Regulatory Reporting Requirements for SAEs .............................32
8.3.5.
Pregnancy ...................................................................................32
8.4.
Treatment of Overdose...............................................................................33
8.5.
Pharmacokinetics .......................................................................................33
8.5.1.
Blood Sample Collection..............................................................33
8.5.2.
Sample Analysis ..........................................................................33
8.6.
Palatability Questionnaire ...........................................................................34
8.7.
Pharmacodynamics ....................................................................................34
8.8.
Genetics .....................................................................................................34
8.9.
Biomarkers .................................................................................................34
8.10.
Health Economics or MEDICAL Resource Utilization and Health 
Economics..................................................................................................34
9.
STATISTICAL CONSIDERATIONS........................................................................34
9.1.
Statistical Hypotheses.................................................................................34
9.2.
Sample Size Determination ........................................................................35
9.2.1.
Sample Size Assumptions ...........................................................35
9.2.2.
Sample Size Sensitivity................................................................35
9.2.3.
Sample Size Re-estimation or Adjustment...................................36
9.3.
Populations for Analyses ............................................................................36
9.4.
Statistical Analyses.....................................................................................36
9.4.1.
Pharmacokinetic Analyses...........................................................36
9.5.
Interim Analyses .........................................................................................37
9.6.
Safety Analyses..........................................................................................37
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...............................................................................................38
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations............................................................................................38
10.1.1.
Regulatory and Ethical Considerations ........................................38
10.1.2.
Financial Disclosure.....................................................................38
 
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10.1.3.
Informed Consent Process ..........................................................39
10.1.4.
Data Protection............................................................................39
10.1.5.
Dissemination of Clinical Study Data ...........................................39
10.1.6.
Data Quality Assurance ...............................................................40
10.1.7.
Source Documents ......................................................................41
10.1.8.
Study and Site Closure ................................................................41
10.1.9.
Publication Policy.........................................................................41
10.2.
Appendix 2: Clinical Laboratory Tests.........................................................42
10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................44
10.3.1.
Definition of AE............................................................................44
10.3.2.
Definition of SAE..........................................................................45
10.3.3.
Recording and Follow-Up of AE and SAE....................................46
10.3.4.
Reporting of SAE to GSK.............................................................48
10.4.
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................49
10.4.1.
Definitions:...................................................................................49
10.4.2.
Contraception Guidance: .............................................................50
10.4.3.
Collection of Pregnancy Information: ...........................................50
10.5.
Appendix 5: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................52
10.6.
Appendix 6: Abbreviations and Trademarks................................................54
10.7.
Appendix 7: Palatability Questionnaire........................................................57
11. REFERENCES.......................................................................................................58
 
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1.
PROTOCOL SUMMARY
1.1.
Synopsis
Protocol Title: An open-label, randomized three period cross-over relative 
bioavailability study to compare the pharmacokinetic parameters of a lower dose
formulation of ambrisentan (GSK1325760) with marketed ambrisentan in healthy adult 
participants
Short Title: Relative bioavailability study of marketed and lower dose ambrisentan in 
healthy adult participants
Rationale:
Adult treatments are widely used off label for treatment of pulmonary arterial 
hypertension (PAH) in children; however, conventional drug delivery methods are not 
always suitable for younger patients who have difficulties with swallowing conventional 
tablet formulations.  Therefore, the aim is to develop an ambrisentan (AMB) tablet for 
use in children <8 years, which may be dispersed in water or swallowed (dependent on 
the age or preference of the child), in order to improve patient compliance and 
acceptability, whilst maintaining safety and efficacy.  
The primary objective of this study is to provide clinically relevant information on the 
pharmacokinetic (PK) and safety profile of a new lower dose formulation AMB tablet, 
which is intended for paediatric use.  The study will compare the relative bioavailability 
of the lower dose tablet, dispersed in water and administered orally, with the reference 
marketed AMB tablet in healthy adults. This study is part of a Paediatric Investigational 
Plan (PIP) agreed with the European Medicines Agency’s Paediatric Committee (PDCO).
Objectives and Endpoints:
Objective
Endpoint
Primary

To compare the relative bioavailability of 
AMB (1 mg x 5 tablets) as tablets
dispersed in water or administered orally,
with marketed AMB (5 mg x 1 tablet)
administered orally, in healthy adult 
participants under fasted conditions.

Plasma pharmacokinetic parameters of 
AMB, as data permit: Cmax, tmax, AUC (0-
∞), AUC(0-t)and t½.
 
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Objective
Endpoint
Secondary

To monitor the safety and tolerability of 
AMB (1 mg x 5 tablets) as tablets 
dispersed in water or administered orally,
compared with marketed AMB (5 mg x 1 
tablet) administered orally, in healthy 
adult participants.

Adverse events (AE), vital signs, 
electrocardiogram (ECG), and clinical 
laboratory values
Overall Design:
This is a single centre, open-label, randomised, single dose, 3-period cross over study in 
healthy participants to compare the PK of a new lower dose formulation AMB tablet 
(dispersed in water and administered orally) with the reference marketed AMB tablet
(administered orally).
Disclosure Statement: This is a cross-over relative bioavailability study with 3 arms
with no masking.
Number of Participants:
Approximately 24 participants will be randomly assigned to study intervention, such that 
20 evaluable participants complete the study. 
Intervention Groups and Duration:
Each participant will have 3 treatment periods (single oral doses), and will be randomised 
to one of the following study interventions in each period:
Test 1 (F1):  5 mg (5 x 1 mg tablets) AMB tablet dispersed in water
Test 2 (F2):  5 mg (5 x 1 mg tablets) AMB tablet administered orally
Reference (R):  5 mg (1 x 5 mg tablet) AMB tablet administered orally
Each participant will:
be screened (within 28 days of their first dose);
have 3 treatment periods (3 overnight clinic stays, and 1 out-patient visit per treatment 
period) with a minimum of 7 days between doses in each treatment period; and
have a follow-up visit (within 7 to 14 days after their last dose). The total study 
duration for each participant is expected to be approximately 9 weeks. 
Data Monitoring Committee: No
 
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1.2.
Schema
Fasted from midnight prior to dose to 4 
hours post dose
Follow up
(7-14 days post 
last dose)
Screening
(Up to 28 days 
before first dose)
Treatment 
Period 1
72 hours
Treatment 
Period 2
72 hours
Treatment 
Period 3
72 hours
7 Day
washout 
between 
doses
7 Day
washout 
between 
doses
 
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1.3.
Schedule of Activities (SoA)
1.3.1.
Screening and Follow-up Schedule of Activities 
Procedure 
Screening1
(up to 28 days before first 
dose)
Follow up/Early Withdrawal
(7-14 days post last dose)
Notes
Informed consent
X
Inclusion and exclusion criteria
X
Demography
X
Medical history (includes substance usage)
X
Substances: Drugs, Alcohol, tobacco
Full physical exam, including height and weight
X
Brief physical exam
X
HIV, Hep B and Hep C screen
X
Clinical chemistry, haematology and urinalysis 
X
X
Only screening tests need to be fasted
FSH
X
Required only in women to confirm postmenopausal status
Alcohol breath test 
X
Urine drugs test
X
Vital signs (blood pressure, heart rate and 
temperature)
X
X
Triplicate blood pressure and heart rate required at 
screening. 
12-lead ECG
X
X
Triplicate ECG required at screening.
Concomitant Medication review 
X
X
Con meds before dosing can be recorded in medical 
history
AE/SAE review
X
X
Refer to Section 8.3.1
1.
Screening assessments may be conducted at multiple visits, if required.
 
 
 
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1.3.2.
Treatment Periods 1, 2 and 3 (minimum of 7 days washout between doses)
Procedure
Day –1
Day 1 (hours)
Day 2
Day 3 Day 4
Notes
Pre-
dose
0
0.5
1
1.5
2
2.5
4
8
12
18
24
36
48
72
Clinic Visits
Out-patient Visit
X
Admission to clinic
X
Discharge from clinic 
X
If more convenient for participants, 
they can remain in the unit until 
72 h, at the discretion of the 
investigator
Study Intervention
Randomisation
X
Can be done on Day –1 or Pre-
dose Day 1.  Only in Treatment 
Period 1
Study Intervention
X
Fasted from midnight until 4 h 
post-dose, except for water, 
allowed ad libitum, except for 1 h 
before and after dosing
Safety Assessments
Vital signs (blood pressure, 
heart rate and temperature)
X
X
X
X
X
X
X
X
X
X
Triplicate pre-dose. Single 
measurements at other timepoints, 
unless out of range, then 
triplicates should be performed
12-lead ECG
X
X
X
X
X
X
X
Clinical chemistry, 
haematology and urinalysis 
X
X
Fasting not required
Brief physical examination
X
Alcohol breath test 
X
Urine drugs test
X
 
 
 
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Procedure
Day –1
Day 1 (hours)
Day 2
Day 3 Day 4
Notes
Pre-
dose
0
0.5
1
1.5
2
2.5
4
8
12
18
24
36
48
72
Concomitant Medication 
◄==================================================================================►
Con meds before dosing can be 
recorded in medical history
SAE/AE review
◄==================================================================================►
Refer to Section 8.3.1
Other Assessments
PK blood samples
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Palatability Questionnaire
X
Questionnaire only to be 
completed in the Treatment Period 
dosing AMB tablets dispersed in 
water. To be completed within 10 
min of dosing 

When scheduled at the same time-points, 12-lead ECGs and vital signs should be completed before any blood draws.

The timing of assessments should allow PK samples to be taken as close as possible to the nominal time-point.

The timing and number of planned safety assessments and pharmacokinetic samples may be altered during the course of the 
study based on newly available data (e.g., to obtain data closer to the time of peak plasma concentrations) to ensure appropriate 
monitoring. 

Any changes in the timing or addition of time points for any planned study assessments as the result of emerging 
pharmacokinetic data from this study must be documented and approved by the relevant study team member and then archived in 
the sponsor and site study files but will not constitute a protocol amendment. The Competent Authority (CA) and ethics 
committee (EC) will be informed of any safety issues that constitute a substantial amendment and require alteration of the safety 
monitoring scheme or amendment of the informed consent form (ICF). The changes will be approved by the CA and the EC 
before implementation.
 
 
 
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2.
INTRODUCTION
Ambrisentan (AMB) (Volibris tablets) is an oral, once daily, propanoic acid-based, 
Endothelin Receptor Antagonist (ERA), which is selective for Endothelin Receptor 
Type A.  AMB targets the phospholipase-C-dependent endothelin pathway, which is 
known to play an essential role in mammalian cardiovascular physiology.  It is indicated 
for treatment of pulmonary arterial hypertension (PAH) in adult patients of World Health 
Organization (WHO) Functional Class (FC) II to III, to improve exercise capacity, 
decrease the symptoms of PAH, and delay clinical worsening, including use in 
combination treatment. Efficacy has been shown in idiopathic PAH (IPAH) and in PAH 
associated with connective tissue disease [Volibris, 2018]. AMB is marketed in the 
European Union (EU), Japan and over thirty further countries by GlaxoSmithKline 
(GSK), and in the United States (US) by Gilead Sciences Inc, as Letairis.
2.1.
Study Rationale
Adult treatments are widely used off label for treatment of PAH in children; however,
conventional drug delivery methods are not always suitable for younger patients who 
have difficulties with swallowing conventional tablet formulations.  Therefore, the aim is 
to develop an AMB tablet for use in children <8 years, which may be dispersed in water
or swallowed (dependent on the age or preference of the child), in order to improve 
patient compliance and acceptability, whilst maintaining safety and efficacy.
The primary objective of this study is to provide clinically relevant information on the PK
and safety profile of a new lower dose formulation AMB tablet, which is intended for 
paediatric use. The study will compare the relative bioavailability of the lower dose 
tablet, dispersed in water and administered orally, with the reference marketed AMB
tablet in healthy adults. This study is part of a Paediatric Investigation Plan (PIP) agreed 
with the European Medicines Agency’s Paediatric Committee (PDCO).
An exploratory objective of this study is to assess the palatability of the new lower dose 
formulation AMB tablet dispersed in water.  
2.2.
Background
PAH is a rare, progressive, highly debilitating and life-threatening disease characterized 
by pulmonary vascular functional and structural changes resulting in increased 
pulmonary vascular resistance (PVR) and eventual right-sided heart failure (RHF) and 
premature death [Moledina, 2010; Newman, 2004; Vorhies, 2014].
Epidemiological data estimates PAH incidence in Europe ranges from 1.1 to 7.6 per 
million; prevalence ranges from 6.6 to 26 per million [Hoeper, 2016]. 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 IPAH 
management and survival in the UK, the incidence was 0.48 cases per million children 
per year, and the prevalence was 2.1 cases per million children [Moledina, 2010].
 
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Despite the emergence of new treatments, PAH still has a poor long-term prognosis (akin 
to many cancers). A recent meta-analysis estimates survival for untreated 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].
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 remodeling and pulmonary 
vasoconstriction. Although its role is not fully understood, endothelin is considered 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 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.
Treatments currently approved for the treatment of PAH target 3 biological pathways: 
endothelin, nitric oxide, and prostacyclin pathways. 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, or multiple inhalations) present substantial challenges to their 
successful use in a pediatric population.
The efficacy profile of AMB in adults is broadly comparable with other targeted oral 
treatments, but it has potentially important advantages. AMB is associated with a
favourable liver safety profile and a low risk of drug-drug interactions. Data from the 
TRAX1 database indicates that the risk of elevated aminotransferases with bosentan 
(another marketed ERA) is lower in children than adults [Beghetti, 2008]. Nevertheless, 
the liver safety profile of AMB in adults has been favorable to bosentan, 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 AMB, may provide a 
therapeutic option that simplifies treatment in this complex disease.
A detailed description of the pharmacology, efficacy, and safety of AMB is provided in 
the Volibris European Medicines Agency (EMA) Summary of Product Characteristics
[SmPC, 2018].
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 hospitalization [Segal, 2005].
 
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2.3.
Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of AMB (GSK1325760) may be found in the 
Volibris EMA Summary of Product Characteristics [SmPC, 2018].
 
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2.3.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) AMB (GSK1325760)
Identified and potential risks, from European Union Risk 
Management Plan (EURMP) for Volibris:
Teratogenicity
Decreased haemoglobin/haematocrit, anaemia, including 
anaemia requiring transfusion
Hepatotoxicity
Testicular tubular atrophy/Male infertility
Consistent with the mechanism of action for AMB, there is a 
potential risk of hypotension in healthy participants.

Refer to EURMP for Volibris v8.1
(EURMP, 2019)

Refer to Volibris EMA Summary of 
Product Characteristics (SmPC, 
2018)
Exclusion criteria, ongoing safety 
assessments, study design and medical
supervision.  Specifically:
The use of single doses in this study.
Exclusion of women of child bearing 
potential.
Exclusion of potentially anaemic 
participants.
Haemoglobin reduction withdrawal 
criterion for individual participants.
Inclusion criteria to prevent enrolment of 
hypotensive participants.
Hypotension withdrawal criterion for 
individual participants.
Laboratory assessments per protocol.
Physical assessment per protocol.
Routine vital signs per protocol.
Participants remain in the clinical unit, 
under medical supervision, for all doses
and until completion of safety 
assessments at 48 hrs post dose.
Study Procedures
Risk associated with blood draws
Fainting, mild pain, bruising, irritation 
or redness at phlebotomy site, may be 
associated with blood draws.
Experienced site staff will follow standard 
approaches for managing events related to 
blood draws.
 
 
 
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2.3.2.
Benefit Assessment
There is no clinical benefit for healthy participants taking part in this study. However, 
participants will undergo a medical evaluation during screening (including a physical 
examination, electrocardiogram (ECG), vital signs and laboratory assessments), which 
may provide important health information.  
2.3.3.
Overall Benefit: Risk Conclusion
Taking into account the measures taken to minimize risk to participants participating in 
this study, the potential risks identified in association with AMB are justified by the 
anticipated benefits that may be afforded to paediatric patients with PAH.
3.
OBJECTIVES AND ENDPOINTS
Objective
Endpoint
Primary

To compare the relative bioavailability of 
AMB (1 mg x 5 tablets) administered as 
tablets dispersed in water or administered 
orally, with marketed AMB (5 mg x 1 
tablet) administered orally, in healthy 
adult participants under fasted conditions.

Plasma pharmacokinetic parameters of 
AMB, as data permit:  Cmax, tmax, AUC (0-
∞), AUC(0-t)and t½.
Secondary

To monitor the safety and tolerability of 
AMB (1 mg x 5 tablets) administered as 
tablets dispersed in water or administered 
orally, compared with marketed AMB 
(5 mg x 1 tablet) administered orally, in 
healthy adult participants.

Adverse events (AE), vital signs, 
electrocardiogram (ECG), and clinical 
laboratory values. 
Exploratory

To investigate palatability of AMB (1 mg x 
5 tablets) dispersed in water, in healthy 
adult participants.

Palatability questionnaire scores 
4.
STUDY DESIGN
4.1.
Overall Design
This is a single centre, open-label, randomised, single dose, 3-period cross over study in 
healthy participants to compare the PK of a new lower dose formulation AMB tablet
 
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(dispersed in water and administered orally) with the reference marketed AMB tablet
(administered orally).  Each participant will have 3 treatment periods (single oral doses), 
and be randomised to one of the following study interventions in each period:
Test 1 (F1):  5 mg (5 x 1 mg tablets) AMB tablet dispersed in water
Test 2 (F2):  5 mg (5 x 1 mg tablets) AMB tablet administered orally
Reference (R):  5 mg (1 x 5 mg tablet) AMB tablet administered orally
Each participant will:
be screened (within 28 days of their first dose);
have 3 treatment periods (3 overnight clinic stays, and 1 out-patient visit per treatment 
period), with a minimum of 7 days between doses in each treatment period; and
have a follow-up visit (within 7 to 14 days after their last dose).
The total study duration for each participant is expected to be approximately 9 weeks. 
4.2.
Scientific Rationale for Study Design
This open-label, randomized, cross-over design is well-established for the evaluation of 
relative bioavailability of different oral dosage forms. Randomization of the treatment 
sequences is an attempt to prevent bias. No blinding or placebo control will be used, as 
these are not required for the primary study objective (PK assessment).  The washout of 
7 days between doses should eliminate the possibility of carryover of drug exposure from 
the previous dosing period, because AMB t½ is 17 h. 
4.3.
Justification for Dose
The approved doses of AMB for the treatment of adult PAH patients are 5 mg and 10 mg, 
once daily [SmPC, 2018]. AMB is not approved for the treatment of paediatric PAH 
patients. An alternate tablet that may be dispersed in water or swallowed is therefore in 
development for paediatric patients <8 years old, who may have difficulty swallowing 
tablet formulations.  The 5 mg AMB tablet has been studied in paediatric patients (8 to
18 years old) in GSK Study AMB112529 [Volibris, 2018].
The current study will compare the relative bioavailability of 5 x 1 mg tablets dispersed 
in water (administered as ‘disperse in water and immediately take’) and 5 x 1 mg tablets 
(administered orally), with that of 1 x 5 mg marketed tablet (reference) (administered 
orally).
Using the 5 mg AMB tablet as the reference dose allows assessment of the relative 
bioavailability comparison with the lower dose tablet but requires participants to take 
only 5 x 1 mg tablets – rather than 10 tablets (which would have been required if the 
10 mg AMB tablet had been selected as the reference).  This decreases the participant 
burden for the study.  The reference 5 mg AMB tablet is quantitatively proportional to the 
10 mg AMB tablet, and so, 2 x 5 mg tablets are equivalent to 1 x 10 mg tablet (Studies
EE-001, EE-002 and AMB-103) [Volibris, 2018]. 
 
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4.4.
End of Study Definition
A participant is considered to have completed the study if he/she has completed all 
phases of the study including the follow-up visit.
The end of the study is defined as the date of the last visit of the last participant in the 
study.
5.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Age
1.
Participant must be 18 to 65 years of age inclusive, at the time of signing the 
informed consent.
Type of Participant and Disease Characteristics
2.
Participants who are overtly healthy as determined by medical evaluation including 
medical history, physical examination, laboratory tests, vital signs and cardiac 
monitoring (refer to Section 5.4 for information about rescreening).
3.
Average systolic blood pressure between 100-160 mmHg and diastolic between 55-
90 mmHg (inclusive) over 3 readings at screening.
Weight
4.
Body weight 50 kg for men and ≥ 45kg for women, and body mass index (BMI) 
within the range 18-30 kg/m2 (inclusive).
Sex
5.
Male or female
a. Male participants:
Male participants are eligible to participate if they agree to the following during the 
study and for at least 13 weeks afterwards corresponding to time needed to eliminate 
study intervention (5 terminal half-lives) plus an additional 90 days (a 
spermatogenesis cycle): 
 
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
Refrain from donating sperm
PLUS either:

Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent 
OR

Must agree to use contraception/barrier, as follows:
Agree to use a male condom; and
Female partner to use an additional highly effective contraceptive method 
with a failure rate of <1% per year as described in Appendix 4.
b. Female participants:
A female participant is eligible to participate if she is not a woman of childbearing 
potential (WOCBP), as defined in Appendix 4.
Informed Consent
6.
Capable of giving signed informed consent as described in Appendix 1 which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol.
5.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, 
endocrine, haematological, or neurological disorders capable of significantly altering 
the absorption, metabolism, or elimination of drugs; constituting a risk when taking 
the study intervention or interfering with the interpretation of data
2.
History or presence of palpitations or tachyarrhythmias
3.
Haemoglobin (Hb) below the normal range (Hb <133 g/L for male participants; and 
Hb <114 g/L for female participants) 
4.
Alanine transaminase (ALT) >1.5x upper limit of normal (ULN) 
5.
Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%) 
6.
Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones)
7.
QTc >450 msec
 
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NOTES:

The QTc is the QT interval corrected for heart rate according to Bazett’s formula 
(QTcB), Fridericia’s formula (QTcF), and/or another method, machine-read or 
manually over-read.

The specific formula that will be used to determine eligibility and 
discontinuation for an individual subject should be determined prior to initiation 
of the study. In other words, several different formulae cannot be used to 
calculate the QTc for an individual subject and then the lowest QTc value used 
to include or discontinue the subject from the trial.
Prior / Concomitant Therapy
8.
Past or intended use of over-the-counter or prescription medication (including 
vitamins and dietary or herbal supplements but excluding paracetamol 2 g/day)
within 7 days (or 14 days if the drug is a potential enzyme inhibitor) or 5 half-lives 
(whichever is longer) prior to the first dose of study medication, unless approved by 
the Investigator in conjunction with GSK Medical Monitor.
Prior / Concurrent Clinical Study Experience
9.
Participation in the study would result in loss of blood or blood products in excess of 
500 mL within a 56-day period
10. Exposure to more than 4 new chemical entities within 12 months prior to the first 
dosing day
11. Current enrolment or past participation within 30 days before screening in any other 
clinical study involving an investigational study intervention or any other type of 
medical research
Diagnostics Assessments
12. Presence of Hepatitis B surface antigen (HBsAg) at screening or within 3 months 
prior to first dose of study intervention
13. Positive Hepatitis C antibody test result at screening or within 3 months prior to first 
dose of study intervention.
NOTE:  Subjects with positive Hepatitis C antibody due to prior resolved disease can be 
enrolled, only if a confirmatory negative Hepatitis C RNA test is obtained
14. Positive Hepatitis C RNA test result at screening or within 3 months prior to first 
dose of study intervention.
NOTE: Test is optional and subjects with negative Hepatitis C antibody test are not 
required to also undergo Hepatitis C RNA testing
15. Positive human immunodeficiency virus (HIV) antibody test
 
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16. Positive pre-study drug/alcohol screen
17. Regular use of known drugs of abuse
OTHER EXCLUSIONS
18. Regular alcohol consumption within 6 months prior to the study defined as: 

An average weekly intake of >14 units.  One unit is equivalent to 8 g of alcohol: 
a half-pint (~240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of 
spirits. 
19. Smoking > 5 cigarettes per week (or equivalent) and participants must be able to 
abstain from smoking for a 24-hour period prior to dose and any time whilst in the 
clinical unit.
20. Sensitivity to any of the study interventions, or components thereof, or drug or other 
allergy that, in the opinion of the investigator or medical monitor, contraindicates 
participation in the study
5.3.
Lifestyle Considerations
5.3.1.
Meals and Dietary Restrictions

Refrain from consumption of red wine, Seville oranges, grapefruit or grapefruit 
juice, pomelos, exotic citrus fruits, grapefruit hybrids, or fruit juices from 7 days
before the start of study intervention until after the final dose.

Participants will be required to fast from midnight before each dose until 4 hours 
afterwards, with the exception of water, which will be allowed ad libitum, except for 
1 hour before and after dosing. At all other times whilst participants are in the unit 
they will receive standardised meals. The timing of the meals is at the unit’s 
discretion.

Participants will be required to fast for at least 6 hours before screening laboratory 
tests.
5.3.2.
Caffeine, Alcohol, and Tobacco

During each treatment period, participants will abstain from ingesting caffeine- or 
xanthine-containing products (e.g., coffee, tea, cola drinks, and chocolate) for
24 hours before each dose until after collection of the final PK sample.

During each treatment period, participants will abstain from alcohol for 24 hours 
before each dose until after collection of the final PK sample. 

Participants who use tobacco products will be instructed that use of nicotine-
containing products (including nicotine patches and other delivery devices such as 
vaporizers) will not be permitted while they are in the clinical unit. Use of tobacco 
 
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products will not be allowed from 24 hours before each dose and whilst participants 
are in the clinic.
5.3.3.
Activity

Participants will abstain from strenuous exercise for 48 hours before each blood 
collection for clinical laboratory tests. Participants may participate in light 
recreational activities during studies (e.g., walking, watching television, reading).
5.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized into the study. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any serious adverse 
events (SAEs).
Participants who fail eligibility may be rescreened once (restriction for rescreening not 
applicable for reserves).  If rescreening is performed, participants must be assigned a 
different unique subject identification number for the rescreening, and all screening 
procedures must be repeated (unless agreed otherwise by the investigator and GSK 
medical monitor).  See the study reference manual (SRM) for more details.
In the event of out-of-range results of safety tests, the tests may be repeated once within 
the screening window.  If a retest result is again outside the reference range and 
considered clinically significant by the investigator and GSK medical monitor, the 
subject will be considered a screen failure.
6.
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol.
6.1.
Study Intervention(s) Administered
ARM Name
Test 1 (Dispersed)
Test 2 
(Administered Orally)
Reference 
(Administered Orally)
Intervention 
Name
Ambrisentan tablet
dispersed in water
(GSK1325760)
Ambrisentan tablet 
(GSK1325760)
Volibris* 5 mg film-
coated tablet
Type 
Drug
Drug
Drug
 
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ARM Name
Test 1 (Dispersed)
Test 2 
(Administered Orally)
Reference 
(Administered Orally)
Dose 
Formulation
Tablet
Tablet
Tablet
Unit Dose 
Strength(s)
1 mg
1 mg
5 mg
Dosage 
Level(s)
Single dose, 5 mg 
(5 x 1 mg)
Single dose, 5 mg 
(5 x 1 mg)
Single dose, 5 mg 
(1 x 5 mg)
Route of 
Administration
oral
oral
oral
Use
Experimental
Experimental
Experimental
IMP and NIMP
IMP
IMP
IMP
Sourcing
Provided centrally by the 
Sponsor 
Provided centrally by the 
Sponsor 
Provided centrally by the 
Sponsor 
Packaging and 
Labelling
Study Intervention will 
be provided in bottles. 
Each bottle will be 
labelled as required per 
country requirement.
Study Intervention will 
be provided in bottles. 
Each bottle will be 
labelled as required per 
country requirement.
Study Intervention will 
be provided in blister 
packs. Each blister pack
will be labelled as 
required per country 
requirement.
* Volibris is the trademarked name for ambrisentan.
Detailed instructions for dosing will be provided in the SRM.
6.2.
Preparation/Handling/Storage/Accountability
1.
The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention.
2.
Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with 
access limited to the investigator and authorized site staff.
3.
The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records).
 
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4.
Further guidance and information for the final disposition of unused study 
intervention are provided in the Study Reference Manual.
Under normal conditions of handling and administration, study intervention is not 
expected to pose significant safety risks to site staff.  Take adequate precautions to avoid 
direct eye or skin contact and the generation of aerosols or mists. In the case of 
unintentional occupational exposure notify the monitor, Medical Monitor and/or GSK 
study contact.
A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from GSK.
6.3.
Measures to Minimize Bias: Blinding and Randomization
6.3.1.
Blinding
As this is an open label study, there will be no blinding. 
6.3.2.
Randomization 
Pre-dose on Day 1 (or on Day –1, if needed), participants will be assigned a unique 
number (randomization number) in ascending numerical order. The randomization 
number encodes the participant’s assignment to one of the treatment sequences,
according to the randomization schedule generated prior to the study by the Statistics 
Department at GSK. In each Treatment Period, each participant will be dispensed study 
intervention, labelled with his/her unique randomization number.
6.3.3.
Treatment Sequences
The treatment key is shown in Table 1.
Table 1
Treatment Key
Treatment
Description
F1
5 mg (5 x 1 mg tablets) AMB tablet dispersed in water
F2
5 mg (5 x 1 mg tablets) AMB tablet administered orally
R
5 mg (1 x 5 mg tablet) AMB tablet administered orally
The treatment sequence assignments, based on the Latin Squares balanced for carry-over 
effect, are shown in Table 2.
 
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Table 2
Treatment Sequences
Number of Treatments
Sequence Assignments
Allocation ratio
6
F1 / F2 / R
F2 / R / F1
R / F1 / F2
F1 / R / F2
F2 / F1 / R
R / F2 / F1
1:1:1:1:1:1
6.4.
Study Intervention Compliance
The individual doses for a participant will be prepared from a bulk supply; therefore, the 
preparation of the dose will be confirmed by a second member of the study clinic staff. 
Participants will be dosed at the clinic and will receive study intervention directly from 
the investigator or designee, under medical supervision.  The date and time of each dose 
administered in the clinic will be recorded in the source documents.  The dose of study 
intervention and study participant identification will be confirmed at the time of dosing 
by a member of the study clinic staff other than the person administering the study 
intervention.  Study site personnel will examine each participant’s mouth to ensure that 
the study intervention was ingested.
6.5.
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrolment or receives during the study must be recorded along with:

reason for use

dates of administration including start and end dates

dosage information including dose and frequency
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
Participants must abstain from taking prescription or non-prescription drugs (including 
vitamins and dietary or herbal supplements) within 7 days (or 14 days if the drug is a 
potential enzyme inducer) or 5 half-lives (whichever is longer) before the start of study 
intervention until completion of the follow-up visit, unless, in the opinion of the 
investigator and sponsor, the medication will not interfere with the study. 
Paracetamol, at doses of 2grams/day, is permitted for use any time during the study. 
Other concomitant medication may be considered on a case-by-case basis by the 
investigator in consultation with the Medical Monitor if required.
 
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6.6.
Dose Modification
Not applicable
6.7.
Intervention after the End of the Study
As this is a healthy participant study, no intervention will be given to participants 
following the end of study. Participants will receive a follow up visit 7–14 days after 
their last dose.
7.
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1.
Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. If study intervention is permanently discontinued, the participant will not 
remain in the study.  The participant will remain at the clinic until the investigator or
delegate discharges the participant.  An early withdrawal visit should be conducted (see 
SOA).
7.1.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology.
Discontinuation of study intervention for abnormal liver tests is required when:

a participant meets one of the conditions outlined in the algorithm; or

when in the presence of abnormal liver chemistries not meeting protocol-specified 
stopping rules, the investigator believes study intervention discontinuation is in 
the best interest of the participant.
 
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Phase 1 Liver Chemistry Stopping Criteria – Liver Stopping Event Algorithm
Abbreviations: ALT = alanine transaminase; INR = international normalized ratio; SAE = serious adverse 
event; ULN = upper limit of normal.
Refer to Appendix 5 for required Liver Safety Actions and Follow up Assessments 
7.1.1.1.
Study Intervention Restart or Rechallenge after liver stopping criteria 
met
Study intervention restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study is not allowed.
7.1.2.
QTc Stopping Criteria
A participant that meets either bulleted criterion based on the average of triplicate ECG 
readings will be withdrawn from study intervention.  

QTc, QTcB, QTcF > 500 msec,

Change from baseline: QTc >60 msec

The same QT correction formula must be used for each individual participant to 
determine eligibility for and discontinuation from the study.  This formula may not 
be changed or substituted once the participant has been enrolled.

For example, if a participant is eligible for the protocol based on QTcB, then 
QTcB must be used for discontinuation of this individual participant as well.

Once the QT correction formula has been chosen for a participant’s eligibility, 
the same formula must continue to be used for that participant for all QTc data 
being collected for data analysis.  Safety ECGs and other non-protocol specified 
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
The QTc should be based on the average of triplicate ECG readings obtained over a 
brief (e.g., 5-10 minute) recording period.  
7.1.3.
Hypotension Stopping Criteria
A participant that meets the criterion below will be withdrawn from study intervention:

systolic <90 mmHg and diastolic <50 mmHg confirmed by triplicate readings (taken 
up to 5 minutes apart) and is judged clinically significant / symptomatic by the 
investigator.
7.1.4.
Haemoglobin Stopping Criteria
A participant that meets the criterion below will be withdrawn from the study 
intervention:

Decrease in haemoglobin from baseline of 10.4 g/L over the course of the study.
7.1.5.
Temporary Discontinuation
Withdrawal from study intervention will require the participant to withdraw from the 
study.
7.2.
Participant Discontinuation/Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request, or 
may be withdrawn at any time at the discretion of the investigator for safety, 
behavioural, compliance or administrative reasons. This is expected to be 
uncommon.

At the time of discontinuing from the study, if possible, an early discontinuation 
visit should be conducted, as shown in the SoA. See SoA for data to be 
collected at the time of study discontinuation and follow-up.

The participant will be permanently discontinued both from the study 
intervention and from the study at that time.

If the participant withdraws consent for disclosure of future information, the 
sponsor may retain and continue to use any data collected before such a 
withdrawal of consent.

If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site 
study records.
7.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
 
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The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee 
must make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study. 
Information regarding discontinuation of the study as a whole is given in Appendix 1.
8.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA. 

Protocol waivers or exemptions are not allowed.

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study intervention.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening 
log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 

Procedures conducted as part of the participant’s routine clinical management (e.g., 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and was 
performed within the time frame defined in the SoA.

The maximum amount of blood collected from each participant over the duration of 
the study, including any extra assessments that may be required, will not exceed 
500 mL.

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.
8.1.
Efficacy Assessments
Not applicable
 
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8.2.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA.
8.2.1.
Physical Examinations

A full physical examination will include, at a minimum, assessments of the Skin, 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. Height 
and weight will also be measured and recorded.

A brief physical examination will include, at a minimum, assessments of the 
skin, lungs, cardiovascular system, and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
8.2.2.
Vital Signs

Vital signs will be measured in a semi-supine position after 5 minutes rest and 
will include temperature, systolic and diastolic blood pressure, and pulse.

At screening and pre-dose, three readings of blood pressure and pulse will be 
taken.  At screening, the average of the three blood pressure readings will be 
used to confirm eligibility.  At all other time-points, single measurements will be 
taken, unless values go out of range, then triplicates should be performed.
8.2.3.
Electrocardiograms

An ECG machine that automatically calculates the heart rate and measures PR, 
QRS, QT, and QTc intervals will be used. Refer to Section 7 for QTc
withdrawal criteria and additional QTc readings that may be necessary.

ECGs will be recorded in a semi-supine position after 5 minutes rest.

Triplicate 12-lead ECGs will be obtained at screening and pre-dose.  At all other 
time-points, single measurements will be taken, unless values go out of range, 
then triplicates should be performed.  Triplicate ECGs should be obtained over a 
brief (e.g 5 to 10 minute) recording period.
8.2.4.
Clinical Safety Laboratory Assessments

Refer to Appendix 2 for the list of clinical laboratory tests to be performed and 
to the SoA for the timing and frequency. 

The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the CRF. The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those which 
are not associated with the underlying disease, unless judged by the investigator 
to be more severe than expected for the participant's condition.
 
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
All laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 7–14 days after the last dose of study 
intervention should be repeated until the values return to normal or baseline or 
are no longer considered significantly abnormal by the investigator or medical 
monitor. 

If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the aetiology should be identified and the sponsor 
notified.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the local laboratory manual and the SoA.
8.3.
Adverse Events and Serious Adverse Events
The definitions of an AE or SAE can be found in Appendix 3.
The investigator and any qualified designees are responsible for detecting, documenting, 
and reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study intervention or the 
study, or that caused the participant to discontinue the study (see Section 7). 
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from the start of intervention until the follow-up visit
at the time points specified in the SoA (Section 1.3).  However, any SAEs 
assessed as related to study participation (e.g., study intervention, protocol-
mandated procedures, invasive tests, or change in existing therapy) or related to 
a GSK product will be recorded from the time a subject consents to participate 
in the study.

All AEs will be collected from the start of intervention until the follow-up visit 
at the time points specified in the SoA (Section 1.3).

Medical occurrences that begin before the start of study intervention but after 
obtaining informed consent will be recorded as Medical History.

All SAEs will be recorded and reported to the sponsor or designee immediately 
and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3. The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available.

Investigators are not obligated to actively seek AEs or SAEs after the conclusion 
of the study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has been discharged from the 
study, and he/she considers the event to be reasonably related to the study 
intervention or study participation, the investigator must promptly notify the 
sponsor.
 
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8.3.2.
Method of Detecting AEs and SAEs

The method of recording, evaluating, and assessing causality of AEs and SAEs 
and the procedures for completing and transmitting SAE reports are provided in 
Appendix 3.

Care will be taken not to introduce bias when detecting AE and/or SAE. Open-
ended and non-leading verbal questioning of the participant is the preferred 
method to inquire about AE occurrence. 
8.3.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, will be followed until the event is 
resolved, stabilized, otherwise explained, or the participant is lost to follow-up (as 
defined in Section 7.3). Further information on follow-up procedures is given in 
Appendix 3.
8.3.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study intervention under clinical investigation are 
met. 

The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study intervention
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), and 
investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and 
sponsor policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or 
other specific safety information e.g., summary or listing of SAE) from the 
sponsor will review and then file it in the Investigator Site File and will notify 
the IRB/IEC, if appropriate according to local requirements.
8.3.5.
Pregnancy

Details of all pregnancies in female partners of male participants will be collected 
after the start of study intervention and until the follow-up visit.

If a pregnancy is reported, the investigator should inform GSK within 24 hours of
learning of the pregnancy and should follow the procedures outlined in Appendix 4.

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE.
 
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8.4.
Treatment of Overdose
For this study, any dose of AMB (GSK1325760) greater than the protocol defined dose
will be considered an overdose.
Due to the mechanism of action, an overdose of AMB could potentially result in 
hypotension. In case of pronounced hypotension, active cardiovascular support may be 
required. There are no specific antidotes available for AMB. 
In the event of an overdose, the investigator/treating physician should:
1.
Contact the Medical Monitor immediately.
2.
Closely monitor the participant for AE/SAE and laboratory abnormalities until AMB 
(GSK1325760) can no longer be detected systemically (at least 3 days).
3.
Obtain a plasma sample for PK analysis within 3days from the date of the last dose 
of study intervention if requested by the Medical Monitor (determined on a case-by-
case basis).
4.
Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant.
8.5.
Pharmacokinetics
8.5.1.
Blood Sample Collection
Blood samples for pharmacokinetic (PK) analysis of AMB will be collected at the time 
points indicated in the SOA (Section 1.3). The actual date and time of each blood sample 
collection will be recorded. 
For analysis of AMB, 2.7 mL of blood will be collected into sodium citrate tubes. 
Processing, storage and shipping procedures are provided in the SRM.
8.5.2.
Sample Analysis
Plasma analysis will be performed under the control of In vitro/In vivo Translation 
(IVIVT) and Third Party Resource, GlaxoSmithKline.  Concentrations of AMB will be 
determined in plasma samples using the currently approved bioanalytical method. Raw 
data will be archived at the bioanalytical site (detailed in the SRM).
Once the plasma has been analysed for AMB, any remaining plasma may be analysed for 
other compound-related metabolites and the results reported under a separate IVIVT, 
GlaxoSmithKline protocol.
 
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8.6.
Palatability Questionnaire
Participants will complete a palatability questionnaire after dosing of AMB tablets 
dispersed in water.  Participants will complete 3 short questions about the smell, taste and 
feel of the study intervention. 
Participants will be shown the questionnaire before dosing, so they know to consider the 
smell, taste and feel of the study intervention during dosing.  Participants will complete 
the questionnaire within 10 min of dosing. Refer to Appendix 7 for the palatability 
questionnaire.
8.7.
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8.
Genetics
Genetics will not be evaluated in this study.
8.9.
Biomarkers
Biomarkers are not evaluated in this study.
8.10.
Health Economics or MEDICAL Resource Utilization and 
Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study.
9.
STATISTICAL CONSIDERATIONS
9.1.
Statistical Hypotheses
No formal hypothesis will be tested. An estimation approach will be used to i) estimate 
the bioavailability of the test formulation relative to the reference formulation, and ii) for 
each primary pharmacokinetic endpoint, point estimates and corresponding 90% 
confidence intervals will be constructed for the ratio of the geometric mean of the test 
formulation to the geometric mean of the reference formulation. 
Success for this study is defined quantitatively as the observed AUC and Cmax geometric 
mean ratio of the test formulation to reference formulation falling within 0.6 to 2.5.  Both 
AUC and Cmax will be used, but AUC (average concentration) is most relevant, because 
AMB is administered chronically.
The lower and upper limits of success are defined accordingly:

Lower limit of success (based on efficacy):  PKPD analysis of adult AMB data 
(reference formulation) did not show a correlation between exposure and efficacy.  
However, the lowest approved dose (in Japan), which has shown efficacy is 2.5 mg.  
 
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Therefore, we have assumed our lower limit to be the 2.5 mg PK exposure.  In 
relation to the therapeutic dose of 5 mg (to be tested in this study), and assuming 
linearity (observed in the adult studies), a 0.5-fold change in PK exposure (AUC or 
Cmax) for the test formulation relative to the reference formulation, is the lower limit 
for success.

Upper limit of success (based on safety):  In the first time in human study (EE-001), 
doses up to 15 mg were generally well tolerated (higher doses were associated with 
an increased frequency of AEs, although there were no SAEs).  As the dose to be 
tested in this study is 5 mg, and 15 mg is considered a tolerated dose, a 3-fold 
increase in PK exposure (AUC or Cmax) for the test formulation relative to the 
reference formulation, is the upper limit for success.
Therefore, the PK exposure (AUC and Cmax) will be considered both safe and efficacious 
if the observed geometric mean ratio of test formulation to reference formulation falls 
within 0.5 to 3.
9.2.
Sample Size Determination
Approximately 24 participants will be randomly assigned to study intervention such that 
20 evaluable participants complete the study.
An evaluable participant is one who receives at least one active dose of AMB for whom a 
pharmacokinetic sample was obtained and provides data on pharmacokinetic parameters.
9.2.1.
Sample Size Assumptions
The sample size assumptions are based on previously reported estimates of within subject 
CV for AUC (0-∞) and Cmax for AMB (study GS-US-300-0112, 2008) [Volibris, 2018]. 
Table 3 summarizes the estimates of within subject CV for the primary endpoints AUC 
(0-∞) and Cmax.
Table 3
Estimates of within subject CV for the primary endpoints AUC (0-∞) 
and Cmax
CVw: within subject CV
AMB
Cmax
22%
AUC (0-∞)
15%
The largest of the within subject CV estimates is about 22%, which translate to a standard
deviation (SD) of 0.217 on the natural log scale. Based on this SD, the half width of the
90% confidence interval will be 12.5% of the point estimate, approximately 24 subjects
will be enrolled to provide at least 20 statistically evaluable subjects.
9.2.2.
Sample Size Sensitivity
Assuming the within subject CV differs from 22% and the number of statistically 
evaluable subjects is lower than 20, then Table 4 shows the precision (the half width of 
the 90% confidence interval) for a range of evaluable subjects.
 
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Table 4
Sample Size Sensitivity
Evaluable Subjects
CVw
Precision
20
22%
12.5%
20
34%
19.6%
18
22%
13.2%
18
32%
19.6%
16
22%
14.2%
16
30%
19.6%
Assuming a within subject CV for AUC of 15% (see Section 9.2.1), and with a sample 
size of 20, if the observed mean AUC ratio of test formulation to reference is 0.6, the 
probability of the true mean ratio being < 0.5 is < 0.5%. Similarly, if the observed mean 
AUC ratio of test formulation to reference is 2.5-fold, the probability of the true mean 
ratio being > 3 is < 0.5%.  So, there is at least 99% probability that the observed AUC 
will not exceed the boundary of (0.5, 3).  
Assuming a within subject CV for Cmax of 22% (see Section 9.2.1), and with a sample 
size of 20, the probability of observing a mean Cmax ratio of test formulation to reference 
below 0.5 is < 2% when the true PK ratio is 0.6. Similarly, if the observed Cmax ratio of 
test formulation to reference is 2.5-fold, the probability of the true mean ratio being > 3-
fold is < 2%.  So, there is at least 98% probability that the observed Cmax will not 
exceed the boundary of (0.5, 3).
9.2.3.
Sample Size Re-estimation or Adjustment
No sample size re-estimation is planned to be performed.
9.3.
Populations for Analyses
Population
Description
Safety
All randomized participants who take at least 1 dose of study 
intervention. Participants will be analysed according to the 
intervention they received.
Pharmacokinetic 
Concentration 
The PK Concentration Population will include all participants for 
whom at least one PK sample was obtained and analysed.
Pharmacokinetic Parameter
For each PK parameter, the PK Parameter Population will include all 
participants who provide PK parameter data.
9.4.
Statistical Analyses
9.4.1.
Pharmacokinetic Analyses 
Pharmacokinetic analysis will be the responsibility of the Clinical Pharmacokinetics
Modelling and Simulation Department, CPKMS, GlaxoSmithKline. Statistical analyses 
 
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of the pharmacokinetic parameter data will be the responsibility of Clinical Statistics, 
GlaxoSmithKline. 
Plasma concentration time data for AMB will be analysed by non-compartmental 
methods with WinNonlin [version 6.3 or above]. Calculations will be based on the actual
sampling times recorded during the study although supplementary analysis will be
available based on the nominal times. From the plasma concentration-time data, the
following pharmacokinetic parameters will be determined, as data permit: maximum
observed plasma concentration (Cmax), time to Cmax (tmax), area under the plasma
concentration-time curve [AUC(0-t) and AUC (0-∞)], and apparent terminal phase half-
life (t1/2).
The PK parameters, AUC (0-∞), AUC(0-t), Cmax, and t½ will be transformed using natural 
logarithms. Missing PK parameters will not be imputed.  All data from withdrawn 
subjects will be listed.  No adjustment for multiple tests or comparisons is planned. 
Pharmacokinetic data will be presented in graphical and/or tabular form and will be 
summarized descriptively by treatment. Descriptive summary table, graphics, and 
treatment will also be provided. 
Data will be listed and summarized according to GlaxoSmithKline reporting standards, 
where applicable. Listings will be sorted by subject, period, noting treatment. 
Summaries will be presented by treatment. Unless stated otherwise, descriptive 
summaries will include n, mean, standard deviation (SD), coefficient of variation (CV), 
median, minimum, and maximum for continuous variables, n and percent for categorical 
variables and geometric mean, 95% confidence interval (CI), and the between-subject CV 
(CVb) based on geometric mean for the log-transformed PK parameters. 
Version 9.3 (or higher) of the SAS system will be used for statistical analysis of the data 
as well as to generate tables, figures, and listings. 
Any deviation(s) from the original analyses planned in the protocol will be reported in the 
Reporting and Analysis Plan (RAP) and/or in the Clinical Pharmacology Study Report. 
All pharmacokinetic data will be stored in the Archives, GlaxoSmithKline 
Pharmaceuticals R&D.  
9.5.
Interim Analyses
No interim analyses are planned.
9.6.
Safety Analyses
Safety data will be presented in tabular and/or graphical format and summarized 
descriptively according to GSK’s IDSL standards.
 
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10.
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations
10.1.1.
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (e.g., advertisements) must be submitted to an IRB/IEC by 
the investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 

Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC

Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations
10.1.2.
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
 
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10.1.3.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to 
the participant and answer all questions regarding the study. 

Participants must be informed that their participation is voluntary. Participants 
will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance 
Portability and Accountability Act (HIPAA) requirements, where applicable, 
and the IRB/IEC or study centre. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study. 

A copy of the ICF(s) must be provided to the participant. 

Participants who are rescreened are required to sign a new ICF.
10.1.4.
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred. 

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant. 

The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities.
10.1.5.
Dissemination of Clinical Study Data

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.
 
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
The procedures and timing for public disclosure of the protocol and results 
summary and for development of a manuscript for publication for this study will 
be in accordance with GSK Policy.

GSK intends to make anonymized patient-level data from this trial available to 
external researchers for scientific analyses or to conduct further research that can 
help advance medical science or improve patient care. This helps ensure the data 
provided by trial participants are used to maximum effect in the creation of 
knowledge and understanding
10.1.6.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (e.g., laboratory 
data). The investigator is responsible for verifying that data entries are accurate 
and correct by physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 

The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 

Monitoring details describing strategy (e.g., risk-based initiatives in operations 
and quality such as Risk Management and Mitigation Strategies and Analytical 
Risk-Based Monitoring), methods, responsibilities and requirements, including 
handling of noncompliance issues and monitoring techniques (central, remote, or 
on-site monitoring) are provided in the Monitoring Plan.

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

The sponsor assumes accountability for actions delegated to other individuals 
(e.g., Contract Research Organizations).

Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 

Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years from the issue of the final 
Clinical Study Report (CSR)/ equivalent summary unless local regulations or 
institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the 
sponsor. No records may be transferred to another location or party without 
written notification to the sponsor. 
 
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10.1.7.
Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current 
medical records must be available.

Definition of what constitutes source data can be found in Source Document 
Agreement.
10.1.8.
Study and Site Closure
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development
10.1.9.
Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.

The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicentre studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.
 
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10.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 5 will be performed by the local laboratory. 

Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 5 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
Table 5
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Platelet Count
RBC Indices:
MCV
MCH
%Reticulocytes
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Haemoglobin
Haematocrit
Clinical 
Chemistry1
BUN
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-Oxaloacetic 
Transaminase
(SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase
(SGPT)
Total Protein
Glucose (fasting 
at screening)
Calcium
Alkaline phosphatase
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones, by dipstick

Microscopic examination (if blood or protein is abnormal)
Other 
Screening (or 
Pre-dose) Tests

Follicle-stimulating hormone (as needed in women of non-childbearing 
potential only)

Urine drug screen (to include at minimum: amphetamines, barbiturates, 
cocaine, opiates, cannabinoids and benzodiazepines)

Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis 
C virus antibody)
 
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NOTES :
1.
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 7.1 and Appendix 5. All events of ALT 3 × upper limit of normal (ULN) and 
bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and international normalized ratio (INR) >1.5, if INR 
measured, which may indicate severe liver injury (possible Hy’s Law), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis).
 
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10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
10.3.1.
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study intervention, whether or not considered related to 
the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not related 
to progression of underlying disease).

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 study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae.
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.
 
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
Situations in which 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.
10.3.2.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
o
Results in death
o
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant 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.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant 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 
outpatient setting. Complications that occur during hospitalization are AE. 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.
Results in persistent disability/incapacity

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, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
Is a congenital anomaly/birth defect
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
 
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not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious.
Examples of such events include 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.
10.3.3.
Recording and Follow-Up of AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK /AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.
 
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Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE.

A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK with a copy of any post-mortem 
findings including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information.
 
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10.3.4.
Reporting of SAE to GSK
SAE Reporting to GSK via Electronic Data Collection Tool

The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

The investigator or medically-qualified sub-investigator must show evidence within 
the eCRF (e.g., check review box, signature, etc.) of review and verification of the 
relationship of each SAE to IP/study participation (causality) within 72 hours of SAE 
entry into the eCRF.

After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the medical monitor by telephone.

Contacts for SAE reporting can be found in SRM.
SAE Reporting to GSK via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the medical monitor.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in SRM.
 
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10.4.
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information
10.4.1.
Definitions:
Women in the following categories are not considered WOCBP
1.
Premenarchal
2.
Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other 
than the above, (e.g., mullerian agenesis, androgen insensitivity), investigator 
discretion should be applied to determining study entry.
Note: Documentation can come from the site personnel’s: review of the 
participant’s medical records, medical examination, or medical history interview.
3.
Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. 

A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not 
using hormonal contraception or hormonal replacement therapy (HRT). 
However, in the absence of 12 months of amenorrhea, confirmation with 
more than one FSH measurement in the postmenopausal range is 
required. 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-oestrogen hormonal highly effective contraception 
methods if they wish to continue their HRT during the study. Otherwise, they 
must discontinue HRT to allow confirmation of postmenopausal status before 
study enrolment.
 
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10.4.2.
Contraception Guidance:
CONTRACEPTIVES a REQUIRED DURING THE STUDY FOR FEMALE PARTNERS OF MALE 
PARTICIPANTS:

Highly Effective Methods b That Have Low User Dependency Failure rate of <1% per year 
when used consistently and correctly.

Implantable progestogen-only hormone contraception associated with inhibition of ovulationc

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)c

Bilateral tubal occlusion

Highly Effective Methods b That Are User Dependent Failure rate of <1% per year when 
used consistently and correctly.

Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation
oral
intravaginal
transdermal

injectable

Progestogen-only hormone contraception associated with inhibition of ovulation
oral

injectable
a.
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies.
b.
Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those when 
used consistently and correctly.
Note: Periodic abstinence (calendar, sympto-thermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception. Male 
condom and female condom should not be used together (due to risk of failure with friction)
10.4.3.
Collection of Pregnancy Information:
Male participants with partners who become pregnant

Investigator will attempt to collect pregnancy information on any male participant’s 
female partner of a male study participant who becomes pregnant while participating 
in this study. 

After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 24 hours of learning of the partner’s 
pregnancy. 

The female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK.
 
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
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated
delivery date. Any termination of the pregnancy will be reported regardless of foetal
status (presence or absence of anomalies) or indication for procedure. 
 
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10.5.
Appendix 5: Liver Safety: Required Actions and Follow-up 
Assessments 
Phase 1 Liver chemistry stopping criteria have been designed to assure subject safety and 
to evaluate liver event etiology
Phase 1 liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria 
ALT-absolute
ALT≥3xULN
If ALT≥3xULN AND bilirubin1,2 2xULN (>35% direct bilirubin) or 
international normalized ratio (INR) >1.5, Report as an SAE.
See additional Actions and Follow Up Assessments listed below
Required Actions and Follow up Assessments 
Actions
Follow Up Assessments

Report the event to GSK within 24 hours

Complete the liver event CRF, and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the participant until liver chemistries 
resolve, stabilise, or return to within baseline
(Day –1) (see MONITORING below)
MONITORING:
If ALT≥3xULN AND bilirubin 2xULN or INR 
>1.5

Repeat liver chemistries (include ALT, 
aspartate transaminase [AST], alkaline 
phosphatase, bilirubin and INR) and perform 
liver event follow up assessments within 24 
hours

Monitor participant twice weekly until liver 
chemistries resolve, stabilise or return to 
within baseline (Day –1)

A specialist or hepatology consultation is 
recommended
If ALT≥3xULN AND bilirubin < 2xULN and INR 
≤1.5:

Viral hepatitis serology3

Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend

Obtain blood sample for pharmacokinetic 
(PK) analysis, obtained within 96 hrs of last 
dose of last dose4 

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 liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on 
the concomitant medications report form 
including acetaminophen, herbal remedies, 
other over the counter medications.

Record alcohol use on the liver event 
alcohol intake case report form
 
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Liver Chemistry Stopping Criteria 

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin and INR) and 
perform liver event follow up assessments 
within 24-72 hours

Monitor participant weekly until liver 
chemistries resolve, stabilize or return to 
within baseline (Day –1)
If ALT≥3xULN AND bilirubin 2xULN or INR 
>1.5:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG) or gamma 
globulins.

Serum acetaminophen adduct high 
performance liquid chromatography 
(HPLC) assay (quantifies potential 
acetaminophen contribution to liver injury 
in subjects with definite or likely 
acetaminophen use in the preceding week)
[James, 2009]. Not required if participant 
has been in the clinical unit, and agreed 
by the GSK Medical Monitor.

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study intervention for that subject if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary bilirubin on 
dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, which 
may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding studies of hepatic 
impairment or cirrhosis); the INR threshold value stated will not apply to subjects receiving anticoagulants
3.
Includes: Hepatitis A immunoglobulin (gM) antibody; HBsAg and HBcAb; Hepatitis C RNA; Cytomegalovirus IgM 
antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile antibody or 
monospot testing) and Hepatitis E IgM antibody 
4.
Record the date/time of the PK blood sample draw and the date/time of the last dose of study intervention prior to 
PK blood sample draw on the CRF. If 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 SRM.
 
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10.6.
Appendix 6: Abbreviations and Trademarks
AE
Adverse event
ALT
Alanine aminotransferase
AMB
Ambrisentan
AST
Aspartate aminotransferase
AUC
Area under the plasma concentration-time curve
CA
Competent Authority
CFR
Code of Federal Regulation
CI
Confidence Interval
CIOMS
Council for International Organizations of Medical Sciences
Cmax
Maximum observed plasma concentration
CONSORT
Consolidated Standards of Reporting Trials
CRF
Case report form
CSR
Clinical Study Report
CV
Coefficient of Variation
CVb
Between subject coefficient of variation
EC
Ethics committee
ECG
Electrocardiogram
EMA
European Medicines Agency
ERA
Endothelin receptor antagonist
ET-1
Endothelin-1
EU
European Union
EURMP
European Union Risk Management Plan
FC
Functional Class
FSH
Follicle stimulating hormone
g/L
Gram per Litre
GCP
Good clinical practice
GSK
GlaxoSmithKline
h
Hour
Hb
Haemoglobin
HBsAg
Hepatitis B surface antigen
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human immunodeficiency virus
HPLC
High performance liquid chromatography
HRT
Hormonal replacement therapy
IB
Investigator’s brochure
ICF
Informed consent form
ICH
International Council on Harmonisation
IRB
Institutional Review Boards
IEC
Independent ethics committee
Ig
Immunoglobulin
INR
International normalised ratio
IP
Investigational product
iPAH
Idiopathic pulmonary arterial hypertension
IUD
Intrauterine device
 
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IUS
Intrauterine hormone-releasing system
IVIVT
In vitro/In vivo Translation 
Kg
Kilogram
LSLV
Last subject last visit
LV
Left ventricular
m
Metre
MCH
Mean corpuscular haemoglobin
MCV
Mean corpuscular volume
mg
Milligram
min
Minute
mL
Millilitre
mmHg
millimetre of mercury
MSDS
Material Safety Data Sheet
PAH
Pulmonary arterial hypertension
PAP
Pulmonary artery pressure
PDCO
Paediatric Committee
PIP
Paediatric Investigation Plan
PK
Pharmacokinetic
PKPD
Pharmacokinetic Pharmacodynamic analysis  
PVR
Pulmonary vascular resistance
QTc
Corrected QT interval
QTcB
QT interval corrected for heart rate according to Bazett’s 
formula
QTcF
QT interval corrected for heart rate according to Fridericia’s 
formula
RAP
Reporting and analysis plan
RHF
Right-sided heart failure
RNA
Ribonucleic acid
SA
Safety analysis
SAE
Serious adverse event
SD
Standard deviation
SGOT
Serum Glutamic-Oxaloacetic Transaminase
SGPT
Serum Glutamic-Pyruvic Transaminase
SUSAR
Suspected unexpected serious adverse reactions
SRM
Study reference manual
Tmax
Time to Cmax
t1/2
Apparent terminal phase half-life
ULN
Upper limit of normal
US
United States
WBC
Whir Blood Cells
WHO
World Health Organisation
WOCBP
Woman of childbearing potential
 
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Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
None
Letairis
VOLIBRIS is a trade mark of Gilead 
Sciences, Inc.
 
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10.7.
Appendix 7: Palatability Questionnaire
 
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11.
REFERENCES
Beghetti M, Hoeper MM, Kiely DG, Carlesen J, Schwierin B, Segal ES, et al. 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.
Clinical study report EE-001: A randomized, double-blind, placebo-controlled single 
ascending dose trial to investigate the tolerability, pharmacodynamics, pharmacokinetics 
and possible food effect of the endothelin receptor antagonist BSF 208075 in healthy 
male volunteers. 14 February 2001.
Clinical study report EE-002: A randomized, double-blind, placebo-controlled, multiple 
ascending dose trial to investigate the tolerability, safety, pharmacokinetics and –
dynamics of oral BSF 208075 in healthy male subjects. 6 February 2001.
Dingemanse J, van Giersbergen P. Clinical pharmacology of bosentan, a dual endothelin
receptor antagonist. Clin Pharmacokinet. 2004;43(15):1089-1115.
European Union Risk Management Plan (EURMP) for VOLIBRIS (ambrisentan). 
Version 8.1. 2019.
Fraisse A, Xavier J, Schliech JM, di Flippo S, Maragnes P, Beghetti M, et al. 
Characteristics and prospective 2-year follow-up of children with pulmonary arterial 
hypertension in France. Arch Cardiovasc Dis (2010), doi:10.1016/j.acvd.2009.12.001; in 
press
Galiè N, Manes A, Branzi A. The endothelin system in pulmonary arterial hypertension.
Cardiovasc Res. 2004;61:227–37.
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.
Hoeper MM, Huscher D, Pittrow D., Incidence and prevalence of pulmonary arterial 
hypertension in Germany. International Journal of Cardiology. 2016; 203:612-13
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA,et al. 
Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose 
and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
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
 
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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.
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
Volibris Investigators Brochure. Seventeenth Edition. March 2018.
Volibris Summary of Product Characteristics (SmPC). Electronic Medicines 
Compendium. Nov 2018.
Vorhies EE and Ivy DD. Drug Treatment of Pulmonary Hypertension in Children. 
Paediatric Drugs. 2014;16(1):43-65
 
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SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
205019
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for a randomized open-label relative 
bioavailability study to compare the pharmacokinetic parameters of 
a lower dose formulation of ambrisentan (GSK1325760) with 
marketed ambrisentan in healthy adult participants
Compound Number 
:
GSK1325760
Effective Date 
:
14-JAN-2020
Description:

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 205019

This RAP is intended to describe the analyses for primary and secondary endpoints 
required for the study. 

This RAP will be provided to the study team members to convey the content of the
Statistical Analysis Complete (SAC) deliverable.
RAP Author(s):
Author
Date
Manager (CPMS)
24-OCT-2019
18-OCT-2019
Associate Statistician (FPD, Biostatistics)
Copyright 2020 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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205019
2
RAP Team Approvals (Method: E-mail):
Approver
Date
22-OCT-2019
Project Statistician (FPD, Biostatistics)
25-OCT-2019
Study Accountable Person (Operations and 
Science Lead, GCSD)
22-OCT-2019
Medical Monitor (Clinical Sciences)
29-OCT-2019
DQL (Global Clinical & Data Operations)
Senior Director (CPMS)
23-OCT-2019
Clinical Statistics and Clinical Programming Line Approvals (Method: Pharma 
TMF e-signature):
Approver
Date
13-JAN-2020
Statistics Line Manager (FPD, Biostatistics)
14-JAN-2020
Programming Line Manager (FPD, Biostatistics)
 
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TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................5
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................5
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................5
2.2.
Study Objective(s) and Endpoint(s)...............................................................5
2.3.
Study Design ................................................................................................6
2.4.
Statistical Hypotheses / Statistical Analyses .................................................7
3.
PLANNED ANALYSES ............................................................................................7
3.1.
Interim Analyses ...........................................................................................7
3.2.
Final Analyses ..............................................................................................7
4.
ANALYSIS POPULATIONS .....................................................................................7
4.1.
Protocol Deviations.......................................................................................8
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.......................................................................................................9
5.1.
Study Treatment & Sub-group Display Descriptors.......................................9
5.2.
Baseline Definitions ......................................................................................9
6.
STUDY POPULATION ANALYSES .......................................................................10
6.1.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................10
6.2.
Overview of Planned Study Population Analyses........................................10
7.
SAFETY ANALYSES .............................................................................................11
7.1.
Adverse Events Analyses ...........................................................................11
7.2.
Clinical Laboratory Analyses.......................................................................11
7.3.
Other Safety Analyses ................................................................................11
8.
PHARMACOKINETIC ANALYSES.........................................................................12
8.1.
Primary Pharmacokinetic Analyses.............................................................12
8.1.1.
Endpoint / Variables.....................................................................12
8.1.1.1.
Drug Concentration Measures....................................12
8.1.1.2.
Derived Pharmacokinetic Parameters.........................12
8.1.2.
Summary Measure ......................................................................13
8.1.3.
Strategy for Intercurrent (Post Randomization) Events ................13
8.1.4.
Population of Interest...................................................................14
8.1.5.
Statistical Analyses / Methods .....................................................14
8.1.5.1.
Statistical Methodology Specification..........................14
9.
REFERENCES.......................................................................................................16
10. APPENDICES........................................................................................................17
10.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................17
10.2.
Appendix 2: Schedule of Activities ..............................................................18
10.2.1.
Protocol Defined Schedule of Events...........................................18
 
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10.2.2.
Screening and Follow-up Schedule of Events..............................18
10.2.3.
Treatment Periods 1, 2 and 3 (minimum of 7 days 
washout between doses) .............................................................19
10.3.
Appendix 3: Assessment Windows .............................................................21
10.4.
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................22
10.4.1.
Study Phases ..............................................................................22
10.4.1.1.
Study Phases for Concomitant Medication .................22
10.4.2.
Treatment Emergent Flag for Adverse Events .............................22
10.5.
Appendix 5: Data Display Standards & Handling Conventions....................23
10.5.1.
Reporting Process .......................................................................23
10.5.2.
Reporting Standards....................................................................23
10.5.3.
Reporting Standards for Pharmacokinetic....................................24
10.6.
Appendix 6: Derived and Transformed Data ...............................................25
10.6.1.
General........................................................................................25
10.6.2.
Study Population..........................................................................25
10.6.3.
Safety ..........................................................................................26
10.6.4.
Pharmacokinetic ..........................................................................26
10.7.
Appendix 7: Reporting Standards for Missing Data.....................................27
10.7.1.
Premature Withdrawals................................................................27
10.7.2.
Handling of Missing Data.............................................................27
10.7.2.1.
Handling of Missing and Partial Dates ........................27
10.8.
Appendix 8: Values of Potential Clinical Importance ...................................29
10.8.1.
Laboratory Values........................................................................29
10.8.2.
ECG.............................................................................................30
10.8.3.
Vital Signs....................................................................................30
10.9.
Appendix 9: Abbreviations & Trade Marks ..................................................31
10.9.1.
Abbreviations...............................................................................31
10.9.2.
Trademarks .................................................................................32
10.10 Appendix 10: List of Data Displays..............................................................33
10.10.1 Data Display Numbering ................................................................33
10.10.2
Mock Example Shell Referencing ................................................33
10.10.3
Deliverables.................................................................................33
10.10.4
Study Population Tables..............................................................34
10.10.5
Safety Tables...............................................................................35
10.10.6
Safety Figures .............................................................................39
10.10.7
Pharmacokinetic Tables...............................................................40
10.10.8
Pharmacokinetic Figures .............................................................41
10.10.9
ICH Listings .................................................................................42
10.10.10 Non-ICH Listings..........................................................................45
10.11 Appendix 11: Example Mock Shells for Data Displays ................................46
 
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1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be included in the 
Clinical Study Report for Protocol 2017N346964_00.
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
There were no changes or deviations to the originally planned statistical analysis specified in the protocol
(Dated: 21/Jun/2019).
Note: Although all PK parameters are included in the primary endpoints, only AUC and Cmax will be 
analysed by statistics in line with success definition in the protocol and the rest PK parameters will be 
reported and treated as of secondary importance. 
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

To compare the relative bioavailability 
of Ambrisentan (AMB 1 mg x 5 
tablets) administered as tablets 
dispersed in water or administered 
orally, with marketed Ambrisentan 
(AMB 5 mg x 1 tablet) in healthy adult 
participants under fasted conditions

Plasma pharmacokinetic parameters of AMB as data 
permits: Maximum observed plasma concentration 
(Cmax), Time to Cmax (tmax), Area under 
concentration-time curve from time zero (predose) 
extrapolated to infinite time(AUC (0-∞)), area under the 
concentration-time curve from time zero (predose) to 
last time of quantifiable concentration AUC(0-t) and
Terminal phase half-life (t½.), time of last quantifiable 
concentration (tlast)
Secondary Objectives
Secondary Endpoints

To monitor the safety and tolerability 
of Ambrisentan (AMB 1 mg x 5 
tablets) administered as tablets 
dispersed in water or administered 
orally, compared with marketed 
Ambrisentan (AMB 5 mg x 1 tablet) 
administered orally, in healthy adult

Adverse events (AE), vital signs, electrocardiogram 
(ECG), and clinical laboratory values.
Exploratory Objectives
Exploratory Endpoints
To investigate palatability of AMB (1 
mg x 5 tablets) dispersed in water, in 
healthy adult participants.

Palatability questionnaire scores
 
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2.3.
Study Design
Overview of Study Design and Key Features
Design
Features
This is a single centre, open-label, randomised, single dose, 3-period cross over study in 
healthy participants to compare the PK of a new lower dose formulation AMB tablet 
(dispersed in water and administered orally) with the reference marketed AMB tablet
(administered orally)
Each participant will have 3 treatment periods (single oral doses) in a treatment sequence 
in which subjects will be randomised to one of the following study interventions in each 
treatment period:

Test 1 (F1):  5 mg (5 x 1 mg tablets) AMB tablet dispersed in water

Test 2 (F2):  5 mg (5 x 1 mg tablets) AMB tablet administered orally

Reference (R):  5 mg (1 x 5 mg tablet) AMB tablet administered orally
Each participant will:

be screened (within 28 days of their first dose)

have 3 treatment periods (3 overnight clinic stays, and 1 out-patient visit per treatment 
period.  A minimum of 7 days between doses in each treatment period); and 
have a follow-up visit (within 7 to 14 days after their last dose)
Dosing
The investigational drug is GSK1325760(AMB)
Each participant will have 3 treatment periods and will be randomised to one of the study 
interventions in each period:

Test 1 (F1):  5 mg (5 x 1 mg tablets) AMB tablet dispersed in water

Test 2 (F2):  5 mg (5 x 1 mg tablets) AMB tablet administered orally

Reference (R): 5 mg (1 x 5 mg tablet) AMB tablet administered orally
Palatability Questionnaire only to be completed in the Treatment Period dosing AMB 
tablets dispersed in water. To be completed within 10
min of dosing.
Time & 
Events

Refer to Appendix 2: Schedule of Activities
Treatment 
Assignment

This is an open label study and each participant will have 3 treatment periods (single 
oral doses) in a treatment sequence in which subjects will be randomised to one of the 
study interventions in each treatment period
Interim 
Analysis

No Interim analysis will be performed in this study
 
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2.4.
Statistical Hypotheses / Statistical Analyses
This is an investigative study to study the pharmacokinetic parameters of a new formulation of AMB. Due to 
its descriptive nature, there will be no formal statistical hypothesis tested.
An estimation approach will be used to i) estimate the bioavailability of the test formulation relative to the
reference formulation, and ii) for AUC (0-inf), AUC(0-t) and Cmax, point estimates and corresponding 90% 
confidence intervals will be constructed for the ratio of the geometric mean of the test formulation to the 
geometric mean of the reference formulation. 
3.
PLANNED ANALYSES
3.1.
Interim Analyses
No Interim Analysis is planned for this study
3.2.
Final Analyses
The final planned primary analyses will be performed after the completion of the following sequential steps:
1.
All participants have completed the study as defined in the protocol.
2.
All required database cleaning activities have been completed and final database release (DBR) and 
database freeze (DBF) has been declared by Data Management.
3.
Randomization codes have been distributed according to RandAll NG procedures.
4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
Screened 

All participants who were screened for eligibility

Screen failures
Randomized 

All participants who were randomly assigned to 
treatment in the study.

This population will be based on the treatment the 
participant was randomized to.

Study 
Population
Safety

All randomized participants who take at least 1 dose of 
study intervention. Participants will be analysed 
according to the intervention they actually received.

Safety 
Population
Pharmacokinetic 
Concentration (PK)

The PK Concentration Population will include all 
participants for whom at least one PK sample was 
obtained and analysed.

PK
Pharmacokinetic 
Parameter 
(PK_PAR)

For each PK parameter, the PK Parameter Population 
will include all participants who provide PK parameter 
data.

PK_PAR
Refer to Appendix 10: List of Data Displays which details the population used for each display.
 
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4.1.
Protocol Deviations
Important protocol deviations (including deviations related to study inclusion/exclusion criteria, conduct of 
the trial, patient management or patient assessment) will be summarised and listed.
Protocol deviations will be tracked by the study team throughout the conduct of the study in accordance with 
the Protocol Deviation Management Plan final version, 27-SEP-2019.

Data will be reviewed prior to Database Release (DBR) to ensure all important deviations are 
captured and categorised on the protocol deviations dataset. 

This dataset will be the basis for the summaries and listings of protocol deviations.
A separate listing of all inclusion/exclusion criteria deviations will also be provided. This listing will be based 
on data as recorded on the inclusion/exclusion page of the electronic case report form eCRF.
 
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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
5.1.
Study Treatment & Sub-group Display Descriptors
Treatment comparisons will be displayed as follows using the descriptors as specified:
Treatment Group Descriptions
RandAll NG
Data Displays for Reporting 
Code
Description
Description
Order in TLF 
F1
GSK1325760 5 mg dispersed in water
Dispersed GSK1325760
1
F2
GSK1325760 5 mg administered orally
Oral GSK1325760
2
R
Marketed AMB
Marketed AMB
3
1.
Dispersed GSK1325760 vs Marketed AMB (F1 vs R)
2.
Oral GSK1325760 vs Marketed AMB (F2 vs R)
Note: Relevant footnotes to be added in all the displays as:
Dispersed GSK1325760: 5 mg (5 x 1 mg tablets) AMB tablet dispersed in water
Oral GSK1325760: 5 mg (5 x 1 mg tablets) AMB tablet administered orally
Marketed AMB: 5 mg (1 x 5 mg tablet) AMB tablet administered orally
5.2.
Baseline Definitions
For all endpoints (except as noted in baseline definitions) the baseline value will be the latest pre-dose 
assessment with a non-missing value.If time is not collected, Day 1 assessments are assumed to be taken 
prior to first dose and used as baseline.
Parameter
Study Assessments Considered as Baseline
Baseline Used in 
Data Display
Screening
Day -1
Day 1 (Pre-Dose)
Safety
Vital Signs
X[1]
X[1]
Day 1 (mean of the 
pre-dose)[2]
ECG
X[1]
X[1]
Day 1 (worst case
pre-dose)[2]
Haematology+ Clinical 
Chemistry +
Urinalysis[3]
X
X
Day-1
NOTES:
[1] Taken in triplicate
[2] Worst case of the triplicate pre-dose assessments for ECG will be the maximum value of the three          
measurements for each of the ECG parameter and mean of the pre-dose for Vital signs
[3] Urinalysis baseline value required only when microscopic examination done
 
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6.
STUDY POPULATION ANALYSES
6.1.
Other Considerations for Data Analyses and Data Handling 
Conventions
Other considerations for data analyses and data handling conventions are outlined in the appendices:
Section
Component
10.4
Appendix 4: Study Phases and Treatment Emergent Adverse Events
10.5
Appendix 5: Data Display Standards & Handling Conventions
10.6
Appendix 6: Derived and Transformed Data
10.7
Appendix 7: Reporting Standards for Missing Data
10.8
Appendix 8: Values of Potential Clinical Importance
6.2.
Overview of Planned Study Population Analyses
The study population analyses will be based on the randomized population, unless otherwise specified.
Study population analyses including analyses of subject’s disposition, protocol deviations, demographic and 
baseline characteristics, prior and concomitant medications, and exposure and treatment compliance will be 
based on GSK Core Data Standards.  Details of the planned displays are presented in Appendix 10: List of 
Data Displays.
 
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7.
SAFETY ANALYSES
The safety analyses will be based on the Safety population, unless otherwise specified.
7.1.
Adverse Events Analyses
Adverse events analyses including the analysis of adverse events (AEs), Serious (SAEs) will be based on 
GSK Core Data Standards. The details of the planned displays are provided in Appendix 10: List of Data 
Displays.
7.2.
Clinical Laboratory Analyses
Laboratory evaluations including the analyses of Chemistry laboratory tests, Hematology laboratory tests, 
Urinalysis, and liver function tests will be based on GSK Core Data Standards. The details of the planned
displays are in Appendix 10: List of Data Displays.
7.3.
Other Safety Analyses
The analyses of non-laboratory safety test results including ECGs and vital signs will be based on GSK 
Core Data Standards, unless otherwise specified. The details of the planned displays are presented in
Appendix 10: List of Data Displays.
 
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8.
PHARMACOKINETIC ANALYSES
8.1.
Primary Pharmacokinetic Analyses
The pharmacokinetic (PK) analyses will be based on the “Pharmacokinetic Concentration (PK)” population, 
unless otherwise specified.
Table below provides an overview of the planned analysis, with the full details being presented in Appendix
10: List of Data Displays:
8.1.1.
Endpoint / Variables
8.1.1.1.
Drug Concentration Measures
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 10.5.3 Reporting Standards 
for Pharmacokinetic)
Concentrations of ambrisentan in plasma will be listed and summarised by treatment and actual time. 
Standard summary statistics will be calculated (i.e. arithmetic mean, standard deviation, median, minimum 
and maximum).
Refer to the PK Guidance document, titled Non-Compartmental Analysis of Pharmacokinetic Data 
(GUI_51487) for more information regarding the treatment of concentrations below the assay’s lower limit of 
quantification (NQ).
Individual plasma concentration-time profiles and median/mean profiles by treatment will be plotted. Each of 
the figures will contain one plot on the untransformed scale (i.e. a linear plot) and one plot on the loge-
transformed scale (i.e., log-linear plot). In addition, a plot showing all individual subjects for each treatment 
will be produced (both linear and log-linear).
8.1.1.2.
Derived Pharmacokinetic Parameters
Pharmacokinetic parameters will be calculated by standard non-compartmental analysis according to 
current working practices and using the currently supported version of WinNonlin [version 8.1 or above]. All 
 
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calculations of non-compartmental parameters will be based on actual sampling times. Pharmacokinetic 
parameters will be determined from the plasma concentration-time data, as data permits, for each subject 
and treatment unless otherwise specified. If parameters cannot be determined, a flag will be present in the 
data.
Parameter
Parameter Description
AUC(0-t)
Area under the concentration-time curve from time zero to the time of the last 
quantifiable concentration (C(t)) will be calculated using the linear trapezoidal rule for 
each incremental trapezoid and the log trapezoidal rule for each decremental trapezoid.
AUC(0-inf)
Area under the concentration-time curve extrapolated to infinity will be calculated as: 
AUC(0-inf) = AUC(0-t) + Ct / lambda_z
where Ct is the last observed quantifiable concentration.
Cmax
Maximum observed concentration determined directly from the concentration-time data.
Tmax
Time to reach Cmax, determined directly from the concentration-time data.
t1/2*
Apparent terminal half-life will be calculated as: 
t1/2 = ln2 / lambda_z
%AUCext
The percentage of AUC(0-∞) obtained by extrapolation (%AUCex) will be calculated
as: 
[AUC(0-∞) – AUC(0-t)] / AUC(0-∞) x 100
Ct
The last observed quantifiable concentration
Tlast
Time of last quantifiable concentration
* associated parameters lambda_z, lambda_z_lower, lambda_x_upper, No_points_lambda_z to be listed.
NOTES:
Additional parameters may be included as required.
Lambda_z is the terminal phase rate constant.
Derived pharmacokinetic parameters will be listed by subject and treatment. Listings will also include the 
individual subject ratios for AUC(0-inf), AUC (0-t) and Cmax, and the first point, last point and number of 
points used in the determination of λz.
8.1.2.
Summary Measure

For each of the parameters AUC (0-inf), AUC (0-t), t1/2 and Cmax, the following summary statistics 
will be calculated and tabulated by treatment:

Untransformed Data : N, n, arithmetic mean, 95% confidence interval (CI) for the arithmetic 
mean, SD, median, minimum, maximum

Loge-transformed Data: Geometric mean, 95% CI for the geometric mean, SD of loge-
transformed data and %CVb
For tmax, the summary statistics specified for untransformed data above will be   generated.
As per the intercurrent events observed as defined in Section 8.1.3, relevant datapoints will be 
excluded from the pharmacokinetic parameters summary tables.

Relative bioavailability of the new formulation of AMB and referenced or marketed AMB will be 
analysed by using AUC(0-t), AUC (0-∞), Cmax parameters
8.1.3.
Strategy for Intercurrent (Post Randomization) Events
Participants who experienced the following intercurrent events will have data from the relevant treatment 
period excluded from analysis:
 
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
Did not receive full dosing 

Had a vomit within the first 2.5 hours after dose completion

Did not provide an adequate PK concentration profile to allow reliable estimation of PK parameters
8.1.4.
Population of Interest 
The primary statistical analyses will be based on the Pharmacokinetic parameter population (PK_PAR), 
unless otherwise specified.
8.1.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 10: List of Data Displays and will be based on GSK 
Data Standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 8.1.1 will be summarised using 
descriptive statistics, graphically presented (where appropriate) and listed.
8.1.5.1.
Statistical Methodology Specification
The following pharmacokinetic statistical analyses will only be performed if sufficient data is available (i.e. if 
subjects have well defined plasma profiles).
Endpoint / Variables

Loge-transformed AUC(0-t), AUC (0-∞), Cmax PK parameters of test formulation of GSK1325760 (F1, 
F2) and marketed AMB (R)
Model Specification

Will be statistically analyzed separately using a mixed model (MM) for all treatment periods

Terms fitted in the mixed effect ANOVA model will include:
o
Fixed Effect: Treatment (F1, F2, R), Treatment Period
o
Random Effect: Subject

The Kenward and Roger method for approximating the denominator degrees of freedom and 
correcting for bias in the estimated variance-covariance of the fixed effects will be used

Point estimates for the adjusted means on the loge scale, the mean difference between treatments 
and associated 90% confidence interval for the contrast (test-reference) will be constructed using 
the residual variance for the following differences of interest:
o
AMB (1 mg x 5 tablets) administered as tablets dispersed in water(F1) and administered 
orally(F2) versus marketed AMB (R)(5 mg x 1 tablet) administered orally

As per the observed intercurrent events, the strategy in sec 8.1.3 will be followed to exclude data 
points following the definition of intercurrent events
Model Checking & Diagnostics
For the Mixed Model analysis, Model assumptions will be applied, but appropriate adjustments may be 
made based on the data.

Distributional assumptions underlying the model used for analysis will be examined by obtaining a 
normal probability plot of the residuals and a plot of the residuals versus the fitted values (i.e. 
checking the normality assumption and constant variance assumption of the model respectively) to 
gain confidence that the model assumptions are reasonable.

If there are any departures from the distributional assumptions, alternative transformations, such as 
data squared, or square root of data, will be explored
 
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Model Results Presentation

The point estimate and confidence interval obtained from MM analysis will be
exponentially back-transformed to obtain Adjusted (least square) geometric means for each 
treatment

Point estimates (Relative Bioavailability of GSK1325760) and associated 90%
confidence interval for the ratio F1/R and F2/R along with within-subject variability (%CVw) will be 
reported Where
%CVw=100*(SQRT (EXP(σw2)-1)) and σw2 is the mean squares error (MSE) from the statistical 
Mixed model

Geometric Mean along with 90% CI treatment Ratios of GSK1325760 Plasma Derived 
Pharmacokinetic Parameters will also be plotted as in Section 10.10.8
 
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9.
REFERENCES
GlaxoSmithKline Document Number 2017N346964_00: An open-label, randomized three period cross-over 
relative bioavailability study to compare the pharmacokinetic parameters of a lower dose formulation of 
ambrisentan (GSK1325760) with marketed ambrisentan in healthy adult participants.
 
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10.
APPENDICES
10.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population
A Per Protocol Population is not being defined for this study. Please Refer to Section 4.1 for handling and 
Reporting of Protocol Deviations.
 
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10.2.
Appendix 2: Schedule of Activities
10.2.1.
Protocol Defined Schedule of Events
10.2.2.
Screening and Follow-up Schedule of Events
Procedure 
Screening1
(up to 28 days 
before first dose)
Follow up/Early 
Withdrawal
(7-14 days post 
last dose)
Notes
Informed consent
X
Inclusion and exclusion criteria
X
Demography
X
Medical history (includes 
substance usage)
X
Substances: Drugs, Alcohol, 
tobacco
Full physical exam, including 
height and weight
X
Brief physical exam
X
HIV, Hep B and Hep C screen
X
Clinical chemistry, 
haematology and urinalysis 
X
X
Only screening tests need to be 
fasted 
FSH
X
Required only in women to confirm
postmenopausal status
Alcohol breath test 
X
Urine or serum drugs test
X
Vital signs (blood pressure, 
heart rate and temperature)
X
X
Triplicate blood pressure and heart 
rate required at screening. 
12-lead ECG
X
X
Triplicate ECG required at 
screening.
Concomitant Medication
review 
X
X
Con meds before dosing can be 
recorded in medical history
AE/SAE review
X
X
Refer to   protocol Section 8.3.1
1.
Screening assessments may be conducted at multiple visits, if required.
 
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10.2.3.
Treatment Periods 1, 2 and 3 (minimum of 7 days washout between doses)
Procedure
Day –1
Day 1 (hours)
Day 2
Day 3 Day 4
Notes
Pre-
dose
0
0.5
1
1.5
2
2.5
4
8
12
18
24
36
48
72
Clinic Visits
Out-patient Visit
X
Admission to clinic
X
Discharge from clinic 
X
If more convenient for 
participants, they can 
remain in the unit until 72 h, 
at the discretion of the 
investigator
Study Intervention
Randomisation
X
Can be done on Day –1 or 
Pre-dose Day 1.  Only in 
Treatment Period 1
Study Intervention
X
Fasted from midnight until 4 
h afterwards, except for 
water, allowed ad libitum, 
except for 1 h before and 
after dosing
Safety Assessments
Vital signs (blood pressure, 
heart rate and temperature)
X
X
X
X
X
X
X
X
X
X
Triplicate pre-dose. Single 
measurements at other 
timepoints, unless out of 
range, then triplicates 
should be performed
12-lead ECG
X
X
X
X
X
X
X
Clinical chemistry, haematology 
and urinalysis 
X
X
Fasting not required
Brief physical examination
X
 
 
 
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Procedure
Day –1
Day 1 (hours)
Day 2
Day 3 Day 4
Notes
Pre-
dose
0
0.5
1
1.5
2
2.5
4
8
12
18
24
36
48
72
Alcohol breath test 
X
Urine or serum drugs test
X
Concomitant Medication 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Con meds before dosing 
can be recorded in medical 
history
SAE/AE review
◄==================================================================================►
Refer to Protocol Section 
8.3.1
Other Assessments
PK blood samples
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Platability Questionnaire
X
Questionnaire only to be
completed in the Treatment 
Period
dosing AMB tablets 
dispersed in
water. To be completed 
within 10
min of dosing

When scheduled at the same time-points, 12-lead ECGs and vital signs should be completed before any blood draws.

The timing of assessments should allow PK samples to be taken as close as possible to the nominal time-point.

The timing and number of planned safety assessments and pharmacokinetic samples may be altered during the course of the study based on newly 
available data (e.g., to obtain data closer to the time of peak plasma concentrations) to ensure appropriate monitoring. 

Any changes in the timing or addition of time points for any planned study assessments as the result of emerging pharmacokinetic data from this study must 
be documented and approved by the relevant study team member and then archived in the sponsor and site study files but will not constitute a protocol 
amendment.  The Competent Authority (CA) and ethics committee (EC) will be informed of any safety issues that constitute a substantial amendment and 
require alteration of the safety monitoring scheme or amendment of the informed consent form (ICF).  The changes will be approved by the CA and the EC 
before implementation.
 
 
 
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10.3.
Appendix 3: Assessment Windows
Required assessment windows are specified in the Study Reference Manual for this 
study.
 
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10.4.
Appendix 4: Study Phases and Treatment Emergent 
Adverse Events
10.4.1.
Study Phases
Assessments and events will be classified according to the time of occurrence relative to study treatment.
10.4.1.1.
Study Phases for Concomitant Medication
Study Phase
Definition
Prior
If medication end date is not missing and is before 28 days prior to screening visit
Concomitant
Any medication that is not a prior, and up to the last scheduled visit
NOTES: 

Please refer to Appendix 7: Reporting Standards for Missing Data for handling of missing and partial dates for 
concomitant medication. Use the rules in this table if concomitant medication date is completely missing.
10.4.2.
Treatment Emergent Flag for Adverse Events
Flag
Definition
Treatment 
Emergent

If AE onset date is on or after treatment start date & on or before treatment stop
date. (plus, washout or protocol-specified time limit (e.g. half-life of drug, certain
number of days, etc.).

Study Treatment Start Date ≤ AE Start Date ≤ Study Treatment Stop Date+ 1 day

If AE onset is during one period and worsens during a later period it would be
counted in both periods. For the initial period the logic would be as above. For the 
later period the logic would use the treatment dates associated with the later
period:
Treatment Period Start Date ≤ AE Worsening Date ≤ Study Treatment Stop Date+ 
1 day
NOTES: 

If the study treatment stop date is missing, then the AE will be considered to be On-Treatment.

Time of study treatment dosing and start/stop time of AEs should be considered, if collected.
 
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10.5.
Appendix 5: Data Display Standards & Handling 
Conventions
10.5.1.
Reporting Process
Software

The SAS Version 9.4 or above and WinNonlin Version 8.1 or above will be used.
Reporting Area
HARP Server
: uk1salx00175
HARP Compound
: dmwork/gsk1325760/mid205019
Analysis Datasets 

Analysis datasets will be created according to latest IDSL
Generation of RTF Files

RTF files will be generated for final SAC
10.5.2.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx)

4.03 to 4.23: General Principles

5.01 to 5.08: Principles Related to Data Listings

6.01 to 6.11: Principles Related to Summary Tables

7.01 to 7.13: Principles Related to Graphics 
Formats

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for reporting of 
data based on the raw data collected, unless otherwise stated.

Numeric data will be reported at the precision collected on the eCRF.

The reported precision from non eCRF sources will follow the IDSL statistical principles but may be
adjusted to a clinically interpretable number of DP’s. 
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses:

Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled visit days 
on the analyses and interpretation of the results will be assessed as appropriate.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject’s listings. 
Unscheduled Visits

Unscheduled visits will not be included in summary tables and/or figures.

All unscheduled visits will be included in listings.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
 
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Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.
10.5.3.
Reporting Standards for Pharmacokinetic
Reporting of Pharmacokinetic Concentration Data
Descriptive 
Summary Statistics
Refer to IDSL PK Display Standards.
Refer to IDSL Statistical Principle 6.06.1.
Note: Concentration values will be imputed as per GUI_51487 for descriptive 
summary statistics/analysis and summarized graphical displays only. 
Reporting of Pharmacokinetic Parameters
Descriptive 
Summary Statistics 
(Log Transformed)
N, n, geometric mean, 95% CI of geometric mean, standard deviation (SD) of 
logged data and between and or within geometric coefficient of variation (CVb/w 
(%)) will be reported.
[1] CVb (%) = √ (exp(SD2) - 1) * 100
(SD = SD of log transformed data) 
[2] CVw (%) = √ (exp(MSE) - 1) * 100 
(MSE = mean square error from mixed effect model of loge-transformed data).
Parameters Not 
Being Log 
Transformed
Tmax, Tlast, first point, last point, and number of points used in the
determination of λz, %AUCex
Summary Tables
All provided PK parameters will be summarised except Lamz, lamzUL, LamzLL, 
LamzNP and AUC % extrapolated area , Rsq-adjusted (if calculated).
Listings
Additionally, include the first point, last point and number of points used in the 
determination of lambda_z for listings.
 
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10.6.
Appendix 6: Derived and Transformed Data
10.6.1.
General
Multiple Measurements at One Analysis Time Point

Mean of the measurements will be calculated and used in any derivation of summary statistics but if 
listed, all data will be presented.

Participants having both High and Low values for Normal Ranges at any post-baseline visit for safety 
parameters will be counted in both the High and Low categories of “Any visit post-baseline” row of 
related summary tables. This will also be applicable to relevant Potential Clinical Importance summary 
tables.
Study Day

Calculated as the number of days from First Dose Date:

Ref Date = Missing              → Study Day = Missing 

Ref Date < First Dose Date → Study Day = Ref Date – First Dose Date

Ref Data ≥ First Dose Date → Study Day = Ref Date – (First Dose Date) + 1    
Palatability Questionnaire

Time difference between dose and questionnaire will be derived as:
Date/time of assessment - Date/time of dose
If this difference <= 10 min, then this subject will be flagged as Y else N
A separate flag variable for particularly this treatment will record value as Y or N
10.6.2.
Study Population
Demographics
Age

GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed
as follows:

Since Year of Birth is recorded in eCRF, date and month will be imputed as ‘30th June’ of that
Year.

Birth date will be presented in listings as ‘YYYY’.
Body Mass Index (BMI)
Calculated as Weight (kg) / [Height (m)]
2
Extent of Exposure

Number of days of exposure to study drug will be calculated based on the formula:  
Duration of Exposure in Days = Treatment Stop Date – (Treatment Start Date) + 1

Participants who were randomized but did not report a treatment start date will be categorised as 
having zero days of exposure. 
 
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10.6.3.
Safety
Laboratory Parameters
If a laboratory value which is expected to have a numeric value for summary purposes, has a
non-detectable level reported in the database, where the numeric value is missing, but typically
a character value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than x in the
comment field) is present, the number of decimal places in the observed values will be used to
determine how much to add or subtract in order to impute the corresponding numeric value.

Example 1: 2 Decimal Places = ‘< x’ becomes x – 0.01

Example 2: 1 Decimal Places = ‘> x’ becomes x + 0.1

Example 3: 0 Decimal Places = ‘< x’ becomes x – 1
Adverse Events
AE’S OF Special Interest

Not Applicable
ECG Parameters

Machine read values of PR, QRS, QT, QTc, QTcB, QTcF will be captured
10.6.4.
Pharmacokinetic
PK Endpoints

Not required in this section, please refer Section 8.1
 
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10.7.
Appendix 7: Reporting Standards for Missing Data
10.7.1.
Premature Withdrawals
Element
Reporting Detail
General

Participant study completion (i.e. as specified in the protocol) was defined as A 
participant is considered to have completed the study if he/she has completed all 
phases of the study including the follow-up visit.

Withdrawn participants will not be replaced in the study.

All available data from participants who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, unless 
otherwise specified.

Withdrawal visits will be summarised as withdrawal visits.
10.7.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank fields on 
the collection instrument:
o
These data will be indicated by the use of a “blank” in subject listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the table. 
o
Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such.
Outliers

Any participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
10.7.2.1.
Handling of Missing and Partial Dates
Element
Reporting Detail
General

Partial dates will be displayed as captured in subject listing displays.
Adverse 
Events

The eCRF allows for the possibility of partial dates (i.e., only month and year) to be 
recorded for AE start and end dates; that is, the day of the month may be missing. In 
such a case, the following conventions will be applied for calculating the time to onset 
and the duration of the event:
o
Missing Start Day: First of the month will be used unless this is before the start 
date of study treatment; in this case the study treatment start date will be used and 
hence the event is considered On-treatment as per Appendix 4: Study Phases and 
Treatment Emergent Adverse Events.
o
Missing Stop Day: Last day of the month will be used, unless this is after the stop 
date of study treatment; in this case the study treatment stop date will be used.

Completely missing start or end dates will remain missing, with no imputation applied. 
Consequently, time to onset and duration of such events will be missing.
Concomitant 
Medications/

Partial dates for any concomitant medications recorded in the CRF will be imputed 
using the following convention:
 
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Element
Reporting Detail
Medical 
History
o
If the partial date is a start date, a '01' will be used for the day and 'Jan' will be 
used for the month
o
If the partial date is a stop date, a '28/29/30/31' will be used for the day (dependent 
on the month and year) and 'Dec' will be used for the month.

The recorded partial date will be displayed in listings.
 
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10.8.
Appendix 8: Values of Potential Clinical Importance
10.8.1.
Laboratory Values
Haematology
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Hematocrit 
Ratio of 
1
Male
0.54
Female
0.54
∆from BL
> 0.075
Haemoglobin
g/L
Male
180
Female
180
∆from BL
>25
Lymphocytes 
x109/ L
0.8
Neutrophil Count 
x109/ L
1.5
Platelet Count 
x109/ L
100
550
While Blood Cell Count (WBC)
x109/ L
3
20
Clinical Chemistry
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Albumin 
g/L
30
Calcium
mmol/L
2
2.75
Creatinine
umol/L
∆from BL
>44.2
Glucose (fasting at screening)
mmol/L
3
9
Magnesium
mmol/L
0.5
1.23
Phosphorus
mmol/L
0.8
1.6
Potassium
mmol/L
3
5.5
Sodium
mmol/L
130
150
BUN
mmol/L
2x ULN (mmol/L)
Liver Function
Test Analyte
Units
Category
Clinical Concern Range
ALT/SGPT 
U/L
High
>=2xULN
AST/SGOT 
U/L
High
>=2xULN
AlkPhos 
U/L
High
>=2xULN
T Bilirubin 
µmol/L
High
>=1.5xULN
 
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10.8.2.
ECG
ECG Parameter
Units
Clinical Concern Range
Lower
Upper
Absolute
Absolute QTc Interval
msec
500
Absolute PR Interval
msec
110
220
Absolute QRS Interval
msec
75
110
Change from Baseline
Increase from Baseline QTc
msec
>60
10.8.3.
Vital Signs
Vital Sign Parameter
(Absolute)
Units
Clinical Concern Range
Lower
Upper
Systolic Blood Pressure
mmHg
85
160
Diastolic Blood Pressure
mmHg
40
110
Heart Rate
bpm
45
100
Vital Sign Parameter
(Change from Baseline)
Units
Clinical Concern Range
Increase
Lower
Upper
Systolic Blood Pressure
mmHg
>30
Diastolic Blood Pressure
mmHg
>20
 
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10.9.
Appendix 9: Abbreviations & Trade Marks
10.9.1.
Abbreviations
Abbreviation
Description
ADaM
Analysis Data Model
AE
Adverse Event
AIC
Akaike's Information Criteria
A&R
Analysis and Reporting 
AUC(0-inf)
Area under the concentration-time curve from time zero (predose) extrapolated 
to infinite time
AUC(0-t)
Area under the concentration-time curve from time zero (predose) to time of last 
quantifiable concentration within a participant across all treatments
BMI
Body Mass Index
CI
Confidence Interval
Cmax
Maximum observed concentration
CPMS
Clinical Pharmacology Modelling & Simulation
CS
Clinical Statistics
CSR
Clinical Study Report
CTR
Clinical Trial Register
CVb / CVw
Coefficient of Variation (Between) / Coefficient of Variation (Within)
DBF
Database Freeze
DBR
Database Release
DOB
Date of Birth
DP
Decimal Places
eCRF
Electronic Case Record Form
EMA
European Medicines Agency
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Clinical Results Disclosure Requirements
GSK
GlaxoSmithKline
IA
Interim Analysis
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee 
IDSL
Integrated Data Standards Library
IMMS
International Modules Management System
IP
Investigational Product
ITT
Intent-To-Treat
MMRM
Mixed Model Repeated Measures
NQ
Non-quantifiable
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
PK
Pharmacokinetic
PP
Per Protocol
PopPK
Population PK
QC
Quality Control
 
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Abbreviation
Description
QTcF
Frederica’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
RAP
Reporting & Analysis Plan
RAMOS
Randomization & Medication Ordering System 
SAC
Statistical Analysis Complete
SD
Standard deviation
SDSP
Study Data Standardization Plan
SDTM
Study Data Tabulation Model
SOP
Standard Operation Procedure
TA
Therapeutic Area
TFL
Tables, Figures & Listings 
tlag
Lab time before observation of drug concentrations in sampled matrix
tlast
Time of last quantifiable concentration
tmax
Time of occurrence of Cmax
WNL
Windows Non Linear
10.9.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
ADVAIR
SAS
HARP
WinNonlin 8.1 or above
 
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10.10
Appendix 10: List of Data Displays
10.10.1 Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.11
N/A
Safety
3.1 to 3.23
3.1 to 3.2
Pharmacokinetic
4.1 to 4.4
4.1 to 4.6
Section
Listings
ICH Listings
1 to 26
Other Listings
27 to 32
All displays (Tables, Figures & Listings) will use the term 'Subjects'.
10.10.2
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Appendix 11: Example Mock Shells for Data Displays.
Section
Figure
Table
Listing
Study Population
NA
POP_T1
NA
Safety
NA
SAFE_T1
SAFE_L1
Pharmacokinetic
PK_F1
NA
NA
NOTES: 

Non-Standard displays are indicated in the ‘IDSL / Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’
10.10.3
Deliverables
Delivery [Priority] [1]
Description
DR
Dry Run
SAC
Final Statistical Analysis Complete
NOTES: 
1.
Indicates priority (i.e. order) in which displays will be generated for the reporting effort
 
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10.10.4
Study Population Tables
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.1.
Safety
ES1A
Summary of subject Disposition for the subject Conclusion 
Record
ICH E3, FDAAA, EudraCT
DR , SAC 
1.2.
Safety
SD1
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment
ICH E3
DR , SAC 
1.3.
Screened
ES6
Summary of Screening Status and Reasons for Screen Failure
Journal Requirements
DR , SAC 
1.4.
Screened
NS1
Summary of Number of subjects by Country and Site ID
EudraCT/Clinical Operations
DR , SAC 
Population Analysed
1.5.
Screened
SP1
Summary of Study Populations 
IDSL
DR , SAC 
Demographic and Baseline Characteristics
1.6.
Safety
DM3
Summary of Demographic Characteristics
ICH E3, FDAAA, EudraCT
DR , SAC 
1.7.
Randomized
DM11
Summary of Age Ranges
EudraCT
DR , SAC 
1.8.
Safety
DM5
Summary of Race and Racial Combinations
ICH E3, FDA, FDAAA, EudraCT
DR , SAC 
Prior and Concomitant Medications
 
 
 
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Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.9.
Safety
MH1
Summary of Current/Past Medical Conditions
ICH E3
DR , SAC 
Palatability Questionnaire
1.10
Safety
POP_T1
Responder’s Summary of Palatability Questionnaire 
Non-standard
DR , SAC 
1.11
Safety
SAFE_T1
Responder’s compliance to 10 mins for Palatability 
Questionnaire
Non-standard
DR, SAC
10.10.5
Safety Tables
Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events (AEs)
3.1.
Safety
AE1CP
Summary of Treatment Emergent Adverse Events by System 
Organ Class and Preferred Term
ICH E3
DR , SAC 
3.2.
Safety
AE1CP
Summary of Treatment Emergent Drug-Related Adverse Events 
by System Organ Class and Preferred Term/by Overall 
Frequency
ICH E3
DR , SAC 
3.3.
Safety
AE15
Summary of Common (>=2%) Non-serious Treatment Emergent
Adverse Events by System Organ Class and Preferred Term 
(Number of Subjects and Occurrences)
FDAAA, EudraCT
DR , SAC 
Serious and Other Significant Adverse Events
 
 
 
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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.4.
Safety
AE16
Summary of Serious Treatment Emergent Adverse Events by 
System Organ Class and Preferred Term (Number of subjects
and Occurrences)
FDAAA, EudraCT
DR , SAC 
3.5.
Safety
CP_AE1x
Summary of Treatment Emergent Adverse Events Leading to 
Permanent Discontinuation of Study Treatment or Withdrawal 
from Study by System Organ Class and Preferred Term /by 
Overall Frequency
IDSL
DR , SAC 
Laboratory: Chemistry 
3.6.
Safety
LB1
Summary of Chemistry Changes from Baseline 
ICH E3
DR , SAC 
3.7.
Safety
LB1
Summary of Chemistry Values
DR , SAC
3.8.
Safety
LB17
Summary of Worst Case Chemistry Results by PCI Criteria
Post-Baseline Relative to Baseline
ICH E3
DR , SAC 
Laboratory: Hematology
3.9.
Safety
LB1
Summary of Hematology Changes from Baseline
ICH E3
DR , SAC 
3.10.
Safety
LB1
Summary of Hematology Values
DR , SAC
3.11.
Safety
LB17
Summary of Worst Case Hematology Results by PCI Criteria
Post-Baseline Relative to Baseline
ICH E3
DR , SAC 
Laboratory: Urinalysis
3.12.
Safety
UR1
Summary of Worst-Case Urinalysis Results Post-Baseline 
Relative to Baseline
ICH E3
DR , SAC
 
 
 
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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.13.
Safety
LB1
Summary of Urine Concentration Changes from Baseline
ICH E3
Only where microscopic 
examination is done 
DR , SAC 
Laboratory: Hepatobiliary (Liver)
3.14.
Safety
LIVER1
Summary of Liver Monitoring/Stopping Event Reporting
IDSL
DR , SAC 
3.15.
Safety
LIVER10
Summary of Hepatobiliary Laboratory Abnormalities
IDSL
DR , SAC 
ECG
3.16.
Safety
EG1
Summary of ECG Findings 
IDSL
DR , SAC 
3.17.
Safety
EG2
Summary of ECG Values
IDSL
DR , SAC 
3.18.
Safety
EG10
Summary of Maximum QTc Values Post-Baseline Relative to 
Baseline by Category
IDSL
DR , SAC 
3.19.
Safety
CP_EG9
Summary of Change from Baseline in ECG Values by Visit
IDSL
DR , SAC 
3.20.
Safety
EG11
Summary of Maximum Increase in QTc Values Post-Baseline 
Relative to Baseline by Category
IDSL
DR , SAC 
Vital Signs
3.21.
Safety
VS1
Summary of Vital Signs
IDSL 
All vital signs including heart rate and 
temperature to be summarised.
DR, SAC
3.22.
Safety
VS1
Summary of Change from Baseline in Vital Signs
ICH E3
All vital signs including heart rate and 
temperature to be summarised.
DR , SAC 
 
 
 
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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.23.
Safety
VS7
Summary of Worst Case Vital Signs Results by PCI Criteria
Post-Baseline Relative to Baseline
IDSL
DR , SAC 
 
 
 
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10.10.6
Safety Figures
Safety: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Laboratory
3.1.
Safety
LIVER14
Scatter Plot of Maximum vs. Baseline for ALT
IDSL
DR , SAC 
3.2.
Safety
LIVER9
Scatter Plot of Maximum ALT vs. Maximum Total Bilirubin
IDSL
DR , SAC 
 
 
 
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10.10.7
Pharmacokinetic Tables
Pharmacokinetic: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Plasma GSK1325760
4.1.
PK
Pkct1
Summary of Plasma GSK1325760 Concentration-Time data
by treatment
DR , SAC 
4.2.
PK_PAR
Pkpt1
Summary of Untransformed Plasma GSK1325760 Derived 
Pharmacokinetic Parameters by treatment
Parameters with units
DR , SAC 
4.3.
PK_PAR
Pkpt3
Summary of Loge-transformed Plasma GSK1325760 Derived 
Pharmacokinetic Parameters by treatment
Parameters with units
DR , SAC 
PK Statistical Analysis
4.4.
PK_PAR
PK_T1
Summary of Statistical Analysis of Loge-transformed Plasma
GSK1325760 Derived PK Parameters
Footnotes as in example mock shell by 
treatment
DR , SAC 
 
 
 
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10.10.8
Pharmacokinetic Figures
Pharmacokinetic: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Plasma GSK1325760
4.1.
PK
Pkcf6
Individual Subject Plasma GSK1325760 Concentration-Time 
Plots (Linear and Semi-log) by Treatment
Spaghetti plots, all subjects by 
treatment.
DR, SAC 
4.2.
PK
Pkcf1x
Individual Subject GSK1325760 Plasma Concentration-Time 
Plot (Linear and Semi-log) by Subject
Paginate by Subject.
Different point symbol (and colour) to 
be used for each treatment and to be 
mentioned in footnote of the figure.
DR, SAC
4.3.
PK
Pkcf4
Arithmetic Mean(+SD) GSK1325760 Concentration-Time Plots 
(Linear and Semi-log) by Treatment
Different line type (and colour) to be 
used for each treatment and to be 
mentioned in footnote of the figure
All treatments on one page.
DR, SAC 
4.4.
PK
Pkcf5
Median(range) Plasma GSK1325760 Concentration -
time Plot (Linear and Semi-log) by Treatment
Different line type (and colour) to be 
used for each treatment and to be 
mentioned in footnote of the figure
All treatments on one page.
DR, SAC 
4.5.
PK_PAR
Pkpf3
Comparative Plot of Individual Subject GSK1325760 Plasma 
Concentration-Time Derived Parameters vs. Treatment (Linear 
and semi-logarithmic)
Needed for only AUC(0-inf), AUC(0-t) 
and Cmax, each parameter on different 
page.
For each parameter all treatments on 
one page.
DR, SAC
4.6.
PK_PAR
PK_F1
Geometric Mean (90% CI) Treatment Ratios of GSK1325760 
Plasma Derived Pharmacokinetic Parameters
Comparison F1-R, F2-R. Needed for 
only AUC(0-inf), AUC(0-t) and Cmax.
[Non-Standard]
DR, SAC
 
 
 
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10.10.9
ICH Listings
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.
Safety
ES3
Listing of Reasons for Study Withdrawal
ICH E3
DR , SAC 
2.
Safety
SD3
Listing of Reasons for Study Treatment Discontinuation
ICH E3
DR , SAC 
Protocol Deviations
3.
Safety
DV2A
Listing of Important Protocol Deviations 
ICH E3
DR , SAC 
4.
Safety
IE4
Listing of subjects with Inclusion/Exclusion Criteria Deviations
ICH E3
DR , SAC 
Demographic and Baseline Characteristics
5.
Safety
DM4
Listing of Demographic Characteristics
ICH E3
DR , SAC 
6.
Safety
DM10
Listing of Race
ICH E3
DR , SAC 
Prior and Concomitant Medications
7.
Safety
CM5
Listing of Concomitant Medications
IDSL
DR , SAC 
Exposure and Treatment Compliance
8.
Safety
EX4
Listing of Exposure Data
ICH E3
DR , SAC 
Adverse Events
9.
Safety
AE9CP
Listing of All Adverse Events
ICH E3
DR , SAC 
10.
Safety
AE7
Listing of Subject Numbers for Individual Adverse Events
ICH E3
DR , SAC 
 
 
 
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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
11.
Safety
AE2
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text
IDSL
DR , SAC 
Serious and Other Significant Adverse Events
12.
Safety
CP_AE9a
Listing of Fatal Serious Adverse Events
ICH E3
DR , SAC 
13.
Safety
CP_AE9a
Listing of Non-Fatal Serious Adverse Events
ICH E3
DR , SAC 
14.
Safety
AE14
Listing of Reasons for Considering as a Serious Adverse Event
ICH E3
DR , SAC 
15.
Safety
CP_AE9
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment
ICH E3
DR , SAC 
All Laboratory
16.
Safety
CP_LB6
Listing of All Laboratory Data for Subjects with Any Value of 
Potential Clinical Importance/Outside Normal Range
ICH E3
DR , SAC 
17.
Safety
CP_LB6
Listing of Laboratory Values of Potential Clinical Importance
DR , SAC 
18.
Safety
LB14
Listing of Laboratory Data with Character Results
ICH E3
DR , SAC 
19.
Safety
UR2B
Listing of Urinalysis Data for Subjects with Any Value of 
Potential Clinical Importance
ICH E3
Abnormal dipstick findings and 
microscopic results
DR , SAC 
ECG
20.
Safety
CP_EG4
Listing of All ECG Values for Subjects with Any Value of 
Potential Clinical Importance
IDSL
DR, SAC 
21.
Safety
CP_EG4
Listing of ECG Values of Potential Clinical Importance
IDSL
DR, SAC 
22.
Safety
      CP_EG6
Listing of All ECG Findings for Subjects with an Abnormal ECG 
Finding
IDSL
DR, SAC 
 
 
 
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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
23.
Safety
CP_EG6
Listing of Abnormal ECG Findings
IDSL
DR, SAC 
Vital Signs
24.
Safety
CP_VS5
Listing of All Vital Signs Data for Subjects with Any Value of 
Potential Clinical Importance
IDSL
DR, SAC 
25.
Safety
CP_VS5
Listing of Vital Signs of Potential Clinical Importance
IDSL
DR, SAC 
26.
Safety
CP_VS5
Listing of CFB in Vital Signs of Potential Clinical Importance
IDSL
DR, SAC 
 
 
 
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10.10.10
Non-ICH Listings
Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
PK
27.
PK
pkcl1x
Listing of Plasma GSK1325760 Concentration-time Data by 
treatment
List all the concentration data including 
unscheduled
DR, SAC
28.
PK_PAR
pkpl1p
Listing of Derived Plasma GSK1325760 Pharmacokinetic 
Parameters by Treatment
DR, SAC
29.
PK_PAR
Pkpl2
Listing of GSK1325760 Pharmacokinetic Parameter Ratios by 
treatment
DR, SAC
30.
PK_PAR
NA
RAW SAS Output from Statistical Analysis of GSK1325760 
Plasma Pharmacokinetic Parameters
DR, SAC
Study Population
31.
Safety
SAFE_L1
Listing of all subjects with the time of answering palatability 
questionnaire
Footnotes
DR, SAC
 
 
 
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10.11
Appendix 11: Example Mock Shells for Data Displays
Example: POP_T1
Protocol:  205019
Population: Safety
Table 1.10
Responder’s Summary of Palatability Questionnaire 
Question No.
Response
Dispersed GSK1325760
(N=20)
n(%)
   Note:
   Question 1:
   Question 2:
   Question 3: 
 
   Dispersed GSK1325760 : 5 mg (5 x 1 mg tablets) AMB tablet dispersed in water
 
2019N426492_00
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, 
which are protected by third party copyright laws and therefore have been excluded.
CCI
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Example: SAFE_T1
Protocol:    205019
Population: Safety
Table 1.11
Responder’s compliance to 10 mins for Palatability Questionnaire 
Treatment Period
Dispersed GSK1325760
(N=8)
n(%)
Period 1
4(50%)
   
   
              Period 2
     8(100%)
          Period 3                                                                                                  8(100%)
              
Footnote:
Dispersed GSK1325760 : 5 mg (5 x 1 mg tablets) AMB tablet dispersed in water
 
 
 
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Example 
: PK_T1
                                        Page 1 of n
Protocol
: mid205019
Population
: PK_PAR
Table 4.4
Summary of Statistical Analysis of Loge-transformed Plasma GSK1325760 PK Parameters
Parameter
   Comparison
       Adjusted Geometric Mean
               Ratio
90% Confidence
%CVw
Test vs Reference
(Test/Ref)
Interval for the Ratio
          n    Test        n    Ref
AUC(0-inf)(units)  
   Dispersed GSK1325760
        x   xx.xx          x  xx.xx
x.xxxx                 (x.xxxx, x.xxxx)
xx.x
                vs Marketed AMB
AUC(0-t)(units)     
   Oral GSK1325760            
         x   xx.xx          x  xx.xx
x.xxxx
(x.xxxx, x.xxxx)
xx.x
                                                         vs Marketed AMB
FOOTNOTE:
Dispersed GSK1325760: 5mg (5x 1 mg tablets) AMB tablet dispersed in water
Oral GSK1325760: 5mg (5 x 1 mg tablets) AMB tablet administered orally
Marketed AMB: 5 mg (1 x 5 mg tablet) AMB tablet administered orally
Example 
: SAFE_L1
                                        Page 1 of n
Protocol
: mid205019
Population
: Safety
 
 
 
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Listing 32
Listing of all subjects with the time of answering palatability questionnaire
Subj.
{Age(y)/
Sex/
Race}
Treatme
nt 
Period/
Tmt.
Date/Time of 
Dosing
Date/Time of 
Questionnaire
Time between 
dosing and 
questionnaire 
(in mins)
36/
M/
Mixed Race
Period 
1/
Dispersed 
GSK132576
0
xx-xx-xx 
xx:xx:xx
xx-xx-xx 
xx:xx:xx
Xxx
33/
M/
Mixed Race
Period 
2/
Dispersed 
GSK132576
0
xx.xx
xx-xx-xx 
xx:xx:xx
Xxx
24/
M/
Mixed Race
Period 
3/
Dispersed 
GSK132576
0
xx.xx
xx-xx-xx 
xx:xx:xx
xxx
FOOTNOTE:
Dispersed GSK1325760: 5mg (5x 1 mg tablets) AMB tablet dispersed in water
Example 
: PK_F1
                                        Page 1 of n
Protocol
: mid205019
Population
: PK_PAR
Figure 4.6
 
 
 
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Geometric Mean Treatment Ratio and 90% CI of Analyte Matrix PK Parameters
Note: A,B,C are test treatments(in this case F1 and F2) and R is the Reference treatment
FOOTNOTE:
Dispersed GSK1325760: 5mg (5x 1 mg tablets) AMB tablet dispersed in water
Oral GSK1325760: 5mg (5 x 1 mg tablets) AMB tablet administered orally
Marketed AMB: 5 mg (1 x 5 mg tablet) AMB tablet administered orally
 
 
 
2019N426492_00