A Pilot Study to Evaluate Molecular Imaging Methods in Primary Sjögren's Syndrome
Phase: NA
Conditions: Autoimmune Diseases
Sponsor: GlaxoSmithKline

2015N227551_01
CONFIDENTIAL
The GlaxoSmithKline group of companies
203818
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A Pilot Study to Evaluate Molecular Imaging Methods in 
Primary Sjogren's Syndrome
Compound Number:
None
Development Phase:
NA
Effective Date:
24-MAY-2017
Protocol Amendment Number:  01
Author (s):
 
Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2015N227551_00
2016-JUN-13
Original
2015N227551_01
2017-MAY-24
Amendment No. 1

Updates to some T&E windows (pregnancy tests, V1 for FRP and minor salivary 
gland biopsy)

Flexibility to allow follow up for pSS subjects by telephone.

Updates to blood tests as per file notes issued during study.

Typographical error in Section 9.2 changed from “within approximately 0.62 of the 
point estimate” to “within approximately 0.64 of the point estimate”.

Minor formatting changes
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD

PPD
PPD

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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 
Dr 
 
Tel: 
Mobile: 
Mobile: 
 
 
GSK 
Medicines 
Research 
Centre, 
Gunnels 
Wood, 
Stevenage, 
Hertfordshire, 
SG1 2NY, UK
Secondary 
Medical 
Monitor
Dr 
 
Tel: 
Mobile: 
 
SAE 
contact  
information 
[Medical 
monitor 
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):  NA
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 203818
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

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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 203818........................................................8
2.
INTRODUCTION....................................................................................................13
2.1.
Study Rationale ..........................................................................................13
2.2.
Brief Background ........................................................................................13
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................15
4.
STUDY DESIGN ....................................................................................................18
4.1.
Overall Design ............................................................................................18
4.2.
Treatment Arms and Duration.....................................................................19
4.3.
Type and Number of Subjects.....................................................................20
4.4.
Design Justification.....................................................................................21
4.5.
Dose Justification........................................................................................22
4.6.
Benefit:Risk Assessment ............................................................................22
4.6.1.
Risk Assessment .........................................................................23
4.6.2.
Benefit Assessment.....................................................................29
4.6.3.
Overall Benefit: Risk Conclusion..................................................29
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............29
5.1.
Inclusion Criteria.........................................................................................29
5.2.
Exclusion Criteria........................................................................................31
5.3.
Screening/Baseline/Run-in Failures............................................................33
5.4.
Withdrawal/Stopping Criteria.......................................................................33
5.4.1.
Liver Chemistry Stopping Criteria ................................................34
5.4.1.1.
Study Treatment Restart or Rechallenge....................34
5.4.2.
QTc Stopping Criteria ..................................................................34
5.5.
Subject and Study Completion....................................................................34
6.
STUDY TREATMENT ............................................................................................34
6.1.
Investigational Product or other Study Treatment .......................................34
6.2.
Blinding.......................................................................................................35
6.3.
Packaging and Labelling.............................................................................35
6.4.
Preparation/Handling/Storage/Accountability..............................................35
6.5.
Treatment of Study Treatment Overdose....................................................35
6.6.
Treatment after the End of the Study ..........................................................35
6.7.
Lifestyle and/or Dietary Restrictions............................................................36
6.7.1.
Contraceptive Requirements........................................................36
6.7.1.1.
Female Subjects.........................................................36
6.7.1.2.
Male subjects .............................................................36
6.8.
Concomitant Medications and Non-Drug Therapies....................................37
6.8.1.
Permitted Drug Therapies (Group B: Primary Sjögren’s 
Syndrome Subjects) ....................................................................37
6.8.2.
Prohibited Medications and Non-Drug Therapies.........................37
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................38
7.1.
Time and Events Table...............................................................................38
7.2.
Screening and Critical Baseline Assessments ............................................40

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7.2.1.
For all subjects:............................................................................40
7.2.2.
Additional baseline procedures for Group B subjects only 
(pSS Subjects).............................................................................41
7.3.
Safety .........................................................................................................42
7.3.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........42
7.3.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................43
7.3.1.2.
Method of Detecting AEs and SAEs ...........................43
7.3.1.3.
Follow up of AEs and SAEs........................................43
7.3.1.4.
Regulatory Reporting Requirements for SAEs............44
7.3.2.
Pregnancy ...................................................................................44
7.3.3.
Vital Signs....................................................................................44
7.3.4.
Clinical Safety Laboratory Assessments ......................................44
7.4.
Imaging Procedures....................................................................................46
7.4.1.
PET Imaging Procedure...............................................................46
7.4.2.
MRI Imaging Procedure...............................................................47
7.5.
Image Analysis ...........................................................................................47
7.5.1.
PET Image Analysis ....................................................................47
7.5.2.
MRI Image Analysis.....................................................................48
7.6.
Pharmacokinetics .......................................................................................49
7.6.1.
Blood sample collection and 11C-Met radio PK analysis ...............49
7.7.
Salivary gland biopsy (Group B) .................................................................49
7.8.
Biomarker(s)/Pharmacodynamic Markers ...................................................49
7.8.1.
Novel Biomarkers ........................................................................49
7.8.1.1.
Metabolomic Research...............................................49
7.8.1.2.
Proteome Research....................................................50
7.8.1.3.
Salivary gland histological assessment.......................50
8.
DATA MANAGEMENT ...........................................................................................50
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................51
9.1.
Hypotheses.................................................................................................51
9.2.
Sample Size Considerations.......................................................................51
9.2.1.
Sample Size Sensitivity................................................................52
9.2.2.
Sample Size Re-estimation or Adjustment...................................52
9.3.
Data Analysis Considerations .....................................................................53
9.3.1.
Analysis Populations....................................................................53
9.3.2.
Interim Analysis ...........................................................................53
9.4.
Key Elements of Analysis Plan ...................................................................53
9.4.1.
Primary analyses .........................................................................53
9.4.2.
Secondary Analyses ....................................................................54
9.4.3.
Other/Exploratory Analyses .........................................................54
10. STUDY GOVERNANCE CONSIDERATIONS........................................................54
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............54
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................54
10.3.
Quality Control (Study Monitoring) ..............................................................55
10.4.
Quality Assurance.......................................................................................55
10.5.
Study and Site Closure ...............................................................................56
10.6.
Records Retention......................................................................................56

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10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................57
11. REFERENCES.......................................................................................................58
12. APPENDICES........................................................................................................61
12.1.
Appendix 1 – Abbreviations and Trademarks..............................................61
12.2.
Appendix 2: Definition of and Procedures for Recording, Evaluating, 
Follow up and Reporting of Adverse Events ...............................................63
12.2.1.
Definition of Adverse Events........................................................63
12.2.2.
Definition of Serious Adverse Events...........................................64
12.2.3.
Definition of Cardiovascular Events .............................................65
12.2.4.
Recording of AEs and SAEs ........................................................66
12.2.5.
Evaluating AEs and SAEs............................................................67
12.2.6.
Reporting of SAEs to GSK...........................................................68
12.3.
Appendix 3: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in FRP and Collection of Pregnancy Information.......................69
12.3.1.
Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP) ..............69
12.3.2.
Collection of Pregnancy Information ............................................69
12.4.
Appendix 4: Protocol Amendment Changes................................................71

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1.
PROTOCOL SYNOPSIS FOR STUDY 203818
Rationale
This is a pilot imaging study designed to assess whether molecular imaging with 
18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed 
tomography (CT), 11C-Methionine (MET) PET/CT and salivary gland magnetic 
resonance imaging (MRI) have the potential to characterize and quantify disease 
manifestations in primary Sjögren’s syndrome (pSS) subjects.  This will be achieved by 
assessing the associations and consistency between the imaging techniques studied, 
clinical assessments (salivary and tear flow and clinical scores), laboratory biomarkers 
and histological findings on minor salivary gland biopsy.  It is hoped that the 
methodologies may help with the selection of subjects, and/or assessments of treatment 
response in future clinical studies.  For example, subjects with on-going inflammation 
and a degree of gland function might be more suitable for anti-inflammatory therapies.
Objective(s)/Endpoint(s)
Objectives
Endpoints
Primary

To investigate the use of 18F-FDG 
PET/CT in assessing increased glucose 
uptake as a biomarker of inflammation 
in pSS subjects.

Semi-quantitative parameters of 
uptake in selected body areas, 
including salivary glands for 
18F-FDG:

Standardised uptake value (SUV)

Tissue-to-reference ratio

Total inflammatory volume (TIV) 
where anatomically relevant.

To investigate the use of 
11C-Methionine (MET) PET/CT in 
assessing salivary glandular function in 
pSS subjects and healthy volunteers.

Semi-quantitative parameters of uptake 
in selected areas, including salivary 
glands for 11C-MET:

SUV

Tissue-to-reference ratio

TIV where anatomically relevant.

To investigate the use of multi-
parametric MRI in assessing salivary 
gland inflammation, function and 
structure in pSS subjects and healthy 
volunteers.

Quantitative parameters of uptake 
derived from multi-parametric MRI 
in the salivary glands including: 
exchange rate (Ktrans), apparent 
diffusion coefficient (ADC), pure 
diffusion coefficient (D) and 
microvascular volume fraction (f) 
as data permits.

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Objectives
Endpoints
Secondary

To characterize the pharmacokinetics 
of 11C-MET PET tracer in vivo to 
allow static imaging parameters to be 
verified.

Generation of quantitative outcome 
parameters (rate of 11C-MET 
accumulation, as data permits) using a 
full quantitative analysis of dynamic 
PET scans. 

Comparison of static and dynamic 
imaging metrics in 11C-MET.
Exploratory 

To explore the use of novel multi-
parametric MRI in assessing salivary 
gland inflammation, function and 
structure in pSS subjects and healthy 
volunteers.

Quantitative parameters of uptake 
derived from multi-parametric MRI in 
the salivary glands including: initial 
rate of enhancement (IRE), maximal 
signal intensity enhancement (ME), 
lipid content, T1 relaxation, and 
volume, as data permits.

To explore the associations of the 
salivary gland imaging parameters 
with clinical and histological 
parameters of salivary glands. 

Association between 18F-FDG PET/CT 
(pSS subjects only), 11C-MET PET/CT 
and MRI parameters (healthy 
volunteers and pSS subjects) in the 
region of the salivary glands with each 
other and with clinical measures 
including:

Basal and stimulated salivary flow

Histological scores from minor 
salivary gland biopsies including 
but not limited to lymphocyte count 
and focus score (pSS subjects)

Laboratory biomarkers of disease 
activity (including metabolomic 
and/or proteomic profiles where 
applicable)

European League Against 
Rheumatism (EULAR) Sjögren's 
Syndrome Disease Activity Index 
(ESSDAI) and EULAR Sjögren's 
Syndrome Patient Reported Index 
(ESSPRI), in particular 
subcomponents relevant to salivary 
gland function (pSS subjects).

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Objectives
Endpoints

To explore the extent of non-salivary 
gland (systemic) abnormalities 
detected on 18F-FDG PET/CT and 11C-
MET PET/CT, and the association of 
these abnormalities with clinical 
scores/relevant sub-scores and 
laboratory biomarkers in pSS subjects.

Semi-quantitative parameters in 
selected areas systemically for 18F-
FDG and 11C-MET (including but not 
limited to lymph nodes, thyroid, 
lacrimal glands, lungs and pancreas) 
and the associations of these 
parameters with:

Laboratory biomarkers of disease 
activity (including metabolomic 
and/or proteomic profiles where
applicable)

Lacrimal gland function as 
measured by Schirmer’s test

ESSDAI and ESSPRI and 
organ-specific subcomponents 
relating to the area imaged, where 
available.

To compare the metabolomic profiles 
of pSS subjects and healthy volunteers, 
to assess the intra-individual variability 
of the metabolome over time, and the 
ability of samples from different 
bodily sites to discriminate pSS 
subjects from healthy volunteers.

Compare the metabolome/proteome of 
pSS subjects with healthy volunteers.

Assess the variability in the 
metabolome and/or proteomic profile 
of individual subjects taken at 
2 separate time points (Baseline and 
Visit 2).

Compare the metabolome and/or 
proteomic profile from different body 
fluids/sites, and their utility in 
distinguishing pSS subjects from 
healthy volunteers.

Samples collected will be saliva, tears 
and plasma.
Overall Design
Healthy volunteers will be enrolled in Group A and pSS subjects will be enrolled in 
Group B.
The subjects will be required to attend the clinical unit for a Screening/Baseline visit, an 
imaging visit (Visit 1) a sample collection visit (Visit 2) and a Follow up.  The pSS 
subjects will have a minor salivary gland biopsy at Visit 2.  Females of reproductive 
potential (FRP) will be required to have a negative pregnancy test as determined by 
serum hCG test at screening and will be required to have a negative urine pregnancy test 

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3-8 days prior to Visit 1, and on Visit 1. If Visit 1 is split over more than 1 day there must 
be a negative urine pregnancy test on each day, prior to scanning.
All procedures will be performed as outpatient visits. 
No investigational medicinal product (IMP) will be administered to subjects enrolled in 
this study.
Treatment Arms and Duration
Subject Participation Flow
Both groups will undergo a Screening/Baseline visit where they will have measurement 
of basal and stimulated, salivary flow rate (including saliva collection), Schirmer’s test 
and blood samples for biomarkers.  The pSS subjects will also have additional clinical 
scores and patient reported assessments.  
Subjects who have completed the screening/baseline will return for an imaging visit 
(Visit 1).  The imaging visit should occur within 6 weeks (42 days) after the screening 
visit .  The following imaging procedures will be performed:

Group A (healthy volunteers) will undergo an MRI of the salivary glands and 
11C-MET PET/CT (dynamic scan of the salivary glands followed by head to hip 
static scan).  

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
Group B (pSS subjects) will undergo an MRI of the salivary glands, 11C-MET 
PET/CT (as for Group A) and 18F-FDG PET/CT (static scan head to hip).  
Visit 2 will occur within 3 weeks after Visit 1.  Visit 2 will involve measurement of basal 
and stimulated (chewing paraffin) salivary flow rate (including saliva collection), 
Schirmer’s test (including tear collection), blood samples for biomarkers 
(metabolomics/proteomics).  In addition a minor salivary gland biopsy will be performed 
on the pSS subjects (Group B).  If it is not possible, for logistical or other reasons to 
schedule the minor salivary gland biopsy within 3 weeks of Visit 1, then this part of Visit 
2 may be performed up to 6 weeks after Visit 1, with the prior agreement of the medical 
monitor.
There will be a Follow up visit within 2 weeks of Visit 2.  This may be conducted by 
telephone for the healthy volunteers (Group A).  The pSS subjects (Group B) may have 
their Follow up visit conducted in person , or by telephone if the Investigator considers it 
clinically appropriate.  Adverse events (AE) will be reviewed at this visit for all of the 
subjects (Group A and Group B). 
Visit 1 and Visit 2 may be split over more than one day.
The total duration of participation in the study will be a maximum of 11 weeks (up to 14
weeks only if it is necessary to delay the minor salivary gland biopsy), although the visits 
should be completed sooner if feasible.
Type and Number of Subjects
Between approximately 4 to 12 healthy volunteers and between approximately 8 to 12 
pSS subjects will be recruited into the study.  As there is very little data about the 
variability of the imaging parameters, in-stream review of the variability will be 
conducted in order to determine the number of subjects that are required for PET/CT 
and/or MRI.  In order to minimize radiation exposure to healthy volunteers, a maximum 
of 8 healthy volunteer subjects will undergo the 11C MET PET/CT scan component.
As pSS affects females in about 90% of cases, and in order to reduce variability, initially 
only female healthy volunteer subjects will be recruited.  If in the course of the study 
male pSS subjects are recruited, male healthy volunteers may be recruited at the 
discretion of the Sponsor.  The ages of the healthy volunteers will be matched 
approximately to the ages of the pSS subjects as far as is practically possible, and within 
the age restrictions of the protocol.
Healthy volunteers and pSS subjects will be recruited simultaneously.  However, there 
may be some staggering in the recruitment of subjects to allow approximate age and sex 
matching. 
If subjects prematurely discontinue the study, additional replacement subjects may be 
recruited at the discretion of the Sponsor.

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Analysis
This is an exploratory study and therefore no formal sample size calculations have been 
conducted.  Sample size is primarily driven by feasibility and knowledge of disease 
heterogeneity to sufficiently evaluate the primary and supportive secondary objectives of 
the study. 
Descriptive statistics and graphical displays if appropriate will be presented for all 
18F-FDG PET/CT derived parameters across the regions of interest (ROI) for all 
pSS subjects and for all 11C-MET PET/CT and multi-parametric MRI derived parameters 
across the ROI for all healthy volunteers and pSS subjects.  An exploratory comparison 
of pSS subjects vs healthy volunteers may be performed for each 11C-MET PET/CT and 
multi-parametric MRI derived quantitative parameter as data permit, to estimate a 
difference (or ratio if log transformation is needed) with 95% confidence interval.  
Descriptive statistics and graphical displays if appropriate will also be presented for all 
derived parameters from dynamic PET imaging and pharmacokinetic (PK) analyses.  If 
data permits, statistical analyses and/or graphical presentation of radio-PK modelling 
indices with 11C-MET static imaging matrices will be conducted to assess correlation.
2.
INTRODUCTION
2.1.
Study Rationale
This pilot study is designed to assess the potential value of imaging methods in pSS 
subjects.  The selected imaging methods will include:

Positron Emission Tomography (PET) / Computed Tomography (CT) with 11C-
Methionine (MET) imaging to characterize protein synthesis within the salivary 
and other glands as a potential marker of gland function; 

Multi-parametric Magnetic Resonance imaging (MRI) of the salivary glands to 
assess gland function, structure and potential biomarkers of inflammation; and 

PET/CT with 18F-Fluorodeoxyglucose (FDG) as a marker of inflammation to 
assess disease extent in the salivary glands and systemically. 
The aim of the study is to determine whether the imaging methodologies under 
investigation have the potential to characterize and quantify disease manifestations in 
Primary Sjögren’s Syndrome (pSS) subjects.  This will be achieved by assessing the 
associations between the imaging techniques studied, clinical assessments (salivary and 
tear flow and clinical scores), biomarkers (including metabolomics/proteomics) and 
histological findings on minor salivary gland biopsy.  It is hoped that the methodologies 
may help in subject selection and/or assessment of treatment response in future clinical 
studies.  For example subjects with on-going inflammation, and a degree of gland 
function might be more suitable for anti-inflammatory therapies.
2.2.
Brief Background
Primary Sjögren’s Syndrome (pSS) is a chronic systemic disease with a female over male 
preponderance of 9:1 [Vitali, 2002, Helmick, 2008] that primarily involves the salivary 

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(xerostomia) and lacrimal (keratoconjunctivitis sicca) glands caused by inflammation 
[Fox, 2005 and Gomes Pde, 2012].  However, any organ or mucosal surface may be 
involved, with the risk of lymphoma development remaining the most serious 
complication [Ziakas, 2014]. 
There is a need to develop methods that can reduce both the time to diagnosis and assess 
the effect of current and new therapies in these patients in a more quantitative manner, in 
particular for assessing the heterogeneous nature of the disease, and selecting patients 
most likely to respond to therapies (ie those with active disease and a degree of gland 
function).  Molecular imaging methods have the potential to provide 3D high resolution, 
sensitive and quantitative measures of disease manifestations, combined with whole body 
assessment for the PET methods.  This makes them an attractive tool to consider for 
assessing disease status at entry to clinical studies, and potentially for monitoring 
treatment effects. 
The methods under study are 18F-FDG PET/CT as a measure of inflammation, 11C-MET 
PET/CT as a measure of protein synthesis within the glands, and multi-parametric MRI to 
assess both structural and functional changes in salivary glands in pSS.  Ultrasonography 
has been used as a diagnostic tool in pSS, but its role in monitoring treatment effects in 
multicentre studies is more challenging and less clear.
Published literature around use of 18F-FDG, 11C-MET PET and multi-parametric MRI in 
pSS is limited as the methods are more commonly used in other indications: 18F-FDG 
uptake is a marker for increased glucose uptake, which is closely correlated to certain 
types of metabolism such as that of malignant cells but it is also a feature of inflammation 
with inflammatory foci exhibiting high 18F-FDG uptake [Bakheet, 1998].  In pSS, the 
relation of 18F-FDG uptake to inflammation needs to be further explored but a recent 
report by Ziakas [Ziakas, 2014] showing a strong correlation between inflammation and 
FDG uptake in Sjögren's patients treated for salivary lymphomas is encouraging 
[Ziakas, 2014].  In addition, Cohen et al. [Cohen, 2013] reviewed the PET data from 32 
Sjögren’s patients that underwent 18F-FDG PET and showed that 18F-FDG uptake was 
increased in 75% of patients with 60% displaying increased uptake in lymph nodes, 50% 
in the parotid glands, 28% in the submandibular glands, 28% in the lung and 6% in the 
thyroid. 
Salivary gland disease is a hallmark for pSS and PET with 11C-MET can potentially 
assess function with a superior sensitivity and anatomical resolution than the gold 
standard contrast sialography or salivary gland scintigraphy with 99mTc-sodium 
pertechnectate.  11C-MET, a labelled essential amino acid, is most popular for PET 
imaging of brain tumours; events such as cellular proliferation are associated with 
increased protein synthesis and hence avid uptake of these precursors 
[Glaudemans, 2013].  Furthermore, 11C-MET has been used for measuring liver protein 
synthesis and assessing excretory pancreas function [Harris, 2013].  Dynamic 11C-MET 
has been used as a quantitative measure of regional gland function in the major salivary 
glands in head-and-neck cancer patients that underwent loss of salivary gland function as 
a result of radiotherapy [Buus, 2004].  This study aims to determine whether there is a 
disturbance in protein synthesis in salivary glands that correlates to disease activity, 
although the relationship between inflammation and gland function (protein synthesis) in 

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pSS is as yet unclear.  In addition, the ability of PET to image the whole body will also 
allow recording of function in other glands such as the pancreas. 
Magnetic resonance imaging (MRI) offers a superior soft tissue contrast and high 
resolution to assess anatomical organ changes (using T1 or T2 weighted) in vivo, also 
non-invasively.  Furthermore, functional imaging techniques are also available using 
MRI: Dynamic Contrast Enhanced (DCE)-MRI provides information about the 
microvasculature of tissues. Since the salivary glands are highly perfused, this technique 
may be adequate for the evaluation of damage to the vessels in the salivary glands 
[Houweling, 2011]. Diffusion Weighted (DW)-MRI maps the diffusion process of 
molecules, mainly water, and yields qualitative and quantitative information reflecting 
tissue cellularity and cell membrane integrity.  The intravoxel incoherent motion (IVIM) 
model of diffusion may be sensitive to early microstructural changes to the parotid gland 
in pSS patients [Su, 2015].  It thereby complements the morphological information 
obtained by conventional MRI.  Roberts and colleagues [Roberts, 2008] compared the 
parotid gland microvascular characteristics in 21 patients with Sjögren's syndrome with 
those in 11 healthy volunteers.  They demonstrated significant differences in DCE 
parameters with patients also displaying greater gland heterogeneity [Roberts, 2008].
3.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Primary

To investigate the use of 18F-FDG 
PET/CT in assessing increased glucose 
uptake as a biomarker of inflammation 
in pSS subjects.

Semi-quantitative parameters of uptake 
in selected body areas, including 
salivary glands for 18F-FDG in selected 
areas:

Standardised Uptake Value (SUV)

Tissue-to-reference ratio

Total Inflammatory Volume (TIV) 
where anatomically relevant.

To investigate the use of 11C- MET
PET/CT in assessing salivary 
glandular function in pSS subjects and 
healthy volunteers.

Semi-quantitative parameters of uptake 
in selected areas, including  salivary 
glands for 11C-MET :

SUV

Tissue-to-reference ratio

TIV where anatomically relevant.

To investigate the use of 
multi-parametric MRI in assessing 
salivary gland inflammation, function 
and structure in pSS subjects and 
healthy volunteers.

Quantitative parameters of uptake 
derived from multi-parametric MRI in 
the salivary glands including: 
Exchange rate (Ktrans), Apparent 
Diffusion Coefficient (ADC), pure 

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Objectives
Endpoints
diffusion coefficient (D) and 
microvascular volume fraction (f) as 
data permits.
Secondary

To characterize the pharmacokinetics 
of 11C-MET PET tracer in vivo to 
allow static imaging parameters to be 
verified.

Generation of quantitative outcome 
parameters (rate of 11C-MET 
accumulation, as data permits) using a 
full quantitative analysis of dynamic 
PET scans. 

Comparison of static and dynamic 
imaging metrics in 11C-MET.
Exploratory 

To explore the use of novel multi 
parametric MRI in assessing salivary 
gland inflammation, function and 
structure in pSS subjects and healthy 
volunteers.

Quantitative parameters of uptake 
derived from multi-parametric MRI 
in the salivary glands including, 
Initial Rate of Enhancement (IRE), 
maximal signal intensity 
enhancement (ME), lipid content, 
T1 relaxation and volume, as data 
permits.

To explore the associations of the 
salivary gland imaging parameters 
with clinical and histological 
parameters of salivary glands.

Association between 18F-FDG PET/CT 
(pSS subjects only), 11C-MET PET/CT 
and MRI parameters (healthy 
volunteers and pSS subjects) in the 
region of the salivary glands with each 
other and with clinical measures 
including:

Basal and stimulated salivary flow

Histological scores from minor 
salivary gland biopsies including 
but not limited to lymphocyte count 
and focus score (pSS subjects)

Laboratory biomarkers of disease 
activity (including metabolomic 
and/or proteomic profiles where 
applicable)
European League Against Rheumatism 
(EULAR) Sjögren's Syndrome Disease 
Activity Index (ESSDAI) and EULAR 
Sjögren's Syndrome Patient Reported 
Index (ESSPRI), in particular 

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Objectives
Endpoints
subcomponents relevant to salivary 
gland function (pSS subjects).

To explore the extent of non-salivary 
gland (systemic) abnormalities 
detected on 18F-FDG PET/CT and 11C-
MET PET/CT, and the association of 
these abnormalities with clinical 
scores/relevant sub-scores and 
laboratory biomarkers in pSS subjects.

Semi-quantitative parameters in 
selected areas systemically for 18F-
FDG and 11C-MET (including but not 
limited to lymph nodes, thyroid, 
lacrimal glands, lungs and pancreas) 
and the associations of these 
parameters with:

Laboratory biomarkers of disease 
activity (including metabolomic 
and/or proteomic profiles where 
applicable)

Lacrimal gland function as 
measured by Schirmer’s test

ESSDAI and ESSPRI and 
organ-specific subcomponents 
relating to the area imaged, where 
available.

To compare the metabolomic profiles 
of pSS subjects and healthy volunteers, 
to assess the intra-individual variability 
of the metabolome over time, and the 
ability of samples from different 
bodily sites to discriminate pSS 
subjects from healthy volunteers.

Compare the metabolome/proteome of 
pSS subjects with healthy volunteers.

Assess the variability in the 
metabolome and/or proteomic profile 
of individual subjects taken at 
2 separate time points (Baseline and 
Visit 2).

Compare the metabolome and/or 
proteomic profile from different body 
fluids/sites, and their utility in 
distinguishing pSS subjects from 
healthy volunteers.

Samples collected will be saliva, tears 
and plasma.

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4.
STUDY DESIGN
4.1.
Overall Design
Healthy volunteers will be enrolled in Group A and pSS subjects will be enrolled in 
Group B.  
The subjects will be required to attend the clinical unit for a Screening/Baseline visit, an 
imaging visit (Visit 1) a sample collection visit (Visit 2) and a Follow up visit.  
If Females of Reproductive Potential (FRP) are included they must have a negative 
pregnancy test as determined by serum human chorionic gonadotropin (hCG) test at 
screening, and a negative urine pregnancy test 3-8 days prior to Visit 1, and on Visit 1.  If 
Visit 1 is split over more than 1 day there must be a negative urine pregnancy test on each 
day, prior to scanning.
The follow up may be conducted by telephone for the healthy volunteers (Group A).  The 
pSS subjects (Group B) may have their Follow up visit conducted in person, or by 
telephone if the Investigator considers it clinically appropriate. 
All assessments will be done as outpatient visits.
No investigational medicinal product (IMP) will be administered to subjects enrolled in 
this study.

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4.2.
Treatment Arms and Duration
Figure 1
Study Schematic
Screening/Baseline
Both groups of subjects will undergo a Screening/Baseline visit.  At this visit, following 
the subject providing written consent to be enrolled on the study, the eligibility of the 
subjects will be assessed and baseline assessments will be performed (See Time and 
Events tables, Section 7.1.).  
Visits
Subjects who have completed the Screening/Baseline and are eligible for the study will 
have an imaging visit (Visit 1).

Group A (healthy volunteers) will undergo an MRI of the salivary glands and 
11C-MET PET/CT (dynamic scan of the salivary glands followed by head to hip 
static scan).  

Group B (pSS subjects) will undergo an MRI of the salivary glands, 11C-MET 
PET/CT (as for Group A) and 18F-FDG PET/CT (static head to hip scan).  

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Visit 2 will occur within 3 weeks after the completion of the assessments performed at 
Visit 1.  The assessments will include vital signs measurement, pregnancy test (FRP 
only), plasma collection for the measurement of metabolomics/proteomics, measurement 
of basal and stimulated (chewing paraffin) salivary flow rate (including saliva collection) 
and Schirmer’s test (including tear collection).  Concomitant medication and adverse 
event details will be recorded.  
In addition, a minor salivary gland biopsy will be performed on the pSS subjects 
(Group B).  If it is not possible, for logistical or other reasons to schedule the minor 
salivary gland biopsy within 3 weeks of Visit 1, then this part of Visit 2 may be 
performed up to 6 weeks after Visit 1, with the prior agreement of the medical monitor.
Visit 1 and Visit 2 may be split over more than one day.  The total duration of 
participation in the study will be a maximum of 11 weeks (14 only if it becomes 
necessary to delay the minor salivary gland biopsy), although the visits should be 
completed sooner if feasible.
The details of the samples to be collected and the procedures to be performed are 
included in Section 7.
Follow up
Within 2 weeks of Visit 2 there will be a follow up visit.  This may be conducted by 
telephone for the healthy volunteers (Group A).  The pSS subjects (Group B) may have 
their Follow up visit in person, or by telephone if the Investigator considers it clinically 
appropriate.  Adverse events (AE) will be reviewed at this visit for all of the subjects 
(Group A and Group B)
The total duration of the study will be up to 11 weeks (14 only if it becomes necessary to 
delay the minor salivary gland biopsy), although ideally the study should be completed as 
soon as practicable within the time windows.
4.3.
Type and Number of Subjects
Between approximately 4 to 12 healthy volunteers, and between approximately 8 to 
12 pSS subjects will be recruited into the study.  As there is very little data about the 
variability of the imaging parameters, in-stream review of the variability of PET/CT and 
MRI data will be conducted in order to determine the number of subjects that are required 
for PET/CT and/or MRI (see Section 9.2.2).  In order to minimize radiation exposure to 
healthy volunteers, a maximum of 8 healthy volunteer subjects will undergo the 11C-MET 
PET/CT scan component.
As pSS affects females in about 90% of cases, and in order to reduce variability, initially 
only female healthy volunteer subjects will be recruited.  If in the course of the study 
male pSS subjects are recruited, male healthy volunteers may be recruited at the 
discretion of the Sponsor.  The ages of the healthy volunteers will be matched 
approximately to the ages of the pSS subjects as far as is practically possible, and within 
the age restrictions of the protocol. The procedure for approximate age matching will be 
described in the Study Reference Manual (SRM).

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Healthy volunteers and pSS subjects will be recruited simultaneously.  However, there 
may be some staggering in the recruitment of subjects to allow approximate age and sex 
matching. 
If subjects prematurely discontinue the study, additional replacement subjects may be 
recruited at the discretion of the Sponsor.
4.4.
Design Justification
An 18F-FDG-PET/CT is being used as a biomarker of inflammation to assess disease 
extent systemically.  As 18F-FDG is well characterized as a tracer, there is no need in this 
study to carry out this investigation in a control (healthy volunteer) group.  Therefore, 
this investigation is restricted to the pSS subjects.  In contrast there is a need to determine 
the kinetics and distribution of the 11C-MET PET tracer in healthy volunteers and to 
define normal uptake of this tracer in the glands of interest, thus justifying the use of this 
imaging technique in the healthy volunteers.  Similarly, it will be important to have 
control data from healthy volunteers when interpreting the DCE/DW MRI salivary gland 
data in the pSS subjects.  Radiation exposure will be minimized by in-stream review of 
the variability of imaging parameters to determine the optimal sample size for each scan 
type.
Performing 18F-FDG, 11C-MET PET/CT scans, the salivary gland MRI scan as well as 
the minor salivary gland biopsy, laboratory biomarkers (including metabolomics and 
proteomics) and clinical assessments in the same pSS subject should allow assessment of 
associations between these endpoints.  For example, in the same subject it should be 
possible to determine whether there are changes suggestive of salivary gland 
inflammation on 18F-FDG-PET/CT or MRI, correlate this with the histology, and 
secondly to determine whether these inflammatory changes have an impact on function as 
determined by protein synthesis within the glands and salivary flow/symptoms.  It will 
also be possible to understand whether there is a decrease in protein synthesis in the 
gland in the absence of inflammation (eg. inactive scarred disease).  Looking at these 
potential associations between the imaging, histology and clinical assessments (eg. 
salivary flow) should help to determine whether they would be useful to characterize the 
disease in proof of mechanism studies in patients with pSS.
The study will also help to define whether there is inflammation in glandular structures or 
organs systemically, to correlate this with ESSDAI and subcomponents, and to assess 
whether gland function (protein synthesis) in these organs is impacted by any potential 
inflammation.
Published literature suggests there is a correlation between increased age and reduced 
salivary flow [Affoo, 2015], based on data from a meta-analysis of a large number of 
studies, and of a degree of potential relevance.  Therefore, an attempt will be made to 
match the mean age of the healthy volunteers to the pSS subjects’ where possible, whilst 
restricting the age range of healthy volunteers to ≥ 40 years of age. 

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4.5.
Dose Justification
An investigational medicinal product (IMP) will not be administered to subjects enrolled 
in this study.
Radiaton Exposure
The total radiation exposure for the pSS subjects who are subjected to the studies with 
18F-FDG and 11C-MET including its associated low-dose CT scans is expected to be 
9.7mSv, below 10mSv which falls within the Goup IIb, intermediate risk category as per 
the International Commission of Radiological Protection (ICRP) and generally 
considered ethically acceptable also for healthy volunteers ie 5.2mSv for the 18F-FDG 
and associated CT, and 4.5mSv for the 11C-MET components. 
The healthy volunteers undergoing PET/CT will only receive 11C-MET with its 
associated low-dose CT scans and hence be exposed to 4.5mSv.
The average yearly radiation exposure from naturally occurring background radiation in 
the United Kingdom (UK)  is 2.3mSv.  Approval will also be obtained from the UK 
Administration of Radioactive substances Advisory Committee (ARSAC) prior to 
commencement of the study.
4.6.
Benefit:Risk Assessment
The following section outlines the risk assessment and mitigation strategy for this 
protocol: 

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4.6.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Procedures
Minor salivary gland biopsy (Group B only)
This procedure is associated with (a low) 
incidence of complications including 
discomfort, bleeding and haematoma 
formation.
Subject selection:

Subjects with bleeding disorders will be 
excluded from the study (exclusion # 4).

Subjects with an abnormal clotting 
screen or low platelet counts will be 
excluded from the study (exclusion #21).

Subjects who are unable to discontinue 
anti-coagulant medication to allow 
biopsy will be excluded(exclusion #16).
Subject management

Local anaesthetic will be administered to 
reduce discomfort.

The biopsy will be performed by 
qualified physicians, surgeons or 
dentists with appropriate training and 
experience in the procedure
Subject exposed to ionizing radiation
Radiation exposure from PET/CT 
scanning:
Radiation exposure from PET/CT scanning 
comes from two sources: the radionuclide 
injected for PET scanning, and the 
exposure to X-rays from the CT component.  
The estimated radiation doses for the whole 
study are 9.7mSv for pSS subjects and 
4.5mSv for healthy volunteers.  A typical 
diagnostic whole body CT scan would result 
in an exposure of around 10-15mSv.
Study design:
1.
Low dose CT will be employed to 
minimize radiation exposure.
2.
Subject age is restricted to ≥40 years for 
healthy volunteers and ≥30 years for 
pSS subjects to restrict radiation 
exposure for younger subjects (inclusion 
#1 and #4).
3.
In stream data reviews will be performed 
to minimize the number of scans 

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
An exposure of 9.7mSv approximates to
4 years of background radiation in the 
United Kingdom, and the additional risk of 
developing a fatal malignancy as a result of 
an exposure of 9.7mSv for the pSS subjects 
has been estimated as approximately 1 in 
2100 for an adult in normal health.  For 
healthy volunteers the total maximum 
effective dose of 4.5mSv is equivalent to 
approximately 2 times the average yearly 
exposure to background radiation and the 
additional risk of developing a fatal 
malignancy as a result of these exposures 
has been estimated at 1 in 4400 for an adult 
in normal health [ICRP, 2007].  To put this 
into context, in developed countries, the 
overall population risk of dying of cancer is 
1 in 5 for females and 1 in 4 for males.  
Exposures of less than 10mSv are 
generally considered acceptable for 
research in healthy volunteers
(for discussion of potential foetal toxicity 
see separate section below).
involving ionizing radiation that will be 
conducted
Potential radiation exposure to foetus of 
pregnant subject
Ionizing radiation from CT scans and 
PET tracers
The potential risks of concern from foetal 
exposure to ionizing radiation are 
non-cancer adverse effects (eg miscarriage, 
malformation), and risks of childhood 
cancer.  
If for any reason a pregnant subject is 
Study design:

Pregnant females are not eligible for the 
study (inclusion # 9).

Female subjects considering the study 
will be advised about the need to avoid 
pregnancy during the study until Follow 
up, and about the contraceptive and 
pregnancy testing requirements of the 

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
scanned, radiation exposure to the foetus 
from the whole study would be in the order 
of 10mGy or less for the pSS subjects, and 
lower for healthy volunteers.  No non-
cancer foetal adverse effects of radiation 
exposure (eg miscarriage, foetal 
malformation) have been detected below 
50mGy exposure.
For a foetus exposed in utero to 10mGy of 
radiation, the absolute risk of cancer at 
ages 0-15 years of age is about 1 excess 
cancer death per 1700 exposed (Annals of 
the IRCP, Volume 30, 1, 2000 (ICRP, 2000).
study before consent.

Females of reproductive potential will be 
required to use highly effective methods 
of contraception (as specified in the 
protocol) for 28 days prior to Visit 1 until 
Follow up.
Subject monitoring and management:

Females of reproductive potential will 
undergo pregnancy testing to exclude 
pregnancy prior to scanning as 
described in inclusion #9.

Withdrawal criteria:
In the event of a pregnancy in a female 
subject in the study, the subject will be 
withdrawn.
Subject exposed to gadolinium containing 
MRI contrast agents
The study uses DOTAREM (gadoterate 
meglumine) as an MRI contrast agent.
Non clinical data (source:  gadoterate 
meglumine Summary of Product 
Characteristics (SPC)
The recommended clinical dose is 
0.1mmol/kg (ie 0.2mL/kg).  The 
administration of DOTAREM in rats and in 
dogs at daily doses up to 3mL/kg (ie
15 times the dose laid down in clinical 
conditions) and for 28 days cause no other 
effect than a reversible vacuolisation of the 
proximal tubular cells of the kidney.
Subject selection:

Subjects with impaired renal function 
(estimated glomerular filtration rate 
[eGFR] <60 mL/minute/1.73m2) are 
excluded by the eligibility criteria 
(exclusion #20).

Subjects with a history of sensitivity to 
gadoterate meglumine containing 
contrast agents will be excluded from 
the study (exclusion #18).  
The site(s) will be responsible for following 
any additional safety guidelines for the 
specific gadoterate meglumine containing 
contrast agent used at the site and not scan 

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Preclinical studies have demonstrated that 
DOTAREM is non-toxic for gestating 
females, non embryo-toxic and non 
teratogenic for the foetus.  No prior peri-
and post-natal toxicity and fertility studies 
have been carried out (source:  SPC).
Clinical data:
Use of MRI contrast agents in subjects with 
severely impaired renal function Glomerular 
Filtration Rate (GFR) <30mL/minute has 
been associated with Nephrogenic 
Systemic Fibrosis (NSF)] (this is a class risk 
rather than specific for this particular agent).  
In subjects with severely impaired renal 
function, the benefits of the use of contrast 
agents should be carefully weighed against 
the risks.
Gadolinium (Gd) contrast agents can be 
associated with anaphylactoid or 
hypersensitivity or other idiosyncratic 
reactions, characterized by cardiovascular 
respiratory or cutaneous manifestations, 
and ranging to severe reactions including 
shock.  The risk of hypersensitivity 
reactions may be higher in case of previous 
history of reactions, bronchial asthma and 
history of allergic disorders.  Most of these 
reactions occur within half an hour of 
administration.  Delayed reactions (after 
hours or several days) have been rarely 
subjects if contra-indicated(exclusion #19).
Subject monitoring and management

The MRI procedure will be conducted 
under the supervision of trained and 
qualified clinical staff who are trained to 
appropriately manage an allergic 
reaction.

MRI contrast at a dose less than or 
equal to 0.1mmoL/kg will be used. If it is 
necessary for technical reasons to 
repeat the MRI (no more than once), 
gadolinium contrast administration will 
not be repeated within a 24 hour period.
For pregnancy risk mitigations please see 
section above (potential radiation exposure 
to foetus of pregnant subject).

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
observed
Subject exposed to a high field MRI magnet
Certain prostheses or foreign bodies might 
be incompatible with the MRI scanner
Subject selection:
All participants will be screened according 
to local scanner criteria and trial 
inclusion/exclusion before entering the MRI 
room to ensure they are able to have the 
MRI conducted.  Subjects with non-MR 
compatible metal implants or implantable 
electronic devices (eg pacemaker, 
defibrillator) will not be included in the study 
(exclusion #8).
Administration of PET tracers 18F-FDG and 
11C-METhionine (including potential risks to 
a fetus of a pregnant subject)
18F-FDG PET Tracer:
Nonclinical data: Toxicological studies with 
a single intravenous (IV) injection of 
18F-FDG at 50-fold human dose in dogs and 
1000-fold human dose in mice have not 
identified potential risks of clinical 
significance. 
11C-MET PET tracer
Methionine is an essential amino acid that 
is not synthesized de novo in humans, who 
must ingest methionine or methionine 
containing proteins.  The daily adult 
requirement of methionine is 10mg/kg 
[Protein and amino acid requirements in 
human nutrition.  Report of a joint Food and 
Agriculture Organization of the United 
Nations (FAO)/ World Health Organisation 
(WHO)/ United Nations University (UNU) 
expert consultation [WHO, 2007].  The dose 
Study design:

The 11C-MET will be produced according 
to Good Manufacturing Practice (GMP), 
and the specifications in the European 
Union (EU) Pharmacopoeia.

18F-FDG is purchased from a 
commercial producer, in accordance 
with product labelling.

The radiotracers will be administered at 
doses according to product labelling 
(where available) and the EU 
Pharmacopoeia.

Staff handling the tracers will have the 
necessary training and authorizations in 
their use.

For pregnancy risk mitigations please 
see section above (potential radiation 
exposure to foetus of pregnant subject).

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
administered is several hundred fold less 
than the recommended daily intake of this 
essential amino acid.  It is not anticipated 
that there will be any risks (reproductive or 
other) of the molecule itself (excluding 
ionizing radiation), although no foetal 
reproductive toxicity data is available

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4.6.2.
Benefit Assessment
This study does not involve the use of an investigational medicine; therefore, 
participation will provide no therapeutic or direct medical benefit to participating 
individuals.  However, it is anticipated that the data collected from this investigation will 
improve understanding of the relationship between structure, function and inflammation 
in pSS.  Furthermore, subjects completing the study will potentially aid future 
improvement of the quality of care of pSS subjects by contributing to the development of 
improved imaging methods. 
4.6.3.
Overall Benefit: Risk Conclusion
Based upon the safety strategies and risk mitigations inherent to this protocol, 
GlaxoSmithKline (GSK) concludes the Benefit:Risk for a subject’s participation in the 
GSK study 203818 is adequate and supports the study conduct.
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
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
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
GROUP A: Healthy Volunteers
AGE
1. Subjects for both PET/CT and MRI: Aged >=40 years inclusive at the time of 
signing the informed consent.
2. Subjects for MRI, without PET/CT: Aged >=30 years inclusive at the time of 
signing the informed consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY 
3. Healthy as defined by the investigator, or medically qualified designee, based on a 
medical evaluation including medical history, physical examination, and laboratory 
tests.  A subject with a clinical abnormality or laboratory parameter(s) which is/are 
not specifically listed in the inclusion/exclusion criteria may be included only if the 
investigator in consultation with the GSK Medical Monitor, if required, agree and 
document that the finding is unlikely to introduce additional risk factors and will not 
interfere with the study procedures.

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GROUP B:  Primary Sjögren’s Syndrome Patients
AGE
4. Age >=30 years, at the time of signing the informed consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY 
5. Diagnosis of primary Sjögren’s Syndrome according to the American-European 
Consensus Group criteria [Vitali, 2002].
6. Baseline unstimulated salivary flow >0.0mL/min or evidence of glandular reserve 
function (stimulated baseline salivary flow >0.05mL/min).
7. Systemically active disease, ESSDAI >=5 points.
All Subjects
WEIGHT
8. Body weight >=50 kg and body mass index (BMI) within the range 18.5 to 35 kg/m2
(inclusive).
SEX
9. Male or Female, where one of the following conditions apply:
A female subject is eligible to participate if she is not pregnant (as confirmed by a 
negative serum human chorionic gonadotrophin (hCG) test) at screening, and a negative 
urine pregnancy test 3-8 days prior to Visit 1, on the day of Visit 1 (on each day of 
scanning), on Visit 2, is 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 
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 

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allow confirmation of post-menopausal status prior to study enrolment.
b.
Reproductive potential and agrees to use a male condom PLUS one of the options 
listed in the Modified List of Highly Effective Methods for Avoiding Pregnancy in 
Females of Reproductive Potential (FRP), Section 12.3 (Appendix 3: Modified List 
of Highly Effective Methods for Avoiding Pregnancy in FRP and Collection of 
Pregnancy Information) from at least 28 days prior to Visit 1, until after the 
completion of the follow-up visit.

The investigator is responsible for ensuring that subjects understand how to 
properly use these methods of contraception. 
INFORMED CONSENT
10. Capable of giving written informed consent, which includes compliance with the 
requirements and restrictions listed in the Informed Consent Form (ICF).
5.2.
Exclusion Criteria
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. Diagnosis of secondary Sjögren’s Syndrome.
2. Diagnosis of another systemic autoimmune disease, apart from pSS, including but not 
limited to, systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis or 
systemic vasculitis.  For Group B subjects, autoimmune conditions associated with 
pSS (for example autoimmune thyroiditis, primary biliary cirrhosis or coeliac 
disease), are not included in this exclusion, but should be described in the medical 
history taken baseline.  If in doubt please consult the medical monitor.
3. Subjects with active life-threatening or organ-threatening effects of pSS meaning that 
they may not be able to complete the study visits according to the protocol (as 
determine by the investigator) (Group B).
4. History of coagulation or bleeding disorders which would increase the risk of minor 
salivary gland biopsy (for example but not limited to Haemophilia A or B, Von 
Willibrand’s disease, platelet function disorders) (Group B).
5. History of malignancy within 5 years of screening that, in the view of the 
investigator, in consultation with the medical monitor if required, could confound the 
results of the 18F-FDG PET/CT scan (including lymphoma associated with pSS).  
This does not include cervical carcinoma in situ or non-melanoma skin malignancy 
that has been treated with curative surgical treatment.
6. History of unresolved acute or chronic infection that, in the view of the investigator in 
consultation with the medial monitor, if required, could confound the results of the 
18F-FDG PET/CT.
7. Subject has diabetes mellitus requiring insulin therapy.
8. Contraindications to MRI scanning (as assessed by MRI safety questionnaire).

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9. History of, or suffers from, claustrophobia or feel that they will be unable to lie still in 
the PET or MRI scanner for a period of up to 1 to 2 hours.
10. Where participation in the study would result in donation of blood or blood products 
in excess of 500mL within a 56 day period.
11. Previous inclusion in a research protocol involving nuclear medicine, PET or 
radiological investigations, or as a result of occupational exposure with a significant 
radiation burden (a significant radiation burden being defined as 10mSv in addition to 
natural background radiation, in the previous 3 years including the dose from this 
study). A clinical procedure where the subject received a direct benefit (eg diagnostic 
test) will not be included in the calculation of exposure.
12. Lack of adequate peripheral venous access for cannulation.
13. Current participation in a study with an investigational product, or recent participation 
within 5 half lives of discontinuation the drug, or within twice the duration of the 
biological effect of the drug, whichever is longer.
CONCOMITANT MEDICATIONS
14. Group A: healthy volunteers.  Subject is unable to refrain from taking prescription or 
non-prescription drugs (including vitamins and dietary or herbal supplements), within 
7 days prior to Visit 1 until completion of Visit 2, unless in the opinion of the 
investigator and Sponsor the medication will not interfere with the study.
15. Group B- pSS subjects taking immunomodulatory treatment at screening are excluded 
unless they have been on stable doses of these medicines for 6 weeks prior to 
Screening/Baseline and are expected to remain on stable doses of these medications 
until the Follow up visit.  This would include drugs such as glucocorticoids, 
immunosuppressive agents (for example hydroxychloroquine, azathioprine, 
methotrexate, mycophenolate mofetil, and biologic therapies).  Permitted medications 
are listed in Section 6.8.  If in doubt please discuss with the Medical Monitor.
16. Group B: pSS subjects.  Receiving treatment with anti-coagulant medications, 
including but not limited to warfarin, heparin, thrombin inhibitors, and Factor Xa 
inhibitors, and aspirin, unless the subjects is able to discontinue these medications one 
week prior to minor salivary gland biopsy, or according to local guidelines.  The 
treatment may be restarted 3 days after the biopsy, or according to local guidelines.
RELEVANT HABITS
17. History of alcohol, prescription or non-prescription drug abuse which could interfere 
with participation in the trial according to the protocol, or in the opinion of the 
investigator impacts on the physical or mental wellbeing of the subject.
CONTRAINDICATIONS 
18. History of allergy/hypersensitivity to study medications including local anaesthesia 
(Group B), radio-isotopes or gadolinium-containing contrast agents (all subjects).
19. Contraindications to gadolinium-containing contrast agents in accordance with
product labelling and local guidelines.

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DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
20. Estimated GFR [Modification of Diet in Renal Disease (MDRD) calculation] of less 
than 60mL/min/1.73m2 at screening.
21. Platelet count below the laboratory normal range at screening, or prothrombin time 
above the laboratory normal range at screening (Group B).
22. Subject with a fasting blood sugar >11.1mmol/L at screening (defined as fasting for a 
minimum of 6 hours, excluding unflavoured water).
5.3.
Screening/Baseline/Run-in Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomized.  In order to ensure transparent reporting of screen 
failure subjects meets the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and to 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 (SAE) (see 
Section 7.3.1.4).
Subjects that are not enrolled into the study within the allotted screening window may be 
re-screened once.  If re-screening is performed, subjects are assigned a different unique 
subject ID number for the re-screening, and all screening procedures must be repeated. 
See the SRM for specific details.
5.4.
Withdrawal/Stopping Criteria

A subject may withdraw from the study at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, 
behavioural or administrative reasons.

The subject becomes pregnant.

The subject develops an allergic reaction to imaging contrast agents or any study 
administered treatments (radio-isotope, gadolinium, local anaesthesia), including 
anaphylaxis.

The subject experiences a clinically significant severe AE or SAE that has a 
reasonable possibility of being related to study procedures.

The study is discontinued by the Sponsor.
The following actions must be taken in relation to a subject who fails to attend the site 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 the subject wishes to continue in the study. 

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
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 
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”. 
5.4.1.
Liver Chemistry Stopping Criteria
There is no IMP in this study therefore there are no liver chemistry stopping or increased 
monitoring criteria.
5.4.1.1.
Study Treatment Restart or Rechallenge
Not Applicable
5.4.2.
QTc Stopping Criteria
There is no IMP in this study therefore there are no QTc stopping criteria for this study.
5.5.
Subject and Study Completion
A completed subject is one who has completed all phases of the study including the 
Follow up.
The end of the study is defined as the last subject’s last visit.
6.
STUDY TREATMENT
6.1.
Investigational Product or other Study Treatment
There is no IMP in this study.  Imaging agents are listed in Table 1.

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Table 1
Study Treatments
Study Treatment
Product name:
(Generic name and trade)
18F-FDG
(Group B only)
11C-MET
Gadoterate meglumine 
(Dotarem)
[Formulation description:]
Refer to the summary 
of product 
characteristics 
(SmPC).
In accordance with EU 
Pharmacopoeia.
Refer to SmPC.
Dosage form:
Refer to SmPC.
Refer to study 
procedures manual 
(SRM)
Refer to SmPC.
Unit dose strength(s)/Dosage 
level(s):
200MBq.
500MBq.
Dose less than or equal to 
0.1mmol/kg
Route of administration
For IV injection
For IV injection
For IV injection
Dosing instructions:
Refer to SmPC
Please refer to SRM
Please refer to SmPC
Physical description:
Refer to SmPC
Refer to SmPC
Refer to SmPC
Method for individualizing 
dosage:
None
None
Dose on mg/kg basis.
6.2.
Blinding
This will be an open-label study.
6.3.
Packaging and Labelling
18F-FDG and DOTAREM will be purchased from commercial suppliers.  11C-MET will 
be produced by Imanova, and the contents of the label will be in accordance with all 
applicable regulatory requirements.
6.4.
Preparation/Handling/Storage/Accountability
Imaging agents will be prepared, handled and stored according to product labels, where 
available, and applicable regulatory requirements. 
6.5.
Treatment of Study Treatment Overdose
Imaging agent overdose will be managed according to product labels, where available, 
and local SOPs.
6.6.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study because no medicinal products are being investigated in this study.
The investigator is responsible for ensuring that consideration has been given to the 
post-study care of the subject’s medical condition.

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6.7.
Lifestyle and/or Dietary Restrictions

Subjects should refrain from alcohol in the 24 hours prior to all study visits.

Subjects will be asked to eat a meal prior to the 11C-MET scan in order to stimulate 
salivary gland function (details in SRM). Subjects should advise of any dietary 
restrictions so that a suitable meal can be organised (or if necessary can bring their 
own food by arrangement).

Group B (pSS) patients will be asked to fast (with the exception of unflavoured 
water), for a minimum of 6 hours prior to the 18F-FDG PET/CT scan.

At the Screening/Baseline visit and Visit 2, the following restrictions apply, until 
after the collection of tears, saliva and plasma samples:
-
Subjects should fast for a minimum of 6 hours (with the exception of unflavoured 
water) until after sample collection.
-
Subjects will be required to withhold dosing with oral muscarinic agonists (such 
as pilocarpine and cevimiline) in the 12 hours prior to the Screening/Baseline 
visit and Visit 2.
-
For at least 2 hours prior to saliva collection, subjects should not brush their teeth 
or use oral hygiene products (including saliva substitutes or oral gels) or chewing 
gum, and not smoke.
-
Subjects should not use topical eye drops for 2 hours prior to tear collection until 
after tear collection.
-
Not apply eye makeup on the day of the visits, until after the tear collection.
-
Not wear contact lenses on the day of the visits, until after the tear collection.
6.7.1.
Contraceptive Requirements
6.7.1.1.
Female Subjects
Refer to eligibility criterion number 9 and Section 12.3 (Appendix 3: Modified List of 
Highly Effective Methods for Avoiding Pregnancy in FRP and Collection of Pregnancy 
Information).  The allowed methods of contraception are only effective when used 
consistently, correctly and in accordance with the product label.  The investigator is 
responsible for ensuring subjects understand how to properly use these methods of 
contraception.
6.7.1.2.
Male subjects
There are no contraceptive requirements for male subjects in this study.

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6.8.
Concomitant Medications and Non-Drug Therapies
6.8.1.
Permitted Drug Therapies (Group B: Primary Sjögren’s Syndrome 
Subjects)

Stable doses of potentially immunomodulatory treatments are permitted (stable 
from 6 weeks prior to screening until follow up).  This includes potentially disease 
modifying drugs such as glucocorticoids, immunosuppressive agents (eg
hydroxychloroquine, azathioprine, methotrexate, mycophenolate mofetil, and 
biologic therapies).  The investigator should discuss drug therapies with the 
Medical Monitor if they have any safety concerns or are unsure about the potential 
impact on the scientific validity of the study data.

Topical symptomatic therapies (such as [a] non-medicated ocular topical drops: 
saline or glucane; [b] non-pharmacologic oral topical agents: chewing gum, saliva 
substitutes) are permitted.  Subjects will be required to withhold dosing with these 
agents in the 2 hours prior to collection of saliva and tear samples at 
Screening/Baseline visit and Visit 2.

Oral muscarinic agonists (such as pilocarpine and cevimiline) are permitted.  
Subjects will be required to withhold dosing with these agents in the 12 hours 
prior to the Screening/Baseline visit and Visit 2.

Anticholinergic agents, such as tricyclic antidepressants, buproprion, 
antihistamines, phenothiazines, antiparkinsonian drugs, anti-asthmatic 
medications, or gastrointestinal medications that cause xerostomia in more than 
10% of patients are permitted provided that a subject is on a stable regimen for at 
least 4 weeks prior to Screening/Baseline visit until follow up  has been
completed.
6.8.2.
Prohibited Medications and Non-Drug Therapies
Group A:  Healthy Volunteers

Healthy volunteers are to refrain from taking prescription or non-prescription 
drugs (including vitamins and dietary or herbal supplements), within 7 days prior 
to Visit 1 until after Visit 2, unless in the opinion of the investigator and Sponsor 
the medication will not interfere with the study. 
Group B: Primary Sjögren’s Syndrome Subjects

Treatment with anti-coagulant medications, including but not limited to warfarin, 
heparin, thrombin inhibitors, and Factor Xa inhibitors, and aspirin, unless the 
subjects are able to discontinue these medications one week prior to minor 
salivary gland biopsy (Visit 2), or according to local guidelines.  The treatment 
may be restarted 3 days after the biopsy, or according to local guidelines.

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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 tables, is 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 Table 2 and Table 3
The change in timing or addition of time points for any planned study assessments must 
be documented in a Note to File 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 Institutional Review Board (IRB)/Independent Ethics Committee (IEC) will be 
informed of any safety issues that require alteration of the safety monitoring scheme or 
amendment of the ICF. 
No more than 500 mL of blood will be collected over the duration of the study, including 
any extra assessments that may be required.
7.1.
Time and Events Table
Table 2
Time and Events Table – Screening and Baseline Assessments
Procedure
Screening/Baseline
Visit
Baseline 2 
(FRP only)
Within 3-8 days prior to 
Visit 1
Informed consent
X
Inclusion and exclusion criteria
X
Demography
X
Medical history including past and current 
medical conditions
X
Full physical exam (including height and weight)
X
MRI safety questionnaire
X
Vital signs
X
Concomitant medication review
X
ESSDAI
X1
ESSPRI
X1
Oral dryness numerical rating
X1
Ocular dryness numerical rating
X1
Patient global assessment 
X1
Physician’s global assessment
X1
Basal salivary flow
X
Stimulated salivary flow (including saliva 
collection)
X
Schirmer’s test (including tear collection)
X
Plasma metabolomics/proteomics
X
Haematology/clinical chemistry [see Table 4]
X
Blood biomarkers for ESSDAI  
[see Table 4]
X1

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Procedure
Screening/Baseline
Visit
Baseline 2 
(FRP only)
Within 3-8 days prior to 
Visit 1
Autoantibody screen (anti-Sjögren’s-syndrome-
related antigen A [Anti-SSa], anti Sjögren's 
syndrome type B [SSb])
X1
FSH/oestradiol (post-menopausal women only)
X
Serum pregnancy test (FRP)
X2
Urine pregnancy test( FRP)
X2
Urinalysis
X3
AE = adverse event; FSH = follicle stimulating hormone; MRI = magnetic resonance imaging; FRP = females of 
reproductive potential; .ESSDAI = European League Against Rheumatism (EULAR) Sjögren's Syndrome Disease 
Activity Index; ESSPRI =EULAR Sjögren's Syndrome Patient Reported Index
1.
pSS subjects only
2.
Females of reproductive potential only.
3.
Urine to be sent for urine protein:creatinine ratio if ≥trace proteinuria by dipstick.
Table 3
Time and Events Table – Study Assessments
Procedure
Visit 1
Visit 2
Follow up
Within 6 weeks after 
baseline 
Within 3 weeks 
after Visit 1
Within 2 weeks 
after Visit 2
MRI safety questionnaire5
X
Vital signs
X
X
Concomitant medication review
X
X
Basal salivary flow
X
Stimulated salivary flow (including saliva 
collection)
X
Schirmer’s test (including tear collection)
X
Plasma metabolomics/proteomics
X
Urine pregnancy test (FRP)
X1
X1
Multi-parametric MRI scan (including 
contrast)
X
Meal prior to 11C-MET PET/CT
X
Intravenous injection of 11C-MET PET tracer
X
11C-MET PET/CT scan (dynamic and static)
X
Radio-PK (11C-MET) sampling (dynamic scan)
X2
Measure concentration of 11C-MET tracer in 
blood
X3
Blood glucose (bedside glucometer)
X4
Injection of 18F-FDG tracer
X4
18F-FDG PET/CT scan
X4
Measure concentration of 18F-FDG in blood
X3,4
Salivary gland biopsy
X4
AE review
X
AE = adverse event; CT = computed Tomography; FDG = flurodeoxyglucose; FRP = females of reproductive potential; 
FSH = follicle stimulating hormone; MET = methionine; MRI = magnetic resonance imaging; PET = positron 
emission tomography; PK = pharmacokinetics.
1.
Females of reproductive potential only

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2.
Radio-PK sampling (5mL per sample) to be taken at 1, 2, 5, 10, 15, 20, 30 and 40 minutes after 
injection of 11C-MET PET tracer (number and sampling times are subject to change dependent on 
emerging data, but no more than 100 mL overall will be taken).
3.
To be taken within 5 minutes after the static PET/CT scan (exact time to be recorded).
4.
pSS subjects only.  If it is not possible to schedule the minor salivary gland biopsy within the 3 week 
window after Visit 1, this procedure may be performed up to 6 weeks after Visit 1, subject to prior 
agreement of the medical monitor.
5.
The MRI safety questionnaire will not be databased.
7.2.
Screening and Critical Baseline Assessments
7.2.1.
For all subjects:
Information collected during the Screening/Baseline assessments described below 
represents key data that identifies and defines subject baseline status.  This information is 
critical for the evaluation and comparison of subsequent imaging assessments.  
Additional assessments will be performed as detailed in the Time and Events tables, 
Table 2 and Table 3.
Informed Consent: Informed consent will be obtained from the subject prior to the 
initiation of any study procedures or study-specific data collection.  Subjects who give 
written informed consent will undergo screening assessments within 42 days  prior to 
Visit 1.  At screening the following assessments will be performed.
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 5.1 and Section 5.2.  A complete medical history will be taken at 
the screening visit.  Information from the medical history is important to establish the 
baseline condition of the subject.  Any significant medical conditions affecting the 
subject in the past 5 years should be recorded on the Medical Conditions page of the 
eCRF.  The history should include the following (where applicable, for Group A or 
Group B):

Past or current conditions, including Sjögren’s syndrome history.

Prior surgical procedures.

Pharmacotherapy and chronic or recent use of any medication or herbal 
preparation.

Prior immunosuppressive therapies, including type, number, and duration.

Allergies and significant allergic reactions.

Significant infections (requiring inpatient treatment, or history of recurrent 
infection, including urinary and respiratory tract infections).

Smoking history (current or previous smoker, number of cigarettes smoked per 
day).

Cardiovascular medical history/risk factors (as detailed in the eCRF).

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Serum and urine pregnancy test: A test will be performed for women of child-bearing 
potential at Screening/Baseline.  A urine pregnancy test will be repeated 3 to 8 days prior 
to Visit 1.
Full physical examination: will include complete assessment of all organ systems 
including assessments of the head and neck (including eyes, ears, nose, throat, and 
thyroid gland), skin, musculoskeletal (including evaluation of both small and large 
joints), neurological, respiratory, and cardiovascular systems, gastrointestinal system and 
abdomen (including liver and spleen), lymph nodes and extremities.
Urinalysis: will be performed as related to the eligibility criteria listed in Section 5.1 and 
Section 5.2.
In addition, urinalysis will be performed in subjects included in Group B in order to 
calculate the ESSDAI score.  If proteinuria is detected on dipstick (≥trace), quantification 
of the spot urine protein:creatinine ratio will be needed in the laboratory to calculate the 
ESSDAI score.
Haematology (including coagulation screen) and blood chemistry (clinical safety 
laboratory assessments): will be performed as related to the eligibility criteria listed in 
Section 5.1 and Section 5.2.
Female subjects:  
FSH and oestradiol (females of non-reproductive potential only). 
Serum hCG (at screening only) and urine hCG pregnancy test at other times as required 
(for females of reproductive potential).
Estimated Glomerular filtration rate (eGFR): will be calculated using the 
modification of diet in MDRD formula.
Unstimulated and stimulated salivary flow: Salivary flow rate will be assessed as an 
eligibility criterion for pSS subjects and a baseline procedure for all subjects.  Subjects 
with 0.0mL/min unstimulated salivary flow rate may qualify for the study if their 
stimulated salivary flow is greater than 0.05mL/min.  Details of the collection procedure 
will be further specified in the SRM.
Schirmer’s test: This is an assessment of lacrimal gland function as a baseline procedure 
in which a strip of filter paper is applied under the eyelid to measure the quantity of tear 
production.  The technique for administration of this test will be described in the SRM.
MRI safety questionnaire: in order to confirm eligibility for the MRI scan.
7.2.2.
Additional baseline procedures for Group B subjects only (pSS 
Subjects)
American European Consensus Group (AECG) criteria: The 2002 American 
European Consensus Group criteria [Vitali, 2002] will be evaluated by the investigator to 

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verify the subject’s diagnosis of Primary Sjögren’s Syndrome.  The AECG criteria 
provide an assessment of six different parameters including: oral and ocular symptoms, 
oral and ocular signs, and objective measures of histopathology and biomarkers.
ESSDAI: subjects are required to have systemically active disease as determined by an 
ESSDAI score of at least 5 points.  The ESSDAI [Seror, 2014] is an assessment of 
disease activity across twelve different clinically relevant domains for subjects with 
Sjögren’s syndrome.  ESSDAI will be assessed by the investigator.  Details and guidance 
regarding the application of the ESSDAI assessment will be provided in the SRM. A 
recent user’s guide has also been published [Seror, 2014].
ESSPRI: the EULAR Sjögren’s Syndrome Patient Reported Index [Seror, 2014] is an 
assessment of the severity of patients’ symptoms in primary Sjögren’s syndrome over the 
past 2 weeks, including dryness, pain (joint or muscular pains in arms or legs), and 
fatigue, on a 0 to 10 Numeric Rating Scale (NRS) for each symptom.  The ESSPRI 
assessment tool will be detailed in the SRM.
Blood biomarkers (in order to confirm diagnosis and to calculate ESSDAI score: 
Quantification of serum autoantibodies (including anti-SS-A, SS-B), and immunological 
testing required for ESSDAI (including serum immunoglobulins [Total Immunoglobulin 
(Ig), IgG, IgA, IgM], protein electrophoresis, complement C3, C4, CH50 and C-reactive 
protein), bicarbonate and chloride.  Cryoglobulin and urine electrophoresis testing is only 
needed if required for the calculation of ESSDAI score.
Oral and Ocular Dryness: will be reported by subjects on a numerical rating scale from 
0 to 10.  A description of the instrument anchors and technique for administering these 
scales will be described in the SRM.
Physician global assessment of disease activity: the Physician Global Assessment is a 
physician reported visual analogue scale that provides an overall measure of disease 
severity.  The assessment instrument and technique for administration will be described 
in the SRM.
Patient global assessment of disease activity: the Patient Global Assessment is a patient 
reported visual analogue scale that provides an overall measure of disease severity.  The 
assessment instrument and technique for administration will be described in the SRM.
7.3.
Safety
Planned time points for all safety assessments are listed in the Time and Events tables 
(Table 2 and Table 3 ).  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 and SAE can be found in Section 12.2.

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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 (eg protocol-mandated 
procedures, invasive tests, or change in existing therapy) 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 Visit 1 until the follow up contact (see 
Section 7.3.1.4), at the time points specified in the Time and Events Tables (Table 
2 and Table 3).

Medical occurrences that begin prior to Visit 1 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 
Section 12.2 (Appendix 2: Definition of and Procedures for Recording, 
Evaluating, Follow up and Reporting of Adverse Events).

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
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 2.
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 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 

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given in Section 12.2 (Appendix 2: Definition of and Procedures for Recording, 
Evaluating, Follow up and Reporting of Adverse Events).
7.3.1.4.
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. 
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.  An IMP 
will not be administered to the subjects in this study.  GSK will comply with country 
specific regulatory requirements relating to safety reporting to the regulatory authority, 
IRB/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 (eg summary or listing of SAEs) from GSK will file it with 
the Investigator Brochure (IB) and will notify the IRB/IEC, if appropriate according to 
local requirements.
7.3.2.
Pregnancy
Details of all pregnancies in female subjects will be collected from Visit 1 and until 
follow up.
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 Section 12.3
(Appendix 3: Modified List of Highly Effective Methods for Avoiding Pregnancy in FRP 
and Collection of Pregnancy Information).
7.3.3.
Vital Signs
Single assessment of vital signs will be performed at the times indicated in the Time and 
Events Tables (Table 2 and Table 3).  Vital signs will be measured in the semi-supine 
position after 5 minutes rest and will include temperature, systolic and diastolic blood 
pressure and pulse rate and respiratory rate. 
7.3.4.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 4 must be conducted in 
accordance with the SRM, and the Protocol Time and Events Schedule (Table 2 and 
Table 3).  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 of samples are detailed in the SRM.  

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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 (eg SAE or AE) the results must be 
recorded in the CRF.
Haematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed in Table 4.
Table 4
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Full blood count indices
Red blood cell count 
Indices:
White blood cell count 
with Differential:
White blood count
Mean corpuscular volume 
(MCV)
Neutrophils
Platelet Count
Mean corpuscular 
haemoglobin 
Lymphocytes
Haemoglobin
Mean corpuscular 
haemoglobin 
concentration
Monocytes
Haematocrit
Eosinophils
Coagulation screen
Basophils
Prothrombin time, 
Activated partial 
thromboplastin time 
Clinical 
Chemistry
Urea
Potassium
Aspartate aminotransferase
Total  bilirubin
Creatinine
Sodium
Alanine aminotransferase 
Total Protein
Glucose 
(fasting for 
6 h 
[excluding 
unflavoured 
water])
Calcium
Alkaline phosphatase
Albumin
Creatine 
kinase
C-reactive 
protein
Chloride (pSS patients only)
Bicarbonate (pSS 
patients only)
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood and ketones by dipstick

Microscopic examination (if blood or protein is abnormal) and send urine for 
spot urinary protein:creatinine ratio
Other Screening 
Tests

Follicle-stimulating hormone and oestradiol (as needed in females of 
reproductive potential only)

Serum human chorionic gonadotropin (hCG) [at screening only] and urine hCG 
pregnancy test (as needed for females of reproductive potential)

Group B only: anti-Sjögren’s-syndrome-related antigen A (Anti-SSa), 

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Laboratory 
Assessments
Parameters
anti-Sjögren's syndrome type B (SSb), total immunoglobulin (Ig), IgG, IgA, IgM, 
serum protein electrophoresis, complement C3, C4, CH50

Optional additional tests in Group B (if needed for calculation of ESSDAI):
cyroglobulins, urine electrophoresis, urinary protein creatinine ratio (if dipstick 
≥trace protein).

Estimated glomerular filtration rate will be calculated using the modification of 
diet in renal disease (MDRD) formula.
NOTES :
European League Against Rheumatism (EULAR) primary Sjögren's syndrome disease activity [ESSDAI]
Safety laboratory tests are only conducted at screening in this study.  Subjects with values 
that are considered clinically significantly abnormal will be assessed according to the 
inclusion/exclusion criteria.  In the event of clinically significant laboratory values the 
investigator will advise the subject of appropriate clinical care.
7.4.
Imaging Procedures
7.4.1.
PET Imaging Procedure
Positron Emission Tomography scans will be acquired on a PET/CT scanner at the 
imaging centre.  The details of the PET imaging procedure, image processing and 
analysis will be provided by the imaging centre in a PET Imaging Manual. 
Subjects will be given a meal before the 11C-MET tracer injection to stimulate salivary 
gland function.
Prior to the commencement of the PET scan a venous cannula will be inserted into the 
subjects arm for administration of 18F-FDG or 11C-MET.  An additional venous cannula 
will also be inserted prior to the scan start from which blood samples will be collected at 
the time points described in the Time and Events tables Table 2 and Table 3.  The subject 
will be positioned in the scanner and sufficient padding will be used to minimize 
movements during image acquisition.  The subject will be monitored continuously by a 
qualified PET technician.
For 11C-MET PET scanning, a low-dose CT attenuation scan centred on the salivary 
glands will be performed for subsequent attenuation and scatter correction of the PET 
data.  Thereafter, the PET scan will commence with an intravenous bolus administration 
of 11C-MET (500 MBq) and dynamic scanning of the salivary gland region for 
approximately 40 minutes.  The static scan will follow (within approximately 5 minutes) 
with the whole body CT followed by the PET covering the head to hip with a duration of 
same range for approximately 20 to 30 minutes.
For 18F-FDG PET scanning, scanning will start 60 minutes after intravenous bolus 
administration of 200 MBq of 18F-FDG.  Blood glucose (bedside glucometer) will be 
measured before injection of 18F-FDG tracer. If the glucometer blood glucose is greater 
than 11.1mmol/l, the 18F-FDG cannot be injected, and it will be necessary to reschedule 

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the scan. Advice for Investigators regarding diabetics on oral hypoglycaemic agents will 
be described in the SRM, and the scan will be scheduled in the morning for these subjects 
wherever possible. Firstly, a low-dose CT attenuation scan of the area to be scanned 
(head to hip) will be performed.  Thereafter, the PET scan will commence with static 
scanning acquired for up to 30 to 40 minutes.
After the PET scans, a blood sample will be taken for measurement of radioactivity in 
blood and plasma (See Section 7.6).
After the scan the subjects will be allowed home at the discretion of clinical staff at the 
imaging facility.
7.4.2.
MRI Imaging Procedure
As part of the study, eligible subjects will undergo multi-parametric MRI scanning, 
including administration of a gadolinium based contrast agent at the imaging centre to 
assess salivary gland inflammation, function and structure in pSS subjects and healthy 
volunteers.  Additionally, the images may be used to identify and delineate the 
anatomical Regions of Interest (ROI) for individual PET images and to aid in image 
analysis.  
On attendance at the MRI department, subjects will be placed in the scanner and will be 
prepared for intravenous contrast agent administration.  The scanning protocol will 
include routine localizers, T1 measurement sequences, DCE-MRI acquisition, DW-MRI 
acquisition, and additional exploratory MRI endpoints, as detailed in the Imaging 
Acquisition Manual.  The total scan time should not exceed 1 hour.
If a scanning failure occurs, if feasible a rescan is allowed within 7 days after the failed 
scan.  There will be a minimum of 24 hours between scans where gadolinium contrast is 
used. 
7.5.
Image Analysis
All MRI and PET scans will be available at site, and will be reported at the site by a 
radiologist for clinical abnormalities per local standard procedures.  If a significant 
clinical abnormality is identified that requires further investigation, the Investigator will 
be informed such that they can arrange appropriate investigations and medical care of the 
subject.
7.5.1.
PET Image Analysis
Following reconstruction, scatter correction and attenuation correction, the PET data will 
be corrected for motion (if required) and if possible co-registered to each subject’s 
structural MRI image.  Anatomic regions of interest (ROIs) will be defined using a 
combination of each subject’s PET/CT and MRI.  Those ROIs will then be applied to the 
PET emission data to derive decay-corrected regional time-activity curves.  

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For the static head to hip 18F-FDG and 11C-MET scans, semi quantitative imaging 
outcome parameters (including standardized uptake value) will be generated from the 
decay corrected single time point activity measurement.
The primary structures to be included in the analysis include the different salivary glands, 
lymph nodes and pancreas whenever feasible with respect to size and signal intensity. 
Specific areas of increased FDG uptake in different areas of the body, for example 
including but not limited to the lungs will also be recorded and measured when possible.
Regions in normal structures like liver and blood pool in aorta may be included.
For the dynamic 11C-MET scan, a radiometabolite-corrected plasma input function will 
be generated for each subject.  The decay corrected time-activity curves will be analysed 
using a range of kinetic models including compartmental models and reference tissue 
models if a valid reference region is available in the field of view of the scan.  The 
primary image outcome parameters will depend on the kinetics of the tracer in the region 
of interest and will be decided using quantitative criteria of model selection.
7.5.2.
MRI Image Analysis
Reconstructed MR images for the various sequences will first be corrected for geometric 
distortion and subject motion, as needed and appropriate.  Quality assurance procedures 
may be followed to assert image-characteristic consistency over the course of the study. 
These procedures may include checks on imaging metadata, as well as checks on the 
image data itself.  Anatomical ROIs will be defined on structural MR imaging for 
salivary glands including both parotids glands and other major salivary glands if possible.
For the gadolinium enhanced perfusion sequence, a multiparametric model will be fitted 
for subject and for each point in the anatomical ROIs.  This model will describe the 
wash-in of contrast medium following injection, the efflux of contrast medium from the 
capillaries to the extravascular space, and finally the wash-out of the medium from the 
tissue.  The parametric maps obtained from the model, including maps for Ktrans, IRE 
and ME may then be used to calculate aggregate measurements per ROI. 
Similarly, imaging data for the diffusion sequence will also be used to fit a 
multiparametric model. This model will describe the total diffusion of water as a 
composition of pure water diffusion and pseudo diffusion, ie the incoherent motion of 
water molecules due to capillary blood flow.  Again, parametric maps, including maps for 
ADC, D and f may be used to compute aggregate measurements for each of the ROIs.  
To investigate the complimentary relation between both imaging models, various 
combined models may be explored.  This may include model based approaches such as 
alternative diffusion models that are informed by the tracer kinetic DCE model, but may 
also include data driven approaches such as higher level statistical analyses that are based 
on the parametric maps of both primary models. 
These complimentary models are exploratory, but have the potential to generate outcome 
measures for future trials.

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7.6.
Pharmacokinetics
7.6.1.
Blood sample collection and 11C-Met radio PK analysis
Blood sample collection and analysis will be performed at Imanova Ltd.
Static 18F-FDG and 11C-MET acquisitions: At the end of each PET/CT scan, a single 
venous blood sample (3 mL) will be acquired for determination of whole blood and 
plasma radioactivity concentration.
Dynamic 11C-MET acquisition: During the dynamic 11C-MET PET acquisition, venous 
blood samples will be collected. Blood will be drawn in 5mL volumes at 1, 2, 5, 10, 15, 
20, 30 and 40 minutes after injection of PET tracer.  Sampling times and number of 
samples are subject to change, dependant on emerging data, but no more than 100 mL 
overall will be taken.  The details of the time windows for the collection of these blood 
samples will be included in the SRM.
Tracer radioactivity concentration will be measured in plasma and whole blood, using a 
counter previously cross-calibrated with the scanner.  In addition, metabolite analysis will 
be conducted on the plasma samples via High Performance Liquid Chromatography 
(HPLC).  The timing of pharmacokinetics (PK) samples may be altered and/or PK 
samples may be obtained at additional time points to ensure thorough PK monitoring.  In
all instances, the actual time of each blood sample collection will be recorded.  Blood 
samples collected during PET/CT imaging will be analysed immediately, and will not be 
stored.  Processing and storage procedures are provided in the SRM.
7.7.
Salivary gland biopsy (Group B)
A minor salivary gland biopsy will be performed on Visit 2 (pSS subjects only).  The 
salivary gland biopsy surgical technique and sample handling will be described in the 
SRM and a training video will be made available with details of the procedure.  Biopsy 
tissue will be shipped to a histopathology laboratory for processing and assessment.  
Histological assessments performed on salivary gland tissues will be conducted as 
described in Section 7.8.1.3.
7.8.
Biomarker(s)/Pharmacodynamic Markers
7.8.1.
Novel Biomarkers
7.8.1.1.
Metabolomic Research
Biofluid (saliva, tears and plasma) metabolome studies may be performed by nuclear 
magnetic resonance spectroscopy (NMR), mass spectrometry (MS, Liquid 
Chromatography [LC]-MS, Gas Chromatography [GC]-MS and/or Fourier Transform 
[FT]/MS) and/or equivalent methods.  This may be done to compare the metabolome of 
pSS subjects with healthy volunteers, as well as to assess the variability in the 
metabolome and/or proteomic profile of individual subjects taken at 2 separate time 
points (Baseline and Visit 2).  A comparison of the metabolomic and/or proteomic profile 
from different body fluids (saliva, tears and plasma), and their utility in distinguishing 

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pSS subjects from healthy volunteers may also be investigated.  Associations between the 
metabolome data with proteomic data, clinical, serum biomarker, histological and 
imaging parameters may be studied.
7.8.1.2.
Proteome Research
Biofluid (saliva, tears and plasma) proteome studies may be performed by 2-D gel 
separation, and/or peptide mass mapping, or an alternative equivalent procedure.  These 
differentially expressed proteins may be identified by mass spectrometry or equivalent 
technology.  Intra-subject variability may be assessed by comparing the proteomic profile 
of individuals at two different time points (Screening/Baseline and Visit 2).  Comparisons 
may be made between the proteomic profiles of pSS subjects and healthy volunteers.  
Association of the observed proteomic parameters with clinical, imaging and 
immunological, serum biomarker, metabolome and histological parameters may be 
performed.  Samples for longitudinal analysis will be collected and stored as described in 
the SRM and may be analysed at the end of the study.
The same samples may also be used to confirm findings by application of alternative 
technologies.
7.8.1.3.
Salivary gland histological assessment
Histological assessments of salivary gland tissue will include a determination of 
lymphocyte infiltrate by Immune Histochemistry (IHC) (B and T cell subsets) and 
assessed through haematoxylin and eosin staining for foci scoring.  The IHC assessment 
may include, (but not be limited to): B cell markers: CD20, IgG, IgM, IgA and CD38; 
T cell markers: CD3; markers of germinal centre formation: CD21 and markers of 
dividing cells: Ki67.  Confocal microscopy or other specialist imaging techniques may be 
employed to image immunofluorescence stained sections.
8.
DATA MANAGEMENT

For this study subject data will be entered into GSK defined eCRFs, transmitted 
electronically to GSK or designee and combined with data provided from other 
sources in a validated data system.  

Management of clinical data will be performed in accordance with applicable 
GSK standards and data cleaning procedures to ensure the integrity of the data, 
e.g., removing errors and inconsistencies in the data.

Adverse events and concomitant medications terms will be coded using Medical 
Dictionary for Regulatory Activities (MedDRA) and an internal validated 
medication dictionary, GSKDrug.  

Case report forms (including queries and audit trails) will be retained by GSK, 
and copies will be sent to the investigator to maintain as the investigator copy.  
Subject initials will not be collected or transmitted to GSK according to GSK 
policy.

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9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1.
Hypotheses
This study is designed to explore the use of 18F-FDG PET/CT, 11C-MET PET/CT, and 
multi-parametric MRI in pSS subjects and/or healthy volunteers.  Due to the exploratory 
nature of this study, there are no formal hypotheses being tested. 
For 11C-MET PET/CT and multi-parametric MRI, summary statistics will be used to 
interpret each derived parameter.  An exploratory comparison of pSS subjects vs healthy 
volunteers may performed for each 11C-MET PET/CT and multi-parametric MRI derived 
quantitative parameter as data permits, to estimate difference (or ratio if log 
transformation is needed) with 95% confidence interval. 
For 18F-FDG PET/CT where only pSS subjects will be scanned, summary statistics will 
be used to present each derived parameter.
9.2.
Sample Size Considerations
This is an exploratory study and therefore no formal sample size calculations have been 
conducted.  Sample size is primarily driven by feasibility and knowledge of disease 
heterogeneity to sufficiently evaluate the primary and supportive secondary objectives of 
the study. 
Group A: Healthy Volunteers:
Approximately 4 to 12 subjects will be recruited.  After approximately 4 subjects have 
been scanned, the variability in the imaging parameters will be assessed, after which up 
to 8 additional subjects may be recruited as following: a maximum of an additional 4 for 
11C-MET PET/CT plus MRI (total maximum of 8 subjects for 11C-MET PET/CT), with 
the option for 4 extra for MRI only (total maximum of approximately 12 subjects for 
MRI).  
Group B: Primary Sjögren’s Syndrome Subjects
Approximately 8 to 12 pSS subjects will be recruited.  Due to anticipated greater 
variability amongst patients, the variability of the imaging parameters will be assessed 
after approximately 8 subjects have been recruited, and consequently up to an additional 
4 subjects may be recruited.
Following a literature review the following information was obtained for the imaging 
modalities of interest in the parotid glands in different populations.  This historical 
information can be used in the variability assessment as outlined above.

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Imaging 
modality; 
Parameter
Healthy
Volunteers
Mean [SD]
Patients
(not pSS)
Mean [SD] n
Patients
(pSS)
Mean [SD] n
Reference
18F-FDG PET; 
SUVmax
n/a
1.80
[0.53] n=25
n/a
Basu, 2008
18F-FDG PET; 
SUVmax
n/a
2.00
[not stated]
2.75
[0.61] n=32
Cohen, 2013
18F-FDG PET; 
SUV 
n/a
1.90
[0.68] n=78
n/a
Nakamoto, 2005
11C-MET PET; 
SUVmax
6.00
[1.5] n=11
n/a
n/a
Isohashi, 2013
DCE MRI, Ktrans
0.20
[0.04] n=11
n/a
0.26
[0.05] n=21
Roberts, 2008
SD=Standard Deviation
Using estimates of parameter (this can be any parameter, SUVmean, SUV, Ktrans) 
variability, the precision of these estimates calculated as half width of a 95% confidence 
interval for the mean and expressed as distance from mean to limits, for 4, 8 and 12
subjects has been calculated (Table 5). 
Table 5
Estimated Precision for the Mean of an Imaging Parameter
SD
Precision of Mean
N=4
N=8
N=12
0.05
0.08
0.04
0.03
0.5
0.80
0.42
0.32
1
1.59
0.84
0.64
1.5
2.39
1.25
0.95
For example, based upon the estimate of variability of 1 and a sample size of 12, it is 
estimated that the lower and upper bounds of the 95% confidence interval for the means 
of the imaging parameter (e.g. SUVmean, SUV, Ktrans) will be within approximately 0.64 
of the point estimate.
9.2.1.
Sample Size Sensitivity
No sample size sensitivity has been performed.
9.2.2.
Sample Size Re-estimation or Adjustment
The variability of healthy volunteers will be assessed for the 11C-MET PET/CT and
multi-parametric MRI imaging modalities after approximately 4 healthy volunteers have 
been scanned, and with the aid of precision estimates for the observed variability outlined 
in Table 5, a recommendation may be made to increase the total healthy volunteers 
sample size to up to 8 (for both PET/CT and MRI).  In this event, a further review of the 
multi-parametric MRI results may be performed after 8 healthy volunteers and a 

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recommendation made to increase to a total of 12 for this imaging modality only.  For 
feasibility reasons in the interests of limiting the exposure of healthy volunteers to 
radiation, a cap of 8 healthy volunteers is set for PET/CT.
Similarly the variability of pSS subjects will be assessed for the 11C-MET PET/CT, 18F-
FDG PET/CT and multi-parametric MRI imaging modalities after approximately 8 pSS 
subjects have been scanned, and with the aid of precision estimates for the observed 
variability outlined in Table 5, a recommendation may be made to increase the total pSS 
subjects to 12.  
For both groups, if sufficient data is collected for one or both PET/CT techniques, but not 
the other assessments (for example MRI), the additional subjects will only undergo the 
investigations needed (eg MRI and Visit 2 procedures without one or both PET/CT 
techniques), in order to minimize radiation exposure.
9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations
Population 
Definition / Criteria 
Safety 

Comprised of all subjects who receive/undergo any Visit 1 procedure.
Pharmacokinetic (PK)

Subjects in the ‘Safety’ population for whom a radio-pharmacokinetic 
sample was obtained and analysed. 
Additional analysis population(s) maybe defined in the Reporting and Analysis Plan
(RAP).
9.3.2.
Interim Analysis
No formal interim analysis will be performed, however a review of the imaging results 
will be performed for sample adjustment depending on the variability of the data as 
described in Section 9.2.2.
9.4.
Key Elements of Analysis Plan
9.4.1.
Primary analyses
Data for FDG PET/CT will be listed and summarized by quantitative parameter and 
Region of Interest (ROI).  The data will be further explored graphically to examine:

The parameter values across relevant ROI for each pSS subject

The between-subject variability in parameter values by ROI

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
Summary measures calculated across all relevant ROI (eg. maximum uptake, 
average uptake, total inflammatory volume, total number of lesions) and how 
these summary measures vary between patients.

Asymmetry in parameter values between left and right parotid glands
Similar analyses may be performed for quantitative data from 11C-MET PET/CT and 
multi-parametric MRI.  For those imaging modalities, both HV and pSS are scanned, 
such that all displays will additionally denote group.  An exploratory comparison of pSS 
vs HV may be performed for each quantitative parameter as data permit, to estimate a 
difference (or ratio if log transformation is needed) with 95% confidence interval.  
Further details are outlined in the reporting analysis plan (RAP).
9.4.2.
Secondary Analyses
Descriptive statistics and/or graphical displays will be generated for all derived 
parameters from dynamic PET imaging and PK analyses.  If data permits, statistical 
analyses of 11C-MET PET radio-PK modelling indices with 11C-MET static imaging 
matrices will be conducted to assess correlation.
9.4.3.
Other/Exploratory Analyses
Details of the planned analyses for exploratory objectives to compare imaging 
parameters, explore their potential associations and the correlation of signals to clinical 
assessment measures and laboratory markers will be defined in the RAP.
Further details of proposed analyses will be specified in the RAP.
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 enrolment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
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 International Conference for 
Harmonisation (ICH) 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 favourable opinion/approval of the study protocol and 
amendments as applicable.

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
Obtaining signed informed consent.

Investigator reporting requirements (eg reporting of AEs/SAEs/protocol 
deviations to IRB/IEC).

GSK will provide full details of the above procedures, either verbally, in writing, 
or both.

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 the 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. 

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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.
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 multicentre 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 images in 
digital form will also be retained and may be used for future further analysis.
The records must be maintained to allow easy and timely retrieval, when needed (eg 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 (eg 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 

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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.
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.
Exploratory endpoints may be evaluated and reported outside the main Clinical Study 
Report.

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11.
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rates in young and older adults..  Journal of the American Geriatrics Society. 2015: 63, 
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Bakheet, S. M. and J. Powe . "Benign causes of 18-FDG uptake on whole body imaging." 
Semin Nucl Med 1998, 28(4): 352-358.
Basu, S., Houseni, M. and Alavi, A. Significance of incidental fluorodeoxyglucose 
uptake in the parotid glands and its impact on patient management. Nuclear Medicine 
Communications, 2008, 29(4), pp.367-373.
Buus, S., C. Grau, O. L. Munk, D. Bender, K. Jensen and S. Keiding. "11C-MET PET, a 
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and neck cancer." Radiother Oncol 2004, 73(3): 289-296.
Cohen, C., Mekinian, A., Uzunhan, Y., Fauchais, A., Dhote, R., Pop, G., Eder, V., Nunes, 
H., Brillet, P., Valeyre, D., Fain, O. and Soussan, M. 18F-fluorodeoxyglucose positron 
emission tomography/computer tomography as an objective tool for assessing disease 
activity in Sjögren's syndrome. Autoimmunity Reviews, 2013, 12(11), pp.1109-1114.
Deloar HM, Fujiwara T, Nakamura T, Itoh M, Imai D, Miyake M, Watanuki S. 
Estimation of internal absorbed dose of L-[methyl-11C]methionine using whole-body 
positron emission tomography. Eur J Nucl Med. 1998 Jun;25(6):629-33.  PMID 
DOTAREM  Summary of product characteristics (SPC) [http://www.mhra.gov.uk/spc-
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Glaudemans, A. W., R. H. Enting, M. A. Heesters, R. A. Dierckx, R. W. van Rheenen, A. 
M. Walenkamp and R. H. Slart. "Value of 11C-MET PET in imaging brain tumours and 
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Harris, S. M., J. C. Davis, S. E. Snyder, E. R. Butch, A. L. Vavere, M. Kocak and B. L. 
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12.
APPENDICES
12.1.
Appendix 1 – Abbreviations and Trademarks
Abbreviations
ADC
Apparent Diffusion Coefficient
AE
Adverse Event
AECG
American European Consensus Group
ALT
Alanine Transaminase
Anti-SSa
Anti-Sjögren’s-syndrome-related antigen A
ARSAC
Administration of Radioactive substances Advisory 
Committee
AST
Aspartate aminotransferase
BMI
Body Mass Index
CI
Confidence Interval
CONSORT
Consolidated Standards of Reporting Trials
CRF
Case Report Form
CT
Computed Tomography
CV%
Percentage Coefficient of Variation
D
Pure Diffusion Coefficient
DCE
Dynamic Contrast Enhanced
DW
Diffusion Weighted
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
ESSDAI
EULAR Sjögren's Syndrome Disease Activity Index
ESSPRI
EULAR Sjögren's Syndrome Patient Reported Index
EU
European Union
EULAR
European League Against Rheumatism
f
Microvascular Volume Fraction
FAO
Food and Agriculture Organization of the United Nations
FDG
Fluorodeoxyglucose
FRP
Females of Reproductive Potential
FSH
Follicle Stimulating Hormone
FT
Fourier Transform
GC
Gas chromatography
GCP
Good Clinical Practice
Gd
Gadolinium
GFR
Glomerular Filtration Rate
GSK
GlaxoSmithKline
hCG
Human Chorionic Gonadotropin
HRT
Hormone Replacement Therapy
HV
Healthy Volunteers
IB
Investigators Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation

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ICRP
International Commission on Radiological Protection
IEC
Independent Ethics Committee
Ig
Immunoglobulin
IHC
Immune Histochemistry
IMP
Investigational Medicinal Product
INR
International Normalized Ratio
IRB
Institutional Review Board
IRE
Initial Rate of Enhancement
IV
Intravenous
IVIM
Intravoxel Incoherent Motion
Ktrans
Exchange Rate
M
Meter
MedDRA
Medical Dictionary for Regulatory Activities
ME
Maximal Signal Intensity Enhancement
MET
Methionine
MRI
Magnetic Resonance Imaging
MS
Mass Spectroscopy
mSv
Millisievert
NRS
Numeric Rating Scale
PET
Positron Emission Tomography
PK
Pharmacokinetic
pSS
Primary Sjögren’s Syndrome
RAP
Reporting Analysis Plan
ROI
Region of Interest
SAE
Serious Adverse Event
SD
Standard Deviation
SmPC
Summary of Product Characteristics
SPC
Summary of product characteristics
SRM
Study Reference Manual
SSb
anti Sjögren's syndrome type B
TIV
Total Inflammatory Volume
UK
United Kingdom
ULN
Upper Limit of Normal
UNU
United Nations University
WHO
World Health Organisation
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
Dotarem

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12.2.
Appendix 2: Definition of and Procedures for Recording, 
Evaluating, Follow up and Reporting of Adverse Events
12.2.1.
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 unfavourable 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 (haematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g. electrocardiograms (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).

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE.  However, the signs and symptoms and/or clinical 
sequelae resulting from lack of efficacy will be reported if they fulfil the definition 
of an AE or SAE.

The signs and symptoms and/or clinical sequelae resulting from lack of efficacy will 
be reported if they fulfil the definition of an AE or SAE.  Also, "lack of efficacy" or 
"failure of expected pharmacological action" also constitutes an AE or SAE.
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 

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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).

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.
12.2.2.
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 fulfils any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.

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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, diarrhoea, influenza, 
and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday 
life functions but do not constitute a substantial disruption
e. Is a congenital anomaly/birth defect
f.
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:

Alanine Transaminase (ALT) 3x Upper Limit of Normal (ULN) and total 
bilirubin* 2xULN (>35% direct), or

ALT 3xULN and International Normalised Ratio (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.
12.2.3.
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

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
Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
12.2.4.
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 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.

Subject-completed Value Evidence and Outcomes questionnaires and the collection 
of AE data are independent components of the study.

Responses to each question in the Value Evidence and Outcomes questionnaire will 
be treated in accordance with standard scoring and statistical procedures detailed by 
the scale’s developer.

The use of a single question from a multidimensional health survey to designate a 
cause-effect relationship to an AE is inappropriate.

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12.2.5.
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.
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.

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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.
12.2.6.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data collection 
tool

If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax it to the Medical Monitor or the SAE 
coordinator.

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of 
the SAE.

After the study is completed at a given site, the electronic data collection tool (e.g. 
InForm system) will be taken off-line to prevent the entry of new data or changes to 
existing data

If a site receives a report of a new SAE from a study subject or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, the site can report this information on a paper SAE form or to the Medical 
Monitor or the SAE coordinator by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.

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12.3.
Appendix 3: Modified List of Highly Effective Methods for 
Avoiding Pregnancy in FRP and Collection of Pregnancy 
Information
12.3.1.
Modified List of Highly Effective Methods for Avoiding Pregnancy 
in Females of Reproductive Potential (FRP)
The list does not apply to FRP with same sex partners or for subjects who are and will 
continue to be abstinent from penile-vaginal intercourse on a long term and persistent 
basis, when this is their preferred and usual lifestyle. Periodic abstinence (e.g. calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.
1. Contraceptive subdermal implant
2. Intrauterine device or intrauterine system
3. Combined oestrogen and progestogen oral contraceptive [Hatcher, 2011])
4. Injectable progestogen [Hatcher, 2011]
5. Contraceptive vaginal ring [Hatcher, 2011]
6. Percutaneous contraceptive patches [Hatcher, 2011]
7. Male partner sterilization with documentation of azoospermia prior to the female 
subject's entry into the study, and this male is the sole partner for that subject 
[Hatcher, 2011]. The documentation on male sterility can come from the site 
personnel’s: review of subject’s medical records, medical examination and/or semen 
analysis, or medical history interview provided by her or her partner.
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
12.3.2.
Collection of Pregnancy Information
Female Subjects Enrolled on the Study

Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study

Information will be recorded on the appropriate form and submitted to GSK within 
2 weeks of learning of a subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow- up information on mother and infant, which will be 
forwarded to GSK.  Generally, follow up will not be required for longer than 6 to 
8 weeks beyond the estimated delivery date. 

Any termination of pregnancy will be reported, regardless of foetal status (presence 
or absence of anomalies) or indication for procedure.

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
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  
Any SAE occurring as a result of a post-study pregnancy which is considered reasonably 
related to the study treatment by the investigator, will be reported to GSK. While the 
investigator is not obligated to actively seek this information in former study participants, 
he or she may learn of an SAE through spontaneous reporting.

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12.4.
Appendix 4: Protocol Amendment Changes
Protocol Amendment 1 (24-MAY-2017) from the original protocol (13-Jun-2016)
Where the Amendment Applies
This amendment applies to all subjects who will participate in this study in all countries.
List of Specific Changes: (bold indicates text added and strikethrough indicates text 
removed)
Summary of Protocol Amendment Changes with Rationale
There are updates to some T&E windows (pregnancy tests, V1 for FRP and minor 
salivary gland biopsy) and blood tests as per file notes issued during study.
Typographical error in Section 9.2 changed from “within approximately 0.62 of the point 
estimate” to “within approximately 0.64 of the point estimate”. There are also minor 
formatting changes.
Section 4.1
Overall Design
Rationale for change
Pregnancy test window has been increased to allow additional flexibility around when the 
subjects need to attend the clinic.
There is no need for FRP to wait for 28-42 days after screening for Visit 1, as long as 
they fulfil the requirements in eligibility criterion #9 for 28 days prior to Visit 1 as listed.
In line with clinical practice, a physical visit is no longer considered necessary for follow 
up for pSS subjects.  Flexibility to allow follow up to be conducted by telephone if 
deemed appropriate by the Investigator has been incorporated.
These changes have been updated throughout the protocol.
Revised Text
Third paragraph
If Females of Reproductive Potential (FRP) are included they must have a negative 
pregnancy test as determined by serum human chorionic gonadotropin (hCG) test at 
screening, and a negative urine pregnancy test 3-8 4-7 days prior to Visit 1, and on Visit 
1 (which will occur 28-42 days after screening).  If Visit 1 is split over more than 1 day 
there must be a negative urine pregnancy test on each day, prior to scanning.

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Fourth Paragraph
The follow up may be conducted by telephone for the healthy volunteers (Group A).  The 
pSS subjects (Group B) may have their Follow up visit conducted in person, or by 
telephone if the Investigator considers it clinically appropriate will return to the 
clinical unit for Follow up to allow for the examination of the salivary gland biopsy site. 
Section 4.2
Treatment Arms and Duration, Visits
Rationale for change
Due to logistical difficulties experienced in scheduling the salivary gland biopsy within 3 
weeks of visit 1, and the fact that the study team do not consider that a short delay would 
affect the scientific integrity of the study, additional flexibility around timing of the 
biopsy has been incorporated.
These changes have been updated throughout the protocol.
Revised Text
Third paragraph
In addition, a minor salivary gland biopsy will be performed on the pSS subjects 
(Group B).  If it is not possible, for logistical or other reasons to schedule the minor 
salivary gland biopsy within 3 weeks of Visit 1, then this part of Visit 2 may be 
performed up to 6 weeks after Visit 1, with the prior agreement of the medical 
monitor.
Fourth paragraph
Visit 1 and Visit 2 may be split over more than one day.  The total duration of 
participation in the study will be a maximum of 11 weeks (14 only if it becomes 
necessary to delay the minor salivary gland biopsy), although the visits should be 
completed sooner if feasible.
Section 4.2
Treatment Arms and Duration, Follow up
Second paragraph
The total duration of the study will be up to 11 weeks (14 only if it becomes necessary 
to delay the minor salivary gland biopsy), although ideally the study should be 
completed as soon as practicable within the time windows.

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Section 4.6.
Benefit: Risk Assessment
Section 4.6.1 Risk Assessment
Rationale for change
Typographical error corrected.
Revised Text
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
Potential radiation exposure 
to foetus of pregnant 
subject
Ionizing radiation from CT 
scans and PET tracers
The potential risks of 
concern from foetal 
exposure to ionizing 
radiation are non-cancer 
adverse effects (eg
miscarriage, malformation), 
and risks of childhood 
cancer.  
If for any reason a pregnant 
subject is scanned, 
radiation exposure to the 
foetus from the whole study 
would be in the order of 
10mGy or less for the pSS 
subjects, and lower for 
healthy volunteers.  No 
non-cancer foetal adverse 
effects of radiation 
exposure (eg miscarriage, 
foetal malformation) have 
been detected below 
50mGy exposure.
For a foetus exposed in 
utero to 10mGy of radiation, 
the absolute risk of cancer 
at ages 0-15 years of age is 
about 1 excess cancer 
death per 1700 exposed 
(Annals of the IRCP, 
Volume 30, 1, 2000 (ICRP, 
2000).
Study design:

Pregnant females are 
not eligible for the 
study (inclusion # 9).

Female subjects 
considering the study 
will be advised about 
the need to avoid 
pregnancy during the 
study until Follow up, 
and about the 
contraceptive and 
pregnancy testing 
requirements of the 
study before consent.

Females of 
reproductive potential 
will be required to use 
highly effective 
methods of 
contraception (as 
specified in the 
protocol) for 28 30
days prior to Visit 1 
until Follow up.
Subject monitoring and 
management:

Females of 
reproductive potential 
will undergo pregnancy 
testing to exclude 
pregnancy prior to 
scanning as described 
in inclusion #9.

Withdrawal criteria:
In the event of a 
pregnancy in a female 

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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
subject in the study, the 
subject will be withdrawn.
Section 7.3.
Safety
Rationale for change
No central laboratory manual is used in this study, details are given in the SRM.
The listing of the additional blood biomarkers required, or potentially required for pSS 
subjects (Group B) to calculate the ESSDAI score was incomplete in the original 
approved protocol.  
Thrombin Time and Direct Bilirubin tests are not part of the standard coagulation screen 
or liver screen, respectively, but are used to further investigate abnormalities.  For the 
purposes of this protocol they are unnecessary and have been removed from Table 4.
These changes have been updated throughout the protocol.
Revised Text
Section 7.3.4 Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 4 must be conducted in 
accordance with the Laboratory Manual SRM, and the Protocol Time and Events 
Schedule (Table 2 and Table 3).  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 of samples are detailed in the SRM.
Table 4
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Full blood count 
indices
Red blood cell count 
Indices:
White blood cell count 
with Differential:
White blood count
Mean corpuscular 
volume (MCV)
Neutrophils
Platelet Count
Mean corpuscular 
haemoglobin 
Lymphocytes
Haemoglobin
Mean corpuscular 
haemoglobin 
concentration
Monocytes
Haematocrit
Eosinophils
Coagulation screen
Basophils

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Laboratory 
Assessments
Parameters
Prothrombin time, 
Activated partial 
thromboplastin time 
Thrombin time
Clinical 
Chemistry
Urea
Potassium
Aspartate 
aminotransferase
Total and direct
bilirubin
Creatinine
Sodium
Alanine aminotransferase 
Total Protein
Glucose 
(fasting for 
6 h 
[excluding 
unflavoured 
water])
Calcium
Alkaline phosphatase
Albumin
Creatine 
kinase
C-reactive 
protein
Chloride (pSS patients 
only)
Bicarbonate (pSS 
patients only)
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood and ketones by dipstick

Microscopic examination (if blood or protein is abnormal) and send urine 
for spot urinary protein:creatinine ratio
Other Screening 
Tests

Follicle-stimulating hormone and oestradiol (as needed in females of 
reproductive potential only)

Serum human chorionic gonadotropin (hCG) [at screening only] and urine 
hCG pregnancy test (as needed for females of reproductive potential)

Group B only: anti-Sjögren’s-syndrome-related antigen A (Anti-SSa), 
anti-Sjögren's syndrome type B (SSb), total immunoglobulin (Ig), IgG, IgA, 
IgM, serum protein electrophoresis, complement C3, C4, CH50

Optional additional tests in Group B (if needed for calculation of ESSDAI): 
cyroglobulins, urine electrophoresis, urinary protein creatinine ratio (if 
dipstick ≥trace protein).

Estimated glomerular filtration rate will be calculated using the modification 
of diet in renal disease (MDRD) formula.
NOTES :
European League Against Rheumatism (EULAR) primary Sjögren's syndrome disease activity 
[ESSDAI]
Section 9.2.
Sample Size Considerations
Rationale for change
Typographical error corrected.

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Revised Text
Table 5
Estimated Precision for the Mean of an Imaging Parameter
SD
Precision of Mean
N=4
N=8
N=12
0.05
0.08
0.04
0.03
0.5
0.80
0.42
0.32
1
1.59
0.84
0.64
1.5
2.39
1.25
0.95
For example, based upon the estimate of variability of 1 and a sample size of 12, it is 
estimated that the lower and upper bounds of the 95% confidence interval for the means 
of the imaging parameter (e.g. SUVmean, SUV, Ktrans) will be within approximately 0.64
0.62 of the point estimate.

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GlaxoSmithKline group of companies
203818
1
TITLE PAGE
Division: Worldwide Development
Information Type: Clinical Protocol
Title:
A Pilot Study to Evaluate Molecular Imaging Methods in 
Primary Sjögren’s Syndrome
Compound Number:
None
Development Phase
Not applicable
Effective Date:
13-JUN-2016
Author(s):
 
Copyright 2016 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD

PPD
PPD

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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 
Dr 
 
Tel: 
Mobile: 
Mobile: 
GSK 
Medicines 
Research 
Centre, 
Gunnels 
Wood, 
Stevenage, 
Hertfordshire, 
SG1 2NY, UK
Secondary 
Medical 
Monitor
Dr 
 
Tel: 
Mobile: 
 
SAE 
contact  
information 
[Medical 
monitor
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):  NA
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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INVESTIGATOR PROTOCOL AGREEMENT PAGE

I confirm agreement to conduct the study in compliance with the protocol.

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 Signature
Date

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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 203818........................................................8
2.
INTRODUCTION....................................................................................................14
2.1.
Study Rationale ..........................................................................................14
2.2.
Brief Background ........................................................................................14
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................16
4.
STUDY DESIGN ....................................................................................................18
4.1.
Overall Design ............................................................................................18
4.2.
Treatment Arms and Duration.....................................................................19
4.3.
Type and Number of Subjects.....................................................................20
4.4.
Design Justification.....................................................................................21
4.5.
Dose Justification........................................................................................21
4.6.
Benefit:Risk Assessment ............................................................................22
4.6.1.
Risk Assessment .........................................................................23
4.6.2.
Benefit Assessment.....................................................................29
4.6.3.
Overall Benefit:Risk Conclusion...................................................29
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............29
5.1.
Inclusion Criteria.........................................................................................29
5.2.
Exclusion Criteria........................................................................................31
5.3.
Screening/Baseline/Run-in Failures............................................................33
5.4.
Withdrawal/Stopping Criteria.......................................................................33
5.4.1.
Liver Chemistry Stopping Criteria ................................................34
5.4.1.1.
Study Treatment Restart or Rechallenge....................34
5.4.2.
QTc Stopping Criteria ..................................................................34
5.5.
Subject and Study Completion....................................................................34
6.
STUDY TREATMENT ............................................................................................34
6.1.
Investigational Product or other Study Treatment .......................................34
6.2.
Blinding.......................................................................................................35
6.3.
Packaging and Labelling.............................................................................35
6.4.
Preparation/Handling/Storage/Accountability..............................................35
6.5.
Treatment of Study Treatment Overdose....................................................35
6.6.
Treatment after the End of the Study ..........................................................35
6.7.
Lifestyle and/or Dietary Restrictions............................................................36
6.7.1.
Contraceptive Requirements........................................................36
6.7.1.1.
Female Subjects.........................................................36
6.7.1.2.
Male subjects .............................................................36
6.8.
Concomitant Medications and Non-Drug Therapies....................................37
6.8.1.
Permitted Drug Therapies (Group B: Primary Sjögren’s 
Syndrome Subjects) ....................................................................37
6.8.2.
Prohibited Medications and Non-Drug Therapies.........................37
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................38
7.1.
Time and Events Table...............................................................................39
7.2.
Screening and Critical Baseline Assessments ............................................41
7.2.1.
For all subjects:............................................................................41

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7.2.2.
Additional baseline procedures for Group B subjects only 
(pSS Subjects).............................................................................42
7.3.
Safety .........................................................................................................43
7.3.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........43
7.3.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................43
7.3.1.2.
Method of Detecting AEs and SAEs ...........................44
7.3.1.3.
Follow up of AEs and SAEs........................................44
7.3.1.4.
Regulatory Reporting Requirements for SAEs............44
7.3.2.
Pregnancy ...................................................................................45
7.3.3.
Vital Signs....................................................................................45
7.3.4.
Clinical Safety Laboratory Assessments ......................................45
7.4.
Imaging Procedures....................................................................................47
7.4.1.
PET Imaging Procedure...............................................................47
7.4.2.
MRI Imaging Procedure...............................................................48
7.5.
Image Analysis ...........................................................................................48
7.5.1.
PET Image Analysis ....................................................................48
7.5.2.
MRI Image Analysis.....................................................................49
7.6.
Pharmacokinetics .......................................................................................49
7.6.1.
Blood sample collection and 11C-Met radio PK analysis ...............49
7.7.
Salivary gland biopsy (Group B) .................................................................50
7.8.
Biomarker(s)/Pharmacodynamic Markers ...................................................50
7.8.1.
Novel Biomarkers ........................................................................50
7.8.1.1.
Metabolomic Research...............................................50
7.8.1.2.
Proteome Research....................................................50
7.8.1.3.
Salivary gland histological assessment.......................51
8.
DATA MANAGEMENT ...........................................................................................51
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................51
9.1.
Hypotheses.................................................................................................51
9.2.
Sample Size Considerations.......................................................................52
9.2.1.
Sample Size Sensitivity................................................................53
9.2.2.
Sample Size Re-estimation or Adjustment...................................53
9.3.
Data Analysis Considerations .....................................................................54
9.3.1.
Analysis Populations....................................................................54
9.3.2.
Interim Analysis ...........................................................................54
9.4.
Key Elements of Analysis Plan ...................................................................54
9.4.1.
Primary analyses .........................................................................54
9.4.2.
Secondary Analyses ....................................................................55
9.4.3.
Other/Exploratory Analyses .........................................................55
10. STUDY GOVERNANCE CONSIDERATIONS........................................................55
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............55
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................55
10.3.
Quality Control (Study Monitoring) ..............................................................56
10.4.
Quality Assurance.......................................................................................56
10.5.
Study and Site Closure ...............................................................................56
10.6.
Records Retention......................................................................................57
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................58

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11. REFERENCES.......................................................................................................59
12. APPENDICES........................................................................................................62
12.1.
Appendix 1 – Abbreviations and Trademarks..............................................62
12.2.
Appendix 2: Definition of and Procedures for Recording, Evaluating, 
Follow up and Reporting of Adverse Events ...............................................64
12.2.1.
Definition of Adverse Events........................................................64
12.2.2.
Definition of Serious Adverse Events...........................................65
12.2.3.
Definition of Cardiovascular Events .............................................66
12.2.4.
Recording of AEs and SAEs ........................................................67
12.2.5.
Evaluating AEs and SAEs............................................................67
12.2.6.
Reporting of SAEs to GSK...........................................................69
12.3.
Appendix 3: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in FRP and Collection of Pregnancy Information.......................70
12.3.1.
Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP) ..............70
12.3.2.
Collection of Pregnancy Information ............................................70

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1.
PROTOCOL SYNOPSIS FOR STUDY 203818
Rationale
This is a pilot imaging study designed to assess whether molecular imaging with 
18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed 
tomography (CT), 11C-Methionine (MET) PET/CT and salivary gland magnetic 
resonance imaging (MRI) have the potential to characterize and quantify disease 
manifestations in primary Sjögren’s syndrome (pSS) subjects.  This will be achieved by 
assessing the associations and consistency between the imaging techniques studied, 
clinical assessments (salivary and tear flow and clinical scores), laboratory biomarkers
and histological findings on minor salivary gland biopsy.  It is hoped that the 
methodologies may help with the selection of subjects, and/or assessments of treatment 
response in future clinical studies.  For example, subjects with on-going inflammation 
and a degree of gland function might be more suitable for anti-inflammatory therapies.
Objective(s)/Endpoint(s)
Objectives
Endpoints
Primary

To investigate the use of 18F-FDG 
PET/CT in assessing increased glucose 
uptake as a biomarker of inflammation 
in pSS subjects.

Semi-quantitative parameters of 
uptake in selected body areas, 
including salivary glands for
18F-FDG:

Standardised uptake value (SUV)

Tissue-to-reference ratio

Total inflammatory volume (TIV) 
where anatomically relevant.

To investigate the use of 
11C-Methionine (MET) PET/CT in 
assessing salivary glandular function in 
pSS subjects and healthy volunteers.

Semi-quantitative parameters of uptake 
in selected areas, including salivary 
glands for 11C-MET:

SUV

Tissue-to-reference ratio

TIV where anatomically relevant.

To investigate the use of multi-
parametric MRI in assessing salivary 
gland inflammation, function and 
structure in pSS subjects and healthy 
volunteers.

Quantitative parameters of uptake 
derived from multi-parametric MRI 
in the salivary glands including: 
exchange rate (Ktrans), apparent 
diffusion coefficient (ADC), pure 
diffusion coefficient (D) and
microvascular volume fraction (f)
as data permits.

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Secondary

To characterize the pharmacokinetics 
of 11C-MET PET tracer in vivo to 
allow static imaging parameters to be 
verified.

Generation of quantitative outcome 
parameters (rate of 11C-MET 
accumulation, as data permits) using a 
full quantitative analysis of dynamic 
PET scans. 

Comparison of static and dynamic 
imaging metrics in 11C-MET.
Exploratory 

To explore the use of novel multi-
parametric MRI in assessing salivary 
gland inflammation, function and 
structure in pSS subjects and healthy 
volunteers.

Quantitative parameters of uptake 
derived from multi-parametric MRI in 
the salivary glands including: initial 
rate of enhancement (IRE), maximal 
signal intensity enhancement (ME), 
lipid content, T1 relaxation, and 
volume, as data permits.

To explore the associations of the 
salivary gland imaging parameters 
with clinical and histological 
parameters of salivary glands. 

Association between 18F-FDG PET/CT 
(pSS subjects only), 11C-MET PET/CT 
and MRI parameters (healthy 
volunteers and pSS subjects) in the 
region of the salivary glands with each 
other and with clinical measures 
including:

Basal and stimulated salivary flow

Histological scores from minor 
salivary gland biopsies including 
but not limited to lymphocyte count
and focus score (pSS subjects)

Laboratory biomarkers of disease 
activity (including metabolomic 
and/or proteomic profiles where 
applicable)

European League Against
Rheumatism (EULAR) Sjögren's 
Syndrome Disease Activity Index 
(ESSDAI) and EULAR Sjögren's 
Syndrome Patient Reported Index 
(ESSPRI), in particular 
subcomponents relevant to salivary 
gland function (pSS subjects).

To explore the extent of non-salivary 

Semi-quantitative parameters in 

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gland (systemic) abnormalities 
detected on 18F-FDG PET/CT and 11C-
MET PET/CT, and the association of 
these abnormalities with clinical 
scores/relevant sub-scores and 
laboratory biomarkers in pSS subjects.
selected areas systemically for 18F-
FDG and 11C-MET (including but not 
limited to lymph nodes, thyroid, 
lacrimal glands, lungs and pancreas) 
and the associations of these 
parameters with:

Laboratory biomarkers of disease 
activity (including metabolomic 
and/or proteomic profiles where 
applicable)

Lacrimal gland function as 
measured by Schirmer’s test

ESSDAI and ESSPRI and 
organ-specific subcomponents 
relating to the area imaged, where 
available.

To compare the metabolomic profiles 
of pSS subjects and healthy volunteers, 
to assess the intra-individual variability 
of the metabolome over time, and the 
ability of samples from different 
bodily sites to discriminate pSS 
subjects from healthy volunteers.

Compare the metabolome/proteome of 
pSS subjects with healthy volunteers.

Assess the variability in the 
metabolome and/or proteomic profile 
of individual subjects taken at 
2 separate time points (Baseline and 
Visit 2).

Compare the metabolome and/or 
proteomic profile from different body 
fluids/sites, and their utility in 
distinguishing pSS subjects from 
healthy volunteers.

Samples collected will be saliva, tears
and plasma.
Overall Design
Healthy volunteers will be enrolled in Group A and pSS subjects will be enrolled in 
Group B.
The subjects will be required to attend the clinical unit for a Screening/Baseline visit, an 
imaging visit (Visit 1) a sample collection visit (Visit 2) and a Follow up.  The pSS 
subjects will have a minor salivary gland biopsy at Visit 2.  Females of reproductive 
potential (FRP) will be required to have a negative pregnancy test as determined by 
serum hCG test at screening and will be required to have a negative urine pregnancy test 
4-7 days prior to Visit 1, and on Visit 1 (which will occur 28-42 days after screening). If 
Visit 1 is split over more than 1 day there must be a negative urine pregnancy test on each 
day, prior to scanning.

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All procedures will be performed as outpatient visits.
No investigational medicinal product (IMP) will be administered to subjects enrolled in 
this study.
Treatment Arms and Duration
Subject Participation Flow
Both groups will undergo a Screening/Baseline visit where they will have measurement 
of basal and stimulated, salivary flow rate (including saliva collection), Schirmer’s test 
and blood samples for biomarkers.  The pSS subjects will also have additional clinical 
scores and patient reported assessments.  
Subjects who have completed the screening/baseline will return for an imaging visit 
(Visit 1). The imaging visit should occur within 6 weeks (42 days) after the screening 
visit (28-42 days after screening for FRP).  The following imaging procedures will be 
performed:

Group A (healthy volunteers) will undergo an MRI of the salivary glands and 
11C-MET PET/CT (dynamic scan of the salivary glands followed by head to hip 
static scan).  

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
Group B (pSS subjects) will undergo an MRI of the salivary glands, 11C-MET
PET/CT (as for Group A) and 18F-FDG PET/CT (static scan head to hip). 
Visit 2 will occur within 3 weeks after Visit 1. Visit 2 will involve measurement of basal 
and stimulated (chewing paraffin) salivary flow rate (including saliva collection),
Schirmer’s test (including tear collection), blood samples for biomarkers 
(metabolomics/proteomics).  In addition a minor salivary gland biopsy will be performed 
on the pSS subjects (Group B).
There will be a Follow up visit within 2 weeks of Visit 2.  This may be conducted by 
telephone for the healthy volunteers (Group A).  The pSS subjects (Group B) will return 
to the clinical unit to allow the assessment of the salivary gland biopsy site.  Adverse 
events (AE) will be reviewed at this visit for all of the subjects (Group A and Group B). 
Visit 1 and Visit 2 may be split over more than one day.
The total duration of participation in the study will be a maximum of 11 weeks, although 
the visits should be completed sooner if feasible.
Type and Number of Subjects
Between approximately 4 to 12 healthy volunteers and between approximately 8 to 12 
pSS subjects will be recruited into the study.  As there is very little data about the 
variability of the imaging parameters, in-stream review of the variability will be 
conducted in order to determine the number of subjects that are required for PET/CT 
and/or MRI.  In order to minimize radiation exposure to healthy volunteers, a maximum 
of 8 healthy volunteer subjects will undergo the 11C MET PET/CT scan component.
As pSS affects females in about 90% of cases, and in order to reduce variability, initially 
only female healthy volunteer subjects will be recruited.  If in the course of the study 
male pSS subjects are recruited, male healthy volunteers may be recruited at the 
discretion of the Sponsor.  The ages of the healthy volunteers will be matched 
approximately to the ages of the pSS subjects as far as is practically possible, and within 
the age restrictions of the protocol.
Healthy volunteers and pSS subjects will be recruited simultaneously.  However, there 
may be some staggering in the recruitment of subjects to allow approximate age and sex 
matching. 
If subjects prematurely discontinue the study, additional replacement subjects may be 
recruited at the discretion of the Sponsor.
Analysis
This is an exploratory study and therefore no formal sample size calculations have been 
conducted.  Sample size is primarily driven by feasibility and knowledge of disease 
heterogeneity to sufficiently evaluate the primary and supportive secondary objectives of 
the study. 

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Descriptive statistics and graphical displays if appropriate will be presented for all 
18F-FDG PET/CT derived parameters across the regions of interest (ROI) for all 
pSS subjects and for all 11C-MET PET/CT and multi-parametric MRI derived parameters 
across the ROI for all healthy volunteers and pSS subjects.  An exploratory comparison 
of pSS subjects vs healthy volunteers may be performed for each 11C-MET PET/CT and 
multi-parametric MRI derived quantitative parameter as data permit, to estimate a 
difference (or ratio if log transformation is needed) with 95% confidence interval.  
Descriptive statistics and graphical displays if appropriate will also be presented for all 
derived parameters from dynamic PET imaging and pharmacokinetic (PK) analyses.  If 
data permits, statistical analyses and/or graphical presentation of radio-PK modelling 
indices with 11C-MET static imaging matrices will be conducted to assess correlation.

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2.
INTRODUCTION
2.1.
Study Rationale
This pilot study is designed to assess the potential value of imaging methods in pSS 
subjects.  The selected imaging methods will include:

Positron Emission Tomography (PET) / Computed Tomography (CT) with 11C-
Methionine (MET) imaging to characterize protein synthesis within the salivary 
and other glands as a potential marker of gland function; 

Multi-parametric Magnetic Resonance imaging (MRI) of the salivary glands to 
assess gland function, structure and potential biomarkers of inflammation; and 

PET/CT with 18F-Fluorodeoxyglucose (FDG) as a marker of inflammation to 
assess disease extent in the salivary glands and systemically. 
The aim of the study is to determine whether the imaging methodologies under 
investigation have the potential to characterize and quantify disease manifestations in 
Primary Sjögren’s Syndrome (pSS) subjects.  This will be achieved by assessing the 
associations between the imaging techniques studied, clinical assessments (salivary and 
tear flow and clinical scores), biomarkers (including metabolomics/proteomics) and 
histological findings on minor salivary gland biopsy.  It is hoped that the methodologies 
may help in subject selection and/or assessment of treatment response in future clinical 
studies.  For example subjects with on-going inflammation, and a degree of gland 
function might be more suitable for anti-inflammatory therapies.
2.2.
Brief Background
Primary Sjögren’s Syndrome (pSS) is a chronic systemic disease with a female over male 
preponderance of 9:1 [Vitali, 2002, Helmick, 2008] that primarily involves the salivary 
(xerostomia) and lacrimal (keratoconjunctivitis sicca) glands caused by inflammation 
[Fox, 2005 and Gomes Pde, 2012].  However, any organ or mucosal surface may be 
involved, with the risk of lymphoma development remaining the most serious 
complication [Ziakas, 2014]. 
There is a need to develop methods that can reduce both the time to diagnosis and assess 
the effect of current and new therapies in these patients in a more quantitative manner, in 
particular for assessing the heterogeneous nature of the disease, and selecting patients 
most likely to respond to therapies (ie those with active disease and a degree of gland 
function).  Molecular imaging methods have the potential to provide 3D high resolution, 
sensitive and quantitative measures of disease manifestations, combined with whole body 
assessment for the PET methods.  This makes them an attractive tool to consider for 
assessing disease status at entry to clinical studies, and potentially for monitoring 
treatment effects. 
The methods under study are 18F-FDG PET/CT as a measure of inflammation, 11C-MET
PET/CT as a measure of protein synthesis within the glands, and multi-parametric MRI to 
assess both structural and functional changes in salivary glands in pSS.  Ultrasonography 

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has been used as a diagnostic tool in pSS, but its role in monitoring treatment effects in 
multicentre studies is more challenging and less clear.
Published literature around use of 18F-FDG, 11C-MET PET and multi-parametric MRI in 
pSS is limited as the methods are more commonly used in other indications: 18F-FDG 
uptake is a marker for increased glucose uptake, which is closely correlated to certain 
types of metabolism such as that of malignant cells but it is also a feature of inflammation 
with inflammatory foci exhibiting high 18F-FDG uptake [Bakheet, 1998].  In pSS, the 
relation of 18F-FDG uptake to inflammation needs to be further explored but a recent 
report by Ziakas [Ziakas, 2014] showing a strong correlation between inflammation and 
FDG uptake in Sjögren's patients treated for salivary lymphomas is encouraging 
[Ziakas, 2014].  In addition, Cohen et al. [Cohen, 2013] reviewed the PET data from 32 
Sjögren’s patients that underwent 18F-FDG PET and showed that 18F-FDG uptake was 
increased in 75% of patients with 60% displaying increased uptake in lymph nodes, 50% 
in the parotid glands, 28% in the submandibular glands, 28% in the lung and 6% in the 
thyroid. 
Salivary gland disease is a hallmark for pSS and PET with 11C-MET can potentially 
assess function with a superior sensitivity and anatomical resolution than the gold 
standard contrast sialography or salivary gland scintigraphy with 99mTc-sodium 
pertechnectate. 11C-MET, a labelled essential amino acid, is most popular for PET 
imaging of brain tumours; events such as cellular proliferation are associated with 
increased protein synthesis and hence avid uptake of these precursors 
[Glaudemans, 2013].  Furthermore, 11C-MET has been used for measuring liver protein 
synthesis and assessing excretory pancreas function [Harris, 2013].  Dynamic 11C-MET
has been used as a quantitative measure of regional gland function in the major salivary 
glands in head-and-neck cancer patients that underwent loss of salivary gland function as 
a result of radiotherapy [Buus, 2004].  This study aims to determine whether there is a 
disturbance in protein synthesis in salivary glands that correlates to disease activity, 
although the relationship between inflammation and gland function (protein synthesis) in 
pSS is as yet unclear.  In addition, the ability of PET to image the whole body will also 
allow recording of function in other glands such as the pancreas. 
Magnetic resonance imaging (MRI) offers a superior soft tissue contrast and high 
resolution to assess anatomical organ changes (using T1 or T2 weighted) in vivo, also 
non-invasively.  Furthermore, functional imaging techniques are also available using 
MRI: Dynamic Contrast Enhanced (DCE)-MRI provides information about the 
microvasculature of tissues. Since the salivary glands are highly perfused, this technique 
may be adequate for the evaluation of damage to the vessels in the salivary glands 
[Houweling, 2011]. Diffusion Weighted (DW)-MRI maps the diffusion process of 
molecules, mainly water, and yields qualitative and quantitative information reflecting 
tissue cellularity and cell membrane integrity.  The intravoxel incoherent motion (IVIM) 
model of diffusion may be sensitive to early microstructural changes to the parotid gland 
in pSS patients [Su, 2015].  It thereby complements the morphological information 
obtained by conventional MRI.  Roberts and colleagues [Roberts, 2008] compared the 
parotid gland microvascular characteristics in 21 patients with Sjögren's syndrome with 
those in 11 healthy volunteers.  They demonstrated significant differences in DCE 
parameters with patients also displaying greater gland heterogeneity [Roberts, 2008].

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3.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Primary

To investigate the use of 18F-FDG 
PET/CT in assessing increased glucose 
uptake as a biomarker of inflammation 
in pSS subjects.

Semi-quantitative parameters of uptake 
in selected body areas, including 
salivary glands for 18F-FDG in selected 
areas:

Standardised Uptake Value (SUV)

Tissue-to-reference ratio

Total Inflammatory Volume (TIV)
where anatomically relevant.

To investigate the use of 11C- MET 
PET/CT in assessing salivary 
glandular function in pSS subjects and 
healthy volunteers.

Semi-quantitative parameters of uptake 
in selected areas, including  salivary 
glands for 11C-MET :

SUV

Tissue-to-reference ratio

TIV where anatomically relevant.

To investigate the use of 
multi-parametric MRI in assessing 
salivary gland inflammation, function 
and structure in pSS subjects and 
healthy volunteers.

Quantitative parameters of uptake
derived from multi-parametric MRI in 
the salivary glands including: 
Exchange rate (Ktrans), Apparent 
Diffusion Coefficient (ADC), pure 
diffusion coefficient (D) and 
microvascular volume fraction (f) as 
data permits.
Secondary

To characterize the pharmacokinetics 
of 11C-MET PET tracer in vivo to 
allow static imaging parameters to be 
verified.

Generation of quantitative outcome 
parameters (rate of 11C-MET 
accumulation, as data permits) using a 
full quantitative analysis of dynamic 
PET scans. 

Comparison of static and dynamic 
imaging metrics in 11C-MET.
Exploratory 

To explore the use of novel multi 
parametric MRI in assessing salivary 
gland inflammation, function and 
structure in pSS subjects and healthy 

Quantitative parameters of uptake 
derived from multi-parametric MRI 
in the salivary glands including, 
Initial Rate of Enhancement (IRE), 

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volunteers.
maximal signal intensity 
enhancement (ME), lipid content, 
T1 relaxation and volume, as data 
permits.

To explore the associations of the 
salivary gland imaging parameters 
with clinical and histological 
parameters of salivary glands. 

Association between 18F-FDG PET/CT 
(pSS subjects only), 11C-MET PET/CT 
and MRI parameters (healthy 
volunteers and pSS subjects) in the 
region of the salivary glands with each 
other and with clinical measures 
including:

Basal and stimulated salivary flow

Histological scores from minor 
salivary gland biopsies including 
but not limited to lymphocyte count 
and focus score (pSS subjects)

Laboratory biomarkers of disease 
activity (including metabolomic 
and/or proteomic profiles where 
applicable)
European League Against Rheumatism 
(EULAR) Sjögren's Syndrome Disease 
Activity Index (ESSDAI) and EULAR 
Sjögren's Syndrome Patient Reported 
Index (ESSPRI), in particular 
subcomponents relevant to salivary 
gland function (pSS subjects).

To explore the extent of non-salivary 
gland (systemic) abnormalities 
detected on 18F-FDG PET/CT and 11C-
MET PET/CT, and the association of 
these abnormalities with clinical 
scores/relevant sub-scores and 
laboratory biomarkers in pSS subjects.

Semi-quantitative parameters in 
selected areas systemically for 18F-
FDG and 11C-MET (including but not 
limited to lymph nodes, thyroid, 
lacrimal glands, lungs and pancreas) 
and the associations of these 
parameters with:

Laboratory biomarkers of disease 
activity (including metabolomic 
and/or proteomic profiles where 
applicable)

Lacrimal gland function as 
measured by Schirmer’s test

ESSDAI and ESSPRI and 
organ-specific subcomponents 

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relating to the area imaged, where 
available.

To compare the metabolomic profiles 
of pSS subjects and healthy volunteers, 
to assess the intra-individual variability 
of the metabolome over time, and the 
ability of samples from different 
bodily sites to discriminate pSS 
subjects from healthy volunteers.

Compare the metabolome/proteome of 
pSS subjects with healthy volunteers.

Assess the variability in the 
metabolome and/or proteomic profile 
of individual subjects taken at 
2 separate time points (Baseline and 
Visit 2).

Compare the metabolome and/or 
proteomic profile from different body 
fluids/sites, and their utility in 
distinguishing pSS subjects from 
healthy volunteers.

Samples collected will be saliva, tears 
and plasma.
4.
STUDY DESIGN
4.1.
Overall Design
Healthy volunteers will be enrolled in Group A and pSS subjects will be enrolled in 
Group B.  
The subjects will be required to attend the clinical unit for a Screening/Baseline visit, an 
imaging visit (Visit 1) a sample collection visit (Visit 2) and a Follow up visit.  
If Females of Reproductive Potential (FRP) are included they must have a negative 
pregnancy test as determined by serum human chorionic gonadotropin (hCG) test at 
screening, and a negative urine pregnancy test 4-7 days prior to Visit 1, and on Visit 1 
(which will occur 28-42 days after screening). If Visit 1 is split over more than 1 day 
there must be a negative urine pregnancy test on each day, prior to scanning.
The follow up may be conducted by telephone for the healthy volunteers (Group A).  The 
pSS subjects (Group B) will return to the clinical unit for Follow up to allow for the 
examination of the salivary gland biopsy site. 
All assessments will be done as outpatient visits.
No investigational medicinal product (IMP) will be administered to subjects enrolled in 
this study.

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4.2.
Treatment Arms and Duration
Figure 1
Study Schematic
Screening/Baseline
Both groups of subjects will undergo a Screening/Baseline visit.  At this visit, following 
the subject providing written consent to be enrolled on the study, the eligibility of the 
subjects will be assessed and baseline assessments will be performed (See Time and 
Events tables, Section 7.1.).  
Visits
Subjects who have completed the Screening/Baseline and are eligible for the study will 
have an imaging visit (Visit 1).

Group A (healthy volunteers) will undergo an MRI of the salivary glands and 
11C-MET PET/CT (dynamic scan of the salivary glands followed by head to hip 
static scan).  

Group B (pSS subjects) will undergo an MRI of the salivary glands, 11C-MET
PET/CT (as for Group A) and 18F-FDG PET/CT (static head to hip scan).  

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Visit 2 will occur within 3 weeks after the completion of the assessments performed at 
Visit 1. The assessments will include vital signs measurement, pregnancy test (FRP
only), plasma collection for the measurement of metabolomics/proteomics, measurement 
of basal and stimulated (chewing paraffin) salivary flow rate (including saliva collection) 
and Schirmer’s test (including tear collection).  Concomitant medication and adverse 
event details will be recorded.
In addition, a minor salivary gland biopsy will be performed on the pSS subjects
(Group B).
Visit 1 and Visit 2 may be split over more than one day.  The total duration of 
participation in the study will be a maximum of 11 weeks, although the visits should be 
completed sooner if feasible.
The details of the samples to be collected and the procedures to be performed are 
included in Section 7.
Follow up
Within 2 weeks of Visit 2 there will be a follow up visit. This may be conducted by 
telephone for the healthy volunteers (Group A). The pSS subjects (Group B) will return 
to the clinical unit for follow up to allow for the examination of the salivary gland biopsy 
site.  Adverse events (AE) will be reviewed at this visit for all of the subjects (Group A 
and Group B)
The total duration of the study will be up to 11 weeks, although ideally the study should 
be completed as soon as practicable within the time windows.
4.3.
Type and Number of Subjects
Between approximately 4 to 12 healthy volunteers, and between approximately 8 to 
12 pSS subjects will be recruited into the study.  As there is very little data about the 
variability of the imaging parameters, in-stream review of the variability of PET/CT and 
MRI data will be conducted in order to determine the number of subjects that are required 
for PET/CT and/or MRI (see Section 9.2.2).  In order to minimize radiation exposure to 
healthy volunteers, a maximum of 8 healthy volunteer subjects will undergo the 11C-MET 
PET/CT scan component.
As pSS affects females in about 90% of cases, and in order to reduce variability, initially 
only female healthy volunteer subjects will be recruited.  If in the course of the study 
male pSS subjects are recruited, male healthy volunteers may be recruited at the 
discretion of the Sponsor.  The ages of the healthy volunteers will be matched 
approximately to the ages of the pSS subjects as far as is practically possible, and within 
the age restrictions of the protocol. The procedure for approximate age matching will be 
described in the Study Reference Manual (SRM).
Healthy volunteers and pSS subjects will be recruited simultaneously.  However, there 
may be some staggering in the recruitment of subjects to allow approximate age and sex 
matching. 

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If subjects prematurely discontinue the study, additional replacement subjects may be 
recruited at the discretion of the Sponsor.
4.4.
Design Justification
An 18F-FDG-PET/CT is being used as a biomarker of inflammation to assess disease 
extent systemically.  As 18F-FDG is well characterized as a tracer, there is no need in this 
study to carry out this investigation in a control (healthy volunteer) group.  Therefore, 
this investigation is restricted to the pSS subjects.  In contrast there is a need to determine 
the kinetics and distribution of the 11C-MET PET tracer in healthy volunteers and to 
define normal uptake of this tracer in the glands of interest, thus justifying the use of this 
imaging technique in the healthy volunteers.  Similarly, it will be important to have 
control data from healthy volunteers when interpreting the DCE/DW MRI salivary gland 
data in the pSS subjects.  Radiation exposure will be minimized by in-stream review of 
the variability of imaging parameters to determine the optimal sample size for each scan 
type.
Performing 18F-FDG, 11C-MET PET/CT scans, the salivary gland MRI scan as well as 
the minor salivary gland biopsy, laboratory biomarkers (including metabolomics and 
proteomics) and clinical assessments in the same pSS subject should allow assessment of 
associations between these endpoints.  For example, in the same subject it should be 
possible to determine whether there are changes suggestive of salivary gland 
inflammation on 18F-FDG-PET/CT or MRI, correlate this with the histology, and 
secondly to determine whether these inflammatory changes have an impact on function as 
determined by protein synthesis within the glands and salivary flow/symptoms.  It will 
also be possible to understand whether there is a decrease in protein synthesis in the 
gland in the absence of inflammation (eg. inactive scarred disease).  Looking at these 
potential associations between the imaging, histology and clinical assessments (eg.
salivary flow) should help to determine whether they would be useful to characterize the 
disease in proof of mechanism studies in patients with pSS.
The study will also help to define whether there is inflammation in glandular structures or 
organs systemically, to correlate this with ESSDAI and subcomponents, and to assess 
whether gland function (protein synthesis) in these organs is impacted by any potential 
inflammation.
Published literature suggests there is a correlation between increased age and reduced 
salivary flow [Affoo, 2015], based on data from a meta-analysis of a large number of 
studies, and of a degree of potential relevance.  Therefore, an attempt will be made to 
match the mean age of the healthy volunteers to the pSS subjects’ where possible, whilst 
restricting the age range of healthy volunteers to ≥40 years of age. 
4.5.
Dose Justification
An investigational medicinal product (IMP) will not be administered to subjects enrolled 
in this study.

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Radiaton Exposure
The total radiation exposure for the pSS subjects who are subjected to the studies with 
18F-FDG and 11C-MET including its associated low-dose CT scans is expected to be 
9.7mSv, below 10mSv which falls within the Goup IIb, intermediate risk category as per 
the International Commission of Radiological Protection (ICRP) and generally 
considered ethically acceptable also for healthy volunteers ie 5.2mSv for the 18F-FDG 
and associated CT, and 4.5mSv for the 11C-MET components. 
The healthy volunteers undergoing PET/CT will only receive 11C-MET with its 
associated low-dose CT scans and hence be exposed to 4.5mSv.
The average yearly radiation exposure from naturally occurring background radiation in 
the United Kingdom (UK) is 2.3mSv.  Approval will also be obtained from the UK 
Administration of Radioactive substances Advisory Committee (ARSAC) prior to 
commencement of the study.
4.6.
Benefit:Risk Assessment
The following section outlines the risk assessment and mitigation strategy for this 
protocol: 

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4.6.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Procedures
Minor salivary gland biopsy (Group B only)
This procedure is associated with (a low) 
incidence of complications including 
discomfort, bleeding and haematoma 
formation.
Subject selection:

Subjects with bleeding disorders will be 
excluded from the study (exclusion # 4).

Subjects with an abnormal clotting 
screen or low platelet counts will be 
excluded from the study (exclusion #21).

Subjects who are unable to discontinue 
anti-coagulant medication to allow 
biopsy will be excluded(exclusion #16).
Subject management

Local anaesthetic will be administered to 
reduce discomfort.

The biopsy will be performed by 
qualified physicians, surgeons or 
dentists with appropriate training and 
experience in the procedure
Subject exposed to ionizing radiation
Radiation exposure from PET/CT 
scanning:
Radiation exposure from PET/CT scanning 
comes from two sources: the radionuclide 
injected for PET scanning, and the 
exposure to X-rays from the CT component.  
The estimated radiation doses for the whole 
study are 9.7mSv for pSS subjects and 
4.5mSv for healthy volunteers.  A typical 
diagnostic whole body CT scan would result 
in an exposure of around 10-15mSv.
Study design:
1.
Low dose CT will be employed to 
minimize radiation exposure.
2.
Subject age is restricted to ≥40 years for 
healthy volunteers and ≥30 years for 
pSS subjects to restrict radiation 
exposure for younger subjects (inclusion 
#1 and #4).
3.
In stream data reviews will be performed 
to minimize the number of scans 

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
An exposure of 9.7mSv approximates to
4 years of background radiation in the 
United Kingdom, and the additional risk of 
developing a fatal malignancy as a result of 
an exposure of 9.7mSv for the pSS subjects
has been estimated as approximately 1 in 
2100 for an adult in normal health.  For 
healthy volunteers the total maximum 
effective dose of 4.5mSv is equivalent to 
approximately 2 times the average yearly 
exposure to background radiation and the 
additional risk of developing a fatal 
malignancy as a result of these exposures 
has been estimated at 1 in 4400 for an adult 
in normal health [ICRP, 2007].  To put this 
into context, in developed countries, the 
overall population risk of dying of cancer is 
1 in 5 for females and 1 in 4 for males.  
Exposures of less than 10mSv are 
generally considered acceptable for 
research in healthy volunteers
(for discussion of potential foetal toxicity 
see separate section below).
involving ionizing radiation that will be 
conducted
Potential radiation exposure to foetus of 
pregnant subject
Ionizing radiation from CT scans and 
PET tracers
The potential risks of concern from foetal
exposure to ionizing radiation are 
non-cancer adverse effects (eg miscarriage, 
malformation), and risks of childhood 
cancer.  
If for any reason a pregnant subject is 
Study design:

Pregnant females are not eligible for the 
study (inclusion # 9).

Female subjects considering the study 
will be advised about the need to avoid 
pregnancy during the study until Follow 
up, and about the contraceptive and 
pregnancy testing requirements of the 

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
scanned, radiation exposure to the foetus
from the whole study would be in the order 
of 10mGy or less for the pSS subjects, and 
lower for healthy volunteers.  No non-
cancer foetal adverse effects of radiation 
exposure (eg miscarriage, foetal 
malformation) have been detected below 
50mGy exposure.
For a foetus exposed in utero to 10mGy of 
radiation, the absolute risk of cancer at 
ages 0-15 years of age is about 1 excess 
cancer death per 1700 exposed (Annals of 
the IRCP, Volume 30, 1, 2000 (ICRP, 2000).
study before consent.

Females of reproductive potential will be 
required to use highly effective methods 
of contraception (as specified in the 
protocol) for 30 days prior to Visit 1 until 
Follow up.
Subject monitoring and management:

Females of reproductive potential will 
undergo pregnancy testing to exclude 
pregnancy prior to scanning as 
described in inclusion #9.

Withdrawal criteria:
In the event of a pregnancy in a female 
subject in the study, the subject will be 
withdrawn.
Subject exposed to gadolinium containing 
MRI contrast agents
The study uses DOTAREM (gadoterate 
meglumine) as an MRI contrast agent.
Non clinical data (source: gadoterate 
meglumine Summary of Product 
Characteristics (SPC)
The recommended clinical dose is 
0.1mmol/kg (ie 0.2mL/kg).  The 
administration of DOTAREM in rats and in 
dogs at daily doses up to 3mL/kg (ie
15 times the dose laid down in clinical 
conditions) and for 28 days cause no other 
effect than a reversible vacuolisation of the 
proximal tubular cells of the kidney.
Subject selection:

Subjects with impaired renal function 
(estimated glomerular filtration rate 
[eGFR] <60 mL/minute/1.73m2) are 
excluded by the eligibility criteria
(exclusion #20).

Subjects with a history of sensitivity to 
gadoterate meglumine containing 
contrast agents will be excluded from 
the study (exclusion #18).  
The site(s) will be responsible for following 
any additional safety guidelines for the 
specific gadoterate meglumine containing 
contrast agent used at the site and not scan 

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Preclinical studies have demonstrated that 
DOTAREM is non-toxic for gestating 
females, non embryo-toxic and non 
teratogenic for the foetus.  No prior peri-
and post-natal toxicity and fertility studies 
have been carried out (source: SPC).
Clinical data:
Use of MRI contrast agents in subjects with 
severely impaired renal function Glomerular 
Filtration Rate (GFR) <30mL/minute has 
been associated with Nephrogenic 
Systemic Fibrosis (NSF)] (this is a class risk 
rather than specific for this particular agent).  
In subjects with severely impaired renal 
function, the benefits of the use of contrast 
agents should be carefully weighed against 
the risks.
Gadolinium (Gd) contrast agents can be 
associated with anaphylactoid or 
hypersensitivity or other idiosyncratic 
reactions, characterized by cardiovascular 
respiratory or cutaneous manifestations, 
and ranging to severe reactions including 
shock.  The risk of hypersensitivity 
reactions may be higher in case of previous 
history of reactions, bronchial asthma and 
history of allergic disorders.  Most of these 
reactions occur within half an hour of 
administration.  Delayed reactions (after 
hours or several days) have been rarely 
subjects if contra-indicated(exclusion #19).
Subject monitoring and management

The MRI procedure will be conducted 
under the supervision of trained and 
qualified clinical staff who are trained to 
appropriately manage an allergic 
reaction.

MRI contrast at a dose less than or 
equal to 0.1mmoL/kg will be used. If it is 
necessary for technical reasons to 
repeat the MRI (no more than once), 
gadolinium contrast administration will 
not be repeated within a 24 hour period.
For pregnancy risk mitigations please see 
section above (potential radiation exposure 
to foetus of pregnant subject).

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
observed
Subject exposed to a high field MRI magnet
Certain prostheses or foreign bodies might 
be incompatible with the MRI scanner
Subject selection:
All participants will be screened according 
to local scanner criteria and trial 
inclusion/exclusion before entering the MRI 
room to ensure they are able to have the 
MRI conducted.  Subjects with non-MR 
compatible metal implants or implantable 
electronic devices (eg pacemaker, 
defibrillator) will not be included in the study
(exclusion #8).
Administration of PET tracers 18F-FDG and 
11C-METhionine (including potential risks to 
a fetus of a pregnant subject)
18F-FDG PET Tracer:
Nonclinical data: Toxicological studies with 
a single intravenous (IV) injection of 
18F-FDG at 50-fold human dose in dogs and 
1000-fold human dose in mice have not 
identified potential risks of clinical
significance. 
11C-MET PET tracer
Methionine is an essential amino acid that 
is not synthesized de novo in humans, who 
must ingest methionine or methionine 
containing proteins.  The daily adult 
requirement of methionine is 10mg/kg 
[Protein and amino acid requirements in 
human nutrition.  Report of a joint Food and 
Agriculture Organization of the United 
Nations (FAO)/ World Health Organisation 
(WHO)/ United Nations University (UNU)
expert consultation [WHO, 2007].  The dose 
Study design:

The 11C-MET will be produced according 
to Good Manufacturing Practice (GMP), 
and the specifications in the European 
Union (EU) Pharmacopoeia.

18F-FDG is purchased from a 
commercial producer, in accordance 
with product labelling.

The radiotracers will be administered at 
doses according to product labelling 
(where available) and the EU 
Pharmacopoeia.

Staff handling the tracers will have the 
necessary training and authorizations in 
their use.

For pregnancy risk mitigations please 
see section above (potential radiation 
exposure to foetus of pregnant subject).

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
administered is several hundred fold less 
than the recommended daily intake of this 
essential amino acid.  It is not anticipated 
that there will be any risks (reproductive or 
other) of the molecule itself (excluding 
ionizing radiation), although no foetal
reproductive toxicity data is available

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4.6.2.
Benefit Assessment
This study does not involve the use of an investigational medicine; therefore, 
participation will provide no therapeutic or direct medical benefit to participating 
individuals.  However, it is anticipated that the data collected from this investigation will 
improve understanding of the relationship between structure, function and inflammation 
in pSS.  Furthermore, subjects completing the study will potentially aid future 
improvement of the quality of care of pSS subjects by contributing to the development of 
improved imaging methods. 
4.6.3.
Overall Benefit:Risk Conclusion
Based upon the safety strategies and risk mitigations inherent to this protocol, 
GlaxoSmithKline (GSK) concludes the Benefit:Risk for a subject’s participation in the 
GSK study 203818 is adequate and supports the study conduct.
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
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
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
GROUP A: Healthy Volunteers
AGE
1. Subjects for both PET/CT and MRI: Aged >=40 years inclusive at the time of 
signing the informed consent.
2. Subjects for MRI, without PET/CT: Aged >=30 years inclusive at the time of 
signing the informed consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY 
3. Healthy as defined by the investigator, or medically qualified designee, based on a 
medical evaluation including medical history, physical examination, and laboratory 
tests.  A subject with a clinical abnormality or laboratory parameter(s) which is/are 
not specifically listed in the inclusion/exclusion criteria may be included only if the 
investigator in consultation with the GSK Medical Monitor, if required, agree and 
document that the finding is unlikely to introduce additional risk factors and will not 
interfere with the study procedures.

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GROUP B:  Primary Sjögren’s Syndrome Patients
AGE
4. Age >=30 years, at the time of signing the informed consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY 
5. Diagnosis of primary Sjögren’s Syndrome according to the American-European 
Consensus Group criteria [Vitali, 2002].
6. Baseline unstimulated salivary flow >0.0mL/min or evidence of glandular reserve 
function (stimulated baseline salivary flow >0.05mL/min).
7. Systemically active disease, ESSDAI >=5 points.
All Subjects
WEIGHT
8. Body weight >=50 kg and body mass index (BMI) within the range 18.5 to 35 kg/m2
(inclusive).
SEX
9. Male or Female, where one of the following conditions apply:
A female subject is eligible to participate if she is not pregnant (as confirmed by a 
negative serum human chorionic gonadotrophin (hCG) test) at screening, and a negative 
urine pregnancy test 4-7 days prior to Visit 1, on the day of Visit 1 (on each day of 
scanning), on Visit 2, is 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 
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 

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allow confirmation of post-menopausal status prior to study enrolment.
b.
Reproductive potential and agrees to use a male condom PLUS one of the options 
listed in the Modified List of Highly Effective Methods for Avoiding Pregnancy in 
Females of Reproductive Potential (FRP), Section 12.3 (Appendix 3: Modified List 
of Highly Effective Methods for Avoiding Pregnancy in FRP and Collection of 
Pregnancy Information) from at least 28 days prior to Visit 1, until after the 
completion of the follow-up visit.

The investigator is responsible for ensuring that subjects understand how to 
properly use these methods of contraception.
INFORMED CONSENT
10. Capable of giving written informed consent, which includes compliance with the 
requirements and restrictions listed in the Informed Consent Form (ICF).
5.2.
Exclusion Criteria
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. Diagnosis of secondary Sjögren’s Syndrome.
2. Diagnosis of another systemic autoimmune disease, apart from pSS, including but not 
limited to, systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis or
systemic vasculitis.  For Group B subjects, autoimmune conditions associated with 
pSS (for example autoimmune thyroiditis, primary biliary cirrhosis or coeliac 
disease), are not included in this exclusion, but should be described in the medical 
history taken baseline. If in doubt please consult the medical monitor.
3. Subjects with active life-threatening or organ-threatening effects of pSS meaning that 
they may not be able to complete the study visits according to the protocol (as 
determine by the investigator) (Group B).
4. History of coagulation or bleeding disorders which would increase the risk of minor 
salivary gland biopsy (for example but not limited to Haemophilia A or B, Von 
Willibrand’s disease, platelet function disorders) (Group B).
5. History of malignancy within 5 years of screening that, in the view of the 
investigator, in consultation with the medical monitor if required, could confound the 
results of the 18F-FDG PET/CT scan (including lymphoma associated with pSS).  
This does not include cervical carcinoma in situ or non-melanoma skin malignancy 
that has been treated with curative surgical treatment.
6. History of unresolved acute or chronic infection that, in the view of the investigator in 
consultation with the medial monitor, if required, could confound the results of the 
18F-FDG PET/CT.
7. Subject has diabetes mellitus requiring insulin therapy.

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8. Contraindications to MRI scanning (as assessed by MRI safety questionnaire).
9. History of, or suffers from, claustrophobia or feel that they will be unable to lie still in 
the PET or MRI scanner for a period of up to 1 to 2 hours.
10. Where participation in the study would result in donation of blood or blood products 
in excess of 500mL within a 56 day period.
11. Previous inclusion in a research protocol involving nuclear medicine, PET or 
radiological investigations, or as a result of occupational exposure with a significant 
radiation burden (a significant radiation burden being defined as 10mSv in addition to 
natural background radiation, in the previous 3 years including the dose from this 
study). A clinical procedure where the subject received a direct benefit (eg diagnostic 
test) will not be included in the calculation of exposure.
12. Lack of adequate peripheral venous access for cannulation.
13. Current participation in a study with an investigational product, or recent participation 
within 5 half lives of discontinuation the drug, or within twice the duration of the 
biological effect of the drug, whichever is longer.
CONCOMITANT MEDICATIONS
14. Group A: healthy volunteers. Subject is unable to refrain from taking prescription or 
non-prescription drugs (including vitamins and dietary or herbal supplements), within 
7 days prior to Visit 1 until completion of Visit 2, unless in the opinion of the 
investigator and Sponsor the medication will not interfere with the study.
15. Group B- pSS subjects taking immunomodulatory treatment at screening are excluded
unless they have been on stable doses of these medicines for 6 weeks prior to 
Screening/Baseline and are expected to remain on stable doses of these medications 
until the Follow up visit.  This would include drugs such as glucocorticoids, 
immunosuppressive agents (for example hydroxychloroquine, azathioprine, 
methotrexate, mycophenolate mofetil, and biologic therapies).  Permitted medications 
are listed in Section 6.8.  If in doubt please discuss with the Medical Monitor.
16. Group B: pSS subjects.  Receiving treatment with anti-coagulant medications, 
including but not limited to warfarin, heparin, thrombin inhibitors, and Factor Xa 
inhibitors, and aspirin, unless the subjects is able to discontinue these medications one 
week prior to minor salivary gland biopsy, or according to local guidelines.  The 
treatment may be restarted 3 days after the biopsy, or according to local guidelines.
RELEVANT HABITS
17. History of alcohol, prescription or non-prescription drug abuse which could interfere 
with participation in the trial according to the protocol, or in the opinion of the 
investigator impacts on the physical or mental wellbeing of the subject.
CONTRAINDICATIONS 
18. History of allergy/hypersensitivity to study medications including local anaesthesia 
(Group B), radio-isotopes or gadolinium-containing contrast agents (all subjects).
19. Contraindications to gadolinium-containing contrast agents in accordance with 

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product labelling and local guidelines.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
20. Estimated GFR [Modification of Diet in Renal Disease (MDRD) calculation] of less 
than 60mL/min/1.73m2 at screening.
21. Platelet count below the laboratory normal range at screening, or prothrombin time 
above the laboratory normal range at screening (Group B).
22. Subject with a fasting blood sugar >11.1mmol/L at screening (defined as fasting for a 
minimum of 6 hours, excluding unflavoured water).
5.3.
Screening/Baseline/Run-in Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomized. In order to ensure transparent reporting of screen 
failure subjects meets the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and to 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 (SAE) (see 
Section 7.3.1.4).
Subjects that are not enrolled into the study within the allotted screening window may be 
re-screened once. If re-screening is performed, subjects are assigned a different unique 
subject ID number for the re-screening, and all screening procedures must be repeated. 
See the SRM for specific details.
5.4.
Withdrawal/Stopping Criteria

A subject may withdraw from the study at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, 
behavioural or administrative reasons.

The subject becomes pregnant.

The subject develops an allergic reaction to imaging contrast agents or any study 
administered treatments (radio-isotope, gadolinium, local anaesthesia), including 
anaphylaxis.

The subject experiences a clinically significant severe AE or SAE that has a 
reasonable possibility of being related to study procedures.

The study is discontinued by the Sponsor.
The following actions must be taken in relation to a subject who fails to attend the site for 
a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as 
soon as possible. 

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
The site must counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether the subject wishes to 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 
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”. 
5.4.1.
Liver Chemistry Stopping Criteria
There is no IMP in this study therefore there are no liver chemistry stopping or increased 
monitoring criteria.
5.4.1.1.
Study Treatment Restart or Rechallenge
Not Applicable
5.4.2.
QTc Stopping Criteria
There is no IMP in this study therefore there are no QTc stopping criteria for this study.
5.5.
Subject and Study Completion
A completed subject is one who has completed all phases of the study including the 
Follow up.
The end of the study is defined as the last subject’s last visit.
6.
STUDY TREATMENT
6.1.
Investigational Product or other Study Treatment
There is no IMP in this study.  Imaging agents are listed in Table 1.

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Table 1
Study Treatments
Study Treatment
Product name:
(Generic name and trade)
18F-FDG
(Group B only)
11C-MET
Gadoterate meglumine 
(Dotarem)
[Formulation description:]
Refer to the summary 
of product 
characteristics 
(SmPC).
In accordance with EU 
Pharmacopoeia.
Refer to SmPC.
Dosage form:
Refer to SmPC.
Refer to study 
procedures manual 
(SRM)
Refer to SmPC.
Unit dose strength(s)/Dosage 
level(s):
200MBq.
500MBq.
Dose less than or equal to 
0.1mmol/kg
Route of administration
For IV injection
For IV injection
For IV injection
Dosing instructions:
Refer to SmPC
Please refer to SRM
Please refer to SmPC
Physical description:
Refer to SmPC
Refer to SmPC
Refer to SmPC
Method for individualizing 
dosage:
None
None
Dose on mg/kg basis.
6.2.
Blinding
This will be an open-label study.
6.3.
Packaging and Labelling
18F-FDG and DOTAREM will be purchased from commercial suppliers.  11C-MET will 
be produced by Imanova, and the contents of the label will be in accordance with all 
applicable regulatory requirements.
6.4.
Preparation/Handling/Storage/Accountability
Imaging agents will be prepared, handled and stored according to product labels, where 
available, and applicable regulatory requirements. 
6.5.
Treatment of Study Treatment Overdose
Imaging agent overdose will be managed according to product labels, where available, 
and local SOPs.
6.6.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study because no medicinal products are being investigated in this study.
The investigator is responsible for ensuring that consideration has been given to the 
post-study care of the subject’s medical condition.

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6.7.
Lifestyle and/or Dietary Restrictions

Subjects should refrain from alcohol in the 24 hours prior to all study visits.

Subjects will be asked to eat a meal prior to the 11C-MET scan in order to stimulate 
salivary gland function (details in SRM). Subjects should advise of any dietary 
restrictions so that a suitable meal can be organised (or if necessary can bring their 
own food by arrangement).

Group B (pSS) patients will be asked to fast (with the exception of unflavoured 
water), for a minimum of 6 hours prior to the 18F-FDG PET/CT scan.

At the Screening/Baseline visit and Visit 2, the following restrictions apply, until 
after the collection of tears, saliva and plasma samples:
-
Subjects should fast for a minimum of 6 hours (with the exception of unflavoured
water) until after sample collection.
-
Subjects will be required to withhold dosing with oral muscarinic agonists (such 
as pilocarpine and cevimiline) in the 12 hours prior to the Screening/Baseline 
visit and Visit 2.
-
For at least 2 hours prior to saliva collection, subjects should not brush their teeth 
or use oral hygiene products (including saliva substitutes or oral gels) or chewing 
gum, and not smoke.
-
Subjects should not use topical eye drops for 2 hours prior to tear collection until 
after tear collection.
-
Not apply eye makeup on the day of the visits, until after the tear collection.
-
Not wear contact lenses on the day of the visits, until after the tear collection.
6.7.1.
Contraceptive Requirements
6.7.1.1.
Female Subjects
Refer to eligibility criterion number 9 and Section 12.3 (Appendix 3: Modified List of 
Highly Effective Methods for Avoiding Pregnancy in FRP and Collection of Pregnancy 
Information). The allowed methods of contraception are only effective when used 
consistently, correctly and in accordance with the product label.  The investigator is 
responsible for ensuring subjects understand how to properly use these methods of 
contraception.
6.7.1.2.
Male subjects
There are no contraceptive requirements for male subjects in this study.

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6.8.
Concomitant Medications and Non-Drug Therapies
6.8.1.
Permitted Drug Therapies (Group B: Primary Sjögren’s Syndrome 
Subjects)

Stable doses of potentially immunomodulatory treatments are permitted (stable 
from 6 weeks prior to screening until follow up).  This includes potentially disease 
modifying drugs such as glucocorticoids, immunosuppressive agents (eg
hydroxychloroquine, azathioprine, methotrexate, mycophenolate mofetil, and 
biologic therapies).  The investigator should discuss drug therapies with the 
Medical Monitor if they have any safety concerns or are unsure about the potential 
impact on the scientific validity of the study data.

Topical symptomatic therapies (such as [a] non-medicated ocular topical drops: 
saline or glucane; [b] non-pharmacologic oral topical agents: chewing gum, saliva 
substitutes) are permitted. Subjects will be required to withhold dosing with these 
agents in the 2 hours prior to collection of saliva and tear samples at 
Screening/Baseline visit and Visit 2.

Oral muscarinic agonists (such as pilocarpine and cevimiline) are permitted.  
Subjects will be required to withhold dosing with these agents in the 12 hours
prior to the Screening/Baseline visit and Visit 2.

Anticholinergic agents, such as tricyclic antidepressants, buproprion, 
antihistamines, phenothiazines, antiparkinsonian drugs, anti-asthmatic 
medications, or gastrointestinal medications that cause xerostomia in more than 
10% of patients are permitted provided that a subject is on a stable regimen for at 
least 4 weeks prior to Screening/Baseline visit until follow up has been 
completed.
6.8.2.
Prohibited Medications and Non-Drug Therapies
Group A:  Healthy Volunteers

Healthy volunteers are to refrain from taking prescription or non-prescription 
drugs (including vitamins and dietary or herbal supplements), within 7 days prior 
to Visit 1 until after Visit 2, unless in the opinion of the investigator and Sponsor 
the medication will not interfere with the study. 
Group B: Primary Sjögren’s Syndrome Subjects

Treatment with anti-coagulant medications, including but not limited to warfarin, 
heparin, thrombin inhibitors, and Factor Xa inhibitors, and aspirin, unless the 
subjects are able to discontinue these medications one week prior to minor 
salivary gland biopsy (Visit 2), or according to local guidelines.  The treatment 
may be restarted 3 days after the biopsy, or according to local guidelines.

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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 tables, is 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 Table 2 and Table 3
The change in timing or addition of time points for any planned study assessments must 
be documented in a Note to File 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 Institutional Review Board (IRB)/Independent Ethics Committee (IEC) will be 
informed of any safety issues that require alteration of the safety monitoring scheme or 
amendment of the ICF. 
No more than 500 mL of blood will be collected over the duration of the study, including 
any extra assessments that may be required.

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7.1.
Time and Events Table
Table 2
Time and Events Table – Screening and Baseline Assessments
Procedure
Screening/Baseline
Visit
Baseline 2 
(FRP only)
Within 4-7 days prior to 
Visit 1
Informed consent
X
Inclusion and exclusion criteria
X
Demography
X
Medical history including past and current 
medical conditions
X
Full physical exam (including height and weight)
X
MRI safety questionnaire
X
Vital signs
X
Concomitant medication review
X
ESSDAI
X1
ESSPRI
X1
Oral dryness numerical rating
X1
Ocular dryness numerical rating
X1
Patient global assessment 
X1
Physician’s global assessment
X1
Basal salivary flow
X
Stimulated salivary flow (including saliva 
collection)
X
Schirmer’s test (including tear collection)
X
Plasma metabolomics/proteomics
X
Haematology/clinical chemistry [see Table 4]
X
Blood biomarkers for ESSDAI  
[see Table 4]
X1
Autoantibody screen (anti-Sjögren’s-syndrome-
related antigen A [Anti-SSa], anti Sjögren's 
syndrome type B [SSb])
X1
FSH/oestradiol (post-menopausal women only)
X
Serum pregnancy test (FRP)
X2
Urine pregnancy test( FRP)
X2
Urinalysis
X3
AE = adverse event; FSH = follicle stimulating hormone; MRI = magnetic resonance imaging; FRP = females of 
reproductive potential; .ESSDAI = European League Against Rheumatism (EULAR) Sjögren's Syndrome Disease 
Activity Index; ESSPRI =EULAR Sjögren's Syndrome Patient Reported Index
1.
pSS subjects only
2.
Females of reproductive potential only.
3.
Urine to be sent for urine protein:creatinine ratio if ≥trace proteinuria by dipstick.

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Table 3
Time and Events Table – Study Assessments
Procedure
Visit 1
Visit 2
Follow up
Within 6 weeks after baseline 
(4-6 weeks for FRP)
Within 3 weeks after Visit 1
Within 2 weeks after Visit 2
MRI safety questionnaire5
X
Vital signs
X
X
Concomitant medication review
X
X
Basal salivary flow
X
Stimulated salivary flow (including saliva collection)
X
Schirmer’s test (including tear collection)
X
Plasma metabolomics/proteomics
X
Urine pregnancy test (FRP)
X1
X1
Multi-parametric MRI scan (including contrast)
X
Meal prior to 11C-MET PET/CT
X
Intravenous injection of 11C-MET PET tracer
X
11C-MET PET/CT scan (dynamic and static)
X
Radio-PK (11C-MET) sampling (dynamic scan)
X2
Measure concentration of 11C-MET tracer in blood
X3
Blood glucose (bedside glucometer)
X4
Injection of 18F-FDG tracer
X4
18F-FDG PET/CT scan
X4
Measure concentration of 18F-FDG in blood
X3,4
Salivary gland biopsy
X4
AE review
X
AE = adverse event; CT = computed Tomography; FDG = flurodeoxyglucose; FRP = females of reproductive potential; FSH = follicle stimulating hormone; MET = methionine; MRI = 
magnetic resonance imaging; PET = positron emission tomography; PK = pharmacokinetics;.
1.
Females of reproductive potential only
2.
Radio-PK sampling (5mL per sample) to be taken at 1, 2, 5, 10, 15, 20, 30 and 40 minutes after injection of 11C-MET PET tracer (number and sampling times are 
subject to change dependent on emerging data, but no more than 100 mL overall will be taken).
3.
To be taken within 5 minutes after the static PET/CT scan (exact time to be recorded).
4.
pSS subjects only
5.
The MRI safety questionnaire will not be databased

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7.2.
Screening and Critical Baseline Assessments
7.2.1.
For all subjects:
Information collected during the Screening/Baseline assessments described below 
represents key data that identifies and defines subject baseline status. This information is 
critical for the evaluation and comparison of subsequent imaging assessments.  
Additional assessments will be performed as detailed in the Time and Events tables, 
Table 2 and Table 3.
Informed Consent: Informed consent will be obtained from the subject prior to the 
initiation of any study procedures or study-specific data collection.  Subjects who give 
written informed consent will undergo screening assessments within 42 days (28-42 days 
for FRP) prior to Visit 1.  At screening the following assessments will be performed.
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 5.1 and Section 5.2.  A complete medical history will be taken at 
the screening visit.  Information from the medical history is important to establish the 
baseline condition of the subject.  Any significant medical conditions affecting the 
subject in the past 5 years should be recorded on the Medical Conditions page of the 
eCRF.  The history should include the following (where applicable, for Group A or 
Group B):

Past or current conditions, including Sjögren’s syndrome history.

Prior surgical procedures.

Pharmacotherapy and chronic or recent use of any medication or herbal 
preparation.

Prior immunosuppressive therapies, including type, number, and duration.

Allergies and significant allergic reactions.

Significant infections (requiring inpatient treatment, or history of recurrent 
infection, including urinary and respiratory tract infections).

Smoking history (current or previous smoker, number of cigarettes smoked per 
day).

Cardiovascular medical history/risk factors (as detailed in the eCRF).
Serum and urine pregnancy test: A test will be performed for women of child-bearing 
potential at Screening/Baseline.  A urine pregnancy test will be repeated 4 to 7 days prior 
to Visit 1.
Full physical examination: will include complete assessment of all organ systems 
including assessments of the head and neck (including eyes, ears, nose, throat, and 
thyroid gland), skin, musculoskeletal (including evaluation of both small and large 
joints), neurological, respiratory, and cardiovascular systems, gastrointestinal system and 
abdomen (including liver and spleen), lymph nodes and extremities.

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Urinalysis: will be performed as related to the eligibility criteria listed in Section 5.1 and 
Section 5.2.
In addition, urinalysis will be performed in subjects included in Group B in order to 
calculate the ESSDAI score.  If proteinuria is detected on dipstick (≥trace), quantification 
of the spot urine protein:creatinine ratio will be needed in the laboratory to calculate the 
ESSDAI score.
Haematology (including coagulation screen) and blood chemistry (clinical safety 
laboratory assessments): will be performed as related to the eligibility criteria listed in 
Section 5.1 and Section 5.2.
Female subjects:  
FSH and oestradiol (females of non-reproductive potential only).
Serum hCG (at screening only) and urine hCG pregnancy test at other times as required
(for females of reproductive potential).
Estimated Glomerular filtration rate (eGFR): will be calculated using the 
modification of diet in MDRD formula.
Unstimulated and stimulated salivary flow: Salivary flow rate will be assessed as an 
eligibility criterion for pSS subjects and a baseline procedure for all subjects.  Subjects 
with 0.0mL/min unstimulated salivary flow rate may qualify for the study if their 
stimulated salivary flow is greater than 0.05mL/min. Details of the collection procedure 
will be further specified in the SRM.
Schirmer’s test: This is an assessment of lacrimal gland function as a baseline procedure 
in which a strip of filter paper is applied under the eyelid to measure the quantity of tear 
production.  The technique for administration of this test will be described in the SRM.
MRI safety questionnaire: in order to confirm eligibility for the MRI scan.
7.2.2.
Additional baseline procedures for Group B subjects only (pSS
Subjects)
American European Consensus Group (AECG) criteria: The 2002 American
European Consensus Group criteria [Vitali, 2002] will be evaluated by the investigator to
verify the subject’s diagnosis of Primary Sjögren’s Syndrome.  The AECG criteria
provide an assessment of six different parameters including: oral and ocular symptoms,
oral and ocular signs, and objective measures of histopathology and biomarkers.
ESSDAI: subjects are required to have systemically active disease as determined by an
ESSDAI score of at least 5 points.  The ESSDAI [Seror, 2014] is an assessment of 
disease activity across twelve different clinically relevant domains for subjects with 
Sjögren’s syndrome.  ESSDAI will be assessed by the investigator.  Details and guidance 
regarding the application of the ESSDAI assessment will be provided in the SRM. A 
recent user’s guide has also been published [Seror, 2014].

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ESSPRI: the EULAR Sjögren’s Syndrome Patient Reported Index [Seror, 2014] is an
assessment of the severity of patients’ symptoms in primary Sjögren’s syndrome over the
past 2 weeks, including dryness, pain (joint or muscular pains in arms or legs), and
fatigue, on a 0 to 10 Numeric Rating Scale (NRS) for each symptom.  The ESSPRI 
assessment tool will be detailed in the SRM.
Blood biomarkers (in order to confirm diagnosis and to calculate ESSDAI score: 
Quantification of serum autoantibodies (including anti-SS-A, SS-B), and immunological 
testing required for ESSDAI (including serum immunoglobulins [Total Immunoglobulin 
(Ig), IgG, IgA, IgM], protein electrophoresis, complement C3, C4 and C-reactive 
protein).  Cryoglobulin testing is only needed if required for the calculation of ESSDAI 
score.
Oral and Ocular Dryness: will be reported by subjects on a numerical rating scale from 
0 to 10.  A description of the instrument anchors and technique for administering these 
scales will be described in the SRM.
Physician global assessment of disease activity: the Physician Global Assessment is a 
physician reported visual analogue scale that provides an overall measure of disease 
severity.  The assessment instrument and technique for administration will be described 
in the SRM.
Patient global assessment of disease activity: the Patient Global Assessment is a patient 
reported visual analogue scale that provides an overall measure of disease severity.  The 
assessment instrument and technique for administration will be described in the SRM.
7.3.
Safety
Planned time points for all safety assessments are listed in the Time and Events tables 
(Table 2 and Table 3 ).  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 and SAE can be found in Section 12.2.
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 (eg protocol-mandated 
procedures, invasive tests, or change in existing therapy) 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 Visit 1 until the follow up contact (see 
Section 7.3.1.4), at the time points specified in the Time and Events Tables (Table 
2 and Table 3).

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
Medical occurrences that begin prior to Visit 1 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 
Section 12.2 (Appendix 2: Definition of and Procedures for Recording, 
Evaluating, Follow up and Reporting of Adverse Events).

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 
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 2.
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 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 Section 12.2 (Appendix 2: Definition of and Procedures for Recording, 
Evaluating, Follow up and Reporting of Adverse Events).
7.3.1.4.
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. 
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.  An IMP 
will not be administered to the subjects in this study.  GSK will comply with country 

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specific regulatory requirements relating to safety reporting to the regulatory authority, 
IRB/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 (eg summary or listing of SAEs) from GSK will file it with 
the Investigator Brochure (IB) and will notify the IRB/IEC, if appropriate according to 
local requirements.
7.3.2.
Pregnancy
Details of all pregnancies in female subjects will be collected from Visit 1 and until 
follow up.
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 Section 12.3
(Appendix 3: Modified List of Highly Effective Methods for Avoiding Pregnancy in FRP 
and Collection of Pregnancy Information).
7.3.3.
Vital Signs
Single assessment of vital signs will be performed at the times indicated in the Time and 
Events Tables (Table 2 and Table 3).  Vital signs will be measured in the semi-supine
position after 5 minutes rest and will include temperature, systolic and diastolic blood 
pressure and pulse rate and respiratory rate. 
7.3.4.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 4 must be conducted in 
accordance with the Laboratory Manual, and the Protocol Time and Events Schedule
(Table 2 and Table 3). 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 of samples are detailed in the SRM.
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 (eg SAE or AE) the results must be 
recorded in the CRF.

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Haematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed in Table 4.
Table 4
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Full blood count indices
Red blood cell count
Indices:
White blood cell count 
with Differential:
White blood count
Mean corpuscular volume
(MCV)
Neutrophils
Platelet Count
Mean corpuscular 
haemoglobin 
Lymphocytes
Haemoglobin
Mean corpuscular 
haemoglobin 
concentration
Monocytes
Haematocrit
Eosinophils
Coagulation screen
Basophils
Prothrombin time,
Activated partial 
thromboplastin time 
Thrombin time
Clinical 
Chemistry
Urea
Potassium
Aspartate aminotransferase
Total and direct 
bilirubin
Creatinine
Sodium
Alanine aminotransferase 
Total Protein
Glucose 
(fasting for 
6 h 
[excluding 
unflavoured 
water])
Calcium
Alkaline phosphatase
Albumin
Creatine 
kinase
C-reactive 
protein
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood and ketones by dipstick

Microscopic examination (if blood or protein is abnormal) and send urine for 
spot urinary protein:creatinine ratio
Other Screening 
Tests

Follicle-stimulating hormone and oestradiol (as needed in females of 
reproductive potential only)

Serum human chorionic gonadotropin (hCG) [at screening only] and urine hCG 
pregnancy test (as needed for females of reproductive potential)

Group B only: anti-Sjögren’s-syndrome-related antigen A (Anti-SSa), 
anti-Sjögren's syndrome type B (SSb), total immunoglobulin (Ig), IgG, IgA, IgM, 
serum protein electrophoresis, complement C3, C4

Optional additional tests in Group B (if needed for calculation of ESSDAI):
cyroglobulins, urinary protein creatinine ratio (if dipstick ≥trace protein).

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
Estimated glomerular filtration rate will be calculated using the modification of 
diet in renal disease (MDRD) formula.
NOTES :
European League Against Rheumatism (EULAR) primary Sjögren's syndrome disease activity 
[ESSDAI]
Safety laboratory tests are only conducted at screening in this study.  Subjects with values 
that are considered clinically significantly abnormal will be assessed according to the 
inclusion/exclusion criteria.  In the event of clinically significant laboratory values the 
investigator will advise the subject of appropriate clinical care.
7.4.
Imaging Procedures
7.4.1.
PET Imaging Procedure
Positron Emission Tomography scans will be acquired on a PET/CT scanner at the 
imaging centre.  The details of the PET imaging procedure, image processing and 
analysis will be provided by the imaging centre in a PET Imaging Manual.
Subjects will be given a meal before the 11C-MET tracer injection to stimulate salivary 
gland function.
Prior to the commencement of the PET scan a venous cannula will be inserted into the 
subjects arm for administration of 18F-FDG or 11C-MET.  An additional venous cannula 
will also be inserted prior to the scan start from which blood samples will be collected at 
the time points described in the Time and Events tables Table 2 and Table 3.  The subject 
will be positioned in the scanner and sufficient padding will be used to minimize 
movements during image acquisition.  The subject will be monitored continuously by a 
qualified PET technician.
For 11C-MET PET scanning, a low-dose CT attenuation scan centred on the salivary 
glands will be performed for subsequent attenuation and scatter correction of the PET 
data. Thereafter, the PET scan will commence with an intravenous bolus administration 
of 11C-MET (500 MBq) and dynamic scanning of the salivary gland region for 
approximately 40 minutes.  The static scan will follow (within approximately 5 minutes) 
with the whole body CT followed by the PET covering the head to hip with a duration of 
same range for approximately 20 to 30 minutes.
For 18F-FDG PET scanning, scanning will start 60 minutes after intravenous bolus 
administration of 200 MBq of 18F-FDG. Blood glucose (bedside glucometer) will be 
measured before injection of 18F-FDG tracer. If the glucometer blood glucose is greater 
than 11.1mmol/l, the 18F-FDG cannot be injected, and it will be necessary to reschedule 
the scan. Advice for Investigators regarding diabetics on oral hypoglycaemic agents will 
be described in the SRM, and the scan will be scheduled in the morning for these subjects 
wherever possible. Firstly, a low-dose CT attenuation scan of the area to be scanned 
(head to hip) will be performed. Thereafter, the PET scan will commence with static 
scanning acquired for up to 30 to 40 minutes.

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After the PET scans, a blood sample will be taken for measurement of radioactivity in 
blood and plasma (See Section 7.6).
After the scan the subjects will be allowed home at the discretion of clinical staff at the 
imaging facility.
7.4.2.
MRI Imaging Procedure
As part of the study, eligible subjects will undergo multi-parametric MRI scanning, 
including administration of a gadolinium based contrast agent at the imaging centre to 
assess salivary gland inflammation, function and structure in pSS subjects and healthy 
volunteers.  Additionally, the images may be used to identify and delineate the 
anatomical Regions of Interest (ROI) for individual PET images and to aid in image 
analysis.  
On attendance at the MRI department, subjects will be placed in the scanner and will be 
prepared for intravenous contrast agent administration.  The scanning protocol will
include routine localizers, T1 measurement sequences, DCE-MRI acquisition, DW-MRI 
acquisition, and additional exploratory MRI endpoints, as detailed in the Imaging 
Acquisition Manual.  The total scan time should not exceed 1 hour.
If a scanning failure occurs, if feasible a rescan is allowed within 7 days after the failed 
scan.  There will be a minimum of 24 hours between scans where gadolinium contrast is 
used. 
7.5.
Image Analysis
All MRI and PET scans will be available at site, and will be reported at the site by a 
radiologist for clinical abnormalities per local standard procedures.  If a significant 
clinical abnormality is identified that requires further investigation, the Investigator will 
be informed such that they can arrange appropriate investigations and medical care of the 
subject.
7.5.1.
PET Image Analysis
Following reconstruction, scatter correction and attenuation correction, the PET data will 
be corrected for motion (if required) and if possible co-registered to each subject’s 
structural MRI image.  Anatomic regions of interest (ROIs) will be defined using a 
combination of each subject’s PET/CT and MRI.  Those ROIs will then be applied to the 
PET emission data to derive decay-corrected regional time-activity curves.  
For the static head to hip 18F-FDG and 11C-MET scans, semi quantitative imaging 
outcome parameters (including standardized uptake value) will be generated from the 
decay corrected single time point activity measurement.
The primary structures to be included in the analysis include the different salivary glands, 
lymph nodes and pancreas whenever feasible with respect to size and signal intensity. 
Specific areas of increased FDG uptake in different areas of the body, for example 
including but not limited to the lungs will also be recorded and measured when possible.

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Regions in normal structures like liver and blood pool in aorta may be included.
For the dynamic 11C-MET scan, a radiometabolite-corrected plasma input function will 
be generated for each subject.  The decay corrected time-activity curves will be analysed 
using a range of kinetic models including compartmental models and reference tissue 
models if a valid reference region is available in the field of view of the scan.  The 
primary image outcome parameters will depend on the kinetics of the tracer in the region 
of interest and will be decided using quantitative criteria of model selection.
7.5.2.
MRI Image Analysis
Reconstructed MR images for the various sequences will first be corrected for geometric 
distortion and subject motion, as needed and appropriate.  Quality assurance procedures 
may be followed to assert image-characteristic consistency over the course of the study. 
These procedures may include checks on imaging metadata, as well as checks on the 
image data itself.  Anatomical ROIs will be defined on structural MR imaging for 
salivary glands including both parotids glands and other major salivary glands if possible.
For the gadolinium enhanced perfusion sequence, a multiparametric model will be fitted 
for subject and for each point in the anatomical ROIs.  This model will describe the 
wash-in of contrast medium following injection, the efflux of contrast medium from the 
capillaries to the extravascular space, and finally the wash-out of the medium from the 
tissue.  The parametric maps obtained from the model, including maps for Ktrans, IRE 
and ME may then be used to calculate aggregate measurements per ROI. 
Similarly, imaging data for the diffusion sequence will also be used to fit a 
multiparametric model.  This model will describe the total diffusion of water as a 
composition of pure water diffusion and pseudo diffusion, ie the incoherent motion of 
water molecules due to capillary blood flow.  Again, parametric maps, including maps for 
ADC, D and f may be used to compute aggregate measurements for each of the ROIs.  
To investigate the complimentary relation between both imaging models, various 
combined models may be explored.  This may include model based approaches such as 
alternative diffusion models that are informed by the tracer kinetic DCE model, but may 
also include data driven approaches such as higher level statistical analyses that are based 
on the parametric maps of both primary models. 
These complimentary models are exploratory, but have the potential to generate outcome 
measures for future trials.
7.6.
Pharmacokinetics
7.6.1.
Blood sample collection and 11C-Met radio PK analysis
Blood sample collection and analysis will be performed at Imanova Ltd.
Static 18F-FDG and 11C-MET acquisitions: At the end of each PET/CT scan, a single 
venous blood sample (3 mL) will be acquired for determination of whole blood and 
plasma radioactivity concentration.

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Dynamic 11C-MET acquisition: During the dynamic 11C-MET PET acquisition, venous 
blood samples will be collected. Blood will be drawn in 5mL volumes at 1, 2, 5, 10, 15, 
20, 30 and 40 minutes after injection of PET tracer.  Sampling times and number of 
samples are subject to change, dependant on emerging data, but no more than 100 mL 
overall will be taken.  The details of the time windows for the collection of these blood 
samples will be included in the SRM.
Tracer radioactivity concentration will be measured in plasma and whole blood, using a 
counter previously cross-calibrated with the scanner.  In addition, metabolite analysis will 
be conducted on the plasma samples via High Performance Liquid Chromatography 
(HPLC). The timing of pharmacokinetics (PK) samples may be altered and/or PK 
samples may be obtained at additional time points to ensure thorough PK monitoring. In 
all instances, the actual time of each blood sample collection will be recorded. Blood 
samples collected during PET/CT imaging will be analysed immediately, and will not be 
stored. Processing and storage procedures are provided in the SRM.
7.7.
Salivary gland biopsy (Group B)
A minor salivary gland biopsy will be performed on Visit 2 (pSS subjects only).  The 
salivary gland biopsy surgical technique and sample handling will be described in the 
SRM and a training video will be made available with details of the procedure.  Biopsy 
tissue will be shipped to a histopathology laboratory for processing and assessment.  
Histological assessments performed on salivary gland tissues will be conducted as 
described in Section 7.8.1.3.
7.8.
Biomarker(s)/Pharmacodynamic Markers
7.8.1.
Novel Biomarkers
7.8.1.1.
Metabolomic Research
Biofluid (saliva, tears and plasma) metabolome studies may be performed by nuclear 
magnetic resonance spectroscopy (NMR), mass spectrometry (MS, Liquid 
Chromatography [LC]-MS, Gas Chromatography [GC]-MS and/or Fourier Transform 
[FT]/MS) and/or equivalent methods.  This may be done to compare the metabolome of 
pSS subjects with healthy volunteers, as well as to assess the variability in the 
metabolome and/or proteomic profile of individual subjects taken at 2 separate time 
points (Baseline and Visit 2).  A comparison of the metabolomic and/or proteomic profile 
from different body fluids (saliva, tears and plasma), and their utility in distinguishing 
pSS subjects from healthy volunteers may also be investigated.  Associations between the 
metabolome data with proteomic data, clinical, serum biomarker, histological and 
imaging parameters may be studied.
7.8.1.2.
Proteome Research
Biofluid (saliva, tears and plasma) proteome studies may be performed by 2-D gel 
separation, and/or peptide mass mapping, or an alternative equivalent procedure.  These 
differentially expressed proteins may be identified by mass spectrometry or equivalent 
technology.  Intra-subject variability may be assessed by comparing the proteomic profile 

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of individuals at two different time points (Screening/Baseline and Visit 2).  Comparisons 
may be made between the proteomic profiles of pSS subjects and healthy volunteers.  
Association of the observed proteomic parameters with clinical, imaging and 
immunological, serum biomarker, metabolome and histological parameters may be 
performed.  Samples for longitudinal analysis will be collected and stored as described in 
the SRM and may be analysed at the end of the study.
The same samples may also be used to confirm findings by application of alternative 
technologies.
7.8.1.3.
Salivary gland histological assessment
Histological assessments of salivary gland tissue will include a determination of 
lymphocyte infiltrate by Immune Histochemistry (IHC) (B and T cell subsets) and
assessed through haematoxylin and eosin staining for foci scoring.  The IHC assessment 
may include, (but not be limited to): B cell markers: CD20, IgG, IgM, IgA and CD38; 
T cell markers: CD3; markers of germinal centre formation: CD21 and markers of 
dividing cells: Ki67.  Confocal microscopy or other specialist imaging techniques may be 
employed to image immunofluorescence stained sections.
8.
DATA MANAGEMENT

For this study subject data will be entered into GSK defined eCRFs, transmitted 
electronically to GSK or designee and combined with data provided from other 
sources in a validated data system.  

Management of clinical data will be performed in accordance with applicable 
GSK standards and data cleaning procedures to ensure the integrity of the data, 
e.g., removing errors and inconsistencies in the data.

Adverse events and concomitant medications terms will be coded using Medical 
Dictionary for Regulatory Activities (MedDRA) and an internal validated 
medication dictionary, GSKDrug.  

Case report forms (including queries and audit trails) will be retained by GSK, 
and copies will be sent to the investigator to maintain as the investigator copy.  
Subject initials will not be collected or transmitted to GSK according to GSK 
policy.
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1.
Hypotheses
This study is designed to explore the use of 18F-FDG PET/CT, 11C-MET PET/CT, and 
multi-parametric MRI in pSS subjects and/or healthy volunteers. Due to the exploratory 
nature of this study, there are no formal hypotheses being tested. 
For 11C-MET PET/CT and multi-parametric MRI, summary statistics will be used to 
interpret each derived parameter.  An exploratory comparison of pSS subjects vs healthy 

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volunteers may performed for each 11C-MET PET/CT and multi-parametric MRI derived 
quantitative parameter as data permits, to estimate difference (or ratio if log 
transformation is needed) with 95% confidence interval. 
For 18F-FDG PET/CT where only pSS subjects will be scanned, summary statistics will 
be used to present each derived parameter.
9.2.
Sample Size Considerations
This is an exploratory study and therefore no formal sample size calculations have been 
conducted.  Sample size is primarily driven by feasibility and knowledge of disease 
heterogeneity to sufficiently evaluate the primary and supportive secondary objectives of 
the study. 
Group A: Healthy Volunteers:
Approximately 4 to 12 subjects will be recruited.  After approximately 4 subjects have 
been scanned, the variability in the imaging parameters will be assessed, after which up 
to 8 additional subjects may be recruited as following: a maximum of an additional 4 for 
11C-MET PET/CT plus MRI (total maximum of 8 subjects for 11C-MET PET/CT), with 
the option for 4 extra for MRI only (total maximum of approximately 12 subjects for 
MRI).  
Group B: Primary Sjögren’s Syndrome Subjects
Approximately 8 to 12 pSS subjects will be recruited.  Due to anticipated greater 
variability amongst patients, the variability of the imaging parameters will be assessed 
after approximately 8 subjects have been recruited, and consequently up to an additional 
4 subjects may be recruited.
Following a literature review the following information was obtained for the imaging 
modalities of interest in the parotid glands in different populations.  This historical
information can be used in the variability assessment as outlined above.
Imaging 
modality; 
Parameter
Healthy
Volunteers
Mean [SD]
Patients
(not pSS)
Mean [SD] n
Patients
(pSS)
Mean [SD] n
Reference
18F-FDG PET; 
SUVmax
n/a
1.80
[0.53] n=25
n/a
Basu, 2008
18F-FDG PET; 
SUVmax
n/a
2.00
[not stated]
2.75
[0.61] n=32
Cohen, 2013
18F-FDG PET; 
SUV 
n/a
1.90
[0.68] n=78
n/a
Nakamoto, 2005
11C-MET PET; 
SUVmax
6.00
[1.5] n=11
n/a
n/a
Isohashi 2013
DCE MRI, Ktrans
0.20
[0.04] n=11
n/a
0.26
[0.05] n=21
Roberts, 2008
SD=Standard Deviation

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Using estimates of parameter (this can be any parameter, SUVmean, SUV, Ktrans) 
variability, the precision of these estimates calculated as half width of a 95% confidence 
interval for the mean and expressed as distance from mean to limits, for 4, 8 and 12 
subjects has been calculated (Table 5). 
Table 5
Estimated Precision for the Mean of an Imaging Parameter
SD
Precision of Mean
N=4
N=8
N=12
0.05
0.08
0.04
0.03
0.5
0.80
0.42
0.32
1
1.59
0.84
0.64
1.5
2.39
1.25
0.95
For example, based upon the estimate of variability of 1 and a sample size of 12, it is 
estimated that the lower and upper bounds of the 95% confidence interval for the means 
of the imaging parameter (e.g. SUVmean, SUV, Ktrans) will be within approximately 0.62 
of the point estimate.
9.2.1.
Sample Size Sensitivity
No sample size sensitivity has been performed.
9.2.2.
Sample Size Re-estimation or Adjustment
The variability of healthy volunteers will be assessed for the 11C-MET PET/CT and 
multi-parametric MRI imaging modalities after approximately 4 healthy volunteers have 
been scanned, and with the aid of precision estimates for the observed variability outlined 
in Table 5, a recommendation may be made to increase the total healthy volunteers 
sample size to up to 8 (for both PET/CT and MRI).  In this event, a further review of the 
multi-parametric MRI results may be performed after 8 healthy volunteers and a 
recommendation made to increase to a total of 12 for this imaging modality only. For 
feasibility reasons in the interests of limiting the exposure of healthy volunteers to 
radiation, a cap of 8 healthy volunteers is set for PET/CT.
Similarly the variability of pSS subjects will be assessed for the 11C-MET PET/CT, 18F-
FDG PET/CT and multi-parametric MRI imaging modalities after approximately 8 pSS 
subjects have been scanned, and with the aid of precision estimates for the observed 
variability outlined in Table 5, a recommendation may be made to increase the total pSS 
subjects to 12.  
For both groups, if sufficient data is collected for one or both PET/CT techniques, but not 
the other assessments (for example MRI), the additional subjects will only undergo the 
investigations needed (eg MRI and Visit 2 procedures without one or both PET/CT 
techniques), in order to minimize radiation exposure.

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9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations
Population 
Definition / Criteria 
Safety 

Comprised of all subjects who receive/undergo any Visit 1 procedure.
Pharmacokinetic (PK)

Subjects in the ‘Safety’ population for whom a radio-pharmacokinetic 
sample was obtained and analysed. 
Additional analysis population(s) maybe defined in the Reporting and Analysis Plan 
(RAP).
9.3.2.
Interim Analysis
No formal interim analysis will be performed, however a review of the imaging results 
will be performed for sample adjustment depending on the variability of the data as 
described in Section 9.2.2.
9.4.
Key Elements of Analysis Plan
9.4.1.
Primary analyses
Data for FDG PET/CT will be listed and summarized by quantitative parameter and 
Region of Interest (ROI).  The data will be further explored graphically to examine:

The parameter values across relevant ROI for each pSS subject

The between-subject variability in parameter values by ROI

Summary measures calculated across all relevant ROI (eg. maximum uptake, 
average uptake, total inflammatory volume, total number of lesions) and how 
these summary measures vary between patients.

Asymmetry in parameter values between left and right parotid glands
Similar analyses may be performed for quantitative data from 11C-MET PET/CT and 
multi-parametric MRI.  For those imaging modalities, both HV and pSS are scanned, 
such that all displays will additionally denote group.  An exploratory comparison of pSS 
vs HV may be performed for each quantitative parameter as data permit, to estimate a 
difference (or ratio if log transformation is needed) with 95% confidence interval.  
Further details are outlined in the reporting analysis plan (RAP).

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9.4.2.
Secondary Analyses
Descriptive statistics and/or graphical displays will be generated for all derived 
parameters from dynamic PET imaging and PK analyses.  If data permits, statistical 
analyses of 11C-MET PET radio-PK modelling indices with 11C-MET static imaging 
matrices will be conducted to assess correlation.
9.4.3.
Other/Exploratory Analyses
Details of the planned analyses for exploratory objectives to compare imaging 
parameters, explore their potential associations and the correlation of signals to clinical 
assessment measures and laboratory markers will be defined in the RAP.
Further details of proposed analyses will be specified in the RAP.
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 enrolment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
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 International Conference for 
Harmonisation (ICH) 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 favourable opinion/approval of the study protocol and 
amendments as applicable.

Obtaining signed informed consent.

Investigator reporting requirements (eg reporting of AEs/SAEs/protocol 
deviations to IRB/IEC).

GSK will provide full details of the above procedures, either verbally, in writing, 
or both.

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.  

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
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 the 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.
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.

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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 multicentre 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 images in 
digital form will also be retained and may be used for future further analysis.
The records must be maintained to allow easy and timely retrieval, when needed (eg 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 (eg 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.
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.

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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.
Exploratory endpoints may be evaluated and reported outside the main Clinical Study 
Report.

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Buus, S., C. Grau, O. L. Munk, D. Bender, K. Jensen and S. Keiding. "11C-MET PET, a 
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Cohen, C., Mekinian, A., Uzunhan, Y., Fauchais, A., Dhote, R., Pop, G., Eder, V., Nunes, 
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emission tomography/computer tomography as an objective tool for assessing disease 
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Estimation of internal absorbed dose of L-[methyl-11C]methionine using whole-body 
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Glaudemans, A. W., R. H. Enting, M. A. Heesters, R. A. Dierckx, R. W. van Rheenen, A. 
M. Walenkamp and R. H. Slart. "Value of 11C-MET PET in imaging brain tumours and 
metastases." Eur J Nucl Med Mol Imaging 2013, 40(4): 615-635.
Gomes Pde, S., G. Juodzbalys, M. H. Fernandes and Z. Guobis. "Diagnostic Approaches 
to Sjögren's syndrome: a Literature Review and Own Clinical Experience." J Oral 
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Harris, S. M., J. C. Davis, S. E. Snyder, E. R. Butch, A. L. Vavere, M. Kocak and B. L. 
Shulkin (2013). "Evaluation of the biodistribution of 11C-MET in children and young 
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Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, editors. 
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Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, Policar MS, 
editors. Contraceptive Technology. 20th edition. Atlanta, Georgia: Ardent Media, Inc., 
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Stone and W. National Arthritis Data. "Estimates of the prevalence of arthritis and other 
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Houweling, A. C., T. Schakel, C. A. van den Berg, M. E. Philippens, J. M. Roesink, C. H. 
Terhaard and C. P. Raaijmakers. "MRI to quantify early radiation-induced changes in the 
salivary glands." Radiother Oncol 2011, 100(3): 386-389.
ICRP. Pregnancy and Medical Radiation. ICRP Publication 2000, 84. Ann. ICRP 30 (1).
ICRP. The 2007 Recommendations of the International Commission on Radiological 
Protection. ICRP Publication 103, 2007. Ann. ICRP 37 (2-4).
Isohashi, K., Shimosegawa, E., Kato, H., Kanai, Y., Naka, S., Fujino, K., Watabe, H. and 
Hatazawa, J. Optimization of [11C]-methionine PET study: appropriate scan timing and 
effect of plasma amino acid concentrations on the SUV. EJNMMI Research, 2013, 3(1), 
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Nakamoto, Y., Tatsumi, M., Hammoud, D., Cohade, C., Osman, M. and Wahl, R. (). 
Normal FDG Distribution Patterns in the Head and Neck: PET/CT Evaluation1. 
Radiology, 2005, 234(3), pp.879-885.
Roberts, C., Parker, G., Rose, C., Watson, Y., O'Connor, J., Stivaros, S., Jackson, A. and 
Rushton, V. Glandular Function in Sjögren Syndrome: Assessment with Dynamic 
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Seror R, Bootsma H, Saraux A, et al. Defining disease activity states and clinically 
meaningful improvement in primary Sjögren's syndrome with EULAR primary Sjögren’s 
syndrome disease activity (ESSDAI) and patient-reported indexes (ESSPRI). Ann Rheum 
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Su GY,  Xu XQ, Wang YY, Hu H, Shen J, Hong XN, Shi HB, and Wu FO. Feasibility 
study of using intravoxel incoherent motion MRI to detect parotid gland abnormalities in 
early-stage Sjögren syndrome patients. J. Magn. Reson. Imaging, 2015. 
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van der Aart J, Hallett WA, Rabiner EA, Passchier J, Comley. RA Radiation dose 
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doi: 10.1016/j.nucmedbio.2011.08.005. Epub 2011 Oct 26. Review.  PMID:  22033023
Vitali C., S. Bombardieri, R. Jonsson, H. M. Moutsopoulos, E. L. Alexander, S. E. 
Carsons, T. E. Daniels, P. C. Fox, R. I. Fox, S. S. Kassan, S. R. Pillemer, N. Talal, M. H. 
Weisman and S. European Study Group on Classification Criteria for Sjögren's . 

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"Classification criteria for Sjogren's syndrome: a revised version of the European criteria 
proposed by the American-European Consensus Group." Ann Rheum Dis 2002, 61(6): 
554-558.
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(WHO Technical Report Series 935). 2007, ISBN: 92 4 120935 6.
Ziakas, P. D., L. S. Poulou and L. Thanos. "Towards integrating positron emission 
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lymphomas." Autoimmun Rev 2014, 13(3): 327-329.

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12.
APPENDICES
12.1.
Appendix 1 – Abbreviations and Trademarks
Abbreviations
ADC
Apparent Diffusion Coefficient
AE
Adverse Event
AECG
American European Consensus Group
ALT
Alanine Transaminase
Anti-SSa
Anti-Sjögren’s-syndrome-related antigen A
ARSAC
Administration of Radioactive substances Advisory 
Committee
AST
Aspartate aminotransferase
BMI
Body Mass Index
CI
Confidence Interval
CONSORT
Consolidated Standards of Reporting Trials
CRF
Case Report Form
CT
Computed Tomography
CV%
Percentage Coefficient of Variation
D
Pure Diffusion Coefficient
DCE
Dynamic Contrast Enhanced
DW
Diffusion Weighted
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
ESSDAI
EULAR Sjögren's Syndrome Disease Activity Index
ESSPRI
EULAR Sjögren's Syndrome Patient Reported Index
EU
European Union
EULAR
European League Against Rheumatism
f
Microvascular Volume Fraction
FAO
Food and Agriculture Organization of the United Nations
FDG
Fluorodeoxyglucose
FRP
Females of Reproductive Potential
FSH
Follicle Stimulating Hormone
FT
Fourier Transform
GC
Gas chromatography
GCP
Good Clinical Practice
Gd
Gadolinium
GFR
Glomerular Filtration Rate
GSK
GlaxoSmithKline
hCG
Human Chorionic Gonadotropin
HRT
Hormone Replacement Therapy
HV
Healthy Volunteers
IB
Investigators Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation

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ICRP
International Commission on Radiological Protection
IEC
Independent Ethics Committee
Ig
Immunoglobulin
IHC
Immune Histochemistry
IMP
Investigational Medicinal Product
INR
International Normalized Ratio
IRB
Institutional Review Board
IRE
Initial Rate of Enhancement
IV
Intravenous
IVIM
Intravoxel Incoherent Motion
Ktrans
Exchange Rate
M
Meter
MedDRA
Medical Dictionary for Regulatory Activities
ME
Maximal Signal Intensity Enhancement
MET
Methionine
MRI
Magnetic Resonance Imaging
MS
Mass Spectroscopy
mSv
Millisievert
NRS
Numeric Rating Scale
PET
Positron Emission Tomography
PK
Pharmacokinetic
pSS
Primary Sjögren’s Syndrome
RAP
Reporting Analysis Plan
ROI
Region of Interest
SAE
Serious Adverse Event
SD
Standard Deviation
SmPC
Summary of Product Characteristics
SPC
Summary of product characteristics
SRM
Study Reference Manual
SSb
anti Sjögren's syndrome type B
TIV
Total Inflammatory Volume
UK
United Kingdom
ULN
Upper Limit of Normal
UNU
United Nations University
WHO
World Health Organisation
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
Dotarem

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12.2.
Appendix 2: Definition of and Procedures for Recording, 
Evaluating, Follow up and Reporting of Adverse Events
12.2.1.
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 unfavourable 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 (haematology, clinical chemistry, or urinalysis)
or other safety assessments (e.g. electrocardiograms (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).

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE.  However, the signs and symptoms and/or clinical 
sequelae resulting from lack of efficacy will be reported if they fulfil the definition 
of an AE or SAE.

The signs and symptoms and/or clinical sequelae resulting from lack of efficacy will 
be reported if they fulfil the definition of an AE or SAE.  Also, "lack of efficacy" or 
"failure of expected pharmacological action" also constitutes an AE or SAE.
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 

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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).

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.
12.2.2.
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:
c.
Results in death
d.
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.
e.
Requires hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting.  Complications that occur during hospitalization are 
AEs.  If a complication prolongs hospitalization or fulfils any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.

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f.
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, diarrhoea, influenza, 
and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday 
life functions but do not constitute a substantial disruption
g.
Is a congenital anomaly/birth defect
h.
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
i.
Is associated with liver injury and impaired liver function defined as:

Alanine Transaminase (ALT) 3x Upper Limit of Normal (ULN) and total 
bilirubin* 2xULN (>35% direct), or

ALT 3xULN and International Normalised Ratio (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.
12.2.3.
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

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
Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
12.2.4.
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 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.

Subject-completed Value Evidence and Outcomes questionnaires and the collection 
of AE data are independent components of the study.

Responses to each question in the Value Evidence and Outcomes questionnaire will 
be treated in accordance with standard scoring and statistical procedures detailed by 
the scale’s developer.

The use of a single question from a multidimensional health survey to designate a 
cause-effect relationship to an AE is inappropriate.
12.2.5.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 

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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.
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 

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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.
12.2.6.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data collection 
tool

If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax it to the Medical Monitor or the SAE 
coordinator.

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of 
the SAE.

After the study is completed at a given site, the electronic data collection tool (e.g.
InForm system) will be taken off-line to prevent the entry of new data or changes to 
existing data

If a site receives a report of a new SAE from a study subject or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, the site can report this information on a paper SAE form or to the Medical 
Monitor or the SAE coordinator by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.

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12.3.
Appendix 3: Modified List of Highly Effective Methods for 
Avoiding Pregnancy in FRP and Collection of Pregnancy 
Information
12.3.1.
Modified List of Highly Effective Methods for Avoiding Pregnancy 
in Females of Reproductive Potential (FRP)
The list does not apply to FRP with same sex partners or for subjects who are and will 
continue to be abstinent from penile-vaginal intercourse on a long term and persistent 
basis, when this is their preferred and usual lifestyle. Periodic abstinence (e.g. calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.

Contraceptive subdermal implant

Intrauterine device or intrauterine system

Combined oestrogen and progestogen oral contraceptive [Hatcher, 2011])

Injectable progestogen [Hatcher, 2011]

Contraceptive vaginal ring [Hatcher, 2011]

Percutaneous contraceptive patches [Hatcher, 2011]

Male partner sterilization with documentation of azoospermia prior to the female 
subject's entry into the study, and this male is the sole partner for that subject 
[Hatcher, 2011]. The documentation on male sterility can come from the site 
personnel’s: review of subject’s medical records, medical examination and/or semen 
analysis, or medical history interview provided by her or her partner.
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
12.3.2.
Collection of Pregnancy Information
Female Subjects Enrolled on the Study

Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study

Information will be recorded on the appropriate form and submitted to GSK within 
2 weeks of learning of a subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow- up information on mother and infant, which will be 
forwarded to GSK.  Generally, follow up will not be required for longer than 6 to 
8 weeks beyond the estimated delivery date. 

Any termination of pregnancy will be reported, regardless of foetal status (presence 
or absence of anomalies) or indication for procedure.

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
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  
Any SAE occurring as a result of a post-study pregnancy which is considered reasonably 
related to the study treatment by the investigator, will be reported to GSK. While the 
investigator is not obligated to actively seek this information in former study participants, 
he or she may learn of an SAE through spontaneous reporting.