Conditions: Hypertension, Pulmonary
Keywords: Idiopathic Pulmonary Arterial Hypertension Biodistribution Positron Emission Tomography [11C]-GSK2256098 Healthy subjects
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 10
Healthy volunteers: yes

Brief summary:
Pulmonary arterial hypertension (PAH) involves the narrowing of blood vessels connected to and within the lungs. Focal adhesion kinase (FAK) is a focal adhesion-associated protein kinase involved in cellular adhesion and spreading processes which leads to stiffening and thickening of blood vessels in lungs. This further increases the blood pressure within the lungs and impairs their blood flow. This study aims to demonstrate biodistribution of FAK inhibitor, GSK2256098, in cardiopulmonary sites i.e. heart and lung tissues. The uptake of 11C-radiolabelled GSK2256098 within the lung and / or heart of healthy subjects and idiopathic pulmonary arterial hypertension (iPAH) patients will be assessed using Positron Emission Tomography (PET). Based on study results the decision as to whether a follow-on phase 2 trial should be initiated to investigate the therapeutic utility of GSK2256098 in iPAH will be decided. Sufficient number of subjects will be screened (up to 30 days prior to scan) to enrol 12 healthy subjects and 12 PAH patients in the study. Enrolled subjects will receive a microdose of \[11C\]-GSK2256098 on a scanning day which will be followed by the follow-up visit (2-4 weeks post-last dose).

Detailed description:

Arms:
arm 1: Subjects will receive single IV bolus injection of \[11C\]-GSK2256098 over about 30 seconds. Each unit dose will contain up to 500 millibecquerel (MBq) of \[11C\]-GSK2256098 with maximum \[11C\]-GSK2256098 mass \<=10 microgram (mcg).

Interventions: intervention 1: [11C]-GSK2256098 500 MBq
Intervention descriptions: intervention 1: \[11C\]-GSK2256098 injection will be provided as IV infusion, 20 mL, containing up to 5% ethanol in saline.

Protocol document:
Prot_002.pdf: 
2015N237824_03
CONFIDENTIAL
The GlaxoSmithKline group of companies
204746
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A microdose Study to Evaluate the Biodistribution of [11C]-
GSK2256098 in the Lungs and Heart of Healthy Subjects and 
Pulmonary Arterial Hypertension (PAH) Patients using Positron 
Emission Tomography (PET)
Compound Number:
GSK2256098
Development Phase:    I
Effective Date:
22-APR-2016
Protocol Amendment Number:  03
Author (s):
 (Clinical Statistics); 
 (AcDPU); 
 
 (CPSSO); 
 (Respiratory TAU); 
 (AcDPU); 
 (II DPU Clinical Imaging)
Revision Chronology
GlaxoSmithKline 
Document Number
Date
Version
2015N237824_00
2015-JUN-15
Original
2015N237824_01
2015-JUL-03
Amendment No. 1
To amend the eligibility criteria
2015N237824_02
2015-NOV-24
Amendment No. 2
To clarify some ambiguous text in the protocol
2015N237824_03
2016-APR-22
Amendment No. 3
To include iPAH patients with QTcF interval up to and including 500 msec. 
Copyright 2016 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD
PPD
PPD
PPD
PPD
PPD
PPD


PPD
PPD


2015N237824_03
CONFIDENTIAL
204746
3
MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information:
Role
Name
Day Time Phone Number 
and email address
After-hours 
Phone/Cell/
Pager Number
Fax 
Number
Site Address
Primary 
Medical 
Monitor 
 
 
M.D.
GSK, 
Gunnels 
Wood Road, 
Stevenage, 
Hertfordshire, 
SG1 2NY
Secondary 
Medical 
Monitor
 
 
M.D.
GSK, 
Gunnels 
Wood Road, 
Stevenage, 
Hertfordshire, 
SG1 2NY
SAE 
contact  
information 
Medical 
monitors 
as above
Sponsor Legal Registered Address:
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate 
Company (or designee). If applicable, the details of the alternative Sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application.   
Regulatory Agency Identifying Number(s):  2015-002626-40
PPD
PPD
PPD
PPD
PPD


2015N237824_03
CONFIDENTIAL
204746
4
INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 204746.
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date


2015N237824_03
CONFIDENTIAL
204746
5
TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 204746........................................................8
2.
INTRODUCTION....................................................................................................11
2.1.
Study Rationale ..........................................................................................11
2.2.
Brief Background ........................................................................................11
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................12
4.
STUDY DESIGN ....................................................................................................12
4.1.
Overall Design ............................................................................................12
4.2.
Treatment Arms and Duration.....................................................................12
4.3.
Type and Number of Subjects.....................................................................12
4.4.
Design Justification.....................................................................................13
4.5.
Benefit:Risk Assessment ............................................................................13
4.5.1.
Risk Assessment .........................................................................14
4.5.2.
Benefit Assessment.....................................................................16
4.5.3.
Overall Benefit:Risk Conclusion...................................................16
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............16
5.1.
Inclusion Criteria.........................................................................................16
5.1.1.
Healthy Volunteers ......................................................................16
5.1.2.
PAH Patients ...............................................................................18
5.2.
Exclusion Criteria........................................................................................20
5.2.1.
Healthy Volunteer Subjects..........................................................20
5.2.2.
PAH Patients ...............................................................................22
5.3.
Screening Failures......................................................................................23
5.4.
Withdrawal/Stopping Criteria.......................................................................23
5.5.
Subject and Study Completion....................................................................24
6.
STUDY TREATMENT ............................................................................................24
6.1.
Investigational Product and Other Study Treatment....................................24
6.2.
Blinding.......................................................................................................24
6.3.
Packaging and Labeling..............................................................................24
6.4.
Preparation/Handling/Storage/Accountability..............................................25
6.5.
Compliance with Study Treatment Administration.......................................25
6.6.
Treatment of Study Treatment Overdose....................................................25
6.7.
Treatment after the End of the Study ..........................................................26
6.8.
Lifestyle Restrictions...................................................................................26
6.8.1.
Activity .........................................................................................26
6.8.2.
Alcohol.........................................................................................26
6.9.
Concomitant Medications and Non-Drug Therapies....................................26
6.9.1.
Permitted Medications and Non-Drug Therapies..........................26
6.9.2.
Prohibited Medications and Non-Drug Therapies.........................26
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................27
7.1.
Time and Events Table...............................................................................28
7.2.
Screening and Critical Baseline Assessments ............................................30
7.3.
Safety .........................................................................................................30


2015N237824_03
CONFIDENTIAL
204746
6
7.3.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........30
7.3.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................30
7.3.1.2.
Method of Detecting AEs and SAEs ...........................31
7.3.1.3.
Follow-up of AEs and SAEs........................................31
7.3.1.4.
Cardiovascular and Death Events ..............................31
7.3.1.5.
Regulatory Reporting Requirements for SAEs............31
7.3.2.
Pregnancy ...................................................................................32
7.3.3.
Physical Exams ...........................................................................32
7.3.4.
Vital Signs....................................................................................32
7.3.5.
Electrocardiogram (ECG).............................................................32
7.3.6.
Clinical Safety Laboratory Assessments ......................................32
7.3.7.
Positron Emission Tomography (PET).........................................33
7.3.8.
Blood Sample Collection..............................................................34
7.4.
Genetics .....................................................................................................34
8.
DATA MANAGEMENT ...........................................................................................34
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................34
9.1.
Hypotheses.................................................................................................34
9.2.
Sample Size Considerations.......................................................................35
9.2.1.
Sample Size Re-estimation or Adjustment...................................35
9.3.
Data Analysis Considerations .....................................................................36
9.3.1.
Interim Analysis ...........................................................................36
9.4.
Key Elements of Analysis Plan ...................................................................36
9.4.1.
Primary Analyses.........................................................................36
9.4.2.
Other Analyses ............................................................................37
10. STUDY GOVERNANCE CONSIDERATIONS........................................................37
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............37
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................37
10.3.
Quality Control (Study Monitoring) ..............................................................38
10.4.
Quality Assurance.......................................................................................38
10.5.
Study and Site Closure ...............................................................................39
10.6.
Records Retention......................................................................................39
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................40
11. REFERENCES.......................................................................................................41
12. APPENDICES........................................................................................................42
12.1.
Appendix 1:Abbreviations and Trademarks.................................................42
12.2.
Appendix 2:Genetic Research ....................................................................45
12.3.
Appendix 3:Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................48
12.3.1.
Definition of Adverse Events........................................................48
12.3.2.
Definition of Serious Adverse Events...........................................49
12.3.3.
Definition of Cardiovascular Events .............................................50
12.3.4.
Recording of AEs and SAEs ........................................................51
12.3.5.
Evaluating AEs and SAEs............................................................51
12.3.6.
Reporting of SAEs to GSK...........................................................53


2015N237824_03
CONFIDENTIAL
204746
7
12.4.
Appendix 4:Collection of Pregnancy Information.........................................54
12.5.
Appendix 5:Radiation Dose ........................................................................55
12.6.
Appendix 6:Protocol Changes.....................................................................56


2015N237824_03
CONFIDENTIAL
204746
8
1.
PROTOCOL SYNOPSIS FOR STUDY 204746
Rationale
Pulmonary Arterial Hypertension (PAH) used to be considered primarily a consequence 
of abnormal pulmonary vasoconstriction, but is now regarded as a disease caused mainly 
by pulmonary vascular remodelling with features analogous to carcinogenesis 
[Guignabert, 2013]. 
The currently available PAH therapies are vasodilators and provide symptomatic support 
but do not fully address the underlying remodelling aspects of the disease where there is a 
significant unmet need for a specific disease modifying PAH therapy. 
In 2011, Novartis submitted an application for use of imatinib (Ruvise), a tyrosine kinase 
inhibitor, as an add-on therapy for the treatment of pulmonary arterial hypertension 
(PAH) to improve exercise capacity in patients with pulmonary vascular resistance who 
remain symptomatic on dual vasodilator therapy. This was based on early clinical data 
indicating improvements in PVR/PAP. This medicine would have been the first disease-
modifying treatment for PAH, but failed to receive a positive opinion (lack of sufficient 
positive risk/benefit evidence) and Novartis withdrew their application in January 2013.
GSK has identified the FAK inhibitor, GSK2256098, currently in development for 
glioblastoma as a candidate for repurposing for PAH.
Focal adhesion kinase (FAK) is a non-receptor kinase intracellular signalling node which 
is important for the initiation and maintenance of vascular smooth muscle cell (SMC) 
switching to the synthetic phenotype. GSK also has in vitro tissue cell data showing 
pulmonary artery smooth muscle cell migration effects, further demonstration of the 
target in disease relevant tissues is important before proceeding to a clinical Ph II study in 
PAH patients.
Therefore, a PET imaging study using a microdose of a 11C-radiolabelled FAK tyrosine 
kinase inhibitor (TKI) GSK2256098 will enable identification of the cardiopulmonary 
sites where there is both expression of autoactivated, signalling-ready, FAK and drug 
exposure. The uptake of 11C –GSK2256098 within the lung and / or heart will inform the 
decision as to whether a follow-on phase 2 trial should be initiated to investigate the 
therapeutic utility of GSK2256098 in iPAH.


2015N237824_03
CONFIDENTIAL
204746
9
Objective(s)/Endpoint(s)
Objectives
Endpoints
Primary

To compare the uptake of [11C]-
GSK2256098 in the heart and lungs of PAH 
patients versus the heart and lungs of 
healthy control subjects

Uptake of [11C]-GSK2256098 in the heart 
and lung (assessed as the volume of 
distribution(VT) and/or standardised uptake 
values (SUV)) as measured by PET
Exploratory

To explore the spatial distribution of [11C]-
GSK2256098 uptake in the heart and lungs 
of PAH patients versus the heart and lungs 
of healthy control subjects.

Qualitative assessment of the spatial 
distribution of [11C]-GSK2256098 uptake in 
the heart and lungs 
Overall Design

This will be a cross-sectional study exploring the uptake of [11C]-GSK2256098 in 
PAH patients and in healthy (age and gender-matched) volunteers.

This is a non-randomised, open label study where all volunteers will receive one 
microdose of the radiolabelled compound.
Treatment Arms and Duration

The total duration of the study for each subject will be approximately 2 months from 
screening to follow-up. The screening period will be followed by 1 scanning day and 
the follow-up visit.

All subjects will receive one microdose of [11C]-GSK2256098. The maximum 
amount of radioactivity injected during the –PET scan will be 500 MBq and 
maximum mass of [11C]-GSK2256098 administered will be ≤10µg.

Subject completion for the primary endpoint is defined as a subject who completes 
the PET-CT scan visit.
Type and Number of Subjects

Up to 12 healthy subjects and 12 PAH patients will be enrolled to provide sufficient 
PET data to quantify the uptake of [11C]-GSK2256098 in the heart and lungs.

If subjects prematurely discontinue the study, additional subjects may be enrolled as 
replacement subjects at the discretion of the Investigator/GSK Medical Monitor


2015N237824_03
CONFIDENTIAL
204746
10
Analysis
Hypotheses
Although a valid scientific hypothesis underpins this study, as expressed in the study 
objectives (viz: “FAK inhibitor uptake is substantially higher in patients than in 
(relatively) well-matched healthy control subjects”), no statistical hypothesis testing will 
be conducted, nor will any p-values be generated. (It would make no sense to “reject” a 
null hypothesis of “no difference in FAK expression between patients and healthy 
volunteers (HVs)” in the absence of a pre-specified threshold of clinical relevance.) 
Instead, we will adopt an estimation approach, and use simple Bayesian methods to 
quantify the evidence which the study generates about the endpoints themselves, and 
about contrasts (probably ratios) of those endpoints. We will evaluate the evidence in as 
close to real-time as is feasible.
Sample Size Considerations
There is little known about the likely mean values of the PET-derived functional primary 
endpoints (Volume of distribution, and/or some form of integrated SUV) in this 
population. Therefore our sample size is driven by a mixture of (i) what is known about 
between-subject variability from relevant, recent PET studies, (ii) feasibility, and (iii) 
flexibility.
An ongoing study investigating the validation and dosimetry of a PET ligand in healthy 
subjects and patients with IPF (study RES116235) has been able to draw firm 
conclusions about similar endpoints (in terms of the estimation methods we describe 
below) using around 5 subjects. Therefore we will set five patients and five age- and 
gender-matched HVs as our initial target sample size. 
From that point onwards, the data will be monitored continuously (or as near as possible 
given practicalities of study operationalisation), and at each step the following decisions 
will be made: 

Stop, and conclude that there is strong evidence of differential FAK uptake (as 
measured by the study endpoints) between patients and HVs.

Stop, and conclude that there is insufficient evidence of any great difference, and 
furthermore (conditional on observed data i.e. in a formal Bayesian sense) there is 
low probability that an increase in sample size will reverse such a conclusion

Continue to enrol patient-HV pairs, and re-evaluate the decision.
This iterative cycle will be followed up until a maximum of twelve patients and twelve 
HVs have been recruited into the study.


2015N237824_03
CONFIDENTIAL
204746
11
2.
INTRODUCTION
GSK2256098 is a FAK inhibitor being considered for the treatment PAH.
2.1.
Study Rationale
Focal adhesion kinase (FAK) is a non-receptor kinase intracellular signalling node which 
is important for the initiation and maintenance of vascular SMC switching to the 
synthetic phenotype. GSK also has in vitro tissue cell data showing pulmonary artery 
smooth muscle cell migration effects, further demonstration of the target in disease 
relevant tissues is important before proceeding to a clinical Ph II study in PAH patients.
Therefore, a PET imaging study using a microdose of a 11C-radiolabelled FAK tyrosine 
kinase inhibitor (TKI) GSK2256098 will enable identification of the cardiopulmonary 
sites where there is both expression of autoactivated, signalling-ready, FAK and drug 
exposure. The uptake of 11C –GSK2256098 within the lung and / or heart will inform the 
decision as to whether a follow-on phase 2 trial should be initiated to investigate the
therapeutic utility of GSK2256098 in iPAH.
2.2.
Brief Background
Pulmonary Arterial Hypertension (PAH) used to be considered primarily a consequence 
of abnormal pulmonary vasoconstriction, but is now regarded as a disease caused mainly 
by pulmonary vascular remodelling with features analogous to carcinogenesis 
[Guignabert, 2013]. 
The currently available PAH therapies are vasodilators and provide symptomatic support 
but do not fully address the underlying remodelling aspects of the disease where there is a 
significant unmet need for a specific disease modifying PAH therapy. This is particularly 
important since increasing pulmonary artery pressures leads to progressive, and 
sometimes maladaptive, right ventricle remodelling which increases the risk of QTcF 
interval prolongation (Rich, 2013), and is probably one of the factors which contributes 
to the increased risk of sudden death in this population.
In 2011, Novartis submitted an application for use of imatinib (Ruvise), a tyrosine kinase 
inhibitor, as an add-on therapy for the treatment of pulmonary arterial hypertension 
(PAH) to improve exercise capacity in patients with pulmonary vascular resistance who 
remain symptomatic on dual vasodilator therapy. This was based on early clinical data 
indicating improvements in PVR/PAP. This medicine would have been the first disease-
modifying treatment for PAH, but failed to receive a positive opinion, due to lack of 
positive risk/benefit and Novartis withdrew their application in January 2013.
GSK has identified the FAK inhibitor, GSK2256098, currently in development for 
glioblastoma as a candidate for repurposing for PAH.


2015N237824_03
CONFIDENTIAL
204746
12
3.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Primary

To compare the uptake of [11C]-
GSK2256098 in the heart and lungs of PAH 
patients versus the heart and lungs of 
healthy control subjects

Uptake of [11C]-GSK2256098 in the heart 
and lung (assessed as the volume of 
distribution(VT) and/or standardised uptake 
values (SUV)) as measured by PET
Exploratory

To explore the spatial distribution of [11C]-
GSK2256098 uptake in the heart and lungs 
of PAH patients versus the heart and lungs 
of healthy control subjects.

Qualitative assessment of the spatial 
distribution of [11C]-GSK2256098 uptake in 
the heart and lungs  
4.
STUDY DESIGN
4.1.
Overall Design

This will be a cross-sectional study exploring the uptake of [11C]-GSK2256098 in 
PAH patients and in healthy (age and gender-matched) volunteers.

This is a non-randomised, open label study where all volunteers will receive one 
microdose of the radiolabelled compound.
4.2.
Treatment Arms and Duration

The total duration of the study for each subject will be approximately 2 months from 
screening to follow-up. The screening period will be followed by 1 scanning day and 
the follow-up visit.

All subjects will receive one microdose of [11C]-GSK2256098. The maximum 
amount of radioactivity injected during the –PET scan will be 500 MBq and 
maximum mass of [11C]-GSK2256098 administered will be ≤10µg.
4.3.
Type and Number of Subjects

Up to 12 healthy subjects and 12 PAH patients (including those with a prolonged 
QTcF interval ≤ 500ms) will be enrolled to provide sufficient PET data to quantify 
the uptake of [11C]-GSK2256098 in the heart and lungs.

If subjects prematurely discontinue the study, additional subjects may be enrolled as 
replacement subjects at the discretion of the Investigator/GSK Medical Monitor.


2015N237824_03
CONFIDENTIAL
204746
13
4.4.
Design Justification
The study will be open-label and non-randomised as there is no intention of performing 
inference about the safety or efficacy profile of an NCE or other test therapeutic vs any 
form of control. A sufficient number of subjects will be recruited, based on feasibility, to 
permit adequate quantification of the uptake of [11C]-GSK2256098 in target organs 
within the patient population, and those levels of expression will be compared with those 
measured in a set of age and gender-matched healthy controls. This form of case 
matching is intended to reduce the variance in the estimate of uptake by imposing a form 
of biological control on the signal derived from the subjects.
4.5.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
GSK2256098 can be found in the Investigator’s Brochure. Of note the amount of 
GSK2256098 administered is a tracer dose and is not expected to result in any clinically 
significant pharmacology. The following section outlines the risk assessment and 
mitigation strategy for this protocol: 


2015N237824_03
CONFIDENTIAL
204746
14
4.5.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Procedures
Subjects will be exposed to an additional 
dose of ionising radiation as a consequence 
of their participation in this study
The majority of the radiation dose comes 
from the administered radioligand, while a 
smaller portion comes from a low dose CT 
scan performed to estimate tissue 
attenuation.
Subjects < 40 years will not be eligible for 
the study.  
In addition, the study will exclude subjects 
who have previously participated in a 
research protocol involving nuclear 
medicine, PET and/or HRCT or radiological 
investigations or occupational exposure 
resulting in radiation exposure greater than 
10 mSv over the past 3 years or greater than 
10 mSv in a single year including the 
proposed study (clinical exposure from 
which the subject receives potential direct 
benefit is not included in these calculations).
The study will exclude women of 
childbearing potential.
The maximal dose of ionising radiation that 
subjects in this study may be exposed to is 
outlined in Appendix 5.
Arterial cannulation
Arterial blood for quantitative analysis will 
be sampled from a cannula in the radial 
artery.
Subject suitability to undergo radial artery 
cannulation will be assessed by means of an 
Allen’s test assessment and testing the 


2015N237824_03
CONFIDENTIAL
204746
15
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
subjects blood coagulation profile. Arterial 
cannulation will be performed by suitably 
trained staff under local anaesthetic, using 
best practice. On completion of the PET 
scan, the radial artery cannula will be 
removed and subjects observed until 
haemostasis obtained. The PAH patients 
will be at an increased risk of bruising and 
will not be discharged until the Investigator 
is happy with the cannulation site. The total 
amount of blood collected for all of the 
study procedures will not exceed 500 mL.
Warfarin will be discontinued in subjects on 
prophylactic doses about 5 days before the 
arterial cannulation.  Arterial cannulation 
will be performed with an INR ideally ≤ 2.  
In situations where, anticoagulation is 
administered with a therapeutic intent 
(rather than simply prophylaxis), warfarin 
will be substituted by Low Molecular 
weight heparin starting up to 5 days prior to 
until a time after completion of the PET 
scan when therapeutic anti-coagulation is 
considered to have been achieved in the 
views of the clinician.


2015N237824_03
CONFIDENTIAL
204746
16
4.5.2.
Benefit Assessment

Participating in this study will contribute to the process of developing new therapies 
for PAH – an area of unmet need.
4.5.3.
Overall Benefit:Risk Conclusion
Taking into account the measures taken to minimise risk to subjects participating in this 
study, the potential risks identified in association with study participation are justified by 
the anticipated benefits that may be afforded in the future to PAH patients
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the IB.
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
5.1.
Inclusion Criteria
5.1.1.
Healthy Volunteers
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
AGE
1. Healthy subjects enrolled between 40 to 70 years inclusive at the time of signing the 
informed consent. Healthy subjects will be recruited to be age (5 years) and gender 
matched to PAH patients.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. Healthy as determined by the investigator or medically qualified designee based on a 
medical evaluation including medical history, physical examination, laboratory tests 
and cardiac monitoring.
3. Normal spirometry at Screening (FEV1 and FVC ≥ 80% of predicted – measurements 
to be taken in triplicate and the highest value must be ≥ 80% of predicted).
4. A subject with a clinical abnormality or laboratory parameter(s) outside the reference 
range for the population being studied may be included only if the investigator, in 
consultation with the medical monitor if deemed necessary, agree and document that 
the finding is unlikely to introduce additional risk factors and will not interfere with 
the study procedures.
5. Subject is ambulant and capable of attending for PET-CT imaging.
6. A negative Allen’s test in at least one arm for arterial blood sampling (indicating 
adequate collateral circulation to the hand from both the radial and ulnar arteries).


2015N237824_03
CONFIDENTIAL
204746
17
WEIGHT
7. Body weight 50 kg and body mass index (BMI) within the range 18.5 – 35 kg/m2 
(inclusive).
SEX
8. Male or Female
Males:
Male subjects with female partners of child bearing potential must comply with the 
following contraception requirements from the time of first dose of study medication 
until 3 months after the scan. In addition, they must not plan to father a child, or donate 
sperm, for 3 months after the scan. 
a. Vasectomy with documentation of azoospermia.  
b. Male condom plus partner use of one of the contraceptive options below:

Contraceptive subdermal implant 

Intrauterine device or intrauterine system 

Oral Contraceptive, either combined or progestogen alone [Hatcher, 2007a] 
Injectable progestogen [Hatcher, 2007a]

Contraceptive vaginal ring [Hatcher, 2007a]

Percutaneous contraceptive patches [Hatcher, 2007a]
This is an all-inclusive list of those methods that meet the following GSK definition of 
highly effective: having a failure rate of less than 1% per year when used consistently and 
correctly and, when applicable, in accordance with the product label. For non-product 
methods (e.g., male sterility), the investigator determines what is consistent and correct 
use. The GSK definition is based on the definition provided by the ICH [ICH, M3 (R2) 
2009].”
The investigator is responsible for ensuring that subjects understand how to properly use 
these methods of contraception.
Females: 
a.
Non-reproductive potential defined as:
Pre-menopausal females with one of the following:
Documented tubal ligation
Documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion 
Hysterectomy
Documented Bilateral Oophorectomy


2015N237824_03
CONFIDENTIAL
204746
18
Postmenopausal defined as 12 months of spontaneous amenorrhea in 
questionable cases a blood sample with simultaneous follicle stimulating 
hormone (FSH) and estradiol levels consistent with menopause (refer to 
laboratory reference ranges for confirmatory levels).  Females on hormone 
replacement therapy (HRT) and whose menopausal status is in doubt will be 
required to use one of the highly effective contraception methods if they wish to 
continue their HRT during the study.  Otherwise, they must discontinue HRT to 
allow confirmation of post-menopausal status prior to study enrolment.
The investigator is responsible for ensuring that subjects understand how to properly use 
these methods of contraception.
INFORMED CONSENT
9. Capable of giving signed informed consent as described in Section 10.2 which 
includes compliance with the requirements and restrictions listed in the consent form 
and in this protocol.
5.1.2.
PAH Patients
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
AGE
1. PAH patients enrolled between 40 to 70 years inclusive at the time of signing the 
informed consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. Subjects medically diagnosed with idiopathic or inherited PAH, and clinically 
Functional Class II-IV, as defined in the guidelines of the ESC and ERS; Table 4, 
Categories 1.1 and 1.2 [Galiè, 2009].
3. Subject is ambulant and capable of attending for PET-CT imaging.
4. A negative Allen’s test in at least one arm for arterial blood sampling (indicating 
adequate collateral circulation to the hand from both the radial and ulnar arteries).
WEIGHT
5. Body weight 50 kg and body mass index (BMI) within the range 18.5 – 35 kg/m2 
(inclusive).


2015N237824_03
CONFIDENTIAL
204746
19
SEX
6. Male or Female
Males:
a. Male subjects with female partners of child bearing potential must comply with 
the following contraception requirements from scan until 3 months after the last 
dose of study medication. In addition, they must not plan to father a child, or 
donate sperm, for 3 months after the scan.
b. Vasectomy with documentation of azoospermia.  
c. Male condom plus partner use of one of the contraceptive options below:

Contraceptive subdermal implant 

Intrauterine device or intrauterine system 

Oral Contraceptive, either combined or progestogen alone [Hatcher, 2007a] 
Injectable progestogen [Hatcher, 2007a]

Contraceptive vaginal ring [Hatcher, 2007a]

Percutaneous contraceptive patches [Hatcher, 2007a]
This is an all-inclusive list of those methods that meet the following GSK definition of 
highly effective: having a failure rate of less than 1% per year when used consistently and 
correctly and, when applicable, in accordance with the product label. For non-product 
methods (e.g., male sterility), the investigator determines what is consistent and correct 
use. The GSK definition is based on the definition provided by the ICH [ICH, M3 (R2) 
2009].”
The investigator is responsible for ensuring that subjects understand how to properly use 
these methods of contraception.
Females: 
A female subject of non-child bearing potential is eligible to participate if she is not 
pregnant (as confirmed by a negative urine human chorionic gonadotrophin (hCG) test), 
not lactating, and at least one of the following conditions applies:
a.
Non-reproductive potential defined as:
Pre-menopausal females with one of the following:
Documented tubal ligation
Documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion 
Hysterectomy
Documented Bilateral Oophorectomy
Postmenopausal defined as 12 months of spontaneous amenorrhea in 
questionable cases a blood sample with simultaneous follicle stimulating 


2015N237824_03
CONFIDENTIAL
204746
20
hormone (FSH) and estradiol levels consistent with menopause (refer to 
laboratory reference ranges for confirmatory levels).  Females on hormone 
replacement therapy (HRT) and whose menopausal status is in doubt will be 
required to use one of the highly effective contraception methods if they wish to 
continue their HRT during the study.  Otherwise, they must discontinue HRT to 
allow confirmation of post-menopausal status prior to study enrolment.
The investigator is responsible for ensuring that subjects understand how to properly use 
these methods of contraception.
INFORMED CONSENT
7. Capable of giving signed informed consent as described in Section 10.2 which 
includes compliance with the requirements and restrictions listed in the consent form 
and in this protocol.
5.2.
Exclusion Criteria
5.2.1.
Healthy Volunteer Subjects
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL) 
1. Presence or history, of any significant or uncontrolled medical condition which in the 
opinion of the investigator would increase the potential risk to the subject or affect the 
study outcomes.
2. Previous pulmonary embolus
3. Current or chronic history of intrinsic liver disease, or known hepatic or biliary 
abnormalities, including coagulation abnormalities (with the exception of Gilbert’s 
syndrome).
4. Established diagnosis of systemic hypertension or known Left Ventricular 
Hypertrophy (LVH).
5. Estimated GFR <60mL/min based on clinical chemistry
CONCOMITANT MEDICATIONS
6. Use of prohibited medication (Section 6.9)


2015N237824_03
CONFIDENTIAL
204746
21
RELEVANT HABITS
7. Current smoker or a history of smoking within 6 months of Screening, or a total pack 
year history of >10 pack years.
[number of pack years = (number of cigarettes per day/20) x number of years 
smoked]
8. Subjects that do not wish to consume alcohol by I.V administration for personal 
reasons.
9. The subject has a positive pre-study drug/alcohol screen. A minimum list of drugs 
that will be screened for include cannabinoids, amphetamines, barbiturates, cocaine 
and opiates. The detection of drugs (e.g. benzodiazepines, opiates) taken for a 
legitimate medical purpose would not necessarily be an exclusion to study 
participation. The detection of alcohol would not be an exclusion at screening but 
would need to be negative pre-dose and during the study
10. History of regular alcohol consumption within 6 months of the study defined as:
For UK sites: an average weekly intake of >21 units for males or >14 units for 
females.  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
CONTRAINDICATIONS 
11. History of sensitivity to heparin or heparin-induced thrombocytopenia.
12. History of sensitivity to any of the study medications, or components thereof or a 
history of drug or other allergy that, in the opinion of the investigator or Medical 
Monitor, contraindicates their participation.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
13. Subject with QTcF of >450ms (or QTcF of > 480msec in subjects with Bundle 
Branch Block) or other 12-lead ECG abnormalities (with the exception of right 
bundle-branch block) which, in the opinion of the investigator, is clinically significant 
(e.g. LVH) in that they may increase safety risk or affect study outcomes.
14. Have donated blood or have taken part in a study of an experimental medicine in the 
last 3 months, or plan to do so in the 3 months after this study.
15. Have had a serious reaction to any medicine.
16. Unable or unfit to undergo PET scans, or found to be unsuitable for PET scanning in 
the opinion of the Investigator.
17. History of or suffers from claustrophobia or subject feels unable to lie flat and still on 
their back for a period of up to 2 hours in the PET/CT scanner.
Previous inclusion in a research and/or medical protocol involving nuclear medicine, PET 
or radiological investigations or occupational exposure resulting in radiation exposure 
greater than 10 mSv over the past 3 years or greater than 10 mSv in a single year 
including the proposed study. Clinical exposure from which the subject receives a direct 
benefit is not included in these calculations.


2015N237824_03
CONFIDENTIAL
204746
22
5.2.2.
PAH Patients
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL) 
1. Presence of any uncontrolled co-morbid condition (e.g. unstable coronary artery 
disease or systemic hypertension) which in the opinion of the investigator would 
increase the potential risk to the subject
2. Airways or interstitial lung disease, including adult asthma, COPD, emphysema, 
bronchiectasis, pulmonary fibrosis or chronic thromboembolic disease.
3. Current or chronic history of intrinsic liver disease (with the exception of Gilbert's 
syndrome or gallstones)
4. LVH on 2D-Echocardiogram in the past 12 months
5. Estimated GFR < 40mL/min based on clinical chemistry
6. Change in PAH medication within 28 days of scanning
7. A syncopal episode within 28 days of scanning
8. Subjects who require continuous oxygen.
CONCOMITANT MEDICATIONS
9. Use of prohibited medication (Section 6.9)
RELEVANT HABITS
10. Current smoker or a history of smoking within 6 months of Screening, or a total pack 
year history of >10 pack years.
[number of pack years = (number of cigarettes per day/20) x number of years 
smoked]
11. Subjects that do not wish to consume alcohol by I.V administration for personal 
reasons.
12. The subject has a positive pre-study drug/alcohol screen. A minimum list of drugs 
that will be screened for include cannabinoids, amphetamines, barbiturates, cocaine 
and opiates. The detection of drugs (e.g. benzodiazepines, opiates) taken for a 
legitimate medical purpose would not necessarily be an exclusion to study 
participation. The detection of alcohol would not be an exclusion at screening but 
would need to be negative pre-dose and during the study
13. History of regular alcohol consumption within 6 months of the study defined as:
For UK sites: an average weekly intake of >21 units for males or >14 units for 
females. 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
CONTRAINDICATIONS 
14. History of sensitivity to heparin or heparin-induced thrombocytopenia.


2015N237824_03
CONFIDENTIAL
204746
23
15. History of sensitivity to any of the study medications, or components thereof or a 
history of drug or other allergy that, in the opinion of the investigator or Medical 
Monitor, contraindicates their participation.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
16. Subjects with QTcF of > 500ms (irrespective of bundle branch block status),or other 
12-lead ECG abnormalities (with the exception of right bundle-branch block) which, 
in the opinion of the investigator is clinically significant in that they may increase 
safety risk.
18. Have donated blood or have taken part in a study of an experimental medicine in the 
last 3 months, or plan to do so in the 3 months after this study.
19. Have had a serious reaction to any medicine.
20. Unable or unfit to undergo PET scans, or found to be unsuitable for PET scanning in 
the opinion of the Investigator.
21. History of or suffers from claustrophobia or subject feels unable to lie flat and still on 
their back for a period of up to 2 hours in the PET/CT scanner.
22. Previous inclusion in a research and/or medical protocol involving nuclear medicine, 
PET or radiological investigations or occupational exposure resulting in radiation 
exposure greater than 10 mSv over the past 3 years or greater than 10 mSv in a single 
year including the proposed study. Clinical exposure from which the subject receives 
a direct benefit is not included in these calculations.
5.3.
Screening Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently scanned. In order to ensure transparent reporting of screen failure 
subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements, and respond to queries from Regulatory authorities, a minimal set of screen 
failure information is required including Demography, Screen Failure details, Eligibility 
Criteria, and Serious Adverse Events (see Section 7.3.1.5).
5.4.
Withdrawal/Stopping Criteria
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as 
soon as possible. 

The site must counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or should 
continue in the study. 

In cases where the subject is deemed ‘lost to follow up’, the investigator or 
designee must make every effort to regain contact with the subject (where 
possible, 3 telephone calls and if necessary a certified letter to the subject’s last 


2015N237824_03
CONFIDENTIAL
204746
24
known mailing address or local equivalent methods). These contact attempts 
should be documented in the subject’s medical record. 

Should the subject continue to be unreachable, only then will he/she be considered 
to have withdrawn from the study with a primary reason of “Lost to Follow-up”. 
A subject may withdraw from study treatment at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioural or 
administrative reasons. If a subject withdraws from the study, he/she may request 
destruction of any samples taken, and the investigator must document this in the site 
study records. 
5.5.
Subject and Study Completion
Subject completion for the primary endpoint is defined as a subject who completes the 
PET-CT scan visit.
The end of the study is defined as the last subject’s last visit.
6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design. Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments. In this study, the ‘study treatment’ is considered a microdose.
Product Name:
[11C]-GSK2256098 Injection
Formulation description:
Up to 5% Ethanol in saline
Dosage Form:
IV
Unit dose strength:
Up to 500 MBq of [11C]-GSK2256098
Route:
IV / single dose
Unit mass:
< 10 µg of GSK2256098
Administration:
Intravenous bolus over about 30 seconds
Physical description:
IV infusion, 20 mL
Manufacturer / source of 
procurement:
Imanova, London, UK1
1.
According to the appropriate current Good Manufacturing Practice (cGMP) guidelines for the preparation of radio-
pharmaceutical products to be administered to humans.
6.2.
Blinding
This will be an open-label study. 
6.3.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.


2015N237824_03
CONFIDENTIAL
204746
25
6.4.
Preparation/Handling/Storage/Accountability
A description of the methods required for the preparation of [11C]GSK2256098 will be 
detailed in Imanova manufacturing documentation and will be accompanied by a Quality 
agreement.

Only subjects enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment.  All study 
treatments must be stored in a secure environmentally controlled and monitored 
(manual or automated) area in accordance with the labelled storage conditions 
with access limited to the investigator and authorized site staff. 

The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (i.e. receipt, reconciliation and final disposition records).  

Further guidance and information for final disposition of unused study treatment 
are provided in the SRM. 

Under normal conditions of handling and administration, study treatment 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.
6.5.
Compliance with Study Treatment Administration
When the individual dose for a subject is prepared from a bulk supply, the preparation of 
the dose will be confirmed by a second member of the study site staff. 
When subjects are dosed at the site, they will receive study treatment 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 
treatment and study subject identification will be confirmed at the time of dosing by a 
member of the study site staff other than the person administering the study treatment.  
[11C]-GSK2256098 will be intravenously administered to subjects at the site.  
Administration will be documented in the source documents and reported in the CRF.
6.6.
Treatment of Study Treatment Overdose
For this study, any dose of [11C]-GSK2256098 > 10µg within a 24 hour time period will 
be considered an overdose.
GSK does not recommend specific treatment for an overdose


2015N237824_03
CONFIDENTIAL
204746
26
6.7.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study.
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition, whether or not GSK is providing specific 
post-study treatment.
6.8.
Lifestyle Restrictions
6.8.1.
Activity
Subjects will abstain from strenuous exercise for 48 hours prior to each blood collection 
for clinical laboratory tests.  Subjects may participate in light recreational activities 
during studies (e.g., watch television, read).
6.8.2.
Alcohol
Subjects will abstain from alcohol for 24 hours prior to each study visit.
6.9.
Concomitant Medications and Non-Drug Therapies
6.9.1.
Permitted Medications and Non-Drug Therapies
Paracetamol, at doses of up to 2 grams/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.
Use of prescription contraceptives and HRT are permitted during the study.
PAH patients may continue all their usual treatment (except warfarin).
6.9.2.
Prohibited Medications and Non-Drug Therapies
PAH patients on continuous oxygen are excluded from the study. Patients on warfarin 
will be asked to discontinue for a period prior to the scanning day to ensure appropriate 
INR values.


2015N237824_03
CONFIDENTIAL
204746
27
7.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct.
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Table (Section 7.1).
The timing and number of planned study assessments, including safety, or other 
assessments may be altered during the course of the study based on newly available data 
to ensure appropriate monitoring. The change in timing or addition of time points for any 
planned study assessments must be documented in a Note to File which is approved by 
the relevant GSK study team member and then archived in the study sponsor and site 
study files, but this will not constitute a protocol amendment. The IRB/IE will be 
informed of any safety issues that require alteration of the safety monitoring scheme or 
amendment of the Informed Consent Form. No more than 500 mL of blood will be 
collected over the duration of the study, including any extra assessments that may be 
required.


2015N237824_03
CONFIDENTIAL
204746
28
7.1.
Time and Events Table
Procedure
Screening (up to 30 
days prior to scan)
Scanning visit 
Follow-up
(2-4 weeks post-last dose)
Notes
Informed consent
X
Inclusion and exclusion criteria
X
Demography
X
Brief physical
X
X
X
On the scanning day, to be completed pre-scan, prior 
to the administration of the peptide.
Medical / Medical history 
X
Vital signs
X
X
On the scanning day, to be conducted pre and post 
scan.
12-lead ECG
X
Alcohol breath test
X
X
Urine drug and cotinine screen
X
Healthy subjects only: spirometry 
X
Coagulation profile
X
This will include PT (Prothrombin time), APTT 
(Activated Partial Thromboplastin Time) and Thrombin 
Time (TT)
PAH patients only (who have been on 
Warfarin): INR
X
Sample to confirm suitability for scanning day can be 
done up to 3 days prior to the day of the scan
HIV, Hep B and Hep C screen
X
If test otherwise performed within 3 months prior to 
first dose of study treatment, testing at screening is 
not required
Clinical chemistry and Haematology 
X
Urinalysis
X
Allen’s test
X
X
i.v dose of [11C]-GSK2256098
X
PET scan
X
PET scanning will be started at the same time as 
injection of the radioligand and PET data will be 
collected for up to 90 minutes post administration.


2015N237824_03
CONFIDENTIAL
204746
29
Procedure
Screening (up to 30 
days prior to scan)
Scanning visit 
Follow-up
(2-4 weeks post-last dose)
Notes
Attenuation CT scan
X
Lasting seconds to minute prior to start of PET scan.  
If subject gets off the bed for a comfort break midway 
through the PET scan, another CT scan will be 
performed prior to re-starting acquisition of PET data
Genetics sample
X
Genetic Informed consent must be obtained before 
collecting a sample
Samples for plasma radioactivity 
measurements & whole blood
X
Blood samples will be collected during scanning for 
plasma and whole blood radioactivity measurements.
AE/SAE review
X
X
Concomitant medication review
X
X
X


2015N237824_03
CONFIDENTIAL
204746
30
7.2.
Screening and Critical Baseline Assessments
Cardiovascular medical history/risk factors (as detailed in the CRF) will be assessed at 
screening.
The following demographic parameters will be captured: year of birth, sex, race and 
ethnicity.
Medical/medication/family history will be assessed as related to the inclusion/exclusion 
criteria listed in Section 5.
Procedures conducted as part of the subject’s routine clinical management (e.g. MRI, 
INR) and obtained prior to signing of informed consent may be utilized for Screening or 
baseline purposes provided the procedure meets the protocol-defined criteria and has 
been performed in the timeframe of the study.
7.3.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1).  Additional time points for safety tests (such as vital signs, physical exams
and laboratory safety tests) may be added during the course of the study based on newly 
available data to ensure appropriate safety monitoring.
7.3.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 3.
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 
7.3.1.1.
Time period and Frequency for collecting AE and SAE information

Any SAEs assessed as related to study participation (e.g., 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 up to and including any follow-up contact. 

AEs will be collected from the start of  the PET scan until the follow-up contact 
(see Section 7.3.1.3), at the timepoints specified in the Time and Events Table 
(Section 7.1).

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the CRF.

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Appendix 3.

Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the 


2015N237824_03
CONFIDENTIAL
204746
31
event reasonably related to the study treatment or study participation, the 
investigator must promptly notify GSK.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 3.
7.3.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:

“How are you feeling?” 

“Have you had any (other) medical problems since your last visit/contact?” 

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?” 
7.3.1.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All SAEs, and non-serious AEs of special interest 
(as defined in Section 4.5.1) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up 
(as defined in Section 5.4). Further information on follow-up procedures is given in 
Appendix 3.
7.3.1.4.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 3 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF will 
be required to be completed. These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death. 
The CV CRFs are presented as queries in response to reporting of certain CV MedDRA 
terms. The CV information should be recorded in the specific cardiovascular section of 
the CRF within one week of receipt of a CV Event data query prompting its completion. 
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
7.3.1.5.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK of SAEs related to study treatment (even 
for non- interventional post-marketing studies) is essential so that legal obligations and 
ethical responsibilities towards the safety of subjects and the safety of a product under 
clinical investigation are met. 


2015N237824_03
CONFIDENTIAL
204746
32
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
7.3.2.
Pregnancy

Details of all pregnancies in female partners of male subjects will be collected 
after the PET scan and until the follow-up visit.

If a pregnancy is reported then the investigator should inform GSK within 2 
weeks of learning of the pregnancy and should follow the procedures outlined in 
Appendix 4.
7.3.3.
Physical Exams

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
7.3.4.
Vital Signs

Vital signs will be measured in semi-supine position after 5 minutes rest and will 
include temperature, systolic and diastolic blood pressure, pulse rate and 
respiratory rate. 
7.3.5.
Electrocardiogram (ECG)

Single 12-lead ECGs will be obtained at each timepoint during the study using an 
ECG machine that automatically calculates the heart rate and measures PR, QRS, 
QT, and QTcF intervals. 
7.3.6.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 1, must be conducted in 
accordance with the Laboratory Manual, and Protocol Time and Events Schedule.
Laboratory requisition forms must be completed and samples must be clearly labelled
with the subject number, protocol number, site/centre number, and visit date. Details for 
the preparation and shipment of samples will be provided by the laboratory and are 
detailed in the site SOPs. Reference ranges for all safety parameters will be provided to 
the site by the laboratory responsible for the assessments.


2015N237824_03
CONFIDENTIAL
204746
33
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the CRF.
Refer to the site SOPs for appropriate processing and handling of samples to avoid 
duplicate and/or additional blood draws.
Haematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed in Table 1. 
Table 1
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Platelet Count
RBC Indices:
WBC count with Differential:
RBC Count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes
Hematocrit
MCHC
Monocytes
Eosinophils
Basophils
Clinical 
Chemistry 
BUN
Potassium
AST (SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
ALT (SGPT)
Total Protein
Glucose 
Calcium
Albumin
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood and ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Other 
Screening 
Tests

HIV

Hepatitis B (HBsAg)

Hepatitis C (Hep C antibody)

FSH and estradiol (as needed in women of non-child bearing 
potential only)

Pregnancy test

Alcohol and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, benzidiazepines and cannabinoids)
7.3.7.
Positron Emission Tomography (PET)
Prior to the commencement of the PET scan a venous cannula will be inserted in to the 
subjects arm for administration of [11C]-GSK2256098. A radial arterial cannula will also 
be inserted prior to the scan start under local anaesthesia from which blood samples will 
be collected throughout the scan to enable the quantification of the total unmetabolised 
[11C]-GSK2256098 related radioactivity in the whole blood and plasma throughout the 
duration of the PET scan. Initially an X-ray topogram of the area will be performed to 
localise the area to be scanned followed by a low- dose CT attenuation scan of the area to 


2015N237824_03
CONFIDENTIAL
204746
34
be scanned.  Thereafter the PET scan will commence with the administration of [11C]-
GSK2256098 intravenously and the emission data will be acquired for up to 90 minutes 
post-administration. The data provided from the arterial blood samples collected will be 
used to derive an input function for the analysis of emission PET data. At the end of the 
scan, the cannulae will be removed.
Ideally, subjects will complete the PET scan without a break. However, subjects may be 
removed from the scanner once for a period of rest and repositioned to continue the PET 
scan if absolutely necessary. The primary discomfort arises from the need for subjects to 
lie supine during the scan. The scan will be stopped or abandoned if the subject is unable 
to complete the scan.
The subjects will be monitored for approximately one hour after completion of the scan 
and will be allowed home at the Investigator’s discretion.  
7.3.8.
Blood Sample Collection
Continuous and discrete arterial samples will be collected during this study. Samples 
collected during the [11C]-GSK2256098 scan will be assayed for total blood and plasma 
radioactivity.  Some of the discrete blood samples will be assayed to determine the 
fraction of labelled parent and metabolites of [11C]-GSK2256098 in plasma, over time, 
using HPLC and/or TLC.  
7.4.
Genetics
Information regarding genetic research is included in Appendix 2.
8.
DATA MANAGEMENT

For this study data will be double-entered into a clinical database management 
system (ClinPlus Version 3.3 ).  

Management of clinical data will be performed in accordance with applicable 
HMR standards and data cleaning procedures to ensure the integrity of the data, 
e.g., removing errors and inconsistencies in the data.

Original CRFs will be retained by GSK, while HMR will retain a copy.  Subject 
initials will not be collected or transmitted to GSK according to GSK policy
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1.
Hypotheses
Although a valid scientific hypothesis underpins this study, as expressed in the study 
objectives (viz: “FAK uptake is substantially higher in patients than in (relatively) well-
matched healthy control subjects”), no statistical hypothesis testing will be conducted, 
nor will any p-values be generated. (It would make no sense to “reject” a null hypothesis 


2015N237824_03
CONFIDENTIAL
204746
35
of “no difference in FAK expression between patients and HVs” in the absence of a pre-
specified threshold of clinical relevance.) 
Instead, we will adopt an estimation approach, and use simple Bayesian methods to 
quantify the evidence which the study generates about the endpoints themselves, and 
about contrasts (probably ratios) of those endpoints. We will evaluate the evidence in as 
close to real-time as the study operationalisation permits.
9.2.
Sample Size Considerations
There is little known about the likely mean values of the PET-derived functional primary 
endpoints (Volume of distribution, and/or some form of integrated SUV) in this 
population. Therefore our sample size is driven by a mixture of (i) what is known about 
between-subject variability from relevant, recent PET studies, (ii) feasibility, and (iii) 
flexibility.
An ongoing study investigating the validation and dosimetry of a PET ligand in healthy 
subjects and patients with IPF (study RES116235) has been able to draw firm 
conclusions about similar endpoints (in terms of the estimation methods we describe 
below) using around 5 subjects. Therefore we will set five patients and five age matched 
HVs as our initial target sample size. 
From that point onwards, the data will be monitored continuously (or as near as possible 
given practicalities of study operationalisation), and at each step the following decisions 
will be made: 

Stop, and conclude that there is strong evidence of differential FAK expression (as 
measured by the study endpoints) between patients and HVs.

Stop, and conclude that there is insufficient evidence of any great difference, and 
furthermore (conditional on observed data i.e. in a formal Bayesian sense) there is 
low probability that an increase in sample size will reverse such a conclusion

Continue to enrol patient-HV pairs, and re-evaluate the decision.
This iterative cycle will be followed up until a maximum of twelve patients and twelve 
HVs have been recruited into the study. 
9.2.1.
Sample Size Re-estimation or Adjustment
The first statistical evaluation of the data will occur once five patients and five healthy 
volunteers have been studied in the PET scanner, and the relevant functionals of their 
scan data (such as VT) derived by Imanova scientists. At this point, the statistical analysis 
(set out below) will be carried out, and, based on those results, the team may decide to 
recruit more subjects, up to a total of twelve patients and twelve healthy volunteers.


2015N237824_03
CONFIDENTIAL
204746
36
9.3.
Data Analysis Considerations
9.3.1.
Interim Analysis
No formal interim “testing” of any statistical hypothesis will be performed. But we will 
be reviewing the strength of evidence in the data (about differential expression levels 
between patients and HVs) as data accrue (and as practicalities of data management 
permit).
9.4.
Key Elements of Analysis Plan
9.4.1.
Primary Analyses
For any important endpoint, we describe our uncertainty concerning its true value with a 
probability density function, p(t), say. (Suppose ‘t’ represents Volume of Distribution, 
derived from the PET and blood sample data. The following argument will apply to any 
such endpoint which takes numerical values on the real line.) Pre-study start, we will 
characterise p(t) in such a way that our “prior belief” about the true endpoint’s value is 
entirely diffuse over the real line (this approach implies that all conclusions about the 
endpoint are driven only by the data gathered in the study.)
We will gather evidence about the endpoint in the data from the study, which we will 
characterise via its likelihood function (derived from the relevant sampling distribution, 
l(x|t), say, where ‘x’ stands for ‘data’) From the likelihood function are derived the usual 
summary statistics for the endpoint.  
It is highly likely, based on similar PET studies, that a Normal likelihood function will be 
suitable (that is will provide a reasonable fit to the observed data.) A conjugate Normal 
prior density function with mean zero and a vast variance will be adopted, leading to the 
standard Normal posterior density functions for the endpoints of interest. (Should the data 
not support a Normal likelihood function, alternative parametric forms, such as a log-
Normal density, will be investigated.) 
We will apply Bayes’ theorem to derive the (constantly evolving) posterior density 
function p(t | x), and use this to produce the following quantities of inferential interest:

What is currently (as a function of accruing data) the most probable true value of the 
endpoint? These point estimates, given the vagueness of the prior density, will be 
both the maximum likelihood, and the Bayesian maximum a posteriori, estimates of 
the parameters (the true values of the endpoints.) 

What is a range of plausible values for the true value of the endpoint, such that there 
is a 95% chance that the true value lies within that range? These intervals will be the 
95% highest posterior density intervals for each parameter.

What is the probability that the ratio of the endpoint in patients compared to the 
endpoint in HVs exceeds one, given the current data? Similarly, we will derive the 
95% highest posterior density range for that ratio. Since the ratio of two Normally-
distributed endpoints will not itself be Normally distributed, it is likely that some 


2015N237824_03
CONFIDENTIAL
204746
37
simple Monte Carlo Markov Chain methods will be applied to derive these point and 
interval estimates. 

What does the graph of “probability that this ratio exceeds x”, plotted against x, look 
like, for x in the range 0.5 to 2 (say – other ranges may be explored as data permits)? 

Given the current sample size, how likely, were we to recruit a further n patients, are 
those estimates to change substantially, for n in the range 2, 4, 6...up to a maximum 
sample size of 12. For this question, we will derive the predictive posterior density 
function for the ratio. 
Full details of these approaches will be provided in the RAP.
9.4.2.
Other Analyses
All other data will be listed and summarized as per GSK standards.
10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a site, GSK will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki.  This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable

Obtaining signed informed consent

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol 
deviations to IRB/IEC)

GSK will provide full details of the above procedures, either verbally, in writing, 
or both.


2015N237824_03
CONFIDENTIAL
204746
38

Signed informed consent must be obtained for each subject prior to participation 
in the study

The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.  

Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.  

Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities.  In this situation, 
written approval of the clinical protocol should state that approval of optional 
assessments is being deferred and the study, with the exception of the optional 
assessments, can be initiated.
10.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK monitors will contact the site prior to the start of the study to review with the 
site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and GSK requirements.  

When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which CRF will 
serve as the source document.
GSK will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any 
other study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents
10.4.
Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK 
may conduct a quality assurance assessment and/or audit of the site records, and 
the regulatory agencies may conduct a regulatory inspection at any time during or 
after completion of the study.

In the event of an assessment, audit or inspection, the investigator (and institution) 
must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all 
relevant documents and to allocate their time and the time of their staff to discuss 
the conduct of the study, any findings/relevant issues and to implement any 
corrective and/or preventative actions to address any findings/issues identified.


2015N237824_03
CONFIDENTIAL
204746
39
10.5.
Study and Site Closure

Upon completion or premature discontinuation of the study, the GSK monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and GSK Standard 
Operating Procedures.

GSK reserves the right to temporarily suspend or prematurely discontinue this 
study at any time for reasons including, but not limited to, safety or ethical issues 
or severe non-compliance. For multicenter studies, this can occur at one or more 
or at all sites.  

If GSK determines such action is needed, GSK will discuss the reasons for taking 
such action with the investigator or the head of the medical institution (where 
applicable).  When feasible, GSK will provide advance notification to the 
investigator or the head of the medical institution, where applicable, of the 
impending action.

If the study is suspended or prematurely discontinued for safety reasons, GSK will 
promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action.  

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation.
10.6.
Records Retention

Following closure of the study, the investigator or the head of the medical 
institution (where applicable) must maintain all site study records (except for 
those required by local regulations to be maintained elsewhere), in a safe and 
secure location.  

The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review 
in conjunction with assessment of the facility, supporting systems, and relevant 
site staff.  

Where permitted by local laws/regulations or institutional policy, some or all of 
these records can be maintained in a format other than hard copy (e.g., microfiche, 
scanned, electronic); however, caution needs to be exercised before such action is 
taken.  

The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, 
including re-generating a hard copy, if required.  Furthermore, the investigator 
must ensure there is an acceptable back-up of these reproductions and that an 
acceptable quality control process exists for making these reproductions.


2015N237824_03
CONFIDENTIAL
204746
40

GSK will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements.  The minimum retention time 
will meet the strictest standard applicable to that site for the study, as dictated by 
any institutional requirements or local laws or regulations, GSK 
standards/procedures, and/or institutional requirements.  

The investigator must notify GSK of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of 
ownership of the records in the event the investigator is no longer associated with 
the site.
10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
A manuscript will be progressed for publication in the scientific literature if the results 
provide important scientific or medical knowledge.


2015N237824_03
CONFIDENTIAL
204746
41
11.
REFERENCES
Chen H, Yu KD, Xu GZ. Association between Variant Y402H in Age-Related Macular 
Degeneration (AMD) Susceptibility Gene CFH and Treatment Response of AMD: A 
Meta-Analysis. PloS ONE 2012; 7: e42464 Gorin MB. 
Galiè, Nazzareno, Hoeper, M.M., et al., 2009. Guidelines for the diagnosis and treatment 
of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of 
Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European 
Respiratory Society (ERS), endorsed by the International Society of Heart and Lung 
Transplantation (ISHLT). European heart journal, 30(20), pp.2493–2537.
Gorin, N.B. Genetic insights into age-related macular degeneration: Controversies 
addressing risk, causality, and therapeutics. Mol. Asp. Med. 2012; 33: 467-486.
Guignabert C, Tu L, Le Hiress M, Ricard N, Sattler C, Seferian A, Huertas A, Humbert 
M and Montani D. 2013. Pathogenesis of Pulmonary Arterial Hypertension: lessons from 
cancer. Eur Respir Rev. 22(130):543-551.
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, editors. 
Contraceptive Technology. 19th edition. New York: Ardent Media, 2007(a): 24. Table 3-
2.
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, editors. 
Contraceptive Technology. 19th edition. New York: Ardent Media, 2007(b): 28.
ICH GUIDANCE ON NONCLINICAL SAFETY STUDIES FOR THE CONDUCT OF 
HUMAN CLINICAL TRIALS AND MARKETING AUTHORIZATION FOR 
PHARMACEUTICALS M3(R2). 11 June 2009.
Rich J.D., Thenappan T, Freed B., Patel A.R., Thisted R.A., Childers R., Archer S.L. 
2013. QTc prolongation is associated with impaired right ventricular function and 
predicts mortality in pulmonary hypertension. International Journal of Cardiology, 167 
(2013) 669–676.


2015N237824_03
CONFIDENTIAL
204746
42
12.
APPENDICES
12.1.
Appendix 1:Abbreviations and Trademarks
Abbreviations
µg
Microgram
AE
Adverse Event
ALT
Alanine aminotransferase (SGPT)
AST
Aspartate aminotransferase (SGOT)
AUC
Area under concentration-time curve
BMI
Body mass index
BUN
Blood urea nitrogen
cGMP
Current Good Manufacturing Practice
Cmax
Maximum observed concentration 
CO2
Carbon dioxide
CONSORT
Consolidated Standards of Reporting Trials
COPD
Chronic Obstructive Pulmonary disease
CPDS
Clinical Pharmacology Data Sciences
CPK
Creatine phosphokinase
CRF
Case Report Form
CS
Clinical Statistics
CT
Computed Tomography
CV
Coefficient of variance
ECG
Electrocardiogram
FAK
Focal adhesion kinase
FDA
Food and Drug Administration
FSH
Follicle Stimulating Hormone
FTIH
First time in humans
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GGT
Gamma glutamyltransferase
GLP
Good Laboratory Practice
GSK
GlaxoSmithKline
h/hr
Hour(s)
HBsAg
Hepatitis B surface antigen
HIV
Human Immunodeficiency Virus
HPLC
High-performance liquid Chromatography
HR
Heart rate
HRT
Hormone Replacement Therapy
IB
Investigator’s Brochure
ICH
International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use
IU
International Unit
IUD
Intra Uterine Device
IUS
Intra Uterine System


2015N237824_03
CONFIDENTIAL
204746
43
IV
Intravenous
Kg
Kilogram
LFTs
Liver function tests
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
Mg
Milligrams
mL
Milliliter
MSDS
Material Safety Data Sheet
msec
Milliseconds
NCBP
Non Child Bearing Potential
NCE
New chemical entity
PAH
Pulmonary artery hypertension
PAP
Pulmonary arterial pressure
PET
Positron Emission Tomography
PVR
Pulmonary vascular resistance
QTcF
QT duration corrected for heart rate by Fridericia’s formula
RAP
Reporting and Analysis Plan
RBC
Red blood cells
REC
Research Ethics Committee
SAE
Serious adverse event(s)
SAO2
Oxygen saturation levels
SGOT
Serum glutamic-oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SOP
Standard Operating Procedure
SPM
Study Procedures Manual
SUV
Standardized uptake values
T
Infusion duration
t
Time of last observed quantifiable concentration
t½
Terminal phase half-life
TKI
Tyrosine kinase inhibitor
TLC
Thin Layer Chromatography
tmax
Time of occurrence of Cmax
ULN
Upper limit of normal
vSMC
Vascular smooth muscle cell
VT
Volume of distribution
WBC
White blood cells
τ
Dosing interval


2015N237824_03
CONFIDENTIAL
204746
44
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
None


2015N237824_03
CONFIDENTIAL
204746
45
12.2.
Appendix 2:Genetic Research
Genetics – Background
Naturally occurring genetic variation may contribute to inter-individual variability in 
response to medicines, as well as an individual's risk of developing specific diseases. 
Genetic factors associated with disease characteristics may also be associated with 
response to therapy, and could help to explain some clinical study outcomes. For 
example, genetic variants associated with age-related macular degeneration (AMD) are 
reported to account for much of the risk for the condition [Gorin, 2012] with certain 
variants reported to influence treatment response [Chen, 2012]. Thus, knowledge of the 
genetic etiology of disease may better inform understanding of disease and the 
development of medicines. Additionally, genetic variability may impact the 
pharmacokinetics (absorption, distribution, metabolism, and elimination), or 
pharmacodynamics (relationship between concentration and pharmacologic effects or the 
time course of pharmacologic effects) of a specific medicine and/or clinical outcomes 
(efficacy and/or safety) observed in a clinical study.
Genetic Research Objectives and Analyses
The objectives of the genetic research are to investigate the relationship between genetic 
variants and: 

GSK2256098 binding affinity, response to medicine, including GSK22560982 or 
any concomitant medicines;

PAH susceptibility, severity, and progression and related conditions
Genetic data may be generated while the study is underway or following completion of 
the study.  Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses). Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above.  Analyses may be performed using data 
from multiple clinical studies of PAH or related conditions to investigate these research 
objectives.
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in a Reporting and Analysis Plan 
(RAP) prior to initiation of the analysis. Planned analyses and results of genetic 
investigations will be reported either as part of the clinical RAP and study report, or in a 
separate genetics RAP and report, as appropriate.
Study Population
Any subject who is enrolled in the study can participate in genetic research.  Any subject 
who has received an allogeneic bone marrow transplant must be excluded from the 
genetic research.


2015N237824_03
CONFIDENTIAL
204746
46
Study Assessments and Procedures
A key component of successful genetic research is the collection of samples during 
clinical studies. Collection of samples, even when no a priori hypothesis has been 
identified, may enable future genetic analyses to be conducted to help understand 
variability in disease and medicine response.  

A 6 ml blood sample will be taken for Deoxyribonucleic acid (DNA) extraction. 
A Blood sample is collected, after the subject has been enrolled and provided 
informed consent for genetic research. Instructions for collection and shipping of 
the genetic sample are described in the laboratory manual. The DNA from the 
blood sample may undergo quality control analyses to confirm the integrity of the 
sample. If there are concerns regarding the quality of the sample, then the sample 
may be destroyed. The blood sample is taken on a single occasion unless a 
duplicate sample is required due to an inability to utilize the original sample.  
The genetic sample is labelled (or “coded”) with the same study specific number used to 
label other samples and data in the study.   This number can be traced or linked back to 
the subject by the investigator or site staff. Coded samples do not carry personal 
identifiers (such as name or social security number). 
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study, or GSK may destroy the samples sooner.  GSK or those working 
with GSK (for example, other researchers) will only use samples collected from the study 
for the purpose stated in this protocol and in the informed consent form.  Samples may be 
used as part of the development of a companion diagnostic to support the GSK medicinal 
product.
Subjects can request their sample to be destroyed at any time.
Informed Consent
Subjects who do not wish to participate in the genetic research may still participate in the 
study.  Genetic informed consent must be obtained prior to any blood being taken.
Subject Withdrawal from Study
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample, if already 
collected:

Continue to participate in the genetic research in which case the genetic DNA 
sample is retained

Discontinue participation in the genetic research and destroy the genetic DNA 
sample 
If a subject withdraws consent for genetic research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 


2015N237824_03
CONFIDENTIAL
204746
47
destruction within the timeframe specified by GSK and maintain the documentation in 
the site study records. 
Genotype data may be generated during the study or after completion of the study and 
may be analyzed during the study or stored for future analysis. 

If a subject withdraws consent for genetic research and genotype data has not been 
analyzed, it will not be analyzed or used for future research.  

Genetic data that has been analyzed at the time of withdrawn consent will 
continue to be stored and used, as appropriate. 
Screen and Baseline Failures
If a sample for genetic research has been collected and it is determined that the subject 
does not meet the entry criteria for participation in the study, then the investigator should 
instruct the subject that their genetic sample will be destroyed. No forms are required to 
complete this process as it will be completed as part of the consent and sample 
reconciliation process.  In this instance a sample destruction form will not be available to 
include in the site files.
Provision of Study Results and Confidentiality of Subject’s Genetic Data
GSK may summarize the genetic research results in the clinical study report, or 
separately and may publish the results in scientific journals. 
GSK may share genetic research data with other scientists to further scientific 
understanding in alignment with the informed consent. GSK does not inform the subject, 
family members, insurers, or employers of individual genotyping results that are not 
known to be relevant to the subject’s medical care at the time of the study, unless 
required by law. This is due to the fact that the information generated from genetic 
studies is generally preliminary in nature, and therefore the significance and scientific 
validity of the results are undetermined.  Further, data generated in a research laboratory 
may not meet regulatory requirements for inclusion in clinical care.


2015N237824_03
CONFIDENTIAL
204746
48
12.3.
Appendix 3:Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.3.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a patient or clinical investigation 
subject, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator.

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 treatment administration even 
though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae).
Events NOT meeting definition of an AE include:

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 subject’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 subject’s 
condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).


2015N237824_03
CONFIDENTIAL
204746
49

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.
12.3.2.
Definition of Serious Adverse Events
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, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c.
Requires hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting.  Complications that occur during hospitalization are 
AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d.
Results in disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday 
life functions but do not constitute a substantial disruption
e.
Is a congenital anomaly/birth defect


2015N237824_03
CONFIDENTIAL
204746
50
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition.  These should also be considered 
serious.

Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse
g.
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** > 1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick.  If fractionation is unavailable and ALT 3xULN 
and total bilirubin 2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.
12.3.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization


2015N237824_03
CONFIDENTIAL
204746
51
12.3.4.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the CRF

It is not acceptable for the investigator to send photocopies of the subject’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 instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to 
submission of to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs,
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.
12.3.5.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. - an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.


2015N237824_03
CONFIDENTIAL
204746
52
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence 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 natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of 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 when 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 
prior to the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.

The investigator is obligated to assist.  This may include additional laboratory tests 
or investigations, histopathological examinations or consultation with other health 
care professionals.

If a subject 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 the designated 
reporting time frames.


2015N237824_03
CONFIDENTIAL
204746
53
12.3.6.
Reporting of SAEs to GSK
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

Initial notification via the 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 receipt can be found at this beginning of the protocol on the 
Sponsor/Medical Monitor Contact Information page.


2015N237824_03
CONFIDENTIAL
204746
54
12.4.
Appendix 4:Collection of Pregnancy Information

Investigator will attempt to collect pregnancy information on any female partner of a 
male study subject who becomes pregnant while participating in this study.  This 
applies only to subjects who are randomized to receive study medication. 

After obtaining the necessary signed informed consent from the female partner 
directly, the investigator will record pregnancy information on the appropriate form 
and submit it to GSK within 2 weeks of learning of the partner’s pregnancy

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. 

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 fetal 
status (presence or absence of anomalies) or indication for procedure.


2015N237824_03
CONFIDENTIAL
204746
55
12.5.
Appendix 5:Radiation Dose
Subjects will be exposed to an additional dose of ionising radiation as a consequence of 
their participation in this study.  The ionising radiation dose from PET/CT scanning 
comes from two sources. The majority of the radiation dose comes from the administered 
radiotracer ([11C]GSK2256098). The remaining radiation dose coming from a low dose 
CT scan performed in order to correct the PET data for tissue attenuation. If the subject 
needs to be removed from the scanner and repositioned during the scan than a second low 
dose CT scan may be performed.The doses chosen for this study aim to deliver a minimal 
radiation exposure, compatible with a good quality PET and CT signal. 
Each subject will have a single PET-CT scan. The dosimetry estimate for a study such as 
this, involving a novel tracer, is necessarily uncertain but a conservative approach has 
been taken by using a dose conversion factor of 6 Sv/MBq injected activity based on 
preclinical data. This results in an effective dose of 3 mSv for a 500 MBq administration. 
A low-dose attenuation CT scan of the lung results in an effective dose of 1.2 mSv. If the 
subject leaves the scanner during the scan and is repositioned, the CT scan will be 
repeated which would result in a further effective dose of 1.2 mSv . The total effective 
dose to each participant will therefore be up to 3.0 + 2.4 = 5.4 mSv. All of this exposure 
is over and above standard practice. 
This total exposure of 5.4 mSv is equivalent to just under 2 and a half times the average 
yearly exposure (2.3 mSv) from natural background radiation in the United Kingdom. For 
an adult in good health this exposure would result in a risk of around 1 in 3700 of 
contracting a fatal cancer. The reduced life expectancy of the study patient group will 
result in a lower risk for these individuals.
The total exposure falls into category IIb (upper limit 10 mSv) of the guidance published 
by the International Committee for Radiation Protection (ICRP). There is no dose limit 
for research purposes in the UK, but like many EU member states, the UK follows the 
ICRP 62 guidance that recommends 10 mSv (or less) per study where research subjects 
are not expected to benefit personally.


2015N237824_03
CONFIDENTIAL
204746
56
12.6.
Appendix 6:Protocol Changes
Amendment 01
The purpose of this amendment is to correct the eligibility criteria.
Summary of Changes
Section 5.2.1 Healthy Volunteer Subjects (Exclusion)
CHANGE FROM
4. Established diagnosis of systemic hypertension or known Left Ventricular 
Hypertrophy (LVH).
a. Or undiagnosed subjects with the average of triplicate BP readings which 
is > 140 / 90 at screening
CHANGE TO
4. Established diagnosis of systemic hypertension or known Left Ventricular 
Hypertrophy (LVH).
Section 5.2.2 PAH patients (Exclusion)
CHANGE FROM
1. Presence of any uncontrolled co-morbid condition (e.g. severe or unstable coronary 
artery disease) which in the opinion of the investigator would increase the potential 
risk to the subject.
2. Airways or interstitial lung disease, including adult asthma, COPD, emphysema, 
bronchiectasis and pulmonary fibrosis or any secondary cause of PAH.
3. Previous significant pulmonary embolus
4. Current or chronic history of intrinsic liver disease, or known hepatic or biliary 
abnormalities (with the exception of Gilbert’s syndrome).
5. Systemic hypertension.
6. Estimated GFR <40mL/min based on clinical chemistry
7. Change in vasodilator and/or diuretic medication / dosage within 12 weeks of the 
scanning visit.
8. A syncopal or presyncopal episode within 4 weeks of screening.
9. Subjects who require continuous oxygen.


2015N237824_03
CONFIDENTIAL
204746
57
CHANGE TO
1. Presence of any uncontrolled co-morbid condition (e.g. unstable coronary artery 
disease or systemic hypertension) which in the opinion of the investigator would 
increase the potential risk to the subject
2. Airways or interstitial lung disease, including adult asthma, COPD, emphysema, 
bronchiectasis, pulmonary fibrosis or chronic thromboembolic disease.
3. Current or chronic history of intrinsic liver disease (with the exception of Gilbert's 
syndrome or gallstones)
4. LVH on 2D-Echocardiogram in the past 12 months
5. Estimated GFR < 40mL/min based on clinical chemistry
6. Change in PAH medication within 28 days of scanning
7. A syncopal episode within 28 days of scanning
8. Subjects who require continuous oxygen.


2015N237824_03
CONFIDENTIAL
204746
58
Amendment 02
The purpose of this amendment is to correct some typographical errors in the study title 
and the eligibility criteria. These changes do not impact subject safety, the study design 
or the integrity of the design. Therefore, this amendment is considered non-substantial.
Summary of Changes
Title
CHANGE FROM
A microdose Study to Evaluate the Biodistribution of [11C]- GSK2256098 in the Lungs 
and Heart of Healthy Subjects and Idiopathic Pulmonary Arterial Hypertension (PAH) 
Patients using Positron Emission Tomography (PET).
CHANGE TO
A microdose Study to Evaluate the Biodistribution of [11C]- GSK2256098 in the Lungs 
and Heart of Healthy Subjects and Pulmonary Arterial Hypertension (PAH) Patients 
using Positron Emission Tomography (PET)
Section 5.1.1 Healthy Volunteer Subjects (Inclusion)
CHANGE FROM
1. Healthy subjects enrolled between 40 to 70 years inclusive at the time of signing the 
informed consent. Healthy subjects will be recruited to be age (5 years) and gender 
matched to idiopathic PAH patients
CHANGE TO
1. Healthy subjects enrolled between 40 to 70 years inclusive at the time of signing the 
informed consent. Healthy subjects will be recruited to be age (5 years) and gender 
matched to PAH patients
Section 5.1.2 PAH Patients (Inclusion)
CHANGE FROM
2. Subjects medically diagnosed with idiopathic and inherited PAH, and clinically 
Functional Class II-IV, as defined in the guidelines of the ESC and ERS; Table 4, 
Categories 1.1 and 1.2 [Galiè, 2009].
CHANGE TO
2. Subjects medically diagnosed with idiopathic or inherited PAH, and clinically 
Functional Class II-IV, as defined in the guidelines of the ESC and ERS; Table 4, 
Categories 1.1 and 1.2 [Galiè, 2009].


2015N237824_03
CONFIDENTIAL
204746
59
Section 5.2.1 Healthy Volunteer subjects (Exclusion)
CHANGE FROM
7. Current smoker or a history of smoking within 6 months of Screening, or a total pack 
year history of >5 pack years.
[number of pack years = (number of cigarettes per day/20) x number of years 
smoked]
CHANGE TO
7. Current smoker or a history of smoking within 6 months of Screening, or a total pack 
year history of >10 pack years.
[number of pack years = (number of cigarettes per day/20) x number of years 
smoked]
Section 5.2.2 PAH patients (Exclusion)
CHANGE FROM
10. Current smoker or a history of smoking within 6 months of Screening, or a total pack 
year history of >5 pack years.
[number of pack years = (number of cigarettes per day/20) x number of years 
smoked]
CHANGE TO
10. Current smoker or a history of smoking within 6 months of Screening, or a total pack 
year history of >10 pack years.
[number of pack years = (number of cigarettes per day/20) x number of years 
smoked].


2015N237824_03
CONFIDENTIAL
204746
60
Amendment 03
The purpose of this amendment is to amend the QTc exclusion criteria (criteria number
16) for PAH patients only to a QTcF interval up to and including 500 msec. Te 
amendment is considered substantial.
Summary of Changes
Section 2.2 Brief Background
PREVIOUS TEXT
The currently available PAH therapies are vasodilators and provide symptomatic support 
but do not fully address the underlying remodelling aspects of the disease where there is a 
significant unmet need for a specific disease modifying PAH therapy.
REVISED TEXT
The currently available PAH therapies are vasodilators and provide symptomatic support 
but do not fully address the underlying remodelling aspects of the disease where there is a 
significant unmet need for a specific disease modifying PAH therapy. This is 
particularly important since increasing pulmonary artery pressures leads to 
progressive, and sometimes maladaptive, right ventricle remodelling which 
increases the risk of QTcF interval prolongation (Rich et al, 2013), and is probably 
one of the factors which contributes to the increased risk of sudden death in this 
population.
Section 4.3 Type and Number of Subjects
CHANGE FROM

Up to 12 healthy subjects and 12 PAH patients will be enrolled to provide sufficient 
PET data to quantify the uptake of [11C]-GSK2256098 in the heart and lungs.
CHANGE TO

Up to 12 healthy subjects and 12 PAH patients (including those with a prolonged 
QTcF interval ≤ 500ms) will be enrolled to provide sufficient PET data to quantify 
the uptake of [11C]-GSK2256098 in the heart and lungs.


2015N237824_03
CONFIDENTIAL
204746
61
Section 5.2.2 PAH patients (Exclusion)
CHANGE FROM
16. Subject with QTcF of >450ms (or QTcF of > 480msec in subjects with Bundle 
Branch Block) or other 12-lead ECG abnormalities (with the exception of right 
bundle-branch block) which, in the opinion of the investigator is clinically significant
in that they may increase safety risk.
CHANGE TO
16. Subjects with QTcF of > 500ms (irrespective of bundle branch block status),or other 
12-lead ECG abnormalities (with the exception of right bundle-branch block) which, 
in the opinion of the investigator is clinically significant in that they may increase 
safety 

SAP_003.pdf: 
H M R c o de: 1 5 -5 0 5  
S p o ns or c o de: 2 0 4 7 4 6   
Ha m mers mit h Me dici nes Res earc h  
0 4 Oct o ber 2 0 1 6   
P a ge 1 of 4 6  
St ati sti c al A n al y si s Pl a n  
Cli nical trial pr ot oc ol title:   
A micr o d ose St u d y t o E v al uate t he Bi o distri b uti o n of 
[1 1C] - G S K 2 2 5 6 0 9 8 i n t he L u n gs a n d Heart of H ealt h y 
S u bjects a n d P ul m o nar y Arterial H y p erte nsi o n ( P A H) 
Patie nts usi n g P ositr o n E missi o n T o m o gra p h y ( P E T) 
H M R c o de:  
1 5- 5 0 5 
E u dra C T n o: 
2 0 1 5- 0 0 2 6 2 6- 4 0 
C R O details:  
Ha m mers mit h Me dici nes Researc h  
C u m berla n d A ve n ue 
L o n d o n N W 1 0 7 E W 
S p o ns or details: 
Gla x o S mit h Kli ne Researc h & D e vel o p me nt Li mite d  
9 8 0 Great West R oa d  
Bre ntf or d  
Mi d dlese x, T W 8 9 G S 
U K  
Iss u e d:  
4 Oct o ber 2 0 1 6 
Versi o n:  
1. 1 
Base d o n: 
Pr ot oc ol A me n d me nt 0 3, 2 2 A pril 2 0 1 6 
N u m ber of pa ges:  
4 6 
P P D
Pre pare d b y:  
 


HMR code: 15-505 
Sponsor code: 204746  
Hammersmith Medicines Research  
04 October 2016  
Page 2 of 46 
Table of contents 
1 
LIST OF ABBREVIATIONS .............................................................................4 
2 
SIGNATURES ......................................................................................................5 
3 
INTRODUCTION ................................................................................................6 
4 
STUDY OBJECTIVE(S) AND ENDPOINT(S) ................................................6 
4.1 
Study Objective(s) .....................................................................................6 
4.1.1 
Primary Objective(s) .......................................................................................... 6 
4.1.2 
Exploratory Objective(s) .................................................................................... 6 
4.2 
Study Endpoint(s) ......................................................................................7 
4.2.1 
Primary Endpoint(s) ........................................................................................... 7 
4.2.2 
Exploratory Endpoint(s) ..................................................................................... 7 
4.3 
Statistical Hypotheses ................................................................................7 
5 
STUDY DESIGN ..................................................................................................7 
6 
TIME AND EVENTS TABLE ............................................................................8 
7 
PLANNED ANALYSES ....................................................................................10 
7.1 
Interim Analyses ......................................................................................10 
7.1.1 
Persons responsible for analysis ....................................................................... 10 
7.2 
Final Analysis ..........................................................................................10 
7.2.1 
Persons responsible for analysis ....................................................................... 10 
8 
SAMPLE SIZE CONSIDERATIONS .............................................................10 
8.1 
Sample Size Re-estimation or Adjustment ..............................................11 
9 
ANALYSIS POPULATIONS ...........................................................................12 
9.1 
Analysis Datasets .....................................................................................12 
10 
TREATMENT COMPARISONS .....................................................................12 
11 
GENERAL CONSIDERATIONS FOR DATA ANALYSES ........................12 
11.1 
Data Display Group Descriptors ..............................................................12 
11.2 
Conventions for Summary Statistics and Data Displays .........................13 
12 
DATA HANDLING CONVENTIONS ............................................................13 
12.1 
Premature Withdrawal and Missing Data ................................................13 
12.2 
Derived and Transformed Data ...............................................................13 
12.3 
Assessment Windows ..............................................................................14 
12.4 
Values of Potential Clinical Importance ..................................................14 
13 
STUDY POPULATION ....................................................................................14 
13.1 
Disposition of Subjects ............................................................................14 
13.2 
Protocol Deviations .................................................................................15 


HMR code: 15-505 
Sponsor code: 204746  
Hammersmith Medicines Research  
04 October 2016  
Page 3 of 46 
13.3 
Demographic and Baseline Characteristics .............................................15 
13.4 
Treatment Compliance ............................................................................16 
14 
SAFETY ANALYSES .......................................................................................16 
14.1 
Adverse Events ........................................................................................16 
14.2 
Deaths, Cardiovascular and Serious Adverse Events ..............................16 
14.3 
Other Safety Measures .............................................................................17 
14.3.1 
Clinical Laboratory Evaluations ....................................................................... 17 
14.3.2 
Vital signs ......................................................................................................... 17 
14.3.3 
Physical examination ........................................................................................ 17 
14.4 
Positron Emission Tomography ..............................................................17 
15 
REFERENCES ...................................................................................................19 
16 
ATTACHMENTS ..............................................................................................19 
16.1 
Data Display Requirements .....................................................................19 
16.2 
Table of Contents for Data Display Specifications .................................20 
16.3 
Data Display Specifications .....................................................................24 
16.3.1 
Table Outlines .................................................................................................. 24 
16.3.2 
Figure Outlines ................................................................................................. 33 
16.3.3 
Listing Outlines ................................................................................................ 35 
APPENDIX A: LABORATORY RANGES ................................................................44 
APPENDIX B: SAMPLE PAGE LAYOUT ...............................................................46 
 


HMR code: 15-505 
Sponsor code: 204746  
Hammersmith Medicines Research  
04 October 2016  
Page 4 of 46 
1 
List of abbreviations 
AE 
Adverse Event 
APTT 
Activated Partial Thromboplastin Time 
BMI 
Body Mass Index 
CRF 
Case Report Form 
CT 
Computerised Tomography 
CTR 
Clinical Trial Report 
       ECG 
Electrocardiogram 
FAK 
Focal adhesion kinase 
GSK  
GlaxoSmithKline 
HIV 
Human Immunodeficiency Virus 
HMR 
Hammersmith Medicines Research 
HPD 
Highest Posterior Density 
 
 
HV 
Healthy Volunteers 
ICH 
International Conference on Harmonization 
IMP 
Investigational Medicine Product 
INR 
International Normalised Ratio 
IPF 
Idiopathic Pulmonary Fibrosis 
MCMC 
Monte Carlo Markov Chain 
MedDRA 
Medical Dictionary for Regulatory Activities 
N 
Number of subjects 
n 
Number of observed subjects 
PAH 
Pulmonary Arterial Hypertension  
PDF 
Portable Document Format 
PET 
Positron Emission Tomography  
PT 
Prothrombin Time 
Q1 
Lower quartile 
Q3 
Upper quartile 
ROI 
Region of Interest 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SUV 
Standardised Uptake Value 
TEAE 
Treatment-Emergent Adverse Event 
TT 
Thrombin time 
 
 VT 
Volume of Distribution 
 
 


P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


HMR code: 15-505 
Sponsor code: 204746  
Hammersmith Medicines Research  
04 October 2016  
Page 6 of 46 
3 
Introduction 
This Statistical Analysis Plan (SAP) is based on the current trial protocol (Amendment 3, 
22Apr2016) and CRF (version 1, 28Sep2015).  Where statistical methods differ substantially 
between this SAP and the protocol, that will be identified in this document. 
This SAP describes the datasets and the statistical methods to be used for the reporting and 
analysis of all data collected during the trial except then genetics sample data.   
If a future protocol amendment necessitates a substantial change to the statistical analysis of 
the trial data, this SAP will be amended accordingly.  If, after database lock, additional 
analyses are required to supplement the planned analyses described in this SAP, those 
unplanned analyses will not be described in an amended SAP, but they will be identified in 
the integrated clinical trial report (CTR).  Any deviations from this SAP will be documented 
in the CTR. 
This SAP has been written in consideration of the following guidelines:   
• International Conference on Harmonization (ICH) E9, Guidance for Industry:  Statistical 
Principles for Clinical Trials (ICH E9 1998)1; and  
• ICH E3, Guidance for Industry: Structure and Content of Clinical Study Reports (ICH E3 
1995)2. 
Statistical analysis will be done using SAS 9.3 on a Windows PC. 
4 
Study Objective(s) and Endpoint(s) 
4.1 
Study Objective(s) 
4.1.1 Primary Objective(s) 
To compare the uptake of [11C]-GSK2256098 in the heart and lungs of PAH patients versus 
the heart and lungs of healthy control subjects 
4.1.2 Exploratory Objective(s) 
To explore the spatial distribution of [11C]-GSK2256098 uptake in the heart and lungs of 
PAH patients versus the heart and lungs of healthy control subjects. 


HMR code: 15-505 
Sponsor code: 204746  
Hammersmith Medicines Research  
04 October 2016  
Page 7 of 46 
4.2 
Study Endpoint(s) 
4.2.1 Primary Endpoint(s) 
Uptake of [11C]-GSK2256098 in the heart and lung (assessed as the volume of distribution 
(VT) and/or standardised uptake values (SUV)) as measured by PET 
4.2.2 Exploratory Endpoint(s) 
Qualitative assessment of the spatial distribution of [11C]-GSK2256098 uptake in the heart 
and lungs 
4.3 
Statistical Hypotheses 
No formal statistical testing will be done.  Instead an estimation approach has been adopted.  
Simple Bayesian methods will be used to quantify the evidence which the study generates 
about the endpoints themselves, and about contrasts (probability ratios) of these endpoints. 
5 
Study Design 
This is cross-sectional study exploring the uptake of [11C]-GSK2256098 in PAH patients and 
in healthy (age and gender-matched) volunteers. 
It is a non-randomised, open label study where all volunteers will receive one microdose of 
the radiolabelled compound. 
Up to 12 healthy subjects and 12 PAH patients (including those with a prolonged 
QTcF interval ≤ 500ms) will be enrolled to provide sufficient PET data to quantify 
the uptake of [11C]-GSK2256098 in the heart and lungs.


H M R c o de: 1 5 -5 0 5  
S p o ns or c o de: 2 0 4 7 4 6   
Ha m mers mit h Me dici nes Res earc h  
 
0 4 Oct o ber 2 0 1 6   
P a ge 8 of 4 6  
6 
Ti m e a n d E v e nt s T a bl e   
Pr oce d ure  
Scree ni n g ( u p t o 3 0 
da ys pri or t o sca n)  
Sca n ni n g visit  
F oll o w -u p  
( 2-4 wee ks p ost -last d ose) 
N otes  
I nf or me d c o nse nt 
X  
 
 
 
I ncl usi o n a n d e xcl usi o n criteria 
X  
 
 
 
De m o gra p h y  
X  
 
 
 
Brief p h ysical  
X 
X 
X  
O n t he sca n ni n g da y, t o be c o m plete d pre -sca n, 
pri or t o t he a d mi nistrati o n of t he pe pti de.  
Me dical / Me dical hist or y  
X 
 
 
 
Vital si g ns  
X 
X 
 
O n t he sca n ni n g da y, t o be c o n d ucte d pre a n d p ost 
sca n. 
1 2 -lea d E C G 
X 
 
 
 
Alc o h ol breat h test  
X  
X  
 
 
Uri ne dr u g a n d c oti ni ne scree n  
X  
 
 
 
He alt h y s u bjects o nl y: s pir o metr y  
X  
 
 
 
C oa g ulati o n pr ofile  
X 
 
 
T his will i ncl u de P T ( Pr ot hr o m bi n ti me), A P T T 
( Acti vate d P artial T hr o m b o plasti n Ti me) a n d 
T hr o m bi n Ti me ( T T)  
P A H p atie nts o nl y ( w h o h a ve bee n o n 
W arf ari n):  I N R 
 
X 
 
Sa m ple t o c o nfir m s uita bilit y f or sca n ni n g da y ca n 
be d o ne u p t o 3 da ys pri or t o t he da y of t he sca n  
HI V, He p B a n d He p C scree n  
X 
 
 
If test ot her wise perf or me d wit hi n 3 m o nt hs pri or t o 
first d ose of st u d y treat me nt, t esti n g at scree ni n g is 
n ot re q uire d  
Cli nical c he mistr y a n d Hae mat ol o g y  
X  
 
 
 
Uri nal ysis  
X  
 
 
 
Alle n’s test  
X  
X  
 
 
i. v d ose of [1 1C] -G S K 2 2 5 6 0 9 8  
 
X 
 
 
P E T sca n  
 
X 
 
P E T sca n ni n g will be starte d at t he sa me ti me as 
i nj ecti o n of t he ra di oli ga n d a n d P E T data will be 
c ollecte d f or u p t o 9 0 mi n utes p ost a d mi nistrati o n.  


H M R c o de: 1 5 -5 0 5  
S p o ns or c o de: 2 0 4 7 4 6   
Ha m mers mit h Me dici nes Res earc h  
 
0 4 Oct o ber 2 0 1 6   
P a ge 9 of 4 6  
Pr oce d ure  
Scree ni n g ( u p t o 3 0 
da ys pri or t o sca n)  
Sca n ni n g visit  
F oll o w -u p  
( 2-4 wee ks p ost -last d ose) 
N otes  
Atte n uati o n C T sca n  
 
X 
 
Lasti n g sec o n ds t o mi n ute pri or t o start of P E T 
sca n.  If s u bj ect gets off t he be d f or a c o mf ort brea k 
mi d wa y t hr o u g h t he P E T sca n, a n ot her C T sca n 
will be perf or me d pri or t o re -starti n g ac q uisiti o n of 
P E T data  
Ge netics sa m ple  
 
X 
 
Ge netic I nf or me d c o nse nt m ust be o btai ne d bef ore  
c ollecti n g a sa m ple  
Sa m ples f or plas ma ra di oacti vit y 
meas ure me nts & w h ole bl o o d  
 
X 
 
Bl o o d sa m ples will be c ollecte d d uri n g sca n ni n g f or 
plas ma a n d w h ole bl o o d ra di oacti vit y 
meas ure me nts.  
A E/ S A E re vie w  
 
X  
X  
 
C o nc o mita nt me dicati o n re vie w  
X  
X  
X  
 
 
 


H M R c o de: 1 5 -5 0 5  
S p o ns or c o de: 2 0 4 7 4 6   
Ha m mers mit h Me dici nes Res earc h  
0 4 Oct o ber 2 0 1 6   
P a ge 1 0  of 4 6  
7 
Pl a n n e d A n al y s e s  
7. 1  
I nt eri m A n al y s e s 
N o f or mal i nteri m “testi n g” of a n y statistical h y p ot hesis will be perf or me d.  
 
T he stre n gt h of e vi d e nce i n t he  P E T data (a b o ut differe ntial e x pressi o n le vels  bet wee n 
patie nts a n d H Vs) will be re vie we d o n ce fi ve patie nts a n d fi ve healt h y v ol u nteers ha v e bee n 
st u die d i n t he P E T sca n ner, a n d t he rele v a nt f u ncti o nal e n d p oi nts ha ve bee n deri ve d  b y 
I ma n o v a scie ntists f or h eart c ha m ber a n d w h ol e l u n g re gi o ns. Fr o m t hat p oi nt o n war ds, t he 
data will be m o nit ore d c o nti n u o usl y ( or as n ear as p ossi ble  gi ve n practicalities of st u d y 
o perati o nalisati o n)  
 
7. 1. 1  Pers o ns res p o nsi ble f or a n al ysis  
 ( H M R) 
Statisticia n  
  
 
S A S Pr o gra m mer  
 
7. 2  
Fi n al A n al y si s  
T he data bas e will be l oc k e d o nce all s u bjects ha ve c o m plete d t he st u d y, d ata ha ve bee n 
e ntere d a n d all q ueries res ol ve d.  T he fi nal a n al ysis will be carrie d o ut f oll o wi n g dat a base 
l oc k. 
7. 2. 1  Pers o ns res p o nsi ble f or a n al ysis  
 ( H M R) 
Statisticia n  
 ( H M R) 
S A S Pr o gra m mer  
 ( H M R) 
D ata Ma na ger  
 
8 
S a m pl e Si z e C o n si d er ati o n s  
P P D
T here is little k n o w n a b o ut t he li kel y mea n v al ues of t he P E T- deri ve d f u ncti o nal pri mar y 
e n d p oi nts ( V ol u me of distri b uti o n, a n d/ or s o me f or m of i nte grate d S U V) i n t his 
P P D
P P D
P P D
P P D
P P D


HMR code: 15-505 
Sponsor code: 204746  
Hammersmith Medicines Research  
04 October 2016  
Page 11 of 46 
population. Therefore our sample size is driven by a mixture of: 
(i) 
what is known about between-subject variability from relevant, recent PET 
studies, 
(ii) 
feasibility, and 
(iii) 
flexibility. 
 
An ongoing study investigating the validation and dosimetry of a PET ligand in healthy 
subjects and patients with IPF (study RES116235) has been able to draw firm conclusions 
about similar endpoints (in terms of the estimation methods we describe below) using around 
5 subjects. Therefore we will set five patients and five age-matched HVs as our initial target 
sample size. 
 
From that point onwards, the data will be monitored continuously (or as near as possible 
given practicalities of study operationalisation), and at each step the following decisions will 
be made: 
• 
Stop, and conclude that there is strong evidence of differential FAK expression (as 
measured by the study endpoints) between patients and HVs. 
• 
Stop, and conclude that there is insufficient evidence of any great difference, and 
furthermore (conditional on observed data i.e. in a formal Bayesian sense) there is 
low probability that an increase in sample size will reverse such a conclusion 
• 
Continue to enrol patient-HV pairs, and re-evaluate the decision. 
 
This iterative cycle will be followed up until a maximum of twelve patients and twelve HVs 
have been recruited into the study. 
 
8.1 
Sample Size Re-estimation or Adjustment 
The first statistical evaluation of the data will occur once five patients and five healthy 
volunteers have been studied in the PET scanner, and the relevant functional endpoints (such 
as VT) have been derived from their scan data  by Imanova scientists. At this point, the 
statistical analysis (set out below) will be carried out, and, based on those results, the team 
may decide to recruit more subjects, up to a total of twelve patients and twelve healthy 
volunteers. 


HMR code: 15-505 
Sponsor code: 204746  
Hammersmith Medicines Research  
04 October 2016  
Page 12 of 46 
9 
Analysis Populations 
The following populations will be identified: 
Screened Population:  
all subjects who signed an informed consent form and were 
evaluated for study participation. 
Safety Population:  
All patients and subjects who received the microdose of  
study drug.   
The primary endpoint will be analysed using the Safety Population. 
 
9.1 
Analysis Datasets 
All analysis datasets will be based on observed data, except as outlined in Section 12.2. 
10 
Treatment Comparisons 
The comparison of interest is uptake of [11C]-GSK2256098 in PAH patients versus healthy 
volunteers. 
 
11 
General Considerations for Data Analyses 
11.1 Data Display Group Descriptors 
The sort order for groups will be PAH patients then healthy control subjects.  When a total 
column is included, it immediately follows the groups which it aggregates. 
Listings of data will be sorted and displayed by group, subject number, and also by date and 
time if applicable.   
The group descriptions to be used on all tables and listings are:  
Groups  
 
 
PAH Patients 
Healthy Volunteers 
 


HMR code: 15-505 
Sponsor code: 204746  
Hammersmith Medicines Research  
04 October 2016  
Page 13 of 46 
11.2 Conventions for Summary Statistics and Data Displays 
The minimum set of summary statistics for numeric variables will be: n, mean, standard 
deviation (or standard error), median, minimum and maximum 
Categorical data will be summarised in frequency tables with n and percentage.  Summaries 
of a categorical variable will include all recorded values. 
The minimum and maximum values will be presented with the same number of decimal 
places as the raw data collected on the CRF (or to 3 significant figures for derived 
parameters). The mean and percentiles (e.g. median, Q1, and Q3) will be presented using one 
additional decimal place. The standard deviation and standard error will be presented using 
two additional decimal places.  
12 
Data Handling Conventions 
12.1 Premature Withdrawal and Missing Data 
All subjects who withdraw prematurely from the study or study drug will be included in the 
statistical analyses.  
If a subject completes the treatment period but has missing data, then this will be made 
apparent in the subject listings. Missing data will not be imputed except for as outlined in 
Section 12.2.   
If the study is prematurely discontinued, all available data will be listed and a review will be 
carried out to assess which statistical analyses are still considered appropriate. 
Data collected at unscheduled time points during the study will not be used in the summaries 
or data analyses.  They will be included in the listings. 
If time information (i.e. hours and/or minutes) for adverse events or concomitant medication 
is missing, but the day is present, then the time will be calculated in days.    If date 
information is partial or missing, then any derived times (e.g. AE start time from last study 
medication) will be listed as missing.  
12.2 Derived and Transformed Data 
VT and mean SUV will be derived by Imanova for regions including  heart chamber and 
whole lung. 


HMR code: 15-505 
Sponsor code: 204746  
Hammersmith Medicines Research  
04 October 2016  
Page 14 of 46 
The CT images obtained for attenuation correction (AC) of the PET [CT-AC)] are used to 
delineate the left and right lung and both the CT-AC and the region of interest (ROI) image 
are resampled to the PET space. Time activity curves are extracted using the predefined ROI 
image. Standardized uptake values (SUV) are generated by averaging the time activity curves 
between two time points (to be defined depending on the kinetics of the tracer in the lungs) 
and normalising to the injected dose per unit mass. 
An image derived input function is generated using a region of interest in the pulmonary 
artery. This input function is used together with a compartmental model to derive the volume 
of distribution (VT) in each region of interest. 
12.3 Assessment Windows 
No assessment windows are defined for this report. 
12.4 Values of Potential Clinical Importance 
Any laboratory value outside the reference range for that variable  (Appendix B) will be 
flagged as a value of a potential clinical importance 
A vital signs result will be considered to be of potential clinical importance if it falls outside 
the relevant range below: 
Vital Sign 
Range 
Supine/semi-recumbent systolic blood pressure 
85–160 mm Hg 
Supine/semi-recumbent diastolic blood pressure 
40–90 mm Hg 
Supine/semi-recumbent heart rate 
40–100 beats/min 
Respiration rate 
8–20 per min 
Oral temperature 
35.5–37.8°C 
 
13 
Study Population 
13.1 Disposition of Subjects 
All analyses will use the safety population. 


HMR code: 15-505 
Sponsor code: 204746  
Hammersmith Medicines Research  
04 October 2016  
Page 15 of 46 
The disposition of all subjects (patients and healthy volunteers) in the safety population will 
be summarised including  number of subjects screened, the number of subjects who failed 
screening, number completing the study by group, and number withdrawn from the study. 
All subjects who withdraw or are withdrawn from the study will be listed by treatment, with 
the reason for withdrawal.  
A listing of analysis populations will be provided. 
 
13.2 Protocol Deviations 
Before closing the database, data listings will be reviewed to identify any significant 
deviations and determine whether the data should be excluded from any analysis populations.   
Major protocol deviations include subjects who: 
• Entered the study even though they did not satisfy the entry criteria. 
• Met the criteria for withdrawal from the study but were not withdrawn. 
• Received the wrong treatment or incorrect dose. 
• Received an excluded concomitant therapy. 
• Received investigational product(s) past the expiration date. 
• Healthy volunteers who are not matched to a PAH patient on gender or with age not 
within ± 5 years 
 
A summary table of the important deviations will be provided. 
A listing of inclusions/ exclusion deviations will be provided. 
A listing of all important deviations will be provided. 
 
13.3 Demographic and Baseline Characteristics 
Demographic and baseline characteristics (e.g. physical examination, vital signs, Allen’s test 
and INR) will be listed and summarised.  A summary of age ranges of subjects will be 
presented.  
A summary of the difference in ages between the matched pairs will also be presented.   
Subjects who take concomitant medication will be listed.  All non-trial medication will be 
coded by GSK. 


HMR code: 15-505 
Sponsor code: 204746  
Hammersmith Medicines Research  
04 October 2016  
Page 16 of 46 
13.4 Treatment Compliance 
Dates and times of dosing will be listed (Listing 16.2.1.1).  
14 
Safety Analyses 
The dates and times of treatment dosing will be listed to indicate exposure to the study 
medication (Listing 16.2.1.1). 
14.1 Adverse Events 
Adverse events will be coded by GSK. 
All adverse events will be listed.  Subject numbers for specified adverse events will be listed. 
A listing of the relationship between system organ class and verbatim text will also be 
presented. 
The number of subjects with at least one treatment-emergent adverse event (TEAE) will be 
tabulated by actual treatment and MedDRA system organ class.  A treatment-emergent 
adverse event is defined as an event emerging during treatment having been absent pre-
treatment or having worsened relative to pre-treatment1.  
For each of the following, the number of subjects with adverse events will be summarised: 
• TEAEs by system organ class and preferred term 
• IMP-related (as recorded by the Investigator) TEAEs by system organ class and 
preferred term 
Subjects with more than one TEAE will be counted only once, at causality, for each system 
organ class/preferred term.  Multiple TEAEs in a subject will be counted once per system 
organ class and preferred term.  Adverse events with missing severity and/or causality will be 
treated as severe and related to IMP, respectively. 
Summaries will be sorted by system organ class and decreasing total incidence of preferred 
term. 
14.2 Serious Adverse Events 
 Serious Adverse Events will be summarised by by system organ class and preferred term.  
A listing of the reasons for considering a serious adverse event will be provided. 


HMR code: 15-505 
Sponsor code: 204746  
Hammersmith Medicines Research  
04 October 2016  
Page 17 of 46 
 
14.3 Other Safety Measures 
14.3.1 Clinical Laboratory Evaluations 
All laboratory values of potential clinical importance will be listed. 
14.3.2 Vital signs 
Vital signs evaluation pre- and post-scan at the scanning visit will be summarised  by group.  
Vital signs of potential clinical importance will be listed. 
14.3.3 Physical examination 
Abnormal physical examination findings will be listed by group. 
14.4 Positron Emission Tomography 
Positron Emission Tomography (PET) parameters will be summarised using the safety 
population.  
Each PET parameter (VT and mean SUV) will be listed and summarised by region and group. 
A Bayesian approach to the analysis of the PET parameters will be used. 
For any important endpoint, we describe our uncertainty concerning its true value with a 
probability density function, p(θ), say. (Suppose ‘θ’ represents Volume of Distribution, 
derived from the PET and blood sample data. The following argument will apply to any such 
endpoint which takes numerical values on the real line.)  Pre-study start, we will characterise 
p(θ) in such a way that our “prior belief” about the true endpoint’s value is entirely diffuse 
over the real line (this approach implies that all conclusions about the endpoint are driven 
only by the data gathered in the study). 
We will gather evidence about the endpoint in the data from the study, which we will 
characterise via its likelihood function (derived from the relevant sampling distribution,        
l(x| θ), say, where ‘x’ stands for ‘data’).  From the likelihood function the usual summary 
statistics for the endpoint are derived. 
It is highly likely, based on similar PET studies, that a Normal likelihood function will be 
suitable.  This will have an unknown mean and known variance taken from the raw data (i.e. 


HMR code: 15-505 
Sponsor code: 204746  
Hammersmith Medicines Research  
04 October 2016  
Page 18 of 46 
xj ~ N(θj, σj
2) where j is the PAH patient group or the HV group).  An uninformative 
conjugate Normal prior density function with mean zero and a vast variance will be adopted 
for the group mean (P(θj) = N(0, σ0,j
2)) leading to the standard Normal posterior density 
functions for the endpoints of interest (Should the data not support a Normal likelihood 
function, alternative parametric forms, such as a log-Normal density, will be investigated).  In 
order for the prior to be sufficiently non-informative, the variance of the prior will be 
approximately 100 times the variance of the data.  
We will apply Bayes’ theorem to derive the  posterior density function p(θj | xj).  We will use 
PROC MCMC in SAS.  The number of burn-in iterations will be at least 10,000 and the 
number of MCMC iterations, excluding the burn-in iterations will be at least 5000.    These 
samples may be thinned if autocorrelation is high.  An example of the SAS code for a normal 
likelihood function is given below: 
ods output PostSummaries = PostSummaries PostIntervals = PostIntervals             
PosteriorSample = PosteriorSample; 
PROC MCMC data = BayesianTest nmc = 5000 nbi = 10000 monitor=(_parms_ muratio); 
 parms mu1 mu2; 
 muratio = mu1/mu2; 
MODEL PAH ~ norm(mu1, sd = 1; 
MODEL HVs ~ norm(mu2, sd = 1); 
prior mu1 mu2 ~ normal(0, sd = 100); 
preddist outpred = BayesianPred nsim = 5000 covariates = PredCovariates; 
by  endpoint region; 
run; 
The posterior distribution for each endpoint will be summarised by region and group, 
including the mean, median, SD, interquartile range and 95% credible interval based on the 
highest posterior density (HPD) interval.   
Samples from the posterior distribution for the group mean p(θj|xj) for the PAH patients and 
for the HV subjects will be used to determine the posterior distribution for the ratio of group 
means (PAH patients to HV subjects).  The posterior distribution for the ratio of group means 


HMR code: 15-505 
Sponsor code: 204746  
Hammersmith Medicines Research  
04 October 2016  
Page 19 of 46 
will be summarised by region and endpoint.  Plots of the median and 95% credible interval 
for the posterior distribution of the group mean and the ratio of group means will be presented 
for each endpoint and region.  Individual subject data will also be included on the plot using a 
different symbol for each match pairs of subjects.  Each plot will also include the posterior 
distribution of the ratio of the group means.  
Samples from the posterior distribution of the ratio of group means will be used to determine 
the probability that the ratio of the endpoint in PAH patients to HV subjects exceeds 1 for 
each endpoint and region.  This will be repeated for other values to allow us to plot to provide 
a graph of  the “probability that this ratio exceeds a certain value, plotted against ratio, for 
ratios in the range 0.5 to 2 will be presented for each endpoint and region. 
15 
References 
1. International Conference on Harmonization, 1998.  Statistical Principles for Clinical 
Trials - ICH Harmonised Tripartite Guideline. Guidance for Industry, E9, FDA federal 
register, Vol 63, 1998, p49583.  Available at: http://www.fda.gov/cder/guidance. 
2. International Conference on Harmonization, 1995.  Structure and Content of Clinical 
Study Reports - ICH Harmonised Tripartite Guideline. Guidance for Industry, E3, FDA 
federal register, Vol 61, 1996, p37320.  Available at: http://www.fda.gov/cder/guidance. 
 
16 
ATTACHMENTS 
16.1 Data Display Requirements 
Data displays will be stored in individual PDF files with formatting of:  
• pagesize will be 8.5” x 11” (US Letter sized paper) 
• margins will be 1.25" top and bottom and 0.87" right and left on a landscape page  
• 
font will be Arial 10. 
There will be a bookmark to the first page of each display.  Bookmark text will  include 
display type (Table, Figure, Listing), display number and the verbatim text of the data display.  
Bookmarks will link directly to the first page of the data display rather than executing a Java 
script. 


HMR code: 15-505 
Sponsor code: 204746  
Hammersmith Medicines Research  
04 October 2016  
Page 20 of 46 
16.2 Table of Contents for Data Display Specifications 
For overall page layout refer to Appendix A. 
The numbering  in the tables below will take precedence over the numbering in the shells. 
The following tables and figures will be produced (templates provided in Section 16.2 and 
16.3):


H M R c o de: 1 5 -5 0 5  
S p o ns or c o de: 2 0 4 7 4 6   
 
 
Ha m mers mit h Me dici nes Res earc h  
0 4 Oct o ber 2 0 1 6  
P a ge 2 1  of 4 6  
T he f oll o wi n g t a bles a n d fi g ur es will be pr o d uce d (te m plates pr o vi de d i n Secti o n 1 6. 2. 1 a n d 1 6. 2. 2 ): 
T a ble 
Descri pti o n  
P o p ul ati o n 
S o urce 
Listi n g  
Te m pl ate 
( S hells bel o w) 
1 0. 1   
S u m mar y of S u bject Dis p ositi o n  
S cree ne d  
1 6. 2. 1. 2, 
1 6. 2. 3. 1  
T _ S D 1
 
1 0. 2  
S u m mar y of I m p orta nt Pr ot oc ol De viati o ns  
Safet y  
1 6. 2. 2. 2  
T _ D V _ G K  
1 4. 1  
 D E M O G R A P HI C D A T A  
 
 
 
1 4. 1  
S u m mar y of D e m o gra p hi c C haracteristics  
Safet y  
1 6. 2. 4. 1  
T _ D M 1 _ P G
 
1 4. 2  
S u m mar y of A ge Ra n ges  
Safet y  
1 6. 2. 4. 1  
T _ A G E _ G S K  
1 4. 3  
S u m mar y of A ge Matc hi n g  
Safet y  
1 6. 2. 4. 1  
T _ D M 2  
1 4. 3  
 S A F E T Y D A T A  
 
 
 
1 4. 3. 1. 1  
S u m mar y of Treat me nt -E mer ge nt A d verse E ve nts  
Safet y  
1 6. 2. 7. 1  
T _ A E 1
 
1 4. 3. 1. 2  
S u m mar y of Dr u g -Relate d Treat me nt -E mer ge nt A d verse E ve nts  
Safet y  
1 6. 2. 7. 1  
T _ A E 1
 
1 4. 3. 2 
S u m mar y of Seri o us A d verse E ve nts b y S yste m Or ga n Class a n d 
Preferre d Ter m  ( N u m ber of S u bjects a n d Occ urre nces) 
Safet y  
1 6. 2. 7. 1 
T _ A E 2  
1 4. 3. 3  
Narr ati ves of deat hs  a n d ot her seri o us a d v erse e ve nts  
Safet y  
1 6. 2. 7. 1  
- 
1 4. 3. 4  
S u m mar y of Vital Si g ns  at Sca n ni n g Visit  
Safet y  
- 
T _ V S 1
 
1 4. 4  
P E T D A T A  
 
 
 
1 4. 4. 1  
 
S u m mar y of V ol u me of D istri b uti o n ( VT ) a n d M ea n Sta n dar dise d 
U pta ke V al u es ( S U V), b y Gr o u p a n d Re gi o n  
Safet y  
1 6. 2. 9. 1 
T _ P T 1 _ G K  
1 4. 4. 2  
 
 
S u m mar y of t he P osteri or Distri b uti o n f or V ol u me of D istri b uti o n 
( VT )a n d Mea n Sta n dar dise d U pta ke V al ues ( S U V), b y Gr o u p a n d 
Re gi o n   
Safet y  
1 6. 2. 9. 1 
T _ P T 2 _ G K  
1 4. 4. 3  
 
 
S u m mar y of t he P osteri or Distri b uti o n of t he Rati o of Gr o u p M ea ns f or 
V ol u me of D istri b uti o n ( VT ) a n d Mea n Sta n d ar dis e d U pta ke V al ues 
( S U V), b y Re gi o n   
Safet y  
1 6. 2. 9. 1 
T _ P T 3 _ G K  
1 4. 4. 4  
 
 
P osteri or P r o ba bilit y t hat t he R ati o of Gr o u p M ea ns f or V ol u me of 
D istri b uti o n ( VT ) a n d M ea n Sta n dar dise d U pta k e Val ues ( S U V) E x cee ds  
a Certai n Val u e , b y Re gi o n  
Safet y  
1 6. 2. 9. 1 
T _ P T 4 _ G K  
 
 
 
 
 


H M R c o de: 1 5 -5 0 5  
S p o ns or c o de: 2 0 4 7 4 6   
 
 
Ha m mers mit h Me dici nes Res earc h  
0 4 Oct o ber 2 0 1 6  
P a ge 2 2  of 4 6  
Fi g ure  
Descri pti o n  
P o p ul ati o n 
S o urce 
Listi n g  
Te m pl ate 
( S hells bel o w) 
1 4. 1  
 P E T D A T A  
Safet y  
 
 
1 4. 1 . 1. 1 
 
Pl ot of t he P osteri or Distri b uti o n of t he V ol u me of Distri b uti o n  ( VT ) f or 
t he Gr o u p Mea ns  an d t he Rati o of t he Gr o u p Mea ns, b y Re gi o n  
Safet y  
1 6. 2. 9. 1 
F _ P T 1 _ G K  
1 4. 1. 1. 2  
 
 
Pl ot of t he P osteri or Distri b uti o n of t he Mea n Sta n dar dise d U pta k e 
Val ues ( S U V) f or t he Gr o u p Mea ns a n d t he Rati o of t he Gr o u p Mea ns, 
b y Re gi o n  
Safet y  
1 6. 2. 9. 1 
F _ P T 1 _ G K  
1 4. 1 .2. 1  
 
Pl ot of t he P osteri or Pr o ba bilit y t hat t he  Rati o of t he Gr o u p Mea ns 
E x cee ds a Certai n V al ue f or t he V ol u me of Distri b uti o n (V T ), b y Re gi o n 
Safet y  
1 6. 2. 9. 1 
F _ P T 2 _ G K  
1 4. 1. 2. 2  
 
 
Pl ot of t he P osteri or Pr o ba bilit y t hat t he Rati o of Gr o u p Mea ns E x cee ds 
a Certai n Val u e f or Mea n Sta n dar dise d U pta ke Val ues ( S U V ), b y 
Re gi o n  
Safet y  
1 6. 2. 9. 1 
F _ P T 2 _ G K  
 
T he f oll o wi n g a b bre vi ate d listi n gs will be pr o d uce d (te m plates pr o vi de d i n Secti o n 1 6. 2. 3 ): 
Listi n g  
Descri pti o n  
Te m pl ate  ( S hells 
bel o w)  
1 6. 2. 1  
 St u d y d ates & dis p ositi o n of s u bjects  
 
1 6. 2. 1. 1  
Listi n g of St u d y D ates  
L _ S D 1 _ P G  
1 6. 2. 1. 2  
Listi n g of Reas o ns f or Wit h dra wal  
L _ S D 2 _ P G  
1 6. 2. 2  
 Pr ot oc ol de viati o ns  
 
1 6. 2. 2. 1  
Listi n g of S u bjects wit h I ncl usi o n/ E x cl usi o n Criteria De viati o ns  
L _ D V 1 _ P G
 
1 6. 2. 2. 2  
Listi n g of I m p orta nt Pr ot oc ol De viati o ns  
L _ D V 2 _ P G
 
1 6. 2. 3  
 A nal ysis sets, i ncl u di n g s u bjects e x cl u de d fr o m a nal ysis  
 
1 6. 2. 3 . 1 
 Listi n g of A nal ysis P o p ulati o ns  
L _ A N 1 _ P G
 
1 6. 2. 4  
 De m o gra p hic d ata & c o nc o mita nt me dicati o n  
 
1 6. 2. 4. 1  
Listi n g of De m o gra p hic C haracteristics  
L _ D M 1 _ P G
 
1 6. 2. 4. 2  
Listi n g of C o nc o mita nt Me dicati o ns  
L _ C M 1 _ P G
 
1 6. 2. 5  
 St u d y dr u g a d mi nistrati o n  
 
1 6. 2. 5 . 1 
Listi n g of E x p os ure Data  
L _ E X 1 _ P G
 


H M R c o de: 1 5 -5 0 5  
S p o ns or c o de: 2 0 4 7 4 6   
 
 
Ha m mers mit h Me dici nes Res earc h  
0 4 Oct o ber 2 0 1 6  
P a ge 2 3  of 4 6  
 
 
 
 
1 6. 2. 7  
 A d verse e ve nts  
 
1 6. 2. 7. 1  
Listi n g of All A d vers e E ve nts  
L _ A E 1 _ P G
 
1 6. 2. 7. 2  
Listi n g of Seri o us A d verse E ve nts  
L _ A E 1 _ P G  
1 6. 2. 7. 3  
Listi n g of A d verse E ve nts Lea di n g t o Wit h dra wal fr o m St u d y  
L _ A E 1 _ P G  
1 6. 2. 7. 4  
Listi n g of S u bject N u m b ers f or S pecifie d A d v erse E ve nts  
L _ A E 1 _ G S K  
1 6. 2. 7. 5  
Listi n g of Reas o ns f or C o nsi deri n g a Seri o us A d v erse E ve nt  
L _ A E 3 _ G S K  
1 6. 2. 7. 6  
Listi n g of Relati o ns hi p bet wee n S yste m Or ga n Class a n d Ver bati m Te xt  
L _ A E 2 _ G S K  
1 6. 2. 8  
 La b orat or y v al ues  
 
1 6. 2. 8. 1 
Listi n g of Cli nical C he mistr y A b n or m alities of P ote ntial Cli nical 
I m p ort a nce 
L _ L B 1 _ P G  
1 6. 2. 8. 2  
Listi n g of Hae mat ol o g y A b n or malities of P ote ntial Cli nical Si g nifica nce  
L _ L B 1 _ P G  
1 6. 2. 8   
 Vital si g ns , E C Gs a n d p h ysical fi n di n gs  
 
1 6. 2. 8 .1  
Listi n g of Vital Si g ns  of P ote ntial Cli nical I m p orta nce  
L _ V S 1 _ P G
 
1 6. 2. 8. 2  
Listi n g of E C G data  
L _ E G 1 _ P G  
1 6. 2. 6. 3  
Listi n g of A b n or mal E C G F i n di n gs  
L _ E G 2 _ P G  
1 6. 2. 9  
 P E T Data  
 
1 6. 2. 9. 1 
Listi n g  of V ol u me  of  Distri b uti o n  ( V T )  a n d  Mea n  Sta n dar dise d  U pt a ke 
Val ues ( S U V)  
L _ P E T _ G K
 


H M R c o de: 1 5 -5 0 5  
S p o ns or c o de: 2 0 4 7 4 6   
 
 
Ha m mers mit h Me dici nes Res earc h  
0 4 Oct o ber 2 0 1 6  
P a ge 2 4  of 4 6  
 
1 6. 3   D at a Di s pl a y S p e cifi c ati o n s 
1 6. 3. 1  T a ble O utli nes  
T e m pl at e T _ S D 1  
T a bl e   1 0 . 1 
S u m m ar y of S u bj ect Dis p ositi o n  
P o p ul ati o n  
St at us  
R e as o n f or Wit h dr a w al  
P A H P ati e nts  
H e alt hy  
V ol u nt e ers  
All S u bj ects  
Scr e e n e d p o p ul ati o n  
I ncl u d e d 
 
 
 
 
 
F ail e d scr e e ni n g  
 
 
 
 
S af et y  p o p ul ati o n  
I ncl u d e d 
 
 
 
 
C o m pl et e d  
 
 
 
 
Wit h dr a w n  
 
 
 
 
A dv ers e E v e nt  
 
 
 
L ac k of effic ac y 
 
 
 
S u bj ect r e ac h e d pr ot oc ol -
d efi n e d st o p pi n g crit eri a  
 
 
 
St u dy cl os e d/t er mi n at e d  
 
 
 
L ost t o f oll o w-u p  
 
 
 
I nv esti g at or discr eti o n 
 
 
 
Wit h dr e w c o ns e nt  
 
 
 
 
S o urc e: Listi n g 1 6. 2.xx  
Pr o gr a m mi n g n ot es:  
C o nti n u e d wit h all tr e at m e nt gr o u ps .   
 
 
 
 
 


H M R c o de: 1 5 -5 0 5  
S p o ns or c o de: 2 0 4 7 4 6   
 
 
Ha m mers mit h Me dici nes Res earc h  
0 4 Oct o ber 2 0 1 6  
P a ge 2 5  of 4 6  
 
T e m pl at e T _ D V _ G K  
 
 
T a bl e   1 0. 2 
S u m m ar y of I m p ort a nt Pr ot oc ol D evi ati o ns  
 
 
 
 
 
C at e g ory/ S u bc at e g or y  
P A H P atie nts  
( N = x x)   
n ( %)  
H e alt hy V ol u nt e ers  
( N = x x) 
n ( %)  
 
 
 
A ny pr ot oc ol d evi ati o ns  
2 0 ( 2 0 %)  
2 2 ( 2 2 %)  
 
 
 
Ass ess m e nts a n d/ or pr oc e d ur es  
1 0 ( 1 0 %)  
8   ( 8 %) 
F ail ur e t o r e p ort S A E, pr e g n a nc y, or liv er f u ncti o n a b n or m aliti es p er pr ot oc ol  
4   ( 4 %) 
6   ( 6 %) 
R a n d o miz ati o n pr oc e d ur es  
4   ( 4 %) 
6   ( 6 %) 
St u dy tr e at m e nt s u p pl y pr oc e d ur es  
4   ( 4 %) 
6   ( 6 %) 
Ot h er  
 4   ( 4 %) 
6   ( 6 %) 
Eli gi bility crit eri a n ot m et  
6   ( 6 %) 
8   ( 8 %) 
N ot wit h dr a w n aft er d ev el o pi n g wit h dr a w al crit eri a  
1 0 ( 1 0 %)  
8   ( 8 %) 
N ot disc o nti n u e d fr o m st u dy tr e at m e nt  
4   ( 4 %) 
6   ( 6 %) 
N ot wit h dr a w n fr o m st u dy  
6   ( 6 %) 
8   ( 8 %) 
R ec eiv e d wr o n g tr e at m e nt or i nc orr ect d os e  
1 0 ( 1 0 %)  
8   ( 8 %) 
Pr o hi bit e d m e dic ati o n or d evic e  
4   ( 4 %) 
6   ( 6 %) 
Visit Wi n d o w  
1 0 ( 1 0 %)  
8   ( 8 %) 
Ot h er pr ot oc ol d evi ati o n c at e g or y  
6   ( 6 %) 
8   ( 8 %) 
 
S o urc e: Listi n g 1 6. 2.xx  
 
 
 


H M R c o de: 1 5 -5 0 5  
S p o ns or c o de: 2 0 4 7 4 6   
 
 
Ha m mers mit h Me dici nes Res earc h  
0 4 Oct o ber 2 0 1 6  
P a ge 2 6  of 4 6  
T e m pl at e T _ D M 1  
T a bl e   1 4. 1 
S u m m ar y of D e m o gr a p hic C h ar act eristics  
V ari a bl e  
St atistics  
P A H P ati e nts  
( N =xx) 
H e alt hy V ol u nt e ers 
( N =xx) 
All S u bj ects  
( N =xx) 
A g e ( y)  
n  
 
 
 
M e a n  
 
 
 
S D  
 
 
 
M i n 
 
 
 
M e di a n  
 
 
 
M ax  
 
 
 
G e n d er  
 
 
 
 
F e m al e  ( %) 
 
 
 
M al e  ( %) 
 
 
 
R ac e  
A m eric a n I n di a n or Al as k a n 
N ativ e  ( %) 
 
 
 
 
Asi a n  ( %) 
 
 
 
 
Bl ac k  ( %) 
 
 
 
 
N ativ e H a w aii a n or ot h er 
P acific Isl a n d er  ( %) 
 
 
 
 
W hit e  ( %) 
 
 
 
 
Ot h er  ( %) 
 
 
 
Et h nic it y 
His p a nic or L ati n o  ( %) 
 
 
 
N ot His p a nic or L ati n o  ( %) 
 
 
 
H ei g ht  (c m) 
n  
 
 
 
M e a n  
 
 
 
S D  
 
 
 
M i n 
 
 
 
M e di a n  
 
 
 
M ax  
 
 
 
W ei g ht ( k g)  
n  
 
 
 
M e a n  
 
 
 
S D  
 
 
 
M i n 
 
 
 


H M R c o de: 1 5 -5 0 5  
S p o ns or c o de: 2 0 4 7 4 6   
 
 
Ha m mers mit h Me dici nes Res earc h  
0 4 Oct o ber 2 0 1 6  
P a ge 2 7  of 4 6  
V ari a bl e  
St atistics  
P A H P ati e nts  
( N =xx) 
H e alt hy V ol u nt e ers 
( N =xx) 
All S u bj ects  
( N =xx) 
M e di a n  
 
 
 
M ax  
 
 
 
B MI ( k g/ m 2)  
n  
 
 
 
M e a n  
 
 
 
S D  
 
 
 
M i n 
 
 
 
M e di a n  
 
 
 
M ax  
 
 
 
S m o k er  
Y es ( %)  
 
 
 
N o ( %)  
 
 
 
Ci g ar ett es *  
( P ac k Y e ars) 
n  
 
 
 
M e a n  
 
 
 
S D  
 
 
 
M i n 
 
 
 
M e di a n  
 
 
 
M ax  
 
 
 
O pti o n al 
( u nits) 
 
 
 
 
 
*i ncl u d es o nl y t h os e s u bj ects w h o s m o k e  
S o urc e: Listi n g 1 6. 2.xx  
 
Pr o gr a m mi n g n ot es:  
C o nti n u e d wit h all tr e at m e nt gr o u ps  a n d a d diti o n al d e m o gr a p hic c h ar act eristics  
 
 


H M R c o de: 1 5 -5 0 5  
S p o ns or c o de: 2 0 4 7 4 6   
 
 
Ha m mers mit h Me dici nes Res earc h  
0 4 Oct o ber 2 0 1 6  
P a ge 2 8  of 4 6  
 
T e m pl at e T _ A G E _ G S K  
T a bl e  1 4. 3. 6.xx 
S u m m ar y of A g e R a n g es  
 
 
N o Tr e at m e nt  
Tr e at m e nt A  
Tr e at m e nt B  
T ot al  
 
( N = 1) 
( N = 1 0 0) 
( N = 1 0 0) 
( N = 2 0 1) 
A g e R a n g es  
 
 
 
 
I n ut er o                
   0        
 2   ( 2 %)  
 2   ( 2 %)  
 4   ( 2 %)  
Pr et er m n e w b or n i nf a nts ( g est ati o n al a g e < 3 7 w e eks)  
   0        
 1   ( 1 %)  
 1   ( 1 %)  
 2   ( 1 %)  
N e w b or ns ( 0 -2 7 d a ys)  
   0        
 3   ( 3 %)  
 3   ( 3 %)  
 6   ( 3 %)  
I nf a nts a n d t o d dl ers ( 2 8 d a ys-2 3 m o nt hs)  
   0        
 4   ( 4 %)  
 4   ( 4 %)  
 8   ( 4 %)  
C hil dr e n ( 2 -1 1 y e ars)  
   0        
 3   ( 3 %)  
 3   ( 3 %)  
 6   ( 3 %)  
A d ol esc e nts ( 1 2 -1 7 y e ars)  
   0        
 1   ( 1 %)  
 1   ( 1 %)  
 2   ( 1 %)  
A d ult ( 1 8 -6 4 y e ars)      
   0        
5 9  ( 5 9 %)  
5 9  ( 5 9 %)  
       1 1 8  ( 5 9 %)  
> = 6 5 -8 4 y e ars        
   0        
2 6  ( 2 6 %)  
2 6  ( 2 6 %)  
5 2  ( 2 6 %)  
> = 8 5 y e ars       
  1 ( 1 0 0 %)  
 1   ( 1 %)  
 1   ( 1 %)  
 3   ( 1 %)  
 
 
 
 
 
 
 
T e m pl at e T _ D M 2  
T a bl e  1 4. 3. 6.xx 
S u m m ar y of A g e M atc hi n g  
 
Diff er e nc e i n m atc h e d p airs ( P A H -H V)  
n * 
M e a n   
S D  
M e di a n  
Mi n   
M ax  
 
 
 
 
 
 
 
 
 
 
 
 
 
S o urc e: Listi n g 1 6. 2.xx  
 
Pr o gr a m mi n g n ot es:  
A d d t h e f o ot n ot e n * n u m b er of m atc h e d p airs  
 
 
 


H M R c o de: 1 5 -5 0 5  
S p o ns or c o de: 2 0 4 7 4 6   
 
 
Ha m mers mit h Me dici nes Res earc h  
0 4 Oct o ber 2 0 1 6  
P a ge 2 9  of 4 6  
T e m pl at e T _ A E 1  
T a bl e  1 4. 3. 3.xx 
S u m m ar y of Tr e at m e nt -E m er g e nt A dv ers e E v e nts  
 
 
P A H P ati e nts  ( N =xx) 
H e alt hy V ol u nt e ers  
( N =xx) 
Syst e m Or g a n Cl ass  
Pr ef err e d T er m  
n  
%  
n  
%  
N u m b er of s u bj ects wit h A Es  
 
 
 
 
 
G astr oi nt esti n al dis or d ers  
T ot al n u m b er of s u bj ects  
 
 
 
 
 
A b d o mi n al disc o mf ort  
 
 
 
 
 
A b d o mi n al p ai n  
 
 
 
 
 
↓ 
 
 
 
 
N erv o us syst e m dis or d ers  
T ot al n u m b er of s u bj ects  
 
 
 
 
 
Dizzi n ess  
 
 
 
 
 
H e a d ac h e  
 
 
 
 
 
↓ 
 
 
 
 
↓ 
↓ 
 
 
 
 
 
* S u bj ects wit h ≥1 a dv ers e ev e nt ar e c o u nt e d o nl y o nc e p er syst e m or g a n cl ass a n d pr ef err e d t er m.  
S o urc e: Listi n g 1 6. 2.xx  
 
Pr o gr a m mi n g n ot es:  
C o nti n u e d wit h all tr e at m e nt gr o u ps  
 
S O Cs  a n d P Ts ar e s ort e d i n d ecr e asi n g or d er of fr e q u e ncy  
 
Pr es e nt e d f or all a p plic a bl e M e d D R A syst e m or g a n cl ass es a n d t er ms.  
 
 
 


H M R c o de: 1 5 -5 0 5  
S p o ns or c o de: 2 0 4 7 4 6   
 
 
Ha m mers mit h Me dici nes Res earc h  
0 4 Oct o ber 2 0 1 6  
P a ge 3 0  of 4 6  
T e m pl at e T _ A E 2  
T a bl e  1 4. 3. 2x 
S u m m ar y of S eri o us A dv ers e E v e nts by Syst e m Or g a n Cl ass a n d Pr ef err e d T er m  
Syst e m Or g a n Cl ass  
  Pr ef err e d T er m  
 
 
P A H P ati e nts  
( N = 1 0 0) 
H e alt hy V ol u nt e ers  
( N = 2 0 0) 
 
 
 
 
A N Y E V E N T              
N u m b er of S u bj ect wit h S A Es  
4 0 ( 4 0 %)  
4 0 ( 2 0 %)  
    
N u m b er of S A Es  
5 0  
5 0  
 
N u m b er of Dr u g -r el at e d S A Es 
2 0  
2 0  
 
N u m b er of F at al S A Es  
1 0  
1 0  
 
N u m b er of Dr u g -r el at e d F at al S A Es 
 5  
 5  
 
 
 
 
I nf ecti o ns a n d i nf est ati o ns 
 
 
 
  Di a b etic G a n gr e n e  
N u m b er of S u bj ect wit h S A Es  
1 0 ( 1 0 %)  
 1 ( < 1 %)  
 
N u m b er of S A Es  
1 5  
 1  
 
N u m b er of Dr u g -r el at e d S A Es 
 5  
 0  
 
N u m b er of F at al S A Es  
 2  
 0  
 
N u m b er of Dr u g -r el at e d F at al S A Es  
 1  
 0  
  Erysi p el as  
N u m b er of S u bj ect wit h S A Es  
 1 ( < 1 %)  
1 0  ( 5 %)  
 
N u m b er of S A Es  
 1  
1 5  
 
N u m b er of Dr u g -r el at e d S A Es 
 0  
 5  
 
N u m b er of F at al S A Es  
 0  
 2  
 
N u m b er of Dr u g -r el at e d F at al S A Es 
 0  
 1  
 
 
 
 
 
 
T e m pl at e T _ V S 1  
T a bl e  1 4. 3. 6.xx 
S u m m ar y of Vit al Si g ns  at Sc a n ni n g Visit  
 
Gr o u p  
Ti m e p oi nt  
n  
M e a n  
S D  
M e di a n  
Mi n  
M ax  
Syst olic B P ( m m H g) 
P A H P ati e nts   ( N =xx) 
 
 
 
 
 
 
 
 
H e alt hy V ol u nt e ers   ( N =xx) 
 
 
 
 
 
 
 
 
S o urc e: Listi n g 1 6. 2.xx  
 


H M R c o de: 1 5 -5 0 5  
S p o ns or c o de: 2 0 4 7 4 6   
 
 
Ha m mers mit h Me dici nes Res earc h  
0 4 Oct o ber 2 0 1 6  
P a ge 3 1  of 4 6  
Pr o gr a m mi n g n ot es:  
C o nti n u e d wit h all v ari a bl es, tr e at m e nts a n d ti m e p oi nts  
 
T e m pl at e T _ P T 1 _ G K  
T a bl e  1 4. 3. 6.xx 
S u m m ar y of V ol u m e of D istri b uti o n ( VT) a n d M e a n St a n d ar dis e d U pt a k e V al u es ( S U V), by Gr o u p a n d  R e gi o n  
P ar a m et er ( u nits)  
R e gi o n  
Gr o u p  
n  
M e a n  
S D  
M e di a n  
Mi n  
M ax  
M e a n S U V   
 
P A H P ati e nts  ( N =xx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
M e a n S U V is c alc ul at e d ov er a xx mi n ut e p eri o d   
S o urc e: Listi n g 1 6. 2.xx  
 
Pr o gr a m mi n g n ot es:  
C o nti n u e d wit h all v ari a bl es, gr o u ps  a n d ti m e p oi nts .  R e pl ac e xx wit h t h e ti m e p eri o d i n t h e f o ot n ot e  .   
 
T e m pl at e T _ P T 2 _ G K  
T a bl e  1 4. 3. 6.xx  
S u m m ar y of t h e P ost eri or Distri b uti o n f or V ol u m e of D istri b uti o n ( VT) a n d M e a n St a n d ar dis e d U pt a k e V al u es ( S U V), by Gr o u p a n d  R e gi o n  
 
 
 
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ P ost eri or distri b uti o n P( ϴ | /x) __ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
P ar a m et er  
R e gi o n  
Gr o u p  
Pri or Distri b uti o n f or 
ϴ  
V al u e of σ 
us e d i n t h e n 
m o d el  
M e a n  
S D  
M e di a n  
2 5t h 
q u artil e  
7 5t h 
q u artil e  
9 5 % Cr e di bl e I nt erv al  
M e a n S U V  
H e art  C h a m b er  
P A H P ati e nts ( N =xx)  
n or m al( 0, s d = 1 0 0) 
1 
 
 
 
 
 
 
 H e alt hy V ol u nt e ers  
( N =xx) 
n or m al( 0, s d = 1 0 0) 
1 
 
 
 
 
 
 
W h ol e  L u n g 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N u m b er of M C M C it er ati o ns, excl u di n g t h e b ur n -i n it er ati o ns = 5 , 0 0 0.  N u m b er of b ur n-i n it er ati o ns = 1 0, 0 0 0 
T h e P E T p ar a m et ers  ar e  ass u m e d t o f oll o w a n or m al distri b uti o n wit h u nk n o w n m e a n ϴ  a n d k n o w n v ari a nc e σ 2 (i. e. N(ϴ , σ2)) 
P( ϴ | X) is t h e p ost eri or distri b uti o n f or ϴ  giv e n t h e P E T d at a x . 9 5 % cr e di bl e i nt erv als b as e d o n t h e hi g h est p ost eri or d e nsity i nt erv al.  
M e a n S U V is c alc ul at e d ov er a xx mi n ut e p eri o d  
 
S o urc e: Listi n g 1 6. 2.xx  
Pr o gr a m mi n g n ot es:  
C o nti n u e d wit h all e n d p oi nts , r e gi o ns a n d  gr o u p s.  R e pl ac e xx wit h t h e ti m e p eri o d i n t h e f o ot n ot e .   


H M R c o de: 1 5 -5 0 5  
S p o ns or c o de: 2 0 4 7 4 6   
 
 
Ha m mers mit h Me dici nes Res earc h  
0 4 Oct o ber 2 0 1 6  
P a ge 3 2  of 4 6  
 
T e m pl at e T _ P T 3 _ G K  
T a bl e  1 4. 4. 3  
S u m m ar y of t h e P ost eri or Distri b uti o n of t h e R ati o of Gr o u p M e a ns f or V ol u m e of D istri b uti o n ( VT) a n d M e a n St a n d ar dis e d U pt a k e V al u es ( S U V), by R e gi o n 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ P ost eri or Distri b uti o n P( ϴ P A H|x P A H)/ P( ϴH V |x H V ) __ _ _ _ _ _ _ _ _ _ _ _ _  
v ari a bl e  
R e gi o n  
M e a n  
S D  
M e di a n  
Mi n  
M ax  
9 5 % Cr e di bl e I nt erv al  
M e a n S U V  
H e art  C h a m b er  
 
 
 
 
 
 
 
W h ol e  L u n g 
 
 
 
 
 
 
N u m b er of M C M C it er ati o ns, excl u di n g t h e b ur n -i n it er ati o ns = 5 , 0 0 0.  N u m b er of b ur n -i n it er ati o ns = 1 0, 0 0 0 
9 5 % cr e di bl e i nt erv als b as e d o n t h e hi g h est p ost eri or d e nsit y i nt er v al.  
N ot e: P A H = P A H P ati e nts, H V = H e alt hy V ol u nt e ers  
 
S o urc e: Listi n g 1 6. 2.xx  
 
 
T e m pl at e T _ P T 4 _ G K  
T a bl e  1 4. 3. 6.xx  
P ost eri or Pr o b a bilit y t h at t h e R ati o of Gr o u p M e a ns f or V ol u m e of D istri b uti o n ( VT) a n d M e a n St a n d ar dis e d U pt a k e V al u es ( S U V) Exc e e ds a C ert ai n V al u e, by R e gi o n  
P ar a m et er ( u nits)  
R e gi o n  
 P(r ati o) > 0. 5  
P (r ati o) > 1 
P (r ati o) > 2 
M e a n S U V 
 
 
 
 
 
 
 
 
 
N ot e: P (r ati o) > 1 is t h e pr o b a bilit y t h at t h e p ost eri or r ati o of gr o u p m e a ns exc e e ds 1  b as e d o n 5, 0 0 0 si m ul at e d p ost eri or pr e dict e d v al u es  
R ati o of P A H p ati e nts t o H e alt h y V ol u nt e ers.  
M e a n S U V is c alc ul at e d ov er a xx mi n ut e p eri o d  
 
S o urc e: Listi n g 1 6. 2.xx  
 
Pr o gr a m mi n g n ot es:  
C o nti n u e d wit h all v ari a bl es.  R e pl ac e xx wit h t h e ti m e p eri o d i n t h e f o ot n ot e .   
 
 
 
 


H M R c o de: 1 5 -5 0 5  
S p o ns or c o de: 2 0 4 7 4 6   
 
 
Ha m mers mit h Me dici nes Res earc h  
0 4 Oct o ber 2 0 1 6  
P a ge 3 3 of 4 6  
 
 
1 6. 3. 2  Fi g ure O utli nes  
 
T e m pl at e F _ P T 1 _ G K  
Fi g ur e  1 4. 3. 6.xx  
Pl ot of t h e P ost eri or Distri b uti o n of t h e V ol u m e of Distri b uti o n ( V T) f or t h e Gr o u p M e a ns  a n d t h e R ati o of t h e Gr o u p M e a ns, by R e gi o n  
 
 
 9 5 % cr e di bl e i nt erv als b as e d o n t h e hi g h est p ost eri or d e nsit y i nt erv al.    
Pr o gr a m mi n g n ot e: us e t h e s a m e sy m b ols f or e ac h of t h e m atc h e d p airs   
 


H M R c o de: 1 5 -5 0 5  
S p o ns or c o de: 2 0 4 7 4 6   
 
 
Ha m mers mit h Me dici nes Res earc h  
0 4 Oct o ber 2 0 1 6  
P a ge 3 4  of 4 6  
 
T e m pl at e F _ P T 2 _ G K  
Fi g ur e  1 4. 3. 6.xx  
Pl ot of t h e P ost eri or Pr o b a bilit y t h at t h e  R ati o of t h e Gr o u p M e a ns Exc e e ds a C ert ai n V al u e f or t h e V ol u m e of Distri b uti o n ( V T), by R e gi o n 
 
 
 
 


H M R c o de: 1 5 -5 0 5  
S p o ns or c o de: 2 0 4 7 4 6   
 
 
Ha m mers mit h Me dici nes Res earc h  
0 4 Oct o ber 2 0 1 6  
P a ge 3 5  of 4 6  
 
1 6. 3. 3  Listi n g O utli nes  
T e m pl at e L _ S D 1 _ P G 
Listi n g 1 6. 2.x.xx 
Listi n g of St u dy D at es  
Gr o u p  
S u bj ect  
Scr e e ni n g  
Sc a n ni n g visit  
F oll o w U p  
 
T e m pl at e L _ S D2 _ P G  
Listi n g 1 6. 2.x.xx 
Listi n g of R e as o ns f or Wit h dr a w al 
 
Gr o u p  
 
S u bj ect  
D at e of  
Wit h dr a w al     
St u dy  
D a y  
 
                        R e as o n  
 
T e m pl at e L _ D V 1 _ P G 
Listi n g 1 6. 2.x.xx 
Listi n g of S u bj ects wit h I ncl usi o n/ Excl usi o n Crit eri a D evi ati o ns  
Gr o u p  
S u bj ect  
T y p e  
Crit eri o n  
 
 
I ncl usi o n 
 
 
 
Excl usi o n  
 
 
 
 


H M R c o de: 1 5 -5 0 5  
S p o ns or c o de: 2 0 4 7 4 6   
 
 
Ha m mers mit h Me dici nes Res earc h  
0 4 Oct o ber 2 0 1 6  
P a ge 3 6  of 4 6  
 
 
T e m pl at e L _ D V2 _ P G  
Listi n g 1 6. 2. 2. 3 
Listi n g of S u bj ects wit h I m p ort a nt Pr ot oc ol D evi ati o ns  
Gr o u p  
S u bj ect  
                   Pr ot oc ol D evi ati o n  
 
 
 
 
 
 
 
 
T e m pl at e L _ A N 1 _ P G  
Listi n g 1 6. 2.x.xx 
Listi n g of A n al ysis P o p ul ati o ns 
Gr o u p  
S u bj ect  
Scr e e n e d  
P o p ul ati o n  
S af et y 
P o p ul ati o n  
 


H M R c o de: 1 5 -5 0 5  
S p o ns or c o de: 2 0 4 7 4 6   
 
 
Ha m mers mit h Me dici nes Res earc h  
0 4 Oct o ber 2 0 1 6  
P a ge 3 7  of 4 6  
T e m pl at e L _ D M 1 _ P G  
Listi n g 1 6. 2.x.xx 
Listi n g of D e m o gr a p hic C h ar act eristics  
Gr o u p  
S u bj ect  
D at e of 
visit  
Y e ar o f 
birt h  
A g e ( y)  
G e n d er  
R ac e  
Et h nicit y  
H ei g ht (c m)  
W ei g ht ( k g)  
B MI ( k g/ m 2)  
P A H P ati e nts  
 
 
 
 
 
 
 
 
 
 
H e alt hy  
V ol u nt e ers  
 
 
 
 
 
 
 
 
 
 
 
Gr o u p  
S u bj ect  
S m o ki n g 
St at us  
D at e L ast 
S m o k e d  
Ci g ar ett es  
(d ail y ) 
N u m b er Y e ars 
S m o k e d  
Ci g ar ett es 
( P ac k Y e ars)  
All e n’s T est  
I N R ( u nits) 
P A H P ati e nts  
 
 
 
 
 
 
 
 
H e alt hy  
V ol u nt e ers  
 
 
 
 
 
 
 
 
 
 
 
T e m pl at e L _ C M1 _ P G  
Listi n g 1 6. 2.x.xx 
Listi n g of C o nc o mit a nt M e dic ati o ns  
Gr o u p  
S u bj ect  
Dr u g N a m e/  
I n dic ati o n 
D os e/  
U nits/ Fr e q/  
R o ut e  
D at e /ti m e St art e d/  
D at e   St o p p e d  
Ti m e Si nc e L ast 
D os e  
St art e d Pr e - 
Tri al ?  
O n g oi n g 
M e dic ati o n ?  
 
 
 


H M R c o de: 1 5 -5 0 5  
S p o ns or c o de: 2 0 4 7 4 6   
 
 
Ha m mers mit h Me dici nes Res earc h  
0 4 Oct o ber 2 0 1 6  
P a ge 3 8  of 4 6  
T e m pl at e L _ E X 1 _ P G 
Listi n g 1 6. 2.x.xx 
Listi n g of Ex p os ur e D at a  
Gr o u p  
S u bj ect     
St art D at e/  
St art Ti m e of D o s e 
St o p D at e/  
St o p Ti m e of D os e  
D ur - 
ati o n  
( d a ys) 
D os e  
D os e 
U nit  
F or m u l ati o n/ 
R o ut e  
Fr e q u e nc y  
P A H P ati e nts    
     
 
 
4 6  
2 5     
m g     
T a bl et/       
2x d a y  
                             
 
 
 
 
Or al  
 
 
 
T e m pl at e L _ A E 1 _ P G 
Listi n g 1 6. 2.x.xx 
Listi n g of All A dv ers e E v e nts 
Gr o u p  
S u bj ect  
Syst e m O r g a n Cl ass/ 
P r ef err e d Ter m / 
V er b ati m T ext  
O utc o m e/ O ns et 
D at e/ Ti m e/ R es olv e d 
D at e/ Ti m e/ D ur ati o n  
Ti m e S i nc e L ast 
D os e  
S ev erity / 
S eri o us/  
Wit h dr a w al  
Fr e q u e nc y/ Acti o n 
T a k e n  ( 1)/ 
Ot h er Acti o n 
T a k e n  
R el at e d  t o St u dy 
Tr e at m e nt / 
Tr e at m e nt 
E m er g e nt ?  
P A H P ati e nts  
 
G astr oi nt esti n al  dis or d ers  / 
I nt esti n al s p as m/ 
E nt er o -s p as m 
R es olv e d/    
1 3: 0 5/ 
7: 5 0/ 
3 4 d 4 h 5 m  
1 0 d 7 h 3 m  
Mil d/  
N o/  
Y es  
I nt er mitt e nt/ D os e 
n ot c h a n g e d / 
N o n e   
P ossi bly/  
Y es  
( 1) Acti o n T a k e n wit h St u dy Tr e at m e nt  
 
 
P P D
P P D
P P D
P P D
P P D
P P D


H M R c o de: 1 5 -5 0 5  
S p o ns or c o de: 2 0 4 7 4 6   
 
 
Ha m mers mit h Me dici nes Res earc h  
0 4 Oct o ber 2 0 1 6  
P a ge 3 9  of 4 6  
 
T e m pl at e L _ A E 1 _ G S K  
 
1 6. 2. 7. 4 Listi n g of S u bj ect N u m b ers f or S p ecifi e d A dv ers e E v e nts  
 
Syst e m Or g a n Cl ass / 
 Pr ef err e d T er m              
 
Gr o u p  
N o.  
wit h  
E v e nt  
U ni q u e S u bj ect I d.  
 
 
 
 
G astr oi nt esti n al dis or d ers / 
 D ys p e psi a  
P A H P ati e nts  
 
x 
            
 
 
 
T e m pl at e L _ A E 2 _ G S K  
1 6. 2. 7. 6 Listi n g of R el ati o ns hi p b et w e e n S yst e m Or g a n Cl ass a n d V er b ati m T ext  
 
Syst e m Or g a n Cl ass  
Pr ef err e d T er m  
V er b ati m T ext  
Bl o o d a n d ly m p h atic syst e m dis or d ers  
L y m p h a d e n o p at hy 
E NL A R G E D L Y M P H N O D E  
 
 
 
C ar di ac dis or d ers                                
P al pit ati o ns  
T ac hyc ar di a n os  
H E A R T P AL PI T A TI O N  
T A C H Y C A R DI A  
 
 
 
P P D


H M R c o de: 1 5 -5 0 5  
S p o ns or c o de: 2 0 4 7 4 6   
 
 
Ha m mers mit h Me dici nes Res earc h  
0 4 Oct o ber 2 0 1 6  
P a ge 4 0  of 4 6  
T e m pl at e L _ A E 3 _ G S K  
1 6. 2. 7. 5 Listi n g of R e as o ns f or C o nsi d eri n g a S eri o us A dv ers e E v e nt  
 
 
 
Sit e I d./  
U ni q u e 
S u bj ect I d.  
A g e( Y E A R S)/  
S ex/  
R ac e D et ail/  
W ei g ht  
( k g) 
Pr ef err e d T er m/  
V E R B A TI M T E X T  
O utc o m e/  
O ns et D at e/  
D at e of R es ol uti o n/  
D ur ati o n  
D e at h [ 1]  Lif e [ 2] 
H os p [ 3]  
Dis a b [ 4]  
Birt h 
Df ect [ 5]  
M e d I m p 
[ 6] 
Pr ot [ 7]  
5 7/  
M/  
A SI A N - J A P A N E S E 
H E RI T A G E / 
6 2. 0  
A b n or m al liv er f u ncti o n 
t ests/ 
A S T I N C R E A S E D  
F A T AL/  
 
1 9 9 9 
/ 
1 2 0 d  
Y  
Y  
Y  
 
 
 
Y  
 
 
 
 
 
 
 
 
 
 
6 5/  
F/  
M UL TI PL E / 
7 5. 0  
C a n di di asis m o ut h/t hr o at/  
O R AL C A N DI DI A SI S  
R E C O V E R E D/ R E S OL V E D  / 
8 5 d  
 
 
Y  
 
 
Y  
 
 
 
[ 1] R es ult e d i n d e at h. 
[ 2] W as lif e-t hr e at e ni n g. 
[ 3] R e q uir e d h os pit aliz ati o n or pr ol o n g ati o n of existi n g h os pit aliz ati o n. 
[ 4] R es ult e d i n p ersist e nt or si g nific a nt dis a bilit y/i nc a p acit y. 
[ 5] C o n g e nit al a n o m al y/ birt h d ef ect.  
[ 6] Ot h er m e dic all y i m p ort a nt s eri o us ev e nt. 
[ 7] Pr ot oc ol s p ecifi e d s eri o us ev e nt. 
 
 
P P D
P P D
P P D
P P D


H M R c o de: 1 5 -5 0 5  
S p o ns or c o de: 2 0 4 7 4 6   
 
 
Ha m mers mit h Me dici nes Res earc h  
0 4 Oct o ber 2 0 1 6  
P a ge 4 1  of 4 6  
 
T e m pl at e L _L B 1 _ P G  
 
Listi n g 1 6. 2.x.xx 
Listi n g of Cli nic al C h e mistr y A b n or m aliti es of P ot e nti al Cli nic al I m p ort a nc e  
 
 
Gr o u p  
S u bj ect  
L a b t est ( u nits) 
Pl a n n e d  
R el ativ e  
Ti m e  
D at e/ Ti m e  
V al u e  
 R a n g e  
N R  
 
 
Al k P h os ( U/L)  
 
 
 
 
L 
 
 
 
 
 
 
 
H 
 
 
AL T ( U/L)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N R = N or m al R a n g e fl a g  
H = A b o v e r ef er e nc e i nt erv al, L = B el o w r ef er e nc e i nt erv al,  
 
 
T e m pl at e L _ V S 1 _ P G 
Listi n g 1 6. 2.x.xx 
Listi n g of  Vit al Si g ns   of P ot e nti al Cli nic al I m p ort a nc e  
Gr o u p  
S u bj ect  
 
Pl a n n e d R el ativ e 
Ti m e  
 
 
D at e/ Ti m e  
Syst olic  
Bl o o d Pr ess ur e  
( m m H g) 
Di ast olic  
Bl o o d Pr ess ur e  
( m m H g) 
 
Etc  
( u nits) 
P A H P at i e nts 
 
2 4 H  
2 6 S E P 2 0 1 2: 0 9: 5 7 
6 3 
1 4 8 *  
 
* V al u e of p ot e nti al cli nic al i m p ort a nc e 
 
 
 
 
 
P P D


H M R c o de: 1 5 -5 0 5  
S p o ns or c o de: 2 0 4 7 4 6   
 
 
Ha m mers mit h Me dici nes Res earc h  
0 4 Oct o ber 2 0 1 6  
P a ge 4 2  of 4 6  
 
T e m pl at e L _ E G 1 _ P G 
Listi n g 1 6. 2.x.xx 
Listi n g of E C G V al u es  
Tr e at m e nt   
 
S u bj ect  
Pl a n n e d 
R el ativ e Ti m e  
D at e/ Ti m e  
H e art 
R at e 
( b p m) 
P R I nt. 
( ms ec) 
Q R S 
D ur. 
( ms ec) 
Q R S 
Axis 
( d e g) 
Q T i nt 
( ms ec)  
 
Q Tc B 
( ms ec)  
 
Q Tc F 
( ms ec) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pr o gr a m mi n g n ot es:   
 
 
T e m pl at e L _ E G2 _ P G  
Listi n g 1 6. 2.x.xx 
Listi n g of A b n or m al E C G Fi n di n gs  
Tr e at m e nt  
S u bj ect  
 
Pl a n n e d R el ativ e 
Ti m e  
 
 
D at e/ Ti m e  
E C G Fi n di n g  
 
C o m m e nt o n Cli nic al 
Si g nific a n c e  
 
Pr o gr a m mi n g n ot es:  
Lists o nly v al u es wit h N or m al v ari a nt =’ N o’ or wit h c o m m e nt o n E C G r es ult  
 
E C G Fi n di n g c o nt ai ns P h ysici a n’s O pi ni o n fr o m C R F a n d r el at es t o w h ol e tr ac e ( n ot i n divi d u al p ar a m et ers), e. g. N or m al , A b n or m a l -  N CS or  A b n or m al  - CS  
 
 
 
 


H M R c o de: 1 5 -5 0 5  
S p o ns or c o de: 2 0 4 7 4 6   
 
 
Ha m mers mit h Me dici nes Res earc h  
0 4 Oct o ber 2 0 1 6  
P a ge 4 3  of 4 6  
 
T e m pl at e L _ P E 1 _ P G  
Listi n g 1 6. 2.x.xx  
Listi n g of A b n or m al P hysic al Ex a mi n ati o n  Fi n di n gs  
Gr o u p  
S u bj ect  
Pl a n n e d R el ativ e 
Ti m e  
 
D at e/ Ti m e  
Sit e  
 
D et ails   
 
Pr o gr a m mi n g N ot es:  
List o nly fi n di n gs wit h a n ‘ a b n or m al’ r es ult. 
If s u bj ects h a v e m ulti pl e a b n or m al sit es at a giv e n ti m e, cr e at e a s e p ar at e r o w f or e ac h sit e. 
 
 
T e m pl at e L _ P E T _ G K 
Listi n g 1 6. 2.x.xx  
Listi n g of V ol u m e of Distri b uti o n ( V T) a n d M e a n St a n d ar dis e d U pt a k e V al u es ( S U V) 
Gr o u p  
S u bj ect  
D at e/ St art Ti m e  / 
St o p Ti m e  
 
R e gi o n  
M e a n St a n d ar dis e d 
U pt a k e V al u e ( S U V)  
V ol u m e of Distri b uti o n ( V T) 
( mL/c m3) 
 
 
Pr o gr a m mi n g N ot es:  
A d d t h e f o ot n ot e M e a n S U V is c alc ul at e d ov er a xx mi n ut e p eri o d .  N ot e xx i n t h e f o ot n ot e will  b e r e pl ac e d b y t h e ti m e p eri o d  
 


HMR code: 15-505 
Sponsor code: 204746  
 
 
Hammersmith Medicines Research  
04 October 2016  
Page 44 of 46 
 
Appendix A: Laboratory Ranges 
 
Laboratory Assessments Parameters 
Sex 
Max age Normal Range 
Range for potential 
clinical concern 
Unit 
Low 
High 
Haematology  
Platelet Count  
10^9/L 
F 
NA 
163 - 376 
100 
600 
Platelet Count  
10^9/L 
M 
NA 
129-346 
100 
600 
Red blood cell count 
10^12/L 
F 
NA 
3.7-5.1 
NA 
NA 
Red blood cell count 
10^12/L 
M 
NA 
4.4-6.0 
NA 
NA 
Neutrophils 
10^9/L 
Both 
NA 
1.57-6.81 
1.2 
13 
Hemoglobin 
pg 
F 
NA 
114-153 
110 
175 
Hemoglobin 
pg 
M 
NA 
133-170 
125 
185 
Lymphocytes 
10^9/L 
Both 
NA 
0.89-2.88 
0.5 
4 
Hematocrit 
L/L 
F 
NA 
0.338-0.445 
0.3 
0.55 
Hematocrit 
L/L 
M 
NA 
0.386-0.489 
0.35 
0.65 
MCV 
NA 
NA 
MCH 
NA 
NA 
MCHC  
NA 
NA 
Monocytes 
10^9/L 
Both 
NA 
0.09-0.90 
NA 
NA 
Eosinophils 
10^9/L 
Both 
NA 
0.05-0.55 
NA 
0.55 
Basophils 
10^9/L 
Both 
NA 
0.00-0.14 
NA 
NA 
Cinical Chemistry 
BUN (Urea) 
mmol /L 
F 
54 
2.2- 6.7 
NA 
12 
BUN (Urea) 
mmol /L 
F 
120 
3.0-8.6 
NA 
12 
BUN (Urea) 
mmol /L 
M 
54 
2.7-7.6 
NA 
12 
BUN (Urea) 
mmol /L 
M 
120 
3.0-8.6 
NA 
12 
Potassium 
mmol/L 
Both 
NA 
3.5-5.3 
3 
5.5 
AST (SGOT) 
lU/L 
F 
NA 
<=30 
NA 
200 
AST (SGOT) 
lU/L 
M 
NA 
<=62 
NA 
200 
Total bilirubin 
F 
NA 
<= 19.7 
NA 
40 
Total bilirubin 
M 
NA 
<=29.3 
NA 
40 
Direct Bilirubin 
F 
NA 
<=3.9 
NA 
NA 
Direct Bilirubin 
M 
NA 
<=6.2 
NA 
NA 
Creatinine 
F 
NA 
42-72 
NA 
150 
Creatinine 
M 
NA 
53-102 
NA 
150 
Sodium  
mmol/L 
Both 
NA 
133-146 
125 
160 
ALT (SGPT)  
lU/L 
F 
NA 
<=33 
NA 
200 
ALT (SGPT)  
lU/L 
M 
NA 
<=70 
NA 
200 


HMR code: 15-505 
Sponsor code: 204746  
 
 
Hammersmith Medicines Research  
04 October 2016  
Page 45 of 46 
 
Total Protein 
g/L 
Both 
NA 
60-80 
NA 
NA 
Glucose 
mmol/L 
Both 
NA 
2.8-5.8 
2 
10 
Calcium 
mmol/L 
Both 
NA 
2.2-2.6 
2 
2.6 
Albumin 
g/L 
Both 
NA 
35-50 
30 
60 
 


HMR code: 15-505 
Sponsor code: 204746  
 
 
Hammersmith Medicines Research 
04 October 2016 
Page 46 of 46 
 
 
Appendix B: Sample Page Layout 
GlaxoSmithKline Ltd :  204746 
Page x of y* 
Population:  [Pop] 
____________________________________________________________________________________________________________________________ 
 
Table [number] [title] 
 
 
Column headers 
 
 
Main body of output 
 
 
 
Source: Listing [16.2.xx]  
 
 
Footnotes about the table or listing text go here. 
 
____________________________________________________________________________________________________________________________ 
Program:  [Prog Name] 
Produced By:[Username] 
[Date] 
HMR 15-505 
 
*y = last page of individual output